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Document Reviewers: Franz-Josef Neumann (Germany) (CPG Review Coordinator), Udo Sechtem
(Germany) (CPG Review Coordinator), Adrian Paul Banning (United Kingdom), Nikolaos Bonaros
(Austria), Héctor Bueno (Spain), Raffaele Bugiardini (Italy), Alaide Chieffo (Italy), Filippo Crea (Italy),
* Corresponding authors: Juhani Knuuti, Department of Clinical Physiology, Nuclear Medicine and PET and Turku PET Centre, Turku University Hospital, Kiinamyllynkatu 4-8, FI-
20520 Turku, Finland. Tel: þ358 500 592 998, Email: juhani.knuuti@tyks.fi. William Wijns, The Lambe Institute for Translational Medicine and Curam, National University of
Ireland, Galway, University Road, Galway, H91 TK33, Ireland. Tel: þ353 91 524411, Email: william.wyns@nuigalway.ie.
Author/Task Force Member Affiliations: listed in the Appendix.
ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers: listed in the Appendix.
ESC entities having participated in the development of this document:
Associations: Acute Cardiovascular Care Association (ACCA), Association of Cardiovascular Nursing & Allied Professions (ACNAP), European Association of Cardiovascular
Imaging (EACVI), European Association of Preventive Cardiology (EAPC), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Heart Rhythm
Association (EHRA), Heart Failure Association (HFA).
Councils: Council for Cardiology Practice.
Working Groups: Atherosclerosis and Vascular Biology, Cardiovascular Pharmacotherapy, Cardiovascular Surgery, Coronary Pathophysiology and Microcirculation,
Thrombosis.
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Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge, and the evidence available
at the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy, and/or ambiguity between the ESC Guidelines and any other official recom-
mendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encour-
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therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and
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the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent
public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the
health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.
C The European Society of Cardiology 2019. All rights reserved. For permissions please email: journals.permissions@oup.com.
V
2 ESC Guidelines
The disclosure forms of all experts involved in the development of these Guidelines are available on the
ESC website www.escardio.org/guidelines
For the Supplementary Data which include background information and detailed discussion of the data
that have provided the basis for the Guidelines see https://academic.oup.com/eurheartj/article-lookup/doi/
10.1093/eurheartj/ehz425#supplementary-data
...................................................................................................................................................................................................
Keywords Guidelines • chronic coronary syndromes • angina pectoris • myocardial ischaemia • coronary artery
disease • diagnostic testing • imaging • risk assessment • lifestyle modifications • anti-ischaemic drugs •
antithrombotic therapy • lipid-lowering drugs • myocardial revascularization • microvascular angina •
vasospastic angina • screening
..
Table of contents .. 3.1.6.1 Definition of levels of risk . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
.. 3.2 Lifestyle management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
1. Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
.. 3.2.1 General management of patients with coronary artery
..
2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 .. disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.1 What is new in the 2019 Guidelines? . . . . . . . . . . . . . . . . . . . . . . . . . . 8
.. 3.2.2 Lifestyle modification and control of risk factors . . . . . . . . . . 23
..
3. Patients with angina and/or dyspnoea, and suspected .. 3.2.2.1 Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
coronary artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
.. 3.2.2.2 Diet and alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
..
3.1 Basic assessment, diagnosis, and risk assessment . . . . . . . . . . . . . . 10 .. 3.2.2.3 Weight management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
..
3.1.1 Step 1: symptoms and signs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 .. 3.2.2.4 Physical activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
3.1.1.1 Stable vs. unstable angina . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 .. 3.2.2.5 Cardiac rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
..
3.1.1.2 Distinction between symptoms caused by .. 3.2.2.6 Psychosocial factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
epicardial vs. microvascular/vasospastic disease . . . . . . . . . . . . . 13 .. 3.2.2.7 Environmental factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
..
3.1.2 Step 2: comorbidities and other causes of symptoms . . . . . . 13 .. 3.2.2.8 Sexual activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3.1.3 Step 3: basic testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 .. 3.2.2.9 Adherence and sustainability . . . . . . . . . . . . . . . . . . . . . . . . 25
..
3.1.3.1 Biochemical tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 .. 3.2.2.10 Influenza vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3.1.3.2 Resting electrocardiogram and ambulatory .. 3.3 Pharmacological management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
..
monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 .. 3.3.1 Anti-ischaemic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
3.1.3.3 Echocardiography and magnetic resonance .. 3.3.1.1 General strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
..
imaging at rest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 .. 3.3.1.2 Available drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
3.1.3.4 Chest X-ray . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 ... 3.3.1.3 Patients with low blood pressure . . . . . . . . . . . . . . . . . . . . 29
3.1.4 Step 4: assess pre-test probability and clinical likelihood .. 3.3.1.4 Patients with low heart rate . . . . . . . . . . . . . . . . . . . . . . . . . 29
..
of coronary artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 .. 3.3.2 Event prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
3.1.5 Step 5: select appropriate testing . . . . . . . . . . . . . . . . . . . . . . . . . 16
.. 3.3.2.1 Antiplatelet drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
..
3.1.5.1 Functional non-invasive tests . . . . . . . . . . . . . . . . . . . . . . . . 16 .. 3.3.2.2 Anticoagulant drugs in sinus rhythm . . . . . . . . . . . . . . . . . 30
3.1.5.2 Anatomical non-invasive evaluation . . . . . . . . . . . . . . . . . 17
.. 3.3.2.3 Anticoagulant drugs in atrial fibrillation . . . . . . . . . . . . . . . 31
..
3.1.5.3 Role of the exercise electrocardiogram . . . . . . . . . . . . . . 17 .. 3.3.2.4 Proton pump inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.1.5.4 Selection of diagnostic tests . . . . . . . . . . . . . . . . . . . . . . . . . 18
.. 3.3.2.5 Cardiac surgery and antithrombotic therapy . . . . . . . . . 31
..
3.1.5.5 The impact of clinical likelihood on the selection .. 3.3.2.6 Non-cardiac surgery and antithrombotic therapy . . . . 32
of a diagnostic test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
.. 3.3.3 Statins and other lipid-lowering drugs . . . . . . . . . . . . . . . . . . . . 34
..
3.1.5.6 Invasive testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 .. 3.3.4 Renin-angiotensin-aldosterone system blockers . . . . . . . . . . 34
..
3.1.6 Step 6: assess event risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 .. 3.3.5 Hormone replacement therapy . . . . . . . . . . . . . . . . . . . . . . . . . . 35
ESC Guidelines 3
3.4 Revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
.. Basic biochemistry testing in the initial diagnostic management
..
4. Patients with new onset of heart failure or reduced left .. of patients with suspected coronary artery disease . . . . . . . . . . . . . . . . . . 13
..
ventricular function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 .. Resting electrocardiogram in the initial diagnostic management
5. Patients with a long-standing diagnosis of chronic coronary .. of patients with suspected coronary artery disease . . . . . . . . . . . . . . . . . . 14
..
syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 .. Ambulatory electrocardiogram monitoring in the initial
5.1 Patients with stabilized symptoms <1 year after an acute .. diagnostic management of patients with suspected coronary
..
coronary syndrome or patients with recent revascularization . . . . . 38 .. artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
..
FFRCT Computed tomography-based fractional flow .. SIGNIFY Study Assessing the MorbidityMortality Benefits
reserve .. of the If Inhibitor Ivabradine in Patients with
..
GEMINI- A Study to Compare the Safety of Rivaroxaban .. Coronary Artery Disease
ACS Versus Acetylsalicylic Acid in Addition to Either
.. SPECT Single-photon emission computed tomography
..
Clopidogrel or Ticagrelor Therapy in Participants .. VKA Vitamin K antagonist
With Acute Coronary Syndrome
..
..
GFR Glomerular filtration rate ..
Wording to use
©ESC 2019
given treatment or procedure is not
useful/effective, and in some cases
may be harmful.
..
real or potential sources of conflicts of interest. These forms were .. endorsement process of these Guidelines. The ESC Guidelines
compiled into one file and can be found on the ESC website (http:// .. undergo extensive review by the CPG and external experts. After
..
www.escardio.org/guidelines). Any changes in declarations of interest .. appropriate revisions the Guidelines are approved by all the
that arise during the writing period were notified to the ESC and .. experts involved in the Task Force. The finalized document is
..
updated. The Task Force received its entire financial support from .. approved by the CPG for publication in the European Heart
the ESC without any involvement from the healthcare industry. .. Journal. The Guidelines were developed after careful considera-
..
The ESC CPG supervises and coordinates the preparation of .. tion of the scientific and medical knowledge and the evidence
new Guidelines. The Committee is also responsible for the .. available at the time of their dating.
ESC Guidelines 7
post ACS
risk factors, suboptimal
lifestyle modifications
and/or medical therapy,
ACS
Revascularization large area at risk of
myocardial ischaemia
12 month
post ACS
Revascularization
©ESC 2019
Time
Figure 1 Schematic illustration of the natural history of chronic coronary syndromes. ACE = angiotensin-converting enzyme; ACS = acute coronary
syndromes; CCS = chronic coronary syndromes; MI = myocardial infarction.
8 ESC Guidelines
..
categorized as either acute coronary syndromes (ACS) or chronic .. (MI)], and the risk may change over time. Development of an ACS may
coronary syndromes (CCS). The Guidelines presented here refer to .. acutely destabilize each of these clinical scenarios. The risk may increase
..
the management of patients with CCS. The natural history of CCS is .. as a consequence of insufficiently controlled cardiovascular risk factors,
illustrated in Figure 1. .. suboptimal lifestyle modifications and/or medical therapy, or unsuccess-
..
The most frequently encountered clinical scenarios in patients .. ful revascularization. Alternatively, the risk may decrease as a conse-
with suspected or established CCS are: (i) patients with suspected .. quence of appropriate secondary prevention and successful
..
CAD and ‘stable’ anginal symptoms, and/or dyspnoea (see section 3); .. revascularization. Hence, CCS are defined by the different evolutionary
The Guidelines have been revised to focus on CCS instead of stable CAD.
This change emphasizes the fact that the clinical presentations of CAD can be categorized as either ACS or CCS. CAD is a dynamic process of atheroscler-
otic plaque accumulation and functional alterations of coronary circulation that can be modified by lifestyle, pharmacological therapies, and revascularization,
which result in disease stabilization or regression.
In the current Guidelines on CCS, six clinical scenarios most frequently encountered in patients are identified: (i) patients with suspected CAD and ‘stable’ anginal
symptoms, and/or dyspnoea; (ii) patients with new onset of HF or LV dysfunction and suspected CAD; (iii) asymptomatic and symptomatic patients with stabilized
symptoms <1 year after an ACS or patients with recent revascularization; (iv) asymptomatic and symptomatic patients >1 year after initial diagnosis or revasculariza-
tion; (v) patients with angina and suspected vasospastic or microvascular disease; (vi) asymptomatic subjects in whom CAD is detected at screening.
The PTP of CAD based on age, gender and nature of symptoms have undergone major revisions. In addition, we introduced a new phrase ’Clinical likelihood of CAD’
that utilizes also various risk factors of CAD as PTP modifiers. The application of various diagnostic tests in different patient groups to rule-in or rule-out CAD have been
updated.
The Guidelines emphasize the crucial role of healthy lifestyle behaviours and other preventive actions in decreasing the risk of subsequent cardiovascular
events and mortality.
ACS = acute coronary syndromes; CAD = coronary artery disease; CCS = chronic coronary syndromes; HF = heart failure; LV = left ventricular; PTP = pre-test probability.
..
3 Patients with angina and/or .. ACS (step 1). In patients without unstable angina or other ACS,
.. the next step is to evaluate the patient’s general condition and
dyspnoea, and suspected coronary .. quality of life (step 2). Comorbidities that could potentially influ-
..
artery disease ..
..
ence therapeutic decisions are assessed and other potential
.. causes of the symptoms are considered. Step 3 includes basic test-
3.1 Basic assessment, diagnosis, and risk .. ing and assessment of LV function. Thereafter, the clinical likeli-
..
assessment .. hood of obstructive CAD is estimated (step 4) and, on this basis,
The general approach for the initial diagnostic management of .. diagnostic testing is offered to selected patients to establish the
.. diagnosis of CAD (step 5). Once a diagnosis of obstructive CAD
patients with angina and suspected obstructive CAD is presented ..
in Figure 2. The diagnostic management approach includes six .. has been confirmed, the patient’s event risk will be determined
..
steps. The first step is to assess the symptoms and signs, to .. (step 6) as it has a major impact on the subsequent therapeutic
identify patients with possible unstable angina or other forms of .. decisions.
..
ESC Guidelines 11
STEP 1 Assess symptoms and perform clinical investigations Unstable angina? Follow ACS guidelines
Revascularization
STEP 2 Consider comorbidities and quality of life Medical therapya
futile
Coronary CTAf
No diagnostic
Invasive
Choice of the test based on clinical
angiography
likelihood, patient characteristics
STEP 5 (with iwFR/FFR)e
and preference, availability, Testing for ischaemia
as well as local expertised (imaging testing preferred)
©ESC 2019
STEP 6 Choose appropriate therapy based on symptoms and event riskg
Figure 2 Approach for the initial diagnostic management of patients with angina and suspected coronary artery disease. ACS = acute coronary
syndrome; BP = blood pressure; CAD = coronary artery disease; CTA = computed tomography angiography; ECG = electrocardiogram; FFR = frac-
tional flow reserve; iwFR = instantaneous wave-free ratio; LVEF = left ventricular ejection fraction. aIf the diagnosis of CAD is uncertain, establishing
a diagnosis using non-invasive functional imaging for myocardial ischaemia before treatment may be reasonable. bMay be omitted in very young and
healthy patients with a high suspicion of an extracardiac cause of chest pain, and in multimorbid patients in whom the echocardiography result has
no consequence for further patient management. cConsider exercise ECG to assess symptoms, arrhythmias, exercise tolerance, BP response, and
event risk in selected patients. dAbility to exercise, individual test-related risks, and likelihood of obtaining diagnostic test result. eHigh clinical likeli-
hood and symptoms inadequately responding to medical treatment, high event risk based on clinical evaluation (such as ST-segment depression,
combined with symptoms at a low workload or systolic dysfunction indicating CAD), or uncertain diagnosis on non-invasive testing. fFunctional
imaging for myocardial ischaemia if coronary CTA has shown CAD of uncertain grade or is non-diagnostic. gConsider also angina without obstruc-
tive disease in the epicardial coronary arteries (see section 6).
..
After these steps, appropriate therapies are to be initiated, .. exacerbating or relieving factors. The discomfort caused by myo-
which include lifestyle management (see section 3.2), medical .. cardial ischaemia is usually located in the chest, near the sternum,
..
therapy (see section 3.3), and revascularization when indicated .. but may be felt anywhere from the epigastrium to the lower jaw
(see section 3.4). .. or teeth, between the shoulder blades, or in either arm to the
..
.. wrist and fingers. The discomfort is often described as pressure,
.. tightness, or heaviness; sometimes strangling, constricting, or
3.1.1. Step 1: Symptoms and signs
... burning. It may be useful to ask the patient directly about the pres-
A careful history is the cornerstone of the diagnosis of angina. It ..
is possible to achieve a high degree of certainty on a diagnosis .. ence of ‘discomfort’ as many do not feel ‘pain’ or ‘pressure’ in their
.. chest. Shortness of breath may accompany angina, and chest dis-
based on history alone, although physical examination and objec- ..
tive tests are most often necessary to confirm the diagnosis, .. comfort may also be accompanied by less-specific symptoms such
.. as fatigue or faintness, nausea, burning, restlessness, or a sense of
exclude alternative diagnoses, and assess the severity of underly- ..
ing disease. The history should include any manifestation of cardi- .. impending doom. Shortness of breath may be the sole symptom of
.. CAD and it may be difficult to differentiate this from shortness of
ovascular disease (CVD) and risk factors (i.e. family history of ..
CVD, dyslipidaemia, diabetes, hypertension, smoking, and other .. breath caused by other conditions.
.. The duration of the discomfort is brief—<_10 min in the majority
lifestyle factors). ..
The characteristics of discomfort related to myocardial ischae-
.. of cases, and more commonly just a few minutes or less—and
..
mia (angina pectoris) may be divided into four categories: location, .. chest pain lasting for seconds is unlikely to be due to CAD. An
character, duration, and relationship to exertion, and other
.. important characteristic is the relationship to exercise. Symptoms
12 ESC Guidelines
Table 4 Grading of effort angina severity according to the Canadian Cardiovascular Society
Grade Description of angina severity
I Angina only with strenuous exertion Presence of angina during strenuous, rapid, or prolonged ordinary
activity (walking or climbing the stairs).
II Angina with moderate exertion Slight limitation of ordinary activities when they are performed
rapidly, after meals, in cold, in wind, under emotional stress, or
during the first few hours after waking up, but also walking uphill,
climbing more than one flight of ordinary stairs at a normal pace,
and in normal conditions.
III Angina with mild exertion Having difficulties walking one or two blocks, or climbing one
flight of stairs, at normal pace and conditions.
IV Angina at rest No exertion needed to trigger angina.
ESC Guidelines 13
3.1.1.2 Distinction between symptoms caused by epicardial vs. microvas- .. conditions, and to determine prognosis. Haemoglobin as part of a
..
cular/vasospastic disease .. full blood count and—where there is a clinical suspicion of a thy-
A distinction between symptoms caused by an epicardial stenosis and
.. roid disorder—thyroid hormone levels provide information
..
symptoms caused by microvascular or vasospastic disease cannot be .. related to possible causes of ischaemia. Fasting plasma glucose and
made with reasonable certainty. Reliance on ischaemia testing or
.. glycated haemoglobin (HbA1c) should be measured in every
..
depiction of the coronary anatomy is often unavoidable to exclude .. patient with suspected CAD. If both are inconclusive, an additional
obstructive CAD, which can be absent in symptomatic patients.13,14
.. oral glucose tolerance test is recommended.16 Knowledge of glu-
..
Basic biochemistry testing in the initial diagnostic management of patients with suspected coronary artery disease
If evaluation suggests clinical instability or ACS, repeated measurements of troponin, preferably using high-sensitivity or
I A
ultrasensitive assays, are recommended to rule-out myocardial injury associated with ACS.28,29
The following blood tests are recommended in all patients:
• Full blood count (including haemoglobin);30 I B
• Creatinine measurement and estimation of renal function;31,32 I A
• A lipid profile (including LDL-C).33,34 I A
It is recommended that screening for type 2 diabetes mellitus in patients with suspected and established CCS is imple-
mented with HbA1c and fasting plasma glucose measurements, and that an oral glucose tolerance test is added if HbA1c I B
and fasting plasma glucose results are inconclusive.16,35
Assessment of thyroid function is recommended in case of clinical suspicion of thyroid disorders. I C
ACS = acute coronary syndromes; CAD = coronary artery disease; CCS = chronic coronary syndromes; HbA1c = glycated haemoglobin; LDL-C = low-density lipoprotein
cholesterol.
a
Class of recommendation.
b
Level of evidence.
14 ESC Guidelines
..
Management of patients with either angina or HF symptoms, with .. population studied and, thus, the likelihood that a given patient will
reduced LVEF <40% or a mid-range reduced LVEF of 40-49%, is .. actually have CAD. Diagnostic testing is most useful when the likeli-
..
described in section 4 of the Guidelines. .. hood is intermediate. When likelihood is high, a large number of
.. patients need to be studied to identify the few patients that do not
..
Resting echocardiography and cardiac magnetic reso- .. have disease, and a negative test result can seldom rule out the pres-
nance in the initial diagnostic management of patients
.. ence of obstructive CAD (i.e. the negative predictive value is low).
..
with suspected coronary artery disease .. When the likelihood is low, a negative test can rule out the disease,
Table 5 Pre-test probabilities of obstructive coronary artery disease in 15 815 symptomatic patients according to age,
sex, and the nature of symptoms in a pooled analysis64 of contemporary data7,8,62
©ESC 2019
60–69 44% 16% 26% 11% 22% 6% 27% 14%
70+ 52% 27% 34% 19% 24% 10% 32% 12%
©ESC 2019
Clinical likelihood of CAD
Figure 3 Determinants of the clinical likelihood of obstructive coronary artery disease. CAD = coronary artery disease; CT = computed tomography,
CVD = cardiovascular disease, ECG = electrocardiogram, LV = left ventricular; PTP = pre-test probability. aWhen available.
..
(SPECT), positron emission tomography (PET), myocardial con- .. predominantly of exercise ECG.6 Other randomized, prospective clin-
trast echocardiography, or contrast CMR. Ischaemia can be pro- .. ical trials have demonstrated that diagnostic testing with coronary
..
voked by exercise or pharmacological stressors, either by .. CTA is associated with clinical outcomes similar to those for func-
increased myocardial work and oxygen demand, or by heteroge- .. tional imaging in patients with suspected CAD.4,6,76 In patients with
..
neity in myocardial perfusion by vasodilatation. Non-invasive func- .. extensive CAD, coronary CTA complemented by CT-based FFR was
tional tests are associated with high accuracy for the detection of .. non-inferior to ICA and FFR for decision-making, and the identification
..
flow-limiting coronary stenosis compared with invasive functional .. of targets for revascularization.77
testing [fractional flow reserve (FFR)].73 However, lower-grade
..
..
coronary atherosclerosis not linked with ischaemia remains unde- .. 3.1.5.3 Role of the exercise electrocardiogram
tected by functional testing and, in the presence of a negative func-
.. Exercise ECG has inferior diagnostic performance compared with
..
tional test, patients should receive risk-factor modification based .. diagnostic imaging tests, and has limited power to rule-in or rule-out
on commonly applied risk charts and recommendations.
.. obstructive CAD.73 Since the publication of the previous version of
..
.. these Guidelines, randomized clinical trials (RCTs) have compared
3.1.5.2 Anatomical non-invasive evaluation
.. the effects of diagnostic strategies based on exercise ECG or an imag-
..
Anatomical non-invasive evaluation, by visualizing the coronary artery .. ing diagnostic test6,78,79 on clinical outcomes. These studies have
..
lumen and wall using an intravenous contrast agent, can be performed .. shown that the addition of coronary CTA5,6,78,80 or functional
with coronary CTA, which provides high accuracy for the detection .. imaging79 clarifies the diagnosis, enables the targeting of preventive
..
of obstructive coronary stenoses defined by ICA,73 because both tests .. therapies and interventions, and potentially reduces the risk of MI
are based on anatomy. However, stenoses estimated to be 5090% .. compared with an exercise ECG. Some, although not all, registry
..
by visual inspection are not necessarily functionally significant, i.e. they .. studies have also shown similar benefits regarding the use of an imag-
do not always induce myocardial ischaemia.73,74 Therefore, either ... ing diagnostic test in patients treated in everyday clinical practice.81,82
non-invasive or invasive functional testing is recommended for further .. Therefore, these Guidelines recommend the use of an imaging diag-
..
evaluation of angiographic stenosis detected by coronary CTA or .. nostic test instead of exercise ECG as the initial test for to diagnose
invasive angiography, unless a very high-grade (>90% diameter steno- .. obstructive CAD.
..
sis) stenosis is detected via invasive angiography. The presence or .. An exercise ECG alone may be considered as an alternative to
absence of non-obstructive coronary atherosclerosis on coronary .. diagnose obstructive CAD if imaging tests are not available, keeping
..
CTA provides prognostic information, and can be used to guide pre- .. in mind the risk of false-negative and false-positive test results.73,83
ventive therapy.75 The SCOT-HEART (Scottish Computed .. An exercise ECG is of no diagnostic value in patients with ECG
..
Tomography of the HEART) trial demonstrated a significantly lower .. abnormalities that prevent interpretation of the ST-segment changes
rate of the combined endpoint of cardiovascular death or non-fatal MI
.. during stress (i.e. LBBB, paced rhythm, Wolff-Parkinson-White syn-
..
(2.3 vs. 3.9% during 5 year follow-up) in patients in whom coronary .. drome, >_0.1 mV ST-segment depression on resting ECG, or who are
CTA was performed in addition to routine testing, which consisted
.. being treated with digitalis). An exercise ECG provides
..
18 ESC Guidelines
complementary clinically useful information beyond ECG changes .. Coronary CTA is the preferred test in patients with a lower range
..
and valuable prognostic information. Therefore, application of an .. of clinical likelihood of CAD, no previous diagnosis of CAD, and
exercise ECG may be considered in selected patients to complement
.. characteristics associated with a high likelihood of good image quality.
..
clinical evaluation for the assessment of symptoms, ST-segment .. It detects subclinical coronary atherosclerosis, but can also accu-
changes, exercise tolerance, arrhythmias, blood pressure (BP)
.. rately rule out both anatomically and functionally significant CAD
..
response, and event risk. .. (Figure 5). It has higher accuracy values when low clinical likelihood
.. populations are subjected to examination.85 Trials evaluating out-
..
desired Ongoing
No history of CAD symptomsa
Preferentially considered if:
High clinical likelihood and severe
Invasive symptoms refractory to medical therapy
coronary Typical angina at low level of exercise and
Stenosis >90%
or with established
Functional correlation to ischaemia
Drug
therapyb assessment
©ESC 2019
Revascularization
Figure 4 Main diagnostic pathways in symptomatic patients with suspected obstructive coronary artery disease. Depending on clinical conditions and
the healthcare environment, patient workup can start with either of three options: non-invasive testing, coronary computed tomography angiography, or
invasive coronary angiography. Through each pathway, both functional and anatomical information is gathered to inform an appropriate diagnostic and
therapeutic strategy. Risk-factor modification should be considered in all patients. CAD = coronary artery disease; CTA = computed tomography angiog-
raphy; ECG = electrocardiogram; LV = left ventricular. aConsider microvascular angina. bAntianginal medications and/or risk-factor modification.
ESC Guidelines 19
A Test Clinical Likelihood of ICA-significant CAD B Test Clinical Likelihood of FFR-significant CAD
Results 0% 50% 100% Results 0% 50% 100%
Stress Stress
CMR CMR
Stress SPECT
Echocardiography
15% 85%
SPECT
Clinical Likelihood range where test
©ESC 2019
15% 85% can rule-in CAD (Post-test probability will rise above 85%)
Figure 5 Ranges of clinical likelihood of coronary artery disease in which a given test can rule-in (red) or rule-out (green) obstructive coronary
artery disease. (A) Reference standard is anatomical assessment using invasive coronary angiography. (B) Reference standard is functional assess-
ment using fractional flow reserve. Note in (B) that the data with stress echocardiography and single-photon emission computed tomography are
more limited than with the other techniques.73 The crosshairs mark the mean values and their 95% confidence intervals. Figure adapted from
Knuuti et al.73 CAD = coronary artery disease; CMR = cardiac magnetic resonance; CTA = computed tomography angiography; ECG = electrocar-
diogram; FFR = fractional flow reserve; ICA = invasive coronary angiography; PET = positron emission tomography; SPECT = single-photon emis-
sion computed tomography.
..
In addition to diagnostic accuracy and clinical likelihood, the selec- .. However, ICA may be indicated if non-invasive assessment suggests
tion of a non-invasive test depends on other patient characteristics, .. high event risk for determination of options for revascularization.88
..
local expertise, and the availability of tests. Some diagnostic tests may .. In a patient with a high clinical likelihood of CAD, and symptoms
perform better in some patients than others. For example, irregular .. unresponsive to medical therapy or with typical angina at a low level
..
heart rate and the presence of extensive coronary calcification are .. of exercise, and initial clinical evaluation indicates a high event risk,
associated with increased likelihood of non-diagnostic image quality .. early ICA without previous non-invasive risk stratification may be
..
of coronary CTA, and it is not recommended in such patients.85 .. reasonable to identify lesions potentially amenable to revasculariza-
Stress echocardiography or SPECT perfusion imaging can be com- .. tion (Figure 4). Invasive functional assessment should complement
..
bined with dynamic exercise testing, and may be preferred if addi- .. ICA, especially in patients with coronary stenoses of 50 - 90% or mul-
tional information available from the exercise test, such as exercise
.. tivessel disease, given the frequent mismatch between the angio-
..
tolerance or heart rate response to exercise, is considered impor- .. graphic and haemodynamic severities of coronary stenoses.8991
tant. Exercise ECG cannot be used for diagnostic purposes in the
.. Systematic integration of ICA with FFR has been shown to result in
..
presence of ECG abnormalities that prevent the evaluation of ischae- .. changes to the management strategies of 30 - 50% of patients under-
mia. Risks related to different diagnostic tests need to be weighed
.. going elective ICA.92,93 Methods used to perform ICA have improved
..
against the benefits to the individual.87 For example, exposure to ion- .. substantially, resulting in a reduction of complication rates with rapid
izing radiation associated with coronary CTA and nuclear perfusion
.. ambulation. This is especially true for ICA performed via the radial
..
imaging needs to be taken into account, especially in young individu- .. artery.94 The composite rate of major complications associated with
..
als.87 Similarly, contraindications to pharmacological stressors and .. routine femoral diagnostic catheterization—mainly bleeding requir-
contrast agents (iodine-based contrast agents and gadolinium-based .. ing blood transfusions—is still 0.52%.95 The composite rate of
..
chelates) need to be taken into account. When testing is used appro- .. death, MI, or stroke is of the order of 0.10.2%.96 ICA should not be
priately, the clinical benefit from accurate diagnosis and therapy .. performed in patients with angina who refuse invasive procedures,
..
exceeds the projected risks of testing itself.87 .. prefer to avoid revascularization, who are not candidates for percuta-
.. neous coronary intervention (PCI) or coronary artery bypass grafting
..
3.1.5.6 Invasive testing .. (CABG), or in whom revascularization is not expected to improve
For diagnostic purposes, ICA is only necessary in patients with sus- .. functional status or quality of life. Intracoronary techniques for the
..
pected CAD in cases of inconclusive non-invasive testing or, exception- .. diagnostic assessment of coronary anatomy are briefly mentioned in
ally, in patients from particular professions, due to regulatory issues.88 .. the Supplementary Data of this document.
20 ESC Guidelines
Use of diagnostic imaging tests in the initial diagnostic management of symptomatic patients with suspected coronary
artery disease
Non-invasive functional imaging for myocardial ischaemiac or coronary CTA is recommended as the initial test to diagnose
I B
CAD in symptomatic patients in whom obstructive CAD cannot be excluded by clinical assessment alone.4,5,55,73,7880
CAD = coronary artery disease; CT = computed tomography; CTA = computed tomography angiography.
a
Class of recommendation.
b
Level of evidence
c
Stress echocardiography, stress cardiac magnetic resonance, single-photon emission CT, or positron emission tomography.
d
Characteristics determining ability to exercise, likelihood of good image quality, expected radiation exposure, and risks or contraindications.
Use of exercise electrocardiogram in the initial diagnostic management of patients with suspected coronary artery
disease
Exercise ECG is recommended for the assessment of exercise tolerance, symptoms, arrhythmias, BP response, and event
I C
risk in selected patients.c
Exercise ECG may be considered as an alternative test to rule-in and rule-out CAD when non-invasive imaging is not
IIb B
available.73,83
Exercise ECG may be considered in patients on treatment to evaluate control of symptoms and ischaemia. IIb C
Exercise ECG is not recommended for diagnostic purposes in patients with >_0.1 mV ST-segment depression on resting
III C
ECG or who are being treated with digitalis.
..
3.1.6 Step 6: Assessment of event risk .. stratification using clinical evaluation, the assessment of LV function by
Assessment of event risk is recommended in every patient being eval- .. resting echocardiography, and, in the majority of cases, non-invasive
..
uated for suspected CAD or with a newly diagnosed CAD, as it has .. assessment of ischaemia or coronary anatomy. Although the diagnos-
major impacts on therapy decisions. The process of risk stratification .. tic value of an exercise ECG is limited,73 the occurrence of ST-
..
serves to identify patients at high event risk who will benefit from .. segment depression at a low workload combined with exertional
revascularization beyond the amelioration of symptoms. Event risk .. symptoms (angina or dyspnoea), low exercise capacity, complex ven-
..
stratification is usually based on the assessments used to make a diag- .. tricular ectopy, or arrhythmias and abnormal BP response are
Table 6 Definitions of high event risk for different test modalities in patients with established chronic coronary syndro-
mesa 102104
Exercise ECG Cardiovascular mortality >3% per year according to Duke Treadmill Score
SPECT or PET perfusion imaging Area of ischaemia >_10% of the left ventricle myocardium
Stress echocardiography >_3 of 16 segments with stress-induced hypokinesia or akinesia
CMR >_2 of 16 segments with stress perfusion defects or >_3 dobutamine-induced dysfunctional segments
Coronary CTA or ICA Three-vessel disease with proximal stenoses, LM disease, or proximal anterior descending disease
Invasive functional testing FFR <_0.8, iwFR <_0.89
CTA = computed tomography angiography; CMR = cardiac magnetic resonance; ECG = electrocardiogram; FFR = fractional flow reserve; ICA = invasive coronary angiography;
iwFR = instantaneous wave-free ration (instant flow reserve); LM = left main; PET = positron emission tomography; SPECT; single-photon emission computed tomography.
a
For detailed explanations, refer to the Supplementary Data.
SECONDARY PREVENTION
PRIMARY PREVENTION
30 3
15 1,5
10%–14%
10 1
High-risk 5%–9%
5 0,5 0%–0.9% Low-risk
©ESC 2019
3%–4%
Low-to-moderate risk 2%
1%
<1% 0 0
Figure 6 Comparison of risk assessments in asymptomatic apparently healthy subjects (primary prevention) and patients with established chronic coro-
nary syndromes (secondary prevention). Note that in asymptomatic subjects (left panel), SCORE estimates 10 year cardiovascular mortality, while in
symptomatic patients (right panel), annual cardiac mortality is estimated. CCS = chronic coronary syndromes; SCORE = Systematic COronary Risk
Evaluation.
22 ESC Guidelines
..
angina and LV systolic dysfunction in a pattern that indicates CAD are .. The definitions of high event risk based on findings of diagnostic tests in
also at high risk of cardiac mortality.101 ICA for risk stratification will .. symptomatic patients or in patients with established CCS are shown in
..
only be required in a selected subgroup of patients and additional FFR .. Table 6.
may be required for event risk stratification as appropriate (Figure 4). .. Notably, the level of risk is different from the risk assessment based
..
Risk assessment in patients with HF and LV dysfunction, asymptomatic .. on SCORE in asymptomatic individuals without diabetes who are
patients with known CAD, and patients with recurrent symptoms .. apparently healthy (see section 7). SCORE defines 10 year cardiovas-
..
after previous coronary intervention is discussed in sections 4 and 5. .. cular mortality in asymptomatic subjects. Differences in these risk-
Risk stratification is recommended based on clinical assessment and the result of the diagnostic test initially employed to
I B
diagnose CAD.6,75,102,103
Resting echocardiography is recommended to quantify LV function in all patients with suspected CAD. I C
Risk stratification, preferably using stress imaging or coronary CTA (if permitted by local expertise and availability), or
alternatively exercise stress ECG (if significant exercise can be performed and the ECG is amenable to the identification I B
of ischaemic changes), is recommended in patients with suspected or newly diagnosed CAD.6,75,102,106
In symptomatic patients with a high-risk clinical profile, ICA complemented by invasive physiological guidance (FFR) is rec-
ommended for cardiovascular risk stratification, particularly if the symptoms are responding inadequately to medical treat- I A
ment and revascularization is considered for improvement of prognosis.104,107
In patients with mild or no symptoms, ICA complemented by invasive physiological guidance (FFR/iwFR) is recommended
for patients on medical treatment, in whom non-invasive risk stratification indicates a high event risk and revascularization I A
is considered for improvement of prognosis.104,107
ICA complemented by invasive physiological guidance (FFR) should be considered for risk-stratification purposes in
IIa B
patients with inconclusive or conflicting results from non-invasive testing.74
If coronary CTA is available for event risk stratification, additional stress imaging should be performed before the referral
IIa B
of a patient with few/no symptoms for ICA.108,109
Echocardiographic assessment of global longitudinal strain provides incremental information to LVEF and may be consid-
IIb B
ered when LVEF is >35%.110114
Intravascular ultrasound may be considered for the risk stratification of patients with intermediate LM stenosis.115,116 IIb B
ICA is not recommended solely for risk stratification. III C
CAD = coronary artery disease; CTA = computed tomography angiography; ECG = electrocardiogram; FFR = fractional flow reserve; ICA = invasive coronary angiography;
iwFR = instantaneous wave-free ratio; LM = left main; LV = left ventricular; LVEF = LV ejection fraction.
a
Class of recommendation.
b
Level of evidence.
ESC Guidelines 23
..
3.2 Lifestyle management .. Netherlands were found to be as effective as general practitioners in
.. decreasing cardiovascular risk in another randomized study.123
3.2.1 General management of patients with coronary ..
artery disease ..
.. 3.2.2.1 Smoking
General management of CCS aims to reduce symptoms and ..
improve prognosis through appropriate medications and inter- .. Smoking cessation improves the prognosis in patients with CCS,
.. including a 36% risk reduction in mortality for those who quit.124
ventions, and to control risk factors including lifestyle behaviours. ..
Optimal medical therapy in the COURAGE (Clinical Outcomes .. Measures to promote smoking cessation include brief advice, coun-
©ESC 2019
readiness
to quit If alcohol is consumed, limiting intake to <_100 g/week or <15 g/day is
recommended.
Avoid energy-dense foods such as sugar-sweetened soft drinks.
..
3.3 Pharmacological management .. events in most patients with CCS. Supplementary Table 3 in the
The aims of pharmacological management of CCS patients are to
.. Supplementary Data summarizes the principal major side effects,
..
reduce angina symptoms and exercise-induced ischaemia, and to pre- .. contraindications, drugdrug interactions, and precautions relating
.. to anti-ischaemic drugs. Supplementary Table 2 summarizes the main
vent cardiovascular events. ..
Immediate relief of anginal symptoms, or the prevention of symp- .. mechanisms of action of anti-ischaemic drugs.
..
toms under circumstances likely to elicit angina, is usually obtained ..
with rapidly acting formulations of nitroglycerin. Anti-ischaemic .. 3.3.1.2.1 Nitrates.
..
vasoconstriction, postural hypotension, impotence, and masking of .. blockade.232 In the large placebo-controlled ACTION (A Coronary
hypoglycaemia symptoms. .. disease Trial Investigating Outcome with Nifedipine gastrointestinal
..
In certain patients with recent MI and those with chronic HF with .. therapeutic system) trial, addition of long-acting nifedipine [60 mg
reduced ejection fraction, beta-blockers have been associated with a .. o.d. (once a day)] to conventional treatment of angina had no effect
..
significant reduction in mortality and/or cardiovascular events,209215 .. on major cardiovascular event-free survival. Long-acting nifedipine
but the protective benefit in patients with CAD without prior MI or .. proved to be safe, and reduced the need for coronary angiography
..
HF is less well established and lacks placebo-controlled trials.216 A .. and cardiovascular interventions.232 Relative contraindications to
©ESC 2019
Figure 8 Suggested stepwise strategy for long-term anti-ischaemic drug therapy in patients with chronic coronary syndromes and specific baseline char-
acteristics. The proposed stepwise approach must be adapted to each patient’s characteristics and preferences. BB = beta-blocker; bpm = beats per
minute; CCB = [any class of] calcium channel blocker; DHP-CCB = dihydropyridine calcium channel blocker; HF = heart failure; LAN = long-acting nitrate;
LV = left ventricular; NDHP-CCB = non-dihydropyridine calcium channel blocker.
a
Combination of a BB with a DHP-CCB should be considered as first step; combination of a BB or a CCB with a second-line drug may be considered as a
first step; bThe combination of BB and non-DHP-CCB should initially use low doses of each drug under close monitoring of tolerance, particularly heart
rate and blood pressure; cLow dose of ivabradine (2.5 mg) should first be tested, and should not be combined with non-DHP-CCB; dAddition of ivabradine
may only be considered if heart rate is >80 bpm and tolerance is good at step 2.
ESC Guidelines 29
..
nitroglycerin use, longer time to 1 mm ST-segment depression, .. characteristics and preferences, and does not necessarily follow the
higher total work, and longer exercise duration at peak exercise than .. steps indicated in the figure.
..
treatment with the other antianginal drugs for stable angina pecto- ..
ris.255 These results support the use of trimetazidine as a second-line .. 3.3.1.3 Patients with low blood pressure
..
drug in patients with CCS whose symptoms are not adequately con- .. In patients with low BP, it is recommended to start antianginal drugs at
trolled by, or who are intolerant to, other medicines for angina
.. very low doses, with preferential use of drugs with no or limited effects
..
pectoris. .. on BP. A low-dose beta-blocker or low-dose non-DHP-CCB can be
General considerations
Medical treatment of symptomatic patients requires one or more drug(s) for angina/ischaemia relief in association with
I C
drug(s) for event prevention.
It is recommended that patients are educated about the disease, risk factors, and treatment strategy. I C
Timely review of the patient’s response to medical therapies (e.g. 24 weeks after drug initiation) is recommended.262 I C
c
Angina/ischaemia relief
Short-acting nitrates are recommended for immediate relief of effort angina.195,263 I B
First-line treatment is indicated with beta-blockers and/or CCBs to control heart rate and symptoms.205,264 I A
If angina symptoms are not successfully controlled on a beta-blocker or a CCB, the combination of a beta-blocker with a
IIa C
DHP-CCB should be considered.
Initial first-line treatment with the combination of a beta-blocker and a DHP-CCB should be considered.194,198,264 IIa B
Long-acting nitrates should be considered as a second-line treatment option when initial therapy with a beta-blocker and/or a
IIa B
non-DHP-CCB is contraindicated, poorly tolerated, or inadequate to control angina symptoms.200,201
When long-acting nitrates are prescribed, a nitrate-free or low-nitrate interval should be considered to reduce tolerance.201 IIa B
241244,246 248,265 235237 252,255
Nicorandil, ranolazine, ivabradine, or trimetazidine should be considered as a second-line treat-
ment to reduce angina frequency and improve exercise tolerance in subjects who cannot tolerate, have contraindications to, IIa B
or whose symptoms are not adequately controlled by beta-blockers, CCBs, and long-acting nitrates.
In subjects with baseline low heart rate and low BP, ranolazine or trimetazidine may be considered as a first-line drug to
IIb C
reduce angina frequency and improve exercise tolerance.
In selected patients, the combination of a beta-blocker or a CCB with second-line drugs (ranolazine, nicorandil, ivabradine,
IIb B
and trimetazidine) may be considered for first-line treatment according to heart rate, BP, and tolerance.198
Nitrates are not recommended in patients with hypertrophic obstructive cardiomyopathy266 or co-administration of phos-
III B
phodiesterase inhibitors.267
BP = blood pressure; CCB = calcium channel blocker; CCS = chronic coronary syndromes; DHP-CCB = dihydropyridine calcium channel blocker.
a
Class of recommendation.
b
Level of evidence.
c
No demonstration of benefit on prognosis.
30 ESC Guidelines
..
3.3.2 Event prevention .. monotherapy in patients with previous PCI.281 Ticagrelor, with a 180
3.3.2.1 Antiplatelet drugs .. mg loading dose followed by 90 mg b.i.d., achieved greater reduction
..
Platelet activation and aggregation is the driver for symptomatic cor- .. of ischaemic events compared with clopidogrel in aspirin-treated
onary thrombosis, forming the basis for the use of antiplatelet drugs .. ACS patients, regardless of revascularization strategy, at the expense
..
in patients with CCS in view of a favourable balance between the pre- .. of more non-fatal bleeding.282,283 Ticagrelor at doses of 90 or 60 mg
vention of ischaemic events and increased risk of bleeding. Dual anti- .. b.i.d. reduced the 3 year combined incidence of MI, stroke, or cardio-
..
platelet therapy (DAPT) with aspirin and an oral P2Y12 inhibitor is .. vascular death compared with placebo in stable aspirin-treated
..
compared with aspirin and anticoagulation, in preventing stent .. particular NOAC regimen.300 Radial artery access is preferred along
thrombosis led to the latter strategy being abandoned in favour of .. with intraprocedural unfractionated heparin either at a standard dose
..
DAPT following PCI.284 Combination of antiplatelet therapy and .. (70100 U/kg) or, in those with uninterrupted VKA, at a lower dose
standard anticoagulant doses of warfarin or apixaban for secondary .. of 3050 U/kg.300 Pre-treatment with aspirin 75100 mg daily is rec-
..
prevention after ACS was associated with an unfavourable balance of .. ommended, and clopidogrel (300600 mg loading dose if not on
efficacy and bleeding.294,295 However, recently reported studies have .. long-term maintenance therapy) is recommended in preference to
..
renewed interest in combining lower anticoagulant doses with anti- .. prasugrel or ticagrelor.300 VKA-treated patients receiving aspirin and
..
indication (prasugrel stopped >_7 days before; clopidogrel >_5 days .. completed. Usually, this will mean delaying surgery until 6 months
before; ticagrelor >_3 days before; and rivaroxaban, apixaban, edoxa- .. after PCI, but surgery between 36 months may be considered by
..
ban, and dabigatran 12 days before depending on dose and renal .. a multidisciplinary team, including an interventional cardiologist, if
function). Reloading of aspirin after CABG surgery may improve graft .. clinically indicated. In most types of surgery, aspirin should be con-
..
patency.302 The role of DAPT or dual therapy with aspirin and rivar- .. tinued as the benefit outweighs the bleeding risk, but this may not
oxaban after CABG surgery is uncertain as large prospective studies .. be appropriate for procedures associated with extremely high
..
are lacking. However, RCT results have suggested higher graft .. bleeding risk (intracranial procedures, transurethral prostatectomy,
Long-term OAC therapy (NOAC or VKA with time in therapeutic range >70%) should be considered in patients with AF
IIa B
and a CHA2DS2-VASc scoreg of 1 in males and 2 in females.299
Aspirin 75100 mg daily (or clopidogrel 75 mg daily) may be considered in addition to long-term OAC therapy in patients
IIb B
with AF, history of MI, and at high risk of recurrent ischaemic eventsc who do not have a high bleeding risk.d 295,297,299
Antithrombotic therapy in post-PCI patients with AF or another indication for an OAC
It is recommended that peri-procedural aspirin and clopidogrel are administered to patients undergoing coronary stent
I C
AF = atrial fibrillation; b.i.d. = bis in die (twice a day); CAD = coronary artery disease; CCS = chronic coronary syndromes; CHA2DS2-VASc = Cardiac failure, Hypertension,
Age >_75 [Doubled], Diabetes, Stroke [Doubled] Vascular disease, Age 6574 and Sex category [Female]; CKD = chronic kidney disease; DAPT = dual antiplatelet therapy;
eGFR = estimated glomerular filtration rate; HF = heart failure; MI = myocardial infarction; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulant;
o.d. = omni die (once a day); PAD = peripheral artery disease; PCI = percutaneous coronary intervention; VKA = vitamin K antagonist.
a
Class of recommendation.
b
Level of evidence.
c
Diffuse multivessel CAD with at least one of the following: diabetes mellitus requiring medication, recurrent MI, PAD, or CKD with eGFR 1559 mL/min/1.73 m2.
d
Prior history of intracerebral haemorrhage or ischaemic stroke, history of other intracranial pathology, recent gastrointestinal bleeding or anaemia due to possible gastrointes-
tinal blood loss, other gastrointestinal pathology associated with increased bleeding risk, liver failure, bleeding diathesis or coagulopathy, extreme old age or frailty, or renal fail-
ure requiring dialysis or with eGFR <15 mL/min/1.73 m2.
e
At least one of the following: multivessel/diffuse CAD, diabetes mellitus requiring medication, recurrent MI, PAD, HF, or CKD with eGFR 1559 mL/min/1.73 m2.
f
See summary of product characteristics for reduced doses or contraindications for each NOAC in patients with CKD, body weight <60 kg, age >7580 years, and/or drug
interactions.
g
Congestive HF, hypertension, age >_75 years (2 points), diabetes, prior stroke/transient ischaemic attack/embolus (2 points), vascular disease (CAD on imaging or angiogra-
phy,312 prior MI, PAD, or aortic plaque), age 6574 years, and female sex.
h
Risk of stent thrombosis encompasses (i) the risk of thrombosis occurring and (ii) the risk of death should stent thrombosis occur, both of which relate to anatomical, proce-
dural, and clinical characteristics. Risk factors for CCS patients include stenting of left main stem, proximal LAD, or last remaining patent artery; suboptimal stent deployment;
stent length >60 mm; diabetes mellitus; CKD; bifurcation with two stents implanted; treatment of chronic total occlusion; and previous stent thrombosis on adequate antith-
rombotic therapy.
34 ESC Guidelines
Table 9 Treatment options for dual antithrombotic therapy in combination with aspirin 75 2 100 mg daily in patients
who have a higha or moderateb risk of ischaemic events, and do not have a high bleeding riskc
Drug option Dose Indication Additional cautions References
289,290
Clopidogrel 75 mg o.d. Post-MI in patients who have tolerated DAPT for 1 year
289,290,313
Prasugrel 10 mg o.d or 5 mg o.d.; if body Post-PCI for MI in patients who have tolerated Age >75 years
weight <60 kg or age >75 years DAPT for 1 year
3.3.3 Statins and other lipid-lowering drugs .. 3.3.4 Reninangiotensinaldosterone system blockers
..
Dyslipidaemia should be managed according to lipid guidelines with .. ACE inhibitors can reduce mortality, MI, stroke, and HF among patients
pharmacological and lifestyle intervention.315 Patients with estab-
.. with LV dysfunction,328330 previous vascular disease,331333 and high-
..
lished CAD are regarded as being at very high risk for cardiovascular .. risk diabetes.334 It is recommended that ACE inhibitors [or angiotensin
events and statin treatment must be considered, irrespective of LDL-
.. receptor blockers (ARBs) in cases of intolerance] be considered for the
..
C levels. The goal of treatment is to lower LDL-C by at least 50% .. treatment of patients with CCS with coexisting hypertension, LVEF
from baseline and to <1.4 mmol/L (<55 mg/dL) although a lower tar-
.. <_40%, diabetes, or CKD, unless contraindicated (e.g. severe renal
..
get LDL-C of <1.0 mmol/L (<40 mg/dL) may be considered in .. impairment, hyperkalaemia, etc.). However, not all trials have demon-
patients who have experience a second vascular event within 2 years,
.. strated that ACE inhibitors reduce all-cause death, cardiovascular death,
..
not necessarily of the same type as the first event, whilst taking maxi- .. non-fatal MI, stroke, or HF in patients with atherosclerosis and without
..
mally tolerated statin-based therapy. When this level cannot be .. impaired LV function.331,332,335 A meta-analysis, including 24 trials and
achieved, the addition of ezetimibe has been demonstrated to .. 61 961 patients, documented that, in CCS patients without HF,
..
decrease cholesterol and cardiovascular events in post-ACS patients, .. renin-angiotensin system (RAS) inhibitors reduced cardiovascular
and in those with diabetes,316 with no further effect on mortality.317 .. events and death only when compared with placebo, but not when
..
In addition to exercise, diet, and weight control, which should be rec- .. compared with active controls.336 Hence, ACE inhibitor therapy in
ommended to all patients, dietary supplements including phytosterols .. CCS patients without HF or high cardiovascular risk is not generally rec-
..
may lower LDL-C to a lesser extent, but have not been shown to .. ommended, unless required to meet BP targets.
improve clinical outcomes.318 These are also used in patients with .. Neprilysin is an endogenous enzyme that degrades vasoactive pepti-
..
intolerance to statins who constitute a group at higher risk for cardio- .. des such as bradykinin and natriuretic peptides. Pharmacological inhibi-
vascular events.319 Trials published since 2015 have demonstrated .. tion of neprilysin raises the levels of these peptides, enhancing diuresis,
..
that proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors .. natriuresis, myocardial relaxation, and antiremodelling, and reducing
(evolocumab320 and alirocumab321323) are very effective at reducing .. renin and aldosterone secretion. The first in class is LCZ696, which
..
cholesterol, lowering LDL-C in a stable fashion to <_1.3 mmol/L (50 .. combines valsartan and sacubitril (neprilysin inhibitor) in a single pill. In
mg/dL). In outcomes trials, these agents have demonstrated a reduc- .. patients with HF (LVEF <_35%) who remain symptomatic despite opti-
..
tion of cardiovascular and mainly ischaemic events, with little or no .. mal treatment with an ACE inhibitor, a beta-blocker, and a mineralo-
impact on mortality.324 Very low levels of cholesterol are well toler-
.. corticoid receptor antagonist (MRA), sacubitril/valsartan is
..
ated and associated with fewer events,325 but the high cost of PCSK9 .. recommended as a replacement for an ACE inhibitor to further reduce
inhibitors, unaffordable for many health systems,326 and their
.. the risk of HF hospitalization and death in ambulatory patients.337
..
unknown long-term safety have limited their use to date. Low- .. Aldosterone blockade with spironolactone or eplerenone is rec-
density lipoprotein apheresis and new therapies such as mipomersen
.. ommended for use in post-MI patients who are already receiving
..
and lomitapide need further research. .. therapeutic doses of an ACE inhibitor and a beta-blocker, have an
For patients undergoing PCI, high-dose atorvastatin has been
.. LVEF <_35%, and have either diabetes or HF.338,339 Caution should be
..
shown to reduce the frequency of peri-procedural events in both .. exercised when MRAs are used in patients with impaired renal func-
..
statin-naı̈ve patients and patients receiving chronic statin .. tion [estimated GFR (eGFR) <45 mL/min/1.73 m2] and in those with
therapy.327 .. serum potassium levels >_5.0 mmol/L.340
..
.
ESC Guidelines 35
ACE = angiotensin-converting enzyme; ARB = angiotensin-receptor blocker; CCS = chronic coronary syndrome; HF = heart failure; LV = left ventricular; PCSK9 = proprotein
convertase subtilisin-kexin type 9; STEMI = ST-elevation myocardial infarction.
a
Class of recommendation.
b
Level of evidence.
c
The treatment goals are shown in the European Society of Cardiology/European Atherosclerosis Society Guidelines for the management of dyslipidaemias.315
..
3.3.5 Hormone replacement therapy .. with PCI.262 The study highlights a significant placebo component to
The results from large randomized trials have shown that hormone .. the clinical effects, and alerts us to the pitfalls of interpreting end-
..
replacement therapy provides no prognostic benefit and increases .. points subject to bias in the absence of sham control and blinding.
the risk of CVD in women aged >60 years.344 .. However, the ORBITA results cannot inform Guidelines due to the
..
.. limited trial size, short-term observation time until crossover, and
.. insufficient power to assess clinical endpoints.
..
3.4 Revascularization .. Revascularization by either PCI or CABG also aims to effectively
In patients with CCS, optimal medical therapy is key for reducing .. eliminate myocardial ischaemia and its adverse clinical manifestations
..
symptoms, halting the progression of atherosclerosis, and preventing .. among patients with significant coronary stenosis, and to reduce the
atherothrombotic events. Myocardial revascularization plays a cen-
.. risk of major acute cardiovascular events including MI and cardiovas-
..
tral role in the management of CCS on top of medical treatment, but .. cular death. Numerous meta-analyses comparing a strategy of PCI
always as an adjunct to medical therapy without supplanting it. The
.. with initial medical therapy among patients with CCS have found
..
two objectives of revascularization are symptom relief in patients .. no348,349 or a modest104,350,351 benefit, in terms of survival or MI for
with angina and/or improvement of prognosis.
.. an invasive strategy. In this regard, previous Guidelines identified spe-
..
Previous Guidelines support indications for revascularization .. cific subgroups of patients (based on the anatomy of the coronary
mainly in patients with CCS who receive Guideline-recommended
.. tree, LV function, risk factors, etc.) in whom revascularization may
..
optimal medical therapy and continue to be symptomatic, and/or in .. improve prognosis, indicating that in other groups it may not.88
..
whom revascularization may ameliorate prognosis.88 These recom- .. A meta-analysis by Windecker et al. reported an incremental
mendations suggested that revascularization in patients with angina .. reduction of death and MI by revascularization vs. medical therapy
..
and significant stenosis was often a second-line therapy after medical .. only in CCS patients when revascularization was performed with
therapy had been unsuccessful. However, angina is associated with .. CABG or new-generation drug-eluting stents (DES), as opposed to
..
balloon angioplasty, bare-metal stents, or early DES.351 Data
impaired quality of life, reduced physical endurance, mental depres-
...
sion, and recurrent hospitalizations and office visits, with impaired .. reported in 2018 indicate a potentially broader prognostic impact of
clinical outcomes.345,346 .. revascularization strategies. The 5 year follow-up of the FAME 2 trial
..
Revascularization by PCI or CABG may effectively relieve angina, .. confirmed a sustained clinical benefit in patients treated with PCI spe-
reduce the use of antianginal drugs, and improve exercise capacity .. cifically targeting the ischaemia-producing stenoses (i.e. FFR <0.80)
..
and quality of life compared with a strategy of medical therapy .. plus optimal medical therapy vs. optimal medical therapy alone in
alone. In the 5 year follow-up of the FAME 2 (Fractional Flow .. terms of a significantly lower rate of urgent revascularization (hazard
..
Reserve versus Angiography for Multivessel Evaluation 2) trial, revas- .. ratio 0.27, 95% CI 0.180.41), and a lower rate of spontaneous MI
cularization improved quality of life, and reduced the use of antiangi- .. (hazard ratio 0.62, 95% CI 0.390.99).347 In contrast to some of the
..
nal drugs and associated side effects.347 The ORBITA (Objective .. earlier meta-analyses, this signal was confirmed in a patient-level
Randomised Blinded Investigation with optimal medical Therapy or
.. meta-analysis including 2400 subjects, all of whom underwent inva-
..
Angioplasty in stable angina) study, entailing a sham procedure in the .. sive physiological guidance, showing a significant reduction in cardiac
control group, found no significant improvement in exercise capacity
.. death and MI after a median follow-up of 33 months with FFR-guided
36 ESC Guidelines
Angina symptoms
Yes No
Documented Documented
ischaemia ischaemia
Yes No Yes No
Figure 9 Decision tree for patients undergoing invasive coronary angiography. Decisions for revascularization by percutaneous coronary intervention
or coronary artery bypass grafting are based on clinical presentation (symptoms present or absent), and prior documentation of ischaemia (present or
absent). In the absence of prior documentation of ischaemia, indications for revascularization depend on invasive evaluation of stenosis severity or prog-
nostic indications. Patients with no symptoms and ischaemia include candidates for transcatheter aortic valve implantation, valve, and other surgery. CAD
= coronary artery disease; FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio; LV = left ventricle; LVEF = left ventricular ejection fraction;
MVD = multivessel disease.
ESC Guidelines 37
General recommendations for the management of patients with chronic coronary syndromes and symptomatic heart
failure due to ischaemic cardiomyopathy and left ventricular systolic dysfunction
Diuretic therapy is recommended in symptomatic patients with signs of pulmonary or systemic congestion to relieve HF
I B
symptoms.359,360
Beta-blockers are recommended as essential components of treatment due to their efficacy in both relieving angina, and
I A
reducing morbidity and mortality in HF.214,361367
ACE inhibitor therapy is recommended in patients with symptomatic HF or asymptomatic LV dysfunction following MI, to
I A
improve symptoms and reduce morbidity and mortality.333,368
An ARB is recommended as an alternative in patients who do not tolerate ACE inhibition, or an angiotensin recep-
I B
tor-neprilysin inhibitor in patients with persistent symptoms despite optimal medical therapy.337,369
An MRA is recommended in patients who remain symptomatic despite adequate treatment with an ACE inhibitor and
I A
beta-blocker, to reduce morbidity and mortality.360,370
A short-acting oral or transcutaneous nitrate should be considered (effective antianginal treatment, safe in HF).371 IIa A
Ivabradine should be considered in patients with sinus rhythm, an LVEF <_35% and a resting heart rate >70 b.p.m. who
remain symptomatic despite adequate treatment with a beta-blocker, ACE inhibitor, and MRA, to reduce morbidity and IIa B
238,372,373
mortality.
Amlodipine may be considered for relief of angina in patients with HF who do not tolerate beta-blockers, and is consid-
IIb B
ered safe in HF.374,375
Continued
38 ESC Guidelines
ACE inhibitor = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; b.p.m. = beats per minute; CCS = chronic coronary syndromes; CRT = cardiac resynch-
ronization therapy; HF = heart failure; LBBB = left bundle branch block; LV = left ventricular; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MRA = miner-
alocorticoid receptor antagonist.
a
Class of recommendation.
b
Level of evidence.
..
5 Patients with a long-standing .. such as recovery from myocardial stunning or hibernation, which
.. may be reversed by revascularization.52,53 Conversely, cardiac func-
diagnosis of chronic coronary ..
.. tion may have deteriorated given other concomitant CVD (e.g. valvu-
syndromes .. lar disease, infection or inflammation, arrhythmia, etc.). In such cases,
..
.. these other damaging factors need to be identified and treated.
In patients with a long-standing diagnosis of CCS, lifelong treatment .. Likewise, non-invasive assessment of myocardial ischaemia may be
.
and surveillance are required (Figure 10). The clinical course of .. considered after revascularization to rule-out residual ischaemia or
.
patients with CCS may be benign over the course of time. However, .. to document the residual ischaemia as reference for subsequent
.
patients with CCS may develop a variety of cardiovascular complica- .. assessments over time.
.
tions or undergo therapeutic measures, some directly related to the ..
.
underlying CAD, and some having therapeutic or prognostic interac- .. 5.2 Patients >1 year after initial diagnosis
.
tions with the underlying disease. Risk for complications may occur in ..
. or revascularization
an otherwise asymptomatic patient, and thus the assessment of risk ..
.. To assess a patient’s risk, an annual evaluation by a cardiovascular
status applies to symptomatic and asymptomatic patients. .. practitioner (cardiologist, general physician, or nurse) is warranted,
Periodic assessment of the patient’s individual risk may be consid- ..
. even if the patient is asymptomatic. It is recommended that the
ered (Figure 10). Scores that apply clinical parameters have been ..
. annual evaluation should assess the patient’s overall clinical status and
shown to predict outcomes among patients with CCS. Moreover, if ...
medication compliance, as well as the risk profile (as reflected by risk
the clinical parameters are complemented by biomarkers, such a risk ...
score may be even more accurate. In 2017, a biomarker-based risk ...
scores). Laboratory tests—which include a lipid profile, renal func-
model to predict cardiovascular mortality in patients with CCS was ...
tion, a complete blood count, and possibly biomarkers—should be
developed and externally validated.398 .. performed every 2 years.45 A patient with a worsening risk score
.. over time may warrant more intense therapy or diagnostic measures,
..
. although risk score-guided therapy has not yet been proved to ameli-
5.1 Patients with stabilized symptoms <1 ... orate outcomes.
year after an acute coronary syndrome ..
.. A 12 lead ECG should be a part of every such visit to delineate
or patients with recent revascularization ... heart rate and heart rhythm, to detect changes suggestive of silent
After revascularization and/or after stabilized ACS (<1 year), patients ... ischaemia/infarction, and to discern abnormalities in the specific elec-
should be monitored more vigilantly, because they are at greater risk ... trocardiographic segments (e.g. PR, QRS, and QT intervals). It may
for complications and because they are subject to changes in pharma- ... be beneficial to assess LV function (diastolic and systolic), valvular sta-
cological treatment.45 Thus, we recommend at least two visits in the ... tus, and cardiac dimensions in apparently asymptomatic patients
first year of follow-up. In a patient who had LV systolic dysfunction ... every 35 years.52,53 In cases of unexplained reduction in systolic LV
.
before the revascularization procedure or after the ACS, a reassess- .. function, especially if regional, imaging of coronary artery anatomy is
.
ment of LV function must be considered 812 weeks after the inter- .. recommended. Likewise, it may be beneficial to assess non-invasively
.
vention. Cardiac function may have improved, owing to mechanisms . for silent ischaemia in an apparently asymptomatic patient every 35
ESC Guidelines 39
..
years, preferably applying stress imaging. Coronary CTA should not .. to support recommendations for the frequency of reassessment of
be used for follow-up of patients with established CAD given its .. these risk factors, but consensus suggests annual evaluation.
..
strength on morphological insight, but lack of functional information .. Elevated inflammatory markers, particularly of high-sensitivity C-
related to ischaemia. However, coronary CTA may be used for .. reactive protein, have also been associated with an increased event
..
unique cases, such as delineation of patency of coronary artery .. risk in patients with and without CAD in multiple studies,25 although
bypass grafts. .. the robustness of the association has been questioned because of
..
The lipid profile and glycaemia status should be reassessed periodi- .. reporting and publication bias.399 In addition, von Willebrand factor,
9
9
9
or revascularization
Baseline
initial evaluation
of recent CCS
Time from
3 months
6 months
12 months
ACS
Destabilization
Stabilization
Long-standing diagnosis
of CCS (>1 year)
Yearly
Post-ACS CCS
(e.g. >1 year after MI)
Baseline
3 months
of post-ACS CCS
initial evaluation
6 months
Time from
12 months
18 months
24 months
Yearly
Echocardiography Early (e.g. 1-3 months) after revascularization to set as a reference and/or
at rest periodically (e.g. at 1 year if previously abnormal and/or every 3-5 years) to
evaluate LV function, valvular status and haemodynamic status.
Stress test for As necessary, to investigate changes in symptoms level, and/or early
inducible ischaemia (e.g. 1-3 months) after revascularization to set as a reference
and/or periodically (e.g. every 3-5 years) to reassess ischaemia.
Invasive coronary As necessary, for patients at high risk based on noninvasive ischaemia
©ESC 2019
Figure 10 Proposed algorithm according to patient types commonly observed at chronic coronary syndrome outpatient clinics. The frequency of fol-
low-up may be subject to variation based on clinical judgement. ACS = acute coronary syndromes; CCS = chronic coronary syndromes; DAPT = dual anti-
platelet therapy; ECG = electrocardiogram; LV = left ventricular; MI = myocardial infarction; PCI = percutaneous coronary intervention. aCardiologist,
internist, general practitioner, or cardiovascular nurse.
40 ESC Guidelines
..
readily available biomarkers shown to predict prognosis in patients ..
..
6 Angina without obstructive
with CCS include heart rate, haemoglobin, and white cell count.400
.. disease in the epicardial coronary
Scores based on aggregated biomarkers may have greater success ..
than individual biomarkers. A multiple biomarker score combining .. arteries
..
high-sensitivity C-reactive protein, heat shock protein 70, and fibrin ..
degradation products significantly improved C-statistics and the net .. In clinical practice, a marked discrepancy between findings regarding
.. coronary anatomy, the presence of symptoms, and the results of
reclassification index compared with a basic model using clinical ..
A periodic visit to a cardiovascular healthcare professional is recommended to reassess any potential change in the risk
status of patients, entailing clinical evaluation of lifestyle-modification measures, adherence to targets of cardiovascular I C
risk factors, and the development of comorbidities that may affect treatments and outcomes.
In patients with mild or no symptoms receiving medical treatment in whom non-invasive risk stratification indicates a high
risk, and for whom revascularization is considered for improvement of prognosis, invasive coronary angiography (with I C
FFR when necessary) is recommended.
Coronary CTA is not recommended as a routine follow-up test for patients with established CAD. III C
Invasive coronary angiography is not recommended solely for risk stratification. III C
Symptomatic patients
Reassessment of CAD status is recommended in patients with deteriorating LV systolic function that cannot be attributed
I C
to a reversible cause (e.g. long-standing tachycardia or myocarditis).
Risk stratification is recommended in patients with new or worsening symptom levels, preferably using stress imaging or,
I B
alternatively, exercise stress ECG.408
It is recommended to expeditiously refer patients with significant worsening of symptoms for evaluation. I C
Invasive coronary angiography (with FFR/iwFR when necessary) is recommended for risk stratification in patients with
I C
severe CAD, particularly if the symptoms are refractory to medical treatment or if they have a high-risk clinical profile.
CAD = coronary artery disease; CTA = computed tomography angiography; ECG = electrocardiogram; FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio;
LV = left ventricular.
a
Class of recommendation.
b
Level of evidence.
ESC Guidelines 41
..
evidence is seldom reached. Owing to this, patient dismay and .. the challenges in performing a comprehensive assessment of micro-
depression are not rare in this clinical population.410,411 Of note, the .. vascular function is testing the two main mechanisms of dysfunction
..
use of a structured, systematic approach to explore microcirculatory .. separately: impaired microcirculatory conductance and arteriolar
and vasomotor disorders in patients with non-obstructive CAD, as .. dysregulation.424426 Yet, outlining which of these two pathways is
..
delineated below, has been shown to increase diagnostic yield.412,413 .. affected is critically relevant in setting medical treatment to relieve
Furthermore, an RCT, which reported in 2018, found that in patients
.. patient symptoms.414
..
with non-obstructive coronary disease, tailored treatment guided by .. Impaired microcirculatory conductance can be diagnosed by measuring
..
Investigations in patients with suspected coronary micro- .. coronary stenosis. Angiographic documentation of coronary spasm
vascular angina .. requires the use of a provocation test in the catheterization laboratory.
..
.. Given the low sensitivity of hyperventilation and the cold pressor test,
Recommendations Classa Levelb .. intracoronary administration of acetylcholine or ergonovine during
..
Guidewire-based CFR and/or microcirculatory .. ICA are the preferred provocation tests.442 Both pharmacological
resistance measurements should be consid-
.. agents are safe, provided that they are selectively infused into the left
..
ered in patients with persistent symptoms, but .. or right coronary artery, and that triggered spasm is readily controlled
..
7 Screening for coronary artery ..
..
asymptomatic subjects who receive testing and have a positive test
.. result beyond the recommendations listed in these Guidelines.
disease in asymptomatic subjects .. However, the principles of risk stratification, as described above for
.. symptomatic patients, also apply to these individuals.450 It is impor-
In an effort to lower the high burden of coronary deaths in asympto- ..
matic adults, numerous measurements of risk factors and risk markers, .. tant to remember that data demonstrating improved prognosis fol-
.. lowing appropriate management based on new biomarkers are still
as well as stress tests, are often performed as screening investigations. ..
.. lacking.
Total risk estimation using a risk-estimation system such as SCORE is recommended for asymptomatic adults >40 years
I C
of age without evidence of CVD, diabetes, CKD, or familial hypercholesterolaemia.
Assessment of family history of premature CVD (defined as a fatal or non-fatal CVD event, or/and established diagnosis of
CVD in first-degree male relatives before 55 years of age or female relatives before 65 years of age) is recommended as I C
part of cardiovascular risk assessment.
It is recommended that all individuals aged <50 years with a family history of premature CVD in a first-degree relative
(<55 years of age in men or <65 years of age in women) or familial hypercholesterolaemia are screened using a validated I B
clinical score.455,456
Assessment of coronary artery calcium score with computed tomography may be considered as a risk modifierc in the
IIb B
cardiovascular risk assessment of asymptomatic subjects.449,457
Atherosclerotic plaque detection by carotid artery ultrasound may be considered as a risk modifierc in the cardiovascular
IIb B
risk assessment of asymptomatic subjects.458
ABI may be considered as a risk modifierc in cardiovascular risk assessment.459 IIb B
In high-risk asymptomatic adults (with diabetes, a strong family history of CAD, or when previous risk-assessment tests
IIb C
suggest a high risk of CAD), functional imaging or coronary CTA may be considered for cardiovascular risk assessment.
In asymptomatic adults (including sedentary adults considering starting a vigorous exercise programme), an exercise ECG
may be considered for cardiovascular risk assessment, particularly when attention is paid to non-ECG markers such as IIb C
exercise capacity.
Carotid ultrasound IMT for cardiovascular risk assessment is not recommended.460 III A
In low-risk non-diabetic asymptomatic adults, coronary CTA or functional imaging for ischaemia are not indicated for fur-
III C
ther diagnostic assessment.
Routine assessment of circulating biomarkers is not recommended for cardiovascular risk stratification.448,449,461,462 III B
ABI = ankle-brachial index; CAD = coronary artery disease; CKD = chronic kidney disease; CTA = computed tomography angiography; CVD = cardiovascular disease; ECG =
electrocardiogram; IMT = intima-media thickness; SCORE = Systematic COronary Risk Evaluation.
a
Class of recommendation.
b
Level of evidence.
c
Reclassifies patients better into low- or high-risk groups.
44 ESC Guidelines
..
8 Chronic coronary syndromes in ..
..
8.1.2 Valvular heart disease (including planned
transcatheter aortic valve implantation)
specific circumstances ..
.. Coronary angiography for the assessment of CAD is recommended
.. before valve surgery or when percutaneous valvular intervention is
8.1 Cardiovascular comorbidities ..
.. planned, to determine if revascularization is required. Coronary CTA
8.1.1 Hypertension .. may be considered in patients with low risk for CAD, or in patients in
Hypertension is the most prevalent cardiovascular risk factor and is ..
.. whom conventional ICA is technically not feasible or associated with
..
examinations may be useful in assessing cardiac allograft vasculopathy .. >_50% if the baseline LCL-C is between 1.8 and 3.5 mmol/L (70 and
and plaque stability.478 Treatment options for CAD in transplant .. 135 mg/dL).15 For the majority of patients with diabetes and CAD, a
..
recipients include pharmacotherapy and revascularization. PCI in the .. target glycated HbA1c level of <7% (<53 mmol/L) is recom-
transplanted heart has become an established therapy.479 .. mended.483,484 Large safety studies on new glucose-lowering drugs,
..
.. namely sodium-glucose co-transporter-2 and glucagon-like peptide-1
.. receptor agonists, have demonstrated significant reductions in cardi-
..
.. ovascular events. Indications for their clinical use are described in the
8.2.3 Chronic kidney disease .. access-site complications, when choosing an invasive strategy for
..
CAD is highly prevalent in patients with CKD and a growing number .. patient management.506,507 The use of DES, compared with bare-
of patients undergoing PCI have concomitant CKD.493 There is a lin-
.. metal stents, in combination with a short duration of DAPT is associ-
..
ear increase in the risk of cardiovascular mortality with decreasing .. ated with significant safety and efficacy benefits in elderly
GFR.494 Medical treatment for risk-factor control (lipids, BP, and glu-
.. patients.508,509
..
cose) can improve outcomes. Special attention during the workup .
for CKD patients with suspected obstructive CAD should be paid to
..
when new-generation DES were used.517519 The mortality reduc- .. obviously needed, along with safety metrics. To confirm treatment
tions were similar among women and men leaving sex disparities in .. efficacy, trials with a sham-controlled design are desirable, a significant
..
outcomes unchanged.512 Women have higher complication rates fol- .. placebo effect being part of the therapeutic effect. Patients with
lowing CABG and may also have higher mortality risk,520,521 espe- .. refractory angina are best treated in dedicated ‘angina clinics’ by mul-
..
cially in elderly patients. Hormone replacement therapy in post- .. tidisciplinary teams experienced in selecting the most suitable thera-
menopausal women does not reduce the risk of ischaemic myocar- .. peutic approach in the individual patient based on an accurate
..
dial disease (see section 3.3.5), and is therefore not recommended for .. diagnosis of the mechanisms of the pain syndrome. Once conven-
Table 11 Potential treatment options for refractory angina and summary of trial data
Therapy Type of therapy RCT Type of control group Number of
patients enrolled
External counterpulsation Enhanced external counterpulsation MUST524 Sham 139
Extracorporeal shockwave Low-energy extracorporeal shockwave therapy Not available Not available —
Coronary sinus constriction Reducer device COSIRA525 Sham 104
Neuromodulation Spinal cord stimulation STARTSTIM526 Not available 68
Transcutaneous electrical neural stimulation Not available Not available —
Subcutaneous electrical neural stimulation Not available Not available —
Sympathectomy Denby et al.527 Placebo 65
Gene therapy Adenovirus fibroblast growth factor 5 Not available Not available —
Autologous cell therapy Mononuclear bone marrow-derived RENEW528 Placebo 112
haematopoietic progenitor cells
RCT = randomized clinical trial.
48 ESC Guidelines
Enhanced external counterpulsation may be considered for symptom relief in patients with debilitating angina refractory
IIb B
to optimal medical and revascularization strategies.524
A reducer device for coronary sinus constriction may be considered to ameliorate symptoms of debilitating angina refrac-
..
9 Key messages ..
..
(10) Anti-ischaemic treatment must be adapted to the individual patient
based on comorbidities, co-administered therapies, expected tol-
(1) Careful evaluation of patient history, including the characterization
..
.. erance and adherence, and patient preferences. The choice of
of anginal symptoms, and evaluation of risk factors and manifesta- .. anti-ischaemic drugs to treat CCS should be adapted to the
..
tions of CVD, as well as proper physical examination and basic .. patient’s heart rate, BP, and LV function.
testing, are crucial for the diagnosis and management of CCS. .. (11) Beta-blockers and/or CCBs remain the first-line drugs in patients
..
(2) Unless obstructive CAD can be excluded based on clinical evalua- .. with CCS. Beta-blockers are recommended in patients with LV
tion alone, either non-invasive functional imaging or anatomical .. dysfunction or HF with reduced ejection fraction.
..
imaging using coronary CTA may be used as the initial test to rule- .. (12) Long-acting nitrates provoke tolerance with loss of efficacy. This
out or establish the diagnosis of CCS. .. requires prescription of a daily nitrate-free or nitrate-low interval
..
(3) Selection of the initial non-invasive diagnostic test is based on the .. of 1014 h.
PTP, the test’s performance in ruling-in or ruling-out obstructive .. (13) Antithrombotic therapy is a key part of secondary prevention in
..
CAD, patient characteristics, local expertise, and the availability of .. patients with CCS and warrants careful consideration. Patients
the test. .. with a previous MI, who are at high risk of ischaemic events and
..
(4) For revascularization decisions, both anatomy and functional eval- .. low risk of fatal bleeding, should be considered for long-term
uation are to be considered. Either non-invasive or invasive func- .. DAPT with aspirin and either a P2Y12 inhibitor or very low-dose
..
tional evaluation is required for the assessment of myocardial .. rivaroxaban, unless they have an indication for an OAC such as
ischaemia associated with angiographic stenosis, unless very high .. AF.
..
grade (>90% diameter stenosis). .. (14) Statins are recommended in all patients with CCS. ACE inhibitors
(5) Assessment of risk serves to identify CCS patients at high event risk
.. (or ARBs) are recommended in the presence of HF, diabetes, or
..
who are projected to derive prognostic benefit from revasculariza- .. hypertension and should be considered in high-risk patients.
tion. Risk stratification includes the assessment of LV function.
.. (15) Proton pump inhibitors are recommended in patients receiving
(6) Patients at high event risk should undergo invasive investigation for
...
.. aspirin or combination antithrombotic therapy who are at high
consideration of revascularization, even if they have mild or no .. risk of gastrointestinal bleeding.
symptoms.
..
.. (16) Efforts should be made to explain to patients the importance of
(7) Implementation of healthy lifestyle behaviours decreases the risk .. evidence-based prescriptions to increase adherence to treatment,
..
of subsequent cardiovascular events and mortality, and is addi- .. and repeated therapeutic education is essential in every clinical
tional to appropriate secondary prevention therapy. Clinicians .. encounter.
..
should advise on and encourage necessary lifestyle changes in .. (17) Patients with a long-standing diagnosis of CCS should undergo
every clinical encounter. .. periodic visits to assess potential changes in risk status, adherence
..
(8) Cognitive behavioural interventions such as supporting patients to .. to treatment targets, and the development of comorbidities.
set realistic goals, self-monitor, plan how to implement changes .. Repeat stress imaging or ICA with functional testing is recom-
..
and deal with difficult situations, set environmental cues, and .. mended in the presence of worsening symptoms and/or increased
engage social support are effective interventions for behaviour .. risk status.
..
change. .. (18) Assessment of myocardial and valvular function and dimensions, as
(9) Multidisciplinary teams can provide patients with support to make .. well as a functional test to rule-out significant myocardial silent
..
healthy lifestyle changes, and address challenging aspects of behav- .. ischaemia, may be contemplated every 35 years in asymptomatic
iour and risk. .. patients with a long-standing diagnosis of CCS.
..
ESC Guidelines 49
..
(19) An assessment of coronary vasomotor function should be consid- .. of aspirin þ P2Y12 inhibitor with aspirin þ factor Xa inhibitor are
ered in patients with non-significant epicardial CAD and objective .. warranted to determine which subgroups may be preferentially
..
evidence of ischaemia. .. treated with one or other strategy. The potential clinical benefit of
.. ticagrelor monotherapy, while stopping aspirin, remains unproved at
..
.. present.
10 Gaps in the evidence ..
.. The role of biomarkers in stratifying patients’ risk of ischaemic
.. events and bleeding requires clarification, including the role of growth
..
10.10 Comorbidities .. 10.11 Patients with refractory angina
..
The role of PCI in patients with aortic stenosis remains undetermined .. Larger RCTs and registries are required to define the role of additional
with respect to the indication for coronary revascularization and tim- .. treatment modalities for specific subgroups, to decrease non-
..
ing vs. valve intervention. Further information is needed on how to .. responder rates and ascertain benefit beyond potential placebo effects.
adapt cardiovascular therapies in patients with chronic inflammatory ..
..
diseases.
Basic biochemistry testing in the initial diagnostic management of patients with suspected CAD
If evaluation suggests clinical instability or ACS, repeated measurements of troponin, preferably using high-sensitivity or
I A
ultrasensitive assays, are recommended to rule-out myocardial injury associated with ACS.
The following blood tests are recommended in all patients:
• Full blood count (including haemoglobin); I B
• Creatinine measurement and estimation of renal function; I A
• A lipid profile (including LDL-C). I A
It is recommended that screening for type 2 diabetes mellitus in patients with suspected and established CCS is imple-
mented with HbA1c and fasting plasma glucose measurements, and that an oral glucose tolerance test is added if HbA1c I B
and fasting plasma glucose results are inconclusive.
Assessment of thyroid function is recommended in cases where there is clinical suspicion of thyroid disorders. I C
Resting ECG in the initial diagnostic management of patients with suspected CAD
A resting 12 lead ECG is recommended in all patients with chest pain without obvious non-cardiac cause. I C
A resting 12 lead ECG is recommended in all patients during or immediately after an episode of angina suspected to indi-
I C
cate clinical instability of CAD.
ST-segment alterations recorded during supraventricular tachyarrhythmias should not be used as evidence of CAD. III C
Ambulatory ECG monitoring in the initial diagnostic management of patients with suspected CAD
Ambulatory ECG monitoring is recommended in patients with chest pain and suspected arrhythmias. I C
Ambulatory ECG monitoring should not be used as routine examination in patients with suspected CCS. III C
Resting echocardiography and CMR in the initial diagnostic management of patients with suspected CAD
A resting transthoracic echocardiogram is recommended in all patients for:
• Exclusion of alternative causes of angina;
• Identification of regional wall motion abnormalities suggestive of CAD; I B
• Measurement of LVEF for risk-stratification purposes;
• Evaluation of diastolic function.
Chest X-ray in the initial diagnostic management of patients with suspected CAD
Chest X-ray is recommended for patients with an atypical presentation, signs and symptoms of heart failure, or suspicion
I C
of pulmonary disease.
Use of diagnostic imaging tests in the initial diagnostic management of symptomatic patients with suspected CAD
Non-invasive functional imaging for myocardial ischaemia or coronary CTA is recommended as the initial test for diagnos-
I B
ing CAD in symptomatic patients in whom obstructive CAD cannot be excluded by clinical assessment alone.
It is recommended that selection of the initial non-invasive diagnostic test is done based on the clinical likelihood of CAD
I C
and other patient characteristics that influence test performance, local expertise, and the availability of tests.
Functional imaging for myocardial ischaemia is recommended if coronary CTA has shown CAD of uncertain functional sig-
I B
nificance or is not diagnostic.
Invasive angiography is recommended as an alternative test to diagnose CAD in patients with a high clinical likelihood and
severe symptoms refractory to medical therapy, or typical angina at a low level of exercise and clinical evaluation that indi-
I B
cates high event risk. Invasive functional assessment must be available and used to evaluate stenoses before revasculariza-
tion, unless very high grade (>90% diameter stenosis).
Continued
ESC Guidelines 51
Coronary CTA is not recommended when extensive coronary calcification, irregular heart rate, significant obesity, inabil-
III C
ity to cooperate with breath-hold commands, or any other conditions makes good image quality unlikely.
Coronary calcium detection by computed tomography is not recommended to identify individuals with obstructive CAD. III C
Performing exercise ECG in the initial diagnostic management of patients with suspected CAD
Exercise ECG is recommended for the assessment of exercise tolerance, symptoms, arrhythmias, BP response, and event
I C
risk in selected patients.
In patients with mild or no symptoms receiving medical treatment, in whom non-invasive risk stratification indicates a high
risk, and for whom revascularization is considered for improvement of prognosis, ICA (with FFR when necessary) is I C
recommended.
Coronary CTA is not recommended as a routine follow-up test for patients with established CAD. III C
ICA is not recommended solely for risk stratification. III C
Symptomatic patients
Treatment with ACE inhibitors is recommended in CCS patients with diabetes for event prevention. I B
The sodium-glucose co-transporter 2 inhibitors empagliflozin, canagliflozin, or dapagliflozin are recommended in patients
I A
with diabetes and CVD.
A glucagon-like peptide-1 receptor agonist (liraglutide or semaglutide) is recommended in patients with diabetes and
I A
CVD.
Recommendations for CKD in CCS
ACE = angiotensin-converting enzyme; ACS = acute coronary syndromes; AF = atrial fibrillation; ARB = angiotensin receptor blocker; b.i.d. = bis in die (twice a day); BP =
blood pressure; CHA2DS2-VASc = Cardiac failure, Hypertension, Age >_75 [Doubled], Diabetes, Stroke [Doubled] Vascular disease, Age 6574 and Sex category [Female];
CAD = coronary artery disease; CCB = calcium channel blocker; CCS = chronic coronary syndromes; CKD = chronic kidney disease; CMR = cardiac magnetic resonance;
CRT = cardiac resynchronization therapy; CTA = computed tomography angiography; CVD = cardiovascular disease; DAPT = dual antiplatelet therapy; DES = drug-eluting
stent; ECG = electrocardiogram; FFR = fractional flow reserve; GPs = general practitioners; HbA1C = glycated haemoglobin; HF = heart failure; ICA = invasive coronary
angiography; IMT = intima-media thickness; iwFR = instantaneous wave-free ratio (instant flow reserve); LBBB = left bundle branch block; LDL-C = low-density lipoprotein cho-
lesterol; LV = left ventricular; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; NOAC = non-vitamin K antag-
onist oral anticoagulant; OAC = oral anticoagulant; o.d. = omni die (once a day); PCI = percutaneous coronary intervention; PCSK9 = proprotein convertase subtilisin-kexin
type 9; RAS = renin-angiotensin system; VKA = vitamin K antagonist.
a
Class of recommendation.
b
Level of evidence.
..
12 Supplementary data ..
..
University of Bergen, Stavanger, Norway; Thor Edvardsen,
.. Cardiology, Oslo University Hospital, Oslo, Norway; Javier Escaned,
Supplementary Data with additional Supplementary Tables and Figures .. Interventional Cardiology Unit, Hospital Clinico San Carlos, Madrid,
complementing the full text—as well as section 3 on patients with angina .. Spain; Christian Funck-Brentano, Department of Clinical
and/or dyspnoea, and suspected coronary artery disease—are available
..
.. Pharmacology, Sorbonne Université, AP-HP, ICAN and INSERM CIC
on the European Heart Journal website and via the ESC website at www. .. Paris-Est, Paris, France; Bernard J. Gersh, Department of
escardio.org/guidelines. ..
.. Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States of
.. America; Martine Gilard, Cardiology, Brest University, Brest, France;
..
.. David Hasdai, Cardiology, Rabin Medical Center Petah Tikva, Israel;
13 Appendix .. Robert Hatala, Department of Cardiology and Angiology, Slovak
..
Author/Task Force Member affiliations: .. Cardiovascular Institute, Slovak Medical University, Bratislava, Slovakia;
.. Felix Mahfoud, Internal Medicine III, Saarland University, Homburg,
Stephan Achenbach, Department of Cardiology, Friedrich- ..
Alexander-Universit€at Erlangen-Nürnberg, Erlangen, Germany; Stefan .. Germany; Josep Masip, Cardiology Department /Intensive Care
.. Department, Hospital CIMA-Sanitas/Consorci Sanitari Integral/
Agewall, Department of Medicine, Clinical Science, Oslo, Norway; ..
Emanuele Barbato, Advanced Biomedical Sciences, University .. University of Barcelona, Barcelona, Spain; Claudio Muneretto,
..
Federico II, Naples, Italy; Jeroen J. Bax, Cardiology, Leiden University .. Cardiovascular Surgery, University of Brescia Medical School, Brescia,
Medical Center, Leiden, Netherlands; Davide Capodanno, .. Italy; Eva Prescott, Department of Cardiology, Bispebjerg University
..
CardioThoracic-Vascular and Transplant Department, A.O.U. .. Hospital, Copenhagen, Denmark; Antti Saraste, Heart Center, Turku
‘Policlinico-Vittorio Emanuele’, University of Catania, Catania, Italy; .. University Hospital, Turku, Finland; Robert F. Storey, Department of
..
Thomas Cuisset, Cardiology, CHU Timone, Marseille, France; .. Infection, Immunity and Cardiovascular Disease, University of Sheffield,
Christi Deaton, Public Health and Primary Care, University of
.. Sheffield, United Kingdom; Pavel Svitil, Cardiologic Practice, Practice
..
Cambridge School of Clinical Medicine, Cambridge, United Kingdom; .. of General Cardiology, Jihlava, Czech Republic; Marco Valgimigli,
Kenneth Dickstein, Cardiology, Stavanger University Hospital,
.. Inselspital, University of Bern, Bern, Switzerland.
ESC Guidelines 55
..
ESC Committee for Practice Guidelines (CPG): Stephan .. Dikic; Slovakia: Slovak Society of Cardiology, Martin Studencan;
Windecker (Chairperson) (Switzerland), Victor Aboyans (France), .. Slovenia: Slovenian Society of Cardiology, Matjaz Bunc; Spain:
..
Colin Baigent (United Kingdom), Jean-Philippe Collet (France), .. Spanish Society of Cardiology, Fernando Alfonso; Sweden:
Veronica Dean (France), Victoria Delgado (Netherlands), Donna .. Swedish Society of Cardiology, Magnus B€ack; Switzerland: Swiss
..
Fitzsimons (United Kingdom), Christopher P. Gale (United .. Society of Cardiology, Michael Zellweger; Tunisia: Tunisian
Kingdom), Diederick E. Grobbee (Netherlands), Sigrun Halvorsen .. Society of Cardiology and Cardio-Vascular Surgery, Faouzi Addad;
..
(Norway), Gerhard Hindricks (Germany), Bernard Iung (France), .. Turkey: Turkish Society of Cardiology, Aylin Yildirir; Ukraine:
Cosyns; Bosnia and Herzegovina: Association of Cardiologists .. Douglas PS, Hoffmann U, Patel MR, Mark DB, Al-Khalidi HR, Cavanaugh B, Cole J,
.. Dolor RJ, Fordyce CB, Huang M, Khan MA, Kosinski AS, Krucoff MW, Malhotra V,
of Bosnia and Herzegovina, Zumreta Kusljugic; Bulgaria: Bulgarian .. Picard MH, Udelson JE, Velazquez EJ, Yow E, Cooper LS, Lee KL; PROMISE
Society of Cardiology, Vasil Velchev; Cyprus: Cyprus Society of .. Investigators. Outcomes of anatomical versus functional testing for coronary
..
Cardiology, Georgios Panayi; Czech Republic: Czech Society of .. 5. artery disease. N Engl J Med 2015;372:12911300.
SCOT-HEART investigators. CT coronary angiography in patients with suspected
Cardiology, Petr Kala; Denmark: Danish Society of Cardiology, .. angina due to coronary heart disease (SCOT-HEART): an open-label, parallel-
..
Sune Ammentorp Haahr-Pedersen; Egypt: Egyptian Society of .. group, multicentre trial. Lancet 2015;385:23832391.
Cardiology, Hamza Kabil; Estonia: Estonian Society of Cardiology, .. 6. SCOT-HEART investigators, Newby DE, Adamson PD, Berry C, Boon NA,
.. Dweck MR, Flather M, Forbes J, Hunter A, Lewis S, MacLean S, Mills NL, Norrie J,
Tiia Ainla; Finland: Finnish Cardiac Society, Tomi Kaukonen; .. Roditi G, Shah ASV, Timmis AD, van Beek EJR, Williams MC. Coronary CT
France: French Society of Cardiology, Guillaume Cayla; Georgia: .. angiography and 5-year risk of myocardial infarction. N Engl J Med
..
Georgian Society of Cardiology, Zurab Pagava; Germany: .. 7. 2018;379:924933. Reeh J, Therming CB, Heitmann M, Hojberg S, Sorum C, Bech J, Husum D,
German Cardiac Society, Jochen Woehrle; Greece: Hellenic ..
.. Dominguez H, Sehestedt T, Hermann T, Hansen KW, Simonsen L, Galatius S,
Society of Cardiology, John Kanakakis; Hungary: Hungarian .. Prescott E. Prediction of obstructive coronary artery disease and prognosis in
* Corresponding authors: Marco Roffi, Division of Cardiology, University Hospital, Rue Gabrielle Perret-Gentil 4, 1211 Geneva 14, Switzerland, Tel: +41 22 37 23 743, Fax: +41 22 37
27 229, E-mail: Marco.Roffi@hcuge.ch
Carlo Patrono, Istituto di Farmacologia, Università Cattolica del Sacro Cuore, Largo F. Vito 1, IT-00168 Rome, Italy, Tel: +39 06 30154253, Fax: +39 06 3050159, E-mail: carlo.
patrono@rm.unicatt.it
†
Section Coordinators affiliations listed in the Appendix.
ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers listed in the Appendix.
ESC entities having participated in the development of this document:
Associations: Acute Cardiovascular Care Association (ACCA), European Association for Cardiovascular Prevention & Rehabilitation (EACPR), European Association of Cardiovas-
cular Imaging (EACVI), European Association of Percutaneous Cardiovascular Interventions (EAPCI), Heart Failure Association (HFA).
Councils: Council on Cardiovascular Nursing and Allied Professions (CCNAP), Council for Cardiology Practice (CCP), Council on Cardiovascular Primary Care (CCPC).
Working Groups: Working Group on Cardiovascular Pharmacotherapy, Working Group on Cardiovascular Surgery, Working Group on Coronary Pathophysiology and Microcir-
culation, Working Group on Thrombosis.
The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the
ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford
University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC.
Disclaimer: The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at
the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recom-
mendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encour-
aged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or
therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and
accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor
do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent
public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the
health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.
& The European Society of Cardiology 2015. All rights reserved. For permissions please email: journals.permissions@oup.com.
268 ESC Guidelines
Christian Hamm (Germany), David Hildick-Smith (UK), Kurt Huber (Austria), Efstathios Iliodromitis (Greece),
Stefan James (Sweden), Basil S. Lewis (Israel), Gregory Y. H. Lip (UK), Massimo F. Piepoli (Italy), Dimitrios Richter
(Greece), Thomas Rosemann (Switzerland), Udo Sechtem (Germany), Ph. Gabriel Steg (France), Christian Vrints
(Belgium), and Jose Luis Zamorano (Spain)
The disclosure forms of all experts involved in the development of these guidelines are available on the ESC website
http://www.escardio.org/guidelines
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Keywords Acute cardiac care † Acute coronary syndromes † Angioplasty † Anticoagulation † Apixaban † Aspirin †
Atherothrombosis † Beta-blockers † Bivalirudin † Bypass surgery † Cangrelor † Chest pain unit †
Table of Contents
Abbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . . 270 5.1.1 General supportive measures . . . . . . . . . . . . . . . 281
1. Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 5.1.2 Nitrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 5.1.3 Beta-blockers . . . . . . . . . . . . . . . . . . . . . . . . . . 281
2.1 Definitions, pathophysiology and epidemiology . . . . . . . 273 5.1.4 Other drug classes (see Web addenda) . . . . . . . . . 282
2.1.1 Universal definition of myocardial infarction . . . . . . 273 5.1.5 Recommendations for anti-ischaemic drugs in
2.1.1.1 Type 1 MI . . . . . . . . . . . . . . . . . . . . . . . . . 273 the acute phase of non-ST-elevation acute coronary
2.1.1.2 Type 2 MI . . . . . . . . . . . . . . . . . . . . . . . . . 273 syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
2.1.2 Unstable angina in the era of high-sensitivity cardiac 5.2 Platelet inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . 282
troponin assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 5.2.1 Aspirin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
2.1.3 Pathophysiology and epidemiology 5.2.2 P2Y12 inhibitors . . . . . . . . . . . . . . . . . . . . . . . . 282
(see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . . 273 5.2.2.1 Clopidogrel . . . . . . . . . . . . . . . . . . . . . . . . 282
3. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 5.2.2.2 Prasugrel . . . . . . . . . . . . . . . . . . . . . . . . . . 282
3.1 Clinical presentation . . . . . . . . . . . . . . . . . . . . . . . . 273 5.2.2.3 Ticagrelor . . . . . . . . . . . . . . . . . . . . . . . . . 283
3.2 Physical examination . . . . . . . . . . . . . . . . . . . . . . . . 274 5.2.2.4 Cangrelor . . . . . . . . . . . . . . . . . . . . . . . . . 284
3.3 Diagnostic tools . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 5.2.3 Timing of P2Y12 inhibitor administration . . . . . . . . 285
3.3.1 Electrocardiogram . . . . . . . . . . . . . . . . . . . . . . 274 5.2.4 Monitoring of P2Y12 inhibitors
3.3.2 Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 (see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . . 285
3.3.3 ‘Rule-in’ and ‘rule-out’ algorithms . . . . . . . . . . . . . 276 5.2.5 Premature discontinuation of oral antiplatelet
3.3.4 Non-invasive imaging . . . . . . . . . . . . . . . . . . . . . 277 therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
3.3.4.1 Functional evaluation . . . . . . . . . . . . . . . . . . 277 5.2.6 Duration of dual antiplatelet therapy . . . . . . . . . . . 285
3.3.4.2 Anatomical evaluation . . . . . . . . . . . . . . . . . 277 5.2.7 Glycoprotein IIb/IIIa inhibitors . . . . . . . . . . . . . . . 286
3.4 Differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . 278 5.2.7.1 Upstream versus procedural initiation
4. Risk assessment and outcomes . . . . . . . . . . . . . . . . . . . . . 278 (see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . 286
4.1 Clinical presentation, electrocardiogram and biomarkers 278 5.2.7.2 Combination with P2Y12 inhibitors
4.1.1 Clinical presentation . . . . . . . . . . . . . . . . . . . . . 278 (see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . 286
4.1.2 Electrocardiogram . . . . . . . . . . . . . . . . . . . . . . 278 5.2.7.3 Adjunctive anticoagulant therapy
4.1.3 Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 (see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . 286
4.2 Ischaemic risk assessment . . . . . . . . . . . . . . . . . . . . . 279 5.2.8 Vorapaxar (see Web addenda) . . . . . . . . . . . . . . 286
4.2.1 Acute risk assessment . . . . . . . . . . . . . . . . . . . . 279 5.2.9 Recommendations for platelet inhibition in
4.2.2 Cardiac rhythm monitoring . . . . . . . . . . . . . . . . . 279 non-ST-elevation acute coronary syndromes . . . . . . . . . 286
4.2.3 Long-term risk . . . . . . . . . . . . . . . . . . . . . . . . . 280 5.3 Anticoagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
4.3 Bleeding risk assessment . . . . . . . . . . . . . . . . . . . . . 280 5.3.1 Anticoagulation during the acute phase . . . . . . . . . 287
4.4 Recommendations for diagnosis, risk stratification, imaging 5.3.1.1 Unfractionated heparin . . . . . . . . . . . . . . . . 287
and rhythm monitoring in patients with suspected non-ST- 5.3.1.2 Low molecular weight heparin . . . . . . . . . . . . 288
elevation acute coronary syndromes . . . . . . . . . . . . . . . . 280 5.3.1.3 Fondaparinux . . . . . . . . . . . . . . . . . . . . . . . 288
5. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 5.3.1.4 Bivalirudin . . . . . . . . . . . . . . . . . . . . . . . . . 288
5.1 Pharmacological treatment of ischaemia . . . . . . . . . . . 281 5.3.2 Anticoagulation following the acute phase . . . . . . . 289
ESC Guidelines 269
5.3.3 Recommendations for anticoagulation in acute coronary syndrome patients requiring coronary
non-ST-elevation acute coronary syndromes . . . . . . . . . 289 artery bypass surgery . . . . . . . . . . . . . . . . . . . . . . . 299
5.4 Managing oral antiplatelet agents in patients requiring 5.6.6.3 Technical aspects and outcomes
long-term oral anticoagulants . . . . . . . . . . . . . . . . . . . . . 290 (see Web addenda) . . . . . . . . . . . . . . . . . . . . . . . . 299
5.4.1 Patients undergoing percutaneous coronary 5.6.7 Percutaneous coronary intervention vs. coronary
intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 artery bypass surgery . . . . . . . . . . . . . . . . . . . . . . . . 299
5.4.2 Patients medically managed or requiring coronary 5.6.8 Management of patients with cardiogenic shock . . . 300
artery bypass surgery . . . . . . . . . . . . . . . . . . . . . . . . 292 5.6.9 Recommendations for invasive coronary angiography
5.4.3 Recommendations for combining antiplatelet agents and revascularization in non-ST-elevation acute coronary
and anticoagulants in non-ST-elevation acute coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300
syndrome patients requiring chronic oral anticoagulation . 292 5.7 Gender specificities (see Web addenda) . . . . . . . . . . . 301
5.5 Management of acute bleeding events 5.8 Special populations and conditions (see Web addenda) . 301
5.9.1.5 Mineralocorticoid receptor antagonist therapy . 304 CKD chronic kidney disease
5.9.1.6 Antihypertensive therapy . . . . . . . . . . . . . . . 304 CK-MB creatine kinase myocardial band
5.9.1.7 Glucose-lowering therapy in diabetic patients . . 304 COX cyclooxygenase
5.9.2 Lifestyle changes and cardiac rehabilitation . . . . . . . 305 CMR cardiac magnetic resonance
5.9.3 Recommendations for long-term management after CPG Committee for Practice Guidelines
non-ST-elevation acute coronary syndromes . . . . . . . . . 305 CREDO Clopidogrel for the Reduction of Events
6. Performance measures . . . . . . . . . . . . . . . . . . . . . . . . . . 305 During Observation
7. Summary of management strategy . . . . . . . . . . . . . . . . . . . 306 CRUSADE Can Rapid risk stratification of Unstable an-
8. Gaps in evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307 gina patients Suppress ADverse outcomes
9. To do and not to do messages from the guidelines . . . . . . . . 308 with Early implementation of the ACC/AHA
10. Web addenda and companion documents . . . . . . . . . . . . . 309 guidelines
11. Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 CT computed tomography
ISAR-TRIPLE Triple Therapy in Patients on Oral Anticoagula- TIA transient ischaemic attack
tion After Drug Eluting Stent Implantation TIMACS Timing of Intervention in Patients with Acute
i.v. intravenous Coronary Syndromes
LDL low-density lipoprotein TIMI Thrombolysis In Myocardial Infarction
LMWH low molecular weight heparin TRA 2P-TIMI 50 Thrombin Receptor Antagonist in Secondary
LV left ventricular Prevention of Atherothrombotic Ischemic
LVEF left ventricular ejection fraction Events – Thrombolysis in Myocardial Infarc-
MACE major adverse cardiovascular event tion 50
MATRIX Minimizing Adverse Haemorrhagic Events by TRACER Thrombin Receptor Antagonist for Clinical
TRansradial Access Site and Systemic Imple- Event Reduction in Acute Coronary
mentation of angioX Syndrome
MDCT multidetector computed tomography TRILOGY ACS Targeted Platelet Inhibition to Clarify the Op-
presentations include epigastric pain, indigestion-like symptoms and stenosis (mimicking ACS).25 Rarely, a systolic murmur may indicate a
isolated dyspnoea. Atypical complaints are more often observed in mechanical complication (i.e. papillary muscle rupture or ventricular
the elderly, in women and in patients with diabetes, chronic renal septal defect) of a subacute and possibly undetected MI. Physical
disease or dementia.22 – 24 The exacerbation of symptoms by phys- examination may identify signs of non-coronary causes of chest
ical exertion and their relief at rest increase the probability of myo- pain (e.g. pulmonary embolism, acute aortic syndromes, myoperi-
cardial ischaemia. The relief of symptoms after nitrates carditis, aortic stenosis) or extracardiac pathologies (e.g. pneumo-
administration is not specific for anginal pain as it is reported also thorax, pneumonia or musculoskeletal diseases). In this setting,
in other causes of acute chest pain.24 In patients presenting with sus- the presence of a chest pain that can be reproduced by exerting
pected MI to the emergency department, overall, the diagnostic per- pressure on the chest wall has a relatively high negative predictive
formance of chest pain characteristics for MI is limited.24 Older age, value for NSTE-ACS.24,26 According to the presentation, abdominal
male gender, family history of CAD, diabetes, hyperlipidaemia, disorders (e.g. oesophageal spasm, oesophagitis, gastric ulcer, chole-
hypertension, renal insufficiency, previous manifestation of CAD cystitis, pancreatitis) may also be considered in the differential diag-
Low Likelihood
Likelihoo
od High Likelihood
Likelihoo
1. Presentation
2. ECG
3. Troponin
STEMI = ST-elevation myocardial infarction; NSTEMI = non-ST-elevation myocardial infarction; UA = unstable angina.
Figure 1 Initial assessment of patients with suspected acute coronary syndromes. The initial assessment is based on the integration of low-
likelihood and/or high-likelihood features derived from clinical presentation (i.e., symptoms, vital signs), 12-lead ECG, and cardiac troponin. The pro-
portion of the final diagnoses derived from the integration of these parameters is visualized by the size of the respective boxes. “Other cardiac”
includes, among other, myocarditis, Tako-Tsubo cardiomyopathy, or tachyarrhythmias. “Non-cardiac” refers to thoracic diseases such as pneumonia
or pneumothorax. Cardiac troponin should be interpreted as a quantitative marker: the higher the level, the higher the likelihood for the presence of
myocardial infarction. In patients presenting with cardiac arrest or haemodynamic instability of presumed cardiovascular origin, echocardiography
should be performed/interpreted by trained physicians immediately following a 12-lead ECG. If the initial evaluation suggests aortic dissection or
pulmonary embolism, D-dimers and multi-detector computed tomography angiography are recommended according to dedicated algorithms.42,43
ESC Guidelines 275
Table 3 Clinical implications of high-sensitivity Table 4 Conditions other than acute myocardial
cardiac troponin assays infarction type 1 associated with cardiac troponin
elevation
Compared with standard cardiac troponin assays, high-sensitivity assays:
• Have higher negative predictive value for acute MI. Tachyarrhythmias
• Reduce the “troponin-blind” interval leading to earlier detection of acute MI. Heart failure
• Result in a ~4% absolute and ~20% relative increase in the detection of type 1 MI and a Hypertensive emergencies
corresponding decrease in the diagnosis of unstable angina.
Critical illness (e.g. shock/ sepsis/ burns)
• Are associated with a 2-fold increase in the detection of type 2 MI.
Myocarditisa
Levels of high-sensitivity cardiac troponin should be interpreted as quantitative
markers of cardiomyocyte damage (i.e. the higher the level, the greater the Tako-Tsubo cardiomyopathy
likelihood of MI): Structural heart disease (e.g. aortic stenosis)
• Elevations beyond 5-fold the upper reference limit have high (>90%) positive predictive
venoms)
Extreme endurance efforts
obtain it within 10 min of the patient’s arrival in the emergency room
Rhabdomyolysis
or, ideally, at first contact with emergency medical services in the pre-
hospital setting and to have it immediately interpreted by a qualified
Bold = most frequent conditions; CABG ¼ coronary artery bypass surgery; PCI ¼
physician.28 While the ECG in the setting of NSTE-ACS may be nor- percutaneous coronary intervention.
mal in more than one-third of patients, characteristic abnormalities a
includes myocardial extension of endocarditis or pericarditis.
include ST depression, transient ST elevation and T-wave changes.1,18
If the standard leads are inconclusive and the patient has signs or
symptoms suggestive of ongoing myocardial ischaemia, additional
leads should be recorded; left circumflex artery occlusion or right the vast majority of cardiac troponin assays run on automated plat-
ventricular MI may be detected only in V7 – V9 and V3R and V4R, re- forms and are sensitive (i.e. allow for detection of cardiac troponin in
spectively.2 In patients with suggestive signs and symptoms, the 20 – 50% of healthy individuals) or high-sensitivity (detection in
finding of persistent ST elevation indicates STEMI, which mandates 50– 90% of healthy individuals) assays. High-sensitivity assays are
immediate reperfusion.1 Comparison with previous tracings is recommended over less sensitive ones.2,6,8 The majority of currently
valuable, particularly in patients with pre-existing ECG abnormal- used point-of-care assays cannot be considered sensitive or high-
ities. It is recommended to obtain additional 12-lead ECGs in the sensitivity assays.8,35 Therefore the obvious advantage of
case of persistent or recurrent symptoms or diagnostic uncer- point-of-care tests, namely the shorter turnaround time, is counter-
tainty. In patients with bundle branch block or paced rhythm, balanced by lower sensitivity, lower diagnostic accuracy and lower
ECG is of no help for the diagnosis of NSTE-ACS. negative predictive value. Overall, automated assays have been
more thoroughly evaluated as compared with point-of-care tests.2,6,8
As these techniques continue to improve and performance charac-
3.3.2 Biomarkers teristics are both assay and hospital dependent, no recommendation
Biomarkers complement clinical assessment and 12-lead ECG in the regarding the site of measurement (central laboratory vs. bedside)
diagnosis, risk stratification and treatment of patients with suspected can be given.2,6,8,38 Data from large multicentre studies have consist-
NSTE-ACS. Measurement of a biomarker of cardiomyocyte injury, ently shown that sensitive and high-sensitivity cardiac troponin as-
preferably high-sensitivity cardiac troponin, is mandatory in all pa- says increase diagnostic accuracy for MI at the time of presentation
tients with suspected NSTE-ACS.2,6,8 Cardiac troponins are more as compared with conventional assays, especially in patients present-
sensitive and specific markers of cardiomyocyte injury than creatine ing early after chest pain onset, and allow for a more rapid ‘rule-in’
kinase (CK), its MB isoenzyme (CK-MB) and myoglobin.6 If the clin- and ‘rule-out’ of MI (see section 3.3.3 and Table 3).2,6,8,29 – 34
ical presentation is compatible with myocardial ischaemia, then a dy- In most patients with renal dysfunction, elevations in cardiac tropo-
namic elevation of cardiac troponin above the 99th percentile of nin should not be primarily attributed to impaired clearance and con-
healthy individuals indicates MI.2 In patients with MI, levels of cardiac sidered harmless, as cardiac conditions such as chronic coronary or
troponin rise rapidly (i.e. usually within 1 h if using high-sensitivity as- hypertensive heart disease seem to be the most important contribu-
says) after symptom onset and remain elevated for a variable period tor to troponin elevation in this setting.41 Other life-threatening con-
of time (usually several days).2,6 Advances in technology have led to a ditions presenting with chest pain, such as aortic dissection and
refinement in cardiac troponin assays and have improved the ability pulmonary embolism, may also result in elevated troponin levels
to detect and quantify cardiomyocyte injury.2,6,8,10,29 – 37 In Europe, and should be considered as differential diagnoses (Table 4).
276 ESC Guidelines
hs-cTn
hs-cTn<ULN
<ULN hs-cTn
hs-cTn>ULN
>ULN
Pain
Pain>6h
>6h Pain
Pain<6h
<6h
Re-test hs-cTn: 3h
Painfree,
Painfree,GRACE
GRACE<140,
<140,
Work-up
Work-updifferential
differential
differential
differentialdiagnoses
diagnosesexcluded
excluded
diagnoses
diagnoses
Discharge/Stresstesting
Discharge/Stress testing Invasivemanagement
Invasive management
GRACE = Global Registry of Acute Coronary Events score; hs-cTn = high sensitivity cardiac troponin; ULN = upper limit of normal, 99th percentile of healthy controls.
a
Figure 2 0 h/3 h rule-out algorithm of non-ST-elevation acute coronary syndromes using high-sensitivity cardiac troponin assays.
clinical assessment and 12-lead ECG and repeat blood sampling is NSTE-ACS. This imaging modality is useful to identify abnormalities
mandatory in case of ongoing or recurrent chest pain (Table 5, suggestive of myocardial ischaemia or necrosis (i.e. segmental hypo-
see Web addenda). kinesia or akinesia). In the absence of significant wall motion abnor-
Table 5 (see Web addenda) Characteristics of the 0 h/3 h malities, impaired myocardial perfusion detected by contrast
and 0 h/1 h algorithms echocardiography or reduced regional function using strain and
strain rate imaging might improve the diagnostic and prognostic va-
The negative predictive value for MI in patients assigned ‘rule-out’
lue of conventional echocardiography.60,61 Moreover, echocardiog-
exceeded 98% in several large validation cohorts.30 – 34,36,39,51 – 55
raphy can help in detecting alternative pathologies associated with
Used in conjunction with clinical and ECG findings, the 0 h/1 h
chest pain, such as acute aortic dissection, pericardial effusion, aortic
algorithm may allow the identification of candidates for early dis-
valve stenosis, hypertrophic cardiomyopathy or right ventricular
charge and outpatient management. The positive predictive value
dilatation suggestive of acute pulmonary embolism. Similarly, echo-
for MI in those patients meeting the ‘rule-in’ criteria was 75 –
cardiography is the diagnostic tool of choice for patients with
80%.30 – 34,39,53 – 55 Most of the ‘rule-in’ patients with diagnoses other
usual care (n ¼ 1397) in the triage of low- to intermediate-risk pa- and coronary artery spasm are briefly described in section 5.6.4.2,
tients presenting with acute chest pain to emergency departments Web addenda. Stroke may be accompanied by ECG changes, myo-
without signs of ischaemia on ECG and/or inconclusive cardiac tro- cardial wall motion abnormalities and an increase in cardiac troponin
ponins.76 – 79 At a follow-up of 1–6 months, there were no deaths, levels.2,6 The majority of patients presenting with acute chest pain to
and a meta-analysis demonstrated comparable outcomes with the the emergency department have non-cardiac conditions causing the
two approaches (i.e. no difference in the incidence of MI, post- chest discomfort. In many instances the pain is musculoskeletal, and
discharge emergency department visits or rehospitalizations) and therefore benign, self-limiting and does not require hospitalization.
showed that MDCT was associated with a reduction in emergency de- Chest pain characteristics help to some extent in the early identifica-
partment costs and length of stay.80 However, none of these studies tion of those patients.24
used high-sensitivity cardiac troponin assays, which also may reduce
hospital stay. It was also noted that MDCT was associated with an in-
crease in the use of invasive angiography {8.4% vs. 6.3%; odds ratio 4. Risk assessment and outcomes
Table 6 Differential diagnoses of acute coronary syndromes in the setting of acute chest pain
4.1.3 Biomarkers out. The greatest challenge is the integration of clinical presentation
Beyond diagnostic utility, cardiac troponin levels add prognostic in- with information derived from ECG, troponin assessment and imaging
formation in terms of short- and long-term mortality to clinical and modalities into a standardised management strategy.97 Assessment of
ECG variables. While high-sensitivity cardiac troponin T and I seem acute risk guides initial evaluation, selection of the site of care (i.e. cor-
to have comparable diagnostic accuracy, high-sensitivity cardiac onary or intensive care unit, intermediate care unit, inpatient moni-
troponin T has greater prognostic accuracy.89,90 The higher the tored unit or regular unit) and therapy, including antithrombotic
high-sensitivity troponin levels at presentation, the greater the risk treatment and timing of coronary angiography. Risk is highest at the
of death.6,8,10,39 Multiple biomarkers have been associated with time of presentation and may remain elevated for several days, al-
mortality in NSTE-ACS, several of them conferring additive though rapidly declining over time, depending on clinical presentation,
prognostic value to cardiac troponin.8,48 – 50 Serum creatinine and comorbidities, coronary anatomy and revascularization.98 The esti-
estimated glomerular filtration rate (eGFR) should also be deter- mated risk should be communicated to the patient and their family.
mined in all patients with NSTE-ACS because they affect prognosis
arrhythmias and cardiac arrest accompany patients who are trans- coronary angiography, with CRUSADE found to be the most discrim-
ferred between facilities during the time window in which they re- inatory.107 However, in patients medically treated or on oral anticoa-
quire continuous rhythm monitoring. gulants, the predictive value of these scores is not established.
Moreover, the impact on patient outcomes of integrating these
4.2.3 Long-term risk scores has not been investigated. Given these limitations, use of the
In addition to short-term risk factors, a number of conditions are as- CRUSADE bleeding risk score may be considered in patients under-
sociated with long-term risk, including a complicated clinical course, going coronary angiography to quantify bleeding risk.
LV systolic dysfunction, atrial fibrillation, severity of CAD, revascu-
larization status, evidence of residual ischaemia on non-invasive test- 4.4 Recommendations for diagnosis,
ing and non-cardiac comorbidities. At 1 year, the rates of death, MI risk stratification, imaging and rhythm
and recurrent ACS in contemporary NSTE-ACS registries are
.10%. While early events are related to ruptured coronary plaques
monitoring in patients with suspected
non-ST-elevation acute coronary
5.1.4 Other drug classes (see Web addenda) cytochrome P450 (CYP) system to generate an active metabolite (Ta-
5.1.5 Recommendations for anti-ischaemic drugs in the ble 8). An estimated 85% of the prodrug is hydrolysed by esterases
acute phase of non-ST-elevation acute coronary syndromes into an inactive form, leaving only 15% of clopidogrel available for
transformation to the active metabolite, which selectively and irre-
Recommendations for anti-ischaemic drugs in the versibly inactivates platelet P2Y12 receptors and thus inhibits
acute phase of non-ST-elevation acute coronary ADP-induced platelet aggregation.135,136 Dual antiplatelet therapy
syndromes (DAPT) comprising aspirin and clopidogrel has been shown to reduce
recurrent ischaemic events in the NSTE-ACS setting compared with
aspirin alone.137,138 However, up to 10% of patients treated with the
Recommendations Classa Levelb Ref.c combination of aspirin and clopidogrel will have a recurrent ischaemic
Early initiation of beta-blocker event in the first year after an ACS, with a rate of stent thrombosis of
treatment is recommended in patients up to 2%.139 This residual risk may be partly explained by suboptimal
ADP = adenosine diphosphate; AT = antithrombin; GP = glycoprotein; LMWH = low molecular weight heparin; Tx = thromboxane;
UFH = Unfractionated heparin. Vorapaxar is a protease-activated receptor 1 (PAR1) blocker.
Figure 4 Antithrombotic drugs for non-ST-elevation acute coronary syndromes. The figure depicts the targets of available antithrombotic
drugs that can be used to inhibit blood coagulation and platelet aggregation during and after thrombus formation.
5.2.2.3 Ticagrelor drugs metabolized through CYP3A, such as simvastatin, while mod-
Ticagrelor is an oral, reversibly binding P2Y12 inhibitor with a plasma erate CYP3A inhibitors, such as diltiazem, increase ticagrelor plasma
half-life of 6 – 12 h. Ticagrelor also inhibits adenosine reuptake via levels and might delay the offset of effect. In the PLATelet inhibition
equilabrative nucleoside transporter 1 (ENT1) (Table 8). Like prasu- and patient Outcomes (PLATO) trial, 18 624 patients with
grel, ticagrelor has a more rapid and consistent onset of action com- moderate- to high-risk NSTE-ACS (planned for either conservative
pared with clopidogrel, as well as a faster offset of action with more or invasive management) or STEMI were randomized to either clo-
rapid recovery of platelet function.152 Ticagrelor increases levels of pidogrel 75 mg/day, with a loading dose of 300 – 600 mg, or
284 ESC Guidelines
Dosing in CKD
• Stage 3
No dose adjustment No dose adjustment No dose adjustment No dose adjustment
(eGFR 30–59 mL/min/1.73m2)
• Stage 4
No dose adjustment No dose adjustment No dose adjustment No dose adjustment
(eGFR 15–29 mL/min/1.73m2)
Duration of effect 3–10 days 7–10 days 3–5 days 1–2 hours
ADP ¼ adenosine diphosphate; ATP ¼ adenosine triphosphate; CKD ¼ chronic kidney disease; eGFR ¼ estimated glomerular filtration rate.
a
50% inhibition of ADP-induced platelet aggregation.
b
Onset of effect may be delayed if intestinal absorption is delayed (e.g. by opiate).
c
Shortening may be considered if indicated by platelet function tests and low bleeding risk.
d
Affecting the response to platelet transfusion.
e
The distribution phase half-life is reported since it most likely reflects duration of clinically-relevant plasma levels, while the corresponding elimination phase half-life is
approximately 7 hours.
5.2.3 Timing of P2Y12 inhibitor administration In patients undergoing elective non-cardiac surgery, ticagrelor
Initiation of P2Y12 inhibitors soon after the diagnosis of NSTE-ACS and clopidogrel should be discontinued 5 days before surgery, while
irrespective of management strategy has been recommended.162,163 the interval should be increased to 7 days in patients on prasugrel,
This implies pretreatment, defined as P2Y12 inhibitor administration unless the patient is at high risk of stent thrombosis.179 In the latter
before coronary angiography, in patients scheduled for an invasive case, a multidisciplinary decision is required to determine the best
approach. Subsequently the results of the only RCT on P2Y12 inhibi- strategy. Longer discontinuation times (e.g. 7 days for ticagrelor
tor pretreatment in NSTE-ACS, the Comparison of Prasugrel at the and 10 days for clopidogrel or prasugrel) may be appropriate for
Time of Percutaneous Coronary Intervention or as Pretreatment at surgery at extreme risk of bleeding (e.g. some types of neurosur-
the Time of Diagnosis in Patients with Non-ST Elevation Myocardial gery). For NSTE-ACS patients, the risk of bleeds related to surgery
Infarction (ACCOAST) trial, were published.164 The ACCOAST must be balanced against the risk of recurrent ischaemic events
study compared pretreatment with prasugrel 30 mg and a further related to discontinuation of therapy. The type of surgery, the is-
30 mg dose prior to PCI with a regimen of prasugrel 60 mg after chaemic risk and extent of CAD, the time since the acute episode
therapy and 1.5% in the placebo group [HR 1.36 (95% CI 1.00, 1.85), appeared consistent among patients receiving and not receiving
P ¼ 0.05]. The rate of moderate or severe bleeding was increased GPIIb/IIIa inhibitors, the efficacy and safety of GPIIb/IIIa inhibitors
with continued thienopyridine treatment [2.5% vs. 1.6%; HR 1.61 on top of these P2Y12 inhibitors have not been prospectively ad-
(95% CI 1.21, 2.16), P ¼ 0.001]. 184 A meta-analysis including dressed.153,197 In patients treated with prasugrel or ticagrelor,
32 287 patients enrolled in 10 RCTs compared different DAPT GPIIb/IIIa inhibitors should be limited to bailout situations or
durations.185 Nearly 50% of the patients had stable CAD. Studies thrombotic complications during PCI. Dosing in patients with
were stratified according to the DAPT duration in the control group impaired renal function is reported in Table 10. Additional informa-
in order to avoid having 12-month DAPT duration included in both tion on GPIIb/IIIa inhibitors may be found in sections 5.2.7.1 –
study arms. As a consequence, it allowed comparison of outcomes 5.2.7.3, while GPIIb/IIIa inhibitor-related thrombocytopenia is
of either short-term or extended (i.e. beyond 12 months) DAPT described in section 5.8.7.1 (all in the Web addenda).
duration vs. 12-month therapy. Compared with 12-month DAPT,
a shorter course of treatment was associated with a significant re- 5.2.7.1 Upstream versus procedural initiation (see Web addenda)
General recommendations
CKD ¼ chronic kidney disease; eGFR ¼ estimated glomerular filtration rate; i.v. ¼
A proton pump inhibitor in intravenous; kg ¼ kilograms bodyweight.
combination with DAPT is Recommendations for the use of drugs listed in this table may vary depending on
recommended in patients at higher the exact labeling of each drug in the country where it is used.
than average risk of gastrointestinal
bleeds (i.e. history of gastrointestinal
ulcer/haemorrhage, anticoagulant 208,
I B
therapy, chronic NSAID/ 209 5.3 Anticoagulation
corticosteroid use or two or more of
the following: age ≥65 years,
5.3.1 Anticoagulation during the acute phase
dyspepsia, gastro-oesophageal reflux Anticoagulants are used to inhibit thrombin generation and/or activ-
disease, Helicobacter pylori infection, ity, thereby reducing thrombus-related events. There is evidence
chronic alcohol use). that anticoagulation is effective in reducing ischaemic events in
In patients on P2Y12 inhibitors who NSTE-ACS and that the combination with platelet inhibitors is
need to undergo non-emergency more effective than either treatment alone.210 Several anticoagu-
major non-cardiac surgery,f lants, acting at different levels of the coagulation cascade, have
postponing surgery for at least 5 days
been approved or are under investigation for this indication
after cessation of ticagrelor or IIa C
clopidogrel, and for 7 days for (Figure 4). Anticoagulant doses in patients with impaired renal func-
prasugrel, should be considered if tion are reported in Table 11.
clinically feasible and unless the patient
is at high risk of ischaemic events.
5.3.1.1 Unfractionated heparin
In case of a non-cardiac surgical
UFH has a pharmacokinetic profile with large interindividual variabil-
procedure that cannot be postponed
or of a bleeding complication, ity and a narrow therapeutic window. Weight-adjusted i.v. administra-
discontinuation of the P2Y12 inhibitor IIb C tion with an initial bolus of 60–70 IU/kg up to a maximum of 5000 IU,
may be considered after a minimum of 1 followed by an infusion of 12 – 15 IU/kg/h up to a maximum of
and 3 months from PCI with BMS and 1000 IU/h, is recommended. Anticoagulation level is usually moni-
new-generation DES, respectively.
tored in the cardiac catheterization laboratory with activated clotting
time (ACT) and elsewhere with the activated partial thromboplastin
BMS ¼ bare-metal stent; CABG ¼ coronary artery bypass graft; DAPT ¼ dual time (aPTT; therapeutic window is 50–75 s, corresponding to 1.5–
(oral) antiplatelet therapy; DES ¼ drug-eluting stent; GPIIb/IIIa ¼ glycoprotein IIb/
IIIa; NSAID ¼ non-steroidal anti-inflammatory drug; NSTE-ACS ¼ non-ST- 2.5 times the upper limit of normal). UFH remains a widely used anti-
elevation acute coronary syndromes; PCI ¼ percutaneous coronary intervention. coagulant in NSTE-ACS in the context of short delays to coronary
a
Class of recommendation. angiography and short hospital stays despite consistent evidence for
b
Level of evidence.
c
References supporting level of evidence. greater bleeding risk compared with other strategies.211 In the PCI
d
Non-enteric coated formulation; 75–150 mg intravenously if oral ingestion is not setting, UFH is given as an i.v. bolus either under ACT guidance (in
possible. the range of 250–350 s, or 200–250 s if a GPIIb/IIIa inhibitor is given)
e
Contraindications for ticagrelor: previous intracranial haemorrhage or ongoing
bleeds. Contraindications for prasugrel: previous intracranial haemorrhage, previous or in a weight-adjusted manner (usually 70–100 IU/kg, or 50–70 IU/
ischaemic stroke or transient ischaemic attack or ongoing bleeds; prasugrel is kg in combination with a GPIIb/IIIa inhibitor).212,213 UFH should be
generally not recommended for patients ≥75 years of age or with a bodyweight stopped after PCI unless there is an established indication related
,60 kg.
f
Recommendations for cardiac surgery are listed in section 5.6.6.2. to the procedure or to the patient’s condition. For heparin-induced
thrombocytopenia (HIT) see section 5.8.7.2.
288 ESC Guidelines
• Prior to coronary
parinux is contraindicated if eGFR is ,20 mL/min/1.73m2. In the fifth
angiography: 60–70 IU/kg Organization to Assess Strategies in Acute Ischaemic Syndromes
i.v. (max 5000 IU) and
infusion (12–15 IU/kg/h) (OASIS-5) study, which enrolled 20 078 patients with NSTE-ACS,
Unfractionated (max 1000 IU/h), target No dose No dose fondaparinux 2.5 mg s.c. once daily was non-inferior to enoxaparin
heparin aPTT 1.5–2.5x control adjustment adjustment
• During PCI according to with respect to ischaemic events [death, MI or refractory ischaemia
ACT or 70–100 IU/kg i.v. in at 9 days; HR 1.01 (95% CI 0.90, 1.13), P ¼ 0.007], but halved in-
inhibitor. There was no significant difference between UFH/LMWH rivaroxaban 5 mg (4.0%). Non-CABG major bleeds occurred in
plus GPIIb/IIIa inhibitor vs. bivalirudin plus GPIIb/IIIa inhibitor for the 1.8% and 2.4% with 2.5 and 5 mg rivaroxaban, respectively, compared
composite ischaemia endpoint at 30 days [death, MI or unplanned re- with 0.6% with placebo [HR 3.46 for rivaroxaban 2.5 mg (95% CI 2.08,
vascularization for ischaemia 7.3% vs. 7.7%, respectively; RR 1.07 5.77), P , 0.001; HR 4.47 for rivaroxaban 5 mg (95% CI 2.71, 7.36),
(95% CI 0.92, 1.23), P ¼ 0.39] or for major bleeds [5.7% vs. 5.3%; P , 0.001]. Intracranial haemorrhage rates were 0.4% with 2.5 mg
RR 0.93 (95% CI 0.78, 1.10), P ¼ 0.38]. Bivalirudin with bailout use and 0.7% with 5 mg rivaroxaban vs. 0.2% with placebo [HR 2.83
of GPIIb/IIIa inhibitor was non-inferior to UFH/LMWH combined (95% CI 1.02, 7.86), P ¼ 0.04 for 2.5 mg; HR 3.74 (95% CI 1.39,
with a GPIIb/IIIa inhibitor with respect to the composite ischaemia 10.07), P ¼ 0.005 for 5 mg].226 The use of rivaroxaban 2.5 mg twice
endpoint [7.8% vs. 7.3%; RR 1.08 (95% CI 0.93, 1.24), P ¼ 0.32], daily, while not recommended in patients treated with ticagrelor or
but with a significantly lower rate of major bleeds [3.0% vs. 5.7%; prasugrel, might be considered in combination with aspirin and clopi-
RR 0.53 (95% CI 0.43, 0.65), P , 0.001]. In patients not pretreated dogrel if ticagrelor and prasugrel are not available for NSTEMI patients
with clopidogrel prior to PCI, a significant excess in ischaemic events who have high ischaemic and low bleeding risks. It is contraindicated in
Crossover between UFH and LMWH Table 12 Suggested strategies to reduce bleeding risk
III B 216
is not recommended. related to PCI
In NSTEMI patients with no prior
stroke/TIA and at high ischaemic risk • Anticoagulant doses adjusted to bodyweight and renal function,
as well as low bleeding risk receiving especially in women and elderly patients.
aspirin and clopidogrel, low-dose
IIb B 226 • Radial approach preferred.
rivaroxaban (2.5 mg twice daily for
approximately 1 year) may be • Proton pump inhibitors in patients on DAPT at higher than average risk of
gastrointestinal bleeds (i.e. history of gastrointestinal ulcer/haemorrhage,
considered after discontinuation of
anticoagulant therapy, chronic NSAIDs/corticosteroid use, or two or
parenteral anticoagulation. more among age ≥65 years, dyspepsia, gastrooesophageal reflux disease,
Helicobacter pylori infection, and chronic alcohol use).
ACT ¼ activated clotting time; GPIIb/IIIa ¼ glycoprotein IIb/IIIa; i.v. ¼ • In patients on OAC
o PCI performed without interruption of VKAs or NOACs.
anticoagulants
5.4.1 Patients undergoing percutaneous coronary
intervention abnormal renal and liver function (1 point each), stroke, bleeding
Approximately 6 – 8% of patients undergoing PCI have an indica- history or predisposition, labile INR, elderly (.65 years), drugs
tion for long-term OAC with VKA or NOACs due to various con- and alcohol (1 point each)] score} risks (Figure 5).234 In the absence
ditions such as atrial fibrillation, mechanical heart valves or venous of safety and efficacy data, the use of prasugrel or ticagrelor as
thromboembolism. In the periprocedural phase it should be con- part of triple therapy should be avoided. Gastric protection with a
sidered to perform coronary angiography on OAC, because inter- proton pump inhibitor is recommended. The dose intensity
ruption of OAC and bridging with parenteral anticoagulants may of OAC should be carefully monitored with a target INR of
lead to an increase in both thromboembolic episodes and 2.0 – 2.5 in patients treated with VKA (with the exception of
bleeds.232 – 234 The safety of PCI on NOACs without additional individuals with mechanical prosthetic valves in the mitral position).
parenteral anticoagulation is unknown, while no parenteral antic- In patients treated with NOACs, the lowest tested dose for stroke
oagulation is needed if the international normalized ratio (INR) is prevention should be applied.
.2.5 in VKA-treated patients. 235 – 237 Strategies to minimise The choice of stent type (newer-generation DES vs. BMS) in pa-
PCI-related complications in patients on oral anticoagulants are tients requiring long-term anticoagulation is controversial in the
listed in Table 12. setting of NSTE-ACS. In the absence of conclusive data, the deci-
With respect to long-term antithrombotic treatment after PCI, sion for the individual patient should also take into account the es-
a cohort study including 82 854 patients with atrial fibrillation timated probability of subsequent target vessel revascularization
showed that long-term exposure of patients to triple therapy, de- (TVR) due to restenosis. Although in stable CAD patients DAPT
fined as the combination of aspirin, clopidogrel and OAC, was as- is recommended for at least 1 month after BMS and for 6 months
sociated with an increased risk of 1-year major [14.3% vs. 6.9%; HR after DES, the risk of stent thrombosis (and other ischaemic compli-
2.08 (95% CI 1.64, 2.65)] and fatal bleeds [0.9% vs. 0.3%; HR 4.8 cations) during the period beyond 1 month and long-term appears
(95% CI 1.62, 14.02)] as compared with DAPT.238 In the setting similar with both stent types.240 – 242 Data from the DAPT trial indi-
of NSTE-ACS, evidence to guide the management of patients cate a similar impact of prolonged DAPT administration irrespective
undergoing PCI and requiring long-term OAC is limited. 234,239 of stent type (BMS vs. DES).243 In addition, analyses on the risk of
The indication for OAC should be reassessed and treatment con- adverse events among patients with DAPT cessation and patients
tinued only if a compelling indication exists {e.g. paroxysmal, per- undergoing non-cardiac surgery indicate no differences between
sistent or permanent atrial fibrillation with a CHA 2 DS 2 -VASc BMS and DES.177,244 Until data from RCTs become available, new-
[Cardiac failure, Hypertension, Age ≥ 75 (2 points), Diabetes, generation DESs are recommended over BMSs in patients requiring
Stroke (2 points) – Vascular disease, Age 65 – 74, Sex category] OAC at low bleeding risk (HAS-BLED ≤2). For patients at high
score ≥2; mechanical heart valve; recent or a history of recurrent bleeding risk (HAS-BLED ≥3) undergoing PCI who require OAC,
deep venous thrombosis or pulmonary embolism}. Duration of tri- the choice between a BMS and a new-generation DES needs to be
ple therapy should be as limited as possible, depending on the clin- individualised.
ical setting as well as the thromboembolic (CHA2DS2-VASc score) In the Zotarolimus-eluting Endeavor Sprint Stent in Uncertain
and bleeding {e.g. based on the HAS-BLED [hypertension, DES Candidates (ZEUS) trial, 1606 patients at either high bleeding
ESC Guidelines 291
O A C
4 weeks
O A C
6 months Dual
therapy b
Dual
therapy b
Dual
therapy b
O C or A O C or A O C or A
12 months
Lifelong O Monotherapy c
ACS = acute coronary syndrome; CABG = coronary artery bypass graft; CHA2DS2-VASc = Cardiac failure, Hypertension, Age ≥75 [2 points], Diabetes, Stroke [2 points] –
Vascular disease, Age 65–74, Sex category; DAPT = dual antiplatelet therapy; NOACs = non-vitamin K antagonist oral anticoagulants; NSTE-ACS = non-ST-elevation acute
coronary syndrome; PCI = percutaneous coronary intervention;VKAs = vitamin K antagonists. Adapted from Lip et al.234
a
Dual therapy with oral anticoagulation and clopidogrel may be considered in selected patients (low ischaemic risk).
b
Aspirin as an alternative to clopidogrel may be considered in patients on dual therapy (i.e., oral anticoagulation plus single antiplatelet); triple therapy may be considered up to
12 months in very selected patients at high risk of ischaemic events (e.g. prior stent thrombosis on adequate antiplatelet therapy, stenting in the left main or last remaining patent
coronary artery, multiple stenting in proximal coronary segments, two stents bifurcation treatment, or diffuse multivessel disease, especially in diabetic patients).
c
Dual therapy with oral anticoagulation and an antiplatelet agent (aspirin or clopidogrel) beyond one year may be considered in patients at very high risk of coronary events.
In patients undergoing coronary stenting, dual antiplatelet therapy may be an alternative to triple or a combination of anticoagulants and single antiplatelet therapy if the
CHA2DS2-VASc score is 1 (males) or 2 (females).
Figure 5 Antithrombotic strategies in patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) and non-valvular atrial
fibrillation.
risk (52%), high thrombotic risk (17%) or low restenosis risk (31%) and, in particular, in patients at high bleeding risk. While there were
were randomized to implantation with either the zotarolimus- no significant differences in any bleeding events between treatment
eluting stent (n ¼ 802) or a BMS (n ¼ 804).245 Overall, 4.6% of groups, the limited size of the trial does not allow potential differ-
the population never received DAPT, 43.6% and 62.5% discontin- ences in major bleeds to be reliably detected. As an additional limi-
ued it at 1 and 2 months, respectively, with 24.7% remaining on tation, the zotarolimus-eluting stent is no longer marketed in
DAPT beyond 6 months. At 1 year, major adverse cardiovascular Europe. This study suggests that a newer-generation DES may be
events (MACEs) were lower for those implanted with a preferred in patients who cannot tolerate long-term exposure to
zotarolimus-eluting stent compared with a BMS [17.5% vs. 22.1%; DAPT, such as those needing chronic OAC.
HR 0.76 (95% CI 0.61, 0.95), P ¼ 0.011], driven by reductions in Omission of aspirin while maintaining clopidogrel has been eval-
TVR [5.9% vs. 10.7%; HR 0.53 (95% CI 0.37, 0.75), P ¼ 0.001], MI uated in the What is the Optimal antiplatElet and anticoagulant ther-
[2.9% vs. 8.1%; HR 0.35 (95% CI 0.22, 0.56), P , 0.001] and defin- apy in patients with OAC and coronary StenTing (WOEST) trial,
ite/probable stent thrombosis [2.0% vs. 4.1%; HR 0.48 (95% CI which randomized 573 patients to dual therapy with OAC and clo-
0.27, 0.88), P ¼ 0.019]. The benefit of the zotarolimus-eluting stent pidogrel (75 mg/day) or to triple therapy with OAC, clopidogrel and
over the BMS remained consistent across all prespecified subgroups aspirin 80 mg/day.246 Treatment was continued for 1 month after
292 ESC Guidelines
BMS placement (35% of patients) and for 1 year after DES place- recommended in non-emergent cases. In emergency surgery, a com-
ment (65% of patients); follow-up was for 1 year.246 PCI was per- bination of prothrombin complex concentrate of four inactivated fac-
formed on VKA in half of the patients and one-third of them tors (25 IU/kg) and oral vitamin K is required to obtain fast and
presented with NSTE-ACS. The primary endpoint of any TIMI sustained restoration of haemostasis at the time of surgery.180 While
bleeds was significantly reduced in the dual-therapy arm [19.5% experience with urgent major surgery in patients treated with
vs. 44.9%; HR 0.36 (95% CI 0.26, 0.50), P , 0.001], while no signifi- NOACs is limited, it has been suggested to use prothrombin complex
cant differences in major bleeds were observed. The rates of MI, concentrate of activated factors to restore haemostasis.250 In the set-
stroke, TVR or stent thrombosis did not differ significantly, but all- ting of planned CABG, a 48 h interruption of NOACs is recom-
cause mortality was lower in the dual group (2.5% vs. 6.4%, P ¼ mended. In ACS patients with an established indication for OAC,
0.027) at 1 year. Femoral access was used in the majority of patients the antiplatelet agent (commonly aspirin) and then anticoagulation
(74%). While the trial was too small to reliably assess ischaemic out- should be resumed after CABG as soon as the bleeding is controlled,
comes and potential differences in major bleeds, dual therapy with while triple therapy should be avoided. For antithrombotic therapy
Antiplatelet treatment
5.5 Management of acute bleeding events
Following coronary stenting, DAPT
(see Web addenda)
including new P2Y12 inhibitors should 5.5.1 General supportive measures (see Web
be considered as an alternative to addenda)
triple therapy for patients with NSTE- IIa C
ACS and atrial fibrillation with a 5.5.2 Bleeding events on antiplatelet agents (see Web
CHA2DS2-VASc score of 1 (in males) addenda)
or 2 (in females).
5.5.3 Bleeding events on vitamin K antagonists (see Web
If at low bleeding risk (HAS-BLED ≤2), addenda)
triple therapy with OAC, aspirin
(75–100 mg/day) and clopidogrel 5.5.4 Bleeding events on non-vitamin K antagonist
75 mg/day should be considered for 6 IIa C oral anticoagulants (see Web addenda)
extremity leads associated with ST-elevation ≥1 mm in lead aVR patients deteriorated while on medical therapy (crossover), the trials
may indicate either left main coronary artery as the culprit lesion did not include consecutive patients and excluded those with
or proximal occlusion of the left anterior descending coronary ar- very-high-risk features and advances in percutaneous treatment
tery in the presence of severe three-vessel CAD.315,316 The correl- such as single-stent strategy for bifurcation lesions, radial approach,
ation of ECG changes with the culprit lesion is weakened in the new-generation DES as well as more effective P2Y12 inhibitors
presence of left coronary artery dominance, multivessel disease were not available or broadly implemented in the trials. Despite these
and distal location of the culprit lesion.317 Echocardiography or limitations, the results of RCTs and their meta-analyses support the
left ventriculography may also help to identify the culprit lesion cor- broad implementation of a routine invasive strategy and highlight
responding to a regional wall motion abnormality. Finally, approxi- the role of risk stratification in the decision process. Specific sub-
mately 25% of NSTEMI patients have angiographically normal groups of high-risk patients that, while benefiting from an early inva-
epicardial coronary arteries or non-obstructive CAD.164,303,304 A sive management, pose additional challenges in terms of treatment
provocative test, such as with acetylcholine or ergonovine, and newer (e.g. diabetic patients, the elderly, frail patients or those with renal in-
Symptoms Onset
Same-day transfer
High High
Transfer
Intermediate Intermediate
Transfer
optional
Low Low
Therapeutic
strategy
Figure 6 Selection of non-ST-elevation acute coronary syndrome (NSTE-ACS) treatment strategy and timing according to initial risk
stratification.
early and/or delayed intervention in NSTE-ACS patients.304,328,329 analysis of high-risk patients (i.e. one-third of patients with a GRACE
There were no differences with respect to the primary endpoints risk score .140), an early invasive strategy lowered the risk of
based on biomarker elevation after intervention or with respect death, MI or stroke [13.9% vs. 21.0%; HR 0.65 (95% CI 0.48, 0.89),
to secondary clinical outcomes (except for a higher rate of MI in P ¼ 0.006], whereas the difference was not significant for patients
the immediate invasive approach in one of the studies).328 However, with a GRACE risk score ≤140 [7.6% vs. 6.7%; HR 1.12 (95% CI
the design and interpretation of these studies is challenging from a 0.81, 1.56), P ¼ 0.48; P ¼ 0.01 for heterogeneity].303 Importantly,
methodological point of view, because in cases of early intervention, an early invasive strategy did not trigger any safety issue in this trial.
biomarkers had not returned to normal values or were still in the In a post hoc analysis of the ACUITY trial, a delay to PCI .24 h was
ascending phase of the curve. Therefore it may be difficult, if not im- an independent predictor of 30-day and 1-year mortality.330 The ex-
possible, to differentiate between the evolution of the index MI and cess of ischaemic events associated with the PCI .24 h strategy was
an ischaemic complication of the revascularization procedure. most apparent among moderate- and high-risk patients (according
There is evidence to suggest a benefit of an early invasive strategy to the TIMI risk score). Overall, an early invasive strategy is recom-
in patients with a high-risk profile. The largest individual RCT to mended in patients with at least one high-risk criterion (Table 13).
date, Timing of Intervention in Acute Coronary Syndromes (TI- This implies timely transfer for patients admitted to hospitals with-
MACS), randomly assigned 3031 NSTE-ACS patients to an early out onsite catheterization facilities (Figure 6).
(,24 h, median time 14 h) or delayed (median time 50 h) interven-
tion. At 6 months, the primary composite endpoint of death, MI or 5.6.3.3 Invasive strategy (,72 h)
stroke was not different between the early and delayed invasive This is the recommended maximal delay for angiography in patients
strategy [9.6% vs. 11.3%; HR 0.85 (95% CI 0.68, 1.06), P ¼ 0.15]. with at least one intermediate risk criterion, recurrent symptoms or
The secondary endpoint of death, MI, stroke or refractory ischaemia known ischaemia on non-invasive testing.324,327 Even if hospital
was reduced by 28% in favour of the early invasive strategy [9.5% vs. transfer is required, the 72 h window for coronary angiography
12.9%; HR 0.72 (95% CI 0.58, 0.89), P ¼ 0.003]. In the pre-specified should be complied with.
ESC Guidelines 297
5.6.3.4 Selective invasive strategy NSTEMI.333 In 36% of the patients, clopidogrel was prescribed within
Patients with no recurrence of symptoms and none of the criteria 7 days of discharge. In 8562 propensity score–matched patients, pa-
listed in Table 13 are to be considered at low risk of ischaemic tients who were prescribed clopidogrel had lower rates of all-cause
events. In these patients, a non-invasive stress test (preferably mortality [8.3% vs. 13.0%; adjusted HR 0.63 (95% CI 0.54, 0.72), P ,
with imaging) for inducible ischaemia is recommended before decid- 0.01] and the composite of death or MI [13.5% vs. 17.4%; HR 0.74
ing on an invasive strategy.331 (95% CI 0.66, 0.84), P , 0.01], but not MI alone [6.7% vs. 7.2%; HR
0.93 (95% CI 0.78, 1.11), P ¼ 0.30], compared with non-users of clopi-
In summary, available data indicate that an early as opposed to a dogrel. The association between clopidogrel use and the composite of
delayed invasive strategy is safe and associated with a lower risk of death or MI was significant among patients presenting with NSTEMI [HR
refractory ischaemia and a shorter duration of hospital stay. The se- 0.67 (95% CI 0.59, 0.76)] compared with those presenting with unstable
lection of the optimal timing of invasive coronary angiography and angina [HR 1.25 (95% CI 0.94, 1.67), P for interaction ,0.01].
revascularization should be guided by individual risk stratification. The TRILOGY ACS trial randomized 7243 patients with NSTE-
the setting of NSTE-ACS helps to reduce abrupt vessel closure and ACS patients implement a transition from transfemoral to transradial
restenosis associated with balloon angioplasty and it should be con- access. However, proficiency in the femoral approach should be
sidered the standard treatment strategy. Based on at least compar- maintained, as this access is indispensable in a variety of procedures,
able safety and superior efficacy (i.e. prevention of restenosis including intra-aortic balloon counterpulsation implantation, struc-
and need for repeat revascularization), new-generation DESs are tural heart disease interventions and peripheral revascularization pro-
recommended over BMSs in NSTE-ACS.345 – 347 DAPT is recom- cedures. A consensus document has proposed a stepwise approach
mended for 12 months irrespective of stent type, while in patients to favour the transition from a femoral to a radial approach.351
at high ischaemic risk not experiencing bleeding events, DAPT may
be extended (see section 5.2.6). The impact of thrombectomy has 5.6.5.3 Revascularization strategies and outcomes
not been established by adequately sized RCTs in NSTE-ACS. This There is a lack of prospective randomized investigations addressing
treatment modality cannot be recommended considering the lack the type (i.e. complete vs. incomplete) and timing (i.e. simultaneous
of benefit observed in STEMI.348 While FFR is considered the inva- vs. staged) of revascularization in NSTE-ACS. A complete revascular-
characteristics, including older age, female gender, left main coronary 5.6.6.3 Technical aspects and outcomes (see Web addenda)
disease and LV dysfunction compared with patients undergoing elect- 5.6.7 Percutaneous coronary intervention vs. coronary
ive CABG.361 In the absence of randomized data, optimal timing for artery bypass surgery
non-emergent CABG in NSTE-ACS patients should be determined While the main advantages of PCI in the setting of NSTE-ACS are
individually, as detailed in section 5.6.6.1, Web addenda. faster revascularization of the culprit lesion, a lower risk of stroke
and the absence of deleterious effects of cardiopulmonary bypass
on the ischaemic myocardium, CABG may more frequently offer
5.6.6.1 Timing of surgery and antithrombotic drug discontinuation
(see Web addenda) complete revascularization in advanced multivessel CAD. However,
no contemporary RCT comparing PCI with CABG in patients with
5.6.6.2 Recommendations for perioperative management of antiplatelet NSTE-ACS and multivessel CAD is available. Accordingly, in nearly
therapy in non-ST-elevation acute coronary syndrome patients requiring
all trials comparing an early with a delayed invasive strategy, or a
coronary artery bypass surgery
routine invasive with a selective invasive strategy, the decision to
in-hospital mortality in this setting.382 – 384 One or more partial or ,60 mL/min/1.73 m2)
– LVEF ,40% or congestive heart 322,
complete vessel occlusions may result in severe heart failure, espe- failure
I A
324
cially in cases of pre-existing LV dysfunction, reduced cardiac output – early post-infarction angina
and ineffective peripheral organ perfusion. More than two-thirds of – recent PCI
patients have three-vessel CAD. Cardiogenic shock may also be re- – prior CABG
– GRACE risk score .109 and
lated to mechanical complications of NSTEMI, including mitral re-
5.8.3 Chronic kidney disease (see Web addenda) 5.8.4 Left ventricular dysfunction and heart failure
5.8.3.1 Dose adjustment of antithrombotic agents (see Web addenda) (see Web addenda)
5.8.3.2 Recommendations for the management of patients with chronic 5.8.4.1 Recommendations for the management of patients with
kidney disease and non-ST-elevation acute coronary syndromes acute heart failure in the setting of non-ST-elevation acute
coronary syndromes
Recommendations for the management of patients Recommendations for the management of patients
with chronic kidney disease and non-ST-elevation with acute heart failure in the setting of non-ST-
acute coronary syndromes elevation acute coronary syndromes
aPTT ¼ activated partial thromboplastin time; BMS ¼ bare metal stent; CABG ¼
coronary artery bypass graft; CAD ¼ coronary artery disease; CKD ¼ chronic
kidney disease; DES ¼ drug-eluting stent; eGFR ¼ estimated glomerular filtration
rate; GP ¼ glycoprotein; i.v. ¼ intravenous; PCI ¼ percutaneous coronary
intervention; s.c. ¼ subcutaneous; UFH ¼ unfractionated heparin.
a
Class of recommendation.
b
Level of evidence.
c
References supporting level of evidence.
ESC Guidelines 303
5.8.4.2 Recommendations for the management of patients with 5.8.5 Atrial fibrillation (see Web addenda)
heart failure following non-ST-elevation acute coronary syndromes
5.8.5.1 Recommendations for the management of atrial fibrillation in
patients with non-ST-elevation acute coronary syndromes
Recommendations for the management of patients
with heart failure following non-ST-elevation acute Recommendations for the management of atrial
coronary syndromes fibrillation in patients with non-ST-elevation acute
coronary syndromes
5.8.6 Anaemia (see Web addenda) should be increased in those receiving a low- or moderate-intensity
5.8.7 Thrombocytopenia statin treatment at presentation, unless they have a history of in-
tolerance to high-intensity statin therapy or other characteristics
5.8.7.1 Thrombocytopenia related to GPIIb/IIIa inhibitors (Web addenda)
that may influence safety.522,527,528 In this regard, the IMProved Re-
5.8.7.2 Heparin-induced thrombocytopenia (Web addenda) duction of Outcomes: Vytorin Efficacy International Trial
5.8.7.3 Recommendations for the management of thrombocytopenia in (IMPROVE-IT) randomized a total of 18 144 patients with recent
non-ST-elevation acute coronary syndromes ACS (NSTEMI 47%, STEMI 29% and unstable angina 24%) and
LDL cholesterol ,125 mg/dL (,2.5 mmol/L) to either ezetimibe
Recommendations for the management of 10 mg/simvastatin 40 mg or simvastatin 40 mg (simvastatin was
thrombocytopenia in non-ST-elevation acute up-titrated to 80 mg if LDL cholesterol was .79 mg/dL or
coronary syndromes 2.04 mmol/L). Over a period of 7 years, the composite primary end-
point of CV death, MI, hospital admission for unstable angina, coronary
the CV disease, the older the patient, the longer the diabetes dur-
Participation in a well-structured cardiac
ation and the more comorbidities that are present, the less stringent rehabilitation programme to modify
535,
the glucose control should be. IIa A 541–
lifestyle habits and increase adherence
546
Core components and goals of cardiac rehabilitation, including to treatment should be considered.
physical activity counselling, diet/nutrition counselling, smoking ces- In patients with LDL cholesterol
sation, weight control and goals for lipid and blood pressure man- ≥70 mg/dL (≥1.8 mmol/L) despite a
agement should be stated in the discharge letter.534 maximally tolerated statin dose, further IIa B 529
reduction in LDL cholesterol with a
5.9.2 Lifestyle changes and cardiac rehabilitation non-statin agente should be considered.
Enrolment in a well-structured cardiac rehabilitation/secondary pre- A systolic blood pressure goal 547–
IIa B
vention programme after NSTE-ACS should be considered, as it can of ,140 mmHg should be considered. 549
enhance patient compliance with the medical regimen and promote
robust evidence may have larger effects on real-life CV health than pain, hypertension or heart failure. Oxygen therapy should be applied
those seen in selected trial populations, especially with the combined in the presence of a blood oxygen saturation ,90% or respiratory
implementation of several effective treatment modalities. Such pro- distress. Morphine (i.v. or s.c.) or alternative opiates are reserved
grammes have been implemented successfully in several countries, in- for patients with persisting severe chest pain. In patients with ongoing
cluding Sweden [the Swedish Web-system for Enhancement and chest pain and inconclusive ECG, consider immediate echocardiog-
Development of Evidence-based care in Heart disease Evaluated Ac- raphy to exclude alternative diagnoses (if appropriate in conjunction
cording to Recommended Therapies (SWEDEHEART)], the UK with CT angiography) such as pulmonary embolism, pericarditis or
[Myocardial Infarction National Audit Project (MINAP) registry], aortic dissection and at the same time to reinforce the suspicion of
Germany, Italy and Israel on a regional basis, or in intermittent pro- NSTE-ACS (i.e. by identifying a focal wall motion abnormality). In
grammes in many other countries. These performance measure the setting of ongoing myocardial ischaemia or haemodynamic com-
programmes are also proposed and developed by the ESC through promise (the clinical suspicion should be corroborated by the echo-
the continuous ACS Registry within the Euro Heart Survey Program. cardiographic finding of regional wall motion abnormality) the patient
Step 3: Antithrombotic treatment and should not be changed during PCI. In patients pretreated with fon-
The choice of the antithrombotic regimen in NSTE-ACS should be daparinux, UFH must be added before PCI. In anticoagulant-naive pa-
based on the selected management strategy (i.e. conservative vs. in- tients, consider bivalirudin. If CABG is planned and the patient is on a
vasive) as well as the chosen revascularization modality (PCI vs. P2Y12 inhibitor, this should be stopped and surgery deferred if the clin-
CABG). Dosing of antithrombotic agents (Tables 8, 10 and 11) should ical condition and the angiographic findings permit. If coronary angiog-
take into account patient age and renal function. Aspirin and paren- raphy shows no options for revascularization, owing to the extent of
teral anticoagulation are recommended. In patients intended for a the lesions and/or poor distal run-off, freedom from angina should be
conservative treatment and not at high bleeding risk, ticagrelor (pre- aimed for by intensifying medical therapy.
ferred over clopidogrel) is recommended once the NSTEMI diagno-
Step 6: Hospital discharge and
sis is established. In patients intended for an invasive strategy, the
optimal timing of the administration of ticagrelor (preferred over clo-
post-discharge management
Although in NSTE-ACS most adverse events occur in the early
10. Web addenda and companion Cardiology, Lia Bang; Egypt: Egyptian Society of Cardiology, Adel El
Etriby; Estonia: Estonian Society of Cardiology, Toomas Marandi; Fin-
documents land: Finnish Cardiac Society, Mikko Pietilä; Former Yugoslav Re-
public of Macedonia: Macedonian Society of Cardiology, Sasko
All Web figures and Web tables are available in the online addenda
Kedev; France: French Society of Cardiology, René Koning; Georgia:
at: http://www.escardio.org/Guidelines-&-Education/Clinical- Georgian Society of Cardiology, Alexander Aladashvili; Germany:
Practice-Guidelines/Acute-Coronary-Syndromes-ACS-in-patients- German Cardiac Society, Franz-Josef Neumann; Greece: Hellenic Car-
presenting-without-persistent-ST-segm diological Society, Kostantinos Tsioufis; Hungary: Hungarian Society of
Questions and answers companion manuscripts of these guide- Cardiology, Dávid Becker; Iceland: Icelandic Society of Cardiology,
lines are available via this same link. Thorarinn Guðnason; Israel: Israel Heart Society, Shlomi Matetzky;
Italy: Italian Federation of Cardiology, Leonardo Bolognese; Kazakh-
11. Acknowledgements stan: Association of Cardiologists of Kazakhstan, Aisulu Mussagaliyeva;
Kyrgyzstan: Kyrgyz Society of Cardiology, Medet Beishenkulov; Lat-
The CME text ‘2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation’ is accredited by the European
Board for Accreditation in Cardiology (EBAC). EBAC works according to the quality standards of the European Accreditation Council for Continuing Medical Education (EACCME),
which is an institution of the European Union of Medical Specialists (UEMS). In compliance with EBAC/EACCME Guidelines, all authors participating in this programme have disclosed
any potential conflicts of interest that might cause a bias in the article. The Organizing Committee is responsible for ensuring that all potential conflicts of interest relevant to the
programme are declared to the participants prior to the CME activities.
CME questions for this article are available at: European Heart Journal http://www.oxforde-learning.com/eurheartj and European Society of Cardiology http://www.escardio.org/
guidelines.
Atar D, Newby LK, Galvani M, Hamm CW, Uretsky BF, Steg PG, Wijns W,
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Mahaffey KW, Valgimigli M, van ’t Hof A, Widimsky P, Zahger D. ESC guidelines Parkhomenko AN, Vasilieva EJ, Mendis S. Third universal definition of myocardial
for the management of acute myocardial infarction in patients presenting with infarction. Eur Heart J 2012;33:2551 – 2567.
ST-segment elevation. Eur Heart J 2012;33:2569 –2619. 3. Roe MT, Harrington RA, Prosper DM, Pieper KS, Bhatt DL, Lincoff AM,
2. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, Katus HA, Simoons ML, Akkerhuis M, Ohman EM, Kitt MM, Vahanian A, Ruzyllo W,
Apple FS, Lindahl B, Morrow DA, Chaitman BA, Clemmensen PM, Johanson P, Karsch K, Califf RM, Topol EJ. Clinical and therapeutic profile of patients present-
Hod H, Underwood R, Bax JJ, Bonow RO, Pinto F, Gibbons RJ, Fox KA, ing with acute coronary syndromes who do not have significant coronary artery
European Heart Journal (2018) 39, 119–177 ESC GUIDELINES
doi:10.1093/eurheartj/ehx393
* Corresponding authors. The two chairmen contributed equally to the document: Borja Ibanez, Director Clinical Research, Centro Nacional de Investigaciones
Cardiovasculares Carlos III (CNIC), Melchor Fernandez Almagro 3, 28029 Madrid, Spain; Department of Cardiology, IIS-Fundacion Jiménez Dıaz University Hospital, Madrid,
Spain; and CIBERCV, Spain. Tel: þ34 91 453.12.00 (ext: 4302), Fax: þ34 91 453.12.45, E-mail: bibanez@cnic.es or bibanez@fjd.es. Stefan James, Professor of Cardiology,
Department of Medical Sciences, Scientific Director UCR, Uppsala University and Sr. Interventional Cardiologist, Department of Cardiology Uppsala University Hospital UCR
Uppsala Clinical Research Center Dag Hammarskjölds v€ag 14B SE-752 37 Uppsala, Sweden. Tel: þ46 705 944 404, Email: stefan.james@ucr.uu.se
ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers: listed in the Appendix.
ESC entities having participated in the development of this document:
Associations: Acute Cardiovascular Care Association (ACCA), European Association of Preventive Cardiology (EAPC), European Association of Cardiovascular Imaging
(EACVI), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Heart Rhythm Association (EHRA), Heart Failure Association (HFA).
Councils: Council on Cardiovascular Nursing and Allied Professions (CCNAP), Council for Cardiology Practice (CCP).
Working Groups: Cardiovascular Pharmacotherapy, Cardiovascular Surgery, Coronary Pathophysiology and Microcirculation, Myocardial and Pericardial Diseases, Thrombosis.
The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of
the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to
Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC
(journals.permissions@oxfordjournals.org).
Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence avail-
able at the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other offi-
cial recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health
professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of pre-
ventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to
make appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the
patient’s caregiver. Nor do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or
guidelines issued by the competent public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical
and professional obligations. It is also the health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of
prescription.
C The European Society of Cardiology 2017. All rights reserved. For permissions please email: journals.permissions@oxfordjournals.org.
V
120 ESC Guidelines
Andreas Baumbach (UK), Raffaele Bugiardini (Italy), Ioan Mircea Coman (Romania), Victoria Delgado
(The Netherlands), Donna Fitzsimons (UK), Oliver Gaemperli (Switzerland), Anthony H. Gershlick (UK),
Stephan Gielen (Germany), Veli-Pekka Harjola (Finland), Hugo A. Katus (Germany), Juhani Knuuti
(Finland), Philippe Kolh (Belgium), Christophe Leclercq (France), Gregory Y. H. Lip (UK), Joao Morais
(Portugal), Aleksandar N. Neskovic (Serbia), Franz-Josef Neumann (Germany), Alexander Niessner
(Austria), Massimo Francesco Piepoli (Italy), Dimitrios J. Richter (France), Evgeny Shlyakhto (Russian
Federation), Iain A. Simpson (UK), Ph. Gabriel Steg (France), Christian Juhl Terkelsen (Denmark),
Kristian Thygesen (Denmark), Stephan Windecker (Switzerland), Jose Luis Zamorano (Spain),
Uwe Zeymer (Germany).
The disclosure forms of all experts involved in the development of these guidelines are available on the
ESC website www.escardio.org/guidelines
...................................................................................................................................................................................................
Keywords Guidelines • Acute coronary syndromes • Acute myocardial infarction • Antithrombotic therapy •
Antithrombotics • Emergency medical system • Evidence • Fibrinolysis • Ischaemic heart disease • Primary
percutaneous coronary intervention • Quality indicators • MINOCA • Reperfusion therapy • Risk
assessment • Secondary prevention • ST-segment elevation.
..
Table of Contents ..
..
5.4 Coronary artery bypass graft surgery. . . . . . . . . . . . . . . . . . . . . . . . . .142
6. Management during hospitalization and at discharge . . . . . . . . . . . . . . .142
..
Abbreviations and acronyms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .121 .. 6.1 Coronary care unit/intensive cardiac care unit . . . . . . . . . . . . . . . . .142
1. Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .123 .. 6.2 Monitoring. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .142
..
2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .124 .. 6.3 Ambulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .142
2.1 Definition of acute myocardial infarction . . . . . . . . . . . . . . . . . . . . . .124 .. 6.4 Length of stay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .142
..
2.2 Epidemiology of ST-segment elevation myocardial infarction . . .124 .. 6.5 Special patient subsets. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .143
3. What is new in the 2017 version? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .125 .. 6.5.1 Patients taking oral anticoagulation. . . . . . . . . . . . . . . . . . . . . . . .143
..
4. Emergency care. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .126 .. 6.5.2 Elderly patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .143
4.1 Initial diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .126 .. 6.5.3 Renal dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .144
..
4.2 Relief of pain, breathlessness, and anxiety. . . . . . . . . . . . . . . . . . . . . .127 .. 6.5.4 Non-reperfused patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .144
4.3 Cardiac arrest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .128 .. 6.5.5 Patients with diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .146
..
4.4 Pre-hospital logistics of care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .128 .. 6.6. Risk assessment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .146
4.4.1 Delays. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .128
.. 6.6.1 Clinical risk assessment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .146
..
4.4.2 Emergency medical system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .130 .. 6.6.2 Non-invasive imaging in management and risk
4.4.3 Organization of ST-segment elevation myocardial
.. stratification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .146
..
infarction treatment in networks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .130 .. 7. Long-term therapies for ST-segment elevation myocardial
5. Reperfusion therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .131
.. infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .148
..
5.1 Selection of reperfusion strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . .131 .. 7.1 Lifestyle interventions and risk factor control . . . . . . . . . . . . . . . . . .148
5.2 Primary percutaneous coronary intervention and
.. 7.1.1 Smoking cessation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .148
..
adjunctive therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .134 .. 7.1.2 Diet, alcohol, and weight control. . . . . . . . . . . . . . . . . . . . . . . . . .148
..
5.2.1 Procedural aspects of primary percutaneous .. 7.1.3 Exercise-based cardiac rehabilitation . . . . . . . . . . . . . . . . . . . . . .148
coronary intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .134 .. 7.1.4 Resumption of activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .148
..
5.2.2 Periprocedural pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . .136 .. 7.1.5 Blood pressure control. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .148
5.3 Fibrinolysis and pharmacoinvasive strategy . . . . . . . . . . . . . . . . . . . .138 .. 7.1.6 Adherence to treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .148
..
5.3.1 Benefit and indication of fibrinolysis . . . . . . . . . . . . . . . . . . . . . . .138 .. 7.2 Antithrombotic therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .149
5.3.2 Pre-hospital fibrinolysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .139 .. 7.2.1 Aspirin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .149
..
5.3.3 Angiography and percutaneous coronary intervention .. 7.2.2 Duration of dual antiplatelet therapy and antithrombotic
after fibrinolysis (pharmacoinvasive strategy) . . . . . . . . . . . . . . . . . . .140 .. combination therapies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .149
..
5.3.4 Comparison of fibrinolytic agents . . . . . . . . . . . . . . . . . . . . . . . . .141 .. 7.3 Beta-blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .150
5.3.5 Adjunctive antiplatelet and anticoagulant therapies . . . . . . . .141 .. 7.3.1 Early intravenous beta-blocker administration . . . . . . . . . . . . .150
..
5.3.6 Hazards of fibrinolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .141 .. 7.3.2 Mid- and long-term beta-blocker treatment . . . . . . . . . . . . . . .151
5.3.7 Contraindications to fibrinolytic therapy . . . . . . . . . . . . . . . . . .141 .. 7.4 Lipid-lowering therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .151
ESC Guidelines 121
..
SBP systolic blood pressure .. established in order to make all decisions transparent to the user.
s.c. subcutaneous
.. The recommendations for formulating and issuing ESC Guidelines
..
SGLT2 sodium-glucose co-transporter-2 .. can be found on the ESC website (https://www.escardio.org/
SPECT single-photon emission computed tomography
.. Guidelines/Clinical-Practice-Guidelines/Guidelines-development/
..
STEMI ST-segment elevation myocardial infarction .. Writing-ESC-Guidelines). ESC Guidelines represent the official posi-
STREAM STrategic Reperfusion Early After Myocardial
.. tion of the ESC on a given topic and are regularly updated.
..
infarction .. Members of this Task Force were selected by the ESC, including
TIMI Thrombolysis In Myocardial Infarction
.. representation from its relevant ESC sub-specialty groups, in order
..
TNK-tPA Tenecteplase tissue plasminogen activator .. to represent professionals involved with the medical care of patients
.. with this pathology. Selected experts in the field undertook a com-
TOTAL Trial of Routine Aspiration Thrombectomy ..
with PCI versus PCI Alone in Patients with .. prehensive review of the published evidence for management of a
.. given condition according to ESC Committee for Practice Guidelines
..
Table 2 Levels of evidence
.. strategy. The levels of evidence and the strengths of recommenda-
.. tion of particular treatment options were weighed and graded
..
.. according to pre-defined scales, as outlined in Tables 1 and 2. Despite
.. recommendations with a level of evidence being based on expert
..
.. opinion, this Task Force decided to add references to guide the
.. reader regarding data that were taken into consideration for these
..
.. decisions in some cases.
..
..
.. 2.1 Definition of acute myocardial
..
.. infarction
..
.. The term acute myocardial infarction (AMI) should be used when
..
..
presence of emergency medical system (EMS)-based STEMI net- .. toms, up to 30% in some registries,27 and tend to present later than
works, treatment strategy, history of MI, diabetes mellitus, renal fail- .. men.28,29 It is therefore important to maintain a high degree of aware-
..
ure, number of diseased coronary arteries, and left ventricular .. ness for MI in women with potential symptoms of ischaemia. Women
ejection fraction (LVEF). Several recent studies have highlighted a fall
.. also have a higher risk of bleeding complications with PCI. There is an
..
in acute and long-term mortality following STEMI in parallel with .. ongoing debate regarding whether outcomes are poorer in women,
greater use of reperfusion therapy, primary percutaneous coronary
.. with several studies indicating that a poorer outcome is related to
..
intervention (PCI), modern antithrombotic therapy, and secondary .. older age and more comorbidities among women suffering MI.26,30,31
prevention.14,21,22 Nevertheless, mortality remains substantial; the in-
.. Some studies have indicated that women tend to undergo fewer inter-
..
hospital mortality of unselected patients with STEMI in the national .. ventions than men and receive reperfusion therapy less fre-
registries of the ESC countries varies between 4 and 12%,23 while
.. quently.26,32,33 These guidelines aim to highlight the fact that women
..
reported 1-year mortality among STEMI patients in angiography .. and men receive equal benefit from a reperfusion strategy and STEMI-
..
registries is approximately 10%.24,25 .. related therapy, and that both genders must be managed in a similar
patients
stenting
Figure 1 What is new in 2017 STEMI Guidelines. BMS = bare metal stent; DES = drug eluting stent; IRA = infarct related artery; i.v. = intravenous;
LDL = low-density lipoprotein; PCI = percutaneous coronary intervention; SaO2 = arterial oxygen saturation; STEMI = ST-elevation myocardial
infarction; TNK-tPA = Tenecteplase tissue plasminogen activator. For explanation of trial names, see list of.
a
Only for experienced radial operators.
b
Before hospital discharge (either immediate or staged).
c
Routine thrombus aspiration (bailout in certain cases may be considered).
d
In 2012 early discharge was considered after 72h, in 2017 early discharge is 48–72h.
e
If symptoms or haemodynamic instability IRA should be opened regardless time from symptoms onset.
In left and mid panels, below each recommendation, the most representative trial (acronym and reference) driving the indication is
mentioned.
126 ESC Guidelines
..
4. Emergency care ..
..
The presence of a Q-wave on the ECG should not necessarily change
the reperfusion strategy decision.
..
4.1 Initial diagnosis ..
Management—including diagnosis and treatment—of STEMI starts .. Recommendations for initial diagnosis
..
from the point of first medical contact (FMC, defined in Table 4). It is ..
recommended that a regional reperfusion strategy should be estab- .. Recommendations Classa Levelb
lished to maximize efficiency. ...
.. ECG monitoring
A working diagnosis of STEMI (called the ‘STEMI diagnosis’ ..
throughout this document) must first be made. This is usually based .. 12-lead ECG recording and interpretation is
..
on symptoms consistent with myocardial ischaemia (i.e. persistent .. indicated as soon as possible at the point of
chest pain) and signs [i.e. 12-lead electrocardiogram (ECG)].
.. FMC, with a maximum target delay of
I B
..
Important clues are a history of CAD and radiation of pain to the .. 10 min.36,38
interpreted as soon as possible at the time of FMC to facilitate early ... is indicated as soon as possible in the acute
.. phase but should not delay reperfusion
I C
STEMI diagnosis and triage.36–40 ..
In patients with a clinical suspicion of myocardial ischaemia and ST- .. treatment.8
..
segment elevation, reperfusion therapy needs to be initiated as soon ..
as possible.41 If the ECG is equivocal or does not show evidence to
.. ECG = electrocardiogram; FMC = first medical contact; MI = myocardial infarc-
.. tion; RV = right ventricle; STEMI = ST-segment elevation myocardial infarction.
support the clinical suspicion of MI, ECGs should be repeated and, .. a
Class of recommendation.
when possible compared with previous recordings. If interpretation
.. b
.. Level of evidence.
of pre-hospital ECG is not possible on-site, field transmission of the ..
ECG is recommended.42
..
..
ECG criteria are based on changes of electrical currents of the .. The ECG diagnosis may be more difficult in some cases, which
heart (measured in millivolts). Standard calibration of the ECG is
..
.. nevertheless deserve prompt management and triage. Among these:
10mm/mV. Therefore 0.1 mV equals to 1 mm square on the vertical .. Bundle branch block. In the presence of LBBB, the ECG diagno-
..
axis. For simplicity, in this document ECG deviations are expressed in .. sis of AMI is difficult but often possible if marked ST-segment abnor-
mm following the standard calibration. .. malities are present. Somewhat complex algorithms have been offered
..
In the proper clinical context, ST-segment elevation (measured at .. to assist the diagnosis,50,51 but they do not provide diagnostic cer-
the J-point) is considered suggestive of ongoing coronary artery acute .. tainty.52 The presence of concordant ST-segment elevation (i.e. in
..
occlusion in the following cases: at least two contiguous leads with .. leads with positive QRS deflections) appears to be one of the best indi-
ST-segment elevation 2.5 mm in men < 40 years, 2 mm in men .. cators of ongoing MI with an occluded infarct artery.53 Patients with a
..
40 years, or 1.5 mm in women in leads V2 –V3 and/or 1 mm in .. clinical suspicion of ongoing myocardial ischaemia and LBBB should be
the other leads [in the absence of left ventricular (LV) hypertrophy .. managed in a way similar to STEMI patients, regardless of whether the
..
or left bundle branch block LBBB)].8 In patients with inferior MI, it is .. LBBB is previously known. It is important to remark that the presence
recommended to record right precordial leads (V3R and V4R) seek- .. of a (presumed) new LBBB does not predict an MI per se.54
..
ing ST-segment elevation, to identify concomitant right ventricular .. Patients with MI and right bundle branch block (RBBB) have a
(RV) infarction.8,43 Likewise, ST-segment depression in leads V1 –V3 .. poor prognosis.55 It may be difficult to detect transmural ischaemia in
..
suggests myocardial ischaemia, especially when the terminal T-wave .. patients with chest pain and RBBB.55 Therefore, a primary PCI strat-
is positive (ST-segment elevation equivalent), and confirmation by
.. egy (emergent coronary angiography and PCI if indicated) should be
..
concomitant ST-segment elevation 0.5 mm recorded in leads .. considered when persistent ischaemic symptoms occur in the pres-
V7 –V9 should be considered as a means to identify posterior MI.8
.. ence of RBBB.
ESC Guidelines 127
..
Ventricular pacing. Pacemaker rhythm may also prevent .. (1 mm in men, 40 years old)] is recommended to detect ST-
interpretation of ST-segment changes and may require urgent angiog- .. segment elevation consistent with inferior and basal MI.
..
raphy to confirm diagnosis and initiate therapy. Reprogramming the .. Left main coronary obstruction. The presence of ST depres-
pacemaker—allowing an evaluation of ECG changes during intrinsic .. sion 1 mm in eight or more surface leads (inferolateral ST depres-
..
heart rhythm—may be considered in patients who are not depend- .. sion), coupled with ST-segment elevation in aVR and/or V1, suggests
ent on ventricular pacing, without delaying invasive investigation.56,57
.. multivessel ischemia or left main coronary artery obstruction, partic-
..
Non-diagnostic ECG. Some patients with an acute coronary .. ularly if the patient presents with haemodynamic compromise.60
occlusion may have an initial ECG without ST-segment elevation,
.. Blood sampling for serum markers is routinely carried out in the
..
sometimes because they are seen very early after symptom onset (in .. acute phase. This is indicated, but should not delay the reperfusion
which case, one should look for hyper-acute T-waves, which may pre-
.. strategy/treatment.
..
cede ST-segment elevation). It is important to repeat the ECG or .. If in doubt regarding the possibility of acute evolving MI, emergency
monitor for dynamic ST-segment changes. In addition, there is a con-
.. imaging aids the provision of timely reperfusion therapy to these
..
Hypoxia
Symptoms
ECG = electrocardiogram; LBBB = left bundle branch block; RBBB = right bundle
branch block; RV = right ventricular; STEMI = ST-segment elevation myocardial i.v. = intravenous; PaO2 = partial pressure of oxygen; SaO2 = arterial oxygen
infarction. saturation.
a
Class of recommendation.
b
Level of evidence.
128 ESC Guidelines
..
Oxygen is indicated in hypoxic patients with arterial oxygen satu- .. catheterization laboratory. Close attention to anticoagulation needs
ration (SaO2) < 90%. There is some evidence suggesting that hyper- .. to be paid in patients reaching low temperatures.84
..
oxia may be harmful in patients with uncomplicated MI, presumably .. Prevention and improved treatment of out-of-hospital cardiac
due to increased myocardial injury.64–67 Thus, routine oxygen is not .. arrest is crucial to reduce the mortality related to CAD. For a more
..
recommended when SaO2 is 90%. . detailed discussion of these issues, refer to the recent European
Anxiety is a natural response to the pain and the circumstances ... Resuscitation Council Guidelines for resuscitation.74
..
surrounding an MI. Reassurance of patients and those closely associ- ..
ated with them is of great importance. ..
.. Cardiac arrest
A mild tranquillizer (usually a benzodiazepine) should be consid- ..
ered in anxious patients. ..
.. Recommendations Classa Levelb
..
4.3 Cardiac arrest .. A primary PCI strategy is recommended in
..
..
10). If projected target times are not met, then interventions are .. to <_ 10 min. STEMI diagnosis refers to the time when the ECG is
needed to improve performance of the system. Components of the .. interpreted as ST-segment elevation or equivalent and it is the time
..
ischaemic time, delays of initial management, and selection of reperfu- .. zero to guide appropriate therapy.
sion strategy are shown in Figure 2.
.. System delay is more readily modifiable by organizational meas-
..
To minimize patient delay, it is recommended to increase public .. ures than is patient delay, and it is a predictor of outcomes.87
awareness of how to recognize common symptoms of AMI and to
.. When STEMI diagnosis is made in the pre-hospital setting (EMS),
..
call the emergency services. All components of the system delay rep- .. immediate activation of the catheterization laboratory not only
resent the quality of care and it is recommended to measure them as
.. reduces treatment delays but may also reduce patient mortality.88–91
..
quality indicators (see Chapter 10). .. When a STEMI diagnosis is made by the EMS in the pre-hospital set-
In hospitals and EMS participating in the care of STEMI patients,
.. ting and the patient is triaged for a primary PCI strategy, it is indicated
..
the goal is to reduce the delay between FMC and STEMI diagnosis .. to bypass the emergency department and bring the patient straight
.
130 ESC Guidelines
..
Logistics of pre-hospital care
.. 5. Reperfusion therapy
..
..
.. 5.1 Selection of reperfusion strategies
Recommendations Classa Levelb .
... Table 4 lists the definitions of terms relating to reperfusion therapy.
It is recommended that the pre-hospital ..
.. Table 4 Definitions of terms related to reperfusion
management of STEMI patients is based on .. therapy
regional networks designed to deliver ..
..
reperfusion therapy expeditiously and effec- I B ..
tively, with efforts made to make primary
..
..
PCI available to as many patients as ..
possible.100
..
..
..
..
this issue, caution is needed when interpreting available data from .. trial randomized early STEMI presenters without the possibility of
post hoc analyses. A PCI-related time delay potentially mitigating the .. immediate PCI to immediate fibrinolysis (followed by routine early
..
benefits of PCI has been calculated as 60 min117, 110 min,118 and .. angiography) or transfer to primary PCI.121 The median PCI-related
120 min119 in different studies. Registry data estimated this time limit .. delay in this trial was 78 min, and there were no differences in clinical
..
as 114 min for in-hospital patients107 and 120 min in patients present- .. outcomes. This Task Force recognizes the lack of contemporaneous
ing in a non-PCI centre.120 All these data are old and patients under- .. data to set the limit to choose PCI over fibrinolysis. For simplicity, an
..
going fibrinolysis did not undergo routine early angiography, which .. absolute time from STEMI diagnosis to PCI-mediated reperfusion [i.e.
improves outcomes in patients receiving fibrinolysis. The recent .. wire crossing of the infarct-related artery (IRA)] rather than a relative
..
STrategic Reperfusion Early After Myocardial infarction (STREAM) . PCI-related delay over fibrinolysis has been chosen. This limit is set to
ESC Guidelines 133
120 min. Given the maximum limit of 10 min from STEMI diagnosis to .. Recommendations for reperfusion therapy
bolus of fibrinolytics (see below), the 120 min absolute time would ..
..
correspond to a PCI-related delay in the range of 110–120 min, being ..
in the range of the times identified in old studies and registries as the .. Recommendation Classa Levelb
..
limit delay to choose PCI.107,117–120 .. Reperfusion therapy is indicated in all
If the reperfusion strategy is fibrinolysis, the goal is to inject the ..
.. patients with symptoms of ischaemia
I A
bolus of fibrinolytics within 10 min from STEMI diagnosis. This time is .. of <_ 12 h duration and persistent ST-seg-
selected based on the median time from randomization to bolus ..
.. ment elevation.119,138
recorded in the STREAM trial, which was 9 min.121 In previous ESC ..
STEMI guidelines,122 the target time was 30 min, but this was calcu- .. A primary PCI strategy is recommended
..
lated from FMC (as opposed to STEMI diagnosis). STEMI diagnosis .. over fibrinolysis within indicated I A
should occur within 10 min from FMC. .. timeframes.114,116,139,140
..
..
Table 5 Summary of important time targets
.. stent (BMS) is associated with a lower risk of reinfarction and target
.. vessel revascularization but is not associated with a reduction in the
..
.. mortality rate.146,147 In primary PCI, drug-eluting stents (DES) reduce
.. the risk of repeated target vessel revascularization compared with
..
.. BMS.148
.. New-generation DES have shown superior safety and preserved
..
.. or even improved efficacy compared with first-generation DES, in
.. particular with respect to lower risks of stent thrombosis and recur-
..
.. rent MI. In two recent trials—the Effect of biolimus-eluting stents
.. with biodegradable polymer vs. bare-metal stents on cardiovascular
..
.. events among patients with AMI (COMFORTABLE AMI) trial149 and
.. the Everolimus-Eluting Stents Versus Bare-Metal Stents in ST-
..
..
ratio 1.56, 95% CI 1.02–2.42, P =0.04]. However, the interaction P val- .. DANAMI-3–PRIMULTI). Based on these data, revascularization of
ues were 0.32 and 0.34, respectively.162 .. non-IRA lesions should be considered in STEMI patients with multives-
..
In the Taste157 and TOTAL trials159, 1–5% of randomized patients .. sel disease before hospital discharge. As the optimal timing of revascu-
crossed over from PCI alone to thrombus aspiration. Based on these .. larization (immediate vs. staged) has not been adequately investigated,
..
data and the results of a recent meta-analysis,162 routine thrombus .. no recommendation in favour of immediate vs. staged multivessel PCI
aspiration is not recommended, but in cases of large residual throm- .. can be formulated.
..
bus burden after opening the vessel with a guide wire or a balloon, ..
thrombus aspiration may be considered.
.. 5.2.1.5 Intra-aortic balloon pump
..
.. The Counterpulsation to Reduce Infarct Size Pre-PCI-Acute Myocar-
5.2.1.4 Multivessel coronary revascularization
.. dial Infarction (CRISP AMI) trial showed no benefit from a routine
..
Multivessel disease is common (in approximately 50%) in patients .. intra-aortic balloon pump (IABP) in anterior MI without shock,175 but
with STEMI.163,164 While it is recommended to always treat the IRA,
.. there was increased bleeding, which is consistent with previous data
..
non-IRA was done either during the index procedure (PRAMI and
..
..
Compare-Acute), staged during hospital admission (DANAMI- .. Non-IRA strategy
..
3–PRIMULTI), or any time before discharge (immediate or staged) .. Routine revascularization of non-IRA lesions
(CVLPRIT). Indication for PCI in non-IRA was angiography-guided in .. should be considered in STEMI patients with mul- IIa A
.. tivessel disease before hospital discharge.167–173
lesions with 50% stenosis (PRAMI), >70% stenosis (CVLPRIT), or ..
fractional flow reserve (FFR)-guided (DANAMI-3–PRIMULTI and .. Non-IRA PCI during the index procedure should
.. be considered in patients with cardiogenic shock.
IIa C
Compare-Acute). Primary outcome (composite of different end- ..
points) was significantly reduced in the complete revascularization ..
.. CABG should be considered in patients with
group in all four trials. Total mortality was not statistically different in .. ongoing ischaemia and large areas of jeopardized IIa C
any of the four trials. Repeat revascularization was significantly reduced .. myocardium if PCI of the IRA cannot be performed.
..
in the complete revascularization arm in the PRAMI, DANAMI- ..
3–PRIMULTI, and Compare-Acute trials. Non-fatal MI was reduced in .. CABG = coronary artery bypass graft surgery; DES = drug-eluting stent; IRA =
.. infarct-related artery; PCI = percutaneous coronary intervention; STEMI = ST-
the non-IRA PCI group only in PRAMI. The lack of significant treatment ..
effect of non-IRA lesion intervention on death or MI was confirmed by .. segment elevation myocardial infarction.
a
.. Class of recommendation.
three meta-analyses172–174 (none of these meta-analyses included .. b
Level of evidence.
the Compare-Acute trial, and one173 did not include the ..
136 ESC Guidelines
Fibrinolytic therapy
When fibrinolysis is the reperfusion strategy, it is recommended to initiate this treatment as soon as possible after STEMI
I A
diagnosis, preferably in the pre-hospital setting.96,98,123,222
Anticoagulation is recommended in patients treated with lytics until revascularization (if performed) or for the duration of I A
hospital stay up to 8 days.199,224,227–233 The anticoagulant can be:
I A
• Enoxaparin i.v. followed by s.c. (preferred over UFH).227–232
UFH given as a weight-adjusted i.v. bolus followed by infusion.224 I B
•
• In patients treated with streptokinase: fondaparinux i.v. bolus followed by an s.c. dose 24 h later.199,233 IIa B
Transfer to a PCI-capable centre following fibrinolysis is indicated in all patients immediately after fibrinolysis.121,124,126–130,234 I A
Emergency angiography and PCI if indicated is recommended in patients with heart failure/shock.124, 235 I A
Rescue PCI is indicated immediately when fibrinolysis has failed (<50% ST-segment resolution at 60–90 min) or at any time in
I A
the presence of haemodynamic or electrical instability, or worsening ischaemia.121,124,236
Angiography and PCI of the IRA, if indicated, is recommended between 2 and 24 h after successful fibrinolysis.125–128,234 I A
Emergency angiography and PCI if needed is indicated in the case of recurrent ischaemia or evidence of reocclusion after initial
I B
successful fibrinolysis.124
DAPT = dual antiplatelet therapy; IRA = infarct-related artery; i.v. = intravenous; PCI = percutaneous coronary intervention; SBP = systolic blood pressure; s.c. = subcutaneous;
STEMI = ST-segment elevation myocardial infarction; UFH = unfractionated heparin.
a
Class of recommendation.
b
Level of evidence.
c
Clopidogrel is the P2Y12 inhibitor of choice as co-adjuvant and after fibrinolysis, but 48 h after fibrinolysis, switch to prasugrel/ticagrelor may be considered in patients who
underwent PCI.
..
Doses of fibrinolytic agents and antithrombotic co-therapies are .. initiation of fibrinolytic treatment when a reperfusion strategy is indi-
listed in Table 7. .. cated.97,99,100,237 The STREAM trial showed that pre-hospital fibrinol-
..
.. ysis followed by an early PCI strategy was associated with a similar
5.3.2 Pre-hospital fibrinolysis .. outcome as transfer for primary PCI in STEMI patients presenting
..
In a meta-analysis of six randomized trials (n = 6434), pre-hospital .. within 3 h after symptom onset who could not undergo primary PCI
fibrinolysis reduced early mortality by 17% compared with in-hospital
.. within 1 h after FMC.121,238
..
fibrinolysis,123 particularly when administered in the first 2 h of symp- .. If trained medical or paramedical staff are able to analyse the ECG on-
tom onset.138 These and more recent data support pre-hospital
.. site or to transmit the ECG to the hospital for interpretation, it is
140 ESC Guidelines
recommended to initiate fibrinolytic therapy in the pre-hospital .. compared with a ‘watchful waiting’ strategy, in which angiography
..
setting. The aim is to start fibrinolytic therapy within 10 min from STEMI .. and revascularization were indicated only in patients with spontane-
diagnosis.
.. ous or induced severe ischaemia or LV dysfunction, or in those with a
..
.. positive outpatient ischaemia test. The benefits of early routine PCI
.. after fibrinolysis were seen in the absence of an increased risk of
5.3.3 Angiography and percutaneous coronary ..
intervention after fibrinolysis (pharmacoinvasive .. adverse events (stroke or major bleeding), and across patient sub-
.. groups.241 Thus, early angiography with subsequent PCI if indicated is
strategy) ..
Following initiation of lytic therapy, it is recommended to transfer the .. also the recommended standard of care after successful fibrinolysis
..
patients to a PCI centre (Figure 3). In cases of failed fibrinolysis, or if .. (see Figure 3).
there is evidence of reocclusion or reinfarction with recurrence of .. A crucial issue is the optimal time delay between successful lysis and
..
ST-segment elevation, immediate angiography and rescue PCI is indi- .. PCI; there was a wide variation in delay in trials, from a median of 1.3 h
cated.124 In this setting, re-administration of fibrinolysis has not been .. in the Combined Angioplasty and Pharmacological Intervention versus
..
shown to be beneficial and should be discouraged.124 Even if it is .. Thrombolytics ALone in Acute Myocardial Infarction (CAPITAL AMI)
likely that fibrinolysis will be successful (ST-segment resolution .. trial240 to 17 h in the Grupo de Analisis de la Cardiopatıa Isquémica
..
> 50% at 60–90 min; typical reperfusion arrhythmia; and disappear- .. Aguda (GRACIA)-1234 and STREAM trials.121 In a pooled patient-level
ance of chest pain), a strategy of routine early angiography is recom- .. analysis of six randomized trials, very early angiography (<2 h) after
..
mended if there are no contraindications. Several randomized .. fibrinolysis was not associated with an increased risk of 30 day death/
trials126–128,234,239,240 and meta-analyses129,130 have shown that early
.. reinfarction or in-hospital major bleeding, and a shorter time from
..
routine angiography with subsequent PCI (if needed) after .. symptom onset to angiography (<4 h) was associated with reduced
fibrinolysis reduced the rates of reinfarction and recurrent ischaemia
.. 30 day and 1 year death/reinfarction and 30 day recurrent ischaemia.125
ESC Guidelines 141
..
Based on this analysis, as well as on trials having a median delay .. lower weight, female sex, previous cerebrovascular disease, and systolic
between start of lysis and angiography of 2–17 h,121,126–128 a time- .. and diastolic hypertension on admission are significant predictors of
..
window of 2–24 h after successful lysis is recommended. .. intracranial haemorrhage.245 In the latest trials, intracranial bleeding
.. occurred in 0.9–1.0% of the total population studied.121,223,246 In the
..
5.3.4 Comparison of fibrinolytic agents .. STREAM trial, the initial excess in intracranial haemorrhage in patients
A fibrin-specific agent should be preferred.224 Single-bolus weight- .. 75 years was reduced after the protocol amendment to reduce the
..
adjusted tenecteplase tissue plasminogen activator (TNK-tPA) is .. dose of tenecteplase by 50%. Data from a number of studies suggest
equivalent to accelerated tPA in reducing 30 day mortality, but is .. that major non-cerebral bleeds occurred in 4–13% of the patients
..
safer in preventing non-cerebral bleeds and blood transfusion, and is .. treated.121,223,224,246 Administration of streptokinase may be associated
easier to use in the pre-hospital setting.223 .. with hypotension, but severe allergic reactions are rare. Re-
..
.. administration of streptokinase should be avoided because of antibodies
.. that can impair its activity, and because of the risk of allergic reactions.
5.3.5 Adjunctive antiplatelet and anticoagulant therapies ..
..
Logistical issues for hospital stay
.. should be avoided. Loading of aspirin should be done as in all STEMI
.. patients, and clopidogrel is the P2Y12 inhibitor of choice (600 mg
..
.. loading dose) before or at the latest at the time of PCI. Prasugrel and
Recommendations Classa Levelb .. ticagrelor are not recommended. Ideally, a chronic anticoagulation
..
It is indicated that all hospitals participating in the .. regimen should not be stopped during admission. Gastric protection
care of STEMI patients have a CCU/ICCU equipped .. with a proton pump inhibitor (PPI) is recommended.
I C
..
to provide all aspects of care for STEMI patients, .. Maintenance after STEMI: In general, continuation of oral anticoa-
including treatment of ischaemia, severe heart failure, .. gulation in patients with an indication for DAPT (e.g. after STEMI)
arrhythmias, and common comorbidities. ..
.. should be evaluated carefully and continued only if compelling evi-
Transfer back to a referring non-PCI hospital
.. dence exists. Ischaemic and bleeding risks should be taken into con-
..
Same day transfer should be considered appropri-
.. sideration. While there is a considerable overlap of risk factors
.. associated with ischaemic with bleeding outcomes, multiple bleeding
..
Table 9 Recommended doses of antithrombotic agents in the acute care of patients with chronic kidney disease
30 mL/min/1.73 m2)
(eGFR 15 to <30
aPTT = activated partial thromboplastin time; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; GP = glycoprotein; IU = international units; i.v. =
intravenous; PCI = percutaneous coronary intervention; s.c. = subcutaneous; UFH = unfractionated heparin.
a
Double bolus if administered during primary PCI.
patients.273,274 Elderly patients are also at particular risk of bleeding .. (less frequent presentation with chest pain and fewer typical ECG
..
and other complications from acute therapies because bleeding risk .. signs) diagnosis may be delayed.
increases with age, renal function tends to decrease, and the preva-
.. Although decisions on reperfusion in patients with STEMI have to
..
lence of comorbidities is high. Observational studies have shown fre- .. be made before any assessment of renal function is available, it is
quent excess dosing of antithrombotic therapies in elderly
.. important to estimate the GFR as soon as possible. The type and
..
patients.275 Furthermore, they have a higher risk of mechanical .. dose of antithrombotic agent (see Table 9) and the amount of con-
complications.
.. trast agent should be considered based on renal function.277 ACS
..
It is key to maintain a high index of suspicion for MI in elderly .. patients with chronic kidney disease (CKD) receive frequently excess
patients who present with atypical complaints, treating them as rec-
.. dosing with antithrombotics, contributing to the increased bleeding
..
ommended, and using specific strategies to reduce bleeding risk; .. risk.275 Consequently, in patients with known or anticipated reduc-
..
these include paying attention to proper dosing of antithrombotic .. tion of renal function, several antithrombotic agents should either be
therapies, particularly in relation to renal function, frailty, or comor- .. withheld or their doses reduced appropriately. Ensuring proper
..
bidities, and using radial access whenever possible. There is no upper .. hydration during and after primary PCI and limiting the dose of con-
age limit with respect to reperfusion, especially with primary PCI.276 .. trast agents, preferentially low-osmolality contrast agents, are impor-
..
.. tant steps in minimizing the risk of contrast-induced nephropathy.1
..
6.5.3 Renal dysfunction ..
..
Renal dysfunction [estimated glomerular filtration rate (eGFR) .. 6.5.4 Non-reperfused patients
<30 mL/min/1.73 m2] is present in approximately 30–40% of patients
.. Patients who, for specific reasons (e.g. long delay), fail to receive reper-
..
with ACS and is associated with a worse prognosis and increased risk .. fusion therapy within the recommended time (first 12 h) should imme-
of in-hospital complications.277 Owing to differences in presentation
.. diately be evaluated clinically to rule out the presence of clinical,
ESC Guidelines 145
..
haemodynamic, or electrical instability. A primary PCI strategy is indi- .. ischaemia/viability to decide a late invasive strategy or elective coronary
cated in the presence of signs or symptoms suggestive of ongoing myo- .. angiography should be considered. However, routine PCI is not indi-
..
cardial ischaemia, heart failure, haemodynamic instability, or life- .. cated in totally occluded IRA beyond the first 48 h from symptom onset
threatening arrhythmias,141 and should be considered in stable asympto- .. due to the increased risk of late complications (see Figure 4).135,137
..
matic patients between 12–48 h after symptom onset.133,142 After that .. Early echocardiography with LVEF assessment is indicated in all
time, either a non-invasive test for the presence of residual myocardial .. patients. Medical therapy should include DAPT, anticoagulation, and
146 ESC Guidelines
Management of hyperglycaemia
It is recommended to measure glycaemic status at initial evaluation in all patients, and perform frequent monitoring in patients
I C
with known diabetes or hyperglycaemia (defined as glucose levels 11.1 mmol/L or 200 mg/dL)
In patients on metformin and/or SGLT2 inhibitors, renal function should be carefully monitored for at least 3 days after
I C
coronary angiography/PCI.c
Glucose-lowering therapy should be considered in ACS patients with glucose levels >10 mmol/L (>180 mg/dL), while
IIa C
episodes of hypoglycaemia (defined as glucose levels <_3.9 mmol/L or <_ 70 mg/dL) should be avoided.
Less stringent glucose control should be considered in the acute phase in patients with more advanced cardiovascular
IIa C
disease, older age, longer diabetes duration, and more comorbidities.
ACS = acute coronary syndrome; PCI = percutaneous coronary intervention; SGLT2 = sodium-glucose co-transporter-2.
a
Class of recommendation.
b
Level of evidence.
c
A short withdrawal of metformin may be considered after an invasive coronary procedure.
ESC Guidelines 147
controversial. is uncertain.295
The timing of and best imaging technique (echocardiography, Routine echocardiography that delays emergency
SPECT, CMR, or PET) to detect residual ischaemia and myocardial III C
angiography is not recommended.295
viability remains to be determined, but will also depend on local avail-
Coronary CT angiography is not recommended III C
ability and expertise. The best validated and widely available tests are
stress echocardiography and SPECT (both used in combination with During hospital stay (after primary PCI)
exercise or pharmacological stress), but PET and CMR are equally
Routine echocardiography to assess resting LV
indicated. However, in post-MI patients, the detection of residual
and RV function, detect early post-MI mechanical
ischaemia by echocardiography is challenging due to existing wall I B
complications, and exclude LV thrombus is rec-
motion abnormalities.287 LGE-CMR imaging has a high diagnostic
ommended in all patients.296,297
accuracy for assessing the transmural extent of myocardial scar tis-
sue.288 However, the ability to detect viability and predict recovery Emergency echocardiography is indicated in hae-
I C
of wall motion is not significantly superior to other imaging techni- modynamically unstable patients.295
ques.289 The presence of dysfunctional viable myocardium by LGE-
When echocardiography is suboptimal/inconclu-
CMR is an independent predictor of mortality in patients with ischae-
sive, an alternative imaging method (CMR prefera- IIa C
mic LV dysfunction.290
bly) should be considered.
More recently, the presence of wall thinning with limited scar bur-
den was shown to be associated with improved contractility and res- Either stress echo, CMR, SPECT, or PET may be
olution of wall thinning after revascularization, emphasizing the used to assess myocardial ischaemia and viability, IIb C
importance of viability beyond wall thickness and myocardial revascu- including in multivessel CAD.1,298–300
..
7. Long-term therapies for ..
..
with STEMI. However, it has not been established that weight reduc-
tion per se reduces mortality.
ST-segment elevation myocardial ..
..
infarction .. 7.1.3 Exercise-based cardiac rehabilitation
..
.. All AMI patients should participate in an exercise-based cardiac reha-
7.1 Lifestyle interventions and risk factor ..
.. bilitation programme,309 taking into account their age, pre-infarction
control .. level of activity, and physical limitations. A cardiac rehabilitation pro-
Key lifestyle interventions include cessation of smoking, optimal
..
.. gramme preferably includes exercise training, risk factor modification,
blood pressure control, diet advice and weight control, and encour- .. education, stress management, and psychological support.309 In a large
aging physical activity. Detailed recommendations are available from
..
.. meta-analysis, exercise training as part of a cardiac rehabilitation pro-
the ESC Guidelines on prevention.4 During hospitalization, the time .. gramme was associated with a 22% reduction in cardiac mortality rate
..
for implementing secondary prevention is limited and a close collabo- .. in patients with CAD.309 The benefit of cardiac rehabilitation appears
..
patients, adherence to cardiovascular medications was estimated to .. 7.2.2 Duration of dual antiplatelet therapy and
be about 57% after a median of 2 years.319 .. antithrombotic combination therapies
..
It is generally recognized that adherence is determined by the .. DAPT, combining aspirin and a P2Y12 inhibitor (i.e. prasugrel, ticagre-
interplay of socioeconomic, medication-related, condition-related, .. lor, or clopidogrel), is recommended in patients with STEMI who are
..
health system-related, and patient-related factors.320 A strategy to .. undergoing primary PCI (for up to 12 months).186,187 Clopidogrel is
reduce poor adherence is the use of a fixed-dose combination or pol- .. recommended for 1 month in patients treated with fibrinolysis with-
..
ypill, including key medications to reduce cardiovascular risk, as a .. out subsequent PCI.225,226 Expanding the duration of DAPT up to
once-daily dose pill.321,322 The only study dedicated to post-MI .. 12 months should be considered in these patients.
..
patients is the recent phase 2 Fixed-Dose Combination Drug for .. For patients undergoing fibrinolysis and subsequent PCI, DAPT is
Secondary Cardiovascular Prevention (FOCUS) trial,323 in which 695 .. recommended for 12 months. Clopidogrel is the P2Y12 inhibitor of
..
patients post-MI were randomized to usual care or to a polypill- .. choice as co-adjuvant and after fibrinolysis. Potent P2Y12 inhibitors
based strategy [polypill containing aspirin, an angiotensin-converting .. have not been properly tested in patients undergoing fibrinolysis, and
..
..
In the Acute Coronary Syndrome–Thrombolysis In Myocardial .. (METOCARD-CNIC) trial (n = 270) showed that the very early
Infarction 51 (ATLAS ACS 2–TIMI 51) trial (n = 15 526, 50% STEMI), .. administration of i.v. metoprolol (15 mg) at the time of diagnosis
..
a low dose of rivaroxaban (2.5 mg twice daily), on top of aspirin plus .. in patients with anterior STEMI, no signs of heart failure, and
clopidogrel, reduced the composite primary endpoint of cardiovas- .. SBP >120 mmHg was associated with a reduction in infarct
..
cular death, MI, or stroke, but also all-cause mortality, over a mean .. size measured by CMR at 5–7 days (25.6 g vs. 32.0 g; P = 0.012),
follow-up of 13 months.338 Stent thrombosis was reduced by one- .. and higher LVEF at 6 months CMR (48.7% vs. 45.0%; P = 0.018)
..
third. However, this was associated with a three-fold increase in non- .. compared with control treatment.347,348 All patients without con-
CABG-related major bleeding and intracranial haemorrhage.338 .. traindications received oral metoprolol within 24 h. The
..
Based on the ATLAS ACS 2–TIMI 51 trial, in selected patients at low .. incidence of MACE (composite of death, admission as a result of
bleeding risk, the 2.5 mg dose of rivaroxaban may be considered in .. heart failure, reinfarction, or malignant ventricular arrhythmias) at
..
patients who receive aspirin and clopidogrel after STEMI. .. 2 years was 10.8% vs. 18.3% in the i.v. metoprolol and control
.
DAPT in the form of aspirin plus ticagrelor or prasugrel (or clopidogrel if ticagrelor or prasugrel are not available or are contraindicated), is
I A
recommended for 12 months after PCI, unless there are contraindications such as excessive risk of bleeding.186,187
A PPI in combination with DAPT is recommended in patients at high risk of gastrointestinal bleedingc.335–337 I B
In patients with an indication for oral anticoagulation, oral anticoagulants are indicated in addition to antiplatelet therapy.5 I C
In patients who are at high risk of severe bleeding complications, discontinuation of P2Y12 inhibitor therapy after 6 months should be
IIa B
considered.332,339,340
In STEMI patients with stent implantation and an indication for oral anticoagulation, triple therapyd should be considered for 1–6 months
IIa C
(according to a balance between the estimated risk of recurrent coronary events and bleeding).5
DAPT for 12 months in patients who did not undergo PCI should be considered unless there are contraindications such as excessive risk of
IIa C
bleeding.
In patients with LV thrombus, anticoagulation should be administered for up to 6 months guided by repeated imaging.341–343 IIa C
In high ischaemic-risk patientse who have tolerated DAPT without a bleeding complication, treatment with DAPT in the form of ticagrelor
IIb B
60 mg twice a day on top of aspirin for longer than 12 months may be considered for up to 3 years.333
In low bleeding-risk patients who receive aspirin and clopidogrel, low-dose rivaroxaban (2.5 mg twice daily) may be considered.338 IIb B
The use of ticagrelor or prasugrel is not recommended as part of triple antithrombotic therapy with aspirin and oral anticoagulation. III C
AMI = acute myocardial infarction; CAD = coronary artery disease; DAPT = dual antiplatelet therapy; eGFR = estimated glomerular filtration rate; LV = left ventricular; PCI =
percutaneous coronary intervention; PPI = proton pump inhibitor; STEMI = ST-segment elevation myocardial infarction.
a
Class of recommendation.
b
Level of evidence.
c
History of gastrointestinal bleeding, anticoagulant therapy, chronic non-steroidal anti-inflammatory drug/corticosteroid user, and 2 or more of the following: age 65 years,
dyspepsia, gastro-oesophageal reflux disease, H. pylori infection, and chronic alcohol use.
d
Oral anticoagulant, aspirin, and clopidogrel.
e
Defined as age 50 years, and at least one of the following additional high-risk features: age 65 years, diabetes mellitus on medication, a prior spontaneous AMI, multivessel
CAD, or chronic renal dysfunction (eGFR <60 ml/min/1.73 m2).
..
..
7.3 Beta-blockers .. arms (P = 0.065).348 Metoprolol treatment was associated with a
..
7.3.1 Early intravenous beta-blocker administration .. significant reduction in the incidence and extent of MVO.349 The
In patients undergoing fibrinolysis, early i.v. beta-blocker treatment .. Early Intravenous Beta-Blockers in Patients With ST-Segment
..
reduces the incidence of acute malignant ventricular arrhythmias, .. Elevation Myocardial Infarction Before Primary Percutaneous
although there is no clear evidence of long-term clinical .. Coronary Intervention (EARLY-BAMI) trial randomized
..
benefit.344–346 .. 683 patients with STEMI within 12 h of onset to i.v. metoprolol
In patients undergoing primary PCI, the Effect of Metoprolol in .. (5 mg at recruitment and an additional 5 mg immediately before
..
Cardioprotection During an Acute Myocardial Infarction . PCI) or placebo.350 All patients without contraindications
ESC Guidelines 151
..
received oral metoprolol within 12 h. Early i.v. metoprolol admin- .. of early and intensive statin therapy in ACS.364,365 A meta-analysis
istration did not show any benefit in reducing CMR-based .. of trials comparing more- vs. less-intensive LDL-C lowering with
..
infarct size, the trial primary endpoint, available only in 342 .. statins indicated that more-intensive statin therapy produced
patients (55%), or the level of cardiac biomarker release. Early i.v. .. greater reductions in the risks of cardiovascular death, non-fatal
..
metoprolol was associated with a borderline reduction of malig- .. MI, ischaemic stroke, and coronary revascularization.366 For every
nant ventricular arrhythmias (3.6% vs. 6.9%; P = 0.050). Patients .. 1.0 mmol/L reduction in LDL-C, these further reductions in risk
..
treated with i.v. metoprolol showed no increased risk of haemo- .. were similar to the proportional reductions in the trials of statins
dynamic instability, atrioventricular (AV) block, or MACE at .. vs. control. Therefore, statins are recommended in all patients
..
30 days. Post hoc analyses from primary PCI trials testing .. with AMI, irrespective of cholesterol concentration at presenta-
other hypotheses have suggested that early i.v. beta-blocker .. tion. Lipid-lowering treatment should be started as early as possi-
..
administration might be associated with a clinical benefit, but a .. ble, as this increases patient adherence after discharge, and given
selection bias cannot be excluded even after correction for imbal- .. as high-intensity treatment, as this is associated with early and sus-
..
Routine therapies in the acute, subacute, and long-term phases: beta-blockers, angiotensin-converting enzyme
inhibitors, angiotensin II receptor blockers, mineralocorticoid receptor antagonists, and lipid-lowering treatments
after ST-elevation myocardial infarction
Beta-blockers
Oral treatment with beta-blockers is indicated in patients with heart failure and/or LVEF <_40% unless contraindicated.357–361 I A
Intravenous beta-blockers should be considered at the time of presentation in patients undergoing primary PCI without con-
IIa A
traindications, with no signs of acute heart failure, and with an SBP >120 mmHg.346–348,350,403
Intravenous beta-blockers must be avoided in patients with hypotension, acute heart failure or AV block, or severe
III B
bradycardia.344
It is recommended to start high-intensity statin therapyc as early as possible, unless contraindicated, and maintain it long-
I A
term.364,366,368
An LDL-C goal of < 1.8 mmol/L (70 mg/dL) or a reduction of at least 50% if the baseline LDL-C is between 1.8–3.5 mmol/L
I B
(70–135 mg/dL) is recommended.367,369,376,382
It is recommended to obtain a lipid profile in all STEMI patients as soon as possible after presentation.369,406 I C
In patients with LDL-C 1.8 mmol/L (70 mg/dL) despite a maximally tolerated statin dose who remain at high risk, further
IIa A
therapy to reduce LDL-C should be considered.376,382
ACE inhibitors/ARBs
ACE inhibitors are recommended, starting within the first 24 h of STEMI in patients with evidence of heart failure, LV systolic
I A
dysfunction, diabetes, or an anterior infarct.383
An ARB, preferably valsartan, is an alternative to ACE inhibitors in patients with heart failure and/or LV systolic dysfunction,
I B
particularly those who are intolerant of ACE inhibitors.396,407
ACE inhibitors should be considered in all patients in the absence of contraindications.394,395 IIa A
MRAs
MRAs are recommended in patients with an LVEF <_40% and heart failure or diabetes, who are already receiving an ACE inhib-
I B
itor and a beta-blocker, provided there is no renal failure or hyperkalaemia.397
AV = atrioventricular; ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; LDL-C = low-density lipoprotein cholesterol; LV = left ventricular; LVEF
= left ventricular ejection fraction; MRA = mineralocorticoid receptor antagonist; PCI = percutaneous coronary intervention; SBP = systolic blood pressure; STEMI = ST-seg-
ment elevation myocardial infarction.
a
Class of recommendation.
b
Level of evidence.
c
High-intensity statin defined as atorvastatin 40–80 mg and rosuvastatin 20–40 mg.
..
When using MRA, care should be taken with reduced renal func- .. 8. Complications following ST-
tion [creatinine concentration >221 mmol/L (2.5 mg/dL) in men and ..
.. segment elevation myocardial
>177 mmol/L (2.0 mg/dL) in women] and routine monitoring of ..
serum potassium is warranted. .. infarction
..
Figures 5 and 6 present the mostly prescribed interventions ..
(class I and IIa) in patients undergoing primary PCI or fibrinolysis
.. Expanded information about complications following STEMI is pre-
.. sented in the Web Addenda.
strategies. .
154 ESC Guidelines
Recommendations for the management of left ventricular dysfunction and acute heart failure in ST-elevation myocar-
dial infarction
ACE inhibitor (or if not tolerated, ARB) therapy is indicated as soon as haemodynamically stable for all patients with
I A
evidence of LVEF <_40% and/or heart failure to reduce the risk of hospitalization and death.390,396,412,413
Beta-blocker therapy is recommended in patients with LVEF <_40% and/or heart failure after stabilization, to reduce the risk
I A
of death, recurrent MI, and hospitalization for heart failure.358–361,414–416
An MRA is recommended in patients with heart failure and LVEF <_40% with no severe renal failure or hyperkalaemia to reduce
I B
the risk of cardiovascular hospitalization and death.397
Loop diuretics are recommended in patients with acute heart failure with symptoms/signs of fluid overload to improve
I C
symptoms.
Nitrates are recommended in patients with symptomatic heart failure with SBP >90 mmHg to improve symptoms and
I C
reduce congestion.
Oxygen is indicated in patients with pulmonary oedema with SaO2 <90% to maintain a saturation >95%. I C
Patient intubation is indicated in patients with respiratory failure or exhaustion, leading to hypoxaemia, hypercapnia, or acidosis,
I C
and if non-invasive ventilation is not tolerated.
Non-invasive positive pressure ventilation (continuous positive airway pressure, biphasic positive airway pressure) should
be considered in patients with respiratory distress (respiratory rate >25 breaths/min, SaO2 <90%) without IIa B
hypotension.410,411,417–419
Intravenous nitrates or sodium nitroprusside should be considered in patients with heart failure and elevated SBP to control
IIa C
blood pressure and improve symptoms.
Opiates may be considered to relieve dyspnoea and anxiety in patients with pulmonary oedema and severe dyspnoea.
IIb B
Respiration should be monitored.6,408
Inotropic agents may be considered in patients with severe heart failure with hypotension refractory to standard medical
IIb C
treatment.
ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; LV = left ventricular; LVEF = left ventricular ejection fraction; MRA = mineralocorticoid receptor
antagonist; SaO2 = arterial oxygen saturation; SBP = systolic blood pressure; STEMI = ST-segment elevation myocardial infarction.
a
Class of recommendation.
b
Level of evidence.
ESC Guidelines 157
..
mechanical complications, should be treated as appropriate (see .. The first step in patients with cardiogenic shock is to identify
specific sections in this document). .. the mechanism and to correct any reversible cause such as hypo-
..
Severely symptomatic patients with pulmonary congestion may .. volaemia, drug-induced hypotension, or arrhythmias; alternatively,
also need i.v. morphine to reduce dyspnoea and anxiety, but rou- .. initiate the treatment of potential specific causes, such as mechani-
..
tine use is not recommended due to concerns about its safety, as .. cal complications or tamponade.
it may induce nausea and hypopnea.408,409 Non-invasive positive .. Treatments include immediate reperfusion, with primary PCI
..
pressure ventilation (continuous positive airway pressure, bipha- .. whenever possible,248,427 and complete revascularisation if multives-
sic positive airway pressure) or high-flow nasal cannula is effective
.. sel disease is present. In addition, patients at the highest risk for devel-
..
in treating pulmonary oedema and should be considered in .. opment of shock might benefit from an early transfer to tertiary
patients with respiratory distress (respiratory rate >25 breaths/
.. centres before the onset of haemodynamic instability.
..
min, SaO2 <90%) and started soon.410,411 Endotracheal intubation .. Antithrombotic therapy does not differ from that in any STEMI
and ventilatory support may be required in patients unable to
.. patient. The specificities of the management of low-output cardio-
..
..
Recommendations for the management of cardio-
.. 8.3 Management of arrhythmias and
..
genic shock in ST-elevation myocardial infarction .. conduction disturbances in the acute
.. phase
..
Recommendations Classa Levelb .. Arrhythmias and conduction disturbances are common during the
..
Immediate PCI is indicated for patients with
.. early hours of STEMI and are also important prognostic factors.438
.. Despite increased awareness and improved basic and advanced life
cardiogenic shock if coronary anatomy is ..
I B
.. support, the incidence of sudden cardiac death, mainly due to fast
suitable. If coronary anatomy is not suitable .. ventricular tachycardia (VT) and VF in the pre-hospital phase,
for PCI, or PCI has failed, emergency CABG ..
.. remains high.438,439 Early reperfusion therapy reduces the risk of ven-
is recommended.248 .. tricular arrhythmias and cardiovascular death.440,441 The presence of
..
Invasive blood pressure monitoring with an .. life-threatening arrhythmias requires an urgent need for a fast and
I C .. complete revascularization in STEMI.438,442 The evidence for benefits
ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; DAPT = dual antiplatelet therapy; ECG = electrocardiogram; GRACE = Global Registry of
Acute Coronary Events; IRA = Infarct-related artery; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myo-
cardial infarction.
..
(see Web Addenda). Quality indicators are intended to measure and ..
..
11. Gaps in the evidence and areas
compare the quality of health service provision and serve as a founda- ..
..
for future research
tion for quality improvement initiatives.476 Proposed quality indica-
..
tors to assess the quality of the care for patients are presented in .. Despite the great advances in STEMI management over recent deca-
Table 11. .. des, important areas of uncertainty persist that should be explored in
..
Expanded text about quality indicators can be found in the Web .. the future. Here, we identify some, but not all, specific areas that
Addenda. .. should be addressed within the next few years.
164 ESC Guidelines
..
Public awareness and emergency care .. STEMI has not been prospectively tested in dedicated clinical trials of
.. reperfused patients. Similar limitations apply to the use of mainte-
The very early stages of STEMI are the most vulnerable time, when ..
most sudden cardiac deaths occur. Public campaigns aiming to .. nance ACE inhibitors.
..
increase early alerting of patients with ischaemic symptoms should ..
clearly state that the safest way to alert is to call the EMS. While ..
.. Post-STEMI risk stratification
selected centres and geographic areas have made great progress in .. The optimal therapeutic strategy to minimize the risk of sudden
ensuring high-quality rapid care for STEMI patients with routine pre- ..
.. death in patients who develop VT or VF during or early after STEMI
alert of the interventional team, there remains a need for streamlining ..
.. is not entirely clear. Despite the clinical benefit of ICDs in patients
of (pre-)hospital management in a homogeneous fashion worldwide, .. with low LVEF and reduced functional class weeks after STEMI being
including rural areas. Educational programmes and cross-country ..
exchange of experiences should help in this matter. .. well established, there is a need for better sudden death risk stratifi-
.. cation algorithms.
..
13. Evidenced-based ‘to do and not to do’ messages from the Guidelines
Recommendations
Twelve-lead ECG recording and interpretation is indicated as soon as possible at the point of FMC, with a maximum target
I B
delay of 10 min.
A primary PCI strategy is recommended in patients with resuscitated cardiac arrest and an ECG consistent with STEMI. I B
Targeted temperature management is indicated early after resuscitation of cardiac arrest patients who remain unresponsive. I B
Pre-hospital cooling using a rapid infusion of large volumes of cold i.v. fluid immediately after return of spontaneous circulation
III B
is not recommended.
It is recommended that the pre-hospital management of STEMI patients is based on regional networks designed to deliver
reperfusion therapy expeditiously and effectively, with efforts made to make primary PCI available to as many patients as I B
possible.
It is recommended that primary PCI-capable centres deliver a 24/7 service and are able to perform primary PCI without delay. I B
It is recommended that patients transferred to a PCI-capable centre for primary PCI bypass the emergency department and
I B
CCU/ICCU and are transferred directly to the catheterization laboratory.
Reperfusion therapy is indicated in all patients with symptoms of ischaemia of <_ 12 h duration and persistent ST-segment
I A
elevation.
If primary PCI cannot be performed in a timely way after STEMI diagnosis, fibrinolytic therapy is recommended within 12 h of
I A
symptom onset in patients without contraindications.
In asymptomatic patients, routine PCI of an occluded IRA >48 h after onset of STEMI is not indicated. III A
Stenting with new-generation DES is recommended over BMS for primary PCI. I A
Radial access is recommended over femoral access if performed by an experienced radial operator. I A
Recommendations for periprocedural and post-procedural antithrombotic therapy in patients undergoing primary PCI
A potent P2Y12 inhibitor (prasugrel or ticagrelor), or clopidogrel if these are not available or are contraindicated, is recom-
mended before (or at latest at the time of) PCI and maintained over 12 months unless there are contraindications such as I A
excessive risk of bleeding.
Continued
ESC Guidelines 167
Aspirin oral or i.v. (if unable to swallow) is recommended as soon as possible for all patients without contraindications. I B
When fibrinolysis is the reperfusion strategy, it is recommended to initiate this treatment as soon as possible after STEMI diag-
I A
nosis, preferably in the pre-hospital setting.
Transfer to a PCI-capable centre following fibrinolysis is indicated in all patients immediately after fibrinolysis. I A
Emergency angiography and PCI if indicated is recommended in patients with heart failure/shock. I A
Rescue PCI is indicated immediately when fibrinolysis has failed (<50% ST-segment resolution at 60–90 min) or at any time in
I A
the presence of haemodynamic or electrical instability, or worsening ischaemia.
Angiography and PCI of the IRA, if indicated, is recommended between 2–24 h after successful fibrinolysis. I A
Emergency angiography and PCI if needed is indicated in the case of recurrent ischaemia or evidence of reocclusion after initial
I B
successful fibrinolysis.
Routine echocardiography during hospital stay to assess resting LV and RV function, detect early post-MI mechanical complica-
I B
tions, and exclude LV thrombus is recommended in all patients.
It is recommended to identify smokers and provide repeated advice on stopping, with offers to help with the use of follow-up
I A
support, nicotine replacement therapies, varenicline, and bupropion individually or in combination.
DAPT in the form of aspirin plus ticagrelor or prasugrel (or clopidogrel if ticagrelor or prasugrel are not available or are contra-
I A
indicated) is recommended for 12 months after PCI, unless there are contraindications such as excessive risk of bleeding.
A PPI in combination with DAPT is recommended in patients at high risk of gastrointestinal bleeding. I B
Recommendations for routine therapies in the acute, subacute, and long-term phases
Oral treatment with beta-blockers is indicated in patients with heart failure and/or LVEF <_40% unless contraindicated. I A
Intravenous beta-blockers must be avoided in patients with hypotension, acute heart failure, or AV block or severe bradycardia. III B
It is recommended to start high-intensity statin therapy as early as possible, unless contraindicated, and maintain it long-term. I A
An LDL-C goal of < 1.8 mmol/L (70 mg/dL) or a reduction of at least 50% if the baseline LDL-C is between 1.8–3.5 mmol/L
I B
(70–135 mg/dL) is recommended.
ACE inhibitors are recommended, starting within the first 24 h of STEMI in patients with evidence of heart failure, LV systolic
I A
dysfunction, diabetes, or an anterior infarct.
Continued
168 ESC Guidelines
An ARB, preferably valsartan, is an alternative to ACE inhibitors in patients with heart failure and/or LV systolic dysfunction,
I B
particularly those who are intolerant of ACE inhibitors.
MRAs are recommended in patients with an ejection fraction <_40% and heart failure or diabetes, who are already receiving an
I B
ACE inhibitor and a beta-blocker, provided there is no renal failure or hyperkalaemia.
Recommendations for the management of LV dysfunction and acute heart failure in STEMI
ACE inhibitor (or if not tolerated, ARB) therapy is indicated as soon as haemodynamically stable for all patients with evidence
I A
of LVEF <_40% and/or heart failure to reduce the risk of hospitalization and death.
Beta-blocker therapy is recommended in patients with LVEF <_40% and/or heart failure after stabilization, to reduce the risk of
I A
death, recurrent MI, and hospitalization for heart failure.
Immediate PCI is indicated for patients with cardiogenic shock if coronary anatomy is suitable. If coronary anatomy is not suit-
I B
able for PCI, or PCI has failed, emergency CABG is recommended.
Digoxin is ineffective in converting recent onset AF to sinus rhythm and is not indicated for rhythm control. III A
Calcium channel blockers and beta-blockers including sotalol are ineffective in converting recent onset AF to sinus rhythm. III B
Recommendations for management of ventricular arrhythmias and conduction disturbances in the acute phase
Intravenous beta-blocker treatment is indicated for patients with polymorphic VT and/or VF unless contraindicated. I B
Prophylactic treatment with antiarrhythmic drugs is not indicated and may be harmful. III B
Recommendations for long-term management of ventricular arrhythmias and risk evaluation for sudden death
ICD therapy is recommended to reduce sudden cardiac death in patients with symptomatic heart failure (New York Heart
Association class II–III) and LVEF <_35%, despite optimal medical therapy for >3 months and at least 6 weeks after MI, who are I A
expected to survive for at least 1 year with good functional status.
Recommendations with a class I or III and a level of evidence A or B. See ‘Abbreviations and acronyms’ list for explanation of abbreviations.
a
Class of recommendation.
b
Level of evidence.
..
14. Web addenda ..
..
Netherlands), Donna Fitzsimons (UK), Oliver Gaemperli (Switzerland),
Gerhard Hindricks (Germany), Bernard Iung (France), Peter Jüni
All Web figures and Web tables are available in the online Web
..
.. (Canada), Hugo A. Katus (Germany), Juhani Knuuti (Finland), Patrizio
Addenda at: European Heart Journal online and also via the ESC .. Lancellotti (Belgium), Christophe Leclercq (France), Theresa McDonagh
Website at: https://www.escardio.org/Guidelines/Clinical-Practice-
..
.. (UK), Massimo Francesco Piepoli (Italy), Piotr Ponikowski (Poland),
Guidelines/Acute-Myocardial-Infarction-in-patients-presenting-with- .. Dimitrios J. Richter (Greece), Marco Roffi (Switzerland), Evgeny
..
ST-segment-elevation-Ma .. Shlyakhto (Russia), Iain A. Simpson (UK), Jose Luis Zamorano (Spain).
.. ESC National Cardiac Societies actively involved in the
..
15. Appendix .. review process of the 2017 ESC Guidelines for the manage-
.. ment of acute myocardial infarction in patients presenting
..
ESC Committee for Practice Guidelines (CPG): Stephan .. with ST-segment elevation:
Windecker (Chairperson) (Switzerland), Victor Aboyans (France), .. Algeria: Algerian Society of Cardiology, Mohamed Chettibi;
..
Stefan Agewall (Norway), Emanuele Barbato (Italy), Héctor Bueno .. Armenia: Armenian Cardiologists Association, Hamlet G.
(Spain), Antonio Coca (Spain), Jean-Philippe Collet (France), Ioan Mircea
.. Hayrapetyan; Austria: Austrian Society of Cardiology, Bernhard
..
Coman (Romania), Veronica Dean (France), Victoria Delgado (The . Metzler; Azerbaijan: Azerbaijan Society of Cardiology, Firdovsi
ESC Guidelines 169
Cardiology Society of Serbia, Milan Nedeljkovic; Slovakia: Slovak .. 7. Valgimigli M, OTHER AUTHORS TO BE INSERTED HERE. 2017 ESC Focused
.. Update on Dual Antiplatelet Therapy in Coronary Artery Disease in collabora-
Society of Cardiology, Martin Studencan; Slovenia: Slovenian .. tion with the European Association for Cardio-Thoracic Surgery (EACTS). The
Society of Cardiology, Matjaz Bunc; Spain: Spanish Society of
.. Task Force for the Management of Dual Antiplatelet Therapy in Coronary
.. Artery Disease of the European Society of Cardiology (ESC). Eur Heart J 2017.
Cardiology, Ana Maria Garcıa de Castro; Sweden: Swedish Society .. 8. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, Writing
of Cardiology, Petur Petursson; Switzerland: Swiss Society of
..
.. Group on the Joint ESC/ACCF/AHA/WHF Task Force for the Universal
Cardiology, Raban Jeger; Tunisia: Tunisian Society of Cardiology and .. Definition of Myocardial Infarction, Thygesen K, Alpert JS, White HD, Jaffe AS,
* Corresponding authors. Franz-Josef Neumann, Department of Cardiology and Angiology II, University Heart Centre Freiburg-Bad Krozingen, Suedring 15, 79189 Bad Krozingen,
Germany. Tel: þ49 7633 402 2000, Fax: þ49 7633 402 2009, Email: franz-josef.neumann@universitaets-herzzentrum.de. Miguel Sousa-Uva, Cardiac Surgery Department, Hospital
Santa Cruz, Avenue Prof Reynaldo dos Santos, 2790-134 Carnaxide, Portugal. Tel: þ 351 210 433 163, Fax: þ 351 21 424 13 88, Cardiovascular Research Centre, Department of
Surgery and Physiology, Faculty of Medicine-University of Porto, Alameda Prof Hernani Monteiro, 4200-319 Porto, Portugal Email: migueluva@gmail.com.
ESC Committee for Practice Guidelines (CPG), EACTS Clinical Guidelines Committee, and National Cardiac Societies document reviewers: listed in the Appendix.
1
Representing the European Association for Cardio-Thoracic Surgery (EACTS).
ESC entities having participated in the development of this document:
Associations: Acute Cardiovascular Care Association (ACCA), European Association of Preventive Cardiology (EAPC), European Association of Cardiovascular Imaging
(EACVI), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Heart Rhythm Association (EHRA), Heart Failure Association (HFA).
Councils: Council on Cardiovascular Nursing and Allied Professions, Council for Cardiology Practice, Council on Cardiovascular Primary Care, Council on Stroke, Council on
Valvular Heart Disease
Working Groups: Aorta and Peripheral Vascular Diseases, Cardiovascular Pharmacotherapy, Coronary Pathophysiology and Microcirculation, Thrombosis.
Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence avail-
able at the time of their dating. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official rec-
ommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of health care or therapeutic strategies. Health professionals are
encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment as well as in the determination and the implementation of preventive, diagnostic
or therapeutic medical strategies. However, the ESC Guidelines do not override in any way whatsoever the individual responsibility of health professionals to make appropriate
and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and the patient’s caregiver where appropriate and/or necessary.
Nor do the ESC Guidelines exempt health professionals from taking careful and full consideration of the relevant official updated recommendations or guidelines issued by the
competent public health authorities in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obliga-
tions. It is also the health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.
This article has been co-published with permission in the European Heart Journal and European Journal of Cardio-Thoracic Surgery. All rights reserved. V C 2018 European Society of
Cardiology. The articles are identical except for minor stylistic and spelling differences in keeping with each journal’s style. Either citation can be used when citing this article.
88 ESC/EACTS Guidelines
(Germany), Victoria Delgado (The Netherlands), Dariusz Dudek (Poland), Nick Freemantle1 (UK),
Christian Funck-Brentano (France), Oliver Gaemperli (Switzerland), Stephan Gielen (Germany), Martine
Gilard (France), Bulent Gorenek (Turkey), Joerg Haasenritter (Germany), Michael Haude (Germany),
Borja Ibanez (Spain), Bernard Iung (France), Anders Jeppsson1 (Sweden), Demosthenes Katritsis (Greece),
Juhani Knuuti (Finland), Philippe Kolh1 (Belgium), Adelino Leite-Moreira1 (Portugal), Lars H. Lund
(Sweden), Francesco Maisano (Switzerland), Julinda Mehilli (Germany), Bernhard Metzler (Austria), Gilles
Montalescot (France), Domenico Pagano1 (UK), Anna Sonia Petronio (Italy), Massimo Francesco Piepoli
(Italy), Bogdan A. Popescu (Romania), Rafael Sa daba1 (Spain), Evgeny Shlyakhto (Russia), Sigmund Silber
(Germany), Iain A. Simpson (UK), David Sparv (Sweden), Giuseppe Tavilla1 (The Netherlands), Holger
Thiele (Germany), Petr Tousek (Czech Republic), Eric Van Belle (France), Pascal Vranckx (Belgium), Adam
Witkowski (Poland), Jose Luis Zamorano (Spain), Marco Roffi (ESC CPG Supervisor) (Switzerland)
...................................................................................................................................................................................................
Keywords Acute coronary syndromes • Antithrombotic therapy • Bare-metal stents • Coronary artery bypass
grafting • Coronary artery disease • Drug-eluting stents • Guidelines • Heart Team • Myocardial
infarction • Myocardial ischaemia • Myocardial revascularization • Medical therapy • Percutaneous coronary
intervention • Recommendation • Revascularization • Risk stratification • Stents • Stable angina • Stable
coronary artery disease • ST-segment elevation myocardial infarction • SYNTAX score
..
Table of contents ..
..
4.1 Patient information and informed consent . . . . . . . . . . . . . . . . . . . . . 98
4.2 Multidisciplinary decision-making (Heart Team) . . . . . . . . . . . . . . . . 99
..
Abbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 .. 4.3 Timing of revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
1 Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 .. 5 Revascularization for stable coronary artery disease . . . . . . . . . . . . . . .101
..
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 .. 5.1 Rationale for revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .101
2.1 What is new in the 2018 Guidelines? . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 .. 5.2 Evidence basis for revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . .101
..
3 Diagnostic tools to guide myocardial revascularization . . . . . . . . . . . . . . 96 .. 5.2.1 Revascularization with the use of percutaneous coronary
3.1 Non-invasive diagnostic tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 .. intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .102
..
3.1.1 Assessment of myocardial ischaemia . . . . . . . . . . . . . . . . . . . . . . . 96 .. 5.2.2 Revascularization with the use of coronary artery bypass
3.1.2 Assessment of myocardial viability in patients with heart .. grafting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .102
..
failure and coronary artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 .. 5.3 Percutaneous coronary intervention vs. coronary artery
3.2 Invasive diagnostic tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 .. bypass grafting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .102
..
3.2.1 Pressure-derived fractional flow reserve . . . . . . . . . . . . . . . . . . . 96 .. 5.3.1 Criteria for decision making . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .102
3.2.1.1 Use of fractional flow reserve in patients with .. 5.3.1.1 Predicted surgical mortality . . . . . . . . . . . . . . . . . . . . . . . . . .104
..
intermediate-grade coronary stenosis including left main .. 5.3.1.2 Anatomical complexity of coronary artery disease . . . . . .104
stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
.. 5.3.1.3 Completeness of revascularization . . . . . . . . . . . . . . . . . . . .106
..
3.2.1.2 Use of fractional flow reserve to identify lesions .. 5.3.2 Isolated proximal left anterior descending coronary
requiring revascularization in patients with multivessel
.. artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .109
..
coronary artery disease undergoing percutaneous coronary .. 5.3.3 Left main coronary artery disease . . . . . . . . . . . . . . . . . . . . . . . .109
intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
.. 5.3.4 Multivessel coronary artery disease . . . . . . . . . . . . . . . . . . . . . . .109
..
3.2.1.3 Fractional flow reserve-guided management vs. medical .. 5.4 Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .110
therapy in patients with coronary artery disease . . . . . . . . . . . . . . . . 97
.. 6 Revascularization in non-ST-elevation acute coronary syndrome . . .110
..
3.2.2 Other pressure-derived indices . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 .. 6.1 Early invasive vs. conservative strategy . . . . . . . . . . . . . . . . . . . . . . . .110
..
3.2.3 Use of fractional flow reserve and pressure-derived .. 6.2 Timing of angiography and intervention . . . . . . . . . . . . . . . . . . . . . . .110
indices in patients with severe aortic stenosis . . . . . . . . . . . . . . . . . . . 98 .. 6.3 Type of revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .110
..
3.2.4 Use of intravascular imaging for diagnostic assessment .. 6.3.1 Percutaneous coronary intervention . . . . . . . . . . . . . . . . . . . . .110
of stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 .. 6.3.1.1 Technical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .110
..
3.3 Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 .. 6.3.1.2 Revascularization strategies and outcomes . . . . . . . . . . . .111
4 Process for decision-making and patient information . . . . . . . . . . . . . . . . 98 .. 6.3.2 Coronary artery bypass grafting . . . . . . . . . . . . . . . . . . . . . . . . . .111
.
ESC/EACTS Guidelines 89
..
IVUS Intravascular ultrasound imaging .. PIONEER Prevention of bleeding in patients with AF
LAA Left atrial appendage .. undergoing PCI
..
LAD Left anterior descending .. PLATFORM Prospective LongitudinAl Trial of FFRct:
LEAD Lower extremity artery disease .. Outcome and Resource Impacts,
..
LGE-CMR Late gadolinium enhancement cardiac .. PLATO Study of Platelet Inhibition and Patient
magnetic resonance .. Outcomes
..
LIMA Left internal mammary artery .. pLVAD Percutaneous left ventricular assist device
LM/LMS Left main/left main stem .. p.o. Per os (orally)
..
LMWH Low-molecular-weight heparin .. POSEIDON Prevention of Contrast Renal Injury with
LPR Low platelet reactivity .. Different Hydration Strategies
..
LV Left ventricle/left ventricular .. PPI Proton pump inhibitor
LVAD Left ventricular assist device,
.. PRAGUE-18 Comparison of Prasugrel and Ticagrelor in
..
..
intervention in patients with acute coronary .. for an individual patient with a given condition, taking into account
syndromes
.. the impact on outcome as well as the risk–benefit ratio of particular
..
SPECT Single-photon emission computed tomography .. diagnostic or therapeutic means. Clinical practice guidelines are no
SR Sinus rhythm
.. substitutes for textbooks, but complement them, and cover the
..
STEEPLE Safety and Efficacy of Intravenous .. European Society of Cardiology (ESC) Core Curriculum topics. As
Enoxaparin in Elective Percutaneous
.. such they should help physicians to make decisions in their daily prac-
..
Coronary Intervention Randomised .. tice. However, final decisions should be individualized by responsible
.. physicians and the patient.
Evaluation ..
STEMI ST-segment elevation myocardial infarction .. A great number of clinical practice guidelines have been issued in
.. recent years both by the ESC as well as by other societies and organi-
STICH Surgical Treatment for Ischemic Heart Failure ..
STICHES STICH Extension Study .. zations. Because of the impact on clinical practice, quality criteria for
.. the development of guidelines have been established in order to
STS Society of Thoracic Surgeons ..
©ESC 2018
not useful/effective, and in some cases
may be harmful.
Calculation of the Syntax Score, if left Completeness of revascularization Routine non-invasive imaging
main or multivessel revascularization prioritized, when considering CABG surveillance in high-risk patients
is considered vs PCI 6 months after revascularization
Radial access as standard approach NOAC preferred over VKA in patients Double-kissing crush technique
for coronary angiography and PCI with non-valvular AF requiring preferred over provisional T-stenting
anticoagulation and antiplatelet in true left main bifurcations.
DES for any PCI
treatment Cangrelor in P2Y12 -inhibitor naïve
Systematic re-evaluation of patients
after myocardial revascularization patients undergoing PCI
No-touch vein technique, if open vein
The figure does not show changes Current generation BRS for clinical use
compared with the 2014 version of outside clinical studies
the Myocardial Revascularization
Guidelines that were due to updates for
consistency with other ESC Guidelines
©ESC 2018
published since 2014.
ACS = acute coronary syndromes; AF = atrial fibrillation; BRS = bioresorbable scaffolds; CABG = coronary artery bypass grafting; CAD = coronary artery disease;
CKD = chronic kidney disease; DES = drug-eluting stents; FFR = fractional flow reserve; GP = glycoprotein; IRA = infarct-related artery; LVEF = left ventricular
ejection fraction; NOAC = non-vitamin K oral anticoagulants; NSTEMI = non-ST-elevation; PCI = percutaneous coronary intervention; SCAD = stable coronary
artery disease; VKA = vitamin K antagonists.
UPGRADES DOWNGRADES
For PCI of bifurcation lesions, stent implantation in Distal protection devices for PCI of SVG lesions
the main vessel only, followed by provisional balloon
Bivalirudin for PCI in NSTE-ACS
angioplasty with or without stenting of the side branch
Bivalirudin for PCI in STEMI
Immediate coronary angiography and revascularization,
if appropriate, in survivors of out-of-hospital cardiac arrest PCI for MVD with diabetes and SYNTAX score <23
and an ECG consistent with STEMI
Platelet function testing to guide antiplatelet therapy
Assess all patients for the risk of interruption in patients undergoing cardiac surgery
contrast-induced nephropathy
EuroSCORE II to assess in-hospital mortality after CABG
OCT for stent optimization
Class I Class IIa
Class IIb Class III
The figure does not show changes compared with the 2014
version of the Myocardial Revascularization Guidelines
©ESC 2018
CABG = coronary artery bypass grafting; MVD = multivessel coronary artery disease; NSTE-ACS = non-ST-elevation acute coronary syndromes; OCT = optical
coherence tomography; PCI = percutaneous coronary interventions; STEMI = ST-elevation myocardial infarction,
SVG = saphenous vein grafts;
..
3 Diagnostic tools to guide .. contractile reserve.1,5 Assessment of ischaemia provides incremental
.. benefit over viability in mild to moderate CAD, but with extensive
myocardial revascularization ..
.. CAD viability assessment may be sufficient.6 Patients with advanced
.. HF and viable myocardium should first undergo revascularization
The use of diagnostic imaging and functional testing modalities to ..
detect patients with coronary artery disease (CAD) is discussed in .. with coronary artery bypass grafting (CABG) or percutaneous coro-
.. nary intervention (PCI) before being considered for mechanical circu-
detail in the clinical practice Guidelines for patients with SCAD.1 ..
Further diagnostic assessment of patients with obstructive CAD is .. latory support (MCS) or heart transplantation.7,8
.. The PARR-2 (PET and Recovery following Revascularization) trial
critical in order to identify patients and select specific lesions that are ..
likely to benefit from myocardial revascularization, in addition to opti-
.. included patients with severe left ventricular (LV) dysfunction being
.. considered for revascularization or HF/transplantation workups, and
mal medical therapy. ..
.. randomized them to management assisted by fluorodeoxyglucose
.. PET (FDG-PET) or standard care.6 The primary outcome of cardiac
..
..
Multiple studies have shown that PCI can be safely deferred if FFR .. been shown in an observational study.28 Of the 627 patients with
is >0.75.12–15 The DEFER trial enrolled 325 patients scheduled for .. intermediate stenosis that were evaluated, 429 had bypass without
..
PCI of an intermediate stenosis.15 If FFR was >_0.75, patients were .. FFR and 198 had bypass with FFR; in the latter group, the proportion
randomly assigned to deferral (defer group; n = 91) or performance .. of patients with three-vessel disease was reclassified from 94 to 86%.
..
(perform group; n = 90) of PCI. The composite rate of cardiac death .. Outcomes were similar in both groups at 3 years [hazard ratio (HR)
and acute MI (AMI) in the defer and perform groups was 3.3 vs. 7.9% .. for death/MI/target vessel revascularization (TVR) = 1.03, 95% CI
..
(P = 0.21). .. 0.67–1.69], though the group with FFR guidance was associated with
However, most contemporary studies use an FFR cut-off of 0.80. .. a lower number of graft anastomoses and a lower rate of on-pump
..
A recent large-scale observational study supports the use of FFR .. surgery compared with angiography-guided CABG surgery.
>0.80 rather than 0.75 as a cut-off.16 Indeed, the two largest studies ..
..
in this field, DEFINE-FLAIR (Define Functional Lesion Assessment of .. 3.2.1.2 Use of fractional flow reserve to identify lesions requiring revascu-
Intermediate Stenosis to Guide Revascularization DES drug-eluting .. larization in patients with multivessel coronary artery disease undergoing
..
3.2.3 Use of fractional flow reserve and pressure-derived Recommendations Classa Levelb
indices in patients with severe aortic stenosis
When evidence of ischaemia is not avail-
In patients with intermediate coronary stenosis and concomitant
able, FFR or iwFR are recommended to
severe aortic stenosis, although some observational studies exist (see I A
assess the haemodynamic relevance of
section 11), there are no adequate RCT data to support the use of
intermediate-grade stenosis.15,17,18,39
FFR or iwFR for the guidance of revascularization decisions.
FFR-guided PCI should be considered in
3.2.4 Use of intravascular imaging for the diagnostic patients with multivessel disease under- IIa B
assessment of stenosis going PCI.29,31
IVUS is an ultrasound-based modality of intravascular imaging with an IVUS should be considered to assess the
axial resolution of about 150 mm. IVUS imaging allows real-time severity of unprotected left main IIa B
tomographic assessment of vessel size, lumen area, and plaque com- lesions.35–37
position and volume. In comparison with optical coherence tomogra-
phy (OCT), it has more limited spatial resolution, but better
FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio; IVUS =
penetration depth and potential advantages in terms of vessel sizing. intravascular ultrasound; PCI = percutaneous coronary intervention.
a
OCT is a light-based modality of intravascular imaging with higher Class of recommendation.
b
axial resolution compared with IVUS (15 vs. 150 mm). The disadvan- Level of evidence.
..
decision-making process should be encouraged. Patient information .. patients with CAD44 and (ii) inappropriate use of revascularization
needs to be unbiased, evidence-based, up-to-date, reliable, accessible, .. strategies with a lack of case discussions.45 The marked variability in
..
relevant, and consistent with legal requirements. Use of terminology .. PCI-to-CABG ratios between European countries (ranging from
that the patient understands is essential. Short-term procedure- .. 2.4–7.6 in 2013, for example) has raised concerns regarding the
..
related and long-term risks and benefits—such as survival, relief of .. appropriate selection of revascularization strategies.46 Rates for the
angina, quality of life, the potential need for late reintervention, the .. inappropriate use of PCI (10–15%)43,47,48 and CABG (1–2%) are
..
need for prevention measures, and uncertainties associated with dif- .. reported. Multidisciplinary decision-making in a Heart Team can mini-
ferent treatment strategies—should be thoroughly discussed.
.. mize specialty bias and prevent self-referral from interfering with
..
Although current recommendations are mostly based on the ability .. optimal patient care.49
of treatments to reduce adverse events including mortality, there is
.. Several reports from different centres have established that the
..
growing interest in patient-reported outcome measures.40,41 Patients .. treatment recommendations made in multidisciplinary Heart Team
are not only interested to know how recommended treatment
.. discussions are reproducible and implemented in the vast majority of
..
Table 3 Multidisciplinary decision pathways, patient informed consent, and timing of revascularization
ACS
Shock STEMI NSTE-ACS SCAD without ad hoc PCI SCAD with ad hoc PCI
indication according to Heart indication according to
Team protocol Heart Team protocol
Multidisciplinary Not mandatory during the acute Not mandatory during the acute Not mandatory during the acute Required Not required
decision-making phase; mechanical circulatory sup- phase phase; after stabilization, recom-
port according to Heart Team mended as in SCAD
protocol
Informed consent Witnessed verbal informed con- Witnessed verbal informed con- Written informed consenta; in Written informed consenta Written informed consenta
sent or family consent if possible sent may be sufficient unless writ- emergency cases witnessed verbal
without delay ten consent is legally required informed consent may be sufficient
Time to Emergency: no delay Emergency: no delay Urgency: within 2 h to within 72 h Within 2 weeks for high-risk Ad hoc
revascularization depending on the risk criteria patientsb and within 6 weeks for all
other patients
Procedure Proceed with intervention based Proceed with intervention based Proceed with intervention based Allow for enough time from diag- Proceed with intervention
on best evidence/availability. Ad hoc on best evidence/availability. Non- on best evidence/availability. Non- nostic catheterization to decide on according to institutional
treatment of culprit lesion, staged culprit lesions treated according to culprit lesions treated according to the appropriate intervention. protocol defined by Heart
treatment of non-culprit lesions institutional protocol or Heart institutional protocol or Heart Team.
according to institutional protocol Team decision. Team decision.
or Heart Team decision.
ACS = acute coronary syndromes; CCS = Canadian Cardiovascular Society; ESC = European Society of Cardiology; EACTS = European Association for Cardio-Thoracic Surgery; NSTE-ACS = non-ST-segment elevation acute coronary
syndrome; PCI = percutaneous coronary intervention; SCAD = stable coronary artery disease; STEMI = ST-segment elevation myocardial infarction.
a
This may not apply to countries that are not legally required to ask for written informed consent. The ESC and EACTS advocate the documentation of patient consent for all revascularization procedures.
b
Severe symptoms (CCS class 3), anatomy (left main disease or equivalent, three-vessel disease or proximal left anterior descending artery), or depressed ventricular function.
ESC/EACTS Guidelines
It is recommended that patients undergoing coronary angiography are informed about benefits and risks, as well as potential
I C
therapeutic consequences, ahead of the procedure.
It is recommended that patients are adequately informed about short- and long-term benefits and risks of the revascularization
I C
procedure with information about local experience, and allowed enough time for informed decision-making.
It is recommended that institutional protocols are developed by the Heart Team to implement the appropriate revasculariza-
I C
tion strategy in accordance with current Guidelines.
Large area of ischaemia detected by functional testing (>10% LV) or abnormal invasive FFR.d 24,59,84–90 I B
CAD = coronary artery disease; FFR = fractional flow reserve; iwFR = instantaneous wave-free ratio; LAD = left anterior descending coronary artery; LV = left ventricular;
LVEF = left ventricular ejection fraction.
a
Class of recommendation.
b
Level of evidence.
c
With documented ischaemia or a haemodynamically relevant lesion defined by FFR <_0.80 or iwFR <_0.89 (see section 3.2.1.1), or >90% stenosis in a major coronary vessel.
d
Based on FFR <0.75 indicating a prognostically relevant lesion (see section 3.2.1.1).
e
In consideration of patient compliance and wishes in relation to the intensity of anti-anginal therapy.
Table 4 Randomized clinical trials comparing percutaneous coronary intervention with drug-eluting stents vs. surgical revascularization
DES
PES 2009 SYNTAX102 1800 65 22 25 MV 61 LM 39 - Death, MI, stroke, 1 17.8 vs. 12.4% 5 13.9 vs. 11.4% 9.7 vs. 3.8%* 25.9 vs. 2.4 vs. 3.7%
or repeat revasc 13.7%*
SES 2011 Boudriot103 201 68 25 36 LM 100 65 Death, MI, or 1 13.9 vs. 19% 1 2 vs. 5% 3 vs. 3% 14 vs. 5.9% -
repeat revasc
SES 2011 PRECOMBAT104 600 62 24 32 LM 100 61 Death, MI, stroke, 1 8.7 vs. 6.7%b 2 2.4 vs. 3.4% 1.7 vs. 1.0% 9.0 vs. 4.2%* 0.4 vs. 0.7%
or TVR
EES 2015 BEST105 880 64 29 41 MV 100 60 Death, MI, or TVR 2 11.0 vs. 7.9% 5 6.6 vs. 5.0% 4.8 vs 2.7% 13.4 vs. 6.6% 2.9 vs. 3.3%
BES 2016 NOBLE106 1201 66 22 15 LM 100 60 Death, MI, or TVR 5 15.4 vs. 7.2% 5 11.6 vs. 9.5% 6.9 vs. 1.9%*c 16.2 vs. 10.4%* 4.9 vs. 1.7%
EES 2016 EXCEL107 1905 66 24 30 LM 100 57 Death, MI, or stroke 3 15.4 vs. 14.7%b 3 8.2 vs. 5.9% 8.0 vs. 8.3% 13.4 vs. 6.6%* 2.3 vs. 2.9%
Step 1 Dominance The weight of individual coronary segments varies according to coronary artery dominance (right or left). Co-
dominance does not exist as an option in the SYNTAX score.
Step 2 Coronary segment The diseased coronary segment directly affects the score as each coronary segment is assigned a weight depend-
ing on its location, ranging from 0.5 (i.e. the posterolateral branch) to 6 (i.e. left main in case of left dominance).
Step 4 Trifurcation lesion The presence of a trifurcation lesion adds additional points based on the number of diseased segments:
1 segment þ3
2 segments þ4
3 segments þ5
4 segments þ6
Continued
106 ESC/EACTS Guidelines
Step 5 Bifurcation lesion The presence of a bifurcation lesion adds additional points based on the type of bifurcation according to the
Medina classification:126
• Medina 1,0,0–0,1,0–1,1,0 þ1
• Medina 1,1,1–0,0,1–1,0,1–0,1,1 þ2
Moreover, the presence of a bifurcation angle <70 adds one additional point
Step 6 Aorto-ostial lesion The presence of aorto-ostial lesion segments adds one additional point
Step 7 Severe tortuosity The presence of severe tortuosity proximal of the diseased segment adds two additional points
Step 8 Lesion length Lesion length >20 mm adds one additional point
Step 9 Calcification The presence of heavy calcification adds two additional points
Step 11 Diffuse disease/ The presence of diffusely diseased and narrowed segments distal to the lesion (i.e. when at least 75% of the
small vessels length of the segment distal to the lesion has a vessel diameter <2 mm) adds one point per segment number
SYNTAX = Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery.
It is recommended that the STS score is calculated to assess in-hospital or 30 day mortality, and in-hospital morbidity
I B
after CABG.112,114,138
Calculation of the EuroSCORE II score may be considered to assess in-hospital mortality after CABG.112 IIb B
In patients with LM or multivessel disease, it is recommended that the SYNTAX score is calculated to assess the ana-
I B
tomical complexity of CAD and the long-term risk of mortality and morbidity after PCI.117–124
EuroSCORE = European System for Cardiac Operative Risk Evaluation; CABG = coronary artery bypass grafting; CAD = coronary artery disease; LM = left main; PCI = percu-
taneous coronary intervention; STS = Society of Thoracic Surgeons; SYNTAX = Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery.
a
Class of recommendation.
b
Level of evidence.
c
Level of evidence refers to prediction of outcomes.
Recommendation for the type of revascularization in patients with stable coronary artery disease with suitable coro-
nary anatomy for both procedures and low predicted surgical mortalityd
One-vessel CAD
Two-vessel CAD
Left main disease with intermediate SYNTAX score (23 - 32).69,121,122,124,145–148 I A IIa A
Left main disease with high SYNTAX score (>_33).c 69,121,122,124,146–148 I A III B
Three-vessel disease with intermediate or high SYNTAX score (>22).c 102,105,121,123,124,135,149 I A III A
Three-vessel disease with intermediate or high SYNTAX score (>22).c 102,105,121,123,124,135,150–157 I A III A
PCI CABG
©ESC 2018
Ascending aortic pathology with indication for surgery
Concomitant cardiac surgery
CABG = coronary artery bypass grafting; Cx = circumflex; DAPT = dual antiplatelet therapy; EF = ejection fraction; LAD = left anterior descending
coronary artery; LIMA = left internal mammary artery; LV= left ventricular; MVD = multivessel coronary artery disease; PCI = percutaneous
coronary intervention; PDA = posterior descending artery; RA = radial artery; RIMA = right internal mammary artery; SYNTAX = Synergy between
Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery.
a
Consider no-touch off-pump CABG in case of porcelain aorta.
Figure 3 Aspects to be considered by the Heart Team for decision-making between percutaneous coronary intervention and coronary artery
bypass grafting among patients with stable multivessel and/or left main coronary artery disease.
ESC/EACTS Guidelines 109
..
5.3.2 Isolated proximal left anterior descending coronary .. anatomical complexity, the number of patients studied in RCTs is
artery disease .. low due to exclusion criteria; the risk estimates and CIs are impre-
..
Comparing CABG and PCI among patients with isolated proximal .. cise, but suggest a trend towards better survival with CABG.
LAD disease, the available evidence suggests similar outcomes in .. Therefore, PCI in this setting cannot be endorsed as reflected by a
..
terms of death, MI, and stroke, but a higher risk of repeat revasculari- .. class III recommendation. For PCI in LM with intermediate anatomical
zation with PCI.68,70,73,101,139–144 .. complexity, the previous class IIa recommendation was maintained in
..
.. view of the incomplete 5 year follow-up of the two largest RCTs in
5.3.3 Left main coronary artery disease .. this setting.
..
The available evidence from RCTs and meta-analyses comparing ..
CABG with PCI using DES among patients with LM disease suggests .. 5.3.4 Multivessel coronary artery disease
..
equivalent results for the safety composite of death, MI, and stroke .. The observation of a survival advantage of CABG over PCI has been
up to 5 years of follow-up.148 A significant interaction with time is
.. consistent among patients with severe three-vessel CAD (intermedi-
..
..
vs. 11.6%, P = 0.02). Another individual patient data pooled analysis .. 6.1 Early invasive vs. conservative
of SYNTAX and BEST, comparing CABG with PCI using DES among ..
.. strategy
1166 patients with multivessel disease involving the proximal LAD .. An invasive strategy has become the standard of care for high-risk
(88% three-vessel CAD, mean SYNTAX score 28), reported a higher ..
.. patients.158 This approach allows prompt diagnosis of the underlying
risk of the composite of death, MI, and stroke (16.3 vs. 11.5%; HR .. CAD, identification of the culprit lesion, guidance for antithrombotic
1.43, 95% CI 1.05–1.96, P = 0.02), cardiac death, MI, and repeat revas- ..
.. management, and the assessment of the suitability of coronary anat-
cularization in the PCI group at 5 years of follow-up.147 Of note, out- ..
.. omy for PCI or CABG. Numerous factors interplay in the decision-
comes were not significantly different for CABG and PCI for any .. making process, including clinical presentation, comorbidities, risk
endpoint except for MI among the subgroup of patients with low .. stratification (Figure 4), and high-risk features specific for a revasculari-
SYNTAX score (0 - 22). ..
.. zation modality such as frailty, cognitive status, estimated life expect-
The available evidence suggests that in multivessel CAD without .. ancy, and the functional and anatomical severity of CAD.
diabetes and low anatomical complexity, PCI and CABG achieve sim- ..
..
DAPT is recommended for 12 months irrespective of stent type, .. incidence of the primary outcome—the composite of death, MI, or
..
while in patients at high ischaemic risk not experiencing bleeding .. stroke—was significantly lower with CABG than with PCI (13.4 vs.
events, DAPT may be extended (see section 17). There is no evi-
.. 18%, P = 0.036). The findings of this meta-analysis were consistent
..
dence for any additional benefit of thrombectomy in patients under- .. with the main findings of the studies included, thus supporting the
going PCI in the setting of NSTE-ACS.180 While FFR is considered
.. concept that the principles of SCAD should apply to stabilized
..
the invasive gold standard for the functional assessment of lesion .. patients with NSTE-ACS as well.
severity in SCAD, it has been shown to be feasible, reliable, safe, and
.. For complex cases, Heart Team discussion and use of the
..
effective in NSTE-ACS patients with multivessel disease, although its .. SYNTAX score are recommended,195 given its ability to predict
prognostic value is unclear.22,137,181
.. death, MI, and revascularization in patients with NSTE-ACS and mul-
..
.. tivessel disease undergoing PCI. In patients with multivessel disease
..
6.3.1.2 Revascularization strategies and outcomes .. and diabetes in particular, recent evidence suggests a greater benefit
Complete revascularization of significant lesions should be attempted .. of CABG vs. PCI.196
..
..
6.4 Gaps in the evidence .. shock or out-of-hospital cardiac arrest.199 In shock without out-of-
.. hospital cardiac arrest, every 10 min treatment delay between
In the setting of NSTE-ACS, there are no dedicated prospective stud- ..
ies on the revascularization strategy with multivessel disease. Thus, .. 60–180 min from the first medical contact resulted in 3.3 additional
.. deaths per 100 PCI-treated patients, and in 1.3 additional deaths after
current recommendations on the choice of lesions to be treated and ..
treatment modality (PCI or CABG) are based on an analogy to find- .. out-of-hospital cardiac arrest without cardiogenic shock. In stable
.. STEMI patients, time delays were substantially less relevant (0.3 addi-
ings obtained in SCAD or STEMI. Likewise, the prognostic role of ..
FFR and iwFR in guiding myocardial revascularization needs additional .. tional deaths per 100 PCI-treated patients for every 10 min delay
.. between 60–180 min from the first medical contact). Thus, high-risk
clarification. ..
.. STEMI patients with cardiogenic shock or out-of-hospital cardiac
.. arrest are those who benefit most from expediting all steps of the
..
.. care pathway.
7 Revascularization in ST-segment ..
..
elevation myocardial infarction .. 7.2 Selection of reperfusion strategy
..
Myocardial revascularization in patients with STEMI is addressed by
.. Primary PCI, defined as percutaneous catheter intervention in the
.. setting of STEMI without previous fibrinolysis, is the preferred reper-
the 2017 ESC Guidelines on STEMI. After reviewing the subsequent ..
literature, the current Task Force endorses most recommendations
.. fusion strategy. It has replaced fibrinolysis in patients with STEMI, pro-
.. vided it can be performed in a timely manner in high-volume PCI
of these Guidelines.198 ..
.. centres with experienced operators and 24 h/7 days a week catheter-
.. ization laboratory activation.198,200,201 In settings where primary
..
7.1 Time delays .. PCI cannot be performed in a timely fashion, fibrinolysis should be
Delays in the timely implementation of reperfusion therapy are key .. administered as soon as possible. If first medical contact (FMC) is
..
issues in the management of STEMI. Detailed recommendations on .. out-of-hospital, lysis should be implemented pre-hospital (e.g. in the
timelines, logistics, and pre-hospital management have been provided .. ambulance) (Figure 5).202–206 It should be followed by transfer to
..
in the recent ESC STEMI Guidelines (Figure 5).198 .. PCI-capable centres for routine coronary angiography in all patients,
A recent analysis of 12 675 STEMI patients in the FITT-STEMI .. and should be performed without delay for rescue PCI in the case of
..
(Feedback Intervention and Treatment Times in ST-Elevation .. unsuccessful fibrinolysis or within 2–24 h after bolus administra-
Myocardial Infarction) trial emphasizes the strong impact of time
.. tion.198 Emergency CABG may be indicated in selected STEMI
..
delays on mortality, particularly in STEMI patients with cardiogenic . patients unsuitable for PCI.
ESC/EACTS Guidelines 113
7.3 Primary percutaneous coronary .. Four major randomized trials-PRAMI (Preventive Angioplasty in
..
intervention .. Acute Myocardial Infarction),211 CvLPRIT (Complete Versus Lesion-
Key points for optimizing and guiding primary PCI are summarized
.. Only Primary PCI trial),212 DANAMI-3-PRIMULTI (The Third
..
below. .. DANish Study of Optimal Acute Treatment of Patients with ST-
The infarct-related artery (IRA) should be systematically treated
.. segment Elevation Myocardial Infarction: PRImary PCI in
..
during the initial intervention. Patients with extensive CAD in vessels .. MULTIvessel Disease),213 and Compare-Acute214-have consistently
remote from the IRA have an adverse prognosis following primary
.. shown a benefit of complete revascularization (performed immedi-
..
PCI.207 Staged PCI in patients with multivessel disease and no haemo- .. ately or staged) as compared with IRA-only PCI in patients with
..
dynamic compromise is an independent predictor of survival, and .. STEMI and multivessel disease (for details see the Supplementary
more frequent ischaemic events have been reported in direct vs. .. Data). A recent meta-analysis of 10 trials has shown that complete
..
staged revascularization of STEMI patients with multivessel .. revascularization was associated with a lower risk of MACE (RR 0.57,
disease.208–210 .. 95% CI 0.42–0.77), due to a lower risk of urgent revascularization
114 ESC/EACTS Guidelines
..
(RR 0.44, 95% CI 0.30–0.66), with no significant difference in mortal- .. median follow-up of 42 months.221 Routine deferred stenting was
ity (RR 0.76, 95% CI 0.52–1.12) or MI (RR 0.54, 95% CI .. associated with a higher risk of TVR.
..
0.23–1.27).215 This meta-analysis did not include Compare-Acute. .. Thrombus aspiration has been proposed as an adjunct during pri-
Yet, similar to earlier studies, the benefit of complete revasculariza- .. mary PCI to further improve epicardial and myocardial reperfusion
..
tion over culprit-only revascularization seen in Compare-Acute was .. by the prevention of distal embolization of thrombotic material and
driven by a lower need for unplanned reintervention, whereas the .. plaque debris.222 Two landmark RCTs, which were adequately pow-
..
incidences of death and recurrent MI were similar between the two .. ered to detect the superiority of routine manual thrombus aspiration
strategies.214 .. vs. conventional PCI, showed no benefit on clinical outcomes of the
..
Most of the studies support the concept of full revascularization .. routine aspiration strategy overall or in any subgroup of patients indi-
either during the initial hospital stay for STEMI or a staged admis- .. cating high thrombotic risk.223–226 A safety concern emerged in
..
sion,215 but it remains to be determined how clinicians can identify .. TOTAL (Trial of Routine Aspiration Thrombectomy with PCI versus
lesions that should be revascularized beyond the culprit lesion and .. PCI Alone in Patients with STEMI) trial with an increase in the risk of
..
Primary percutaneous coronary intervention for myocardial reperfusion in ST-elevation myocardial infarction: indica-
tions and logistics
Indication
Reperfusion therapy is indicated in all patients with time from symptom onset <12 h duration and persistent ST-seg-
I A
ment elevation.200,201,236
In the absence of ST-segment elevation, a primary PCI strategy is indicated in patients with suspected ongoing
ischaemic symptoms suggestive of MI and at least one of the following criteria present:
• haemodynamic instability or cardiogenic shock
A primary PCI strategy is recommended over fibrinolysis within the indicated time frames.200,201,237,238 I A
In patients with time from symptom onset >12 h, a primary PCI strategy is indicated in the presence of ongoing
I C
symptoms or signs suggestive of ischaemia, haemodynamic instability, or life-threatening arrhythmias.
A routine primary PCI strategy should be considered in patients presenting late (12–48 h) after symptom
IIa B
onset.233,234,239
Logistics
It is recommended that the pre-hospital management of STEMI patients should be based on regional networks that
are designed to deliver reperfusion therapy effectively in a timely fashion, and to offer primary PCI to as many I B
patients as possible.240,241
It is recommended that all EMS, emergency departments, coronary care units, and catheterization laboratories have
I C
a written updated STEMI management protocol, preferably shared within geographical networks.
It is recommended that primary PCI-capable centres deliver a 24 h/7 day service and ensure that primary PCI is per-
I B
formed as fast as possible.242–244
It is recommended that patients transferred to a PCI-capable centre for primary PCI bypass the emergency depart-
I B
ment and CCU/ICCU, and are transferred directly to the catheterization laboratory.245–247
CCU = coronary care unit; EMS = emergency medical services; ICCU = intensive coronary care unit; MI = myocardial infarction; PCI = percutaneous coronary intervention;
STEMI = ST-segment elevation myocardial infarction.
a
Class of recommendation.
b
Level of evidence.
116 ESC/EACTS Guidelines
Primary percutaneous coronary intervention for myocardial reperfusion in ST-elevation myocardial infarction: proce-
dural aspects (strategy and technique)
Strategy
Routine revascularization of non-IRA lesions should be considered in patients with multivessel disease before hospital
IIa A
discharge.211–214
CABG should be considered in patients with ongoing ischaemia and large areas of jeopardized myocardium if PCI of the
IIa C
IRA cannot be performed.
In cardiogenic shock, routine revascularization of non-IRA lesions is not recommended during primary PCI.190
Technique
CABG = coronary artery bypass grafting; IRA = infarct-related artery; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction.
a
Class of recommendation.
b
Level of evidence.
..
8 Myocardial revascularization in ..
..
revascularization with medical therapy in patients with an EF <_40%
showed that there was a significant mortality reduction with CABG
patients with heart failure ... (HR 0.66, 95% CI 0.61–0.72, P <0.001) and PCI (HR 0.73, 95% CI
..
.. 0.62–0.85, P <0.001) vs. medical therapy, though these finding are
8.1 Chronic heart failure .. limited by the predominantly observational nature of the included
8.1.1 Recommendations for myocardial revascularization ..
.. studies and missing information on the completeness of
in patients with chronic heart failure .. revascularization.248
When compared with medical therapy alone, coronary revasculariza- ..
.. A recent observational study investigated outcomes with PCI or
tion is superior in improving survival in patients with HF of ischaemic .. CABG for multivessel CAD and LV dysfunction in 1738 propensity-
origin and is recommended in clinical practice.81,248 However, the ..
.. matched patients with diabetes mellitus.251 Similar to the findings in
optimal revascularization strategy is not defined. The choice between .. the absence of LV dysfunction, when CABG was compared with PCI
CABG and PCI should be made by the Heart Team after careful eval- ..
.. it was associated with a significantly lower risk of MACE, which
uation of the patient’s clinical status and coronary anatomy, expected .. included a significant reduction in mortality. Event curves separated
completeness of revascularization (see section 5.3.1.3), myocardial ..
.. early during the first year and continued to separate out to 12 years.
viability, coexisting valvular disease, and comorbidities. .. PCI should be considered in older patients without diabetes in
Considerations relating to the need for viability testing prior to revas-
..
.. whom complete revascularization can be achieved, whereas CABG is
cularization are discussed in section 3. ..
.. preferred in younger patients with more extensive CAD or those
Randomized clinical trial data comparing revascularization with .. with diabetes. In patients with diabetes and LV moderate or severe
medical therapy exists only for CABG in the setting of the STICH ..
trial.81 One analysis from this trial showed that CABG can be per-
.. dysfunction (EF <50%), CABG is associated with better long-term
.. survival and reduced incidence of MACCE.250,251
formed with acceptable 30 day mortality rates (5.1%) in patients with ..
LV dysfunction (LVEF <_35%).249 Extended follow-up in the STICH
..
..
Extension Study (STICHES) supports a significant survival benefit of .. 8.1.2 Ventricular reconstruction and aneurysm resection
..
CABG combined with medical therapy vs. medical therapy alone in a .. The aim of surgical ventricular reconstruction (SVR) is to restore
10 year observation period.81 .. physiological volume, and achieve an elliptical shape of the LV, by scar
..
There are currently no dedicated randomized clinical trials com- .. resection and LV wall reconstruction on a mannequin of predefined
paring PCI vs. medical therapy in patients with HF with reduced EF .. size. The aim of ventricular aneurysmectomy is to remove fibrous
..
(HFrEF). In addition, CABG vs. PCI randomized trials have excluded .. scars in cases of severe dilatation, thrombus formation, or as a source
patients with severe HF. In one prospective registry including 4616 .. of life-threatening ventricular arrhythmias.
..
patients with multivessel disease and severe HFrEF, propensity .. The STICH trial revealed no difference in the primary outcome
score-matched comparison revealed similar survival (mean follow-up .. (total mortality or cardiac hospitalization) between patients ran-
..
2.9 years) with PCI (using EES) vs. CABG.250 PCI was associated with .. domly allocated to CABG vs. combined CABG and SVR.252
a higher risk of MI, particularly in patients with incomplete revascula- .. Subgroup analyses of patients with a less dilated LV and better LVEF
..
rization, and repeat revascularization. CABG was associated with a .. showed benefit from SVR.253 In the STICH trial, a post-operative LV
higher risk of stroke. The conclusion of the study was that multivessel .. end-systolic volume index <_70 mL/m2, after CABG plus SVR,
..
PCI can be a valuable option in HF patients if complete revasculariza- .. resulted in improved survival compared with CABG alone.252,254 In
tion is possible. A systematic review of studies comparing .. experienced centres, SVR may be done at the time of CABG if HF
ESC/EACTS Guidelines 117
..
symptoms are more predominant than angina, and if myocardial scar .. patients with cardiogenic shock complicating AMI, emergency revas-
and moderate LV remodelling are present. .. cularization with PCI or CABG improved long-term survival when
..
.. compared with initial intensive medical therapy. All-cause mortality
Recommendations on revascularizations in patients .. at 6 months was lower in the group assigned to revascularization
with chronic heart failure and systolic left ventricular ..
dysfunction (ejection fraction 35%)
.. than in the medically treated patients (50.3 vs. 63.1%, respectively;
.. RR 0.80, 95% CI 0.65–0.98, P = 0.03).258
..
.. The revascularization strategy for patients with cardiogenic shock
Recommendations Classa Levelb .. and multivessel disease is addressed in section 7.
..
In patients with severe LV systolic dysfunc- .. A subanalysis of the SHOCK trial comparing patients treated with
.. CABG or PCI showed similar survival rates between the two sub-
tion and coronary artery disease suitable for ..
intervention, myocardial revascularization is
I B .. groups.259 There were more patients with diabetes (48.9 vs. 26.9%;
.. P = 0.02), three-vessel disease (80.4 vs. 60.3%; P = 0.03), and LM cor-
recommended.81,250 ..
..
8.3 Gaps in the evidence .. The anatomical pattern of CAD in patients with diabetes clearly
There is no RCT comparing revascularization with PCI vs. CABG in
.. influences their prognosis and response to revascularization.
..
patients with HF. .. Angiographic studies have demonstrated that patients with diabetes
.. are more likely to have LM disease and multivessel CAD, with more
There is limited evidence on the role of active MCS in patients ..
with cardiogenic shock compared with standard therapy. .. diffuse disease involving smaller vessels.273 In addition, patients with
.. diabetes have a greater atherosclerotic burden and an increased
..
.. number of lipid-rich plaques, which are prone to rupture,274,275 and
Recommendations for the management of patients with .. those with unstable angina have more fissured plaques and intracoro-
cardiogenic shock ..
.. nary thrombi.276 Patients with diabetes undergoing revascularization,
.. either with CABG or PCI, are at greater risk of kidney injury than
Recommendations Classa Levelb ..
.. patients without diabetes.
..
Emergency coronary angiography is indi- ..
..
Recommendation for patients on metformin
.. 10.3 Gaps in the evidence
.. Thus far, patients with CKD have been excluded from randomized
... trials on myocardial revascularization, hence current data are based
Recommendation Classa Levelb ..
.. on observational studies only. A randomized trial on optimal long-
.. term revascularization strategies in patients with moderate-to-severe
It is recommended to check renal function if ..
patients have taken metformin immediately .. stress-induced ischaemia and severe CKD is currently ongoing
I C ..
before angiography and withhold metformin .. (ISCHEMIA-CKD, https://clinicaltrials.gov/ct2/show/NCT01985360).
if renal function deteriorates. .. Moreover, additional randomized evidence on optimal strategies for
..
. CIN prevention is needed.
a
Class of recommendation.
b
Level of evidence. Recommendations for the prevention of contrast-
induced nephropathy
..
Patients with severe CKD (National Kidney Foundation .. 11.2 Primary indication for myocardial
.. revascularization
stage 4) ..
.. 11.2.1 Aortic valve disease
Prophylactic haemofiltra- Fluid replace- ..
.. The recommendations for patients undergoing CABG for the clini-
tion 6 h before complex ment rate 1000 .. cally leading problem of CAD, who also have coexisting severe aortic
PCI may be mL/h without ..
.. stenosis or regurgitation, remain unchanged from those of the 2014
considered.298–300 negative loss .. Guidelines and support replacement of the aortic valve.305 However,
and saline IIb B ..
.. in the current era of rapid developments in transcatheter valve
hydration con- .. implantation technologies, a decision regarding replacement of the
tinued for 24 h ..
.. aortic valve for moderate stenosis/regurgitation should be carefully
after the .. considered on a case-by-case basis in discussion with the Heart
procedure. ..
.. Team. The patient’s age, type of prosthesis, pathogenesis of aortic
..
for and timing of PCI in patients undergoing TAVI is also an area with .. 12 Associated peripheral artery
limited evidence. The long-term outcomes of patients with concomi-
..
.. diseases
tant surgical repair of ischaemic MR are also awaited. ..
..
.. 12.1 Prevention of stroke associated with
..
.. carotid artery disease and myocardial
Recommendations for combined valvular and coronary ..
interventions .. revascularization
.. The early risk of stroke after myocardial revascularization is higher
..
Recommendations Classa Levelb
.. after CABG than after PCI.313 After 30 days, stroke rates between
.. revascularization techniques were similar in a recent individual
..
Primary valve intervention and coro- .. patient data meta-analysis of 11 randomized trials.313
nary revascularization ..
.. Ischaemic stroke after CABG is multifactorial: thrombo-embolism
..
occluded saphenous vein graft (SVG) and any anastomotic site should .. The IMA is the conduit of choice for revascularization during redo
be avoided, if possible, due to concerns regarding embolization or .. CABG if not previously used, or can be salvaged and reused in spe-
..
perforation. Redo surgery should be favoured if the anatomy is .. cific cases.344,345
unsuitable for PCI, if several important grafts are occluded, or in the ..
..
case of clear anastomotic errors. In asymptomatic patients, repeat .. 13.3.2 Percutaneous coronary intervention for saphenous
revascularization should be considered if the artery is of an appropri- ..
.. vein graft lesions
ate size and supplies a large territory of myocardium. .. PCI in SVGs is associated with an increased risk of distal coronary
Further details on the diagnosis and management of perioperative ..
.. embolization, frequently resulting in periprocedural MI.346 PCI of de
MI are provided in a recent ESC position paper.329 .. novo SVG stenosis is considered a high-risk intervention because SVG
..
.. atheroma is friable and more prone to distal embolization. Several
13.2 Acute percutaneous coronary .. different approaches have been evaluated to prevent the distal embo-
..
intervention failure .. lization of particulate debris, including distal occlusion/aspiration,
stenting with new-generation DES were comparable.376 A single .. associated multivessel disease, especially in the presence of other
..
randomized trial of patients undergoing DCB for restenosis within .. complex lesions such as chronic total occlusions—CABG should be
DES showed superior angiographic outcomes in patients who under-
.. considered before a new PCI attempt.
..
went lesion preparation with scoring balloons vs. standard angio- ..
plasty balloons.377
..
.. 13.4.2 Disease progression
Network meta-analysis suggests that repeat stenting with new- ..
generation DES (with EES) and DCB are ranked first and second as
.. Patients with symptomatic disease progression after PCI account for
.. up to 50% of reinterventions.383,384 They should be managed using
the highest efficacy treatments.378,379 The superior angiographic anti- ..
restenotic efficacy of new-generation DES should be weighed against
.. criteria similar to those applied to patients without previous
.. revascularization.
a possible excess of long-term adverse events with repeat stenting ..
..
during longer-term follow-up of these trials.380,381 However, obser- ..
vations in relation to clinical events must be interpreted with caution, .. 13.4.3 Stent thrombosis
..
Repeat revascularization is indicated in patients with a large area of ischaemia or severe symptoms despite medical
I B
therapy.84,334
If considered safe, PCI should be considered as first choice over CABG. IIa C
CABG
IMA is the conduit of choice for redo CABG in patients in whom the IMA was not used previously.344 I B
Redo CABG should be considered for patients without a patent IMA graft to the LAD.340,341,344 IIa B
PCI
Distal protection devices should be considered for PCI of SVG lesions.348,350,351 IIa B
PCI of the bypassed native artery should be considered over PCI of the bypass graft. IIa C
Restenosis
DES are recommended for the treatment of in-stent restenosis of BMS or DES.373,375,378,379 I A
373,375,378,379
Drug-coated balloons are recommended for the treatment of in-stent restenosis of BMS or DES. I A
In patients with recurrent episodes of diffuse in-stent restenosis, CABG should be considered by the Heart Team over
IIa C
a new PCI attempt.
IVUS and/or OCT should be considered to detect stent-related mechanical problems leading to restenosis. IIa C
BMS = bare-metal stent; CABG = coronary artery bypass grafting; DES = drug-eluting stent; ECG = electrocardiogram; IMA = internal mammary artery; IVUS = intravascular
ultrasound; LAD = left anterior descending artery; MI = myocardial infarction; OCT = optical coherence tomography; PCI = percutaneous coronary intervention; SVG = saphe-
nous vein graft.
a
Class of recommendation.
b
Level of evidence.
14 Arrhythmias .. patients with CAD and LVEF <_35%.391 Indirect evidence for a pro-
..
.. tective effect of revascularization was demonstrated in the MADIT II
14.1 Ventricular arrhythmias ..
.. (Multicenter Automatic Defibrillator Implantation Trial II) and SCD-
14.1.1 Revascularization for the prevention of sudden .. HEFT studies (Sudden Cardiac Death in Heart Failure Trial), where
cardiac death in patients with stable coronary artery ..
.. the efficacy of implantation cardioverter defibrillators (ICDs) was
disease and reduced left ventricular function .. reduced if revascularization was performed prior to implanta-
..
Revascularization plays an important role in reducing the frequency .. tion.392,393 CABG in patients with reduced EF reduces cardiac and
of ventricular arrhythmias in patients with normal or mildly reduced .. overall mortality for a follow-up of 10 years.78,81 In view of the pro-
LV function,389,390 as well as the risk of sudden cardiac death in
..
.. tective effect of revascularization on ventricular arrhythmias, patients
.
128 ESC/EACTS Guidelines
..
with ischaemic LV dysfunction (LVEF <_35%) who are considered for .. impaired prognosis and a more than doubling of the risk of death,
primary preventive ICD implantation should be evaluated for ischae- .. congestive HF, and stroke.403
..
mia and/or for potential revascularization targets. .. The use of oral anticoagulation (OAC) for stroke prevention in
.. patients with AF occurring during or after PCI should follow the ESC
..
14.1.2 Revascularization for the treatment of electrical .. Guidelines on Atrial Fibrillation for antithrombotic treatment of AF
storm
.. that occurs outside the setting of PCI,405 although prospective stud-
..
Electrical storm is a life-threatening syndrome related to incessant .. ies are scarce. The combination and duration of anticoagulation and
ventricular arrhythmias, which is most frequently observed in
.. antiplatelet therapy should be assessed according to the clinical situa-
..
patients with ischaemic heart disease, advanced systolic HF, valve dis- .. tion, as outlined in section 17 as well as in the ESC Guidelines on
ease, corrected congenital heart disease, and genetic disorders such
.. Atrial Fibrillation405 and the ESC Focused Update on Dual
..
as Brugada syndrome, early repolarization, and long QT syn- .. Antiplatelet Therapy.410
..
drome.394 Urgent coronary angiography and revascularization should ..
A primary PCI strategy is recommended in patients with resuscitated cardiac arrest and an ECG consistent with
I B
STEMI.395,397,436,437
Urgent angiography (and PCI if indicated) should be considered in patients with resuscitated cardiac arrest without diagnostic
IIa C
ST-segment elevation but with a high suspicion of ongoing myocardial ischaemia.
In patients with electrical storm, urgent coronary angiography and revascularization (as required) should be considered. IIa C
Recommendations for the prevention and treatment of atrial fibrillation in the setting of myocardial revascularization
Perioperative oral beta-blocker therapy is recommended for the prevention of post-operative AF after CABG surgery.412,438 I B
Restoration of sinus rhythm by electrical cardioversion or antiarrhythmic drugs is recommended in post-operative AF with hae-
I C
modynamic instability.
Perioperative amiodarone should be considered as prophylactic therapy to prevent AF after CABG surgery.412,439 IIa A
Long-term anticoagulation should be considered in patients with AF after CABG or PCI who are at risk of stroke, considering
IIa B
the individual stroke and bleeding risk.440,441
Rate control and anticoagulation should be considered as the initial management of asymptomatic post-operative AF.442 IIa B
Antiarrhythmic drugs should be considered for symptomatic post-operative AF after CABG or PCI in an attempt to restore
IIa C
sinus rhythm.
Surgical occlusion or exclusion of the LAA may be considered for stroke prevention in patients with AF undergoing CABG
IIb B
surgery.432–434
AF = atrial fibrillation; CABG = coronary artery bypass grafting; LAA = left atrial appendage; PCI = percutaneous coronary intervention.
a
Class of recommendation.
b
Level of evidence.
..
14.3 Gaps in the evidence .. Perioperative medication and blood management are covered in sep-
The duration of anticoagulation and their combination with antiplate-
.. arate Guidelines.410,444
..
let therapy in patients with new-onset AF after PCI or CABG has not ..
..
been studied sufficiently. Likewise, the role of routine left atrial exclu- .. 15.1 Surgical techniques
sion at surgery for the prevention of stroke is currently unclear. ..
.. 15.1.1 Completeness of revascularization
.. Current surgical practice is largely based on an anatomical definition
..
.. of complete revascularization, and aims to bypass all epicardial vessels
15 Procedural aspects of coronary .. with a diameter exceeding >_1.5 mm and a luminal reduction of >_50%
..
artery bypass grafting .. in at least one angiographic view.131 Depending on the definition of
.. completeness of revascularization, the outcome after CABG in
..
CABG remains the most common cardiac surgical procedure, and .. patients with incomplete revascularization was either similar445–449
the techniques have been refined during 50 years of evolution.443
.. or inferior131,132,449–451 to that of patients with complete
130 ESC/EACTS Guidelines
..
revascularization. Certainly, in some patients with a stenosis in small .. grafting should be considered in patients with a reasonable life
vessels with little myocardium at risk, complete revascularization may .. expectancy and a low risk of sternal wound complications.
..
not be necessary. .. The radial artery constitutes an alternative as the second arterial
FFR-guided surgical revascularization has been associated with .. graft in patients in whom BIMA grafting is not feasible, patients with a
..
improved graft patency, but more studies are needed to investigate .. high risk of sternal wound complications, or as a third arterial graft.
whether it improves clinical outcomes.28,452 Further discussion of .. There is a strong, adverse influence on radial artery patency when
..
FFR-guided revascularization is provided in sections 3.2.1.1 and .. the native coronary artery stenosis is <70%, and therefore its use
5.3.1.3. .. should be limited to coronary artery stenosis >70% and ideally
..
.. >90%.477 Use of the radial artery as the second conduit of choice has
.. been linked to improved survival in registry studies.478–480 Available
..
15.1.2 Conduit selection .. RCTs testing the radial artery vs. saphenous vein graft used angio-
.. graphic patency as the primary endpoint, and none was powered to
In addition to patient-related factors, the outcome following CABG ..
concerning patency rates, most data from meta-analyses and .. 15.1.9 Minimally invasive and hybrid procedures
..
randomized and non-randomized trials do not demonstrate inferior .. Minimally invasive coronary surgery with LIMA, harvested either
clinical outcomes with endoscopic vein harvest.492,493,499,500 If an .. directly or under video-assisted vision, may represent an attractive
..
endoscopic vein graft harvest is performed, it should be undertaken .. alternative to a sternotomy.530 It has a similar safety and efficacy pro-
by experienced surgeons or physician assistants with appropriate
.. file to conventional on-pump and off-pump procedures, with a mark-
..
training and reasonable caseloads.501–503 If an open technique is used, .. edly reduced post-operative length of stay and an early quality of life
the ‘no-touch’ technique has shown superior patency rates in multi-
.. benefit, although spreading of the ribs is associated with increased
..
ple randomized trials,504–507 with a patency rate >80% after 16 .. post-operative pain.531–533 It has been shown to be safe and effective
years.507
.. in the treatment of proximal LAD stenosis or chronically occluded
..
.. LAD arteries.144 Moreover, when compared with PCI in a setting of
..
15.1.6 Cross-Clamping .. single-vessel proximal LAD disease, minimally invasive coronary sur-
.. gery was associated with less need for coronary reinterven-
..
General considerations
CT scans of the ascending aorta should be considered in patients over 70 years of age and/or with signs of extensive
IIa C
Prior to aortic manipulation, epiaortic ultrasound should be considered to identify atheromatous plaques and select the
IIa C
optimal surgical strategy.
Conduit selection
The use of the radial artery is recommended over the saphenous vein in patients with high-grade coronary artery
I B
stenosis.d 482,549,550,552,553
BIMA grafting should be considered in patients who do not have a high risk of sternal wound infection.e 467,547,548,551 IIa B
Vessel harvesting
Skeletonized IMA dissection is recommended in patients with a high risk of sternal wound infection.471,484,485 I B
Endoscopic vein harvesting, if performed by experienced surgeons, should be considered to reduce the incidence of
IIa A
wound complications.490,493,494,500,554
No-touch vein harvesting should be considered when an open technique is used.506,507,555,556 IIa B
Off-pump CABG and preferably no-touch techniques on the ascending aorta, by experienced operators, are recom-
I B
mended in patients with significant atherosclerotic aortic disease.508,509,544,557–559
Off-pump CABG should be considered for subgroups of high-risk patients by experienced off-pump teams.525,557–560 IIa B
Where expertise exists, minimally invasive CABG through limited thoracic access should be considered in patients with
IIa B
isolated LAD lesions or in the context of hybrid revascularization.143,534,535,561
Hybrid procedures, defined as consecutive or combined surgical and percutaneous revascularization, may be consid-
IIb B
ered in specific patient subsets at experienced centres.536,561–563
BIMA = bilateral internal mammary artery; CABG = coronary artery bypass grafting; CT = computed tomography; IMA = internal mammary artery; LAD = left anterior
descending coronary artery.
a
Class of recommendation.
b
Level of evidence.
c
Definitions of complete revascularization are provided in section 5.3.1.3.
d
Particularly in patients with poor vein grafts. The radial artery should not be used if previously catheterized, if the Allen test is positive or if calcific degeneration is present.
e
Patients with diabetes mellitus, chronic pulmonary obstructive disease, previous mediastinal radiation, and obesity, particularly when multiples of these are present.
ESC/EACTS Guidelines 133
Complete revascularization IB
Graft flow measurement IIaB
ml/min
93 ml/min PI 1.3
180
160
140
120
100
80
60
40
20 Radial artery
0
-20
in high-grade
LITA- LAD DF 74%
stenosis IB
Figure 8 Technical aspects of CABG. BIMA = bilateral internal mammary artery; CABG = coronary artery bypass grafting; IMA = internal mam-
mary artery; LAD = left anterior descending coronary artery.
...
16 Procedural aspects of .. selected patients in whom implantation of stents is not technically
.. feasible, or in a vessel that is considered to be too small to be stented.
percutaneous coronary .. Balloon angioplasty is no longer preferred to stenting with DES for
..
intervention ..
..
patients who require urgent non-cardiac surgery as short-duration
.. DAPT may be reasonable with both strategies.565,566
16.1 Percutaneous coronary intervention ..
..
devices .. 16.1.2 Choice of coronary stents
16.1.1 Balloon angioplasty .. Stenting with BMS results in an approximately 30% lower rate of resteno-
..
Plain balloon angioplasty has been superseded in the treatment of de .. sis in comparison with plain balloon angioplasty.564 Although many efforts
novo coronary lesions after demonstration of the superiority of stent- .. have been made to further reduce restenosis by the modification of stent
..
ing in terms of the requirement for repeat revascularization.564 .. designs and materials, reducing the thickness of stent struts has been the
Balloon angioplasty might be considered for the treatment of .. only proven modification capable of reducing restenosis of BMS.567,568
134 ESC/EACTS Guidelines
..
A major reduction in the risk of restenosis has been achieved with .. of reducing or eliminating stent-related adverse events at long-term
DES technology. Early-generation DES released sirolimus569 or pacli- .. follow-up. Current scaffold platforms to have reached clinical testing
..
taxel570 from a permanent polymer matrix coating on a relatively .. are based on two different technologies: bioresorbable, polymer-
thick-strut (120–140 mm) stainless steel backbone. These devices .. based scaffolds (resorption up to 3–4 years) and resorbable, metallic
..
reduced angiographic and clinical restenosis by approximately .. (magnesium) scaffolds (resorption up to 1 year).595 Although a num-
50–70%, but increased the risk of very late stent thrombosis com- .. ber of devices have received approval for use in Europe (see
..
pared with BMS.336,571 .. Supplementary Table 7), randomized trial data are available only with
Early-generation DES have now been supplanted by new-generation .. the Absorb bioresorbable vascular scaffold (BVS) (Abbott Vascular).
..
DES. These stents represented an iterative development of early gener- .. The safety and efficacy profile of the Absorb BVS has been com-
ation technology, including polymers with enhanced biocompatibility .. pared with contemporary DES in several trials. Findings of these trials
..
(permanent or biodegradable), exclusively sirolimus-analogue active .. as well as meta-analyses consistently indicate the inferior efficacy and
drugs, and stent backbones with thin struts (50–100 mm) composed of .. safety of Absorb BVS compared with contemporary DES during
..
..
stenting, with somewhat conflicting results. Findings from one meta- .. this rule, where upfront side branch stenting may be preferable, include
analysis of randomized trials suggested better outcomes with IVUS .. the presence of a large side branch (>_2.75 mm) with a long ostial side
..
guidance in terms of acute procedural results and reduced angiographic .. branch lesion (>5 mm) or anticipated difficulty in accessing an important
restenosis, repeat revascularization, and MACE, with no effect on .. side branch after main branch stenting, and true distal LM bifurcations.
..
death and MI.603,604 In the DES era, meta-analysis of randomized and .. Recently, a multicentre trial conducted in China directly compared a
observational studies also suggests better clinical outcomes with IVUS- .. double-kissing crush two-stent strategy with provisional stenting of the
..
guided vs. angiography-guided PCI.605,606 However, the contribution of .. main branch in 482 patients with distal LM bifurcation disease. Double-
findings from observational studies must be weighed against the likeli- .. kissing crush resulted in a lower risk of the primary endpoint target lesion
..
hood of considerable residual confounding due to treatment selection .. failure at 1 year compared with provisional stenting.620
bias. Similarly, findings of improved outcome in patients undergoing LM .. When a two-stent strategy is necessary, which two-stent technique
..
stem PCI with IVUS-guided PCI vs. angiography-guided PCI from a pro- .. should be preferred is debated. The three most widely used contem-
pensity score matched analysis must be interpreted with caution.35 .. porary two-stent techniques are culotte, crush (classic or double-
..
..
17 Antithrombotic treatments .. ischaemic and bleeding events significantly influence the outcome
.. of CAD patients and their overall mortality risk during and after
Antithrombotic treatment is mandatory in CAD patients undergoing
.. myocardial revascularization.664 Thus, the choice of treatment should
..
myocardial revascularization. The choice of treatment, the combination, .. reflect the ischaemic and bleeding risk. The recommended drugs
the time point of initiation, and the duration depend on the patient’s
..
.. (Figure 9) and doses (Table 7) for anticoagulant and antiplatelet
characteristics, comorbidities, the clinical setting (elective revasculariza- .. drugs used in conjunction with myocardial revascularization are
tion vs. ACS), and the mode (PCI vs. CABG) of revascularization. Both
..
. summarized below.
Table 7 Doses of antiplatelet and anticoagulant drugs used during and after myocardial revascularization
Antiplatelet drugs
Aspirin Loading dose of 150–300 mg orally or 75–150 mg i.v. if oral ingestion is not possible, followed by
a maintenance dose of 75–100 mg/day.
Abciximab Bolus of 0.25 mg/kg i.v. and 0.125 lg/kg/min infusion (maximum 10 lg/min) for 12 h.
Eptifibatide Double bolus of 180 lg/kg i.v. (given at a 10 min interval) followed by an infusion of 2.0 lg/kg/min
for up to18 h.
Tirofiban Bolus of 25 lg/kg over 3 min i.v., followed by an infusion of 0.15 lg/kg/min for up to 18 h.
Cangrelor Bolus of 30 mg/kg i.v. followed by 4 mg/kg/min infusion for at least 2 h or duration of procedure,
whichever is longer.
Bivalirudin 0.75 mg/kg i.v. bolus followed by i.v. infusion of 1.75 mg/kg/h for up to 4 h after the procedure
as clinically warranted.
Vitamin K antagonists (e.g. warfarin, Dosing is based on INR value and the respective clinical indication.
phenprocoumon)
Rivaroxaban Maintenance doses of 20 and 15a mg/day, and 2.5 mg b.i.d. (vascular dose).
a
Specific criteria for reduced dose apply (see recommendation table on page 61).
b.i.d. = twice daily; GP = glycoprotein; INR = international normalized ratio; i.v. = intravenous; PCI = percutaneous coronary intervention.
..
17.1 Percutaneous coronary intervention .. and bivalirudin, have been evaluated for their use in clinical practice.
.. The REPLACE-2 (Randomised Evaluation in PCI Linking Angiomax to
in stable coronary artery disease ..
17.1.1 Choice of treatment and pre-treatment
.. Reduced Clinical Events 2) trial demonstrated that the outcome with
.. bivalirudin and provisional glycoprotein (GP) IIb/IIIa blockade is simi-
DAPT consisting of aspirin and a P2Y12 receptor inhibitor represents ..
the cornerstone of treatment in patients undergoing elective PCI.665
.. lar to that of UFH plus planned GP IIb/IIIa inhibition during elective
.. PCI.669 The ISAR-REACT (Intracoronary Stenting and
The P2Y12 receptor inhibitor clopidogrel is recommended for elec- ..
.. Antithrombotic Regimen Rapid Early Action for Coronary
tive stenting procedures. For routine clopidogrel pre-treatment .. Treatment) 3 trial also showed a similar outcome for bivalirudin vs.
(administration of the drug when the coronary anatomy is unknown), ..
.. UFH treatment.670 In ISAR REACT 3A,671 evaluating a lower dose of
there is no compelling evidence for a significant clinical benefit in .. 100 U/kg UFH, this lower dose showed net clinical benefit compared
SCAD patients.666–668 Thus, pre-treatment may only be an option in ..
.. with the historical control cohort and this benefit was mostly driven
selected patients with high probability of PCI or before staged PCI .. by a reduction in bleeding events. In view of the primary endpoint
procedures. Figures 9 and 10 summarize the commonly used antipla- ..
.. results of the RCTs and in view of a trend towards a lower risk of MI,
telet and anticoagulant drugs in SCAD patients undergoing PCI. ..
.. UFH remains the standard anticoagulant for elective PCI. Based on
.. the results of the STEEPLE (Safety and Efficacy of Intravenous
..
17.1.2 Peri-interventional treatment .. Enoxaparin in Elective Percutaneous Coronary Intervention
While aspirin and clopidogrel are indicated for elective stenting pro- .. Randomised Evaluation) trial, enoxaparin should be considered as an
..
cedures, prasugrel or ticagrelor may only be considered in selected .. alternative anticoagulant drug.672
patients for specific high-risk situations of elective stenting (e.g. com- .. Drugs for parenteral antiplatelet treatment include cangrelor
..
plex PCI procedures such as LM stenting and CTO procedures) or in .. and GP IIb/IIIa inhibitors. Cangrelor is a direct reversible, short-
patients with a history of stent thrombosis on clopidogrel treatment. .. acting P2Y12-inhibitor that has been evaluated during PCI for
..
In parallel with antiplatelet treatment, the use of anticoagulants is .. SCAD and ACS in clinical trials comparing cangrelor with clopi-
standard of care during elective PCI to inhibit thrombin generation
.. dogrel, administered before PCI [CHAMPION (Cangrelor versus
..
and activity. Different agents, including unfractionated heparin (UFH) . Standard Therapy to Achieve Optimal Management of Platelet
ESC/EACTS Guidelines 139
..
Inhibition) PCI] or after PCI (CHAMPION PLATFORM and .. An algorithm for the use of antithrombotic drugs in patients under-
CHAMPION PHOENIX).673 A meta-analysis showed a benefit .. going PCI is shown in Figure 10.
..
with respect to major ischaemic endpoints that is counter- ..
balanced by an increase in relevant bleeding.673 Moreover, the .. 17.1.3 Post-interventional and maintenance treatment
..
benefit of cangrelor with respect to ischaemic endpoints was atte- .. Following elective stenting, DAPT consisting of clopidogrel in addi-
nuated in CHAMPION PCI with upfront administration of clopi- ..
.. tion to aspirin is generally recommended for 6 months, irrespective
dogrel. Nevertheless, due to its proven efficacy in preventing .. of the stent type. In specific clinical scenarios, this standard DAPT
intraprocedural and post-procedural stent thrombosis in P2Y12- ..
.. duration can be shortened (<6 months) or extended (>6–12
inhibitor naı̈ve patients, cangrelor may be considered in P2Y12- .. months). For a more detailed description of the pertinent clinical tri-
inhibitor naı̈ve patients undergoing PCI (for more detailed discus- ..
.. als in the field of DAPT duration, we refer the reader to the 2017
sion see the Supplementary Data). .. ESC Focused Update on Dual Antiplatelet Therapy in Coronary
Available GP IIb/IIIa inhibitors include abciximab, eptifibatide, and tir- ..
.. Artery Disease.410 Following DAPT, a life-long single antiplatelet
Figure 10 Algorithm for the use of antithrombotic drugs in patients undergoing percutaneous coronary intervention. High bleeding risk is consid-
ered as an increased risk of spontaneous bleeding during DAPT (e.g. PRECISE-DAPT score >_25). Colour-coding refers to the ESC classes of recom-
mendations (green = class I; yellow = class IIa; and orange = class IIb).
140 ESC/EACTS Guidelines
Recommendations for antithrombotic treatment in stable coronary artery disease patients undergoing percutaneous
coronary intervention
Treatment with 600 mg clopidogrel is recommended in elective PCI patients once the coronary anatomy is known and
I A
a decision is made to proceed with PCI.667,679,680
Pre-treatment with clopidogrel may be considered if the probability of PCI is high. IIb C
In patients on a maintenance dose of 75 mg clopidogrel, a new loading dose of 600 mg may be considered once the indi-
IIb C
Peri-interventional treatment
An oral loading dose of aspirin (150–300 mg p.o. or 75–250 mg i.v.) is recommended if the patient is not pre-treated. I C
Clopidogrel (600 mg loading dose, 75 mg daily maintenance dose) is recommended for elective stenting.684–688 I A
Prasugrel or ticagrelor may be considered in specific high-risk situations of elective stenting (e.g. history of stent throm-
IIb C
bosis or left main stenting).
Bivalirudin (0.75 mg/kg bolus, followed by 1.75 mg/kg/h for up to 4 h after the procedure) is indicated in the case of hep-
I C
arin-induced thrombocytopenia.
Instruction of patients about the importance of complying with antiplatelet therapy is recommended. I C
In patients with SCAD treated with coronary stent implantation, DAPT consisting of clopidogrel in addition to aspirin is
I A
generally recommended for 6 months, irrespective of the stent type.c 690–694
In patients with SCAD treated with BRS, DAPT should be considered for at least 12 months and up to the presumed
IIa C
full absorption of the BRS, based on an individual assessment of bleeding and ischaemic risk.
In patients with SCAD treated with DCB, DAPT should be considered for 6 months.369,371 IIa B
In patients with SCAD considered at high bleeding risk (e.g. PRECISE-DAPT >_25), DAPT should be considered for 3
IIa A
months.d 695,696
In patients with SCAD who have tolerated DAPT without a bleeding complication and who are at low bleeding risk but
high thrombotic risk, continuation of DAPT with clopidogrel for >6 months and up to 30 months may be IIb A
considered.697–700
In patients with SCAD in whom 3 month DAPT poses safety concerns, DAPT may be considered for 1 month. IIb C
BRS = bioresorbable scaffold; CAD = coronary artery disease; DAPT = dual antiplatelet therapy; DCB = drug-coated balloon; i.v. = intravenous; MI = myocardial infarction;
PCI = percutaneous coronary intervention; p.o. = orally; PRECISE-DAPT = PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual
Anti Platelet Therapy; SCAD = stable coronary artery disease.
a
Class of recommendation.
b
Level of evidence.
c
These recommendations refer to stents that are supported by large-scale randomized trials with clinical endpoint evaluation leading to an unconditional CE mark.
d
The evidence supporting this recommendation comes from two studies where the zotarolimus-eluting Endeavour stent was investigated in conjunction with a 3 month DAPT
regimen.
ESC/EACTS Guidelines 141
..
17.2 Non-ST-segment elevation acute .. not confirmed in VALIDATE-SWEDEHEART and in a contemporary
.. setting of preferred radial access and selective use of GP IIb/IIIa inhibi-
coronary syndrome ..
The activation of blood platelets and the coagulation cascade plays a .. tors. More recently, a meta-analysis updated for the results of
.. VALIDATE-SWEDEHEART confirmed that bivalirudin compared
key role in the initial phase and evolution of an ACS. Hence, sufficient ..
platelet inhibition and anticoagulation is essential during ACS, and .. with heparin was associated with a similar incidence of all-cause death
.. and ischaemic events after PCI for ACS.710 A significant association of
especially in ACS patients undergoing PCI. ..
.. bivalirudin with decreased risk of bleeding was only found with unbal-
.. anced use of GP IIb/IIIa inhibitors in conjunction with heparin. In sum-
17.2.1 Choice of treatment and pre-treatment
..
.. mary and based on the above-mentioned trials, UFH is primarily
For NSTE-ACS patients, DAPT including aspirin and a potent P2Y12 .. recommended as an anticoagulant for PCI. Due to its short half-life
receptor inhibitor (prasugrel or ticagrelor) is recommended (see the
..
.. and favourable results in some of the studies, bivalirudin may be con-
Supplementary Data).701,702 Clopidogrel should only be used when .. sidered as an alternative to UFH in selected cases.
..
Recommendations for antithrombotic treatment in patients with non-ST-elevation acute coronary syndromes under-
going percutaneous coronary intervention
Aspirin is recommended for all patients without contraindications at an initial oral loading dose of 150–300 mg (or
I A
75–250 mg i.v.), and at a maintenance dose of 75–100 mg daily long-term.681,683,721
A P2Y12 inhibitor is recommended in addition to aspirin, maintained over 12 months unless there are contraindica-
I A
tions such as an excessive risk of bleeding.701,702,722,723 Options are:
Prasugrel in P2Y12-inhibitor naı̈ve patients who proceed to PCI (60 mg loading dose, 10 mg daily dose).701 I B
Ticagrelor irrespective of the preceding P2Y12 inhibitor regimen (180 mg loading dose, 90 mg b.i.d.).702
I B
Clopidogrel (600 mg loading dose, 75 mg daily dose) only when prasugrel or ticagrelor are not available or are
contraindicated.722–724 I B
GP IIb/IIIa antagonists should be considered for bail-out if there is evidence of no-reflow or a thrombotic
IIa C
complication.
For pre-treatment in patients with NSTE-ACS undergoing invasive management, ticagrelor administration (180 mg
loading dose, 90 mg b.i.d.), or clopidogrel (600 mg loading dose, 75 mg daily dose) if ticagrelor is not an option, IIa C
should be considered as soon as the diagnosis is established.
GP IIb/IIIa antagonists may be considered in P2Y12-inhibitor naı̈ve patients undergoing PCI. IIb C
Pre-treatment with GP IIb/IIIa antagonists in patients in whom coronary anatomy is not known is not
III A
recommended.713,714,725
Administration of prasugrel in patients in whom coronary anatomy is not known is not recommended.165 III B
Continued
ESC/EACTS Guidelines 143
Peri-interventional therapy
It is recommended that anticoagulation is selected according to both ischaemic and bleeding risks, and according to
I C
the efficacy–safety profile of the chosen agent.
UFH is recommended. I C
In patients on fondaparinux, a single bolus UFH (85 IU/kg, or 60 IU in the case of concomitant use of GP IIb/IIIa
I B
receptor inhibitors) is indicated.727
Bivalirudin (0.75 mg/kg bolus, followed by 1.75 mg/kg/h for up to 4 h after the procedure) may be considered as an
IIb A
alternative to UFH.163,708,710,714,728
b.i.d. = twice daily; GP = glycoprotein; i.v. = intravenous; LMWH = low-molecular-weight heparin; NSTE-ACS = non-ST-segment elevation acute coronary syndromes; PCI =
percutaneous coronary intervention; UFH = unfractionated heparin.
a
Class of recommendation.
b
Level of evidence.
Recommendations for post-interventional and maintenance treatment in patients with non-ST-elevation acute coro-
nary syndromes and ST-elevation myocardial infarction undergoing percutaneous coronary intervention
In patients with ACS treated with coronary stent implantation, DAPT with a P2Y12 inhibitor on top of aspirin is rec-
ommended for 12 months unless there are contraindications such as an excessive risk of bleeding (e.g. PRECISE- I A
DAPT >_25).701,702,722,723
In patients with ACS and stent implantation who are at high risk of bleeding (e.g. PRECISE-DAPT >_25), discontinua-
IIa B
tion of P2Y12 inhibitor therapy after 6 months should be considered.729,730
In patients with ACS treated with BRS, DAPT should be considered for at least 12 months and up to the presumed
IIa C
full absorption of the BRS, based on an individual assessment of bleeding and ischaemic risk.
De-escalation of P2Y12 inhibitor treatment (e.g. with a switch from prasugrel or ticagrelor to clopidogrel) guided by
platelet function testing may be considered as an alternative DAPT strategy, especially for ACS patients deemed IIb B
unsuitable for 12-month potent platelet inhibition.717
In patients with ACS who have tolerated DAPT without a bleeding complication, continuation of DAPT for longer
IIb A
than 12 months may be considered.700,731
In patients with MI and high ischaemic riskc who have tolerated DAPT without a bleeding complication, ticagrelor
IIb B
60 mg b.i.d. for longer than 12 months on top of aspirin may be preferred over clopidogrel or prasugrel.732–734
In ACS patients with no prior stroke/TIA, and at high ischaemic risk as well as low bleeding risk, receiving aspirin
and clopidogrel, low-dose rivaroxaban (2.5 mg b.i.d. for approximately 1 year) may be considered after discontinua- IIb B
tion of parenteral anticoagulation.720
ACS = acute coronary syndrome; b.i.d. = twice daily; BRS = bioresorbable scaffold; DAPT = dual antiplatelet therapy; MI = myocardial infarction; PCI = percutaneous coronary
intervention; PRECISE-DAPT = PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy; TIA = transient ischae-
mic attack.
a
Class of recommendation.
b
Level of evidence.
c
Defined as >_50 years of age and having one of the following additional high-risk features: age >_65 years or older, diabetes mellitus requiring medication, a second prior sponta-
neous MI, multivessel coronary artery disease, or chronic renal dysfunction, defined as an estimated creatinine clearance <60 mL/min.
144 ESC/EACTS Guidelines
requires patient-by-patient decisions. Of note, previous randomized ... relevant bleeding events. However, as compared with triple therapy,
..
studies evaluating the duration of triple therapy or the benefit of .. an increase in both MI (4.5 vs. 3.0%, P = 0.09) and stent thrombosis
NOACs vs. vitamin K antagonists (VKAs) were not adequately pow- .. risk (1.5 vs. 0.8%, P = 0.15) was reported for the lower dabigatran
..
ered to assess ischaemic events, and data are lacking on the efficacy .. dose (110 mg b.i.d.), but not for the higher dabigatran dose (150 mg
of dual therapy in patients at high risk of stroke or recurrent .. b.i.d.). Although statistical significance was missed, these findings raise
..
ACS.754–757 In the major trials, there was no interaction between the .. concern about the efficacy of the lower dabigatran dose in combina-
duration of triple therapy and clinical presentation (ACS vs. no ACS). .. tion with single antiplatelet therapy in preventing coronary events.
..
The rate of bleeding events peaked within the first 30 days of initia- .. Thus, the 150 mg b.i.d. dose of dabigatran is preferred. At present,
tion of triple therapy, and was twice as high when compared with the .. evidence for a dual treatment approach is available for VKA,755 rivar-
..
rate of acute coronary events including recurrent MI and stent .. oxaban,756 and dabigatran,757 but none of these studies were pow-
thrombosis. For these reasons, the duration of triple therapy should .. ered to assess the efficacy of preventing stent thrombosis or
..
be minimized depending on bleeding and ischaemic risks (see Tables 8 .. thrombo-embolic events and only RE-DUAL used a NOAC dose
Assess ischaemic and bleeding risks using validated risk predictors (e.g. CHA2DS2-VASc, ABC, and HAS-BLED) with a focus on modifiable risk
factors.
Keep triple therapy duration as short as possible; dual therapy after PCI (OAC and clopidogrel) to be considered instead of triple therapy.
One should consider the use of a NOAC instead of a VKA when NOACs are not contraindicated.
Consider a target INR in the lower part of the recommended target range and maximize time in the therapeutic range (i.e. >65%)
when a VKA is used.
Table 9 High-risk features for ischaemic events Dual antiplatelet therapy duration in patients with indi-
cation for oral anticoagulation
Prior stent thrombosis on adequate antiplatelet therapy
Recommendations Classa Levelb
Stenting of the last remaining patent coronary artery
It is recommended that periprocedural aspirin
Diffuse multivessel disease, especially in diabetic patients and clopidogrel are administered to patients I C
undergoing coronary stent implantation.
Chronic kidney disease (i.e. creatinine clearance <60 mL/min)
In patients treated with coronary stent implan-
At least three stents implanted tation, triple therapy with aspirin, clopidogrel,
IIa B
and an OAC should be considered for 1 month,
At least three lesions treated
irrespective of the type of stent used.755
STEMI = ST-elevation myocardial infarction. Dual therapy with clopidogrel 75 mg/day and
an OAC should be considered as an alterna-
tive to 1-month triple antithrombotic ther- IIa A
apy in patients in whom the bleeding risk
outweighs the ischaemic risk.754,756,757
ACS = acute coronary syndrome; AF = atrial fibrillation; b.i.d. = twice daily; INR
= international normalized ratio; OAC = oral anticoagulant; NOAC = non-vita-
min K oral anticoagulant; q.d. = once daily; VKA = vitamin K antagonist.
a
Class of recommendation.
b
Level of evidence.
c
Apixaban 5 mg b.i.d. or apixaban 2.5 mg b.i.d. if at least two of the following: age
>_80 years, body weight <_60 kg, or serum creatinine level >_1.5 mg/dL (133 mmol/
L); dabigatran 110 mg or 150 mg b.i.d.; and edoxaban 60 mg q.d. or edoxaban 30
mg q.d. if any of the following: creatinine clearance of 30–50 mL/min; body weight
<_60 kg; concomitant use of verapamil, quinidine, or dronedarone; and rivaroxa-
ban 20 mg q.d. or rivaroxaban 15 mg q.d. if creatinine clearance 30–49 mL/min.
148 ESC/EACTS Guidelines
Concerns about
ischaemic risk3 Concerns about bleeding risk4 prevailing
prevailing
Time from
treatment
initiation
3 months A C O C O OR A O
Triple Therapy Dual Therapy
up to 6 months up to 12 months
Class IIa B Class IIa A
6 months
C O A O
Dual Therapy up to 12 months
Class IIa A
12 months
Beyond O
12 months OAC monotherapy
Class IIa B
©ESC 2018
A = Aspirin C = Clopidogrel O = Oral anticoagulation1
Colour-coding refers to the number of concomitant antithrombotic medication(s). Triple therapy denotes treatment with DAPT plus oral anticoagulant (OAC). Dual
therapy denotes treatment with a single antiplatelet agent (aspirin or clopidogrel) plus OAC.
ABC = Age, Biomarkers, Clinical history; AF = atrial fibrillation; HAS-BLED = Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition,
Labile INR, Elderly, Drugs/alcohol concomitantly; VKA = vitamin K antagonist.
1
Non-vitamin K antagonist oral anticoagulant (NOAC) preferred over VKA in patients with non-valvular AF. (Class IIaA).
2
Periprocedural administration of aspirin and clopidogrel during PCI is recommended irrespective of the treatment strategy.
3
High ischaemic risk is considered as an acute clinical presentation or anatomical/procedural features which might increase the risk for myocardial infarction.
4
Bleeding risk can be estimated by HAS-BLED or ABC score.
Figure 11 Algorithm for dual antiplatelet therapy in patients with an indication for oral anticoagulation undergoing percutaneous coronary
intervention.
17.5.2 Revascularization in patients with renal .. 17.5.4 Surgery in patients on dual antiplatelet therapy
..
failure .. See 2017 ESC Focused Update on Dual Antiplatelet Therapy in
See the Supplementary Data.
.. Coronary Artery Disease.410
..
..
..
17.5.3 Monitoring of antiplatelet drugs (platelet function .. 17.6 Gaps in the evidence
testing and genotyping)
.. The value of pre-hospital pre-treatment with prasugrel in STEMI
..
See the Supplementary Data. . patients, as well as the safety and efficacy of ticagrelor given at
ESC/EACTS Guidelines 149
CABG
It should be considered that CABG be performed at institutions with annual institutional volumes of >_200 CABG cases. IIa C
PCI
It should be considered that PCI for ACS be performed by trained operators with annual volumes of >_75 procedures
at institutions performing >_400 PCIs per year with an established 24 h/7 day service for the treatment of patients with IIa C
ACS.
It should be considered that institutions with annual volumes of <400 PCIs collaborate in networks with higher-volume
IIa C
institutions (>400 PCIs per year), with shared written protocols and exchange of operators and support staff.
It should be considered that PCI for LM be performed by trained operators with an annual volume of >_25 LM PCI cases
IIa C
per year.
It should be considered that non-emergency high-risk PCI procedures—such as for LM disease, single remaining patent
coronary artery, and complex chronic total occlusions—are only performed by adequately experienced operators at IIa C
centres that have access to circulatory support and intensive care treatment.
ACS = acute coronary syndromes; CABG = coronary artery bypass grafting; LM = left main; PCI = percutaneous coronary intervention; SCAD = stable coronary artery
disease.
a
Class of recommendation.
b
Level of evidence.
Training in CABG
It is recommended that trainees in cardiac surgery and interventional cardiology follow a competency-driven residency
I C
programme with regular evaluation of progression.
It should be considered that trainees in cardiac surgery perform >_200 CABG procedures under supervision before
IIa C
being independent.
Training in PCI
It should be considered that trainees in interventional cardiology perform >_200 PCI procedures as first operator, with
IIa C
one-third of PCI procedures in emergency or ACS patients under supervision, before being independent.
It should be considered that trainees in interventional cardiology complete formal training according to a 1–2 year cur-
riculum at institutions with >_800 PCIs per year and an established 24 h/7 day service for the treatment of patients with IIa C
ACS.
ACS = acute coronary syndrome; CABG = coronary artery bypass grafting; PCI = percutaneous coronary intervention.
a
Class of recommendation.
b
Level of evidence.
ESC/EACTS Guidelines 151
Recommendations for outcome registration, monitor- Strategies for follow-up and management in patients
ing, and benchmarking after myocardial revascularization
It is recommended that specific quality per- After CABG or PCI for AMI, participation in
formance measures for CABG are adopted a cardiac rehabilitation programme is rec-
I C I A
at a national level to allow outcome moni- ommended to improve patient
toring and benchmarking. outcomes.777
..
19.1 Gaps in the evidence .. (5) In some instances, both PCI and CABG are equally reasonable, or
In all studies to date on the optimal follow-up after PCI, the gain from
.. sometimes even equally problematic, options. This calls for the
..
discovering patients with restenosis is obscured by the high rate .. Heart Team to be consulted to develop individualized treatment
.. concepts, with respect for the preferences of the patient who has
of false positive exercise ECG tests indicating ischaemia. Therefore, ..
simple exercise ECG testing is not recommended for follow-up and .. been informed about early and late outcomes.
.. (6) Timely PCI of the culprit lesion remains the mainstay of treatment
a non-invasive imaging approach is preferred. Specific studies to ..
clarify which subset of patients benefits more from a specific follow- .. of ACS.
.. (7) After PCI of the culprit lesion in ACS, the choice of further revas-
up approach are missing. More studies are needed to assess the role ..
of CT angiography in patient surveillance after myocardial .. cularization modality should follow the criteria applied to patients
.. with SCAD.
revascularization. ..
.. (8) Radial access is preferred for any PCI irrespective of clinical pre-
.. sentation, unless there are overriding procedural considerations.
..
21 Evidence-based ‘to do’ and ‘not to do’ messages from the Guidelines
Risk models to assess short- and long-term outcomes after myocardial revascularization Classa Levelb
When evidence of ischaemia is not available, FFR or iwFR are recommended to assess the haemodynamic relevance
I A
of intermediate-grade stenosis.
It is recommended that the STS score is calculated to assess in-hospital or 30 day mortality, and in-hospital morbidity,
I B
after CABG.
In patients with LM or multivessel disease, it is recommended that the SYNTAX score is calculated to assess the
I B
anatomical complexity of CAD and the long-term risk of mortality and morbidity after PCI.
Two- or three-vessel disease with stenosis >50%c with impaired LV function (LVEF <_35%).c I A
d
Large area of ischaemia detected by functional testing (>10% LV) or abnormal invasive FFR. I B
For symptoms Any haemodynamically significant coronary stenosis in the presence of limiting angina or angina equivalent,
I A
with an insufficient response to optimized medical therapy.
Continued
ESC/EACTS Guidelines 153
Type of revascularization (CABG or PCI) in patients with SCAD with suitable coronary anatomy for both
procedures and low predicted surgical mortality
One-vessel CAD
LM CAD
An early invasive strategy (<24 h) is recommended in patients with at least one high-risk criterion (Figure 4). I A
An invasive strategy (<72 h after first presentation) is indicated in patients with at least one intermediate-risk
I A
criterion (Figure 4) or recurrent symptoms.
It is recommended that the revascularization strategy (ad hoc culprit-lesion PCI/multivessel PCI/CABG) is based
on the patient’s clinical status and comorbidities, as well as the disease severity, i.e. distribution and I B
angiographic lesion characteristics (e.g. SYNTAX score), according to the principles for SCAD.
In cardiogenic shock, routine revascularization of non-IRA lesions is not recommended during primary PCI. III B
Continued
154 ESC/EACTS Guidelines
Indication
Reperfusion therapy is indicated in all patients with time from symptom onset <12 h duration and persistent ST-seg-
I A
ment elevation.
Logistics
It is recommended that the pre-hospital management of STEMI patients be based on regional networks that are
It is recommended that primary PCI-capable centres deliver a 24 h/7 day service and ensure that primary PCI is per-
I B
formed as fast as possible.
Patients transferred to a PCI-capable centre for primary PCI should bypass the emergency department and be trans-
I B
ferred directly to the catheterization laboratory.
Strategy/technique
In cardiogenic shock, routine revascularization of non-IRA lesions is not recommended during primary PCI. III B
Recommendations on revascularizations in patients with chronic heart failure and systolic LV dysfunction (EF 35%)
In patients with severe LV systolic dysfunction and coronary artery disease suitable for intervention, myocardial revas-
I B
cularization is recommended.
CABG is recommended as the first revascularization strategy choice in patients with multivessel disease and acceptable
I B
surgical risk.
Emergency invasive evaluation is indicated in patients with acute heart failure or cardiogenic shock complicating ACS. I B
Emergency PCI is indicated for patients with cardiogenic shock due to STEMI or NSTE-ACS, independent of time delay
I B
of symptom onset, if coronary anatomy is amenable.
Emergency CABG is recommended for patients with cardiogenic shock if the coronary anatomy is not amenable to
I B
PCI.
Routine use of IABP in patients with cardiogenic shock due to ACS is not recommended. III B
Severe CKD
In patients undergoing CABG, carotid DUS is recommended in patients with recent (<6 months) history of stroke/TIA. I B
Continued
ESC/EACTS Guidelines 155
Repeat revascularization is indicated in patients with extensive ischaemia or severe symptoms despite medical therapy. I B
IMA is the conduit of choice for redo CABG in patients in whom the IMA was not used previously. I B
DES are recommended for the treatment of in-stent restenosis within BMS or DES. I A
Drug-coated balloons are recommended for the treatment of in-stent restenosis within BMS or DES. I A
A primary PCI strategy is recommended in patients with resuscitated cardiac arrest and an ECG consistent with STEMI. I B
Perioperative oral b-blocker therapy is recommended for the prevention of post-operative AF after CABG surgery. I B
Use of the radial artery is recommended over the saphenous vein in patients with high-degree stenosis. I A
Skeletonized IMA dissection is recommended in patients with high risk of sternal wound infection. I B
DESf are recommended over BMS for any PCI irrespective of:
• clinical presentation
• lesion type
I A
• planned non-cardiac surgery
• anticipated duration of DAPT
• concomitant anticoagulant therapy.
Radial access is recommended as the standard approach, unless there are overriding procedural considerations. I A
Stent implantation in the main vessel only, followed by provisional balloon angioplasty with or without stenting of the
I A
side branch, is recommended for PCI of bifurcation lesions.
Treatment with 600 mg clopidogrel is recommended in elective PCI patients once anatomy is known and the decision
I A
has been made to proceed with PCI.
Clopidogrel (600 mg loading dose and 75 mg daily maintenance dose) is recommended for elective stenting. I A
In patients with SCAD treated with coronary stent implantation, DAPT consisting of clopidogrel in addition to aspirin is
I A
generally recommended for 6 months, irrespective of the stent type.
Aspirin is recommended for all patients without contraindications at an initial oral loading dose of 150–300 mg (or
I A
75–250 mg i.v.) and at a maintenance dose of 75–100 mg daily long-term, regardless of treatment strategy.
Continued
156 ESC/EACTS Guidelines
A P2Y12 inhibitor is recommended in addition to aspirin, maintained over 12 months unless there are contraindications
I A
such as an excessive risk of bleeding. Options are:
Prasugrel in P2Y12-naı̈ve patients who proceed to PCI (60 mg loading dose and 10 mg daily dose) I B
Ticagrelor irrespective of the pre-treatment and revascularization strategy (180 mg loading dose, 90 mg twice daily) I B
Clopidogrel (600 mg loading dose and 75 mg daily dose), only when prasugrel or ticagrelor are not available or are
I B
contraindicated.
Pre-treatment with GP IIb/IIIa antagonists in patients in whom coronary anatomy is not known is not recommended. III A
Administration of prasugrel to patients in whom coronary anatomy is not known is not recommended. III B
In patients on fondaparinux (2.5 mg daily s.c.), a single bolus UFH (85 IU/kg, or 60 IU in the case of concomitant use of
I B
GP IIb/IIIa receptor inhibitors) is indicated.
In patients with ACS treated with coronary stent implantation, DAPT with a P2Y12 inhibitor on top of aspirin is recom-
mended for 12 months unless there are contraindications such as an excessive risk of bleeding (e.g. PRECISE-DAPT I A
>_25).
Aspirin is recommended for all patients without contraindications at an initial oral loading dose of 150–300 mg (or
I A
75–250 mg i.v.), and at a maintenance dose of 75–100 mg daily long-term regardless of treatment strategy.
A potent P2Y12 inhibitor (prasugrel or ticagrelor), or clopidogrel if these are not available or are contraindicated, is rec-
ommended before (or at the time of PCI at the latest) PCI and should be maintained over 12 months, unless there are I A
contraindications such as an excessive risk of bleeding.
After CABG or PCI for AMI, participation in a cardiac rehabilitation programme is recommended to improve patient
I A
outcomes.
It is recommended that secondary prevention measures, including medical therapy and lifestyle changes, are started and
I A
reinforced after myocardial revascularization.
ACS = acute coronary syndrome; AF = atrial fibrillation; AMI = acute myocardial infarction; BMS = bare-metal stent; CABG = coronary artery bypass grafting; CAD = coronary
artery disease; CKD = chronic kidney disease; DAPT = dual antiplatelet therapy; DES = drug eluting stents; DUS = duplex ultrasound; ECG = electrocardiogram; EF = ejection
fraction; FFR = fractional flow reserve; GP = glycoprotein; IABP = intra-aortic balloon pump; iwFR = instantaneous wave-free radio; IMA = internal mammary artery; IRA =
infarct-related artery; i.v. = intravenous; LAD = left anterior descending; LM = left main; LMWH = low-molecular-weight heparin; LV = left ventricular; LVEF = left ventricular
ejection fraction; NSTE-ACS = non-ST-elevation acute coronary syndrome; PCI = percutaneous coronary intervention; PRECISE-DAPT = PREdicting bleeding Complications
In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy; s.c. = subcutaneous; SCAD = stable coronary artery disease; STEMI = ST-elevation myo-
cardial infarction; STS = Society of Thoracic Surgeons; SYNTAX = Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery; TIA = transient
ischaemic attack; UFH = unfractionated heparin.
a
Class of recommendation.
b
Level of evidence.
c
With documented ischaemia, a haemodynamically relevant lesion defined by FFR <_0.80 or iwFR <_0.89, or >90% stenosis in a major coronary vessel.
d
Based on FFR <0.75 indicating a prognostically relevant lesion.
e
PCI should be considered, if the Heart Team is concerned about the surgical risk or if the patient refuses CABG after adequate counselling by the Heart Team.
f
These recommendations refer to stents that are supported by large-scale randomized trials with clinical endpoint evaluation leading to an unconditional CE mark.
..
22 Appendix ..
..
Gaemperli (Switzerland), Gerhard Hindricks (Germany), Bernard
.. Iung (France), Peter Jüni (Canada), Hugo A. Katus (Germany),
ESC Committee for Practice Guidelines (CPG): .. Juhani Knuuti (Finland), Patrizio Lancellotti (Belgium), Christophe
Stephan Windecker (Chairperson) (Switzerland), Victor Aboyans .. Leclercq (France), Theresa A. McDonagh (UK), Massimo Francesco
..
(France), Stefan Agewall (Norway), Emanuele Barbato (Italy), Héctor .. Piepoli (Italy), Piotr Ponikowski (Poland), Dimitrios J. Richter
Bueno (Spain), Antonio Coca (Spain), Jean-Philippe Collet (France), .. (Greece), Marco Roffi (Switzerland), Evgeny Shlyakhto (Russia),
..
Ioan Mircea Coman (Romania), Veronica Dean (France), Victoria .. Miguel Sousa-Uva (Portugal), Iain A. Simpson (UK), Jose Luis
Delgado (The Netherlands), Donna Fitzsimons (UK), Oliver .. Zamorano (Spain).
.
ESC/EACTS Guidelines 157
Robert Henderson.
.. nating myocardium. Circ Cardiovasc Imaging 2013;6:363–372.
.. 12. Ahn JM, Park DW, Shin ES, Koo BK, Nam CW, Doh JH, Kim JH, Chae IH, Yoon
.. JH, Her SH, Seung KB, Chung WY, Yoo SY, Lee JB, Choi SW, Park K, Hong TJ,
.. Lee SY, Han M, Lee PH, Kang SJ, Lee SW, Kim YH, Lee CW, Park SW, Park SJ;
23. References .. IRIS-FFR Investigators. Fractional flow reserve and cardiac events in coronary
1. Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A,
.. artery disease: Data from a prospective IRIS-FFR Registry (Interventional Cardiology
..
Bugiardini R, Crea F, Cuisset T, Di Mario C, Ferreira JR, Gersh BJ, Gitt AK, .. Research Incooperation Society Fractional Flow Reserve). Circulation 2017;135:
Hulot JS, Marx N, Opie LH, Pfisterer M, Prescott E, Ruschitzka F, Sabate M, .. 2241–2251.
Senior R, Taggart DP, van der Wall EE, Vrints CJ. 2013 ESC guidelines on the .. 13. Bech GJ, De Bruyne B, Bonnier HJ, Bartunek J, Wijns W, Peels K, Heyndrickx
management of stable coronary artery. Eur Heart J 2013;34:2949–3003. . GR, Koolen JJ, Pijls NH. Long-term follow-up after deferral of percutaneous
European Heart Journal (2019) 40, 237–269 EXPERT CONSENSUS DOCUMENT
doi:10.1093/eurheartj/ehy462
* Corresponding authors. Kristian Thygesen, Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard, DK-8200 Aarhus N, Denmark. Tel: þ45
78452262, Fax: þ45 78452260, Email: kthygesen@oncable.dk; kristhyg@rm.dk. Joseph S. Alpert, Department of Medicine, University of Arizona College of Medicine, 1501 N.
Campbell Ave., P.O. Box 245037, Tucson AZ 85724-5037, USA. Tel: þ1 5206262763, Email: jalpert@email.arizona.edu. Harvey D. White, Green Lane Cardiovascular Service,
Auckland City Hospital, Private Bag 92024, 1030 Auckland, New Zealand. Tel: þ64 96309992, Fax: 00 64 9 6309915, Email: harveyw@adhb.govt.nz.
The content of this ESC/ACC/AHA/WHF Expert Consensus Document has been published for personal and educational use only. No commercial use is authorized. No part of
the ESC/ACC/AHA/WHF Expert Consensus Document may be translated or reproduced in any form without written permission from the ESC or ACC or AHA or WHF.
Permission can be obtained upon submission of a written request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle
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issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the ESC/
ACC/AHA/WHF Expert Consensus Document fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive,
diagnostic, or therapeutic medical strategies; however, the ESC/ACC/AHA/WHF Expert Consensus Document does not override, in any way whatsoever, the individual responsi-
bility of health professionals to make appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where
appropriate and/or necessary, the patient’s caregiver. Nor does the ESC/ACC/AHA/WHF Expert Consensus Document exempt health professionals from taking into full and
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C 2018 European Society of Cardiology, American College of Cardiology, American Heart Association, Inc., and World Heart Foundation. The articles are identical except for
V
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238 Expert consensus document
Document Reviewers: David Hasdai (CPG Review Co-ordinator) (Israel), Victor Aboyans (France),
Stephan Achenbach (Germany), Stefan Agewall (Norway), Thomas Alexander (India), Alvaro Avezum
(Brazil), Emanuele Barbato (Italy), Jean-Pierre Bassand (France), Eric Bates (USA), John A. Bittl (USA),
Güenter Breithardt (Germany), Héctor Bueno (Spain), Raffaele Bugiardini (Italy), Mauricio G. Cohen
(USA), George Dangas (USA), James A. de Lemos (USA), Victoria Delgado (Netherlands), Gerasimos
Filippatos (Greece), Edward Fry (USA), Christopher B. Granger (USA), Sigrun Halvorsen (Norway), Mark
A. Hlatky (USA), Borja Ibanez (Spain), Stefan James (Sweden), Adnan Kastrati (Germany), Christophe
Leclercq (France), Kenneth W. Mahaffey (USA), Laxmi Mehta (USA), Christian Müller (Switzerland),
~ eiro (Argentina), Marco Roffi
Carlo Patrono (Italy), Massimo Francesco Piepoli (Italy), Daniel Pin
(Switzerland), Andrea Rubboli (Italy), Samin Sharma (USA), Iain A. Simpson (UK), Michael Tendera
(Poland), Marco Valgimigli (Switzerland), Allard C. van der Wal (Netherlands), Stephan Windecker
(Switzerland)
...................................................................................................................................................................................................
Keywords Expert Consensus Document • Myocardial infarction • Type 1 MI • Type 2 MI • Type 3 MI • Type 4a
MI • Type 4b MI • Type 4c MI • Type 5 MI • Cardiac troponin • High sensitivity cardiac troponin •
Myocardial injury • Prior myocardial infarction • Silent myocardial infarction • Recurrent myocardial
infarction • Re-infarction • Cardiac procedural myocardial injury • Takotsubo syndrome • Myocardial infarc-
tion with non-obstructive coronary arteries (MINOCA)
..
Table of contents .. 12 Myocardial infarction associated with coronary artery bypass
.. grafting (type 5 myocardial infarction) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
..
Abbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 .. 13 Other definitions of myocardial infarction related to percutaneous
1 What is new in the Universal Definition of Myocardial .. coronary intervention or coronary artery bypass grafting . . . . . . . . . . . 252
..
Infarction? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 .. 14 Recurrent myocardial infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
2 Universal definitions of myocardial injury and myocardial
.. 15 Re-infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
..
infarction: summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 .. 16 Myocardial injury and infarction associated with cardiac
3 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
.. procedures other than revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
..
4 Pathological characteristics of myocardial ischaemia and .. 17 Myocardial injury and infarction associated with
infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
.. non-cardiac procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
..
5 Biomarker detection of myocardial injury and infarction . . . . . . . . . . 243 .. 18 Myocardial injury or infarction associated with heart failure . . . . . . 253
6 Clinical presentations of myocardial infarction . . . . . . . . . . . . . . . . . . . . 245
.. 19 Takotsubo syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
..
7 Clinical classification of myocardial infarction . . . . . . . . . . . . . . . . . . . . . 245 .. 20 Myocardial infarction with non-obstructive coronary arteries . . . . 254
7.1 Myocardial infarction type 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
.. 21 Myocardial injury and/or infarction associated with
..
7.2 Myocardial infarction type 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246 .. kidney disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
..
7.3 Myocardial infarction type 2 and myocardial injury . . . . . . . . . . . . 248 .. 22 Myocardial injury and/or infarction in critically ill patients . . . . . . . . 254
7.4 Myocardial Infarction type 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 .. 23 Biochemical approach for diagnosing myocardial injury
..
8 Coronary procedure-related myocardial injury . . . . . . . . . . . . . . . . . . . 249 .. and infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
9 Myocardial infarction associated with percutaneous coronary .. 24 Analytical issues of cardiac troponins . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
..
intervention (type 4a myocardial infarction) . . . . . . . . . . . . . . . . . . . . . . . . 250 .. 25 The 99th percentile upper reference limit . . . . . . . . . . . . . . . . . . . . . . . 256
10 Stent/scaffold thrombosis associated with percutaneous .. 26 Operationalizing criteria for myocardial injury and infarction . . . . . 256
..
coronary intervention (type 4b myocardial infarction) . . . . . . . . . . . . . . 251 .. 27 Electrocardiographic detection of myocardial infarction . . . . . . . . . 257
11 Restenosis associated with percutaneous coronary intervention .. 28 Application of supplemental electrocardiogram leads . . . . . . . . . . . . 258
..
(type 4c myocardial infarction) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 . 29 Electrocardiographic detection of myocardial injury . . . . . . . . . . . . . 259
Expert consensus document 239
Updated concepts
• Type 1 myocardial infarction: Emphasis on the causal relationship of plaque disruption with coronary athero-thrombosis; new Figure 3.
• Type 2 myocardial infarction: Settings with oxygen demand and supply imbalance unrelated to acute coronary athero-thrombosis;
new Figures 4 and 5.
• Type 2 myocardial infarction: Relevance of presence or absence of coronary artery disease to prognosis and therapy.
• Differentiation of myocardial injury from type 2 myocardial infarction; new Figure 6.
• Type 3 myocardial infarction: Clarify why type 3 myocardial infarction is a useful category to differentiate from sudden cardiac death.
• Types 4–5 myocardial infarction: Emphasis on distinction between procedure-related myocardial injury and procedure-related
myocardial infarction.
• Cardiac troponin: Analytical issues for cardiac troponins; new Figure 7.
• Emphasis on the benefits of high-sensitivity cardiac troponin assays.
• Considerations relevant to the use of rapid rule-out and rule-in protocols for myocardial injury and myocardial infarction.
• Issues related to specific diagnostic change ('delta') criteria for the use of cardiac troponins to detect or exclude acute myocardial
injury.
• Consideration of new non-rate-related right bundle branch block with specific repolarization patterns.
• ST-segment elevation in lead aVR with specific repolarization patterns, as a STEMI equivalent.
• ECG detection of myocardial ischaemia in patients with an implantable cardiac defibrillator or a pacemaker.
• Enhanced role of imaging including cardiac magnetic resonance imaging for the diagnosis of myocardial infarction; new Figure 8.
New sections
©ESC/ACC/AHA/WHF 2018
• Takotsubo syndrome.
• MINOCA.
• Chronic kidney disease.
• Atrial fibrillation.
• Regulatory perspective on myocardial infarction.
• Silent or unrecognized myocardial infarction.
ECG = electrocardiogram; MINOCA = myocardial infarction with non-obstructive coronary arteries; STEMI = ST-elevation myocardial infarction.
Expert consensus document 241
The term acute myocardial infarction should be used when there is acute myocardial injury with clinical evidence of acute myocardial
ischaemia and with detection of a rise and/or fall of cTn values with at least one value above the 99th percentile URL and at least one of
the following:
• Symptoms of myocardial ischaemia;
• New ischaemic ECG changes;
• Development of pathological Q waves;
• Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an
ischaemic aetiology;
• Identification of a coronary thrombus by angiography or autopsy (not for types 2 or 3 MIs).
Post-mortem demonstration of acute athero-thrombosis in the artery supplying the infarcted myocardium meets criteria for type 1 MI.
Evidence of an imbalance between myocardial oxygen supply and demand unrelated to acute athero-thrombosis meets criteria for type 2 MI.
Cardiac death in patients with symptoms suggestive of myocardial ischaemia and presumed new ischaemic ECG changes before cTn
values become available or abnormal meets criteria for type 3 MI.
Any one of the following criteria meets the diagnosis for prior or silent/unrecognized MI:
• Abnormal Q waves with or without symptoms in the absence of non-ischaemic causes.
• Imaging evidence of loss of viable myocardium in a pattern consistent with ischaemic aetiology.
• Patho-anatomical findings of a prior MI.
CABG = coronary artery bypass grafting; cTn = cardiac troponin; ECG = electrocardiogram; MI = myocardial infarction; PCI = percutaneous coronary intervention; URL =
upper reference limit.
242 Expert consensus document
..
3 Introduction .. Cardiology (ACC) collaborated to redefine MI using a biochemical
.. and clinical approach, and reported that myocardial injury detected
In the late 19th century, post-mortem examinations demonstrated a
.. by abnormal biomarkers in the setting of acute myocardial ischaemia
..
possible relationship between thrombotic occlusion of a coronary ... should be labelled as MI.9 The principle was further refined by the
artery and myocardial infarction (MI).1 However, it was not until the .. Global MI Task Force, leading to the Universal Definition of
beginning of the 20th century that the first clinical descriptions
..
.. Myocardial Infarction Consensus Document in 2007, introducing a
appeared describing a connection between the formation of a throm- .. novel MI classification system with five subcategories.10 This docu-
bus in a coronary artery and its associated clinical features.2,3 Despite
..
.. ment, endorsed by the ESC, the ACC), the American Heart
these landmark observations, considerable time elapsed before gen- .. Association (AHA), and the World Heart Federation (WHF), was
..
eral clinical acceptance of this entity was achieved, in part due to one .. adopted by the WHO.11 The development of even more sensitive
autopsy study that showed no thrombi in the coronary arteries of .. assays for markers of myocardial injury made further revision of the
..
31% of deceased patients with an MI.4 The clinical entity was referred .. document necessary, particularly for patients who undergo coronary
Figure 1 History of documents on the definition of myocardial infarction. ACC = American College of Cardiology; AHA = American Heart
Association; ESC = European Society of Cardiology; ISFC = International Society and Federation of Cardiology; MONICA = MONItoring of trends
and determinants in CArdiovascular disease; NHLBI = National Heart, Lung, and Blood Institute; UDMI = Universal Definition of Myocardial
Infarction; WHF = World Heart Federation; WHO = World Health Organization.
Expert consensus document 243
..
patients with increased cTn values, clinicians must distinguish whether .. reported to occur following injury to non-cardiac tissues. The situa-
patients have suffered a non-ischaemic myocardial injury or one of the .. tion is more complex for cTnT. Biochemical data indicate that injured
..
MI subtypes. If there is no evidence to support the presence of myo- .. skeletal muscle expresses proteins that are detected by the cTnT
cardial ischaemia, a diagnosis of myocardial injury should be made. .. assay, leading to some situations where elevations of cTnT could
..
This diagnosis can be changed if subsequent evaluation indicates crite- .. emanate from skeletal muscle.23–27 Recent data suggest that the fre-
ria for MI. The current Fourth Universal Definition of Myocardial .. quency of such elevations in the absence of ischaemic heart disease
..
Infarction Consensus Document reflects these considerations through .. may be higher than originally thought.28,29 cTnI and cTnT are the pre-
adhering to the clinical approach of the definition of MI. .. ferred biomarkers for the evaluation of myocardial injury,12,21,22,30
..
.. and high-sensitivity (hs)-cTn assays are recommended for routine
.. clinical use.22 Other biomarkers, e.g. creatine kinase MB isoform
..
Clinical criteria for MI .. (CK-MB), are less sensitive and less specific.31 Myocardial injury is
.. defined as being present when blood levels of cTn are increased
..
infarction
MI is defined pathologically as myocardial cell death due to prolonged
ischaemia. Diminished cellular glycogen, and relaxed myofibrils and or chronic, in the setting of persistently elevated cTn levels.
sarcolemmal disruption, are the first ultrastructural changes and are Although elevated cTn values reflect injury to myocardial cells,
seen as early as 10–15 min after the onset of ischaemia.16 they do not indicate the underlying pathophysiological mechanisms,
Mitochondrial abnormalities are observed as early as 10 min after and can arise following preload-induced mechanical stretch or phys-
coronary occlusion by electron microscopy and are progressive.17 It iological stresses in otherwise normal hearts.32–34 Various causes
can take hours before myocyte necrosis can be identified by post- have been suggested for the release of structural proteins from the
mortem examination in humans; this is in contrast to animal models, myocardium, including normal turnover of myocardial cells, apopto-
in which biochemical evidence of myocardial cell death due to apop- sis, cellular release of cTn degradation products, increased cellular
tosis can be detected within 10 min of induced myocardial ischaemia wall permeability, the formation and release of membranous blebs,
in association with myocyte death.15 Experimentally, necrosis pro- and myocyte necrosis.27,35 Yet, it is not clinically possible to distin-
gresses from the subendocardium to the subepicardium over several guish which increases of cTn levels are due to which mechanisms.36
hours. The time course may be prolonged by increased collateral However, regardless of the mechanism, acute myocardial injury,
flow, reduced determinants of myocardial oxygen consumption, and when associated with a rising and/or falling pattern of cTn values with
intermittent occlusion/reperfusion, which can precondition the at least one value above the 99th percentile URL and caused by myo-
heart.18 Timely implementation of reperfusion therapy, when appro- cardial ischaemia, is designated as an acute MI.12,21,22,30 Histological
priate, reduces ischaemic injury of the myocardium.19,20 evidence of myocardial injury with myocyte death can be detected in
clinical conditions associated with non-ischaemic mechanisms of
myocardial injury as well37,38 (Figure 2).
5 Biomarker detection of Myocardial ischaemic or non-ischaemic conditions associated with
myocardial injury and infarction increased cTn values are presented in Table 1. The complexity of clin-
ical circumstances may sometimes make it difficult to discriminate
Cardiac troponin I (cTnI) and T (cTnT) are components of the con- specific individual mechanism(s) of myocardial injury. In this situation,
tractile apparatus of myocardial cells and are expressed almost exclu- the multifactorial contributions resulting in myocardial injury should
sively in the heart.21,22 Increases in cTnI values have not been be described in the patient record.
244 Expert consensus document
No myocardial injurya
Increased cTn =
Hypoxaemia myocardial injuryb Anaemia
Clinical evidence
©ESC/ACC/AHA/WHF 2018
Kidney Heart
disease failure
Figure 2 Spectrum of myocardial injury, ranging from no injury to myocardial infarction. Various clinical entities may involve these myocardial cate-
gories, e.g. ventricular tachyarrhythmia, heart failure, kidney disease, hypotension/shock, hypoxaemia, and anaemia. cTn = cardiac troponin; URL =
upper reference limit. aNo myocardial injury = cTn values <_ 99th percentile URL or not detectable. bMyocardial injury = cTn values > 99th percentile
URL. cMyocardial infarction = clinical evidence of myocardial ischaemia and a rise and/or fall of cTn values > 99th percentile URL.
Expert consensus document 245
..
Table 1 Reasons for the elevation of cardiac troponin
.. rest, or an ischaemic equivalent such as dyspnoea or fatigue. Often,
.. the discomfort is diffuse; not localized, nor positional, nor affected by
values because of myocardial injury ..
.. movement of the region. However, these symptoms are not specific
.. for myocardial ischaemia and can be observed in other conditions
..
Myocardial injury related to acute myocardial ischaemia .. such as gastrointestinal, neurological, pulmonary, or musculoskeletal
.. complaints. MI may occur with atypical symptoms such as palpitations
Atherosclerotic plaque disruption with thrombosis. ..
.. or cardiac arrest, or even without symptoms.12 Very brief episodes
Myocardial injury related to acute myocardial ischaemia
.. of ischaemia too short to cause necrosis can also cause cTn release
..
because of oxygen supply/demand imbalance .. and elevations. The involved myocytes can subsequently die due to
.. apoptosis.42
Reduced myocardial perfusion, e.g. ..
• Coronary artery spasm, microvascular dysfunction .. If myocardial ischaemia is present clinically or detected by ECG
• Coronary embolism
.. changes together with myocardial injury, manifested by a rising and/
..
• Stroke, subarachnoid haemorrhage .. (STEMI) (see section 27). In contrast, patients without ST-segment
• Pulmonary embolism, pulmonary hypertension ..
• Infiltrative diseases, e.g. amyloidosis, sarcoidosis .. elevation at presentation are usually designated non-ST-elevation MI
• Chemotherapeutic agents .. (NSTEMI). The categories of patients with STEMI, NSTEMI, or unsta-
• Critically ill patients
..
.. ble angina are customarily included in the concept of ACS. In addition
• Strenuous exercise ..
.. to these categories, MI may be classified into various types based on
.. pathological, clinical, and prognostic differences, along with different
For a more comprehensive listing, see39–41
..
.. treatment strategies.
..
..
.. 7.1 Myocardial infarction type 1
6 Clinical presentations of ..
.. MI caused by atherothrombotic coronary artery disease (CAD) and
.. usually precipitated by atherosclerotic plaque disruption (rupture or
myocardial infarction ..
.. erosion) is designated as a type 1 MI. The relative burden of athero-
Onset of myocardial ischaemia is the initial step in the development .. sclerosis and thrombosis in the culprit lesion varies greatly, and the
..
of MI and results from an imbalance between oxygen supply and .. dynamic thrombotic component may lead to distal coronary emboli-
demand. Myocardial ischaemia in a clinical setting can most often be .. zation resulting in myocyte necrosis.44,45 Plaque rupture may
..
identified from the patient’s history and from the ECG. Possible .. not only be complicated by intraluminal thrombosis but also by
ischaemic symptoms include various combinations of chest, upper .. haemorrhage into the plaque through the disrupted surface
..
extremity, mandibular, or epigastric discomfort during exertion or at . (Figure 3).44,45
246 Expert consensus document
©ESC/ACC/AHA/WHF 2018
Plaque rupture/erosion with
non-occlusive thrombus
..
Criteria for type 1 MI .. demand has been classified as type 2 MI.10,12 By definition, acute athe-
.. rothrombotic plaque disruption is not a feature of type 2 MI. In
Detection of a rise and/or fall of cTn values with at least one ..
value above the 99th percentile URL and with at least one of the
.. patients with stable known or presumed CAD, an acute stressor
.. such as an acute gastrointestinal bleed with a precipitous drop in hae-
following: ..
.. moglobin, or a sustained tachyarrhythmia with clinical manifestations
• Symptoms of acute myocardial ischaemia; .. of myocardial ischaemia, may result in myocardial injury and a type 2
..
• New ischaemic ECG changes; .. MI. These effects are due to insufficient blood flow to the ischaemic
• Development of pathological Q waves; .. myocardium to meet the increased myocardial oxygen demand of
..
• Imaging evidence of new loss of viable myocardium or new .. the stressor. Ischaemic thresholds may vary substantially in individual
regional wall motion abnormality in a pattern consistent with .. patients depending on the magnitude of the stressor, the presence of
an ischaemic aetiology;
..
.. non-cardiac comorbidities, and the extent of underlying CAD and
• Identification of a coronary thrombus by angiography includ- .. cardiac structural abnormalities.
ing intracoronary imaging or by autopsy.a
..
.. Studies have shown variable occurrences of type 2 MI depending
.. on criteria used for diagnosis. Some reports rely on specific predeter-
..
cTn = cardiac troponin; ECG = electrocardiogram; URL = upper .. mined oxygen mismatch criteria,48,49 whereas others apply more lib-
reference limit. .. eral criteria. Most studies show a higher frequency of type 2 MI in
..
a
Post-mortem demonstration of an atherothrombus in the artery .. women. The short- and long-term mortality rates for patients with
supplying the infarcted myocardium, or a macroscopically large cir-
.. type 2 MI are generally higher than for type 1 MI patients in most but
..
cumscribed area of necrosis with or without intramyocardial hae- .. not all studies due to an increased prevalence of comorbid con-
..
morrhage, meets the type 1 MI criteria regardless of cTn values. .. ditions.49–57 Coronary atherosclerosis is a common finding in type 2
.. MI patients selected for coronary angiography. In general, these
..
It is essential to integrate the ECG findings with the aim of classify- .. patients have a worse prognosis than those without CAD.54–57
ing type 1 MI into STEMI or NSTEMI in order to establish the appro- .. Prospective evaluations of the importance of CAD with type 2 MI
priate treatment according to current Guidelines.46,47
..
.. using consistent definitions and approaches are needed.
.. It has been shown that the frequency of ST-segment elevation in
..
7.2 Myocardial infarction type 2 .. type 2 MI varies from 3–24%.53 In some cases, coronary embolism
The pathophysiological mechanism leading to ischaemic myocardial
.. caused by thrombi, calcium or vegetation from the atria or ventricles,
..
injury in the context of a mismatch between oxygen supply and . or acute aortic dissection may result in a type 2 MI. Spontaneous
Expert consensus document 247
..
coronary artery dissection with or without intramural haematoma is .. hypertrophy. In patients who undergo timely coronary angiography,
another non-atherosclerotic condition that may occur, especially in .. description of a ruptured plaque with thrombus in the infarct-related
..
young women. It is defined as spontaneous dissection of the coronary .. artery may be helpful in making the distinction between type 2 MI vs.
artery wall with accumulation of blood within the false lumen, which .. type 1 MI, but angiography is not always definitive, clinically indicated,
..
can compress the true lumen to varying degrees (Figure 4).58 .. or required to establish the diagnosis of type 2 MI.
All of the clinical information available should be considered in dis- .
tinguishing type 1 MI from type 2 MI. The context and mechanisms of
type 2 MI should be considered when establishing this diagnosis Criteria for type 2 MI
(Figure 5). The myocardial oxygen supply/demand imbalance attribut- Detection of a rise and/or fall of cTn values with at least one value
able to acute myocardial ischaemia may be multifactorial, related above the 99th percentile URL, and evidence of an imbalance
either to: reduced myocardial perfusion due to fixed coronary athe- between myocardial oxygen supply and demand unrelated to acute
rosclerosis without plaque rupture, coronary artery spasm, coronary coronary athero-thrombosis, requiring at least one of the following:
Vasospasm or coronary
microvascular dysfunction
Non-atherosclerotic
coronary dissection
©ESC/ACC/AHA/WHF 2018
Oxygen supply/demand
imbalance alone
Severe bradyarrhythmia
Respiratory failure
©ESC/ACC/AHA/WHF 2018
a
Severe anaemia
Ischaemic thresholds vary substantially in
relation to the magnitude of the stressor and the Hypotension/Shock
extent of underlying cardiac disease.
Figure 5 Framework for type 2 myocardial infarction considering the clinical context and pathophysiological mechanisms attributable to acute
myocardial ischaemia. The illustration above is modified from Januzzi and Sandoval.59
..
It appears advisable in the acute setting to treat the underlying .. Type 2 MI and non-ischaemic myocardial injury may coexist. It should
ischaemic imbalance of oxygen supply and demand. This treatment .. be recognized that some disease entities may be on both sides of the
..
may include volume adjustment, blood pressure management, admin- .. diagram, e. g. acute heart failure that may occur in the context of
istration of blood products, heart-rate control, and respiratory sup- .. acute myocardial ischaemia. Nevertheless, abnormal cTn values in
..
port.47,48 Depending on the clinical situation, coronary evaluations .. the setting of acute and/or chronic heart failure are often better cate-
may be indicated to assess the likelihood of CAD. If it is present, the .. gorized as a myocardial injury condition. Few studies have compared
..
MI Guidelines may be applied in accordance with the ECG findings of .. the incidence and clinical features of type 2 MI vs. myocardial injury
STEMI or NSTEMI.46,47 However, if CAD is absent, the benefits of .. without acute myocardial ischaemia.
..
cardiovascular risk reduction strategies with type 2 MI remain ..
uncertain. ..
.. 7.4 Myocardial infarction type 3
..
.. The detection of cardiac biomarkers in the blood is fundamental for
7.3 Myocardial infarction type 2 and .. establishing the diagnosis of MI.10,12 However, patients can manifest a
..
myocardial injury .. typical presentation of myocardial ischaemia/infarction, including pre-
Type 2 MI and myocardial injury are frequently encountered in clini- .. sumed new ischaemic ECG changes or ventricular fibrillation, and die
..
cal practice and both are related to a poor outcome.13,14,49,51,56 .. before it is possible to obtain blood for cardiac biomarker determina-
A conceptual model to facilitate the clinical distinction between acute .. tion; or the patient may succumb soon after the onset of symptoms
..
ischaemic myocardial injury with or without an acute atherothrom- .. before an elevation of biomarker values has occurred. Such patients
botic event (type 1 or type 2 MI) vs. conditions without acute ischae- .. are designated as having a type 3 MI, when suspicion for an acute
..
mic myocardial injury is displayed in Figure 6. Acute MI requires a .. myocardial ischaemic event is high, even when cardiac biomarker evi-
rising and/or falling pattern of cTn values. Acute myocardial injury
.. dence of MI is lacking.10,12 This category allows the separation of fatal
..
may also manifest such a pattern but if the injury is related to struc- .. MI events from the much larger group of sudden death episodes that
tural heart disease, the cTn values may be stable and unchanging.
.. may be cardiac (non-ischaemic) or non-cardiac in origin. When a
Expert consensus document 249
Oxygen supply
Atherosclerosis
and demand
+ thrombosis
imbalance
©ESC/ACC/AHA/WHF 2018
Type 1 MI: triggers Type 2 MI: examples Examples Examples
• Plaque rupture • Severe hypertension • Acute heart failure • Structural heart disease
• Plaque erosion • Sustained tachyarrhythmia • Myocarditis • Chronic kidney disease
Figure 6 A model for interpreting myocardial injury. Ischaemic thresholds vary substantially in relation to the magnitude of the stressor and the
extent of underlying cardiac disease. MI = myocardial infarction; URL = upper reference limit. aStable denotes <_ 20% variation of troponin values in
the appropriate clinical context. bIschaemia denotes signs and/or symptoms of clinical myocardial ischaemia.
..
type 3 MI is diagnosed and a subsequent autopsy reveals recent evi- .. 8 Coronary procedure-related
dence of an MI, with a fresh or recent thrombus in the infarct-related ..
.. myocardial injury
artery, the type 3 MI should be reclassified to a type 1 MI. Original ..
investigations addressing the incidence of type 3 MI are sparse, but a
..
.. Cardiac procedural myocardial injury related to coronary revasculari-
study showed an annual incidence below 10/100 000 person-years .. zation procedures, whether percutaneous coronary intervention
and a frequency of 3 – 4% among all types of MI.60
..
.. (PCI) or coronary artery bypass grafting (CABG), may be temporally
.. related to the procedure itself, reflecting periprocedural issues, or
..
Criteria for type 3 MI .. may occur later reflecting complications of a device, such as early or
.. late stent thrombosis or in-stent restenosis for PCI, or graft occlusion
Patients who suffer cardiac death, with symptoms suggestive of ..
myocardial ischaemia accompanied by presumed new ischaemic
.. or stenosis with CABG. Late gadolinium enhancement (LGE) cardiac
..
ECG changes or ventricular fibrillation, but die before blood sam- .. magnetic resonance (CMR) allows assessment of procedural myocar-
ples for biomarkers can be obtained, or before increases in car-
.. dial injury.61–63 When quantifying procedural injury using LGE-CMR
..
diac biomarkers can be identified, or MI is detected by autopsy .. before and shortly after PCI or CABG, it was found that 32% of
examination.
.. patients had evidence of procedural myocardial injury.63 Furthermore,
..
. it has been shown that patients with elevation of cTnI values after PCI
250 Expert consensus document
..
or after CABG have evidence of procedural myocardial injury on .. normal baseline values or, in patients with elevated pre-procedure
CMR imaging.61,62 For that reason, increased cTn values detected fol- .. cTn in whom the cTn levels are stable (<_ 20% variation) or falling, the
..
lowing a coronary revascularization procedure may reflect procedural .. post-procedure cTn must rise > 20% to an absolute value more than
myocardial injury. Of importance, if the baseline value before the pro- .. five times the 99th percentile URL. In addition, there should be evi-
..
cedure is above the 99th percentile URL, it is essential that cTn levels .. dence of new myocardial ischaemia, either from ECG changes, imag-
are stable prior to the evaluation in order to reliably establish the pres- .. ing evidence, or from procedure-related complications associated
..
ence of acute procedural myocardial injury. It is not possible to deter- .. with reduced coronary blood flow such as coronary dissection,
mine, when intervening in a patient with an acute MI event resulting in .. occlusion of a major epicardial artery or a side branch occlusion/
..
an increased cTn level, how much of any given increase is related to .. thrombus, disruption of collateral flow, slow flow or no-reflow, or
the MI and how much is due to the procedure.
.. distal embolization. The use of hs-cTn assays to diagnose type 4a MI
..
.. (and type 5 MI) is an area of active research. Many hs-cTn assays are
.. available, which have wide dynamic ranges. Different criteria may be
..
..
10 Stent/scaffold thrombosis ..
..
especially cTn appear robust for the detection of procedural myocar-
dial injury and also, in the presence of new myocardial ischaemia, for
associated with percutaneous ..
.. the detection of type 5 MI, a specific cut-off value for all procedures
coronary intervention (type 4b .. and all cTn assays is difficult to define. However, in order to ensure
..
myocardial infarction) .. consistency with the analogous standards of the preceding definition
.. of type 5 MI12 and because of the lack of new scientific evidence that
..
A subcategory of PCI-related MI is stent/scaffold thrombosis, type 4b .. identifies superior criteria for defining this MI subtype, it is suggested
MI, as documented by angiography or autopsy using the same criteria
.. that a cTn value > 10 times the 99th percentile URL is applied as the
..
utilized for type 1 MI. It is important to indicate the time of the occur- .. cut-off point during the first 48 h following CABG, occurring from a
.. normal baseline cTn value (<_ 99th percentile URL), for diagnosing
rence of the stent/scaffold thrombosis in relation to the timing of the ..
PCI procedure. The following temporal categories are suggested: .. type 5 MI. It is important that the post-procedural elevation of cTn
.. values is accompanied by ECG, angiographic, or imaging evidence of
acute, 0–24 h; subacute, > 24 h to 30 days; late, > 30 days to 1 year; ..
..
13 Other definitions of myocardial ..
..
is recommended. A second sample should be obtained 3–6 h later or
earlier with more sensitive cTn assays. If the cTn concentration is ele-
infarction related to percutaneous ..
.. vated, but stable or decreasing at the time of suspected re-infarction,
coronary intervention or coronary .. the diagnosis of re-infarction requires a > 20% increase of the cTn
..
.. value in the second sample.74 If the initial cTn concentration is nor-
artery bypass grafting .. mal, the criteria for new acute MI apply.12
..
There is no universal consensus on the cTn or hs-cTn cut-off points ..
that clearly distinguish cardiac procedural myocardial injury from MI.
..
..
The distinction is made on the basis of an injury created by a flow- .. 16 Myocardial injury and
limiting complication during the procedure that results in sufficient
..
.. infarction associated with cardiac
myocardial ischaemia to generate a procedure-related MI. The size of ..
.. procedures other than
the insult will determine the magnitude of the cTn release. Various ..
..
coexist, e.g. MI-induced TTS or TTS with secondary plaque rupture, .. Diagnosing MI in patients with CKD and elevated cTn levels may
but this occurs where the acute regional wall motion abnormalities .. be difficult if symptoms or ECG changes indicating myocardial ischae-
..
are more extensive than the culprit coronary artery territory, and ful- .. mia are absent. However, studies suggest that serial changes in cTn
fil the pattern and definition of TTS.94 .. levels are equally effective in diagnosing MI in patients with CKD and
..
.. in those with normal renal function.106 If the level of elevated cTn val-
.. ues is unchanging, and the timing of the event makes a rising and/or
..
.. falling pattern unlikely, the elevated level, even if substantial, is likely a
20 Myocardial infarction with ..
.. reflection of chronic myocardial injury. This does not imply that these
non-obstructive coronary arteries ..
..
patients are free of CAD, since renal dysfunction and CAD are corre-
.. lated. However, if a rising and/or falling pattern is present then the
It is increasingly recognized that there is a group of MI patients with .. aetiology of the abnormal cTn values could be acute volume over-
no angiographic obstructive CAD (>_ 50% diameter stenosis in a .. load, congestive HF, or MI. If a rising and falling pattern is seen, and it
..
Very early
sampling Early sampling Later sampling Very late sampling
99th
©ESC/ACC/AHA/WHF 2018
percentile
URL
Figure 7 Illustration of early cardiac troponin kinetics in patients after acute myocardial injury including acute myocardial infarction. The timing of
biomarker release into the circulation is dependent on blood flow and how soon after the onset of symptoms samples are obtained. Thus, the ability
to consider small changes as diagnostic can be problematic. In addition, many comorbidities increase cTn values and, in particular, hs-cTn values, so
that elevations can be present at baseline even in those with myocardial infarction who present early after the onset of symptoms. Changes in cTn
values or deltas can be used to define acute compared with chronic events, and the ability to detect these is indicated in the figure. Increased cTn val-
ues can often be detected for days after an acute event. cTn = cardiac troponin; URL = upper reference limit.
..
elements of the clinical evaluation to establish the diagnosis of acute .. deviation around the measurement of the individual assay at relevant
MI. Criteria for determining a pathological rise between two serial .. values.12,22 For hs-cTn assays, biological variation also needs to be
..
cTn values are assay-dependent and continue to evolve. An idealized .. considered. In most studies, conjoint analytical and biological varia-
view of troponin kinetics in patients with acute MI is shown in
.. tion is in the range of 50 – 60%.
..
Figure 7. .. For that reason, this percentage has been suggested for use when
It should be appreciated that because biomarker release is sub-
.. initial baseline values are <_ the 99th percentile URL.23,31,113
..
stantially dependent on blood flow,111,112 there is significant variabil- .. However, for individuals with an initial value greater than the 99th
ity in the time to peak value (velocity), the time when a normal value
.. percentile URL, a lesser degree of change during serial measurements
..
may become greater than the 99th percentile URL, or when a chang- .. is necessary to achieve improved clinical sensitivity (as compared
ing pattern of values can be observed. The ability to define a changing
.. with individuals with initial values <_ the 99th percentile URL). Thus,
..
pattern will also depend on timing. For example, around peak values, .. an expert consensus group has recommended serial changes > 20%
..
it may be difficult to observe a changing pattern of values. Similarly, .. be used in this situation.22 Absolute changes are assay dependent but
the downslope of the time–concentration curve is much slower than .. appear superior to relative per cent changes with hs-cTn assays,114
..
the upslope. These issues need to be taken into account when defin- .. and in some studies this is especially the case when the initial value is
ing whether or not a changing pattern is present. In addition, it is .. increased.115 The use of a fixed absolute value change criteria trans-
..
important to make sure that a given change is greater than can be .. lates into a smaller percentage or relative change as absolute values
anticipated by variability alone. This is defined for conventional cTn ... rise, and therefore provides greater sensitivity. The use of a changing
assays as a change greater than or equal to three times the standard .. pattern is important in allowing clinicians to differentiate an acute
256 Expert consensus document
..
from a chronic cTn increase above the 99th percentile URL.113–115 .. be difficult to observe over short periods of time in those who
Using criteria less than conjoint analytical and biological variation will .. present early after the onset of symptoms of acute MI, those who
..
reduce the clinical specificity of hs-cTn assays.113,116 An imprecision .. present late and are on the downslope of the time-concentration
of <_ 10% coefficient of variation (CV) at the 99th percentile URL is .. curve, and those who have values near peak where they may be tran-
..
also mandatory for hs-cTn assays.31 The use of non-hs-cTn assays .. sitioning from a rising to a falling pattern.113,123
that do not have imprecision (<_ 10% CV at the 99th percentile URL) ..
..
makes the determination of a significant serial change more difficult ..
but does not cause false positive results. Assays with CVs between .. 25 The 99th percentile upper
..
10 – 20% are acceptable for clinical use. However, assays with CVs > .. reference limit
20% at the 99th percentile URL should not be used.117 ..
..
If a cTn assay is not available, the best alternative is CK-MB meas- .. The 99th percentile URL is designated as the decision level for the
ured by a mass assay. As with cTn, an increased CK-MB value is .. presence of myocardial injury and must be determined for each spe-
..
..
assays shorten the time to diagnosis in many patients to within 3 h of .. can be marked but do not change acutely during serial sampling.
onset of symptoms, but there are still some patients who may rule in .. However, a falling pattern may take longer to be observed in patients
..
late (at 6 h).131 Furthermore, some patients with acute myocardial .. with a high pre-test risk of MI who present late after symptom
injury presenting late after the onset of acute MI (> 12 – 18 h) and .. onset.146 These patients who have cTn values on the downslope of
..
who are on the downslope of the time-concentration curve may .. the time–concentration curve have a slow decline in values (Figure 7).
require longer periods of time for a changing pattern to be .. Thus, detecting a changing pattern over short periods of time may be
..
detected.131 In addition, it should be noted that with the implementa- .. difficult.117 Depending on the extent of myocardial injury, cTn values
tion of cTn and hs-cTn assays, the frequency of unstable angina will .. may remain above the 99th percentile URL for a longer period of
..
decrease and the diagnosis of NSTEMI will increase.132,133 The magni- .. time.22,23 An increased cTn value above the 99th percentile URL,
tude of these changes using hs-cTn assays have been reported in the .. with or without a dynamic change of values, or in the absence of clini-
..
range of 18 – 30%.134 Assuming proper timing of symptoms, acute .. cal evidence of ischaemia, should prompt a search for other diagno-
ischaemia should result in a change in hs-cTn; however, there may be .. ses associated with myocardial injury, as shown in Table 1.
..
..
ST-depression and T wave changes ..
..
New horizontal or downsloping ST-depression ≥ 0 .5 mm .. 28 Application of supplemental
in two contiguous leads and/or T inversion > 1 mm in two ..
contiguous leads with prominent R wave or R/S ratio > 1 .
.. electrocardiogram leads
..
.. Supplemental leads, as well as serial ECG recordings, should be
..
a
When the magnitudes of J-point elevation in leads V2 and V3 are registered .. deployed with a very low threshold in patients who present with
from a prior electrocardiogram, new J-point elevation >_ 1 mm (as compared .. ischaemic chest pain and a non-diagnostic initial ECG.155,156 ECG evi-
with the earlier electrocardiogram) should be considered an ischaemic response.
..
For bundle branch block, see section below.
.. dence of myocardial ischaemia in the distribution of a left circumflex
.. artery is often overlooked. Isolated ST-segment depression >_ 0.5
Expert consensus document 259
©ESC/ACC/AHA/WHF 2018
elevation is recommended in leads V7 –V9; specificity is increased at a Q wave ≥ 0 .03 s and ≥ 1 mm deep or QS complex in leads I,
cut-off point >_ 1 mm ST-elevation and this cut-off point should be II, aVL, aVF or V4 –V6 in any two leads of a contiguous lead
used in men < 40 years old. ST-segment depression in leads V1 –V3 grouping (I, aVL; V1 –V6 ; II, III, aVF).a
may be suggestive of inferobasal myocardial ischaemia (previously
R wave > 0 .04 s in V1 –V2 and R/S > 1 with a concordant
termed posterior infarction), especially when the terminal T wave is positive T wave in absence of conduction defect.
..
frontal QRS axis is between 60–90 . Septal Q waves are small, non- .. depression should not automatically be classified as type 2 MI without
pathological Q waves < 0.03 s and < 0.25 of the R-wave amplitude in .. additional information. In this clinical setting, signs of overt ischaemic
..
leads I, aVL, aVF, and V4–V6. Pre-excitation, cardiomyopathy, TTS, .. symptoms, the timing of symptoms relative to atrial fibrillation onset,
cardiac amyloidosis, LBBB, left anterior hemiblock, LVH, right ventric- .. a changing pattern of cTn, and imaging and/or angiographic findings
..
ular hypertrophy, myocarditis, acute cor pulmonale, or hyperkalae- .. may be helpful in establishing the diagnosis. However, in the absence
mia may be associated with Q waves or QS complexes in the .. of evidence for myocardial ischaemia, the aetiology of the elevated
..
absence of MI. Clinicians should be aware of confounders to the .. cTn values should be attributed to myocardial injury.
ECG diagnosis of myocardial ischaemia, since ST-T wave abnormal-
..
..
ities are commonly observed with different pathological cardiac con- ..
..
ditions, such as pre-excitation, pericarditis, and cardiomyopathy. .. 34 Imaging techniques
..
.. Non-invasive imaging plays many roles in patients with known or sus-
..
..
34.2 Radionuclide imaging .. meta-iodobenzylguanidine,181 imaging of matrix metalloproteinase
.. activation in ventricular remodelling,182,183 and the assessment of
Several radionuclide tracers allow viable myocytes to be imaged ..
directly, including the SPECT tracers 201TI chloride, 99mTc sestamibi, .. myocardial metabolism.184
..
and tetrofosmin, and the PET tracers 18F 2-fluorodeoxyglucose and ..
82
Rb.173 A strength of the radionuclide techniques is that they are the .. 34.3 Cardiac magnetic resonance
..
only commonly available methods for assessing viability directly, .. imaging
although the relatively low resolution of the images limits them for .. The high tissue contrast and resolution of CMR provides an accurate
..
detecting the smallest areas of MI. Phantom studies suggest that myo- .. assessment of myocardial structure and function. Although less com-
cyte loss as little as 4% of the myocardium can be detected, corre- .. monly used in the acute setting, it has similar capabilities to echocar-
..
sponding to 5 – 10 g of muscle.180 ECG-gated imaging provides a .. diography in suspected MI. Paramagnetic contrast agents can be used
reliable assessment of myocardial motion, thickening, and global func-
.. to assess myocardial perfusion and the increase in extracellular space
..
tion. Evolving radionuclide techniques relevant to the assessment of .. that is associated with the fibrosis of prior MI (detected by LGE-
ISCHAEMIC
Transmural Subendocardial Focal Subendocardial
NON-ISCHAEMIC
©ESC/ACC/AHA/WHF 2018
Figure 9 Post-contrast cardiac magnetic resonance images. The gadolinium-based contrasts wash out slowly from myocardium with increased
extracellular space such as fibrosis, thus enhancing areas of scarring (white arrows). The different patterns of scarring are divided into ischaemic and
non-ischaemic. Typically, an ischaemic scar/fibrosis (upper panel) extends from the subendocardium to the epicardium (subendocardial, non-trans-
mural scar vs. transmural scar). Conversely, a non-ischaemic fibrosis/scar can be encountered at the epicardium, in the mid-wall, or at the insertion
points of the right ventricle (lower panel).
262 Expert consensus document
..
MI185,186 and localized delay in contrast enhancement is able to .. be excluded, and unless a new abnormality is detected or can be pre-
detect even small areas of subendocardial MI, thought to be as little .. sumed to have arisen in the setting of other features of acute MI.
..
as 1 g.187 CMR also has the ability to identify the presence and extent .. In the setting of acute MI, CMR can also be used to assess the pres-
of myocardial oedema/inflammation, allowing the distinction of acute .. ence and extent of myocardium at risk (myocardial oedema), myo-
..
vs. chronic myocardial injury. The patterns of LGE when reflecting .. cardial salvage, microvascular obstruction, intramyocardial
ischaemic and non-ischaemic myocardial injury are shown in Figure 9. .. haemorrhage, and infarct size, all markers of myocardial injury that
..
The gadolinium-based contrasts wash out slowly from myocar- .. have prognostic value.190 In patients with possible acute MI but unob-
dium with increased extracellular space such as fibrosis, thus enhanc- .. structed coronary arteries, CMR can help to diagnose alternative
..
ing areas of scarring (white arrows). The different patterns of scarring .. conditions such as myocarditis, TTS, embolic infarction, or MI with
are divided into ischaemic and non-ischaemic. Typically, an ischaemic .. spontaneous recanalization.189
..
scar/fibrosis (upper panel) extends from the subendocardium to the ..
epicardium (subendocardial, non-transmural scar vs. transmural ..
..
..
particular assay to reduce site-to-site variability in the selection of the .. respect to psychological status, life and health insurance, and profes-
MI decision cut-off point. .. sional career, as well as driving and pilot licences. The diagnosis is also
..
Multiples for hs-cTn vs. conventional cTn could have markedly dif- .. associated with societal implications with regards to diagnosis-related
ferent prognostic implications. The assay types should be reported .. coding, hospital reimbursement, public health statistics, sick leave,
..
when possible. Multiples of the 99th percentile URL should be indi- .. and disability attestation. In order to meet these challenges, physi-
cated and reported, both for those with cardiac procedural myocar- .. cians must be adequately informed of the diagnostic criteria. Hence,
..
dial injury and those diagnosed with types 4a and 5 MI. Cumulative .. educational materials will need to be created and treatment guide-
frequency distribution of peak cTn measurements for MI endpoint .. lines must be appropriately adapted.
..
assessments by treatment group should also be provided. This will ..
facilitate the comparison of trials and meta-analyses. ..
..
.. 40 Global perspectives of the
..
.. definition of myocardial infarction
..
are located. Also, use of the electronic medical record as an epide- .. Society of Cardiology, Alexey Yakovlev; San Marino: San Marino
miological and research tool of the future is likely to require efforts .. Society of Cardiology, Marco Zavatta; Serbia: Cardiology Society of
..
to verify the accuracy of an acute MI diagnosis, rather than accepting .. Serbia, Milan Nedeljkovic; Slovenia: Slovenian Society of
the coded diagnoses used for administrative and billing purposes. .. Cardiology, Peter Radsel; Spain: Spanish Society of Cardiology,
..
Such an effort to create a computable phenotype of MI (further cate- .. Alessandro Sionis; Sweden: Swedish Society of Cardiology, Tomas
gorized as types 1 – 5 MI) will require input from informaticians and .. Jemberg; Switzerland: Swiss Society of Cardiology, Christian
..
experts in implementation science to translate the recommendations .. Müller; Tunisia: Tunisian Society of Cardiology and Cardio-Vascular
from this Universal Definition of MI into the routine practice of .. Surgery, Leila Abid; Turkey: Turkish Society of Cardiology, Adnan
..
healthcare delivery and documentation. .. Abaci; Ukraine: Ukrainian Association of Cardiology, Alexandr
Given the evolution of biomarker assays used to support the diag- .. Parkhomenko; United Kingdom: British Cardiovascular Society,
..
nosis of MI, it is important that a consistent approach be used in the .. Simon Corbett.
construction of the computable phenotype of MI so as to reliably ..
.. Approved by the ACC Clinical Policy Approval Committee.
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.. infarction. Eur Heart J 2007;28:2525–2538; Circulation 2007;116:2634–2653; J Am
Beissel; Malta: Maltese Cardiac Society, Philip Dingli; Moldova: .. Coll Cardiol 2007;50:2173–2195.
Moldavian Society of Cardiology, Aurel Grosu; The Netherlands: .. 11. Mendis S, Thygesen K, Kuulasmaa K, Giampaoli S, M€ahönen M, Ngu Blackett K,
.. Lisheng L; Writing group on behalf of the participating experts of the WHO con-
Netherlands Society of Cardiology, Peter Damman; Norway: .. sultation for revision of WHO definition of myocardial infarction. World Health
Norwegian Society of Cardiology, Vibeke Juliebø; Poland: Polish .. Organization definition of myocardial infarction: 2008-09 revision. Int J Epidemiol
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Cardiac Society, Jacek Legutko; Portugal: Portuguese Society of .. 2011;40:139–146.
high-risk population. Are the Sgarbossa Criteria ready for prime time? Am Heart J
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Djambazov S, Petr R, Knot J, Bılkova D, Fischerova M, Vondrak K, Maly M, .. Nathoe HM, Post JC, Nielen T, Beelen D, le Cocq d’Armandville MC, Rood PP,
Lorencova A. Primary angioplasty in acute myocardial infarction with right bundle .. Schultz CJ, Moelker A, Ouhlous M, Boersma E, Nieman K. Coronary CT
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* Corresponding authors: Paulus Kirchhof, Institute of Cardiovascular Sciences, University of Birmingham, SWBH and UHB NHS trusts, IBR, Room 136, Wolfson Drive, Birmingham
B15 2TT, United Kingdom, Tel: +44 121 4147042, E-mail: p.kirchhof@bham.ac.uk; Stefano Benussi, Department of Cardiovascular Surgery, University Hospital Zurich, Rämistrasse
100, 8091 Zürich, Switzerland, Tel: +41(0)788933835, E-mail: stefano.benussi@usz.ch.
1
Representing the European Association for Cardio-Thoracic Surgery (EACTS)
2
Representing the European Stroke Association (ESO)
ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies Reviewers can be found in the Appendix.
ESC entities having participated in the development of this document:
Associations: European Association for Cardiovascular Prevention and Rehabilitation (EACPR), European Association of Cardiovascular Imaging (EACVI), European Heart Rhythm
Association (EHRA), Heart Failure Association (HFA).
Councils: Council on Cardiovascular Nursing and Allied Professions, Council for Cardiology Practice, Council on Cardiovascular Primary Care, Council on Hypertension.
Working Groups: Cardiac Cellular Electrophysiology, Cardiovascular Pharmacotherapy, Grown-up Congenital Heart Disease, Thrombosis, Valvular Heart Disease.
The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC
Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford Uni-
versity Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC (journals.permissions@oup.com).
Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at
the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recom-
mendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encour-
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therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and
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2894 ESC Guidelines
Bulent Gorenek (Turkey), Maxine Guenoun (France), Stefan H. Hohnloser (Germany), Philippe Kolh (Belgium),
Gregory Y. H. Lip (UK), Athanasios Manolis (Greece), John McMurray (UK), Piotr Ponikowski (Poland), Raphael Rosenhek
(Austria), Frank Ruschitzka (Switzerland), Irina Savelieva (UK), Sanjay Sharma (UK), Piotr Suwalski (Poland),
Juan Luis Tamargo (Spain), Clare J. Taylor (UK), Isabelle C. Van Gelder (The Netherlands), Adriaan A. Voors (The
Netherlands), Stephan Windecker (Switzerland), Jose Luis Zamorano (Spain), and Katja Zeppenfeld (The Netherlands)
The disclosure forms of all experts involved in the development of these guidelines are available on the ESC website
http://www.escardio.org/guidelines.
Online publish-ahead-of-print 27 August 2016
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Table of Contents
Abbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . . 4 7.1.1 Patients with atrial fibrillation and heart failure with
1. Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 reduced ejection fraction . . . . . . . . . . . . . . . . . . . . . . 16
2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 7.1.2 Atrial fibrillation patients with heart failure with
3. Epidemiology and impact for patients . . . . . . . . . . . . . . . . . 7 preserved ejection fraction . . . . . . . . . . . . . . . . . . . . . 16
3.1 Incidence and prevalence of atrial fibrillation . . . . . . . . 7 7.1.3 Atrial fibrillation patients with heart failure with mid-
3.2 Morbidity, mortality, and healthcare burden of atrial range ejection fraction . . . . . . . . . . . . . . . . . . . . . . . . 16
fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 7.1.4 Prevention of atrial fibrillation in heart failure . . . . . 16
3.3 Impact of evidence-based management on outcomes in 7.2 Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
atrial fibrillation patients . . . . . . . . . . . . . . . . . . . . . . . . 8 7.3 Valvular heart disease . . . . . . . . . . . . . . . . . . . . . . . 17
3.4 Gender . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 7.4 Diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . 18
4. Pathophysiological and genetic aspects that guide management 9 7.5 Obesity and weight loss . . . . . . . . . . . . . . . . . . . . . . 18
4.1 Genetic predisposition . . . . . . . . . . . . . . . . . . . . . . 9 7.5.1 Obesity as a risk factor . . . . . . . . . . . . . . . . . . . 18
4.2 Mechanisms leading to atrial fibrillation . . . . . . . . . . . . 9 7.5.2 Weight reduction in obese patients with atrial
4.2.1 Remodelling of atrial structure and ion channel fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 7.5.3 Catheter ablation in obese patients . . . . . . . . . . . 18
4.2.2 Electrophysiological mechanisms of atrial fibrillation . 9 7.6 Chronic obstructive pulmonary disease, sleep apnoea, and
4.2.2.1 Focal initiation and maintenance of atrial other respiratory diseases . . . . . . . . . . . . . . . . . . . . . . . 18
fibrillation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 7.7 Chronic kidney disease . . . . . . . . . . . . . . . . . . . . . . 19
4.2.2.2 The multiple wavelet hypothesis and rotors as 8. Integrated management of patients with atrial fibrillation . . . . 19
sources of atrial fibrillation . . . . . . . . . . . . . . . . . . . 10 8.1 Evidence supporting integrated atrial fibrillation care . . . 20
5. Diagnosis and timely detection of atrial fibrillation . . . . . . . . 10 8.2 Components of integrated atrial fibrillation care . . . . . . 21
5.1 Overt and silent atrial fibrillation . . . . . . . . . . . . . . . . 10 8.2.1 Patient involvement . . . . . . . . . . . . . . . . . . . . . . 21
5.2 Screening for silent atrial fibrillation . . . . . . . . . . . . . . 11 8.2.2 Multidisciplinary atrial fibrillation teams . . . . . . . . . 21
5.2.1 Screening for atrial fibrillation by electrocardiogram in 8.2.3 Role of non-specialists . . . . . . . . . . . . . . . . . . . . 21
the community . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 8.2.4 Technology use to support atrial fibrillation care . . . 21
5.2.2 Prolonged monitoring for paroxysmal atrial 8.3 Diagnostic workup of atrial fibrillation patients . . . . . . . 21
fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 8.3.1 Recommended evaluation in all atrial fibrillation
5.2.3 Patients with pacemakers and implanted devices . . . 12 patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5.2.4 Detection of atrial fibrillation in stroke survivors . . . 13 8.3.2 Additional investigations in selected patients with
5.3 Electrocardiogram detection of atrial flutter . . . . . . . . . 13 atrial fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
6. Classification of atrial fibrillation . . . . . . . . . . . . . . . . . . . . 13 8.4 Structured follow-up . . . . . . . . . . . . . . . . . . . . . . . . 22
6.1 Atrial fibrillation pattern . . . . . . . . . . . . . . . . . . . . . 13 8.5 Defining goals of atrial fibrillation management . . . . . . . 22
6.2 Atrial fibrillation types reflecting different causes of the 9. Stroke prevention therapy in atrial fibrillation patients . . . . . . 22
arrhythmia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 9.1 Prediction of stroke and bleeding risk . . . . . . . . . . . . . 22
6.3 Symptom burden in atrial fibrillation . . . . . . . . . . . . . . 14 9.1.1 Clinical risk scores for stroke and systemic embolism 22
7. Detection and management of risk factors and concomitant 9.1.2 Anticoagulation in patients with a CHA2DS2-VASc
cardiovascular diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 score of 1 in men and 2 in women . . . . . . . . . . . . . . . . 22
7.1 Heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 9.1.3 Clinical risk scores for bleeding . . . . . . . . . . . . . . 23
ESC Guidelines 2895
13.6.2 Atrial tachyarrhythmias and atrial septal defects . . . 56 APACHE-AF Apixaban versus Antiplatelet drugs or no
13.6.3 Atrial tachyarrhythmias after Fontan operation . . . 56 antithrombotic drugs after anticoagulation-
13.6.4 Atrial tachyarrhythmias after tetralogy of Fallot associated intraCerebral HaEmorrhage in
correction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 patients with Atrial Fibrillation
13.7 Management of atrial flutter . . . . . . . . . . . . . . . . . . 57 ARB angiotensin receptor blocker
14. Patient involvement, education, and self-management . . . . . 57 ARISTOTLE Apixaban for Reduction in Stroke and Other
14.1 Patient-centred care . . . . . . . . . . . . . . . . . . . . . . . 57 Thromboembolic Events in Atrial Fibrillation
14.2 Integrated patient education . . . . . . . . . . . . . . . . . . 57 ARNI angiotensin receptor neprilysin inhibition
14.3 Self-management and shared decision-making . . . . . . . 57 ARTESiA Apixaban for the Reduction of Thrombo-Em-
15. Gaps in evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 bolism in Patients With Device-Detected
15.1 Major health modifiers causing atrial fibrillation . . . . . . 58 Sub-Clinical Atrial Fibrillation
GUCH grown-up congenital heart disease PREVAIL Prospective Randomized Evaluation of the
HARMONY A Study to Evaluate the Effect of Ranolazine Watchman LAA Closure Device In Patients
and Dronedarone When Given Alone and with AF Versus Long Term Warfarin Therapy
in Combination in Patients With Paroxysmal trial
Atrial Fibrillation PROTECT AF Watchman Left Atrial Appendage System for
HAS-BLED hypertension, abnormal renal/liver function Embolic Protection in Patients With AF trial
(1 point each), stroke, bleeding history or PUFA polyunsaturated fatty acid
predisposition, labile INR, elderly (.65 PVI pulmonary vein isolation
years), drugs/alcohol concomitantly (1 point QoL quality of life
each) RACE Rate Control Efficacy in Permanent Atrial
HEMORR2HAGES Hepatic or renal disease, ethanol abuse, Fibrillation
of educational tools and implementation programmes for the re- 3. Epidemiology and impact for
commendations. To implement the guidelines, condensed pocket
guideline versions, summary slides, booklets with essential mes- patients
sages, summary cards for non-specialists and an electronic version
for digital applications (smartphones, etc.) are produced. These ver- 3.1 Incidence and prevalence of atrial
sions are abridged and thus, if needed, one should always refer to fibrillation
the full text version, which is freely available on the ESC website. In 2010, the estimated numbers of men and women with AF world-
The National Societies of the ESC are encouraged to endorse, wide were 20.9 million and 12.6 million, respectively, with higher in-
translate and implement all ESC Guidelines. Implementation pro- cidence and prevalence rates in developed countries.1,2 One in four
grammes are needed because it has been shown that the outcome middle-aged adults in Europe and the US will develop AF.3 – 5 By 2030,
of disease may be favourably influenced by the thorough application 14 – 17 million AF patients are anticipated in the European Union,
with 120 000–215 000 newly diagnosed patients per year.2,6,7 Esti-
or after the initial event.17,26,27 White matter lesions in the brain, anticoagulation (OAC) with vitamin K antagonists (VKAs) or non-
cognitive impairment, 28 – 30 decreased quality of life, 31,32 and VKA oral anticoagulants (NOACs) markedly reduces stroke and
depressed mood 33 are common in AF patients, and between mortality in AF patients.38,39 Other interventions such as rhythm
10 – 40% of AF patients are hospitalized each year.23,34,35 control and rate control improve AF-related symptoms and may
The direct costs of AF already amount to approximately 1% of to- preserve cardiac function, but have not demonstrated a reduction
tal healthcare spending in the UK, and between 6.0 –26.0 billion US in long-term morbidity or mortality.40,41
dollars in the US for 2008,36,37 driven by AF-related complications In contemporary, well-controlled, randomized clinical trials
(e.g. stroke) and treatment costs (e.g. hospitalizations). These costs in AF, the average annual stroke rate is about 1.5% and the
will increase dramatically unless AF is prevented and treated in a annualized death rate is around 3% in anticoagulated AF patients.40
timely and effective manner. In real life, the annual mortality can be different (both higher and
lower).42 A minority of these deaths are related to stroke, while
effective as VKA
20
Amiodarone not
superior to rate
ARBs do not prevent Dabigatran at least as control in heart Dronedarone
AF or adverse effective as VKA in AF failure improves outcomes
outcomes in patients in non-permanent AF
without hypertension
Lenient rate control AF ablation
acceptable improves Qol
10
20
LVH = left ventricular hypertrophy; NOAC = non-vitamin K antagonist oral anticoagulant; PUFA = polyunsaturated fatty acid; PVI = pulmonary vein isolation;
QoL = quality of life; RF = radiofrequency; SR = sinus rhythm;VKA = vitamin K antagonist.
Figure 1 Timeline of findings from landmark trials in atrial fibrillation management, including treatment of concomitant conditions and preven-
tion (green), anticoagulation (blue), rate control therapy (orange), rhythm control therapy (red), and atrial fibrillation surgery (purple).
ESC Guidelines 2901
3.4 Gender While genomic analysis may provide an opportunity to improve the
In both developed and developing countries, the age-adjusted inci- diagnosis and management of AF in the future,75,76 routine genetic
dence and prevalence of AF are lower in women, while the risk of testing for common gene variants associated with AF cannot be re-
death in women with AF is similar to or higher than that in men with commended at present.77
AF.1,46,47 Female AF patients who have additional stroke risk factors
(particularly older age) are also at greater risk than men of having a 4.2 Mechanisms leading to atrial
stroke,48,49 even those anticoagulated with warfarin50 (see Chapter fibrillation
9 for details). Women with diagnosed AF can be more symptomatic 4.2.1 Remodelling of atrial structure and ion channel
than men and are typically older with more comorbidities.51,52 function
Bleeding risk on anticoagulation is similar in both sexes,49,50,53 but External stressors such as structural heart disease, hypertension,
women appear less likely to receive specialist care and rhythm con- possibly diabetes, but also AF itself induce a slow but progressive
Stroke
Diabetes
Heart
Atrial
fibrillation
AngII = angiotensin II; TF = tissue factor; FXII = factor XII; IL-6 = interleukin 6; PAI-1 = plasminogen activator inhibitor 1;VCAM-1 = vascular cell adhesion molecule 1.
Figure 2 Major mechanisms causing atrial fibrillation that can be considered when choosing therapy. The various aetiological factors (left) cause
a complex array of pathophysiological changes in the atria, including stretch-induced atrial fibrosis, hypocontractility, fatty infiltration, inflamma-
tion, vascular remodelling, ischaemia, ion channel dysfunction, and Ca2+-instability. These changes enhance both ectopy and conduction distur-
bances, increasing the propensity of the atria to develop or maintain AF. At the same time, some of these alterations are involved in the occurrence
of the hypercoagulable state associated with AF. For example, hypocontractility reduces local endothelial shear stress, which increases PAI-1 ex-
pression, and ischaemia-induced inflammation enhances the expression of endothelial adhesion molecules or promotes shedding of endothelial
cells, resulting in tissue factor exposure to the blood stream. These changes contribute to the thrombogenic milieu in the atria of AF patients. AF in
itself can aggravate many of the mechanisms shown, which may explain the progressive nature of the arrhythmia.
with paroxysmal AF,111,112 but is less obvious in unselected patients these phenomena may generate ‘rotors’ picked up by intracar-
with persistent AF.113 diac116,117 or body surface117 recordings.
4.2.2.2 The multiple wavelet hypothesis and rotors as sources of atrial
fibrillation
Moe and Abildskov114 proposed that AF can be perpetuated by
5. Diagnosis and timely detection
continuous conduction of several independent wavelets propagat- of atrial fibrillation
ing through the atrial musculature in a seemingly chaotic manner.
As long as the number of wavefronts does not decline below a crit- 5.1 Overt and silent atrial fibrillation
ical level, they will be capable of sustaining the arrhythmia. Numer- The diagnosis of AF requires rhythm documentation using an elec-
ous experimental and clinical observations can be reconciled with trocardiogram (ECG) showing the typical pattern of AF: Absolutely
the multiple wavelet hypothesis.115 All localized sources of AF (ec- irregular RR intervals and no discernible, distinct P waves. ECG-
topic foci, rotors, or other stable re-entry circuits) cause fibrillatory documented AF was the entry criterion in trials forming the evi-
conduction remote from the source, which is difficult to distinguish dence for these guidelines. By accepted convention, an episode last-
from propagation sustaining AF by multiple wavelets, and either of ing at least 30 s is diagnostic. Individuals with AF may be
ESC Guidelines 2903
Table 4 Pathophysiological alterations in atrial tissue associated with atrial fibrillation and clinical conditions that could
contribute to such alterations
symptomatic or asymptomatic (‘silent AF’). Many AF patients have monitoring of drug effects on ventricular rate; and (4) monitoring of
both symptomatic and asymptomatic episodes of AF.118 – 121 antiarrhythmic drug effects or catheter ablation for rhythm control.
Silent, undetected AF is common,120,122 with severe consequences
such as stroke and death.123 – 125 Prompt recording of an ECG is an ef- 5.2 Screening for silent atrial fibrillation
fective and cost-effective method to document chronic forms of 5.2.1 Screening for atrial fibrillation by electrocardiogram
AF.126 The technology to detect paroxysmal, self-terminating AF epi- in the community
sodes is rapidly evolving (see Chapter 6.1 for a definition of AF pat- Undiagnosed AF is common, especially in older populations and
terns). There is good evidence that prolonged ECG monitoring in patients with heart failure.130 Opportunistic screening for silent AF
enhances the detection of undiagnosed AF, e.g. monitoring for 72 h seems cost-effective in elderly populations (e.g. . 65 years),131 and simi-
after a stroke,27,127 or even longer periods.18,128 Daily short-term lar effects have been reported using single-lead ECG screening in other
ECG recordings increase AF detection in populations over 75 years at-risk populations.132,133 Screening of older populations (mean age 64
of age129 (Web Figure 1). Ongoing studies will determine whether years) yielded a prevalence of 2.3% for chronic forms of AF in 122,571
such early detection alters management (e.g. initiation of anticoagu- participants using either short-term ECG or pulse palpation (followed
lation) and improves outcomes. by ECG in those with an irregular pulse).134 Previously undiagnosed
Once the ECG diagnosis of AF has been established, further ECG AF was found in 1.4% of those aged .65 years, suggesting a number
monitoring can inform management in the context of: (1) a change needed to screen of 70. These findings encourage the further evaluation
in symptoms or new symptoms; (2) suspected progression of AF; (3) of systematic AF screening programmes in at-risk populations.
2904 ESC Guidelines
5.2.2 Prolonged monitoring for paroxysmal atrial detected in 10–15% of pacemaker patients.141 AHRE are associated
fibrillation with an increased risk of overt AF [hazard ratio (HR) 5.56; 95% con-
Paroxysmal AF is often missed.120 Repeated daily ECG recordings fidence interval (CI) 3.78–8.17; P , 0.001] and ischaemic stroke or
increased the detection of silent, asymptomatic paroxysmal AF in systemic embolism (HR 2.49; 95% CI 1.28 – 4.85; P ¼ 0.007). The
an unselected Swedish population aged .75 years.120,135 Several stroke risk in AHRE patients seems lower than the stroke risk in pa-
patient-operated devices136,137 and extended continuous ECG tients with diagnosed AF, and not all AHRE represent AF.142 Strokes
monitoring using skin patch recorders138 have been validated for often occur without AHRE detected within 30 days before the
the detection of paroxysmal AF (Web Figure 1).139 The detection event.143 – 147 Consequently, it is unclear whether AHRE imply the
of asymptomatic AF by new technologies, such as smartphone cases same therapeutic requirements as overt AF,148 and the benefit of
with ECG electrodes, smart watches, and blood pressure machines OAC in patients with AHRE is tested in ongoing clinical trials [e.g.
with AF detection algorithms, has not yet been formally evaluated Apixaban for the Reduction of Thrombo-Embolism in Patients With
against an established arrhythmia detection method.140
No AF detected AF diagnosed
2DS2-VASc = Congestive
Heart failure, hypertension, Age ≥75 (doubled), Diabetes, Stroke (doubled),Vascular disease, Age 65–74, and Sex (female); ECG = electrocardiogram; EHRA = European Heart
Rhythm Association.
*In rare individual circumstances, oral anticoagulation may be considered in patients with AHRE, but without diagnosed AF. This clearly needs discussion with the patient and careful
a
Adapted from the report of the 3rd AFNET/EHRA consensus conference.150
5.2.4 Detection of atrial fibrillation in stroke survivors often show a ‘saw tooth’ morphology, especially in the inferior leads
Sequential stratified ECG monitoring detected AF in 24% (95% CI (II, III, aVF). The ventricular rate can be variable (usual ratio of atrial
17 – 31) of stroke survivors,151 and in 11.5% (95% CI 8.9% – 14.3%) to ventricular contraction 4:1 to 2:1, in rare cases 1:1) and
in another meta-analysis,17 with large variations depending on the macro-re-entrant tachycardias may be missed in stable 2:1 conduc-
timing, duration, and method of monitoring. AF detection is not tion. Vagal stimulation or intravenous adenosine can therefore
uncommon in unselected stroke patients (6.2%, 95% CI 4.4 – be helpful to unmask atrial flutter. The management of atrial flutter
8.3),128 but is more likely in patients with cryptogenic stroke im- is discussed in chapter 13.7. Left or right atrial macro re-entrant
planted with loop recorders or who have had ECG monitors tachycardia is mainly found in patients after catheter ablation for
for several weeks. 18,128,152 Cryptogenic stroke is defined as a AF, AF surgery, or after open heart surgery.158
stroke in which the cause could not be identified after extensive
investigations.153 A broader definition is embolic stroke of un-
determined source.154 Several studies have also found AF in pa- 6. Classification of atrial fibrillation
AF ¼ atrial fibrillation; AHRE ¼ atrial high rate episodes; Long-standing Continuous AF lasting for ≥1 year when it is decided
ECG ¼ electrocardiogram; ICD ¼ implantable cardioverter defibrillator; persistent AF to adopt a rhythm control strategy.
TIA ¼ transient ischaemic attack. Permanent AF AF that is accepted by the patient (and physician).
a
Class of recommendation. Hence, rhythm control interventions are, by
b
Level of evidence.
c definition, not pursued in patients with permanent
Reference(s) supporting recommendations.
AF. Should a rhythm control strategy be adopted, the
arrhythmia would be re-classified as ‘long-standing
persistent AF’.
5.3 Electrocardiogram detection of atrial
flutter AF ¼ atrial fibrillation.
a
Right atrial isthmus-dependent flutter has a typical ECG pattern and The distinction between paroxysmal and persistent AF is often not made correctly
without access to long-term monitoring.163 Hence, this classification alone is often
ventricular rate.158 The prevalence of atrial flutter is less than one-
insufficient to select specific therapies. If both persistent and paroxysmal episodes
tenth of the prevalence of AF.159 Atrial flutter often coexists with or are present, the predominant pattern should guide the classification.
precedes AF.160 In typical, isthmus-dependent flutter, P waves will
2906 ESC Guidelines
AF ¼ atrial fibrillation; LV ¼ left ventricular; LVH ¼ left ventricular hypertrophy. It is recognized that these types of AF will overlap in clinical practice, and that their impact for
management needs to be evaluated systematically.
by long-term ECG monitoring.163 Even less is known about the 6.3 Symptom burden in atrial fibrillation
response to therapy in patients with long-standing persistent Patients with AF have significantly poorer quality of life than
AF or long-standing paroxysmal AF. Despite these inaccuracies, healthy controls, experiencing a variety of symptoms including
the distinction between paroxysmal and persistent AF has been lethargy, palpitations, dyspnoea, chest tightness, sleeping difficul-
used in many trials and therefore still forms the basis of some ties, and psychosocial distress.32,177 – 180 Improved quality of life
recommendations.
There is some evidence suggesting that AF burden may influence
stroke risk44,124,164 and could modify the response to rhythm con-
trol therapy.76,165 The evidence for this is weak. Therefore, AF bur- Table 7 Modified European Heart Rhythm
den should not be a major factor in deciding on the usefulness of an Association symptom scale (modified from Wynn
intervention that is deemed suitable for other reasons. et al.199)
activation of neurohormonal mechanisms, and rate-related impair- rhythm.229 Catheter ablation may be a useful method to restore
ment of left ventricular (LV) function. Patients with AF and concomi- LV function and quality of life in AF patients with HFrEF,185,226 –
228
tant heart failure, both with preserved ejection fraction [LV ejection but further data are needed. Figure 4 summarizes the approach
fraction (LVEF) ≥50%] and reduced ejection fraction (LVEF to patients with AF and heart failure.
,40%),219,220 suffer from a worse prognosis, including increased
mortality.16,221 The recent ESC Guidelines on heart failure222
7.1.2 Atrial fibrillation patients with heart failure with
have also introduced a new category of heart failure with mid-range preserved ejection fraction
ejection fraction (HFmrEF; LVEF 40 – 49%), although data on AF The diagnosis of heart failure with preserved ejection fraction
patients in this group are limited. Prevention of adverse outcomes (HFpEF) in patients with AF is problematic because of the difficulty
and maintenance of a good quality of life are the aims of manage- in separating symptoms that are due to HF from those due to AF.
ment in all patients with AF and concomitant heart failure, regard- Although diagnostic differentiation can be achieved by cardioversion
less of LVEF.223 The general approach to AF management does
Cardiovert if unstable
heart failure.
a
In patients with heart failure and reduced ejection fraction. Also consider combined ARNI in patients able to tolerate an ACE inhibitor or ARB with ongoing symptoms.
Figure 4 Initial management of patients presenting acutely with atrial fibrillation and heart failure. (Adapted from Kotecha and Piccini.128)
7.2 Hypertension some form of valvular heart disease, often detected only by
Hypertension is a stroke risk factor in AF; uncontrolled high blood echocardiogram. 201,253 – 255 AF worsens prognosis in patients
pressure enhances the risk of stroke and bleeding events and may with severe valvular heart disease,256 including those undergoing
lead to recurrent AF. Therefore, good blood pressure control should surgery or transcatheter interventions for aortic or mitral valve
form an integral part of the management of AF patients.247 Inhibition disease.257 – 262 Valvular heart disease can be associated with an in-
of the renin–angiotensin–aldosterone system can prevent structural creased thrombo-embolic risk, which probably also adds to the
remodelling and recurrent AF.236,244 A recent analysis of the Danish stroke risk in AF patients.263 Similar to heart failure, valvular dis-
healthcare database with long-term monitoring of the effect of differ- ease and AF interact with and sustain each other through volume
ent antihypertensive agents on the occurrence of overt AF suggests a and pressure overload, tachycardiomyopathy, and neurohumoral
beneficial effect of ACE inhibitors or ARBs.245 Secondary analyses of factors. 264 – 270 When valve dysfunction is severe, AF can be
ACE inhibitors or ARBs in patients with heart failure or LVH show a regarded as a marker for progressive disease, thus favouring valve
lower incidence of new-onset AF.238,246 In patients with established repair or replacement.271
AF, but without LV dysfunction or heart failure, ARBs do not prevent Traditionally, patients with AF have been dichotomized into
recurrent AF better than placebo.240,241 ACE inhibitors or ARBs may ‘valvular’ and ‘non-valvular’ AF.272 Although slightly different defini-
reduce recurrent AF after cardioversion when co-administered with tions have been used, valvular AF mainly refers to AF patients that
antiarrhythmic drug therapy compared with an antiarrhythmic drug have either rheumatic valvular disease (predominantly mitral sten-
alone.248,249 Meta-analyses driven by these studies suggested a lower osis) or mechanical heart valves. In fact, while AF implies an incre-
risk of recurrent AF,236 – 238,250 but at least one controlled trial failed mental risk for thrombo-embolism in patients with mitral valve
to demonstrate benefit.240,251 stenosis,263,273,274 there is no clear evidence that other valvular dis-
eases, including mitral regurgitation or aortic valve disease, need to
be considered when choosing an anticoagulant or indeed to esti-
7.3 Valvular heart disease mate stroke risk in AF.275 Therefore, we have decided to replace
Valvular heart disease is independently associated with the historic term ‘non-valvular’ AF with reference to the specific
incident AF. 252 Approximately 30% of patients with AF have underlying conditions.
2910 ESC Guidelines
Recommendations for patients with atrial fibrillation Recommendations for patients with kidney disease and
and respiratory diseases atrial fibrillation
8. Integrated management of
7.7 Chronic kidney disease patients with atrial fibrillation
AF is present in 15 – 20% of patients with CKD.316 The definition of Most patients initially access the healthcare system through pharma-
CKD in most AF trials is relatively strict. Although an estimated cists, community health workers, or primary care physicians. As AF
creatinine clearance (CrCl) rate of ,60 mL/min is indicative of is often asymptomatic (“silent AF”), these healthcare professionals
CKD, a number of trials in AF patients have used CrCl ,50 mL/ are important stakeholders to enable the adequate detection of
min to adapt NOAC dosage, usually estimated using the Cock- AF and to ensure consistent management. The initial assessment
roft – Gault formula. CrCl in AF patients can deteriorate over should be performed at the point of first contact with the healthcare
time.317 The management of OAC in patients with CKD is dis- system, and is feasible in most healthcare settings (when an ECG is
cussed in chapter 9.2.4. available). We propose to consider five domains in the initial
Acute rate
and rhythm Haemodynamic stability
control
Manage Lifestyle changes, treatment of Cardiovascular risk Improved life
precipitating underlying cardiovascular conditions reduction expectancy
factors
Antiarrhythmic drugs,
Assess cardioversion, catheter Symptom
symptoms ablation, AF surgery improvement
Figure 5 Acute and chronic management of atrial fibrillation patients, desired cardiovascular outcomes, and patient benefits. Adapted from the
report on the 4th AFNET/EHRA consensus conference.76
2912 ESC Guidelines
Integrated AF management
Access to all treatment
Patient involvement Multidisciplinary teams Technology tools
options for AF
• Central role in care process • Phycisians (general physicians, • Information on AF • Structured support for lifestyle
• Patient education cardiology and stroke AF • Clinical decision support changes
• Encouragement and empowerment specialists, surgeons) and allied • Checklist and communication tools • Anticoagulation
for self-management health professionals work in a • Used by healthcare professionals • Rate control
• Advice and education on lifestyle collaborative practice model and patients • Antiarrhythmic drugs
and risk factor management • • Monitoring of therapy adherence • Catheter and surgical interventions
• Shared decision making skills, education, and experience and effectiveness (ablation, LAA occluder, AF surgery,
etc.)
0.45–0.93; P ¼ 0.017) compared with usual care in a large tertiary 8.2.4 Technology use to support atrial fibrillation care
care centre.330 Integrated AF management appeared cost-effective Technology, such as decision support software, has the potential
in that study.331 However, an Australian RCT showed only a margin- to enhance the implementation of evidence-based care and im-
al effect on unplanned admissions and death using integrated AF prove outcomes, when used to enhance expert advice.338 Elec-
care limited to the initial care period, possibly emphasizing the tronic tools can also ensure coherent communication within the
need for sustained integration of AF care.332 Two observational AF team. With a view to support the wider use of such technol-
studies of integrated AF care found fewer hospitalizations,333,334 ogy, this Task Force is providing digital decision tools, in the form
one study showed fewer cases of stroke,333 and a further non- of freely accessible smartphone apps, to AF healthcare profes-
randomized study identified a trend for a lower rate of the compos- sionals and to AF patients.
ite outcome of death, cardiovascular hospitalization, and AF-related
emergency visits.335 More research is needed, and integrated AF Recommendations for an integrated approach to care
8.3.2 Additional investigations in selected patients with benefit need careful explanation to patients when their benefits
atrial fibrillation are not directly felt. Rhythm control therapy can be successful if
Ambulatory ECG monitoring in AF patients can assess the adequacy symptoms are controlled, even when AF recurs. Explaining the
of rate control, relate symptoms with AF recurrences, and detect expected benefits to each patient at the start of AF management
focal induction of bouts of paroxysmal AF. Transoesophageal echo- will prevent unfounded expectations and has the potential to
cardiography (TOE) is useful to further assess valvular heart disease optimize quality of life.
and to exclude intracardiac thrombi, especially in the LAA, to facili-
tate early cardioversion or catheter ablation.344 Patients with symp-
toms or signs of myocardial ischaemia should undergo coronary 9. Stroke prevention therapy in
angiography or stress testing as appropriate. In patients with AF atrial fibrillation patients
and signs of cerebral ischaemia or stroke, computed tomography
(CT) or magnetic resonance imaging (MRI) of the brain is recom- OAC therapy can prevent the majority of ischaemic strokes in AF
bpm ¼ beats per minute; mEHRA symptoms scale ¼ modified European Heart Rhythm Association symptoms scale; GP ¼ general practitioner; INR ¼ international normalized
ratio; LV ¼ left ventricular; NOAC ¼ non-vitamin K antagonist oral anticoagulant; VKA ¼ vitamin K antagonist.
hence there is strong evidence that patients with a CHA2DS2 - Measurement of cardiac troponin (high-sensitivity troponin T or I)
VASc risk score of 2 or more in men, and 3 or more in women, and N-terminal pro-B-type natriuretic peptide may provide
benefit from OAC. Fortunately, we now have a growing evidence additional prognostic information in selected AF patients.380 – 382
base regarding stroke risk in patients with one clinical risk factor Biomarker-based risk scores may, in the future, prove helpful to bet-
(i.e. a CHA2DS2-VASc score of 1 for men, and 2 for women), al- ter stratify patients (e.g. those at a truly low risk of stroke).75,382
though this relies largely on observed stroke rates in patients not
receiving OAC. In many of these patients, anticoagulation seems
to provide a clinical benefit. 371 – 375 The rates of stroke and 9.1.3 Clinical risk scores for bleeding
thrombo-embolism vary considerably in patients with CHA2DS2- Several bleeding risk scores have been developed, mainly in pa-
VASc scores of 1 or 2 due to differences in outcomes, populations, tients on VKAs. These include HAS-BLED [hypertension, abnor-
and anticoagulation status (Web Table 1.)371,376,377,1041 We there- mal renal/liver function (1 point each), stroke, bleeding history or
fore commissioned an analysis of stroke risk in men and women predisposition, labile INR, elderly (.65 years), drugs/alcohol con-
with one additional stroke risk factor to inform these guidelines comitantly (1 point each)], ORBIT (Outcomes Registry for Better
(Web Table 1, last line). OAC should be considered for men Informed Treatment of Atrial Fibrillation), and more recently, the
with a CHA2DS2-VASc score of 1 and women with a score of 2, ABC (age, biomarkers, clinical history) bleeding score, which also
balancing the expected stroke reduction, bleeding risk, and pa- makes use of selected biomarkers.383 – 385 Stroke and bleeding risk
tient preference. Importantly, age (65 years and older) conveys factors overlap (compare Tables 11 and 12). For example, older
a relatively high and continuously increasing stroke risk that also age is one of the most important predictors of both ischaemic
potentiates other risk factors (such as heart failure and sex). stroke and bleeding in AF patients. 386,387 A high bleeding risk
Hence, an individualized weighing of risk, as well as patient prefer- score should generally not result in withholding OAC. Rather,
ences, should inform the decision to anticoagulate patients with bleeding risk factors should be identified and treatable factors
only one CHA2DS2-VASc risk factor, apart from female sex. Fe- corrected (see chapter 8.5). Table 12 provides details of modifi-
male sex does not appear to increase stroke risk in the absence able bleeding risk factors.
of other stroke risk factors (Web Table 1).378,379
2916 ESC Guidelines
No
a
Congestive heart failure, Hypertension, Age ≥75 years (2 points), Diabetes, prior Stroke/TIA/embolus (2 points),Vascular disease, age 65–74 years, female Sex.
b
Includes women without other stroke risk factors.
c
IIaB for women with only one additional stroke risk factor.
d
IB for patients with mechanical heart valves or mitral stenosis.
Table 11 Clinical risk factors for stroke, transient Table 12 Modifiable and non-modifiable risk factors
ischaemic attack, and systemic embolism in the for bleeding in anticoagulated patients based on
CHA2DS2-VASc score bleeding risk scores
Event rate, Event rate, %/year Event rate, %/ Event rate, %/year Event rate, %/year (HR Event rate, Event rate, %/year (HR Event rate, Event rate, %/year Event rate, %/year
%/year (RR vs. warfarin) year (RR vs. vs. warfarin) %/year vs. warfarin) %/year (HR vs. warfarin) (HR vs. warfarin)
warfarin)
1.54 (0.89,
1.12 (0.65,
0.73–1.09; 2.1 (0.88, 0.75–1.03; 1.27 (0.79, 0.66–0.95; 1.57 (0.87, 0.73–1.04; 2.04 (1.13, 0.96–1.34;
0.52–0.81;
P for non- P for non-inferiority P <0.001 for non- P <0.001 for non- P = 0.005 for non-
Stroke/systemic embolism 1.72 P for non-inferiority 2.4 1.60 1.80
inferiority <0.001, P for inferiority, inferiority, P = 0.08 for inferiority, P = 0.10
and superiority
<0.001) superiority = 0.12) P = 0.01 for superiority) superiority) for superiority)
<0.001)
2.92 (0.80,
3.40 (0.94,
0.70–0.93; 2.13 (0.69, 0.60–0.80; 2.75 (0.80, 0.71–0.91; 1.61 (0.47, 0.41–0.55;
Major bleeding 3.61 0.82–1.08; 3.45 3.60 (1.04; 0.90-2.30; 3.09 3.43
P = 0.003) P <0.001) P <0.001) P <0.001)
P = 0.41) P = 0.58)
Myocardial Infarction 48) trial,321 edoxaban 60 mg once daily and Only the higher dose regimen has been approved for stroke pre-
edoxaban 30 mg once daily (with dose reductions in certain pa- vention in AF.
tients, Table 13), were compared with adjusted-dose warfarin.405
Edoxaban 60 mg once daily was non-inferior to warfarin (Table 13). 9.2.2.4 Rivaroxaban
In an on-treatment analysis, edoxaban 60 mg once daily significant- In the ROCKET-AF (Rivaroxaban Once Daily Oral Direct Fac-
ly reduced stroke or systemic embolism by 21% and significantly tor Xa Inhibition Compared with Vitamin K Antagonism for Pre-
reduced major bleeding events by 20% compared with warfarin, vention of Stroke and Embolism Trial in Atrial Fibrillation) trial,320
while edoxaban 30 mg once daily was non-inferior to warfarin patients were randomized to rivaroxaban 20 mg once daily
for prevention of stroke and systemic embolism but significantly or VKA, with a dose adjustment to 15 mg daily for those with
reduced major bleeding events by 53%. Cardiovascular death estimated CrCl 30 – 49 mL/min by the Cockroft – Gault formula
was reduced in patients randomized to edoxaban 60 mg once (Table 13). Rivaroxaban was non-inferior to warfarin for the pre-
daily or edoxaban 30 mg once daily compared with warfarin. vention of stroke and systemic embolism in the intent-to-treat
ESC Guidelines 2919
analysis, while the per-protocol on-treatment analysis achieved NOACs at centres with poor INR control (interaction P ¼
statistical superiority with a 21% reduction in stroke or systemic 0.022). Notably, the substantial reduction in intracranial haemor-
embolism compared with warfarin. Rivaroxaban did not reduce rhage by NOACs compared with warfarin seems unrelated to the
the rates of mortality, ischaemic stroke, or major bleeding events quality of INR control.408,409
compared to VKA. There was an increase in gastrointestinal
bleeding events, but a significant reduction in haemorrhagic stroke 9.2.4 Oral anticoagulation in atrial fibrillation patients
and intracranial haemorrhage with rivaroxaban compared with with chronic kidney disease
warfarin. Comparable event rates have been reported in post- CKD is associated with stroke and bleeding in large data sets.410,411
authorization analyses, which are part of the post-approval risk Anticoagulation can be safely used in AF patients with moderate or
management process.406,407 moderate-to-severe CKD [glomerular filtration rate (GFR) ≥15
mL/min]: the SPAF (Stroke Prevention in Atrial Fibrillation) III trial
Table 14 Dose adjustment for NOACs as evaluated in the PHASE III trials (adapted from Hart et al.316)
CKD ¼ chronic kidney disease; CrCl ¼ creatinine clearance; GFR ¼ glomerular filtration rate; NA ¼ not available.
2920 ESC Guidelines
with increased mortality in patients on dialysis.417 There are no guided by the estimated GFR of the transplanted kidney. Potential
randomized trials assessing OAC in haemodialysis patients, 418 pharmacokinetic interactions of OAC with immunosuppressive
and no controlled trials of NOACs in patients with severe CKD agents should be considered.
(CrCl ,25 – 30 mL/min).318 – 321 Warfarin use was associated ei-
ther with a neutral or increased risk of stroke in database analyses
of patients on dialysis,419 – 421 including a population-based ana- 9.2.7 Antiplatelet therapy as an alternative to oral
anticoagulants
lysis in Canada (adjusted HR for stroke 1.14; 95% CI 0.78 – 1.67,
The evidence supporting antiplatelet monotherapy for stroke pre-
adjusted HR for bleeding 1.44; 95% CI 1.13 – 1.85).422 In contrast,
vention in AF is very limited.38,428 – 430 VKA therapy prevents stroke,
data from Denmark suggest a benefit of OAC in patients on renal
systemic embolism, myocardial infarction, and vascular death better
replacement therapy.423 Hence, controlled studies of anticoagu-
than single or dual antiplatelet therapy with aspirin and clopidogrel
lants (both VKAs and NOACs) in AF patients on dialysis are
(annual risk of 5.6% for aspirin and clopidogrel vs. 3.9% with VKA
needed.424
In male or female AF patients without additional stroke risk factors, anticoagulant or antiplatelet therapy is not III 368, 371,
B
recommended for stroke prevention. (harm) 376, 377
III 38, 429,
Antiplatelet monotherapy is not recommended for stroke prevention in AF patients, regardless of stroke risk. A
(harm) 430
NOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) are not recommended in patients with mechanical heart valves III 318–321,
B C
(Level of evidence B) or moderate-to-severe mitral stenosis (Level of evidence C). (harm) 400, 404
AF ¼ atrial fibrillation; CHA2DS2-VASc ¼ Congestive Heart failure, hypertension, Age ≥75 (doubled), Diabetes, Stroke (doubled), Vascular disease, Age 65 –74, and Sex (female);
INR ¼ international normalized ratio; NOAC ¼ non-vitamin K antagonist oral anticoagulant; OAC ¼ oral anticoagulation; TTR ¼ time in therapeutic range; VKA ¼ vitamin K
antagonist.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
ESC Guidelines 2921
9.3 Left atrial appendage occlusion and Recommendations for occlusion or exclusion of the
exclusion left atrial appendage
9.3.1 Left atrial appendage occlusion devices
Interventional LAA occlusion, 446 – 449 and limited experience Recommendations Class a Level b Ref C
with percutaneous LAA ligation, has mainly been reported in ob-
After surgical occlusion or exclusion
servational studies and registries. Only one device (Watchmanw)
of the LAA, it is recommended to
has been compared with VKA therapy in randomized trials continue anticoagulation in I B 461, 462
[PROTECT AF (Watchman Left Atrial Appendage System for at-risk patients with AF for stroke
Embolic Protection in Patients With AF trial), see Web Table 2; prevention.
and PREVAIL (Prospective Randomized Evaluation of the Watch- LAA occlusion may be considered
man LAA Closure Device In Patients with AF Versus Long Term for stroke prevention in patients
Figure 9 Initiation or continuation of anticoagulation in atrial fibrillation patients after a stroke or transient ischaemic attack. This approach is
based on consensus rather than prospective data.
stroke are scarce. Parenteral anticoagulants seem to be associated strokes (OR 0.44; 95% CI 0.32–0.62).482 Detailed data for edoxaban
with a non-significant reduction in recurrent ischaemic stroke have not yet been published.321 If a patient suffers a stroke or TIA
when administered 7 – 14 days after the acute stroke [odds ratio whilst taking an anticoagulant, switching to another anticoagulant
(OR) 0.68; 95% CI 0.44 –1.06), with a significant increase in symp- should be considered.
tomatic intracranial bleeding (OR 2.89; 95% CI 1.19 – 7.01), and a
similar rate of death or disability at final follow-up.477 It seems likely 9.4.3 Initiation of anticoagulation after intracranial
that the bleeding risk on parenteral anticoagulation exceeds the haemorrhage
stroke prevention benefit in the first days after a large stroke, No prospective studies have investigated the benefit or risk of the ini-
whereas patients with a TIA or a small stroke may benefit from early tiation of OAC after intracranial haemorrhage,483 and patients with a
(immediate) initiation or continuation of anticoagulation. Therefore, history of intracranial bleeding were excluded from the randomized
we propose to initiate anticoagulation in AF patients between 1 trials comparing NOACs with VKAs. The available evidence indicates
and 12 days after an ischaemic stroke, depending on stroke severity that anticoagulation in patients with AF can be reinitiated after 4–8
(Figure 9).478 We suggest repeat brain imaging to determine the op- weeks, especially when the cause of bleeding or the relevant risk fac-
timal initiation of anticoagulation in patients with a large stroke at tor (e.g. uncontrolled hypertension, see Table 12) has been treated,
risk for haemorrhagic transformation. Long-term OAC with a and that such treatment leads to fewer recurrent (ischaemic) strokes
VKA363,479 – 481 or NOAC482 conveys benefits in AF patients who and lower mortality.460,484 If anticoagulation is resumed, it seems rea-
survived a stroke. NOACs seem to convey slightly better outcomes, sonable to consider anticoagulants with a low bleeding risk.39 Figure 10
mainly driven by fewer intracranial haemorrhages and haemorrhagic depicts a consensus opinion on the initiation or resumption of OAC
ESC Guidelines 2923
after an intracranial haemorrhage. We recommend a multidisciplinary is of particular relevance in anticoagulated patients with AF. Treat-
decision with input from stroke physicians/neurologists, cardiologists, ment according to current guidelines is recommended in patients
neuroradiologists, and neurosurgeons. with known hypertension.489
Figure 10 Initiation or resumption of anticoagulation in atrial fibrillation patients after an intracranial bleed. This approach is based on consensus
opinion and retrospective data. In all patients, evaluation by a multidisciplinary panel is required before treatment (stroke physician/neurologist,
cardiologist, neuroradiologist, and neurosurgeon).
with AF, interruption of anticoagulation was non-inferior to hep- time, activated partial thromboplastin time, and INR. Coagulation
arin bridging for the outcome of arterial thrombo-embolism (inci- tests do not provide much information in patients on NOACs, ex-
dence of 0.4% and 0.3%, respectively) and resulted in a lower risk cept for activated partial thromboplastin time in the case of dabiga-
of major bleeding (1.3% and 3.2%, respectively).502 OAC interrup- tran. More specific coagulation tests do exist, including diluted
tions should be minimized to prevent stroke. thrombin time (HEMOCLOT) for dabigatran and calibrated quanti-
tative anti-factor Xa assays for factor Xa inhibitors.503 However,
these tests are not always readily available and are often unneces-
9.6 Management of bleeding events in sary for bleeding management.504
anticoagulated patients with atrial We propose a simple scheme to manage bleeding events in patients
fibrillation on OAC (Figure 11). Minor bleeding events should be treated with
9.6.1 Management of minor, moderate, and severe bleeding supportive measures such as mechanical compression or minor sur-
General assessment of an anticoagulated patient with AF experien- gery to achieve haemostasis. In patients receiving VKAs, the next dose
cing a bleeding event should include the assessment of bleeding site, of VKA can be postponed. NOACs have a short plasma half-life of ap-
onset, and severity of the bleeding, the time-point of last intake of proximately 12 h, and improved haemostasis is expected within 12–
OAC and other antithrombotic drugs, and other factors influencing 24 h after a delayed or omitted dose. Treatment of moderate bleeding
bleeding risk such as CKD, alcohol abuse, and concurrent medica- events may require blood transfusions and fluid replacement. Specific
tions. Laboratory tests should include haemoglobin, haematocrit, diagnostic and treatment interventions directed against the cause of
platelet count, renal function, and, for VKA patients, prothrombin the bleeding (e.g. gastroscopy) should be performed promptly. If
ESC Guidelines 2925
Delay VKA until INR <2 Minor Delay NOAC for 1 dose or 1 day
FFP = fresh frozen plasma; INR = international normalized ratio; i.v. = intravenous; NOAC = non-vitamin K antagonist oral anticoagulant; OAC = oral anticoagulation; PCC =
prothrombin complex concentrates; VKA = vitamin K antagonist.
Figure 11 Management of active bleeding in patients receiving anticoagulation. Institutions should have an agreed procedure in place.
the intake of NOAC was recent (,2–4 h), charcoal administration Several antidotes to NOACs are under development. Idarucizumab
and/or gastric lavage will reduce further exposure. Dialysis clears da- (approved in 2015 by the US Food and Drug Administration and the
bigatran but is less effective for the other NOACs. European Medicines Agency) is a clinically available humanized anti-
Immediate reversal of the antithrombotic effect is indicated in se- body fragment that binds dabigatran and rapidly and dose-dependently
vere or life-threatening bleeding events. An agreed institutional reverses its effects without over-correction or thrombin gener-
procedure for the management of life-threatening bleeds should be ation.475 Andexanet alpha, a modified recombinant human factor Xa
documented and accessible at all times to ensure adequate initial man- that lacks enzymatic activity, reverses the anticoagulant activity of fac-
agement. For VKAs, administration of fresh frozen plasma restores co- tor Xa antagonists in healthy subjects within minutes after administra-
agulation more rapidly than vitamin K, and prothrombin complex tion and for the duration of infusion, with a transient increase in
concentrates achieve even faster blood coagulation.505 Registry data markers of coagulation activity of uncertain clinical relevance.508 An-
suggest that the combination of plasma and prothrombin complex other agent under development is ciraparantag (PER977), an antidote
concentrates is associated with the lowest case fatality following intra- designed to reverse both direct thrombin and factor Xa inhibitors as
cranial haemorrhage on VKA treatment with an INR ≥1.3.506 In a mul- well as the indirect inhibitor enoxaparin.509 The clinical usefulness of
ticentre randomized trial of 188 patients, four-factor prothrombin these specific antidotes needs further evaluation.
complex concentrates achieved more rapid INR reversal and effective
haemostasis than plasma in patients undergoing urgent surgical or in- 9.6.2 Oral anticoagulation in atrial fibrillation patients at
vasive procedures.507 Administration of prothrombin complex con- risk of or having a bleeding event
centrates may also be considered for severe bleeding on NOAC While anticoagulation therapy should be paused to control active
treatment if specific antidotes are not available. bleeding, absolute contraindications to long-term OAC after a
2926 ESC Guidelines
bleeding episode are rare. When nuisance bleeds are the reason to lives. This scenario requires careful consideration of antithrombotic
stop OAC, a change from one anticoagulant to another seems rea- therapy, balancing bleeding risk, stroke risk, and risk of acute coron-
sonable. Many causes or triggers of major bleeding events can be ary syndromes (ACS).516 Co-prescription of OAC with antiplatelet
treated and/or eliminated, including uncontrolled hypertension, therapy, in particular triple therapy, increases the absolute risk of
gastrointestinal ulcers, and intracranial aneurysms. Reinitiation of an- major haemorrhage.445,517,518 A recent meta-analysis involving 30
ticoagulation after a bleeding event is often clinically justified.460,510 866 patients with a recent ACS evaluated the effects of adding
Difficult decisions, including the discontinuation and recommence- NOAC therapy to single (4135 patients) or dual (26 731 patients)
ment of OAC, should be taken by a multidisciplinary team, balancing antiplatelet therapy.519 The addition of a NOAC increased the
the estimated risk of recurrent stroke and bleeding, and considering bleeding risk by 79–134%, while reducing recurrent ischaemic events
the bleeding risk of different stroke prevention therapies. LAA ex- only marginally in patients without AF. OAC monotherapy, and not
clusion or occlusion might be an alternative in selected patients. combination therapy with antiplatelets, is recommended in AF pa-
Figure 12 Antithrombotic therapy after an acute coronary syndrome in atrial fibrillation patients requiring anticoagulation.
2928 ESC Guidelines
Figure 13 Antithrombotic therapy after elective percutaneous intervention in atrial fibrillation patients requiring anticoagulation.
10. Rate control therapy in atrial diltiazem/verapamil are preferred over digoxin because of their
rapid onset of action and effectiveness at high sympathetic
fibrillation tone.528 – 532 The choice of drug (Table 15) and target heart
Rate control is an integral part of the management of AF patients, rate will depend on patient characteristics, symptoms, LVEF and
and is often sufficient to improve AF-related symptoms. Compared haemodynamics, but a lenient initial approach to heart rate seems
with stroke prevention and rhythm control, very little robust evi- acceptable. Combination therapy may be required (Figure 14). In
dence exists to inform the best type and intensity of rate control patients with HFrEF, beta-blockers, digitalis (digoxin or digitoxin),
treatment, with the majority of data derived from short-term cross- or their combination should be used,218,533 as diltiazem and
over trials and observational studies.41,526 – 528 Pharmacological rate verapamil can have negative inotropic effects in patients with
control can be achieved for acute or long-term rate control with LVEF ,40%.222,534,535 In critically ill patients and those with
beta-blockers, digoxin, the calcium channel blockers diltiazem and severely impaired LV systolic function, intravenous amiodarone
verapamil, or combination therapy (Table 15). A number of antiar- can be used where excess heart rate is leading to haemodynamic
rhythmic drugs also have rate-limiting properties (amiodarone, dro- instability.536 – 538 Urgent cardioversion should be considered in
nedarone, sotalol, and to some extent propafenone), but they unstable patients (see chapter 11.1).
should only be used in patients needing rhythm control therapy
(see Chapter 11). 10.2 Long-term pharmacological rate
control
10.1 Acute rate control 10.2.1 Beta-blockers
In the setting of acute new-onset AF, patients are often in need of Beta-adrenoreceptor blocker monotherapy is often the first-line
heart rate control. Physicians should evaluate underlying causes of rate-controlling agent,539 largely based on observations of better
elevated heart rate, such as infection, endocrine imbalance, anaemia, acute heart rate control than digoxin. Interestingly, the prognostic
and pulmonary embolism. For acute rate control, beta-blockers and benefit of beta-blockers seen in HFrEF patients with sinus rhythm
ESC Guidelines 2929
Therapy Acute intravenous rate Long-term oral rate Side effect profile Comments
control control
Beta-blockersa
Bisoprolol Not available 1.25–20 mg once daily or split.Most common reported adverse Bronchospasm is rare – in cases
symptoms are lethargy, headache, of asthma, recommend beta-1
Carvedilol Not available 3.125–50 mg twice daily.
peripheral oedema, upper selective agents (avoid carvedilol).
Metoprolol 2.5–10 mg intravenous bolus 100–200 mg total daily dose respiratory tract symptoms, Contra-indicated in acute cardiac
(repeated as required). (according to preparation). gastrointestinal upset and failure and a history of severe
Nebivolol Not available 2.5–10 mg once daily or split. dizziness. Adverse effects include bronchospasm.
bradycardia, atrioventricular block
Specific indications
Amiodarone 300 mg intravenously diluted in 200 mg daily Hypotension, bradycardia, nausea, Suggested as adjunctive therapy
250 mL 5% dextrose over 30–60 QT prolongation, pulmonary in patients where heart rate
minutes (preferably via central toxicity, skin discolouration, control cannot be achieved using
venous cannula).b thyroid dysfunction, corneal combination therapy.
deposits and cutaneous reaction
with extravasation.
AF ¼ atrial fibrillation; CKD ¼ chronic kidney disease; i.v. ¼ intravenous; LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction.
a
A number of other beta-blockers are also available, but are not recommended as specific rate control therapy in AF. These include atenolol (25 – 100 mg once daily with a short
biological half-life), propranolol [non-selective, 1 mg over 1 min and repeat up to 3 mg at 2-min intervals (acute) or 10 –40 mg three times daily (long-term)], or labetalol
[non-selective, 1– 2 mg/min (acute)].
b
If ongoing requirement for amiodarone, follow with 900 mg i.v. over 24 h diluted in 500– 1000 mL via a central venous cannula.
is lost in those with AF. In an individual patient-level meta-analysis of patients, based on the potential for symptomatic and functional im-
RCTs, beta-blockers did not reduce all-cause mortality compared provement as a result of rate control, the lack of harm from pub-
to placebo in those with AF at baseline (HR 0.97; 95% CI 0.83 – lished studies, and the good tolerability profile across all ages in
1.14; P ¼ 0.73), whereas there was a clear benefit in patients with sinus rhythm and in AF.23,540
sinus rhythm (HR 0.73; 95% CI 0.67 – 0.80; P , 0.001).23 The ana-
lysis, which included 3066 participants with HFrEF and AF, showed 10.2.2 Non-dihydropyridine calcium channel blockers
consistency across all subgroups and outcomes, with no heterogen- Verapamil or diltiazem provide reasonable rate control in AF pa-
eity between the 10 RCTs included (I2 ¼ 0%). Despite this lack of tients.541 They should be avoided in patients with HFrEF because
prognostic benefit in HFrEF, this Task Force still considers beta- of their negative inotropic effects.222,534,535 Verapamil or diltiazem
blockers as a useful first-line rate control agent across all AF can improve arrhythmia-related symptoms,526 in comparison with
2930 ESC Guidelines
Initial resting heart rate target <110 bpm Initial resting heart rate target <110 bpm
Avoid bradycardia
Perform echocardiogram to
determine further management/
choice of maintenance therapy
Consider need for anticoagulation
See Table 15 for medication dosage. Digitoxin is a suitable alternative to digoxin, where available.
beta-blockers, which reduced exercise capacity and increased higher B-type natriuretic peptide levels, combination carvedilol/
B-type natriuretic peptide in one small trial of low-risk patients digoxin improved LVEF, and digoxin withdrawal reduced LVEF.554
with preserved LVEF.542 Comparisons with other rate control therapies are based on small,
short-duration studies that identify no or marginal differences
10.2.3 Digitalis in exercise capacity, quality of life, or LVEF compared to
Cardiac glycosides such as digoxin and digitoxin have been in use for digoxin.526,554 – 558 Lower doses of digoxin (≤250 mg once daily),
over two centuries, although prescriptions have been declining corresponding to serum digoxin levels of 0.5 – 0.9 ng/mL, may be
steadily over the past 15 years.543 In the randomized Digitalis Inves- associated with better prognosis.225
tigation Group (DIG) trial, digoxin had no effect on mortality com-
pared to placebo in HFrEF patients in sinus rhythm (RR 0.99; 95% CI 10.2.4 Amiodarone
0.91 – 1.07), but reduced hospital admissions (RR 0.72; 95% CI Amiodarone can be useful for rate control as a last resort. The wide
0.66 – 0.79).544,545 There have been no head-to-head RCTs of di- array of extracardiac adverse effects associated with amiodarone
goxin in AF patients.546 Observational studies have associated di- renders it a reserve agent in patients whose heart rate cannot be
goxin use with excess mortality in AF patients,547 – 549 but this controlled with combination therapy (e.g. beta-blocker or verap-
association is likely due to selection and prescription biases rather amil/diltiazem combined with digoxin).
than harm caused by digoxin,550 – 553 particularly as digoxin is com-
monly prescribed to sicker patients.225 In a crossover mechanistic In summary, there is equipoise for the use of different rate control
trial of 47 patients with HFrEF and AF, there were no differences agents in AF. The choice of beta-blocker, diltiazem/verapamil, di-
in heart rate, blood pressure, walking distance, or LVEF between goxin, or combination therapy should be made on an individual ba-
carvedilol and digoxin, although beta-blockers did result in sis, after consideration of patient characteristics and patient
ESC Guidelines 2931
Diltiazem/ Digoxin
Beta-blocker Digoxin Beta-blocker
verapamil
Add diltiazem,
Add
Add digoxin Add digoxin Add digoxin verapamil or
beta-blocker
beta-blocker
See Table 15 for medication dosage. Digitoxin is a suitable alternative to digoxin, where available.
preference. All available therapies have the potential for adverse ef- control is an acceptable initial approach, regardless of heart failure
fects and patients should initially be treated with a low dose and up- status, unless symptoms call for stricter rate control.
titrated to achieve symptom improvement. In practice, achieving a
heart rate ,110 b.p.m. will often require combination therapy
(Figure 15). The benefit of different rate control strategies on symp-
10.4 Atrioventricular node ablation and
toms, quality of life, and other intermediate outcomes is under pacing
investigation.559 Ablation of the atrioventricular node/His bundle and implantation of
a VVI pacemaker can control ventricular rate when medications fail
to control rate and symptoms. It is a relatively simple procedure with
10.3 Heart rate targets in atrial a low complication rate and low long-term mortality risk,563,564 es-
fibrillation pecially when the pacemaker is implanted a few weeks before the AV
The optimal heart rate target in AF patients is unclear. The RACE nodal ablation and the initial pacing rate after ablation is set at 70–90
(Rate Control Efficacy in Permanent Atrial Fibrillation) II study ran- b.p.m.565,566 The procedure does not worsen LV function567 and
domized 614 patients with permanent AF to either a target heart may even improve LVEF in selected patients.568 – 570 In selected
rate ,80 b.p.m. at rest and ,110 b.p.m. during moderate exercise, HFrEF patients treated with biventricular pacing (cardiac resynchro-
or to a lenient heart rate target of ,110 b.p.m. There was no differ- nization therapy), AF can terminate,571 although such a ‘rhythm con-
ence in a composite of clinical events (14.9% in the strict rate con- trol’ effect of cardiac resynchronization therapy is likely to be small
trol group, 12.9% in the lenient group),560 NYHA class, or and clearly needs confirmation.572 AV nodal ablation renders pa-
hospitalizations.560,561 Similar results were found in a pooled ana- tients pacemaker-dependent for the rest of their lives, limiting AV
lysis of the AFFIRM (Atrial Fibrillation Follow-up Investigation of nodal ablation and pacing to patients whose symptoms cannot be
Rhythm Management) and RACE trials (1091 participants), albeit managed by rate-controlling medication or by reasonable rhythm
with smaller heart rate differences and without randomization.562 control interventions (see AF Heart Team, chapter 11.6). The
It is worthwhile to note that many ‘adequately rate-controlled’ pa- choice of pacing therapy (right ventricular or biventricular pacing
tients (resting heart rate 60–100 b.p.m.) are severely symptomatic, with or without an implantable defibrillator) will depend on individ-
calling for additional management.194 Nonetheless, lenient rate ual patient characteristics, including LVEF.573,574
2932 ESC Guidelines
ACS ¼ acute coronary syndromes; AV ¼ atrio-ventricular; IHD ¼ ischaemic heart disease; i.v. ¼ intravenous; LVH ¼ left ventricular hypertrophy; NYHA ¼ New York Heart
Association; SBP ¼ systolic blood pressure.
a
Use a large peripheral vessel and change to oral amiodarone within 24 h of i.v. (central line) administration.
b
Ibutilide is only available in selected European countries.
monophasic waveforms, and have become the industry stand- 11.2 Long-term antiarrhythmic drug
ard.626,628 Anterior–posterior electrode positions generate a stron- therapy
ger shock field in the left atrium than anterolaterally positioned
The aim of antiarrhythmic drug therapy is improvement in
electrodes, and restore sinus rhythm more effectively.626,627,630
AF-related symptoms.41,580 Hence, the decision to initiate long-
Pre-treatment with amiodarone (requiring a few weeks of ther-
term antiarrhythmic drug therapy needs to balance symptom bur-
apy),631,632 sotalol,631 ibutilide,633 or vernakalant634 can improve
den, possible adverse drug reactions, and patient preferences. The
the efficacy of electrical cardioversion, and similar effects are likely
principles of antiarrhythmic drug therapy outlined in the 2010
for flecainide584 and propafenone.635 Beta-blockers,636 verapamil,
ESC AF guidelines369 are still relevant and should be observed:
diltiazem,637 – 639 and digoxin640,641 do not reliably terminate AF
or facilitate electrical cardioversion. When antiarrhythmic drug
(1) Treatment is aimed at reducing AF-related symptoms;
therapy is planned to maintain sinus rhythm after cardioversion, it
(2) Efficacy of antiarrhythmic drugs to maintain sinus rhythm is modest;
seems prudent to start therapy 1 – 3 days before cardioversion
(3) Clinically successful antiarrhythmic drug therapy may reduce ra-
(amiodarone: a few weeks) to promote pharmacological conversion
ther than eliminate the recurrence of AF;
and to achieve effective drug levels.584,601
(4) If one antiarrhythmic drug ‘fails’, a clinically acceptable response
may be achieved with another agent;
11.1.4 Anticoagulation in patients undergoing (5) Drug-induced pro-arrhythmia or extracardiac side-effects are
cardioversion frequent;
Cardioversion carries an inherent risk of stroke in non-anticoagulated (6) Safety rather than efficacy considerations should primarily guide
patients,642 which is reduced substantially by the administration of an- the choice of antiarrhythmic drug.
ticoagulation.643 Immediate initiation of anticoagulation is important
in all patients scheduled for cardioversion.644 – 646 Patients who Antiarrhythmic drug therapy approximately doubles sinus rhythm
have been in AF for longer than 48 h should start OAC at least 3 maintenance compared with no therapy.580 There is no appreciable
weeks before cardioversion and continue it for 4 weeks afterwards effect on mortality or cardiovascular complications, but rhythm
(in patients without a need for long-term anticoagulation). OAC control therapy can slightly increase the risk of hospitalizations (of-
should be continued indefinitely in patients at risk of stroke. This prac- ten for AF).41,578,579,582,589 – 593 To reduce the risk of side-
tice has never been evaluated in controlled trials, but seemed safe in a effects,201,580 a shorter duration of antiarrhythmic drug therapy
large observational data set from Finland.647 When early cardiover- seems desirable. As an example, short-term treatment (4 weeks)
sion is desired, TOE can exclude the majority of left atrial thrombi, with flecainide for 4 weeks after cardioversion of AF was well-
allowing immediate cardioversion.648,649 Ongoing studies will inform tolerated and prevented most (80%) AF recurrences when com-
about the safety and efficacy of newly initiated anticoagulation using pared with long-term treatment.584 Short-term antiarrhythmic
NOACs in patients scheduled for cardioversion. drug therapy is also used to avoid early AF recurrences after
2934 ESC Guidelines
Recent onset AF
Yes Haemodynamic No
instability?
Elective
Urgent
Patient choice
catheter ablation,650 and may be reasonable in patients deemed at less suitable to episodic short-term therapy (unless after catheter
increased risk of antiarrhythmic drug side-effects or in those with ablation),655 probably because of its long biological half-life.
a low perceived risk of recurrent AF.
11.2.1.2 Dronedarone
In addition to antiarrhythmic drug therapy and catheter ablation
Dronedarone maintains sinus rhythm, reduces ventricular rate, and
(see Chapter 11.3), management of concomitant cardiovascular
prevents cardiovascularhospitalizations(mostly duetoAF) and cardio-
conditions can reduce symptom burden in AF and facilitate the
vascular death in patients with paroxysmal or persistent AF or flutter
maintenance of sinus rhythm.203,204,296,312 This includes weight re-
who had at least one relevant cardiovascular comorbidity.583,588,656
duction, blood pressure control, heart failure treatment, increasing
Dronedarone increases mortality in patients with recently decompen-
cardiorespiratory fitness, and other measures (see Chapter 7).
sated heartfailure (with orwithout AF),657 and inpatients with perman-
ent AF in whom sinus rhythm is not restored.658 Dronedarone
11.2.1 Selection of antiarrhythmic drugs for long-term moderately increases serum creatinine, reflecting a reduction in cre-
therapy: safety first! atinine excretion rather than a decline in kidney function.659
Usually, the safety of antiarrhythmic drug therapy determines the 11.2.1.3 Flecainide and propafenone
initial choice of antiarrhythmic drugs (Figure 17). The following ma- Flecainide and propafenone are effective in preventing recurrent
jor antiarrhythmic drugs are available to prevent AF: AF.581,584,620 They should only be used in patients without significant
11.2.1.1 Amiodarone ischaemic heart disease or heart failure to avoid the risk of life-
Amiodarone is an effective multichannel blocker, reduces ven- threatening ventricular arrhythmias.660 High ventricular rates result-
tricular rate, and is safe in patients with heart failure.582,651 Torsades ing from the conversion of AF into atrial flutter with 1:1 conduction
de pointes pro-arrhythmia can occur, and QT interval and TU waves by flecainide or propafenone can be prevented by pre-administering
should be monitored on therapy (see Table 17).652 Amiodarone of- a beta-blocker, verapamil, or diltiazem.
ten causes extracardiac side-effects, especially on long-term ther- 11.2.1.4 Quinidine and disopyramide
apy,653,654 rendering it a second-line treatment in patients who Quinidine and disopyramide have been associated with an increase in
are suitable for other antiarrhythmic drugs. Amiodarone appears all-cause mortality (OR 2.39; 95% CI 1.03– 5.59; number needed to
ESC Guidelines 2935
a
Sotalol requires careful evaluation of proarrhythmic risk.
b
Catheter ablation should isolate pulmonary veins and can be performed using radiofrequency or cryoballoon catheters.
c
d
Amiodarone is a second-choice therapy in many patients because of its extracardiac side-effects.
Figure 17 Initiation of long-term rhythm control therapy in symptomatic patients with atrial fibrillation.
harm 109; 95% CI 34–4985) at 1-year follow-up,580,661 likelydue toven- characteristics mentioned above, monitoring PR, QT, and QRS dura-
tricular arrhythmias (torsades de pointes).580,661 Although this tions during initiation of antiarrhythmic drug therapy can identify pa-
pro-arrhythmic effect is more common at higher doses, they are less tients at higher risk of drug-induced pro-arrhythmia on longer-term
commonly used for rhythm control in AF. Disopyramide may be useful treatment.669 – 671 In addition, the presence of ‘abnormal TU waves’ is
in ‘vagally mediated’ AF (e.g. AF occurring in athletes and/or during a sign of imminent torsades de pointes.652 Periodic ECG analysis for
sleep76), and has been shown to reduce LV outflow gradient and im- pro-arrhythmia signs has been used successfully in recent antiarrhyth-
prove symptoms in patients with hypertrophic cardiomyopathy.662 – 664 mic drug trials.118,584,672 Specifically, ECG monitoring was used system-
11.2.1.5 Sotalol atically on days 1–3 in patients receiving flecainide, propafenone, or
Sotalol has a relevant risk of torsades de pointes [1% in the Pre- sotalol to identify those at risk of pro-arrhythmia.118,584,601 Based on
vention of Atrial Fibrillation After Cardioversion (PAFAC) trial118]. this evaluated practice, we suggest to record an ECG in all patients
Its d-enantiomer is associated with increased mortality compared to before initiation of antiarrhythmic drugs. Scheduled ECGs during the
placebo in patients with LV dysfunction after a myocardial infarc- initiation period seem reasonable (Table 17).
tion,665 probably due to ventricular arrhythmias (OR 2.47; 95% CI
1.2 – 5.05; number needed to harm 166; 95% CI 61 – 1159).580,665
11.2.3 New antiarrhythmic drugs
On the other hand, d,l-sotalol has been used in AF patients without
Several compounds that inhibit the ultrarapid potassium current
safety signals in two controlled trials.581,601
(IKur) and other inhibitors of atypical ion channels are in clinical de-
11.2.1.6 Dofetilide velopment.673 – 675 They are not available for clinical use at present.
Dofetilide is another potassium channel blocker that is mainly The antianginal compound ranolazine inhibits potassium and sodium
available outside of Europe. Dofetilide restores and maintains sinus currents and increases glucose metabolism at the expense of free
rhythm in heart failure patients,666 and occasionally in patients re- fatty acid metabolism, thereby enhancing the efficient use of oxy-
fractory to other antiarrhythmic drugs.667 gen.676,677 Ranolazine was safe in patients with non – ST-segment
elevation myocardial infarction and unstable angina evaluated in
Overall, it seems prudent to limit the use of quinidine, disopyra-
the MERLIN (Metabolic Efficiency With Ranolazine for Less Ische-
mide, dofetilide, and sotalol to specific situations. Furthermore,
mia in Non ST-Elevation Acute Coronary Syndrome) trial.678 In a
combinations of QT-prolonging antiarrhythmic drugs should gener-
post hoc analysis of continuous ECG recordings obtained during
ally be avoided for rhythm control in AF (Table 17).
the first 7 days after randomization, patients assigned to ranolazine
11.2.2 The twelve-lead electrocardiogram as a tool to had a trend towards fewer episodes of AF than those on placebo [75
identify patients at risk of pro-arrhythmia (2.4%) vs. 55 (1.7%) patients; P ¼ 0.08].679 In the HARMONY
Identifying patients at risk of pro-arrhythmia can help to mitigate the (A Study to Evaluate the Effect of Ranolazine and Dronedarone
pro-arrhythmic risk of antiarrhythmic drugs.668 In addition to the clinical When Given Alone and in Combination in Patients With
2936 ESC Guidelines
Table 17 Oral antiarrhythmic drugs used for maintaining sinus rhythm after cardioversion
Drug Dose Main contra-indications and precautions Warning signs AV nodal Suggested ECG
warranting slowing monitoring
discontinuation during initiation
Amiodarone 600 mg in divided Caution when using concomitant therapy with QT prolongation 10–12 bpm Baseline, 1 week,
doses for QT-prolonging drugs and in patients with SAN or AV node >500 ms in AF 4 weeks
4 weeks, 400 mg and conduction disease.
for 4 weeks, The dose of VKAs and of digitalis should be reduced.
then 200 mg Increased risk of myopathy with statins.
once daily Caution in patients with pre-existing liver disease.
Dronedarone 400 mg Contra-indicated in NYHA Class III or IV or unstable heart QT prolongation 10–12 bpm Baseline, 1 week,
AF ¼ atrial fibrillation; AV ¼ atrio-ventricular; bpm ¼ beats per minute; CrCl ¼ creatinine clearance; CYP2D6 ¼ cytochrome P450 2D6; CYP3A4 ¼ cytochrome P450 3A4;
ECG ¼ electrocardiogram; IHD ¼ ischaemic heart disease; LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction; NYHA ¼ New York Heart Association; SAN ¼ sino-
atrial node; VKA ¼ vitamin K antagonist.
Paroxysmal Atrial Fibrillation) trial, the highest tested dose of a com- Thus, ACE inhibitors or ARBs are unlikely to have a relevant direct
bination of ranolazine (750 mg twice daily) and dronedarone antiarrhythmic effect. However, it might be justified to consider adding
(225 mg twice daily) slightly reduced AF burden in 134 subjects ACE inhibitors or ARB therapy to antiarrhythmic drugs to reduce AF
with paroxysmal AF and dual-chamber pacemakers.680 Small, open- recurrences after cardioversion.248,249,687
label studies suggest that ranolazine might enhance the antiarrhythmic Compared with placebo, beta-blockers are associated with a re-
effect of amiodarone for cardioversion,681 – 683 whereas the results duced risk of new-onset AF in patients with HFrEF and sinus
from a controlled trial of ranolazine and the ranolazine–dronedarone rhythm.23 Beta-blockers have also been reported to reduce symp-
combination to prevent AHRE in pacemaker patients were ambigu- tomatic AF recurrences,580,636,688 but this finding may be driven
ous.684 At present, there is insufficient evidence to recommend rano- by the beneficial effect of rate control, which will render AF more
lazine as an antiarrhythmic drug, alone or in combination with other often asymptomatic.
antiarrhythmic drugs. Of note, the ‘funny channel blocker’ ivabradine, Peri-operative statin therapy appeared to reduce the risk of post-
which is used for angina and heart failure, increases the risk of AF.685 operative AF in a number of small RCTs689,690; however, an ad-
equately powered placebo-controlled trial has shown no effect of
11.2.4 Antiarrhythmic effects of non-antiarrhythmic drugs peri-operative rosuvastatin therapy on post-operative AF.691 Statin
ACE inhibitors or ARBs appear to prevent new-onset AF in patients treatment does not prevent AF in other settings.692,693 Similarly,
with LV dysfunction and in hypertensive patients with LV hyper- polyunsaturated fatty acids failed to show convincing bene-
trophy.219,236,237,239,246,250,686 Neprilysin inhibition needs to be fit.241,694 – 698 The role of aldosterone antagonists in the manage-
studied further, but does not seem to enhance this effect.224 A Danish ment of AF has not been extensively investigated in humans.
cohort study also suggested that initial treatment of uncomplicated Although preliminary evidence from trials of eplerenone is encour-
hypertension with ACE inhibitors or ARBs reduces incident AF com- aging for primary prevention,243 at present there is no robust evi-
pared with other hypertensive agents.245 ARB therapy did not reduce dence to make any recommendation for the use of aldosterone
the AF burden in patients with AF without structural heart disease.241 antagonists for secondary prevention of AF.699 – 701
ESC Guidelines 2937
Continued
2938 ESC Guidelines
Adding atrial-based bradycardia pacing to drug treatment that induces or exacerbates sinus node dysfunction should be
IIa B 711, 712
considered to allow continuation of AAD therapy in patients in whom AF ablation is declined or not indicated.
ACE-Is or ARBs are not recommended for the secondary prevention of paroxysmal AF in patients with little or no III
(no B 241, 697
underlying heart disease.
ACE ¼ angiotensin-converting enzyme; AF ¼ atrial fibrillation; ARB ¼ angiotensin receptor blocker; CHA2DS2-VASc ¼ Congestive Heart failure, hypertension, Age ≥75
(doubled), Diabetes, Stroke (doubled), Vascular disease, Age 65 –74, and Sex (female); ECG ¼ electrocardiogram; LV ¼ left ventricular; LVH ¼ left ventricular hypertrophy;
NOAC ¼ non-vitamin K antagonist oral anticoagulant; TOE ¼ transoesophageal echocardiography.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
11.3 Catheter ablation performed in expert centres, justifying catheter ablation as first-line
Since the initial description of triggers in the pulmonary veins that therapy in selected patients with paroxysmal AF who ask for interven-
initiate paroxysmal AF,108 catheter ablation of AF has developed tional therapy. Fewer data are available reporting the effectiveness
from a specialized, experimental procedure into a common treat- and safety of catheter ablation in patients with persistent or long-
ment to prevent recurrent AF.587,715 This is primarily achieved standing persistent AF, but all point to lower recurrence rates after
through isolation of the pulmonary veins, probably requiring com- catheter ablation compared to antiarrhythmic drug therapy with or
plete isolation for full effectiveness,716 and additional ablation in without cardioversion (Web Figure 2).185,717,723 – 726,1039 In patients
the posterior left atrial wall. AF ablation, when performed in experi- who experience symptomatic recurrences of AF despite antiarrhyth-
enced centres by adequately trained teams, is more effective than mic drug therapy, all RCTs showed better sinus rhythm maintenance
antiarrhythmic drug therapy in maintaining sinus rhythm, and the with catheter ablation than on antiarrhythmic drugs.586,713,727,728
complication rate, though not negligible, is similar to the complica- There is no current indication for catheter ablation to prevent cardio-
tion rate for antiarrhythmic drugs.585,717 vascular outcomes (or desired withdrawal of anticoagulation), or to
reduce hospitalization.40,594
AF, but there are insufficient data to guide the use of these at pre-
sent.117,718,719,735 – 737 Extended ablation procedures (beyond PVI) Table 18 Complications related to catheter ablation
consistently require longer procedures and more ionizing radiation, of atrial fibrillation
potentially creating risk for patients. Left atrial macro re-entrant
Complication Rate 727, 748,
tachycardia is relatively uncommon after PVI (≈5%). It also seems Complication type 750, 754-759
severity
rare after cryoballoon ablation,734 but may occur in up to 25% of pa-
Life-threatening Periprocedural death <0.2%
tients after left atrial substrate modification ablation, often due to in-
complications
complete ablation lines. Thus, for patients with persistent AF, ablation Oesophageal injury <0.5%
(perforation/fistula)a
of complex fractionated electrograms, ablation of rotors, or routine
deployment of linear lesions or other additional ablations does not Periprocedural stroke <1%
(including TIA/air embolism)
seem justified in the first procedure.735,738,739 However, additional
ablation on top of complete PVI716 may be considered in patients Cardiac tamponade 1–2%
ablation, heparin should be given to maintain an activated clotting Thus, indications for catheter ablation in HFrEF patients should be
time .300 s. Anticoagulation should be maintained for at least 8 carefully balanced, and the procedures performed in experienced
weeks after ablation for all patients. The true incidence of thrombo- centres.
embolic events after catheter ablation has never been systematically
studied and the expected stroke risk has been adopted from non- 11.3.6 Follow-up after catheter ablation
ablation AF cohorts. Although observational studies suggest a rela- Patients and physicians involved in the follow-up after catheter abla-
tively low stroke rate in the first few years after catheter ablation of tion should know the signs and symptoms of late complications to al-
AF,737,771 – 776 the long-term risk of recurrent AF and the safety pro- low swift referral for treatment (Table 18). Patients should also be
file of anticoagulation in ablated patients need to be considered. In aware that symptomatic and asymptomatic AF recurrences are fre-
the absence of controlled trial data, OAC after catheter ablation quent after catheter ablation.119,781,782 In line with the primary goal
should follow general anticoagulation recommendations, regardless of rhythm control therapy, asymptomatic episodes should generally
Figure 18 A: Surgical lesion sets for the biatrial Cox maze procedure. Surgeon’s view showing left atrial lesions (left panel) and right atrial le-
sions (middle and right panel). B: Left atrial lesions in a thoracoscopic minimally invasive surgical procedure (dashed lines), including left atrial
appendage exclusion (double line).
ESC Guidelines 2941
(Figure 18).783 Thereby, the Cox maze procedure creates an electrical and feasible, via a mini-thoracotomy.786,807,808 Thoracoscopic PVI
labyrinth (maze) of passages through which the sinoatrial node im- with bipolar radiofrequency prevents recurrence of paroxysmal
pulse finds a route to the atrioventricular node while preventing fibril- AF (69 – 91% freedom from arrhythmias at 1 year, see Figure 18B
latory conduction. The Cox maze procedure and other, often for lesion set),468,809,810 and seems effective in patients refractory
simpler, forms of AF surgery have mainly been used in patients under- to catheter ablation.811 The average length of hospital stay for thor-
going other open heart surgical procedures.461,466,784 – 798 In a system- acoscopic ablation varies from 3.6 to 6.0 days.468,812,813 The FAST
atic review commissioned for these guidelines, performing (Atrial Fibrillation Catheter Ablation vs. Surgical Ablation Treat-
concomitant AF surgery resulted in increased freedom from AF, atrial ment) trial,468 and another smaller trial,814 suggested that thoraco-
flutter, and atrial tachycardia compared to no concomitant AF sur- scopic AF surgery could be more effective than catheter ablation for
gery (RR 1.94; 95% CI 1.51–2.49; n ¼ 554 from seven RCTs) (Web the maintenance of sinus rhythm,468,814 while also causing more
Figure 3).1040 Patients undergoing the Cox maze procedure required complications (Table 19).815 To improve results,468,816 – 818 more
pacemaker implantation more often (RR 1.69; 95% CI 1.12–2.54; n ¼
a
AF surgery may be PVI in paroxysmal AF and biatrial maze in persistent or long-standing persistent AF.
b
Oral anticoagulation should be continued in patients at risk of stroke irrespective of AF surgery or LAA exclusion.
Figure 19 Surgical rhythm control in patients with atrial fibrillation undergoing cardiac surgery.
2942 ESC Guidelines
simultaneous ablation shows promise, procedural time and rates of in patients who are in need of further rhythm control therapy after an
bleeding complications are higher.812,823 initial therapy failure.
Selection of further rhythm control therapy after therapy failure to improve symptoms of AF
a
catheter ablation should target PVI. IA for paroxysmal AF, IIaB for persistent and long-standing persistent AF.
b
AF surgery may be PVI (e.g. in paroxysmal AF) or maze surgery (e.g. in therapy-refractory or persistent and long-standing persistent AF).
c
Hybrid therapy involves combination of antiarrhythmic drugs, catheter ablation, and/or AF surgery.
Recommendations for catheter ablation of atrial fibrillation and atrial fibrillation surgery
AF ¼ atrial fibrillation; NOAC ¼ non-vitamin K antagonist oral anticoagulant; VKA ¼ vitamin K antagonist.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
12. Hybrid rhythm control therapy studies have not been done, but a meta-analysis of the available
(weak) evidence suggests slightly better prevention of recurrent AF
AF has many different drivers, which are only partially targeted by in patients treated with antiarrhythmic drugs after catheter ablation.713
antiarrhythmic drugs or catheter ablation.96 Hence, combination Many patients are treated with antiarrhythmic drug therapy after cath-
or ‘hybrid’ rhythm control therapy seems reasonable, although eter ablation (most often amiodarone or flecainide),587 and this seems
there is little evidence from controlled trials supporting its use. a reasonable option in patients with recurrent AF after ablation. It
seems common sense to consider antiarrhythmic drug therapy in pa-
tients who are in need of further rhythm control therapy after catheter
12.1 Combining antiarrhythmic drugs ablation, but controlled trials to confirm this are desirable.
and catheter ablation Combining cavotricuspid isthmus ablation and antiarrhythmic
Antiarrhythmic drug therapy is commonly given for 8 – 12 weeks drugs may lead to improved rhythm control without the need for
after ablation to reduce early recurrences of AF after catheter abla- left atrial ablation in patients who develop ‘drug-induced atrial flut-
tion, supported by a recent controlled trial where amiodarone ter’ on therapy with flecainide, propafenone, or amiodarone,834 – 836 al-
halved early AF recurrences compared with placebo.650 Prospective though recurrent AF is a concern in the long-term.837,838
2944 ESC Guidelines
12.2 Combining antiarrhythmic drugs options in AF, the available data support the use of available rate
and pacemakers and rhythm control interventions, including pacemakers and catheter
ablation, without justification to discriminate by age group. Individual
In selected patients with sick sinus syndrome and fast ventricular re-
patients at older age may present with multiple comorbidities including
sponse during AF paroxysms requiring rate control therapy, the add-
dementia, a tendency to falls, CKD, anaemia, hypertension, diabetes,
ition of a pacemaker not only optimizes rate control but may also help
and cognitive dysfunction. Such conditions may limit quality of life
to control rhythm.711,712 Moreover, when antiarrhythmic drug treat-
more than AF-related symptoms. Impairment of renal and hepatic
ment leads to sinus node dysfunction and bradycardia, pacing may per-
function and multiple simultaneous medications make drug interac-
mit uptitration of the antiarrhythmic drug dose. Such strategies have
tions and adverse drug reactions more likely. Integrated AF manage-
never been prospectively investigated and the existing populations
ment and careful adaptation of drug dosing seem reasonable to
studied are highly selected.839,840 Some patients with AF-induced
reduce the complications of AF therapy in such patients.843
bradycardia may benefit from catheter ablation of AF, obviating the
Table 20 Inherited cardiomyopathies, channelopathies, and pathways associated with atrial fibrillation
of an accessory pathway, urgent catheter ablation of the pathway is effective to suppress symptomatic AF recurrences.880 – 884 Surgical
recommended.869 A documented short pre-excited RR interval treatment of AF may be appropriate in patients with hypertrophic car-
(,250 ms) during spontaneous or induced AF is one of the risk mar- diomyopathy undergoing surgery (e.g. for LV outflow tract obstruction
kers for sudden death in Wolff – Parkinson – White syndrome or mitral valve surgery), but experience is limited.
(WPW) syndrome, in addition to a history of symptomatic tachycar-
dia, the presence of multiple accessory pathways, and Ebstein’s anom- 13.2.3 Channelopathies and arrhythmogenic right
aly. Intravenous procainamide, propafenone, or ajmaline can be used ventricular cardiomyopathy
to acutely slow ventricular rate,873,874 whereas digoxin, verapamil, Many channelopathies and inherited cardiomyopathies are associated
and diltiazem are contraindicated.875 Intravenous amiodarone should with AF. AF prevalence ranges from 5–20% in patients with long QT
be used with caution, as there are case reports of accelerated ven- syndrome or Brugada syndrome, and is up to 70% in short QT syn-
tricular rhythms and ventricular fibrillation in patients with pre- drome (Table 20).853,856 – 858 Penetrance of disease phenotype includ-
excited AF receiving intravenous amiodarone infusion.876 ing AF is variable.61,852,885,886 Both shortening as well as prolongation
WPW syndrome
Catheter ablation of the accessory pathway in WPW patients with AF and rapid conduction over the accessory pathway
I B 892–894
is recommended to prevent sudden cardiac death.
Catheter ablation of the accessory pathway is recommended without delay in WPW patients who survive sudden cardiac
I C 869
death.
Asymptomatic patients with overt pre-excitation and AF should be considered for accessory pathway ablation after careful
IIa B 872, 892
counselling.
Hypertrophic cardiomyopathy
Lifelong oral anticoagulation to prevent stroke is recommended in HCM patients who develop AF. I B 878
Restoration of sinus rhythm by electrical or pharmacological cardioversion to improve symptoms is recommended in
I B 845
HCM patients with symptomatic new-onset AF.
In haemodynamically stable HCM patients with AF, ventricular rate control using beta-blockers and diltiazem/verapamil is
I C 845
recommended.
Treatment of LV outflow tract obstruction should be considered in AF patients with HCM to improve symptoms. IIa B 896
Amiodarone should be considered to achieve rhythm control and maintain sinus rhythm in HCM patients with recurrent
IIa C 845, 897
symptomatic AF.
Inherited cardiomyopathies and channelopathies
Targeted genetic testing should be considered in patients with AF and a suspicion of inherited cardiomyopathies or
IIa A 852
channelopathies based on clinical history, family history or electrocardiographic phenotype.
AF ¼ atrial fibrillation; HCM ¼ hypertrophic cardiomyopathy; LV ¼ left ventricular; WPW ¼ Wolff –Parkinson– White syndrome.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
2946 ESC Guidelines
13.3 Sports and atrial fibrillation heart diseases will probably increase the incidence of AF during
Physical activity improves cardiovascular health, which translates pregnancy in the future.913 Pregnant women with AF should be
into a lower risk of AF.898 Therefore, physical activity is a corner- managed as high-risk pregnancies in close collaboration with cardi-
stone of preventing AF. Intensive sports practice, especially endur- ologists, obstetricians, and neonatologists.
ance sports (.1500 h of endurance sports practice),899 increases
the risk of AF later in life,900 – 902 probably mediated by altered auto- 13.4.1 Rate control
nomic tone, volume load during exercise, atrial hypertrophy, and Owing to a lack of specific data, beta-blockers, verapamil, diltiazem,
dilatation.903,904 This results in a U-shaped relationship of physical and digoxin all carry a US Food and Drug Administration pregnancy
activity and incident AF.214,898,902,905,906 Detraining can reduce AF safety category of C (benefits may outweigh risk), except for atenolol
in models904 and reduces ventricular arrhythmias in athletes,907 (category D: positive evidence of risk). Their use should be at the low-
but the role of detraining for AF in human athletes is unknown. est dose and for the shortest time required. None of the agents are
teratogenic, but they readily cross the placenta.914 Beta-blockers are
13.6 Atrial arrhythmias in grown-up 13.6.2 Atrial tachyarrhythmias and atrial septal defects
patients with congenital heart disease Atrial flutter and fibrillation occur in 14–22% of adults with unoperated
atrial septal defects, especially in older patients,971 and can lead to heart
Atrial arrhythmias (AF, atrial flutter, atrial tachycardias) often occur
failure.972 Early repair can reduce but not eliminate the risk of AF.973
late after surgical repair of congenital heart defects, occurring in 15 –
Biatrial volume overload,974 pulmonary hypertension,975 and possibly
40% of grown-up patients with congenital heart disease (GUCH).
the arrhythmogenic effect of atrial patches can contribute to these ar-
They are associated with heart failure, syncope, thrombo-embolic
rhythmias.976 Anticoagulation should be decided upon based on stroke
events, and sudden death.963 – 967 The pathophysiological substrate
risk factors. In patients with a history of paroxysmal or persistent AF, AF
is complex, associated with hypertrophy, fibrosis, hypoxaemia,
surgery could be considered at the time of surgical closure, or catheter
chronic haemodynamic overload, and surgical scars and patches.
ablationatthetimeofinterventionalatrialseptaldefectclosure.Catheter
Additionally, related primary anomalies in the conduction pathways
ablation of late atrial arrhythmias has been shown to be effective in small
can lead to reentrant atrial and ventricular tachycardia, heart block,
cohorts of patients after surgical atrial septal defect.977
AF ¼ atrial fibrillation; CHA2DS2-VASc ¼ Congestive Heart failure, hypertension, Age ≥75 (doubled), Diabetes, Stroke (doubled), Vascular disease, Age 65 –74, and Sex (female);
GUCH ¼ grown-up patients with congenital heart disease; OAC ¼ oral anticoagulation; TOE ¼ transoesophageal echocardiography.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
ESC Guidelines 2949
13.7 Management of atrial flutter of chronic conditions such as AF will benefit from informed patients
The goals for the management of atrial flutter are similar to those for who are aware of their own responsibilities in the disease manage-
AF.992 Based on the available evidence, the stroke risk in patients with at- ment process.328 Shared decision-making747 and patient-centred
rial flutter is not much different from that in AF.827 Furthermore, many organization of care can help to ensure adherence to management
patients diagnosed with atrial flutter develop AF.993 – 995 Thus, anticoagu- and empower patients, and respect individual patient preferences,
lation should be used in patients with atrial flutter similar to that in pa- needs, and values (see Chapter 8.2).326,1008,1009 Patients in an active
tients with AF. Rate control in atrial flutter is achieved with the same role tend to have better health outcomes and care experiences, and
medicationsas inAF,but is often more difficultto achieve.Flecainide, pro- engagement itself can be considered as an intermediate
pafenone,dofetilide,andintravenousibutilideareusefulforcardioversion outcome.1010
of atrial flutter. They should be combined with a rate-controlling agent to
avoid 1:1 conduction of slowing flutter waves to the ventricles. Ibutilide is 14.2 Integrated patient education
randomized studies are needed to confirm the optimal treatment and such interventions often follow local or operator-specific proto-
strategy in AF patients with carotid disease. cols without clear evidence to support the choice of ablation target
or intervention. There is a clear clinical need to define the best ap-
15.10 Anticoagulation in patients with proach in patients who are in need of a second ablation procedure.
biological heart valves (including
transcatheter aortic valve implantation) 15.15 Combination therapy for
and specific forms of valvular heart disease maintenance of sinus rhythm
The optimal antithrombotic therapy in the first months after bio- In the follow-up after initially successful catheter ablation, even
logical valve replacement (including after catheter-based valve re- when done in experienced centres, many patients will experience
placement) is not known. VKAs remain the mainstay during the symptomatic recurrences of AF. These patients are often managed
initial post-operative period; NOACs probably deliver the same with antiarrhythmic drugs. There is a surprising paucity of data
When patients are treated with a vitamin K antagonist, time in therapeutic range (TTR) should be kept as high as possible and
I A
closely monitored.
Combinations of oral anticoagulants and platelet inhibitors increase bleeding risk and should be avoided in AF patients without III
B
another indication for platelet inhibition. (harm)
In male or female AF patients without additional stroke risk factors, anticoagulant or antiplatelet therapy is not recommended for III
B
stroke prevention. (harm)
III
Antiplatelet monotherapy is not recommended for stroke prevention in AF patients, regardless of stroke risk. A
(harm)
After surgical occlusion or exclusion of the left atrial appendage, it is recommended to continue anticoagulation in at-risk patients
I B
with AF for stroke prevention.
III
Genetic testing before the initiation of vitamin K antagonist therapy is not recommended. B
(no benefit)
In AF patients with severe active bleeding events, it is recommended to interrupt oral anticoagulation therapy until the underlying
I C
cause is resolved.
III
NOACs should be avoided in pregnancy and in women planning a pregnancy. C
(harm)
For patients with atrial flutter, antithrombotic therapy is recommended according to the same risk profile used for AF. I B
Management of typical atrial flutter with ablation of the cavotricuspid isthmus is recommended for patients failing antiarrhythmic
I B
drug therapy or as first-line treatment considering patient preference.
Lifelong oral anticoagulation to prevent stroke is recommended in hypertrophic cardiomyopathy patients who develop AF. I B
III
Anticoagulation with heparin or low-molecular-weight heparin immediately after ischaemic stroke is not recommended in AF patients. A
(harm)
Systemic thrombolysis with a recombinant tissue plasminogen activator is not recommended if the INR is above 1.7 (or, for patients III
C
on dabigatran, if activated partial thromboplastin time is outside the normal range). (harm)
III
After TIA or stroke, combination therapy of OAC and an antiplatelet is not recommended. B
(harm)
continued
ESC Guidelines 2953
Catheter ablation of symptomatic paroxysmal AF is recommended to improve AF symptoms in patients who have symptomatic
recurrences of AF on antiarrhythmic drug therapy (amiodarone, dronedarone, flecainide, propafenone, sotalol) and who prefer
I A
further rhythm control therapy, when performed by an electrophysiologist who has received appropriate training and is performing
the procedure in an experienced centre.
ACE-Is or ARBs are not recommended for the secondary prevention of paroxysmal AF in patients with little or no underlying heart III
B
disease. (no benefit)
Moderate regular physical activity is recommended to prevent AF, while athletes should be counselled that long-lasting, more intense
I A
sports participation can promote AF.
ACE ¼ angiotensin-converting enzyme; AF ¼ atrial fibrillation; AHRE ¼ atrial high rate episodes; ARB ¼ angiotensin receptor blocker; CHA2DS2-VASc ¼ Congestive Heart
failure, hypertension, Age ≥75 (doubled), Diabetes, Stroke (doubled), Vascular disease, Age 65 –74, and Sex (female); ECG ¼ electrocardiogram; EHRA ¼ European Heart
Rhythm Association; ICD ¼ implantable cardioverter defibrillator; INR ¼ international normalized ratio; LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction; LVH ¼ left
ventricular hypertrophy; NOAC ¼ non-vitamin K antagonist oral anticoagulant; OAC ¼ oral anticoagulation; TIA ¼ transient ischaemic attack; TOE ¼ transoesophageal
echocardiography; TTR ¼ time in therapeutic range; VKA ¼ vitamin K antagonist.
2954 ESC Guidelines
* Corresponding authors: Piotr Ponikowski, Department of Heart Diseases, Wroclaw Medical University, Centre for Heart Diseases, Military Hospital, ul. Weigla 5, 50-981 Wroclaw,
Poland, Tel: +48 261 660 279, Tel/Fax: +48 261 660 237, E-mail: piotrponikowski@4wsk.pl.
Adriaan Voors, Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, PO Box 30.001, 9700 RB Groningen, The Netherlands, Tel: +31 50 3612355,
Fax: +31 50 3614391, E-mail: a.a.voors@umcg.nl.
ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers: listed in the Appendix.
ESC entities having participated in the development of this document:
Associations: Acute Cardiovascular Care Association (ACCA), European Association for Cardiovascular Prevention and Rehabilitation (EACPR), European Association of
Cardiovascular Imaging (EACVI), European Heart Rhythm Association (EHRA), Heart Failure Association (HFA).
Councils: Council on Cardiovascular Nursing and Allied Professions, Council for Cardiology Practice, Council on Cardiovascular Primary Care, Council on Hypertension.
Working Groups: Cardiovascular Pharmacotherapy, Cardiovascular Surgery, Myocardial and Pericardial Diseases, Myocardial Function, Pulmonary Circulation and Right Ventricular
Function, Valvular Heart Disease.
The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC
Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford
University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC (journals.permissions@oup.com).
Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at
the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recom-
mendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encour-
aged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or
therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and
accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor
do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent
public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the
health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.
The article has been co-published with permission in European Heart Journal and European Journal of Heart Failure. All rights reserved in respect of European Heart Journal.
& European Society of Cardiology 2016. All rights reserved. For permissions please email: journals.permissions@oup.com.
2130 ESC Guidelines
Maxime Guenoun (France), Gerd Hasenfuss (Germany), Gerhard Hindricks (Germany), Arno W. Hoes
(The Netherlands), Bernard Iung (France), Tiny Jaarsma (Sweden), Paulus Kirchhof (UK/Germany), Juhani Knuuti
(Finland), Philippe Kolh (Belgium), Stavros Konstantinides (Germany/Greece), Mitja Lainscak (Slovenia),
Patrizio Lancellotti (Belgium), Gregory Y. H. Lip (UK), Francesco Maisano (Switzerland), Christian Mueller
(Switzerland), Mark C. Petrie (UK), Massimo F. Piepoli (Italy), Silvia G. Priori (Italy), Adam Torbicki (Poland),
Hiroyuki Tsutsui (Japan), Dirk J. van Veldhuisen (The Netherlands), Stephan Windecker (Switzerland), Clyde Yancy
(USA), Jose Luis Zamorano (Spain)
The disclosure forms of all experts involved in the development of these guidelines are available on the ESC website
http://www.escardio.org/guidelines.
Online publish-ahead-of-print 20 May 2016
Table of Contents
Abbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . .2131 5.9 Cardiac computed tomography . . . . . . . . . . . . . . . . .2144
1. Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2134 5.10 Other diagnostic tests . . . . . . . . . . . . . . . . . . . . . .2145
2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2136 5.10.1 Genetic testing in heart failure . . . . . . . . . . . . . .2145
3. Definition, epidemiology and prognosis . . . . . . . . . . . . . . .2136 6. Delaying or preventing the development of overt heart
3.1 Definition of heart failure . . . . . . . . . . . . . . . . . . . . .2136 failure or preventing death before the onset of symptoms . . . . .2146
3.2 Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2137 7. Pharmacological treatment of heart failure with reduced
3.2.1 Heart failure with preserved, mid-range and reduced ejection fraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2147
ejection fraction . . . . . . . . . . . . . . . . . . . . . . . . . . . .2137 7.1 Objectives in the management of heart failure . . . . . . .2147
3.2.2 Terminology related to the time course of heart 7.2 Treatments recommended in all symptomatic patients
failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2137 with heart failure with reduced ejection fraction . . . . . . . . .2148
3.2.3 Terminology related to the symptomatic severity 7.2.1 Angiotensin-converting enzyme inhibitors . . . . . . .2148
of heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2138 7.2.2 Beta-blockers . . . . . . . . . . . . . . . . . . . . . . . . . .2148
3.3 Epidemiology, aetiology and natural history of heart failure 2138 7.2.3 Mineralocorticoid/aldosterone receptor antagonists .2148
3.4 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2138 7.3 Other treatments recommended in selected symptomatic
4. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2138 patients with heart failure with reduced ejection fraction . . .2148
4.1 Symptoms and signs . . . . . . . . . . . . . . . . . . . . . . . .2138 7.3.1 Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2148
4.2 Essential initial investigations: natriuretic peptides, 7.3.2 Angiotensin receptor neprilysin inhibitor . . . . . . . .2151
electrocardiogram, and echocardiography . . . . . . . . . . . . .2139 7.3.3 If - channel inhibitor . . . . . . . . . . . . . . . . . . . . . .2152
4.3 Algorithm for the diagnosis of heart failure . . . . . . . . .2140 7.3.4 Angiotensin II type I receptor blockers . . . . . . . . .2152
4.3.1 Algorithm for the diagnosis of heart failure in the 7.3.5 Combination of hydralazine and isosorbide
non-acute setting . . . . . . . . . . . . . . . . . . . . . . . . . . .2140 dinitrate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2152
4.3.2 Diagnosis of heart failure with preserved ejection 7.4 Other treatments with less certain benefits in
fraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2140 symptomatic patients with heart failure with reduced ejection
5. Cardiac imaging and other diagnostic tests . . . . . . . . . . . . .2142 fraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2152
5.1 Chest X-ray . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2142 7.4.1 Digoxin and other digitalis glycosides . . . . . . . . . .2152
5.2 Transthoracic echocardiography . . . . . . . . . . . . . . . .2142 7.4.2 n-3 polyunsaturated fatty acids . . . . . . . . . . . . . .2153
5.2.1 Assessment of left ventricular systolic function . . . .2142 7.5 Treatments not recommended (unproven benefit) in
5.2.2 Assessment of left ventricular diastolic function . . .2143 symptomatic patients with heart failure with reduced ejection
5.2.3 Assessment of right ventricular function and fraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2153
pulmonary arterial pressure . . . . . . . . . . . . . . . . . . . .2143 7.5.1 3-Hydroxy-3-methylglutaryl-coenzyme A reductase
5.3 Transoesophageal echocardiography . . . . . . . . . . . . .2143 inhibitors (‘statins’) . . . . . . . . . . . . . . . . . . . . . . . . . .2153
5.4 Stress echocardiography . . . . . . . . . . . . . . . . . . . . .2143 7.5.2 Oral anticoagulants and antiplatelet therapy . . . . . .2153
5.5 Cardiac magnetic resonance . . . . . . . . . . . . . . . . . . .2143 7.5.3 Renin inhibitors . . . . . . . . . . . . . . . . . . . . . . . .2153
5.6 Single-photon emission computed tomography and 7.6 Treatments not recommended (believed to cause harm)
radionuclide ventriculography . . . . . . . . . . . . . . . . . . . . .2143 in symptomatic patients with heart failure with reduced
5.7 Positron emission tomography . . . . . . . . . . . . . . . . .2143 ejection fraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2154
5.8 Coronary angiography . . . . . . . . . . . . . . . . . . . . . . .2144 7.6.1 Calcium-channel blockers . . . . . . . . . . . . . . . . . .2154
ESC Guidelines 2131
8. Non-surgical device treatment of heart failure with reduced 12. Acute heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . .2171
ejection fraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2154 12.1 Definition and classification . . . . . . . . . . . . . . . . . . .2171
8.1 Implantable cardioverter-defibrillator . . . . . . . . . . . . .2154 12.2 Diagnosis and initial prognostic evaluation . . . . . . . . .2172
8.1.1 Secondary prevention of sudden cardiac death . . . .2154 12.3 Management . . . . . . . . . . . . . . . . . . . . . . . . . . . .2176
8.1.2 Primary prevention of sudden cardiac death . . . . . .2155 12.3.1 Identification of precipitants/causes leading to
8.2 Cardiac resynchronization therapy . . . . . . . . . . . . . . .2156 decompensation that needs urgent management . . . . . . .2176
8.3 Other implantable electrical devices . . . . . . . . . . . . . .2157 12.3.2 Criteria for hospitalization in ward vs intensive
9. Treatment of heart failure with preserved ejection fraction . .2157 care/coronary care unit . . . . . . . . . . . . . . . . . . . . . . .2177
9.1 Effect of treatment on symptoms in heart failure with 12.3.3 Management of the early phase . . . . . . . . . . . . .2177
preserved ejection fraction . . . . . . . . . . . . . . . . . . . . . . .2158 12.3.4 Management of patients with cardiogenic shock . .2182
9.2 Effect of treatment on hospitalization for heart failure in 12.4 Management of evidence-based oral therapies . . . . . .2182
AMI acute myocardial infarction CHARM-Preserved Candesartan Cilexetil in Heart Failure Assess-
AMICA Atrial fibrillation Management In Congestive ment of Reduction in Mortality and Morbidity
heart failure with Ablation CI cardiac index
ANP A-type natriuretic peptide CI-AKI contrast-induced acute kidney injury
ANS autonomic nervous system CIBIS II Cardiac Insufficiency Bisoprolol Study II
ARB angiotensin receptor blocker CK creatine kinase
ARNI angiotensin receptor neprilysin inhibitor CKD chronic kidney disease
ARVC arrhythmogenic right ventricular CK-MB creatine kinase MB
cardiomyopathy CMP cardiomyopathy
AST aspartate aminotransferase CMR cardiac magnetic resonance
ASV assisted servo-ventilation COMPANION Comparison of Medical Therapy, Pacing, and
A great number of Guidelines have been issued in recent years by panels. The Committee is also responsible for the endorsement pro-
the European Society of Cardiology (ESC) as well as by other soci- cess of these Guidelines. The ESC Guidelines undergo extensive re-
eties and organisations. Because of the impact on clinical practice, view by the CPG and external experts. After appropriate revisions
quality criteria for the development of guidelines have been estab- the Guidelines are approved by all the experts involved in the Task
lished in order to make all decisions transparent to the user. The re- Force. The finalized document is approved by the CPG for publica-
commendations for formulating and issuing ESC Guidelines can be tion in the European Heart Journal. The Guidelines were developed
found on the ESC website (http://www.escardio.org/Guidelines- after careful consideration of the scientific and medical knowledge
&-Education/Clinical-Practice-Guidelines/Guidelines-development/ and the evidence available at the time of their dating.
Writing-ESC-Guidelines). ESC Guidelines represent the official pos- The task of developing ESC Guidelines covers not only integration
ition of the ESC on a given topic and are regularly updated. of the most recent research, but also the creation of educational tools
Members of this Task Force were selected by the ESC to re- and implementation programmes for the recommendations. To im-
it has been shown that the outcome of disease may be favourably in- (viii) a new algorithm for a combined diagnosis and treatment ap-
fluenced by the thorough application of clinical recommendations. proach of acute HF based on the presence/absence of conges-
Surveys and registries are needed to verify that real-life daily prac- tion/hypoperfusion.
tice is in keeping with what is recommended in the guidelines, thus
We followed the format of the previous ESC 2012 HF Guidelines.
completing the loop between clinical research, writing of guidelines,
Therapeutic recommendations state the treatment effect supported
disseminating them and implementing them into clinical practice.
by the class and level of recommendation in tabular format; in the
Health professionals are encouraged to take the ESC Guidelines
case of chronic HF due to left ventricular systolic dysfunction
fully into account when exercising their clinical judgment, as well as
(LVSD) the recommendations focus on mortality and morbidity
in the determination and the implementation of preventive, diagnos-
outcomes. Detailed summaries of the key evidence supporting gen-
tic or therapeutic medical strategies. However, the ESC Guidelines
erally recommended treatments have been provided. For diagnostic
do not override in any way whatsoever the individual responsibility
recommendations a level of evidence C has been typically decided
conduction can also cause HF (and more than one abnormality is of- characteristics, pathophysiology and treatment of this group of pa-
ten present). Identification of the underlying cardiac problem is cru- tients. Patients with HFmrEF most probably have primarily mild sys-
cial for therapeutic reasons, as the precise pathology determines the tolic dysfunction, but with features of diastolic dysfunction
specific treatment used (e.g. valve repair or replacement for valvular (Table 3.1).
disease, specific pharmacological therapy for HF with reduced EF, Patients without detectable LV myocardial disease may have
reduction of heart rate in tachycardiomyopathy, etc). other cardiovascular causes for HF (e.g. pulmonary hypertension,
valvular heart disease, etc.). Patients with non-cardiovascular path-
ologies (e.g. anaemia, pulmonary, renal or hepatic disease) may have
3.2 Terminology
symptoms similar or identical to those of HF and each may compli-
3.2.1 Heart failure with preserved, mid-range and reduced
cate or exacerbate the HF syndrome.
ejection fraction
The main terminology used to describe HF is historical and is based
Table 3.1 Definition of heart failure with preserved (HFpEF), mid-range (HFmrEF) and reduced ejection fraction
(HFrEF)
BNP ¼ B-type natriuretic peptide; HF ¼ heart failure; HFmrEF ¼ heart failure with mid-range ejection fraction; HFpEF ¼ heart failure with preserved ejection fraction; HFrEF ¼
heart failure with reduced ejection fraction; LAE ¼ left atrial enlargement; LVEF ¼ left ventricular ejection fraction; LVH ¼ left ventricular hypertrophy; NT-proBNP ¼ N-terminal
pro-B type natriuretic peptide.
a
Signs may not be present in the early stages of HF (especially in HFpEF) and in patients treated with diuretics.
b
BNP.35 pg/ml and/or NT-proBNP.125 pg/mL.
2138 ESC Guidelines
(MRA), ivabradine and/or CRT]. ‘Congestive HF’ is a term that is In clinical practice, a clear distinction between acquired and inher-
sometimes used, and may describe acute or chronic HF with evi- ited cardiomyopathies remains challenging. In most patients with a
dence of volume overload. Many or all of these terms may be accur- definite clinical diagnosis of HF, there is no confirmatory role for
ately applied to the same patient at different times, depending upon routine genetic testing, but genetic counselling is recommended in
their stage of illness. patients with hypertrophic cardiomyopathy (HCM), ‘idiopathic’
DCM or arrhythmogenic right ventricular cardiomyopathy
3.2.3 Terminology related to the symptomatic severity (ARVC) (see Section 5.10.1), since the outcomes of these tests
of heart failure may have clinical implications.
The NYHA functional classification (Web Table 3.2) has been used Over the last 30 years, improvements in treatments and their im-
to describe the severity of symptoms and exercise intolerance. plementation have improved survival and reduced the hospitalization
However, symptom severity correlates poorly with many measures rate in patients with HFrEF, although the outcome often remains un-
3.4 Prognosis
3.3 Epidemiology, aetiology and natural Estimation of prognosis for morbidity, disability and death helps pa-
history of heart failure tients, their families and clinicians decide on the appropriate type
and timing of therapies (in particular, decisions about a rapid transi-
The prevalence of HF depends on the definition applied, but is ap-
tion to advanced therapies) and assists with planning of health and
proximately 1–2% of the adult population in developed countries,
social services and resources.
rising to ≥10% among people .70 years of age.14 – 17 Among peo-
Numerous prognostic markers of death and/or HF hospitalization
ple .65 years of age presenting to primary care with breathlessness
have been identified in patients with HF (Web Table 3.5). However,
on exertion, one in six will have unrecognized HF (mainly
their clinical applicability is limited and precise risk stratification in
HFpEF).18,19 The lifetime risk of HF at age 55 years is 33% for
HF remains challenging.
men and 28% for women.16 The proportion of patients with HFpEF
In recent decades, several multivariable prognostic risk scores
ranges from 22 to 73%, depending on the definition applied, the clin-
have been developed for different populations of patients with
ical setting (primary care, hospital clinic, hospital admission), age and
HF,36 – 41 and some are available as interactive online applications.
sex of the studied population, previous myocardial infarction and
Multivariable risk scores may help predict death in patients with
the year of publication.17,18,20 – 30
HF, but remain less useful for the prediction of subsequent HF hos-
Data on temporal trends based on hospitalized patients suggest
pitalizations.37,38 A systematic review examining 64 prognostic
that the incidence of HF may be decreasing, more for HFrEF than
models37 along with a meta-analysis and meta-regression study of
for HFpEF.31,32 HFpEF and HFrEF seem to have different epidemio-
117 prognostic models38 revealed only a moderate accuracy of
logical and aetiological profiles. Compared with HFrEF, patients
models predicting mortality, whereas models designed to predict
with HFpEF are older, more often women and more commonly
the combined endpoint of death or hospitalization, or only hospital-
have a history of hypertension and atrial fibrillation (AF), while a his-
ization, had an even poorer discriminative ability.
tory of myocardial infarction is less common.32,33 The characteristics
of patients with HFmrEF are between those with HFrEF and HFpEF,34
but further studies are needed to better characterize this population. 4. Diagnosis
The aetiology of HF is diverse within and among world regions.
There is no agreed single classification system for the causes of 4.1 Symptoms and signs
HF, with much overlap between potential categories (Table 3.4). Symptoms are often non-specific and do not, therefore, help discrim-
Many patients will have several different pathologies—cardiovascu- inate between HF and other problems (Table 4.1).42 – 46 Symptoms and
lar and non-cardiovascular—that conspire to cause HF. Identifica- signs of HF due to fluid retention may resolve quickly with diuretic
tion of these diverse pathologies should be part of the diagnostic therapy. Signs, such as elevated jugular venous pressure and displace-
workup, as they may offer specific therapeutic opportunities. ment of the apical impulse, may be more specific, but are harder to
Many patients with HF and ischaemic heart disease (IHD) have a detect and have poor reproducibility.18,46,47 Symptoms and signs
history of myocardial infarction or revascularization. However, a may be particularly difficult to identify and interpret in obese indivi-
normal coronary angiogram does not exclude myocardial scar duals, in the elderly and in patients with chronic lung disease.48 – 50
(e.g. by CMR imaging) or impaired coronary microcirculation as al- Younger patients with HF often have a different aetiology, clinical pres-
ternative evidence for IHD. entation and outcome compared with older patients.51,52
ESC Guidelines 2139
DISEASED MYOCARDIUM
Ischaemic heart Myocardial scar
disease
Myocardial stunning/hibernation
Epicardial coronary artery disease
Abnormal coronary microcirculation
Endothelial dysfunction
Toxic damage Recreational substance abuse Alcohol, cocaine, amphetamine, anabolic steroids.
Heavy metals Copper, iron, lead, cobalt.
Radiation
Immune-mediated Related to infection Bacteria, spirochaetes, fungi, protozoa, parasites (Chagas disease), rickettsiae, viruses (HIV/AIDS).
Not related to infection Lymphocytic/giant cell myocarditis, autoimmune diseases (e.g. Graves’ disease, rheumatoid
damage
arthritis, connective tissue disorders, mainly systemic lupus erythematosus), hypersensitivity and
eosinophilic myocarditis (Churg–Strauss).
Related to malignancy
Not related to malignancy Amyloidosis, sarcoidosis, haemochromatosis (iron), glycogen storage diseases (e.g. Pompe disease),
lysosomal storage diseases (e.g. Fabry disease).
Metabolic Hormonal
derangements disease, Addison disease, diabetes, metabolic syndrome, phaeochromocytoma, pathologies related
to pregnancy and peripartum.
Nutritional
(e.g. malignancy, AIDS, anorexia nervosa), obesity.
Genetic abnormalities Diverse forms HCM, DCM, LV non-compaction, ARVC, restrictive cardiomyopathy (for details see respective
expert documents), muscular dystrophies and laminopathies.
ABNORMAL LOADING CONDITIONS
Hypertension
Valve and Acquired Mitral, aortic, tricuspid and pulmonary valve diseases.
myocardium
Congenital Atrial and ventricular septum defects and others (for details see a respective expert document).
structural defects
Pericardial and Pericardial Constrictive pericarditis
endomyocardial Pericardial effusion
pathologies
Endomyocardial
High output states
Volume overload
ARRHYTHMIAS
Tachyarrhythmias Atrial, ventricular arrhythmias.
Bradyarrhythmias Sinus node dysfunctions, conduction disorders.
ARVC ¼ arrhythmogenic right ventricular cardiomyopathy; DCM ¼ dilated cardiomyopathy; EMF ¼ endomyocardial fibrosis; GH ¼ growth hormone; HCM ¼ hypertrophic
cardiomyopathy; HES ¼ hypereosinophilic syndrome; HIV/AIDS ¼ human immunodeficiency virus/acquired immune deficiency syndrome; LV ¼ left ventricular.
A detailed history should always be obtained. HF is unusual in an 4.2 Essential initial investigations:
individual with no relevant medical history (e.g. a potential cause of natriuretic peptides, electrocardiogram
cardiac damage), whereas certain features, particularly previous
myocardial infarction, greatly increase the likelihood of HF in a pa-
and echocardiography
tient with appropriate symptoms and signs.42 – 45 The plasma concentration of natriuretic peptides (NPs) can be used
At each visit, symptoms and signs of HF need to be assessed, with as an initial diagnostic test, especially in the non-acute setting when
particular attention to evidence of congestion. Symptoms and signs echocardiography is not immediately available. Elevated NPs help
are important in monitoring a patient’s response to treatment and establish an initial working diagnosis, identifying those who require
stability over time. Persistence of symptoms despite treatment usu- further cardiac investigation; patients with values below the cut-
ally indicates the need for additional therapy, and worsening of point for the exclusion of important cardiac dysfunction do not
symptoms is a serious development (placing the patient at risk of ur- require echocardiography (see also Section 4.3 and Section 12).
gent hospital admission and death) and merits prompt medical Patients with normal plasma NP concentrations are unlikely to
attention. have HF. The upper limit of normal in the non-acute setting for
2140 ESC Guidelines
Figure 4.1 Diagnostic algorithm for a diagnosis of heart failure of non-acute onset
BNP ¼ B-type natriuretic peptide; CAD ¼ coronary artery disease; HF ¼ heart failure; MI ¼ myocardial infarction; NT-proBNP ¼ N-terminal
pro-B type natriuretic peptide.
a
Patient reporting symptoms typical of HF (see Table 4.1).
b
Normal ventricular and atrial volumes and function.
c
Consider other causes of elevated natriuretic peptides (Table 12.3).
2142 ESC Guidelines
† In case of uncertainty, a stress test or invasively measured ele- Patients with HFpEF are a heterogeneous group with various
vated LV filling pressure may be needed to confirm the diagnosis underlying aetiologies and pathophysiological abnormalities. Based
(for details, see below). on specific suspected causes, additional tests can be performed
(Web Table 4.4).71,88 – 94 However, they can only be recommended
The initial assessment consists of a clinical diagnosis compatible with if the results might affect management.
the algorithm presented above and the assessment of LVEF by echo-
cardiography. The cut-off of 50% for a diagnosis of HFpEF is arbi-
trary; patients with an LVEF between 40 and 49% are often 5. Cardiac imaging and other
classified as HFpEF in clinical trials.79 However, in the present guide- diagnostic tests
lines, we define HFpEF as an LVEF ≥50% and consider patients with
an LVEF between 40 and 49% as a grey area, which could be indi- Cardiac imaging plays a central role in the diagnosis of HF and in guiding
treatment. Of several imaging modalities available, echocardiography is
particularly in patients with regional LV dysfunction and/or LV re- 5.4 Stress echocardiography
modelling. Three-dimensional echocardiography of adequate quality Exercise or pharmacological stress echocardiography may be used
improves the quantification of LV volumes and LVEF and has the for the assessment of inducible ischaemia and/or myocardium viabil-
best accuracy compared with values obtained through CMR.95 ity99 and in some clinical scenarios of patients with valve disease (e.g.
Doppler techniques allow the calculation of haemodynamic vari- dynamic mitral regurgitation, low-flow – low-gradient aortic sten-
ables, such as stroke volume index and cardiac output, based on the osis).99,100 There are also suggestions that stress echocardiography
velocity time integral at the LV outflow tract area. may allow the detection of diastolic dysfunction related to exercise
In recent years, tissue Doppler parameters (S wave) and deform- exposure in patients with exertional dyspnoea, preserved LVEF and
ation imaging techniques (strain and strain rate) have been shown to inconclusive diastolic parameters at rest.85,86
be reproducible and feasible for clinical use, especially in detecting sub-
tle abnormalities in systolic function in the preclinical stage; however, 5.5 Cardiac magnetic resonance
measurements may vary among vendors and software versions.74
Recommendations for cardiac imaging in patients with suspected or established heart failure
TTE is recommended for the assessment of myocardial structure and function in subjects with suspected HF in order to establish
I C
a diagnosis of either HFrEF, HFmrEF or HFpEF.
TTE is recommended to assess LVEF in order to identify patients with HF who would be suitable for evidence-based
I C
pharmacological and device (ICD, CRT) treatment recommended for HFrEF.
TTE is recommended for the assessment of valve disease, right ventricular function and pulmonary arterial pressure in patients with
I C
an already established diagnosis of either HFrEF, HFmrEF or HFpEF in order to identify those suitable for correction of valve disease.
TTE is recommended for the assessment of myocardial structure and function in subjects to be exposed to treatment which
I C
potentially can damage myocardium (e.g. chemotherapy).
Other techniques (including systolic tissue Doppler velocities and deformation indices, i.e. strain and strain rate), should be
IIa C
considered in a TTE protocol in subjects at risk of developing HF in order to identify myocardial dysfunction at the preclinical stage.
CMR is recommended for the assessment of myocardial structure and function (including right heart) in subjects with poor
I C
acoustic window and patients with complex congenital heart diseases (taking account of cautions/contra-indications to CMR).
CMR with LGE should be considered in patients with dilated cardiomyopathy in order to distinguish between ischaemic and non-
IIa C
ischaemic myocardial damage in case of equivocal clinical and other imaging data (taking account of cautions/contra-indications to CMR).
CMR is recommended for the characterization of myocardial tissue in case of suspected myocarditis, amyloidosis, sarcoidosis,
Chagas disease, Fabry disease non-compaction cardiomyopathy, and haemochromatosis (taking account of cautions/contra- I C
indications to CMR).
Non-invasive stress imaging (CMR, stress echocardiography, SPECT, PET) may be considered for the assessment of myocardial
ischaemia and viability in patients with HF and CAD (considered suitable for coronary revascularization) before the decision on IIb B 116–118
revascularization.
Invasive coronary angiography is recommended in patients with HF and angina pectoris recalcitrant to pharmacological
therapy or symptomatic ventricular arrhythmias or aborted cardiac arrest (who are considered suitable for potential coronary I C
revascularization) in order to establish the diagnosis of CAD and its severity.
Invasive coronary angiography should be considered in patients with HF and intermediate to high pre-test probability of CAD and
the presence of ischaemia in non-invasive stress tests (who are considered suitable for potential coronary revascularization) in IIa C
order to establish the diagnosis of CAD and its severity.
Cardiac CT may be considered in patients with HF and low to intermediate pre-test probability of CAD or those with equivocal
IIb C
non-invasive stress tests in order to rule out coronary artery stenosis.
AHF ¼ acute heart failure; CAD ¼ coronary artery disease; CMR ¼ cardiac magnetic resonance; CRT ¼ cardiac resynchronization therapy; CT ¼ computed tomography; HF ¼
heart failure; HFpEF ¼ heart failure with preserved ejection fraction; HFmrEF ¼ heart failure with mid-range ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction;
ICD ¼ implantable cardioverter-defibrillator; LGE ¼ late gadolinium enhancement; LVEF ¼ left ventricular ejection fraction; PET ¼ positron emission tomography; SPECT ¼
single-photon emission computed tomography; TTE ¼ transthoracic echocardiography.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
ESC Guidelines 2145
5.10 Other diagnostic tests sessments and endomyocardial biopsy. The major typical indications
Comprehensive assessment of patients with HF comprises, besides are summarized in the recommendations table for diagnostic tests in
medical history and physical examination, including adequate imaging patients with HF. Although there is extensive research on biomarkers
techniques, a set of additional diagnostic tests, i.e. laboratory vari- in HF (e.g. ST2, galectin 3, copeptin, adrenomedullin), there is no def-
ables, ECG, chest X-ray, exercise testing, invasive haemodynamic as- inite evidence to recommend them for clinical practice.
- TSH
- ferritin, TSAT = TIBC
- natriuretic peptides IIa C
Additional diagnostic tests aiming to identify other HF aetiologies and comorbidities should be considered in individual
IIa C
patients with HF when there is a clinical suspicion of a particular pathology (see Table 3.4 on HF aetiologies).
A 12-lead ECG is recommended in all patients with HF in order to determine heart rhythm, heart rate, QRS morphology, and
I C
QRS duration, and to detect other relevant abnormalities. This information is needed to plan and monitor treatment.
Chest radiography (X-ray) is recommended in patients with HF to detect/exclude alternative pulmonary or other diseases,
which may contribute to dyspnoea. It may also identify pulmonary congestion/oedema and is more useful in patients with I C
suspected HF in the acute setting.
EMB should be considered in patients with rapidly progressive HF despite standard therapy when there is a probability of a
IIa C 93
IIb C 121
Ultrasound measurement of inferior vena cava diameter may be considered for the assessment of volaemia status in patients with HF. IIb C
AHF ¼ acute heart failure; ALT ¼ alanine aminotransferase; AST ¼ aspartate aminotransferase; BNP ¼ B-type natriuretic peptide; ECG ¼ electrocardiogram; eGFR ¼ estimated
glomerular filtration rate; EMB ¼ endomyocardial biopsy; GFR ¼ glomerular filtration rate; GGTP ¼ gamma-glutamyl transpeptidase; HbA1c ¼ glycated haemoglobin; HF ¼
heart failure; HFrEF ¼ heart failure with reduced ejection fraction; QRS ¼ Q, R, and S waves (combination of three of the graphical deflections); TIBC ¼ total iron-binding capacity;
TSAT ¼ transferrin saturation; TSH ¼ thyroid-stimulating hormone; WBC ¼ white blood cell.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
5.10.1 Genetic testing in heart failure sufficiently high and consistent to justify routine targeted genetic
Molecular genetic analysis in patients with cardiomyopathies is re- screening. Recommendations for genetic testing in patients with
commended when the prevalence of detectable mutations is HF are based on the position statement of the European Society
2146 ESC Guidelines
of Cardiology Working Group on Myocardial and Pericardial Dis- hypertensive patients reduces the risk of cardiovascular disease,
eases.94 In most patients with a definite clinical diagnosis of HF, there death and hospitalization for HF.129
is no confirmatory role for routine genetic testing to establish the Recently, empaglifozin (an inhibitor of sodium-glucose cotran-
diagnosis. Genetic counselling is recommended in patients with sporter 2), has been shown to improve outcomes (including the re-
HCM, idiopathic DCM and ARVC. Restrictive cardiomyopathy duction of mortality and HF hospitalizations) in patients with type 2
and isolated non-compaction cardiomyopathies are of a possible diabetes.130 Other hypoglycaemic agents have not been shown con-
genetic origin and should also be considered for genetic testing. vincingly to reduce the risk of cardiovascular events and may in-
HCM is mostly inherited as an autosomal dominant disease with crease the risk of HF. Intensification of hypoglycaemic therapy to
variable expressivity and age-related penetrance. Currently, more drive down glycated haemoglobin (HbA1c) with agents other than
than 20 genes and 1400 mutations have been identified, most of which empagliflozin does not reduce the risk of developing HF (for details
are located in the sarcomere genes encoding cardiac b-myosin heavy see Section 11.6 on diabetes).
chain (MYH7) and cardiac myosin binding protein C (MYBPC3).88,122
In patients with asymptomatic LV systolic dysfunction (LVEF plantable cardioverter-defibrillator (ICD) is recommended to
,30%) of ischaemic origin who are ≥40 days after an AMI, an im- prolong life.149
Recommendations to prevent or delay the development of overt heart failure or prevent death before the onset of
symptoms
126, 129,
Treatment of hypertension is recommended to prevent or delay the onset of HF and prolong life. I A
150, 151
Treatment with statins is recommended in patients with or at high-risk of CAD whether or not they have LV systolic 137–140,
I A
Counselling and treatment for smoking cessation and alcohol intake reduction is recommended for people who smoke or who
I C 131–134
consume excess alcohol in order to prevent or delay the onset of HF.
130, 141,
Treating other risk factors of HF (e.g. obesity, dysglycaemia) should be considered in order to prevent or delay the onset of HF. IIa C
153–155
IIa B 130
ACE-I is recommended in patients with asymptomatic LV systolic dysfunction and a history of myocardial infarction in order to 5, 144,
I A
prevent or delay the onset of HF and prolong life. 145
ACE-I is recommended in patients with asymptomatic LV systolic dysfunction without a history of myocardial infarction, in order
I B 5
to prevent or delay the onset of HF.
ACE-I should be considered in patients with stable CAD even if they do not have LV systolic dysfunction, in order to prevent
IIa A 142
or delay the onset of HF.
Beta-blocker is recommended in patients with asymptomatic LV systolic dysfunction and a history of myocardial infarction, in
I B 146
order to prevent or delay the onset of HF or prolong life.
ACEI ¼ angiotensin-converting enzyme inhibitor; CAD ¼ coronary artery disease; HF ¼ heart failure; ICD ¼ implantable cardioverter-defibrillator; LV ¼ left ventricular;
LVEF ¼ left ventricular ejection fraction; OMT ¼ optimal medical therapy
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
7. Pharmacological treatment of Figure 7.1 shows a treatment strategy for the use of drugs (and de-
vices) in patients with HFrEF. The recommendations for each treat-
heart failure with reduced ejection ment are summarized below.
fraction Neuro-hormonal antagonists (ACEIs, MRAs and beta-blockers)
have been shown to improve survival in patients with HFrEF and
7.1 Objectives in the management of are recommended for the treatment of every patient with HFrEF,
heart failure unless contraindicated or not tolerated. A new compound
(LCZ696) that combines the moieties of an ARB (valsartan) and a
The goals of treatment in patients with HF are to improve their clin-
neprilysin (NEP) inhibitor (sacubitril) has recently been shown to
ical status, functional capacity and quality of life, prevent hospital ad-
be superior to an ACEI (enalapril) in reducing the risk of death
mission and reduce mortality. The fact that several drugs for HF
and of hospitalization for HF in a single trial with strict inclusion/ex-
have shown detrimental effects on long-term outcomes, despite
clusion criteria.162 Sacubitril/valsartan is therefore recommended to
showing beneficial effects on shorter-term surrogate markers, has
replace ACEIs in ambulatory HFrEF patients who remain symptom-
led regulatory bodies and clinical practice guidelines to seek mortal-
atic despite optimal therapy and who fit these trial criteria. ARBs
ity/morbidity data for approving/recommending therapeutic inter-
have not been consistently proven to reduce mortality in patients
ventions for HF. However, it is now recognized that preventing
with HFrEF and their use should be restricted to patients intolerant
HF hospitalization and improving functional capacity are important
of an ACEI or those who take an ACEI but are unable to tolerate an
benefits to be considered if a mortality excess is ruled out.159 – 161
2148 ESC Guidelines
MRA. Ivabradine reduces the elevated heart rate often seen in Practical guidance on how to use ACE inhibitors is given in Web
HFrEF and has also been shown to improve outcomes, and should Table 7.4.
be considered when appropriate.
The above medications should be used in conjunction with diure- 7.2.2 Beta-blockers
tics in patients with symptoms and/or signs of congestion. The use of Beta-blockers reduce mortality and morbidity in symptomatic
diuretics should be modulated according to the patient’s clinical patients with HFrEF, despite treatment with an ACEI and, in
status. most cases, a diuretic,167,168,170,172,173 but have not been tested
The key evidence supporting the recommendations in this in congested or decompensated patients. There is consensus
section is given in Web Table 7.1. The recommended doses of these that beta-blockers and ACEIs are complementary, and can be
disease-modifying medications are given in Table 7.2. The started together as soon as the diagnosis of HFrEF is made.
recommendations given in Sections 7.5 and 7.6 summarize drugs There is no evidence favouring the initiation of treatment
ACEI ¼ angiotensin-converting enzyme inhibitor; HF ¼ heart failure; HFrEF ¼ 7.3 Other treatments recommended in
heart failure with reduced ejection fraction; MRA ¼ mineralocorticoid receptor
antagonist; NYHA ¼ New York Heart Association.
selected symptomatic patients with heart
a
Class of recommendation. failure with reduced ejection fraction
b
Level of evidence. 7.3.1 Diuretics
c
Reference(s) supporting recommendations.
d
Or ARB if ACEI is not tolerated/contraindicated Diuretics are recommended to reduce the signs and symptoms
of congestion in patients with HFrEF, but their effects on
ESC Guidelines 2149
Figure 7.1 Therapeutic algorithm for a patient with symptomatic heart failure with reduced ejection fraction. Green indicates a class I recom-
mendation; yellow indicates a class IIa recommendation. ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker;
ARNI ¼ angiotensin receptor neprilysin inhibitor; BNP ¼ B-type natriuretic peptide; CRT ¼ cardiac resynchronization therapy; HF ¼ heart fail-
ure; HFrEF ¼ heart failure with reduced ejection fraction; H-ISDN ¼ hydralazine and isosorbide dinitrate; HR ¼ heart rate; ICD ¼ implantable
cardioverter defibrillator; LBBB ¼ left bundle branch block; LVAD ¼ left ventricular assist device; LVEF ¼ left ventricular ejection fraction; MR ¼
mineralocorticoid receptor; NT-proBNP ¼ N-terminal pro-B type natriuretic peptide; NYHA ¼ New York Heart Association; OMT ¼ optimal
medical therapy; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia. aSymptomatic ¼ NYHA Class II-IV. bHFrEF ¼ LVEF ,40%. cIf ACE
inhibitor not tolerated/contra-indicated, use ARB. dIf MR antagonist not tolerated/contra-indicated, use ARB. eWith a hospital admission for
HF within the last 6 months or with elevated natriuretic peptides (BNP . 250 pg/ml or NTproBNP . 500 pg/ml in men and 750 pg/ml in women).
f
With an elevated plasma natriuretic peptide level (BNP ≥ 150 pg/mL or plasma NT-proBNP ≥ 600 pg/mL, or if HF hospitalization within recent
12 months plasma BNP ≥ 100 pg/mL or plasma NT-proBNP ≥ 400 pg/mL). gIn doses equivalent to enalapril 10 mg b.i.d. hWith a hospital admis-
sion for HF within the previous year. iCRT is recommended if QRS ≥ 130 msec and LBBB (in sinus rhythm). jCRT should/may be considered if
QRS ≥ 130 msec with non-LBBB (in a sinus rhythm) or for patients in AF provided a strategy to ensure bi-ventricular capture in place (individua-
lized decision). For further details, see Sections 7 and 8 and corresponding web pages.
2150 ESC Guidelines
mortality and morbidity have not been studied in RCTs. A Co- Loop diuretics produce a more intense and shorter diuresis
chrane meta-analysis has shown that in patients with chronic HF, than thiazides, although they act synergistically and the combin-
loop and thiazide diuretics appear to reduce the risk of death ation may be used to treat resistant oedema. However, adverse
and worsening HF compared with placebo, and compared effects are more likely and these combinations should only be
with an active control, diuretics appear to improve exercise used with care. The aim of diuretic therapy is to achieve and main-
capacity.178,179 tain euvolaemia with the lowest achievable dose. The dose of the
diuretic must be adjusted according to the individual needs over
time. In selected asymptomatic euvolaemic/hypovolaemic patients,
the use of a diuretic drug might be (temporarily) discontinued. Pa-
tients can be trained to self-adjust their diuretic dose based on
Table 7.2 Evidence-based doses of disease-modifying monitoring of symptoms/signs of congestion and daily weight
Other pharmacological treatments recommended in selected patients with symptomatic (NYHA Class II-IV) heart
failure with reduced ejection fraction
Digoxin
Digoxin may be considered in symptomatic patients in sinus rhythm despite treatment with an ACE-I (or ARB), a beta-blocker
IIb B 185
and an MRA, to reduce the risk of hospitalization (both all-cause and HF-hospitalizations).
N-3 PUFA
An n-3 PUFAe preparation may be considered in symptomatic HF patients to reduce the risk of cardiovascular hospitalization
IIb B 186
and cardiovascular death.
ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; BNP ¼ B-type natriuretic peptide; bpm ¼ beats per minute; HF ¼ heart failure; HFrEF ¼
heart failure with reduced ejection fraction; LVEF ¼ left ventricular ejection fraction; MRA ¼ mineralocorticoid receptor antagonist; NT-proBNP ¼ N-terminal pro-B type
natriuretic peptide; NYHA ¼ New York Heart Association; PUFA ¼ polyunsaturated fatty acid. OMT ¼ optimal medical therapy (for HFrEF this mostly comprises an ACEI or
sacubitril/valsartan, a beta-blocker and an MRA).
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
d
Patient should have elevated natriuretic peptides (plasma BNP ≥150 pg/mL or plasma NT-proBNP ≥600 pg/mL, or if HF hospitalization within the last 12 months, plasma BNP
≥100 pg/mL or plasma NT-proBNP ≥400 pg/mL) and able to tolerate enalapril 10 mg b.i.d.
e
Applies only to preparation studied in cited trial.
7.3.2 Angiotensin receptor neprilysin inhibitor physiologic effects through binding to NP receptors and the aug-
A new therapeutic class of agents acting on the RAAS and the neu- mented generation of cGMP, thereby enhancing diuresis, natriuresis
tral endopeptidase system has been developed [angiotensin recep- and myocardial relaxation and anti-remodelling. ANP and BNP also
tor neprilysin inhibitor (ARNI)]. The first in class is LCZ696, which is inhibit renin and aldosterone secretion. Selective AT1-receptor
a molecule that combines the moieties of valsartan and sacubitril blockade reduces vasoconstriction, sodium and water retention
(neprilysin inhibitor) in a single substance. By inhibiting neprilysin, and myocardial hypertrophy.187,188
the degradation of NPs, bradykinin and other peptides is slowed. A recent trial investigated the long-term effects of sacubi-
High circulating A-type natriuretic peptide (ANP) and BNP exert tril/valsartan compared with an ACEI (enalapril) on morbidity
2152 ESC Guidelines
and mortality in patients with ambulatory, symptomatic HFrEF Practical guidance on how to use ivabradine is given in Web
with LVEF ≤40% (this was changed to ≤35% during the Table 7.8.
study), elevated plasma NP levels (BNP ≥150 pg/mL or
NT-proBNP ≥600 pg/mL or, if they had been hospitalized 7.3.4 Angiotensin II type I receptor blockers
for HF within the previous 12 months, BNP ≥100 pg/mL or ARBs are recommended only as an alternative in patients intolerant
NT-proBNP ≥400 pg/mL), and an estimated GFR (eGFR) of an ACEI.182 Candesartan has been shown to reduce cardiovascu-
≥30 mL/min/1.73 m 2 of body surface area, who were able lar mortality.182 Valsartan showed an effect on hospitalization for HF
to tolerate separate treatments periods with enalapril (but not on all-cause hospitalizations) in patients with HFrEF receiv-
(10 mg b.i.d.) and sacubitril/valsartan (97/103 mg b.i.d.) during ing background ACEIs.194
a run-in period.162 In this population, sacubitril/valsartan (97/ The combination of ACEI/ARB for HFrEF was reviewed by the
103 mg b.i.d.) was superior to ACEI (enalapril 10 mg b.i.d.) in EMA, which suggested that benefits are thought to outweigh risks
only in a select group of patients with HFrEF in whom other treat-
hospitalization) in patients with AF receiving digoxin.195,196 How- underlying CAD or/and hyperlipidaemia, a continuation of this
ever, this remains controversial, as another recent meta-analysis therapy should be considered.
concluded on the basis of non-RCTs that digoxin has no deleterious
effect on mortality in patients with AF and concomitant HF, most of
whom had HFrEF.197 7.5.2 Oral anticoagulants and antiplatelet therapy
In patients with symptomatic HF and AF, digoxin may be use- Other than in patients with AF (both HFrEF and HFpEF), there is no
ful to slow a rapid ventricular rate, but it is only recommended evidence that an oral anticoagulant reduces mortality/morbidity
for the treatment of patients with HFrEF and AF with rapid ven- compared with placebo or aspirin.206,207 Studies testing the non-
tricular rate when other therapeutic options cannot be pur- vitamin K antagonist oral anticoagulants (NOACs) in patients with
sued. 196,198 – 201 Of note, the optimal ventricular rate for HFrEF are currently ongoing. Patients with HFrEF receiving oral an-
patients with HF and AF has not been well established, but ticoagulation because of concurrent AF or risk of venous thrombo-
embolism should continue anticoagulation. Detailed information is
7.6 Treatments not recommended specific guideline recommendations for other therapeutic technolo-
(believed to cause harm) in symptomatic gies, including baroreflex activation therapy,217 vagal stimulation,218
diaphragmatic pacing219,220 and cardiac contractility modula-
patients with heart failure with reduced tion;221,222 further research is required. Implantable devices to
ejection fraction monitor arrhythmias or haemodynamics are discussed elsewhere
7.6.1 Calcium-channel blockers in these guidelines.
Non-dihydropyridine calcium-channel blockers (CCBs) are not in-
dicated for the treatment of patients with HFrEF. Diltiazem and ver-
apamil have been shown to be unsafe in patients with HFrEF.214 8.1 Implantable cardioverter-defibrillator
There is a variety of dihydropyridine CCBs; some are known to A high proportion of deaths among patients with HF, especially
increase sympathetic tone and they may have a negative safety pro- those with milder symptoms, occur suddenly and unexpectedly.
file in HFrEF. There is only evidence on safety for amlodipine215 and Many of these are due to electrical disturbances, including ven-
CAD ¼ coronary artery disease; CRT ¼ cardiac resynchronization therapy; DCM ¼ dilated cardiomyopathy; HF ¼ heart failure; ICD ¼ implantable cardioverter-defibrillator;
IHD ¼ ischaemic heart disease; LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction; NYHA ¼ New York Heart Association, OMT ¼ optimal medical therapy.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
8.1.1 Secondary prevention of sudden cardiac death survival; the decision to implant should take into account the
Compared with amiodarone treatment, ICDs reduce mortality patient’s view and their quality of life, the LVEF (survival bene-
in survivors of cardiac arrest and in patients who have experi- fit is uncertain when the LVEF is .35%) and the absence of
enced sustained symptomatic ventricular arrhythmias. An ICD other diseases likely to cause death within the following
is recommended in such patients when the intent is to increase year.223 – 225
ESC Guidelines 2155
8.1.2 Primary prevention of sudden cardiac death ICD therapy is not recommended in patients in NYHA Class IV
Although amiodarone may have reduced mortality in older trials of with severe symptoms refractory to pharmacological therapy who
HF,242,243 contemporary studies conducted since the widespread are not candidates for CRT, a ventricular assist device or cardiac
introduction of beta-blockers suggest that it does not reduce mor- transplantation, because such patients have a very limited life ex-
tality in patients with HFrEF.227,244,245 Dronedarone246,247 and class pectancy and are likely to die from pump failure.
I antiarrhythmic agents246,248 should not be used for prevention of Patients with serious co-morbidities who are unlikely to survive
arrhythmias in this population. substantially more than 1 year are unlikely to obtain substantial
Some guideline-recommended therapies, including beta- benefit from an ICD.229 – 233
blockers, MRAs, sacubitril/valsartan and pacemakers with CRT Patients should be counselled as to the purpose of an ICD, com-
(CRT-Ps), reduce the risk of sudden death (see Section 7). plications related to implantation and device activation (predomin-
An ICD reduces the rate of sudden arrhythmic death in patients antly inappropriate shocks) and under what circumstances it might
with HFrEF.249,250 In patients with moderate or severe HF, a reduc-
Recommendations for cardiac resynchronization therapy implantation in patients with heart failure
AF ¼ atrial fibrillation; AV ¼ atrio-ventricular; CRT ¼ cardiac resynchronization therapy; HF ¼ heart failure; HFrEF ¼ heart failure with reduced ejection fraction; ICD ¼
implantable cardioverter-defibrillator; LBBB ¼ left bundle branch block; LVEF ¼ left ventricular ejection fraction; NYHA ¼ New York Heart Association; OMT ¼ optimal medical
therapy; QRS ¼ Q, R and S waves (combination of three of the graphical deflections); RV ¼ right ventricular.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
d
Use judgement for patients with end-stage HF who might be managed conservatively rather than with treatments to improve symptoms or prognosis.
CRT improves cardiac performance in appropriately selected pa- CRT response and was the inclusion criterion in all randomized
tients and improves symptoms286 and well-being286 and reduces trials. But QRS morphology has also been related to a beneficial re-
morbidity and mortality.266 Of the improvement in quality-adjusted sponse to CRT. Several studies have shown that patients with left
life-years (QALYs) with CRT among patients with moderate to se- bundle branch block (LBBB) morphology are more likely to respond
vere HF, two-thirds may be attributed to improved quality of life and favourably to CRT, whereas there is less certainty about patients
one-third to increased longevity.287 with non-LBBB morphology. However, patients with LBBB morph-
Only the COMPANION265 and CARE-HF trials262,263 compared ology often have wider QRS duration, and there is a current debate
the effect of CRT to guideline-advised medical therapy. Most other about whether QRS duration or QRS morphology is the main pre-
trials have compared CRT-D to ICD, and a few have compared dictor of a beneficial response to CRT. Evidence from two IPD
CRT-P to backup pacing. The prevention of lethal bradycardia might meta-analyses indicates that after accounting for QRS duration,
be an important mechanism of benefit shared by all pacing devices. there is little evidence to suggest that QRS morphology or aetiology
In CARE-HF, at baseline, 25% of patients had a resting heart rate of of disease influence the effect of CRT on morbidity or mortal-
≤60 bpm.262 – 264 If prevention of bradycardia is important, the ef- ity.266,273 In addition, none of the landmark trials selected patients
fect of CRT will appear greater in trials where there is no device for inclusion according to QRS morphology, sex or ischaemic aeti-
in the control group. ology, nor were they powered for subgroup analyses.
Most studies of CRT have specified that the LVEF should be ,35%, The Echo-CRT283,284 trial and an IPD meta-analysis266 suggest
but RAFT267 and MADIT-CRT268,269 specified an LVEF ,30%, while possible harm from CRT when QRS duration is ,130 ms, thus im-
REVERSE270 – 272 specified ,40% and BLOCK-HF274 ,50%. Rela- plantation of CRT is not recommended if QRS duration is ,130
tively few patients with an LVEF of 35–40% have been randomized, ms.266,283,284
but an individual participant data (IPD) meta-analysis suggests no If a patient is scheduled to receive an ICD and is in sinus rhythm
diminution of the effect of CRT in this group.266 with a QRS duration ≥130 ms, CRT-D should be considered if
Not all patients respond favourably to CRT.286 Several character- QRS is between 130 and 149 ms and is recommended if QRS is
istics predict improvement in morbidity and mortality, and the ex- ≥150 ms. However, if the primary reason for implanting a CRT
tent of reverse remodelling is one of the most important is for the relief of symptoms, then the clinician should choose
mechanisms of action of CRT. Patients with ischaemic aetiology CRT-P or CRT-D, whichever they consider appropriate. Clinical
will have less improvement in LV function due to myocardial scar tis- practice varies widely among countries. The only randomized trial
sue, which is less likely to undergo favourable remodelling.288 Con- to compare CRT-P and CRT-D265 failed to demonstrate a differ-
versely, women may be more likely to respond than men, possibly ence in morbidity or mortality between these technologies.288 If
due to smaller body and heart size.273,285,289 QRS width predicts the primary reason for implanting CRT is to improve prognosis,
ESC Guidelines 2157
then the majority of evidence lies with CRT-D for patients in enhance contractile performance without activating extra systolic
NYHA Class II and with CRT-P for patients in NYHA Classes contractions. CCM has been evaluated in patients with HFrEF in
III – IV. It is unclear whether CRT reduces the need for an ICD NYHA Classes II – III with normal QRS duration (,120 ms).221,222
(by reducing the arrhythmia burden) or increases the benefit An individual patient data meta-analysis demonstrated an improve-
from an ICD (by reducing mortality rates from worsening HF, lead- ment in exercise tolerance (peak VO2) and quality of life (Minnesota
ing to longer exposure to the risk of arrhythmia). Living with Heart Failure questionnaire). Thus CCM may be consid-
When LVEF is reduced, RV pacing may exacerbate cardiac dyssyn- ered in selected patients with HF. The effect of CCM on HF morbid-
chrony. This can be prevented by CRT, which might improve patient ity and mortality remains to be established.
outcomes.274,275,277,290 However, a difference in outcome was not Most other devices under evaluation involve some modification
observed between CRT and RV pacing in a subgroup analysis of of the activity of the autonomic nervous system (ANS) by targeted
RAFT267 or in patients without HFrEF in BioPACE.291 On balance, electrical stimulation.298,299 These include vagal nerve stimulation,
9.1 Effect of treatment on symptoms and in cardiovascular mortality.130 However, aggressive manage-
in heart failure with preserved ejection ment of dysglycaemia may be harmful.153,320
Myocardial ischaemia may contribute to symptoms, morbidity
fraction and mortality and should be considered when assessing patients.
Diuretics will usually improve congestion, if present, thereby im- However, there is only anecdotal evidence that revascularization
proving symptoms and signs of HF. The evidence that diuretics improves symptoms or outcome. Patients with angina should follow
improve symptoms is similar across the spectrum of LVEF.178,179 the same management route as patients with HFrEF.112
Evidence that beta-blockers and MRAs improve symptoms in Patients with HFpEF and HFmrEF have impaired exercise toler-
these patients is lacking. There is inconsistent evidence for an im- ance, commonly accompanied by an augmented blood pressure re-
provement in symptoms in those treated with ARBs (only for can- sponse to exercise and chronotropic incompetence. Combined
desartan was there an improvement in NYHA class)309,310 and endurance/resistance training appears safe for patients with HFpEF
ACEIs.311
10.1 Atrial fibrillation must not be given. Longer-term infusion of amiodarone should be
AF is the most common arrhythmia in HF irrespective of concomi- given only by central or long-line venous access to avoid peripheral
tant LVEF; it increases the risk of thromboembolic complications vein phlebitis. In patients with haemodynamic collapse, emergency
(particularly stroke) and may impair cardiac function, leading to electrical cardioversion is recommended (see also Section 12).
worsening symptoms of HF.316 Incident HF precipitated by AF is as-
sociated with a more benign prognosis,331 but new-onset AF in a pa- Recommendations for initial management of a
tient with established HF is associated with a worse outcome, rapid ventricular rate in patients with heart failure and
probably because it is both a marker of a sicker patient and because atrial fibrillation in the acute or chronic setting
it impairs cardiac function.332,333 Patients with chronic HF and per-
manent AF have a worse outcome than those in sinus rhythm, al- Recommendations Class a Level b Ref c
though this is largely explained by more advanced age and HF Urgent electrical cardioversion is
ventricular rate to be assessed during rest, exercise and sleep, but cardioversion.343 – 346 When used, the need for continued administra-
the value of routine monitoring has not yet been established. Im- tion of amiodarone should be regularly reviewed and justified.
planted devices such as pacemakers, CRT or ICDs can also be The safety and efficacy of catheter ablation in the atria and pul-
used to measure ventricular rate. monary veins (PV) as a rhythm control strategy in HF is at present
The optimal resting ventricular rate in patients with AF and HF is uncertain except for tachycardia induced cardiomyopathy.316 One
uncertain but may be between 60 – 100 bpm.350,352 – 354 One trial small study suggested that AF ablation was superior to AV node ab-
suggested that a resting ventricular rate of up to 110 bpm might still lation and CRT.360 Another study, including 203 patients with per-
be acceptable,198,202 and 2016 ESC AF guidelines recommend this sistent AF, HF and an ICD or CRT device, showed that AF ablation
threshold as the target for rate control therapy.316 However, this was superior to amiodarone in correcting AF, and this was asso-
Task Force believes that a lower rate for patients with HF may be ciated with fewer hospitalizations for HF and lower mortality.
preferable (60 – 100 bpm). Ventricular rates ,70 bpm are asso- Two small studies of AF ablation compared with rate control met
ciated with a worse outcome.351 This may explain why beta-
10.1.5 Thromboembolism prophylaxis HF and AF who have mechanical heart valves or at least moderate mi-
Patients with HF and AF should generally be anticoagulated and the tral stenosis, only oral vitamin K antagonists should be used for pre-
balance of benefit and risk of bleeding (using CHA2DS2-VASc and vention of thromboembolic stroke.370
HAS-BLED scores; for details, please see Web Tables 10.1 and The dabigatran dose should be reduced to 110 mg b.i.d. when cre-
10.2.) should be evaluated as recommended in the ESC guidelines atinine clearance is 30 –49 mL/min, rivaroxaban to 15 mg daily and
for AF.316 A substantial proportion of patients with HF will have edoxaban to 30 mg daily when creatinine clearance is 30 – 50 mL/
both benefit and risk scores ≥3, indicating that careful consider- min and apixaban to 2.5 mg twice daily if a patient has two or
ation should be given before prescribing an oral anticoagulant and more of the following: age ≥80 years, serum creatinine ≥1.5 mg/
that regular review is subsequently needed (and correctable risk dL or body weight ≤60 kg.370 – 375 The summary of the recommen-
factors for bleeding addressed) if an oral anticoagulant is given. dations for the prevention of thromboembolism in patients with
NOACs are preferred for patients with HF with non-valvular AF, as symptomatic HF and paroxysmal or persistent/permanent AF is
Recommendations for the prevention of thrombo-embolism in patients with symptomatic heart failure (NYHA Class II –
IV) and paroxysmal or persistent/permanent atrial fibrillation
AF ¼ atrial fibrillation; CHA2DS2-VASc ¼ Congestive heart failure or left ventricular dysfunction, Hypertension, Age ≥ 75 (doubled), Diabetes, Stroke (doubled)-Vascular disease,
Age 65 –74, Sex category (female); HAS-BLED ¼ Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio,
Elderly (.65 years), Drugs/alcohol concomitantly (1 point each); HF ¼ heart failure; LMWH ¼ low molecular weight heparin; NOAC ¼ non-vitamin K antagonist oral
anticoagulant; NYHA ¼ New York Heart Association; TOE ¼ transoesophageal echocardiography.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
10.2 Ventricular arrhythmias revascularization for patients with HFrEF have not reduced overall
The initial management of asymptomatic ventricular arrhythmias mortality,107,385 even in subgroups of patients with angina or myo-
is correction of electrolyte abnormalities, particularly low serum cardial ischaemia,115,386 but further analysis did suggest a reduction
potassium and magnesium, withdrawal of agents that might in sudden deaths.387
provoke arrhythmias and, in patients with HFrEF, optimization Amiodarone (often in combination with a beta-blocker) may be
of pharmacological therapy with ACEIs, beta-blockers and used to suppress symptomatic ventricular arrhythmias, but it may
MRAs and sacubitril/valsartan, which all reduce the risk of sudden adversely affect prognosis, especially in patients with more severe
death.174,177,383,384 HF.227,244 Other antiarrhythmic drugs should be avoided.247 Trans-
The clinical relevance of myocardial ischaemia for the provoca- catheter radiofrequency modification of the arrhythmogenic sub-
tion of ventricular arrhythmias is uncertain, although anecdotal strate may reduce the number of appropriate ICD discharges
cases of ischaemia-induced arrhythmias exist. Randomized trials of and may be used to terminate arrhythmic storm in patients with
2162 ESC Guidelines
HF and frequent, recurrent ventricular tachyarrhythmias and amiodarone, digoxin and ivabradine. For patients in AF, a reduction
therefore should be considered in such patients. Seeking the in the dose of beta-blockers allowing the daytime resting ventricular
advice of the members of the HF Team with expertise in electro- rate to rise to 70– 90 bpm may be considered, since evidence that
physiology is recommended in patients with recalcitrant ventricu- beta-blockers improve outcome in patients with AF is lacking.177 For
lar arrhythmias. For further details we refer the reader to the ESC/ patients with pauses but in sinus rhythm, a reduction in the dose of
EHRA guidelines on ventricular arrhythmias and sudden cardiac beta-blockers should be avoided unless the pauses are symptomatic,
death.260 prolonged or frequent, in which case the relative merits of dose re-
duction, beta-blocker withdrawal and (biventricular) pacing may be
considered. However, evidence is lacking to support a strategy of
Recommendations for the management of ventricular
pacing solely to permit initiation or titration of beta-blocker therapy
tachyarrhythmias in heart failure
in the absence of a conventional pacing indication; this strategy is not
Recommendations for the treatment of stable angina pectoris with symptomatic (NYHA Class II-IV) heart failure with
reduced ejection fraction112,113
I A 167–173
bpm ¼ beats per minute; HF ¼ heart failure; HFrEF ¼ heart failure with reduced ejection fraction; NYHA ¼ New York Heart Association.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
11.3 Cachexia and sarcopenia (for frailty, resistance, reduced anabolic drive, prolonged immobilization and
please refer to Section 14) physical deconditioning, together characterized by catabolic/anabol-
ic imbalance.418 Skeletal muscle wasting, when associated with im-
Cachexia is a generalized wasting process affecting all body com-
paired mobility and symptoms (termed sarcopenia or myopenia),
partments [i.e. lean tissue (skeletal muscle), fat tissue (energy re-
occurs in 30 – 50% of patients with HFrEF.419 In its most severe
serves) and bone tissue (osteoporosis)]. It may occur in 5–15% of
form it is associated with frailty and poor morbidity and mortality.420
patients with HF, especially those with HFrEF, and more advanced
Potential treatments may include appetite stimulants, exercise
disease status.414 – 416 This serious complication is associated with
training120 and anabolic agents, including testosterone, in combin-
more severe symptoms and reduced functional capacity, more fre-
ation with the application of nutritional supplements and
quent hospitalization and decreased survival. Cachexia in HF can be
anti-catabolic interventions, although none is of proven benefit
diagnosed and defined as involuntary non-oedematous weight loss
and their safety is unknown.421
≥6% of total body weight within the previous 6–12 months.414 – 417
The causes are multifactorial, and in individual patients they are
difficult to determine. These may include pro-inflammatory immune 11.4 Cancer
activation, neurohormonal derangements, poor nutrition and mal- Certain chemotherapeutic agents can cause (or aggravate) LV sys-
absorption, impaired calorie and protein balance, anabolic hormone tolic dysfunction and HF. The best recognized of these are the
ESC Guidelines 2165
anthracyclines (e.g. doxorubicin), trastuzumab and tyrosine kinase in depressive symptoms or improvement in cardiovascular status
inhibitors.397,422 A recent Cochrane review found that dexrazoxane compared with placebo in HFrEF patients, but this trial was not
may confer some cardioprotection in patients receiving anthracy- powered enough to prove the latter. 435 Similarly, escitalopram
clines.423 Pre- and post-evaluation of LVEF, if available with myocar- had no effect on either depression or clinical outcomes during the
dial strain imaging, is essential in patients receiving cardiotoxic 24-month follow-up as compared with placebo in patients with
chemotherapy, as detailed elsewhere.397,422 A risk score for identi- HFrEF and depression. Importantly, tricyclic antidepressants should
fying women with breast cancer at risk of developing HF during tras- be avoided, because they may cause hypotension, worsening HF and
tuzumab therapy has been developed based on age, chemotherapy arrhythmias.429,435
details, baseline cardiovascular status and other co-morbidities, and
may be helpful. 424 Chemotherapy should be discontinued and 11.6 Diabetes
HFrEF therapy commenced in patients developing moderate to se- Dysglycaemia and diabetes are very common in HF, and diabetes is
As glycaemic derangement progresses, the judgement on gly- The management of acute hyperkalaemia (.6.0 mmol/L) may re-
caemic control should be made according to cardiac conditions, quire a short-term cessation of potassium-retaining agents and
and if the new anti-diabetic drugs are to be prescribed, they have RAAS inhibitors, but this should be minimized and RAAS inhibitors
to be closely monitored by an HF team. should be carefully reintroduced as soon as possible while monitor-
ing potassium levels. A Cochrane review452 found no trial evidence
of major outcome benefits for any emergency therapy regimen for
11.7 Erectile dysfunction
hyperkalaemia. Two new potassium binders (patiromer and sodium
Erectile dysfunction is a common and important component of qual-
zirconium cyclosilicate) are currently under consideration for regu-
ity of life in men with HF.444,445 Its treatment should include optimal
latory approval.453,454 Initial results from patients with HF are avail-
therapies for underlying cardiovascular diseases and other interfer-
able and confirm the efficacy of these therapies in reducing serum
ing co-morbidities (e.g. diabetes) and amelioration of anxiety and
potassium455 and preventing recurrent hyperkalaemia in patients
depressive symptoms. Some drugs applied for HF therapy (e.g. thia-
Recommendations for the treatment of hypertension in patients with symptomatic (NYHA Class II-IV) heart failure with
reduced ejection fraction
ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; HF ¼ heart failure; HFmrEF ¼ heart failure with mid-range ejection fraction; HFpEF ¼ heart failure
with preserved ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction; MRA ¼ mineralocorticoid receptor antagonist; NYHA ¼ New York Heart Association.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
11.12 Iron deficiency and anaemia i.v. iron therapy in HFrEF patients with iron deficiency over up
Iron deficiency is common in HF, as it is with other chronic ill- to 52 weeks showed reduced hospitalization rates and improved
nesses, and it can lead to anaemia and/or skeletal muscle dysfunc- HF symptoms, exercise capacity and quality of life.472 Treatment
tion without anaemia.466 Within an HF population, iron deficiency with FCM may therefore result in sustainable improvement in func-
is associated with a worse prognosis.467,468 Intravenous iron has tional capacity, symptoms and quality of life. Treatment was also
been specifically studied in two RCTs in patients with HF and associated with a significant reduction in hospitalizations for wor-
iron deficiency (serum ferritin ,100 mg/L or ferritin between sening HF. The number of deaths and the incidence of adverse
100 and 299 mg/L and transferrin saturation ,20%)469,470 both events were similar. Neither i.v. iron trial was powered to test
with and without anaemia. Intravenous ferric carboxymaltose for an effect on major outcomes or to evaluate separately the ef-
(FCM) has been shown to improve self-reported patient global as- fects in anaemic and non-anaemic patients. The effect of treating
sessment, quality of life and NYHA class (over 6 months) in the iron deficiency in HFpEF/HFmrEF and the long-term safety of
FAIR-HF trial469 both in anaemic and non-anaemic patients with iron therapy in either HFrEF, HFmrEF or HFpEF is unknown. The
HF, 471 and in the CONFIRM-HF trial 470 , exercise capacity im- safety of i.v. iron is unknown in patients with HF and haemoglobin
proved over 24 weeks. In the analysis of secondary endpoints in .15 g/dL.469,470 Patients with iron deficiency need to be screened
the CONFIRM-HF trial, i.v. iron reduced the risk of HF hospitaliza- for any potentially treatable/reversible causes (e.g. gastrointestinal
tions in iron-deficient patients with HFrEF.470 A meta-analysis of sources of bleeding).
2168 ESC Guidelines
Recommendations for the treatment of other functional status, greater risk of HF hospitalization and reduced sur-
co-morbidities in patients with heart failure vival. A diagnostic workup to seek a cause for any finding of anaemia
is indicated (e.g. occult blood loss, iron deficiency, B12/folate defi-
Recommendations Class a Level b Ref c ciency, blood dyscrasias), although in many patients no specific
cause is found. The erythropoietin-stimulating agent darbepoetin
alfa did not improve clinical outcomes in HFrEF patients with mild
Intravenous FCM should be to moderate anaemia, but led to an excess of thromboembolic
considered in symptomatic patients
events and is therefore not recommended.475
(serum ferritin <100 µg/L, or
ferritin between 100–299 µg/L and IIa A 469, 470
transferrin saturation <20%) in
order to alleviate HF symptoms, 11.13 Kidney dysfunction (including
kidney injury (CI-AKI)]. Renal dysfunction and worsening renal function established that obesity is associated with lower mortality across a
is further discussed in the section about AHF (see Section 12). wide range of body mass indexes (BMIs) (see also cachexia in Section
Prostatic obstruction is common in older men and can interfere 11.3)—the so-called obesity paradox also seen in other chronic ill-
with renal function; it should therefore be ruled out in men with HF nesses.414,416 Obesity should be managed as recommended in the
with deteriorating renal function. a-adrenoceptor blockers cause ESC guidelines on cardiovascular disease prevention,483 if the aim is
hypotension and sodium and water retention, and may not be to prevent future development of HF. However, these guidelines do
safe in HFrEF.458,464,465 For these reasons, 5-a-reductase inhibitors not refer to the HF patient in whom higher BMI is not adverse, and, al-
are generally preferred in the medical treatment of prostatic though often recommended for symptom benefit and risk factor con-
obstruction in patients with HF. trol, weight loss as an intervention has never been prospectively shown
to be either beneficial or safe in HFrEF. When weight loss is occurring
11.14 Lung disease (including asthma and in HF, it is associated with high mortality and morbidity, worse symp-
The safety and efficacy of alternative approaches to treating CSA Primary (organic) mitral regurgitation
in HFrEF patients, such as implantable phrenic nerve stimula- Surgery is indicated in symptomatic patients with severe organic
tion,219,220,492 are presently undergoing clinical investigation and mitral regurgitation with no contra-indications to surgery. The deci-
may require additional long term study. sion of whether to replace or repair depends mostly on valve anat-
omy, surgical expertise available, and the patient’s condition.
11.17. Valvular heart disease When the LVEF is , 30%, a durable surgical repair may improve
Valvular heart disease may cause or aggravate HF. This section brief- symptoms, although its effect on survival is unknown. In this situ-
ly addresses problems particularly relevant to HF, and the reader is ation, the decision to operate should take account of response to
referred to the recent guidelines on valvular disease for more medical therapy, co-morbidities, and the likelihood that the valve
information.493,494 can be repaired (rather than replaced).
Patients with HF and concomitant valvular heart disease constitute a
Secondary mitral regurgitation
high-risk population. Thus, the whole process of decision-making
In patients with severe aortic regurgitation, aortic valve repair or replacement is recommended in all symptomatic patients and
Evidence-based medical therapy in patients with HFrEF is recommended in order to reduce functional mitral regurgitation. I C
Combined surgery of secondary mitral regurgitation and coronary artery bypass grafting should be considered in symptomatic
IIa C
patients with LV systolic dysfunction (LVEF <30%), requiring coronary revascularization for angina recalcitrant to medical therapy.
Isolated surgery of non-ischaemic regurgitant mitral valve in patients with severe functional mitral regurgitation and severe LV systolic
IIb C
dysfunction (LVEF <30%) may be considered in selected patients in order to avoid or postpone transplantation.
HFrEF ¼ heart failure with reduced ejection fraction; LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction; TAVI ¼ transaortic valve implantation.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
AHF refers to rapid onset or worsening of symptoms and/or signs Infection (e.g. pneumonia, infective endocarditis, sepsis).
of HF. It is a life-threatening medical condition requiring urgent
evaluation and treatment, typically leading to urgent hospital Bradyarrhythmia.
admission. Toxic substances (alcohol, recreational drugs).
AHF may present as a first occurrence (de novo) or, more fre-
Drugs (e.g. NSAIDs, corticosteroids, negative inotropic substances,
quently, as a consequence of acute decompensation of chronic cardiotoxic chemotherapeutics).
HF, and may be caused by primary cardiac dysfunction or precipi-
Exacerbation of chronic obstructive pulmonary disease.
tated by extrinsic factors, often in patients with chronic HF. Acute
Pulmonary embolism.
myocardial dysfunction (ischaemic, inflammatory or toxic), acute
valve insufficiency or pericardial tamponade are among the most Surgery and perioperative complications.
frequent acute primary cardiac causes of AHF. Decompensation Increased sympathetic drive, stress-related cardiomyopathy.
of chronic HF can occur without known precipitant factors, but Metabolic/hormonal derangements (e.g. thyroid dysfunction, diabetic
more often with one or more factors, such as infection, uncon- ketosis, adrenal dysfunction, pregnancy and peripartum related
trolled hypertension, rhythm disturbances or non-adherence with abnormalities).
drugs/diet (Table 12.1). Cerebrovascular insult.
A large number of overlapping classifications of AHF based on dif- Acute mechanical cause: myocardial rupture complicating ACS (free wall
ferent criteria have been proposed.510 – 513 In practice the most use- rupture, ventricular septal defect, acute mitral regurgitation), chest trauma
ful classifications are those based on clinical presentation at or cardiac intervention, acute native or prosthetic valve incompetence
secondary to endocarditis, aortic dissection or thrombosis.
admission, allowing clinicians to identify patients at high risk of com-
plications and to direct management at specific targets, which cre-
ACS ¼ acute coronary syndromes; NSAIDs ¼ non-steroidal anti-inflammatory
ates a pathway for personalized care in the AHF setting. In most drugs.
cases, patients with AHF present with either preserved (90 – 140
mmHg) or elevated (.140 mmHg; hypertensive AHF) systolic
blood pressure (SBP). Only 5 – 8% of all patients present with Another approach is to classify patients according to the presence
low SBP (i.e. ,90 mmHg; hypotensive AHF), which is associated of the following precipitants/causes leading to decompensation,
with poor prognosis, particularly when hypoperfusion is also which need to be treated/corrected urgently (see Section 12.3.1):
present.514,515 ACS, hypertensive emergency, rapid arrhythmias or severe
2172 ESC Guidelines
bradycardia/conduction disturbance, acute mechanical cause under- rales and S3 gallop; class III, with frank acute pulmonary oedema;
lying AHF or acute pulmonary embolism. class IV, cardiogenic shock, hypotension (SBP ,90 mmHg) and evi-
Clinical classification can be based on bedside physical examination dence of peripheral vasoconstriction such as oliguria, cyanosis and
in order to detect the presence of clinical symptoms/signs of conges- diaphoresis.
tion (‘wet’ vs. ‘dry’ if present vs. absent) and/or peripheral hypoperfu- Definitions of the terms used in this section related to clinical
sion (‘cold’ vs. ‘warm’ if present vs. absent) (Figure 12.1).514,515 The presentation of patients with AHF are provided in Table 12.2.
combination of these options identifies four groups: warm and wet
(well perfused and congested) —most commonly present; cold and 12.2 Diagnosis and initial prognostic
wet (hypoperfused and congested); cold and dry (hypoperfused with- evaluation
out congestion); and warm and dry (compensated, well perfused with- The diagnostic workup needs to be started in the pre-hospital set-
out congestion). This classification may be helpful to guide therapy in ting and continued in the emergency department (ED) in order to
the initial phase and carries prognostic information.510,514,515 establish the diagnosis in a timely manner and initiate appropriate
Patients with HF complicating AMI can be classified according to management. The greater benefit of early treatment is well estab-
Killip and Kimball13 into class I, no clinical signs of HF; class II, HF with lished in ACS and now needs to be considered in the setting of
ESC Guidelines 2173
Table 12.2 Definitions of the terms used in Section 12 on acute heart failure
Term
Symptoms/signs of congestion (left-sided) Orthopnoea, paroxysmal nocturnal dyspnoea, pulmonary rales (bilateral), peripheral oedema (bilateral).
Symptoms/signs of congestion (right-sided)
symptoms of gut congestion.
Symptoms/signs of hypoperfusion Clinical: cold sweated extremities, oliguria, mental confusion, dizziness, narrow pulse pressure.
Laboratory measures: metabolic acidosis, elevated serum lactate, elevated serum creatinine.
Hypoperfusion is not synonymous with hypotension, but often hypoperfusion is accompanied by hypotension.
Hypotension Systolic BP <90 mmHg
Bradycardia Heart rate <40 bpm
BP ¼ blood pressure; bpm ¼ beats per minute; PaCO2 ¼ partial pressure of carbon dioxide in arterial blood; PaO2 ¼ partial pressure of oxygen in arterial blood; SaO2 ¼ oxygen
saturation.
AHF.516,517 In parallel, coexisting life-threatening clinical conditions † Chest X-ray can be a useful test for the diagnosis of AHF. Pulmon-
and/or precipitants that require urgent treatment/correction need ary venous congestion, pleural effusion, interstitial or alveolar oe-
to be immediately identified and managed (Figure 12.2). Typically, dema and cardiomegaly are the most specific findings for AHF,
an initial step in the diagnostic workup of AHF is to rule out alter- although in up to 20% of patients with AHF, chest X-ray is nearly
native causes for the patient’s symptoms and signs (i.e. pulmonary normal.519 Supine chest radiographs are of limited value in AHF.
infection, severe anaemia, acute renal failure). Chest X-ray is also useful to identify alternative non-cardiac dis-
When AHF is confirmed clinical evaluation is mandatory to select eases that may cause or contribute to the patient’s symptoms
further management. (i.e. pneumonia, non-consolidative pulmonary infections).
It is recommended that initial diagnosis of AHF should be based † ECG is rarely normal in AHF (high negative predictive value).520 It
on a thorough history assessing symptoms, prior cardiovascular his- is also helpful in identifying underlying cardiac disease and poten-
tory and potential cardiac and non-cardiac precipitants, as well as on tial precipitants (rapid AF, acute myocardial ischaemia).
the assessment of signs/symptoms of congestion and/or hypoperfu- † Immediate echocardiography is mandatory only in patients with
sion by physical examination and further confirmed by appropriate haemodynamic instability (particularly in cardiogenic shock)
additional investigations such as ECG, chest X-ray, laboratory as- and in patients suspected of acute life-threatening structural or
sessment (with specific biomarkers) and echocardiography. functional cardiac abnormalities (mechanical complications,
In patients presenting with AHF, early initiation of appropriate acute valvular regurgitation, aortic dissection). Early echocardiog-
therapy (along with relevant investigations) is of key import- raphy should be considered in all patients with de novo AHF and in
ance.516 – 518 those with unknown cardiac function; however, the optimal tim-
Typically, symptoms and signs of AHF reflect fluid overload (pul- ing is unknown (preferably within 48 h from admission, if the ex-
monary congestion and/or peripheral oedema) or, less often, re- pertise is available). Pocket-size echocardiography may be used
duced cardiac output with peripheral hypoperfusion (Table 12.2). as an extension of the clinical examination in the first instance
Since the sensitivity and specificity of symptoms and signs are often where available. Repeated echocardiography is usually not
not satisfactory, careful clinical evaluation needs to be followed by needed unless there is relevant deterioration in clinical status.
these additional investigations: Bedside thoracic ultrasound for signs of interstitial oedema and
2174 ESC Guidelines
Figure 12.2 Initial management of a patient with acute heart failure. aAcute mechanical cause: myocardial rupture complicating acute coronary
syndrome (free wall rupture, ventricular septal defect, acute mitral regurgitation), chest trauma or cardiac intervention, acute native or prosthetic
valve incompetence secondary to endocarditis, aortic dissection or thrombosis, see above.
ESC Guidelines 2175
AHF ¼ acute heart failure; BNP ¼ B-type natriuretic peptide; BUN ¼ blood urea nitrogen; ECG ¼ electrocardiogram; MR-proANP ¼ mid-regional pro A-type natriuretic
peptide; NT-proBNP ¼ N-terminal pro-B type natriuretic peptide; TSH ¼ thyroid-stimulating hormone
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
Recommendations for the management of patients with acute heart failure: oxygen therapy and ventilatory support
AHF ¼ acute heart failure; BiPAP ¼ bilevel positive airway pressure; COPD ¼ chronic obstructive pulmonary disease; CPAP ¼ continuous positive airway pressure; PaCO2 ¼
partial pressure of carbon dioxide in arterial blood; PaO2 ¼ partial pressure of oxygen in arterial blood; SpO2 ¼ transcutaneous oxygen saturation.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
In AHF, oxygen should not be used routinely in non-hypoxaemic pa- mortality rates,543 although data regarding mortality are less
tients, as it causes vasoconstriction and a reduction in cardiac out- conclusive. CPAP is a feasible technique in the pre-hospital
put.546,547 In COPD, hyperoxygenation may increase ventilation – setting, because it is simpler than pressure support positive
perfusion mismatch, suppressing ventilation and leading to hyper- end-expiratory pressure (PS-PEEP) and requires minimal training
capnia. During oxygen therapy, acid –base balance and transcutane- and equipment. On hospital arrival, patients who still show signs
ous SpO2 should be monitored. of respiratory distress should continue with non-invasive ventila-
Non-invasive positive pressure ventilation includes both CPAP tion, preferably PS-PEEP, in case of acidosis and hypercapnia, par-
and bi-level positive pressure ventilation (PPV). Bi-level PPV also al- ticularly in those with a previous history of COPD or signs of
lows inspiratory pressure support that improves minute ventilation fatigue.540
and is especially useful in patients with hypercapnia, most typically Caution should be exercised with regard to side effects of anaes-
COPD patients. thetic drugs, among which propofol can induce hypotension and
Congestion affects lung function and increases intrapulmonary have cardiodepressive side effects. In contrast, midazolam may
shunting, resulting in hypoxaemia. The fraction of inspired oxygen have fewer cardiac side effects and thus is preferred in patients
(FiO2) should be increased up to 100% if necessary, according to with AHF or cardiogenic shock.
SpO2, unless contraindicated. Hyperoxia, however, should be A management algorithm for patients with AHF based on
avoided.546,547 Non-invasive positive pressure ventilation reduces the clinical profile during an early phase is presented in
respiratory distress541 – 545 and may decrease intubation and Figure 12.3.
2178 ESC Guidelines
Figure 12.3 Management of patients with acute heart failure based on clinical profile during an early phase
a
Symptoms/signs of congestion: orthopnoea, paroxysmal nocturnal dyspnoea, breathlessness, bi-basilar rales, an abnormal blood pressure re-
sponse to the Valsalva maneuver (left-sided); symptoms of gut congestion, jugular venous distension, hepatojugular reflux, hepatomegaly, ascites,
and peripheral oedema (right-sided).
ESC Guidelines 2179
Pharmacological therapy
Recommendations for the management of patients with acute heart failure: pharmacotherapy
improve symptoms. It is recommended to regularly monitor symptoms, urine output, renal function and electrolytes during I C
use of i.v. diuretics.
In patients with new-onset AHF or those with chronic, decompensated HF not receiving oral diuretics the initial
Vasodilators
i.v. vasodilators should be considered for symptomatic relief in AHF with SBP >90 mmHg (and without symptomatic
537,
hypotension). IIa B
550–555
Symptoms and blood pressure should be monitored frequently during administration of i.v. vasodilators.
In patients with hypertensive AHF, i.v. vasodilators should be considered as initial therapy to improve symptoms and reduce 537,
IIa B
congestion. 551–554
Inotropic agents – dobutamine, dopamine, levosimendan, phosphodiesterase III (PDE III) inhibitors
Short-term, i.v. infusion of inotropic agents may be considered in patients with hypotension (SBP <90 mmHg) and/or signs/
IIb C
peripheral perfusion and maintain end-organ function.
An intravenous infusion of levosimendan or a PDE III inhibitor may be considered to reverse the effect of beta-blockade
IIb C
if beta-blockade is thought to be contributing to hypotension with subsequent hypoperfusion.
Inotropic agents are not recommended unless the patient is symptomatically hypotensive or hypoperfused because of
III A 556, 557
safety concern.
Vasopressors
A vasopressor (norepinephrine preferably) may be considered in patients who have cardiogenic shock, despite treatment
IIb B 558
with another inotrope, to increase blood pressure and vital organ perfusion.
It is recommended to monitor ECG and blood pressure when using inotropic agents and vasopressors, as they can cause 540,
I C
arrhythmia, myocardial ischaemia, and in the case of levosimendan and PDE III inhibitors also hypotension. 559–563
In such cases intra-arterial blood pressure measurement may be considered. IIb C
Thrombo-embolism prophylaxis
Thrombo-embolism prophylaxis (e.g. with LMWH) is recommended in patients not already anticoagulated and with no
I B 564
contra-indication to anticoagulation, to reduce the risk of deep venous thrombosis and pulmonary embolism.
Other drugs
d
IIa C
b. amiodarone may be considered. IIb B 565–567
Opiates may be considered for cautious use to relieve dyspnoea and anxiety in patients with severe dyspnoea but nausea
IIb B 568, 569
and hypopnea may occur.
AHF ¼ acute heart failure; ECG ¼ electrocardiogram; HF ¼ heart failure; i.v. ¼ intravenous; LMWH ¼ low molecular weight heparin; SBP ¼ systolic blood pressure.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
d
Beta-blockers should be used cautiously, if the patient is hypotensive.
2180 ESC Guidelines
a
Not available in many European countries.
ESC Guidelines 2181
12.3.4 Management of patients with cardiogenic shock 12.4 Management of evidence-based oral
Cardiogenic shock is defined as hypotension (SBP ,90 mmHg) des- therapies
pite adequate filling status with signs of hypoperfusion (Table 12.2).
The pathogenetic scenarios of cardiogenic shock range from low- Recommendations regarding oral evidence-based
output advanced end-stage chronic HF to acute-onset de novo disease-modifying therapies in patients with acute heart
cardiogenic shock most often caused by STEMI, but also by various failure
aetiologies other than ACS. A patient in cardiogenic shock should
undergo immediate comprehensive assessment. ECG and echocar-
Recommendations Class a Level b
diography are required immediately in all patients with suspected
cardiogenic shock. In patients with cardiogenic shock complicating In case of worsening of chronic HFrEF, every
attempt should be made to continue evidence-
ACS, an immediate coronary angiography is recommended (within based, disease-modifying therapies, in the I C
I C
Intravenous inotropic agents (dobutamine) may be considered to increase cardiac output. IIb C
Vasopressors (norepinephrine preferable over dopamine) may be considered if there is a need to maintain SBP in the
IIb B 558
presence of persistent hypoperfusion.
IABP is not routinely recommended in cardiogenic shock. III B 585, 586
Short-term mechanical circulatory support may be considered in refractory cardiogenic shock depending on patient age,
IIb C
comorbidities and neurological function.
ACS ¼ acute coronary syndrome; CCU ¼ coronary care unit; ECG ¼ electrocardiogram; IABP ¼ intra-aortic balloon pump; ICU ¼ intensive care unit; SBP ¼ systolic blood
pressure.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
ESC Guidelines 2183
12.5 Monitoring of clinical status of † once provided with tailored education and advice about self-care.
patients hospitalized due to acute heart Patients should preferably be
failure † enrolled in a disease management programme; follow-up plans
must be in place prior to discharge and clearly communicated
Recommendations regarding monitoring of clinical to the primary care team;
status of patients hospitalized due to acute heart failure † reviewed by their general practitioner within 1 week of discharge;
† seen by the hospital cardiology team within 2 weeks of discharge
Recommendations Class a Level b if feasible.
Standard non-invasive monitoring of heart rate,
rhythm, respiratory rate, oxygen saturation and I C Patients with chronic HF should be followed up within a multipro-
blood pressure is recommended. fessional HF service. Pre- and post-discharge management should
13. Mechanical circulatory support for patients receiving ECMO for refractory cardiogenic shock
(online calculator at http://www.save-score.com).594
and heart transplantation In addition, MCS systems, particularly ECLS and ECMO, can be
used as a ‘bridge to decision’ (BTD) in patients with acute and rap-
13.1 Mechanical circulatory support idly deteriorating HF or cardiogenic shock to stabilize haemo-
For patients with either chronic or acute HF who cannot be stabi- dynamics, recover end-organ function and allow for a full clinical
lized with medical therapy, MCS systems can be used to unload the evaluation for the possibility of either heart transplant or a more
failing ventricle and maintain sufficient end-organ perfusion. Patients durable MCS device.595
in acute cardiogenic shock are initially treated with short-term as- Evidence regarding the benefits of temporary percutaneous MCS
sistance using extracorporeal, non-durable life support systems so in patients not responding to standard therapy, including inotropes,
that more definitive therapy may be planned. Patients with chronic, is limited. In a meta-analysis of three randomized clinical trials
refractory HF despite medical therapy can be treated with a per-
Table 13.2 INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) stages for classifying
patients with advanced heart failure
ECLS ¼ extracorporeal life support; ECMO ¼ extracorporeal membrane oxygenation; INTERMACS ¼ Interagency Registry for Mechanically Assisted Circulatory Support;
LVAD ¼ left ventricular assist device; NYHA ¼ New York Heart Association.
a
Kaplan-Meier estimates with standard error of the mean for 1 year survival with LVAD therapy. Patients were censored at time of last contact, recovery or heart transplantation.
Due to small numbers outcomes for INTERMACS levels 5, 6, 7 were combined610.
for longer-term outcomes. Among patients with continuous-flow INTERMACS class, although the majority of VAD implants are
LVADs, actuarial survival is 80% at 1 year and 70% at 2 years in pre- done at INTERMACS levels 1 – 3.604,610 Additionally, it needs to
dominantly non-transplant-eligible patients. Notably, survival of be remembered that no RCTs exist comparing medical therapy
85% at 2 years was recorded for patients up to 70 years of age with- vs. MCS devices in these transplant-eligible patients (Table 13.2).
out diabetes, renal impairment or cardiogenic shock.601,602 Patients Typically, patients with end-stage HF considered for MCS exhibit
receiving LVAD devices as BTT have a post-transplant survival rate many clinical hallmarks of declining cardiovascular function593 and
similar or better than those not requiring or receiving bridging.599 may already be on continuous inotropic support or manifest a de-
Despite technological improvements, bleeding, thromboembolism cline in end-organ function. Markers of liver and renal dysfunction,
(both of which can cause stroke), pump thrombosis, driveline infec- haematologic and coagulation abnormalities and lower serum albu-
tions and device failure remain significant problems and affect the min levels are associated with worse outcome.611,612
long-term outcome of patients on MCS. 599,603 – 606 It is recom- Evaluation of RV function is crucial since postoperative RV failure
mended that such devices should only be implanted and managed greatly increases perioperative mortality and reduces survival to,
at centres with appropriately trained specialist HF physicians and and after, transplantation. There are, however, multiple approaches
surgeons and an outpatient LVAD clinic with trained nursing staff.607 to assessment of the RV (see Section 5.2.3). If RV failure is expected
In some patients, LV reverse remodelling and functional improve- to be potentially reversible, temporary (days to weeks) extracor-
ment during MCS may permit removal of the LVAD [‘bridge to re- poreal right ventricular assist device (RVAD) support using a centri-
covery’ (BTR)]. This outcome is more likely in younger patients with fugal pump in addition to LVAD implantation may be considered.
an acute fulminant but reversible cause of HF, such as acute myocar- For patients with chronic biventricular failure or a high risk for per-
ditis or peripartum cardiomyopathy.608,609 LVADs may also be used sisting RV failure after LVAD implantation, implantation of a biven-
as a ‘bridge to candidacy’ (BTC) in order to permit recovery of tricular assist device (BiVAD) may be necessary. Patients requiring
end-organ dysfunction, improve RV function and relieve pulmonary long-term BiVAD support must be transplant-eligible, as BiVAD
hypertension, which may allow initially ineligible patients to become therapy is not suitable for destination therapy. The outcomes of Bi-
eligible for heart transplantation. VAD therapy are inferior to those for LVAD therapy and therefore
Earlier ventricular assist device (VAD) implantation in less severe- the indication for VAD therapy should be discussed before RV func-
ly ill patients, e.g. those not yet on inotropic support, was tested in a tion deteriorates. The implantation of a total artificial heart with re-
recent trial that revealed better outcomes than in those patients moval of the native heart should be restricted to selected patients
continuing on medical therapy.605 The INTERMACS registry like- who cannot be treated with an LVAD (unrepairable ventricular sep-
wise shows better outcomes in patients implanted with a higher tal defect, cardiac rupture).
2186 ESC Guidelines
Table 13.3 Patients potentially eligible for Table 13.4 Heart transplantation: indications and
implantation of a left ventricular assist device contra-indications
Patients with >2 months of severe symptoms despite optimal Patients to End-stage HF with severe symptoms, a poor prognosis,
medical and device therapy and more than one of the following: consider and no remaining alternative treatment options.
Motivated, well informed, and emotionally stable.
LVEF <25% and, if measured, peak VO2 <12 mL/kg/min.
Capable of complying with the intensive treatment
≥3 HF hospitalizations in previous 12 months without an obvious required postoperatively.
precipitating cause.
Contra- Active infection.
Dependence on i.v. inotropic therapy. indications Severe peripheral arterial or cerebrovascular disease.
Progressive end-organ dysfunction (worsening renal and/or hepatic Pharmacologically irreversible pulmonary hypertension
(LVAD should be considered with a subsequent re-
HF ¼ heart failure; HFrEF ¼ heart failure with reduced ejection fraction; ICD ¼
The use of mechanical circulatory support, particularly LVAD, implantable cardioverter-defibrillator; LVEF ¼ left ventricular ejection fraction,
should be considered for patients with potentially reversible or IN-TIME ¼ Implant-based multiparameter telemonitoring of patients with heart failure.
a
Class of recommendation.
treatable co-morbidities, such as cancer, obesity, renal failure, b
Level of evidence.
tobacco use and pharmacologically irreversible pulmonary c
Reference(s) supporting levels of evidence.
hypertension, with a subsequent re-evaluation to establish
candidacy.
14.1 Organization of care
The goal of management of HF is to provide a ‘seamless’ system of
14. Multidisciplinary team care that embraces both the community and hospital throughout
the health care journey. The standards of care that patients with HF
management should expect have been published by the ESC HFA.591 To achieve
Non-pharmacological non-device/surgical interventions used in the this goal, other services, such as cardiac rehabilitation and palliative
management of HF (both HFrEF and HFpEF) are summarized in care, must be integrated into the overall provision for patients with
Tables 14.1 and 14.2 and detailed practical recommendations on HF. Fundamental to the delivery of this complete package of care
their use have been published by the HFA of the ESC.591,592 There are multidisciplinary management programmes designed to improve
is no evidence that these on their own improve mortality, morbidity outcomes through structured follow-up with patient education, opti-
or quality of life. For this reason, these interventions have not been mization of medical treatment, psychosocial support and improved
given a recommendation with an evidence level. The exceptions are access to care (Table 14.1). Such strategies reduce HF hospitalization
implementation of care in a multidisciplinary framework, monitoring and mortality in patients discharged from the hospital.624,625
and exercise training (see recommendations table), all of which are Key to the success of these programmes is coordination of care
discussed below. along the continuum of HF and throughout the chain of care
2188 ESC Guidelines
Table 14.2 Key topics and self-care skills to include in patient education and the professional behaviours to optimize
learning and facilitate shared decision making
continued
ESC Guidelines 2189
Table 14.2 Key topics and self-care skills to include in patient education and the professional behaviours to optimize
learning and facilitate shared decision making (continued)
delivered by the various services within the health care system. This exercise tolerance, health-related quality of life and HF hospitaliza-
necessitates close collaboration between HF practitioners (primar- tion rates in patients with HF. A single large RCT618 showed a modest
ily cardiologists, HF nurses and general practitioners) and other ex- and non-significant reduction in the primary composite outcome of
perts, including pharmacists, dieticians, physiotherapists, all-cause mortality or all-cause hospitalization. There was no reduc-
psychologists, palliative care providers and social workers. The con- tion in mortality and no safety concerns were raised.618,633 The
tent and structure of HF management programmes may vary in dif- most recent Cochrane review of exercise training619 included 33
ferent countries and health care settings. The components shown in trials with 4740 patients with HF (predominantly HFrEF). There
Table 14.1 are recommended. HF services should be easily access- was a trend towards a reduction in mortality with exercise in trials
ible to the patient and his/her family and care providers. A telephone with .1 year of follow-up. Compared with the control group, exer-
helpline may facilitate access to professional advice. cise training reduced the rate of overall and HF-specific hospitaliza-
The website http://ww.heartfailurematters.org is an option for tion and improved quality of life. Practical recommendations on
professional information for those patients and families with Inter- exercise training have been published by the HFA.120
net access. There is evidence that in patients with HFpEF, exercise training has
several benefits, including improvements in exercise capacity, as mea-
14.2 Discharge planning sured objectively using peak oxygen consumption, quality of life and
Early readmission after hospital discharge is common and may be ad- diastolic function, assessed by echocardiography.321,620,621,634
dressed through coordinated discharge planning. The standards of Patients with HF, regardless of LVEF, are recommended to perform
care that patients should expect have been published by the HFA properly designed exercise training (see the recommendations table).
and the Acute Cardiac Care Association.540,631 Discharge planning
should commence as soon as the patient’s condition is stable. During 14.5 Follow-up and monitoring
hospital admission, providing patients with information and education Patients with HF benefit from regular follow-up and monitoring of
for self-care improves outcome. Discharge should be arranged for biomedical parameters to ensure the safety and optimal dosing of
when the patient is euvolaemic and any precipitants of the admission medicines and detect the development of complications or disease
have been treated. Hospitals with early physician follow-up after dis- progression that may require a change in management (e.g. the onset
charge show reduced 30-day readmission, and those that initiated of AF or development of anaemia). Monitoring may be undertaken by
programmes to discharge patients with an outpatient follow-up ap- the patients themselves during home visits, in community or hospital
pointment already scheduled experienced a greater reduction in clinics, by remote monitoring with or without implanted devices or
readmissions than those not taking up this strategy.632 by structured telephone support (STS). The optimal method of mon-
itoring will depend on local organizations and resources and will vary
14.3 Lifestyle advice among patients. For example, more frequent monitoring will be re-
There is little evidence that specific lifestyle advice improves quality quired during periods of instability or optimization of medication.
of life or prognosis; however, providing this information has become Older adults may also benefit from more frequent monitoring.
a key component of education for self-care. Patients should be pro- Some patients will be keen and able to participate in self-monitoring.
vided with sufficient up-to-date information to make decisions on High circulating NPs predict unfavourable outcomes in patients
lifestyle adjustment and self-care. Ideally for those patients admitted with HF, and a decrease in NP levels during recovery from circula-
to the hospital, lifestyle advice should begin prior to discharge. Infor- tory decompensation is associated with a better prognosis.588 – 590
mation should be individually tailored to need and take into account Although it is plausible to monitor clinical status and tailor treatment
relevant co-morbidities that may influence retention of information based on changes in circulating NPs in patients with HF, published
(such as cognitive impairment and depression). Practical recommen- studies have provided differing results.635 – 638 This does not enable
dations have been published by the HFA.591 Key topics to include us to recommend a broad application of such an approach.
are recommended in Table 14.2. Telemedicine in HF, which is also termed remote patient manage-
ment, has variable clinical trial results.639 Several meta-analyses sug-
14.4 Exercise training gest clinical benefits, but numerous prospectively initiated clinical
Several systematic reviews and meta-analyses of small studies have trials including .3700 patients have not confirmed this. These clin-
shown that physical conditioning by exercise training improves ical trials include Tele-HF,640 TIM-HF,641 INH,642 WISH643 and
2190 ESC Guidelines
14.7 Palliative and end-of-life care Advanced care planning, taking account of preferences for place of
death and resuscitation (which may include deactivating devices, such as
Palliative care approaches include a focus on symptom management,
emotional support and communication between the patient and his/
her family. Ideally this should be introduced early in the disease trajec-
tory and increased as the disease progresses. A decision to alter the
focus of care from modifying disease progression to optimising quality approach, is required in order to address and optimally coordinate
of life should be made in discussion with the patient, cardiologist, the patient’s care. Recent pilot studies have suggested an improve-
nurse and general practitioner. The patient’s family should be involved ment in symptom burden and quality of life,653,655 but these data are
in such discussions if requested by the patient652,653 (Table 14.4). too limited to provide a recommendation.
Key components of a palliative care service are recommended in Specific therapies and actions may provide palliation of symptoms
Table 14.5. Palliative care has been discussed in detail in a position and improve quality of life but have a limited evidence base:
paper from the ESC HFA.654
Liaison between the specialist palliative care services and the HF † Morphine (with an antiemetic when high doses are needed) can
team and/or the primary care physician, using a shared care be used to reduce breathlessness, pain and anxiety.656
ESC Guidelines 2191
† Increasing the inspired oxygen concentration may provide relief † Targeted therapies for specific aetiologies of HFrEF (e.g. myo-
of dyspnoea. carditis, peripartum cardiomyopathy)
† Diuretic management can be used to relieve severe congestion † Therapies directly improving cardiomyocyte function (e.g.
or optimize symptom control (congestion and thirst). acto-myosin cross-bridge activation, sarco/endoplasmic re-
† Reduce HF drugs that reduce blood pressure to maintain suffi- ticulum Ca2+-ATPase activation, ryanodine receptor stabiliza-
cient oxygenation and reduce the risk of falls. tion, energetic modulation) or targeting non-myocytic
compartment (e.g. anti-fibrosis/matrix remodelling)
Ideally these therapies should be delivered in the patient’s home. In the
† Therapies for HFmrEF/HFpEF (ARNIs, beta-blockers, soluble
majority of cases the whole family should receive social support.652
guanyl cyclase inhibitors, i.v. iron)
A management plan should be developed through discussion with
the patient and family. It should include 4. Devices and interventions
† A discussion about stopping medication that does not have an im-
† Evaluate the comparative clinical effectiveness and cost- † Treatment algorithms for patients with HF excluded by pivotal
effectiveness of different strategies to screen for HF. clinical trials
† Palliative and end-of-life care management and assessment of
3. Pharmacological therapy
outcome
† Identification of non-responders to current guideline-advised † Optimal integration of multidisciplinary care, self-management
medical treatment of patients and their adherence.
2192 ESC Guidelines
Recommendations for cardiac imaging in patients with suspected or established heart failure Class a Level b
TTE is recommended for the assessment of myocardial structure and function in subjects with suspected HF in order to establish a
I C
diagnosis of either HFrEF, HFmrEF or HFpEF.
TTE is recommended for the assessment of LVEF in order to identify patients with HF who would be suitable for evidence-based
I C
pharmacological and device (ICD, CRT) treatment recommended for HFrEF.
Recommendations aiming to prevent or delay the development of overt heart failure or prevent death Class a Level b
before the onset of symptoms
CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS duration ≥150 msec and LBBB QRS morphology and
I A
with LVEF ≤35% despite OMT in order to improve symptoms and reduce morbidity and mortality.
CRT is recommended for symptomatic patients with HF in sinus rhythm with a QRS duration of 130–149 msec and LBBB QRS
I B
morphology and with LVEF ≤35% despite OMT in order to improve symptoms and reduce morbidity and mortality.
CRT rather than RV pacing is recommended for patients with HFrEF regardless of NYHA Class who have an indication for ventricular
I A
continued
ESC Guidelines 2193
Adaptive servo-ventilation is not recommended in patients with HFrEF and a predominant central sleep apnoea because of an
III B
increased all-cause and cardiovascular mortality.
Thiazolidinediones (glitazones) are not recommended in patients with HF, as they increase the risk of HF worsening and HF hospitalization. III A
NSAIDs or COX-2 inhibitors are not recommended in patients with HF, as they increase the risk of HF worsening and HF hospitalization. III B
Recommendations regarding diagnostic measurements in patients with suspected acute heart failure Class a Level b
Upon presentation a measurement of plasma natriuretic peptide level (BNP, NT-proBNP or MR-proANP) is recommended in all
I A
Recommendations for the management of patients with acute heart failure – pharmacotherapy Class a Level b
I C
symptoms. It is recommended to regularly monitor symptoms, urine output, renal function and electrolytes during use of i.v. diuretics.
In patients with new-onset AHF or those with chronic, decompensated HF not receiving oral diuretics the initial recommended dose
should be 20–40 mg i.v. furosemide (or equivalent); for those on chronic diuretic therapy, initial i.v. dose should be at least equivalent to I B
oral dose.
It is recommended to give diuretics either as intermittent boluses or a continuous infusion, and the dose and duration should be
I B
adjusted according to the patients’ symptoms and clinical status.
Inotropic agents are not recommended unless the patient is symptomatically hypotensive or hypoperfused because of safety concern. III A
a
Recommendations regarding management of patients with cardiogenic shock Class Level b
In all patients with suspected cardiogenic shock, immediate ECG and echocardiography are recommended. I C
All patients with cardiogenic shock should be rapidly transferred to a tertiary care centre which has a 24/7 service of cardiac
I C
catheterization, and a dedicated ICU/CCU with availability of short-term mechanical circulatory support.
Recommendations regarding oral evidence-based disease-modifying therapies in patients with acute heart failure Class a Level b
In case of worsening of chronic HFrEF, every attempt should be made to continue evidence-based, disease-modifying therapies, in the
I C
absence of haemodynamic instability or contra-indications.
Recommendations for exercise, multidisciplinary management, and monitoring of patients with heart failure Class a Level b
It is recommended that regular aerobic exercise is encouraged in patients with HF to improve functional capacity and symptoms. I A
It is recommended that regular aerobic exercise is encouraged in stable patients with HFrEF to reduce the risk of HF hospitalization. I A
It is recommended that patients with HF are enrolled in a multidisciplinary care management programme to reduce the risk of HF
I A
hospitalization and mortality.
ACE-I ¼ angiotensin-converting enzyme inhibitor; AHF ¼ acute heart failure;; ARB ¼ angiotensin receptor blocker; AST ¼ aspartate aminotransferase; AV ¼ atrio-ventricular;
BNP ¼ B-type natriuretic peptide; CCU ¼ coronary care unit; COX-2 ¼ cyclooxygenase 2; CRT ¼ cardiac resynchronization therapy; CT ¼ computed tomography; DCM ¼
dilated cardiomyopathy; ECG ¼ electrocardiogram; HF ¼ heart failure; HFmrEF ¼ heart failure with mid-range ejection fraction; HFpEF ¼ heart failure with preserved ejection
fraction; HFrEF ¼ heart failure with reduced ejection fraction; ICD ¼ implantable cardioverter-defibrillator; ICU ¼ intensive care unit; i.v. ¼ intravenous; LBBB ¼ left bundle
branch block; LV ¼ left ventricular; LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction; MRA ¼ mineralocorticoid receptor antagonist; MR-proANP ¼ mid-
regional pro A-type natriuretic peptide; NSAIDs ¼ non-steroidal anti-inflammatory drugs; NT-proBNP ¼ N-terminal pro-B type natriuretic peptide; NYHA ¼ New York Heart
Association; OMT ¼ optimal medical therapy; QRS ¼ Q, R, and S waves (combination of three of the graphical deflections); RV ¼ right ventricular; TTE ¼ transthoracic
echocardiography.
a
Class of recommendation.
b
Level of evidence
c
Or ARB if ACEI is not tolerated/contra-indicated.
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Ahmed A, Bonow RO, Cleland JGF, Cody RJ, Chioncel O, Collins SP, ESCC for P, Reviewers D. ESC Guidelines for the diagnosis and treatment of acute
Dunnmon P, Filippatos G, Lefkowitz MP, Marti CN, McMurray JJ, Misselwitz F, and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of
European Heart Journal (2018) 39, 213–254 ESC GUIDELINES
doi:10.1093/eurheartj/ehx419
Document Reviewers: Lina Badimon (CPG Review Coordinator) (Spain), Pascal Vranckx (CPG Review
Coordinator) (Belgium), Stefan Agewall (Norway), Felicita Andreotti (Italy), Elliott Antman (USA),
Emanuele Barbato (Italy), Jean-Pierre Bassand (France), Raffaele Bugiardini (Italy), Mustafa Cikirikcioglu1
(Switzerland), Thomas Cuisset (France), Michele De Bonis (Italy), Victora Delgado (The Netherlands),
Donna Fitzsimons (UK), Oliver Gaemperli (Switzerland), Nazzareno Galiè (Italy), Martine Gilard (France),
* Corresponding author: Marco Valgimigli, Cardiology, Inselspital, Freiburgstrasse 8, 3010 Bern, Switzerland. Tel: þ41 31 632 3077, Fax: þ41 10 7035258, E-mail: marco.valgimigli@insel.ch.
ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers: listed in the Appendix.
1
Representing the EACTS
ESC entities having participated in the development of this document:
Associations: Acute Cardiovascular Care Association (ACCA), European Association of Preventive Cardiology (EAPC), European Association of Percutaneous Cardiovascular
Interventions (EAPCI).
Working Groups: Cardiovascular Pharmacotherapy, Cardiovascular Surgery, Coronary Pathophysiology and Microcirculation, Peripheral Circulation, Pulmonary Circulation and
Right Ventricular Function, Thrombosis, Valvular Heart Disease.
The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC
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Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available
at the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recom-
mendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encour-
aged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or
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The article has been co-published with permission in the European Heart Journal [DOI: 10.1093/eurheartj/ehx419] on behalf of the European Society of Cardiology and
European Journal of Cardio-Thoracic Surgery [DOI 10.1093/ejcts/ezx334] on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved in respect
of European Heart Journal, V C European Society of Cardiology 2017. The articles are identical except for minor stylistic and spelling differences in keeping with each journal’s
Christian W. Hamm (Germany), Borja Ibanez (Spain), Bernard Iung (France), Stefan James (Sweden),
Juhani Knuuti (Finland), Ulf Landmesser (Germany), Christophe Leclercq (France), Maddalena Lettino
(Italy), Gregory Lip (UK), Massimo Francesco Piepoli (Italy), Luc Pierard (Belgium),
Markus Schwerzmann (Switzerland), Udo Sechtem (Germany), Iain A. Simpson (UK), Miguel Sousa Uva1
(Portugal), Eugenio Stabile (Italy), Robert F. Storey (UK), Michal Tendera (Poland), Frans Van de Werf
(Belgium), Freek Verheugt (The Netherlands), and Victor Aboyans (CPG Supervisor) (France)
The disclosure forms of all experts involved in the development of this focused update are available on
the ESC website http://www.escardio.org/guidelines.
The Addenda and Clinical Cases companion document of this focused update are available at: www.escardio.
org/Guidelines/Clinical-Practice-Guidelines/2017-focused-update-on-dual-antiplatelet-therapy-dapt
...................................................................................................................................................................................................
Keywords Guidelines • Aspirin • Clopidogrel • Ticagrelor • Prasugrel • Dual antiplatelet therapy • Acute coronary
syndromes • Coronary artery bypass grafting • Coronary artery disease • Drug-eluting stents • Myocardial
infarction • Stent thrombosis • Bleeding • Percutaneous coronary intervention • Recommendation
• Revascularization • Risk stratification • Stents • Stable angina • Stable coronary artery disease • Oral
anticoagulant • Triple therapy • DAPT score • PRECISE-DAPT score • Non-cardiac surgery
..
Table of Contents .. 5. Dual antiplatelet therapy and cardiac surgery . . . . . . . . . . . . . . . . . . . . . .234
.. 5.1 Dual antiplatelet therapy in patients treated with coronary
..
Abbreviations and acronyms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .215 .. artery bypass surgery for stable coronary artery disease . . . . . . . . . . .234
1. Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .216
.. 5.2 Dual antiplatelet therapy in patients treated with coronary
..
2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .218 .. artery bypass surgery for acute coronary syndrome . . . . . . . . . . . . . . .234
2.1 Short- and long-term outcomes after percutaneous coronary
.. 5.3 Dual antiplatelet therapy for prevention of graft occlusion. . . . . .237
..
intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .219 .. 5.4 Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .237
2.2 Risk of stent thrombosis in relation to stent type. . . . . . . . . . . . . . .219
.. 6. Dual antiplatelet therapy for patients with medically managed
..
2.3 Short- and long-term outcomes after coronary artery bypass .. acute coronary syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .237
surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .219
.. 7. Dual antiplatelet therapy for patients with indication for oral
..
2.4 Short- and long-term outcomes after medically managed acute .. anticoagulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .238
..
coronary syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .219 .. 7.1 Risk stratification and strategies to improve outcome after
3. Efficacy and safety of dual antiplatelet therapy and risk .. percutaneous coronary intervention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .238
..
stratification tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .219 .. 7.2 Duration of triple therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .239
3.1 Dual antiplatelet therapy for the prevention of stent .. 7.3 Cessation of all antiplatelet agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . .242
..
thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .219 .. 7.4 Type of anticoagulants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .242
3.2 Dual antiplatelet therapy for the prevention of spontaneous .. 7.5 Type of stent. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .242
..
myocardial infarction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .219 .. 8. Elective non-cardiac surgery in patients on dual antiplatelet
3.3 Dual antiplatelet therapy and mortality rate. . . . . . . . . . . . . . . . . . . .219 .. therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .242
..
3.4 Safety of dual antiplatelet therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . .219 .. 9. Gender consideration and special populations. . . . . . . . . . . . . . . . . . . . .245
3.5 Risk stratification tools for ischaemia and bleeding risks . . . . . . . .219 .. 9.1 Gender specificities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .245
..
3.6 Type of P2Y12 inhibitor and timing of initiation . . . . . . . . . . . . . . . . .221 .. 9.2 Diabetes mellitus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .245
3.7 Measures to minimize bleeding while on dual .. 9.3 Lower-extremities artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . .245
..
antiplatelet therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .223 .. 9.4 Complex percutaneous coronary intervention . . . . . . . . . . . . . . . .248
3.8 Switching between oral P2Y12 inhibitors. . . . . . . . . . . . . . . . . . . . . . .225
.. 9.5 Dual antiplatelet therapy decision making in patients with
..
4. Dual antiplatelet therapy and percutaneous coronary .. stent thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .248
intervention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .226
.. 9.6 Patients who develop bleeding while on treatment. . . . . . . . . . . . .248
..
4.1 Dual antiplatelet therapy after percutaneous coronary .. 10. Key messages. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .249
intervention for stable coronary artery disease . . . . . . . . . . . . . . . . . . . .226
.. 11. Evidenced-based ‘to do and not to do’ messages . . . . . . . . . . . . . . . . .249
..
4.2 Dual antiplatelet therapy after percutaneous coronary .. 12. Web addenda and Clinical Cases companion document . . . . . . . . . .251
intervention for acute coronary syndrome . . . . . . . . . . . . . . . . . . . . . . . .231
.. 13. Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .251
..
4.3 Gaps in the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .233 .. 14. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .252
ESC Guidelines 215
..
MATRIX Minimizing Adverse Haemorrhagic Events .. SECURITY Second Generation Drug-Eluting Stent
by TRansradial Access Site and Systemic .. Implantation Followed by Six- Versus
..
Implementation of angioX .. Twelve-Month Dual Antiplatelet Therapy
MI Myocardial infarction .. STEMI ST-segment elevation myocardial
..
NACE Net adverse clinical events .. infarction
NCDR National Cardiovascular Data Registry .. STREAM STrategic Reperfusion Early After
..
NNT Number needed to treat .. Myocardial Infarction
NOAC Non-vitamin K oral anticoagulant .. SYNTAX Synergy Between Percutaneous Coronary
..
NORSTENT NORwegian coronary STENT trial .. Intervention With Taxus and Cardiac
NSTE-ACS Non-ST elevation acute coronary syndrome .. Surgery
..
NSTEMI Non-ST-segment elevation myocardial .. TIA Transient ischaemic attack
infarction .. TIMI Thrombolysis In Myocardial Infarction
..
to endorse, translate and implement all ESC Guidelines. .. 2. Introduction
Implementation programmes are needed because it has been shown
..
..
that the outcome of disease may be favourably influenced by the .. The estimated number of patients requiring dual antiplatelet therapy
thorough application of clinical recommendations.
.. (DAPT), consisting of the combination of aspirin and an oral inhibitor
..
Surveys and registries are needed to verify that real-life daily prac- .. of the platelet P2Y12 receptor for adenosine 5’-diphosphate (ADP), is
.. considerable and has increased over time in Europe. Based on popu-
tice is in keeping with what is recommended in the guidelines, thus ..
completing the loop between clinical research, writing of guidelines .. lation estimates from 2015, in the region of 1 400 000 and 2 200 000
.. patients per year may have an indication for DAPT after coronary
and official focused updates, disseminating them and implementing ..
them into clinical practice. .. intervention or myocardial infarction (MI), respectively.1
.. This year, 2017, is the 21st anniversary of the publication of the
Health professionals are encouraged to take the ESC CPG ..
Guidelines and Focused Updates developed in collaboration with .. first randomized clinical trial to establish the superiority of DAPT
..
EACTS fully into account when exercising their clinical judgment, as .. over anticoagulant therapy among patients undergoing percutaneous
Figure 1 History of dual antiplatelet therapy (DAPT) in patients with coronary artery disease. The size of the circles denotes sample size. The col-
ours of perimeters identify the type of included patient populations within each study. The colours within each circle identify the antiplatelet agent(s)
investigated. Head-to-head studies comparing similar durations of two different antiplatelet strategies are shown with a vertical line, whereas those
investigating different treatment durations are shown with a horizontal line. Studies investigating different treatment strategies or regimens and not
treatment durations or type (e.g. pre-treatment in ACCOAST, tailored therapy in GRAVITAS, double dose of clopidogrel in CURRENT OASIS 7,
etc.) are represented with a single colour indicating the P2Y12 inhibitor, which was tested on top of aspirin.
pts = patients.
ESC Guidelines 219
..
late stent thrombosis occurring after first-generation drug-eluting .. Nonetheless, because continued antiplatelet therapy is also associ-
stent (DES) implantation.3 Yet, the advent of safer newer-generation .. ated with increased bleeding risk, it is necessary to weigh this risk
..
DESs and the results of the most recent randomized controlled trials .. against the potential benefit. Current evidence suggests that the risk
(RCTs) have established a major paradigm shift in the way DAPT .. of bleeding in patients on DAPT is proportionally related to its dura-
..
should be conceived and used in clinical practice. DAPT remains a .. tion both within and beyond 1 year of treatment duration. Since the
highly effective preventive treatment for stent thrombosis across the .. benefits of prolonged DAPT, especially for mortality endpoints,
..
board; however, the risks of late and (even more) very late stent .. appear highly dependent on prior cardiovascular history [such as
thrombosis have declined considerably since the advent of newer- .. prior acute coronary syndrome (ACS)/MI vs. stable CAD], and pre-
..
generation DESs. Hence, the risk of bleeding associated with DAPT .. diction models to estimate on-DAPT bleeding risk have been devel-
prolongation beyond 1 year does not seem to be justified by the small .. oped, an individualized approach based on ischaemic vs. bleeding risk
..
absolute benefit observed in terms of very late stent thrombosis pre- .. assessment is warranted.
vention. On the other hand, there is emerging evidence that DAPT ..
..
Table 3 Risk scores validated for dual antiplatelet therapy duration decision-making
low-risk score (<2) selected patients recruited in the DAPT trial who
.. scores for DAPT type or duration guidance. A high ischaemic risk sta-
..
did not derive any reduction of ischaemic events from prolonging .. tus was observed in roughly 40% of high bleeding risk patients16 and
DAPT, with a significant increase in moderate/major bleeding (NNT
.. as many as 65.3% presented low ischaemic and bleeding risks.16
..
for harm = 64). As DAPT duration was not randomized in the .. Therefore, it remains unclear how DAPT duration should be guided
PROTECT trial, the value of the DAPT score in guiding the duration
.. by the simultaneous assessment of ischaemic and bleeding risk fea-
..
of therapy has so far only been shown for patients recruited to the .. tures according to PARIS.
DAPT trial. Additional validation of the DAPT score to guide DAPT
.. The PRECISE-DAPT (PREdicting bleeding Complications In
..
duration is needed, especially in the context of less well-selected .. patients undergoing Stent implantation and subsEquent Dual Anti
..
patients as compared to those recruited in the DAPT trial and under- .. Platelet Therapy) collaborative study included a total of 14 963
going treatment with new-generation DES only. .. patients with CAD who underwent elective, urgent, or emergent PCI
..
Two independent predictive scores for bleeding [age, body mass .. and generated a five-item (age, CrCl, haemoglobin, white blood cell
index, smoking, anaemia, creatinine clearance (CrCl), and triple ther- .. count, and prior spontaneous bleeding) prediction algorithm for out-
..
of-hospital bleeding in patients treated with DAPT.18
apy at discharge] and MI or stent thrombosis [diabetes mellitus, ACS,
...
smoking, CrCl, prior PCI, and prior coronary artery bypass graft sur- .. The predictive performance of this novel score was assessed in the
gery (CABG)] have also been developed from the Patterns of .. derivation cohort and validated in 8595 and 6172 patients treated with
..
Nonadherence to Antiplatelet Regimens in Stented Patients (PARIS) .. PCI from the PLATelet inhibition and patient Outcomes (PLATO) trial
registry.16 PARIS was a prospective, multicentre, observational study .. and the Bern PCI registry,19,20 respectively. The PRECISE-DAPT score
..
of patients undergoing PCI with stent implantation in the USA and .. showed improved integrated discrimination and reclassification per-
Europe, which was designed to examine the different modes of .. formance as compared to the PARIS bleeding score in both validation
..
DAPT cessation and to investigate the influence of these modes on .. cohorts.18 The usefulness of this score was also assessed within
subsequent clinical adverse events.17 This registry study included .. patients randomized to different DAPT durations (n = 10 081) to iden-
..
patients with an indication for oral anticoagulation. The value of the .. tify the effect on bleeding and ischaemia of a long (12–24 months) or
PARIS bleeding and/or ischaemic risk scores to tailor DAPT duration
.. short (3–6 months) treatment duration in relation to baseline bleeding
..
remains unclear, since therapy duration was not randomized in the .. risk. It was observed that among patients deemed at high bleeding risk
PARIS study and no study to date has applied the results of these
.. based on PRECISE-DAPT (PRECISE-DAPT score >_25), prolonged
ESC Guidelines 221
..
DAPT was associated with no ischaemic benefit but a remarkable .. to 7.1%; relative risk reduction (RRR) 23.9%, 95% CI 12.7–33.7; P <
bleeding burden leading to an NNT for harm of 38.18 On the other .. 0.001).23 There was no difference in the rates of either non-fatal
..
hand, longer treatment in patients without high bleeding risk .. stroke or cardiovascular death.
(PRECISE-DAPT score <25) was associated with no increase in bleed- .. Prasugrel was associated with a significant increase in the rate of
..
ing and a significant reduction in the composite ischaemic endpoint of .. non-CABG-related TIMI major bleeding (2.4% vs. 1.8%; HR 1.32, 95%
MI, definite stent thrombosis, stroke, and target vessel revasculariza- .. CI 1.03–1.68; P = 0.03). Life-threatening bleeding was significantly
..
tion, with an NNT for benefit of 65.18 Selecting a shorter than 12- .. increased under prasugrel compared with clopidogrel (1.4% vs. 0.9%;
month treatment duration in patients deemed at high bleeding risk .. HR 1.52, 95% CI 1.08–2.13; P = 0.01), as was fatal bleeding (0.4% vs.
..
upfront may therefore prevent their exposure to an excessive bleeding .. 0.1%, HR 4.19, 95% CI 1.58–11.11; P = 0.002). CABG-related bleed-
hazard. In turn, patients at non-high bleeding risk might receive a stand- .. ing was also higher in prasugrel-treated patients (13.4% vs. 3.2%; HR
..
ard (i.e. 12 months) or prolonged (i.e. >12 months) course of treat- .. 4.72, 95% CI 1.90–11.82; P < 0.001). There was evidence of net harm
ment if tolerated. .. with prasugrel in patients with a history of cerebrovascular events. In
..
..
intervention were randomly allocated to stop or continue the treat- .. There was no difference in the overall rates of fatal haemorrhage
ment for an additional 18 months.26 The type of P2Y12 inhibitor or stent .. between the groups (0.3% in both groups). The superiority of ticagre-
..
type were not randomized for. However, the largest cohort of prasu- .. lor over clopidogrel with respect to the primary study endpoint as
grel-treated patients (n = 2191) was provided by the TAXUS Liberté .. well as cardiovascular death or overall mortality was consistent across
..
Post Approval Study (TL-PAS), which was a prospective, multicentre, .. management strategies, i.e. patients undergoing PCI, those medically
open-label study developed to review the clinical performance of the .. managed, and patients who underwent CABG.20
..
Taxus Liberté paclitaxel-eluting stent in routine clinical practice in the .. No dedicated study exists assessing the value of early (i.e. before
USA.27 Enrolled TL-PAS patients received open-label prasugrel plus .. coronary angiography) vs. delayed (i.e. after coronary angiography)
..
aspirin for 12 months after stent placement; enrolment was not .. ticagrelor administration in patients with NSTE-ACS. The
restricted to patients presenting with ACS (i.e. those with an approved .. Administration of Ticagrelor in the Cath Lab or in the Ambulance for
..
indication for prasugrel). Rates of death and stroke were similar .. New ST Elevation Myocardial Infarction to Open the Coronary Artery
between groups, but MI was significantly reduced with prolonged prasu- .. (ATLANTIC) study involved 1862 patients with STEMI <6-h duration
..
In patients with ACS, ticagrelor (180 mg loading dose, 90 mg twice daily) on top of aspirinc is recommended, regardless
of initial treatment strategy, including patients pre-treated with clopidogrel (which should be discontinued when ticagre- I B
lor is commenced) unless there are contraindications.20
In patients with ACS undergoing PCI, prasugrel (60 mg loading dose, 10 mg daily dose) on top of aspirin is recom-
mended for P2Y12 inhibitor-naı̈ve patients with NSTE-ACS or initially conservatively managed STEMI if indication for
I B
PCI is established, or in STEMI patients undergoing immediate coronary catheterizationc unless there is a high risk of
life-threatening bleeding or other contraindications.23
Pre-treatment with a P2Y12 inhibitor is generally recommended in patients in whom coronary anatomy is known and
I A
the decision to proceed to PCI is made as well as in patients with STEMI.20,23,38
In patients with NSTE-ACS undergoing invasive management, ticagrelor administration (180 mg loading dose, 90 mg
twice daily), or clopidogrel (600 mg loading dose, 75 mg daily dose) if ticagrelor is not an option, should be considered IIa C
as soon as the diagnosis is established.
In patients with stable CAD, pre-treatment with clopidogrel may be considered if the probability of PCI is high. IIb C
Clopidogrel (600 mg loading dose, 75 mg daily dose) on top of aspirin is recommended in stable CAD patients under-
going coronary stent implantation and in ACS patients who cannot receive ticagrelor or prasugrel, including those with I A
prior intracranial bleeding or indication for OAC.20,23,39,40
Clopidogrel (300 mg loading dose in patients aged <_75, 75 mg daily dose) is recommended on top of aspirin in STEMI
I A
patients receiving thrombolysis.31,32
Ticagrelor or prasugrel on top of aspirin may be considered instead of clopidogrel in stable CAD patients undergoing
PCI, taking into account the ischaemic (e.g. high SYNTAX score, prior stent thrombosis, location and number of IIb C
implanted stents) and bleeding (e.g. according to PRECISE-DAPT score) risks.
In NSTE-ACS patients in whom coronary anatomy is not known, it is not recommended to administer prasugrel.25 III B
ACS = acute coronary syndrome; CAD = coronary artery disease; DAPT = dual antiplatelet therapy; NSTE-ACS = non-ST-elevation acute coronary syndrome; OAC = oral
anticoagulant; PCI = percutaneous coronary intervention; PRECISE-DAPT = PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual
Anti Platelet Therapy; STEMI = ST-elevation myocardial infarction; SYNTAX = Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery.
a
Class of recommendation.
b
Level of evidence.
c
Contraindications for ticagrelor: previous intracranial haemorrhage or ongoing bleeds. Contraindications for prasugrel: previous intracranial haemorrhage, previous ischaemic
stroke or transient ischaemic attack, or ongoing bleeds; prasugrel is not recommended for patients >_75 years of age or with a body weight <60 kg.
224 ESC Guidelines
..
outcome of 30-day net adverse clinical events (NACE) [MACE or .. variability in on-clopidogrel platelet reactivity can be explained by the
non-CABG BARC (Bleeding Academic Research Consortium) major .. differences in genotype.68,69
..
bleeding] was experienced in 9.8% and 11.7% of patients, respectively .. For these reasons, neither platelet function testing nor genetic testing
(RR 0.83, 95% CI 0.73–0.96; P = 0.009). Radial access was associated .. can be recommended for tailoring DAPT. It may be considered in spe-
..
with a lower risk of all-cause mortality (1.6% vs. 2.2%; RR 0.72, 95% CI .. cific situations (e.g. patients suffering from recurrent adverse events) if
0.53–0.99; P = 0.045). Major BARC 3 or 5 bleeding was significantly .. the results may change the treatment strategy. This is the case for
..
reduced in the radial group (1.6% vs. 2.3%; RR 0.67, 95% CI 0.49–0.92; .. patients undergoing CABG who are exposed to DAPT (see Chapter 5).
P = 0.013). Radial access was associated with significantly lower rates .. Proton pump inhibitors and DAPT: Gastrointestinal haemorrhage is
..
of surgical access site repair or transfusion of blood products. An .. the most common serious bleeding complication from the use of
updated meta-analysis including MATRIX found a significant reduction .. long-term antiplatelet therapy.70 RCTs have shown that PPIs reduce
..
in major bleeds; death, MI, or stroke; and in all-cause mortality associ- .. the rate of recurrent gastrointestinal bleeding in high-risk patients
ated with radial as compared to femoral access.44 .. receiving aspirin.71 Similar data exist regarding the use of famotidine,
..
occurred in 1.1% of patients with omeprazole and 2.9% with placebo .. 3.8 Switching between oral P2Y
.. 12
at 180 days after randomization (HR 0.34, 95% CI 0.18–0.63; P < .. inhibitors
0.001).79 ..
.. Differences in the pharmacology of P2Y12 receptor inhibitors with
Furthermore, there was no significant increase in the risk of cardio- .. regard to their binding site, half-life, and speed of onset and offset of
vascular events with concomitant use of clopidogrel and omeprazole ..
.. action are important factors that might lead to drug interactions
(4.9%, 95% CI 3.4–6.4%, in the omeprazole group; and 5.7%, 95% CI .. when switching from one agent to another.
4.0–7.3%, in the placebo group; P = 0.98), a finding that was consistent ..
.. The transition from clopidogrel to ticagrelor is the only switch
even in high-risk subgroups and for individual endpoints. The rate of .. between P2Y inhibitors that has been investigated in a trial pow-
serious adverse events did not differ significantly between the two .. 12
.. ered for clinical endpoint, even if the study was not specifically
groups (10.1% with omeprazole and 9.4% with placebo, P = 0.48), nor ..
did the rate of overall adverse events (41.3 and 42.8%, respectively; P =
.. designed to assess the safety and efficacy of the transition from clo-
.. pidogrel to ticagrelor. In PLATO, nearly 50% of patients randomly
0.33). Diarrhoea was reported in 3.0% of patients receiving omepra- ..
Radial over femoral access is recommended for coronary angiography and PCI if performed by an expert radial operator.43,44 I A
Routine platelet function testing to adjust antiplatelet therapy before or after elective stenting is not recommended.58–60 III A
DAPT = dual antiplatelet therapy; PCI = percutaneous coronary intervention; PPI proton pump inhibitor.
a
Class of recommendation.
b
Level of evidence.
c
While the evidence that a PPI does not increase the risk of cardiovascular events was generated with omeprazole, based on drug–drug interaction studies, omeprazole and
esomeprazole would appear to have the highest propensity for clinically relevant interactions, while pantoprazole and rabeprazole have the lowest.
226 ESC Guidelines
..
should be an exclusion criterion for study entry.23 While registry data .. Stenting (EXCELLENT) trial compared a 6-month DAPT [acetyl-
provide reassuring information with respect to the safety profile of .. salicylic acid (ASA) þ clopidogrel] duration with 1-year DAPT
..
switching from clopidogrel to prasugrel,89–91 no randomized data exist .. after DES.100 With 1443 patients randomized, the rates of target
in the setting of studies powered for clinical endpoint. Similarly, all .. vessel failure—defined as the composite of cardiac death, MI, or
..
other switching possibilities, including between prasugrel and tica- .. ischaemia-driven target vessel revascularization—at 12 months
grelor or from ticagrelor/prasugrel to clopidogrel, have not been .. were 4.8% in the 6-month DAPT group and 4.3% in the 12-month
..
investigated with outcome data.92–94 This practice is therefore dis- .. DAPT group (P = 0.001 for non-inferiority). There was a numeri-
couraged due to a lack of safety/efficacy data. As the need to switch .. cally lower risk of bleeding in the short DAPT arm (HR 0.50, 95%
..
between P2Y12 inhibitors may arise for clinical reasons (i.e. side .. CI 0.09–2.73). There was no signal of heterogeneity for the pri-
effects or drug intolerance), and registry data indicate that switch- .. mary study endpoint with respect to clinical presentation (i.e. sta-
..
ing is not infrequent in practice, switching algorithms based on .. ble CAD, n = 699 patients vs. ACS, n = 744 patients). The
pharmacodynamic studies are provided (Figure 2). .. PROlonging Dual antiplatelet treatment after Grading stent-
..
Figure 2 Algorithm for switching between oral P2Y12 inhibitors in the acute and chronic setting. LD = loading dose; MD = maintenance dose.
Colour-coding refers to the ESC Classes of Recommendations (green = Class I; orange = Class IIb). The green arrow from clopidogrel to ticagrelor
highlights the only switching algorithm for which outcome data are available in patients with acute coronary syndrome. No outcome data (orange
arrows) are available for all other switching algorithms. Acute setting is considered as a switching occurring during hospitalization.
..
Stenting (ISAR-SAFE).104 ISAR-SAFE was the largest of these three .. patients with ACS.104 Consistent results were shown in the
studies, with 4005 randomized patients, and the only double-blind .. ITALIC and SECURITY trials. Two studies, Real Safety and Efficacy
..
investigation. It confirmed that a 12-month course of DAPT did .. of 3-Month Dual Antiplatelet Therapy Following Endeavor
not afford any benefit over a 6-month course with respect to .. Zotarolimus-Eluting Stent Implantation (RESET)105 and
..
ischaemic endpoints. Likewise, the net clinical benefit (composite .. Optimized Duration of Clopidogrel Therapy Following Treatment
of death, MI, stent thrombosis, stroke, and TIMI major bleeding) .. With the Zotarolimus-Eluting Stent in Real-World Clinical
..
was neutral. At subgroup analysis, there was no signal of heteroge- .. Practice (OPTIMIZE),106 investigated a 3-month duration of
neity with respect to the primary study endpoint among the 2394
.. DAPT (ASA þ clopidogrel). RESET randomized 2117 patients to
..
patients who presented with stable CAD as opposed to the 1601 . 3- or 12-month duration of DAPT and did not show significant
228
Figure 3 Algorithm for DAPT in patients with coronary artery disease. ACS = acute coronary syndrome, BMS = bare-metal stent; BRS = bioresorbable vascular scaffold; CABG = Coronary artery
bypass graft; DCB = drug-coated balloon; DES: drug-eluting stent; PCI = percutaneous coronary intervention; Stable CAD = stable coronary artery disease.
High bleeding risk is considered as an increased risk of spontaneous bleeding during DAPT (e.g. PRECISE-DAPT score >_25).
Colour-coding refers to the ESC Classes of Recommendations (green = Class I; yellow = Class IIa; orange = Class IIb).
Treatments presented within the same line are sorted in alphabetic order, no preferential recommendation unless clearly stated otherwise.
1
: After PCI with DCB 6 months. DAPT should be considered (Class IIa B).
2
: If patient presents with Stable CAD or, in case of ACS, is not eligible for a treatment with prasugrel or ticagrelor.
3
: If patient is not eligible for a treatment with prasugrel or ticagrelor.
4
: If patient is not eligible for a treatment with ticagrelor.
ESC Guidelines
Figure 4 Algorithm for dual antiplatelet therapy (DAPT) in patients treated with percutaneous coronary intervention. ACS = acute coronary syn-
drome; BMS = bare-metal stent; BRS = bioresorbable vascular scaffold; CABG = coronary artery bypass graft surgery; DCB = drug-coated balloon;
DES: drug-eluting stent; PCI = percutaneous coronary intervention; Stable CAD = stable coronary artery disease.
High bleeding risk is considered as an increased risk of spontaneous bleeding during DAPT (e.g. PRECISE-DAPT score >_25).
Colour-coding refers to the ESC Classes of Recommendations (green = Class I; yellow = IIa; orange = Class IIb).
Treatments presented within the same line are sorted in alphabetic order, no preferential recommendation unless clearly stated
otherwise.
1
: After PCI with DCB 6 months. DAPT should be considered (Class IIa B).
2
: If patient presents with Stable CAD or, in case of ACS, is not eligible for a treatment with prasugrel or ticagrelor.
3
: If patient is not eligible for a treatment with prasugrel or ticagrelor.
4
: If patient is not eligible for a treatment with ticagrelor.
230 ESC Guidelines
..
harm with the shortened period (composite rates of any death, .. secondary prevention and reduction of stent thrombosis emerges.
MI, or stent thrombosis 0.8% vs. 1.3%; P = 0.48). Similar results .. However, this benefit is counterbalanced by an increased risk of
..
were achieved in OPTIMIZE with 3119 patients randomized. In .. bleeding and by a signal for increased mortality. Thus, systematic
this study, the 1-year incidence of MACE was 8.3% in the short- .. extension of DAPT beyond six months is not justified for all patients
..
term group and 7.4% in the long-term group (HR 1.12, 95% CI .. but should be based on the individual risk profile of the patient (see
0.87–1.45). Both studies mandated the use of the Endeavor .. section 3.5).
..
zotarolimus-eluting stent (ZES) in the 3-month DAPT arms, which .. Impact of type of DES on duration of DAPT: The benefit of
is no longer available on the market. It is not clear to what extent .. extended periods of DAPT varies with stent type. However, there
..
the results of RESET and OPTIMIZE are applicable to other types .. are differences between first- and newer-generation DES. In
of DES. .. PRODIGY, only patients with the paclitaxel-eluting stent benefit-
..
Palmerini et al performed a meta-analysis addressing the outcome .. ted from extended DAPT with a significant reduction of the risk of
of a <_6-month course of DAPT vs. a 1-year course after DES.107 The .. stent thrombosis.114 Likewise, in DAPT, the benefit of extended
..
..
Dual antiplatelet therapy duration and related stent
.. previous guidelines (NSTE-ACS), and data supporting the superiority
.. of ticagrelor and prasugrel over clopidogrel in this setting are dis-
choices in patients with stable coronary artery disease ..
treated with percutaneous coronary intervention .. cussed in section 3.6.
.. Although both prasugrel and ticagrelor significantly increase the
..
Recommendations Classa Levelb
.. risk of TIMI major non-CABG related bleeds, the risk–benefit ratios
.. were favourable with NNT for benefit of 46 and 53, respectively, and
..
In patients with stable CAD treated with .. NNT for harm of 167 for both agents. These data established the 1-
coronary stent implantation, DAPT consist-
.. year course of DAPT, preferably with prasugrel or ticagrelor, for
..
ing of clopidogrel in addition to aspirin is I A .. patients undergoing PCI for ACS, unless there are contraindications
generally recommendedc for 6 months, irre-
.. (Figure 4).
..
spective of the stent type.100,101,104,126–130 .. Mounting evidence for secondary prevention by intensified antiplatelet
.. therapy: In patients presenting with ACS, the cardiovascular risk
..
dose and 238 for the 60 mg dose; the corresponding NNT for harm
.. duration of DAPT was similar among patients with or without MI.
..
was 244 and 322, respectively, with the two ticagrelor doses.29 .. The active comparator was prasugrel in one-third of the patients
With the 90 mg dose, the absolute benefit in terms of the primary
.. with MI and clopidogrel in two-thirds of the patients.
..
efficacy endpoint was in the same order as the absolute harm in .. In patients with MI, extended DAPT as compared with aspirin
..
terms of the primary safety endpoint, and with 60 mg the absolute .. alone reduced stent thrombosis significantly (0.5% vs. 1.9%; P <
benefit was only marginally larger than the absolute harm. However, .. 0.001). There also was a significant reduction of MACCE by extended
..
the relevance of the various endpoints to the patient’s overall well- .. DAPT (3.9% vs. 6.8%; P < 0.001). This included a major reduction in
being may differ and are, therefore, difficult to weigh against one .. the rate of recurrent MI (2.2% vs. 5.2%; P < 0.001). On the other side,
..
another. The impact of MI and bleeding on mortality was comparable .. GUSTO moderate or severe bleeding was significantly increased by
in previous studies.11,138 A post hoc analysis from the Thrombin .. extended DAPT (1.9% vs. 0.8%, P = 0.005). Contrary to the main
..
Receptor Antagonist for Clinical Event Reduction in Acute Coronary .. study, all-cause mortality was similar in the extended DAPT group as
Syndrome (TRACER) trial suggested that while bleeding according to .. compared with the placebo group (1.4% vs. 1.6%; P = 0.61), even if
..
Dual antiplatelet therapy duration in patients with acute coronary syndrome treated with percutaneous coronary
intervention
In patients with ACS treated with coronary stent implantation, DAPT with a P2Y12 inhibitor on top of aspirin is rec-
ommended for 12 months unless there are contraindications such as excessive risk of bleeding (e.g. PRECISE-DAPT I A
>_25).20,23,40
In patients with ACS and stent implantation who are at high risk of bleeding (e.g. PRECISE-DAPT >_25), discontinua-
IIa B
tion of P2Y12 inhibitor therapy after 6 months should be considered.13,18,143
In patients with ACS treated with bioresorbable vascular scaffolds, DAPT for at least 12 months should be
IIa C
considered.
In patients with ACS who have tolerated DAPT without a bleeding complication, continuation of DAPT for longer
IIb A
than 12 months may be considered.26,139
In patients with MI and high ischaemic riskc who have tolerated DAPT without a bleeding complication, ticagrelor
IIb B
60 mg b.i.d. for longer than 12 months on top of aspirin may be preferred over clopidogrel or prasugrel.29,115,142
ACS = acute coronary syndrome; b.i.d. = bis in die; DAPT = dual antiplatelet therapy. MI = myocardial infarction; PRECISE-DAPT = PREdicting bleeding Complications In
patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy.
a
Class of recommendation.
b
Level of evidence.
c
Defined as >_ 50 years of age, and one or more of the following additional high-risk features: age of 65 years or older, diabetes mellitus requiring medication, a second prior
spontaneous myocardial infarction, multivessel coronary artery disease, or chronic renal dysfunction, defined as an estimated creatinine clearance < 60 mL/min.
These recommendations refer to stents that are supported by large-scale randomized trials with clinical endpoint evaluation leading to unconditional CE mark, as detailed in
Byrne et al.134
After an ACS, high bleeding risk status poses even greater 4.3 Gaps in the evidence
challenges with respect to the choice of DAPT duration. The With a marginal overall benefit-to-risk ratio of extended DAPT beyond
risks of shortening DAPT below 1 year have been addressed by 1 year after DES placement, tools to identify ideal candidates for long-
an individual patient data meta-analysis.143 This meta-analysis term or even indefinite DAPT duration are critically needed. The DAPT
comprised six trials comparing three- or six-month DAPT with score15 as well as the subgroup analyses of PEGASUS139,140,144,145 are
12-month DAPT including 11 473 patients, 4758 of whom had important steps forward, but prospective validation in contemporary
ACS. In patients with ACS, shortening DAPT to <_ 6 months was cohorts of newer-generation DES patients is needed.
234 ESC Guidelines
..
subpopulation was consistent with the overall results of the study.147 .. where a discontinuation period of 24 - 72 h was recommended. In a sin-
Further support has been presented in two meta-analyses.148,149 In the .. gle institution Dutch registry encompassing 705 consecutive patients
..
CABG substudies of the TRITON-TIMI 38 and the PLATO trials where, .. who underwent isolated on-pump CABG, ticagrelor discontinuation
respectively, prasugrel and ticagrelor were tested against clopidogrel in .. >72 h and clopidogrel discontinuation >120 h before surgery were not
..
combination with ASA, both newer P2Y12 inhibitors were more effec- .. associated with an increased risk of bleeding-related complications.153
tive than clopidogrel in preventing fatal outcomes, with a higher risk for .. Further evidence comes from a prospective, multicentre clinical
..
bleeding in the former but not the latter trial.150,151 .. trial performed at 15 European centres, where discontinuation of
Continuation of DAPT until CABG increases the risk of excessive .. ticagrelor >2 days before surgery was not associated with increased
..
perioperative bleeding, transfusions, and re-exploration for bleeding .. bleeding.160
as shown in RCTs,147,150,151 observational studies,152,153 and meta- .. It is unlikely that the optimal discontinuation period for any of
..
analyses.154,155 Therefore, it is recommended that the P2Y12 inhibitor .. the P2Y12 inhibitors will ever be tested in an RCT. As mentioned
be discontinued whenever possible before elective CABG.156,157 .. above, current guidelines recommend DAPT in all patients with
..
MI (OR 0.56, 95% CI 0.33–0.96) but not the mortality risk (OR 1.16,
.. Taken together, the evidence indicates that continuation of ASA
..
95% CI 0.42–3.22), while post-operative bleeding, red blood cell .. until cardiac surgery is associated with a moderately increased risk of
transfusions, and surgical re-explorations increased with ASA. The
.. bleeding complications and a significant reduction in the risk of perio-
..
authors pointed out that included studies had low methodological .. perative MI. If bleeding occurs during surgery, platelet transfusion has
quality. The recent Aspirin and Tranexamic Acid for Coronary
.. been shown to effectively counteract ASA effects.166–168 This finding
..
Artery Surgery (ATACAS) trial compared administration of ASA .. further supports the possibility of continuing ASA throughout the
..
(100 mg) on the day of surgery vs. placebo in CABG patients.164 The .. perisurgical period as ASA allows direct antiplatelet effect reversal if
study showed no significant effect of ASA treatment on perioperative .. clinically indicated. The increased risk of bleeding complications if
..
bleeding. On the other hand, ASA treatment did not reduce the inci- .. ASA and other antithrombotic drugs are not discontinued should be
dence of thrombotic events. It should be pointed out that the study .. weighed against the potentially increased risk of thrombotic compli-
..
did not directly compare discontinuation vs. no discontinuation, since .. cations during the pre-operative cessation period.
the included patients were only eligible for the trial if they were not .. Platelet function testing: Besides the variance in platelet inhibitory
..
Dual antiplatelet therapy in patients treated with cardiac surgery with stable or unstable coronary artery disease
It is recommended that the heart team estimates the individual bleeding and ischaemic risks, and guides the timing of
I C
CABG as well as the antithrombotic management.
In patients on aspirin who need to undergo non-emergent cardiac surgery, it is recommended to continue aspirin at a low
I C
daily regimen throughout the perioperative period.
In patients treated with DAPT after coronary stent implantation who subsequently undergo cardiac surgery, it is recom-
mended to resume P2Y12 inhibitor therapy post-operatively as soon as is deemed safe so that DAPT continues until the I C
recommended duration of therapy is completed.
In patients with ACS (NSTE-ACS or STEMI) treated with DAPT, undergoing CABG, and not requiring long-term OAC ther-
apy, resumption of P2Y12 inhibitor therapy as soon as is deemed safe after surgery and continuation up to 12 months is I C
recommended.
In patients on P2Y12 inhibitors who need to undergo non-emergent cardiac surgery, postponing surgery for at least 3
days after discontinuation of ticagrelor, at least 5 days after clopidogrel, and at least 7 days after prasugrel should be IIa B
considered.152,153,160
In CABG patients with prior MI who are at high risk of severe bleeding (e.g. PRECISE-DAPT >_25), discontinuation of P2Y12
IIa C
inhibitor therapy after 6 months should be considered.
Platelet function testing may be considered to guide decisions on timing of cardiac surgery in patients who have recently
IIb B
received P2Y12 inhibitors.169,172–174
In patients perceived to be at high ischaemic risk with prior MI and CABG, who have tolerated DAPT without a bleed-
IIb C
ing complication, treatment with DAPT for longer than 12 and up to 36 months may be considered.
ACS = acute coronary syndrome; CABG = coronary artery bypass graft surgery; DAPT = dual antiplatelet therapy; MI = myocardial infarction; NSTE-ACS = non-ST-elevation
acute coronary syndrome; OAC = oral anticoagulant; PRECISE-DAPT = PREdicting bleeding Complications in patients undergoing Stent implantation and subsEquent Dual Anti
Platelet Therapy; STEMI = ST-elevation myocardial infarction.
a
Class of recommendation.
b
Level of evidence.
ESC Guidelines 237
..
bleeding complications in clopidogrel-172–174 and ticagrelor- .. clopidogrel,40,95 TRILOGY for prasugrel,24 and PLATO and
treated169 ACS patients, and a strategy based on pre-operative plate- .. PEGASUS for ticagrelor studies.20,29 There is no evidence in
..
let function testing, to determine the timing of CABG in clopidogrel- .. favour of prasugrel treatment in patients with ACS who are medi-
treated patients, led to a 50% shorter waiting time than that sug- .. cally managed, based on the negative results of the TRILOGY
..
gested by a simple discontinuation time-based strategy.175 It should .. study and the exclusion of this patient subset in the TRITON
be pointed out that the different platelet function tests and their .. study.23,24 The CURE study showed a consistent benefit in ACS
..
respective cut-off levels are not interchangeable.176 Taken together, .. patients undergoing an average mean of 9 months DAPT in the
these results suggest that platelet function testing in ACS patients
.. form of aspirin and clopidogrel as compared to 1-month therapy
..
referred for CABG is of potential value to guide the timing of surgery .. in NSTE-ACS patients, irrespective of the final management strat-
in patients treated with P2Y12 inhibitors. However, randomized stud-
.. egy, including or not including coronary revascularization.40 The
..
ies with clinically relevant endpoints are lacking. .. post-MI subset of patients in the CHARISMA trial derived signifi-
.. cant benefit with an NNT for benefit in the range of 100, which
..
Dual antiplatelet therapy duration in patients with acute coronary syndrome undergoing medical therapy
management.
In patients with ACS who are managed with medical therapy alone and treated with DAPT, it is recommended to con-
I A
tinue P2Y12 inhibitor therapy (either ticagrelor or clopidogrel) for 12 months.20,40
Ticagrelor is recommended over clopidogrel, unless the bleeding risk outweighs the potential ischaemic benefit.20 I B
In patients with medically managed ACS who are at high risk of bleeding (e.g. PRECISE-DAPT >_25), DAPT for at least
IIa C
1 month should be considered.
In patients with prior MI not treated with coronary stent implantation, who have tolerated DAPT without a bleeding complica-
tion and who are not eligible for treatment with ticagrelor, continuation of clopidogrel on top of aspirin for longer than IIb C
12 months may be considered.
ACS = acute coronary syndrome; b.i.d. = bis in die; CrCl = creatinine clearance; DAPT = dual antiplatelet therapy; MI = myocardial infarction; PRECISE-DAPT = PREdicting
bleeding Complications In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy.
a
Class of recommendation.
b
Level of evidence.
c
Defined as >_ 50 years of age, and one or more of the following additional high-risk features: age of 65 years or older, diabetes mellitus requiring medication, a second prior
spontaneous myocardial infarction, multivessel coronary artery disease, or chronic renal dysfunction, defined as an estimated creatinine clearance < 60 mL/min.
..
7. Dual antiplatelet therapy for .. scores also predict bleeding outcomes in AF,187 suggesting consider-
.. able overlap among risk factors associated with ischaemic and bleeding
patients with indication for oral ..
.. outcomes, multiple bleeding risk scores,188 including the HAS-BLED189
anticoagulation .. [Hypertension, Abnormal renal and liver function (1 point each),
..
.. Stroke, Bleeding history or predisposition, Labile INR, Elderly (>
7.1 Risk stratification and strategies to .. 65 years), Drugs and alcohol (1 point each)] score, have been shown
..
improve outcome after percutaneous .. to outperform CHADS2 [Cardiac failure, Hypertension, Age, Diabetes,
.. Stroke (Doubled)] or CHA2DS2-VASc in predicting bleeding risk.
coronary intervention ..
Approximately 6–8% of patients undergoing PCI have an indication for
.. Importantly, HAS-BLED draws attention to the reversible bleeding
..
long-term oral anticoagulants (OACs) due to various conditions such .. risk factors to be addressed by the responsible clinician during the fol-
as AF, mechanical heart valves, or venous thromboembolism.
.. low-up. Risk is not static and, particularly for bleeding, many risk factors
..
Compared with oral anticoagulation therapy alone, the addition of .. can be modified. Hence, a high risk of bleeding (e.g. HAS-BLED score
DAPT to OAC therapy results in at least a two- to threefold increase
.. >_3) is not a reason to withhold OAC; instead, such patients should be
..
in bleeding complications.183–186 Therefore, these patients should be .. ‘flagged-up’ for more careful review and follow-up.
.. More recently, the novel biomarker-based ABC [Age, Biomarkers
considered at high risk of bleeding, and the indication for OAC should ..
be reassessed and treatment continued only if a compelling indication .. (GDF-15, cTnT-hs, and haemoglobin), and Clinical history (previous
.. bleeding)]190 bleeding risk score has been generated and validated in
exists {e.g. paroxysmal, persistent, or permanent AF with a CHA2DS2- ..
VASc [Cardiac failure, Hypertension, Age >_75 (2 points), Diabetes, .. a broad AF population treated with both vitamin K antagonist (VKA)
.. and non-vitamin K oral anticoagulants (NOACs), and has shown
Stroke (2 points)–Vascular disease, Age 65–74, Sex category] score ..
>_1 in men, >_2 in women; mechanical heart valve; recent (i.e. 6 months) .. superior prediction capability as compared to HAS-BLED. However,
..
or a history of recurrent deep venous thrombosis or pulmonary .. similar to all other bleeding risk scores, none of these risk prediction
embolism}. Conversely, every effort should be undertaken to imple- .. models developed for OAC patients has been prospectively tested in
..
ment strategies to minimize PCI-related complications in these patients .. the setting of prospective RCTs. Therefore, their value in improving
(Table 4). In particular, the duration of triple therapy should be limited .. patient outcomes remains unclear.
..
or omitted after hospital discharge (i.e. confined to the periprocedural .. A comprehensive list of all risk factors that have been associated
phase with aspirin being stopped thereafter), taking into account the .. with greater bleeding risk has been previously published.162
..
ischaemic (e.g. complexity of treated CAD, amount of disease left .. In the absence of safety and efficacy data from RCTs [only 6% of
untreated, technical considerations regarding stent implantation techni-
.. patients were treated at baseline with ticagrelor or prasugrel in the
..
ques, and results) as well as the bleeding risks. While ischaemic risk . Rivaroxaban and a dose-adjusted oral VKA treatment strategy in
ESC Guidelines 239
..
.. lowest effective tested dose for stroke prevention should be applied
.. and criteria for drug accumulation for each approved NOAC should
..
.. be carefully assessed. Lower NOAC regimens as compared to those
.. tested in approval studies are expected to decrease bleeding risk, but
..
.. the trade-off between bleeding and ischaemic (i.e. stroke prevention)
.. outcomes remains largely undefined. The PIONEER AF-PCI study191
..
.. (described in detail below) tested two lower rivaroxaban doses
Figure 6 Algorithm for dual antiplatelet therapy (DAPT) in .. (15 mg o.d. and 2.5 mg b.i.d.) as compared to the approved drug regi-
patients with acute coronary syndrome undergoing medical manage- ..
.. men in AF patients (20 mg q.d.). The Evaluation of Dual Therapy With
ment. High bleeding risk is considered as an increased risk of sponta- .. Dabigatran vs. Triple Therapy With Warfarin in Patients With AF
neous bleeding during DAPT (e.g. PRECISE-DAPT score >_25). ..
Colour-coding refers to the ESC Classes of Recommendations
.. That Undergo a PCI With Stenting (REDUAL-PCI; NCT02164864)
.. will compare two dabigatran doses (150 mg b.i.d. and 110 mg b.i.d.) vs.
(green = Class I; yellow = IIa; orange = Class IIb). Treatments pre- ..
sented within the same line are sorted in alphabetic order, no prefer- .. VKA and will provide additional insights with respect to the balance
.. between efficacy and safety for each one. Whether there are differ-
ential recommendation unless clearly stated otherwise. ..
1: if patient is not eligible for a treatment with ticagrelor .. ences according to the type of OAC (NOACs vs. VKA) or stent plat-
..
.. form as well the duration of triple therapy is further discussed. These
.. considerations do not pertain to medically managed patients or to
subjects with atrial fibrillation who undergo percutaneous coronary ..
.. patients eligible for CABG surgery in whom DAPT should be avoided
intervention (PIONEER AF-PCI) study191] and worrisome bleeding .. on top of OAC.
signals in registries, the use of prasugrel or ticagrelor as part of triple ..
..
therapy should be avoided.192 Gastric protection with a PPI is recom- ..
mended. The dose intensity of OAC should be carefully monitored .. 7.2 Duration of triple therapy
..
with a target international normalized ratio (INR) in the lower part of .. Cessation of aspirin after PCI while maintaining clopidogrel has been
the recommended target range; in patients treated with NOACs, the .. evaluated in the What is the Optimal antiplatElet and anticoagulant
240 ESC Guidelines
therapy in patients with OAC and coronary StenTing (WOEST) trial, .. More recently, the PIONEER AF-PCI study randomized 2124
which randomized 573 patients (of whom 69% of patients had AF) to
... patients with non-valvular AF who had undergone PCI with stenting
..
dual therapy with OAC and clopidogrel (75 mg/day) or to triple ther- .. to receive, in a 1:1:1 ratio: low-dose rivaroxaban (15 mg o.d.) plus a
apy with OAC, clopidogrel, and aspirin 80 mg/day.193 Treatment was
.. P2Y12 inhibitor (and no ASA) for 12 months; very-low-dose rivaroxa-
..
continued for 1 month after BMS placement and for 1 year after DES .. ban (2.5 mg b.i.d.) plus DAPT for 1, 6, or 12 months; or standard ther-
placement (65% of patients). PCI was performed on VKA therapy in
.. apy with a dose-adjusted VKA plus DAPT for 1, 6, or 12 months.191
..
half of the patients. The primary endpoint of any TIMI bleeds assessed .. The primary safety endpoint, consisting of TIMI clinically significant
at 1-year follow-up was significantly reduced in the dual-therapy arm
.. bleeding, was lower in the two groups receiving rivaroxaban than in
..
(19.5% vs. 44.9%; HR 0.36, 95% CI 0.26–0.50; P < 0.001), while no sig- .. the group receiving standard therapy [16.8% in patients treated with
..
nificant difference in major bleeding was observed. The rates of MI, .. rivaroxaban 15 mg, 18% in patients treated with rivaroxaban 2.5 mg,
stroke, target vessel revascularization, or stent thrombosis did not .. and 26.7% in patients treated with triple therapy (HR 0.59, 95% CI
..
differ significantly, but all-cause mortality was lower in the dual- .. 0.47–0.76; P < 0.001, and HR 0.63, 95% CI 0.50–0.80; P < 0.001,
therapy group (2.5% vs. 6.4%; P = 0.027) at 1 year. .. respectively)]. It is worth mentioning that as many as 49% of patients
ESC Guidelines 241
..
Table 5 High-risk features of stent-driven recurrent
.. underpowered for ischaemic endpoints. Therefore, no conclusion can
.. be made on the advantages and limitations of each OAC as compared
ischaemic events ..
.. to others. However, there was an excess of stroke events in the 2.5 mg
.. b.i.d. rivaroxaban arm in combination with 6-month DAPT as compared
..
.. to VKA and 6-month DAPT (6 vs. 0 events; P = 0.02).
.. In the four phase III NOAC AF trials, no interactions were demon-
..
.. strated between treatment effect and outcome according to prior
.. coronary status (ACS vs. no ACS), and it is likely that the benefit of
..
.. NOAC over VKA is preserved in CAD patients with AF.199–202 At
.. least, this was the case among patients exposed to antiplatelet ther-
..
.. apy. There is no strong evidence for choosing one NOAC over
.. another. Dabigatran is the only NOAC that has been tested in a
..
..
Surgical interventions can be divided into low-risk, intermediate-risk, .. group, these findings are potentially influenced by the type and
and high-risk groups, with estimated 30-day cardiac event rates .. urgency of the surgical procedures. To overcome this limitation, two
..
for cardiac death or MI of < 1%, 1–5%, and >_5%, respectively.205,209 .. large matched cohorts of patients undergoing surgery were recently
A practical classification of the bleeding risk associated with each type .. reported. Using Danish population-based registries and individual-
..
of non-cardiac surgery has been recently proposed by the Stent .. based record linkage of Danish registries, 4303 DES-PCI-treated
After Surgery group.210 .. patients who underwent a surgical procedure within 12 months were
..
In surgical procedures with low bleeding risk, every effort should be .. identified and were compared with a control group of patients with-
taken not to discontinue DAPT perioperatively. In surgical procedures .. out established stable CAD undergoing similar surgical procedures (n
..
with moderate bleeding risk, patients should be maintained on aspirin .. = 20 232).226 This evaluation of the comparative risk associated with
while P2Y12 inhibitor therapy should be discontinued whenever possi- .. surgery in DES-PCI-treated patients vs. patients without known sta-
..
ble. More challenging decision making is to be faced among patients on .. ble CAD revealed an increased overall risk for MI and cardiac death
DAPT who undergo high bleeding risk non-cardiac surgeries, including .. in the patients with previous DES-PCI, owing to higher MI rates but
..
Figure 8 Timing for elective non-cardiac surgery in patients A multidisciplinary expert team should be
treated with dual antiplatelet therapy (DAPT) after percutaneous considered for pre-operative evaluation of
IIa C
coronary intervention (PCI). Colour-coding refers to the ESC patients with an indication for DAPT before
Classes of Recommendations (green = Class I; yellow = IIa; orange elective surgery.
= Class IIb).
ACS = acute coronary syndromes. In patients with recent MI or other high
1
Availability of H24 cath-lab service in place is suggested in ischaemic risk featuresc requiring DAPT,
IIb C
case of major surgery within 6 months after PCI. elective surgery may be postponed for up
2
High ischaemic risk features are presented in Table 5. to 6 months.17,214,215,234
..
9. Gender consideration and .. presence of diabetes should affect decision making with respect to
.. the choice of P2Y12 inhibitors.
special populations ..
.. As it related to DAPT duration, the DAPT study found a slightly
.. lower relative risk reduction for MI endpoint in patients with diabetes
9.1 Gender specificities ..
.. as compared to those without diabetes (Pint = 0.02).242 However,
There is no convincing evidence for a gender-related difference in the .. there was no signal for heterogeneity with respect to the concomitant
efficacy and safety of currently available DAPT type or duration across ..
.. presence of diabetes mellitus across all other ischaemic or safety end-
studies. No single trial or pooled analysis of investigations assessing a .. points. Finally, no difference with respect to the presence or absence
shorter than 1 year vs. at least 1 year DAPT duration has shown heter- ..
.. of diabetes was observed for the primary efficacy endpoint in the
ogeneous findings across genders.26,112,240,241 In the DAPT trial, there .. PEGASUS study (P = 0.99).145 Altogether, current evidence suggests
was a borderline quantitative interaction suggesting a lower relative .. int
.. that diabetes mellitus should not be the only appraised patient-specific
treatment benefit for stent thrombosis reduction with prolonged .. feature when deciding upon the type or duration of DAPT.
DAPT in female as compared to male patients (Pint =0.04).26 ..
..
However, no such signal was apparent for MACCE (Pint = 0.46) or ..
bleeding (Pint = 0.40) endpoints. Within the PEGASUS trial, there was ..
.. 9.3 Lower-extremities artery disease
no signal suggesting heterogeneity across the primary study endpoint .. Patients with LEAD are at heightened risk of ischaemic complications
with respect to gender (Pint = 0.84).29 On the other hand, there was a ..
.. and mortality. The combination of symptomatic LEAD and CAD is
positive quantitative interaction (Pint = 0.03) suggesting that female .. associated with further heightened ischaemic risk beyond that associ-
patients may derive a relatively greater treatment benefit with respect
..
.. ated with symptomatic disease in either vascular bed alone.243 In 3096
to stroke prevention from prolonged treatment with aspirin and tica- ..
grelor as compared to aspirin alone. However, no such signal was evi-
.. patients with LEAD included in the CHARISMA trial, DAPT was asso-
.. ciated with a lower rate of MI and hospitalization for ischaemic events
dent for cardiovascular death, MI, or safety endpoints. ..
.. but not the overall composite primary endpoint. There was no differ-
.. ence between the groups in moderate, severe, or fatal bleeding, but
..
9.2 Diabetes mellitus .. there was an increase in minor bleeding in the DAPT group.244 The
Patients with diabetes mellitus presenting with both stable and unsta- .. PEGASUS investigators recently examined a subgroup of 1143 patients
..
ble CAD carry a worse prognosis in terms of short- and long-term .. with LEAD and found that patients with prior MI with LEAD had a 60%
risks of fatal and non-fatal ischaemic events, with enhanced platelet .. increased risk of MACE relative to patients without LEAD, even after
..
hyperactivity playing a putative causal role. In the CURE trial, patients .. adjusting for differences in baseline characteristics.140 This increased
with diabetes derived a similar treatment benefit from the addition of .. ischaemic risk translated into a robust absolute risk reduction of 5.2%
..
clopidogrel on top of aspirin as compared to patients without.40 No .. at 3 years with ticagrelor 60 mg b.i.d. compared with placebo. In the set-
signal for greater treatment benefit was apparent in TRITON-TIMI .. ting of this robust ischaemic risk reduction, there were significant
..
38 in patients with diabetes as compared to those without with .. reductions in cardiovascular and all-cause mortality. Treatment with
respect to the study primary endpoint, and a consistent lack of heter-
.. ticagrelor vs. placebo reduced the risk of adverse limb events in addi-
..
ogeneity signal with respect to diabetes mellitus was observed in the .. tion to the benefits observed for MACE and mortality. Reductions in
PLATO trial.20,23 Hence, there is no convincing evidence that the
.. acute limb ischaemia have also been shown with other antiplatelet
246 ESC Guidelines
Figure 10 Practical recommendations for the management of bleeding in patients treated with dual antiplatelet therapy with or without concomi-
tant oral anticoagulation. Practical recommendations for the management of bleeding in patients treated with dual antiplatelet therapy with or with-
out concomitant oral anticoagulation. Blue boxes refer to management of antiplatelet therapy. Dark-red boxes refer to the management of oral
anticoagulation. Light-green boxes refer to general recommendation for patients’ safety.
ACS = acute coronary syndrome; CHA2DS2-VASc= cardiac failure, hypertension, age >_75 (2 points), diabetes, stroke (2 points)–vascu-
lar disease, age 65–74, sex category; DAPT = dual antiplatelet therapy; GI = gastrointestinal; HB = haemoglobin; INR = international
normalized ratio; i.v. = intravenous; OAC = oral anticoagulant; NOAC = non-vitamin-K antagonist; PPI = proton pump inhibitor; RBC
= red blood cell; SAPT = single antiplatelet therapy.
ESC Guidelines 247
Figure 10 Continued
agents, such as vorapaxar, demonstrating that this morbidity is modifi- .. Prolonged vs. short DAPT conveyed a lower risk of the primary effi-
..
able with potent and prolonged antithrombotic strategies.245 In the all- .. cacy endpoint in LEAD patients (16.1% vs. 27.3%; HR 0.54, 95% CI
comer PRODIGY trial, 246 (12.5%) patients were included with symp-
.. 0.31–0.95; P = 0.03) but not in patients without LEAD (9.3% vs. 7.4%;
..
tomatic LEAD. LEAD status was associated with a higher risk of death .. HR 1.28, 95% CI 0.92–1.77; P = 0.14), with positive interaction (P =
and ischaemic events (HR 2.80, 95% CI 2.05–3.83; P < 0.001).246
.. 0.01). The risk of definite or probable stent thrombosis as well as
248 ESC Guidelines
overall mortality was significantly lower in LEAD patients treated with .. cannot be regarded as an effective treatment option. Considering the
..
prolonged DAPT as compared with those receiving short DAPT. .. long-term risk of recurrence after first stent thrombosis, it may be rea-
.. sonable to make every effort to maintain DAPT for a very long-term
..
9.4 Complex percutaneous coronary .. period in this highly selected high-risk patient population, if tolerated.
..
intervention ..
..
While high PCI complexity intuitively represents a driver for favouring .. 9.6 Patients who develop bleeding while
a prolonged over a shortened DAPT duration, the evidence regarding ..
.. on treatment
optimal DAPT duration based on complexity of intervention is limited. .. Patients who develop bleeding complications while on DAPT repre-
In a patient-level meta-analysis from six RCTs investigating DAPT ..
.. sent a challenging patient population for whom no guidance from
durations after coronary stenting, including 9577 patients, complex .. RCTs is available.
PCI was defined as the composite of at least three stents implanted, at ..
.. The decision to withhold or continue DAPT in this setting largely
..
10. Key messages .. therapy may be considered in ACS patients who have tolerated
.. DAPT without a bleeding complication.
(1) Benefits and risks of DAPT: DAPT reduces the risk of stent throm- .. (9) Patients with indication for oral anticoagulation: Compared with
..
bosis across the entire spectrum of events, from acute to very late .. OAC therapy alone, the addition of DAPT to OAC therapy results
occurrences. However, treatment with DAPT beyond 1 year after .. in at least a two- to three-fold increase in bleeding complications.
..
MI, or after PCI, exerts the majority of its benefit by reducing the .. Therefore, these patients should be considered at high risk of
rate of spontaneous MI. The risk of bleeding in patients on DAPT is
.. bleeding and the indication for OAC should be reassessed and
..
proportionally related to its duration both within and beyond .. treatment continued only if a compelling indication exists.
1 year of treatment duration. Since the benefits of prolonged
.. The duration of triple therapy should be limited up to a maximum
..
DAPT, especially for mortality endpoints, appear highly dependent .. of 6 months or omitted after hospital discharge, taking into account
on prior cardiovascular history (such as prior ACS/MI vs. stable
..
.. the ischaemic (e.g. complexity of treated CAD, amount of disease
CAD), and prediction models to estimate on-DAPT bleeding risk .. left untreated, technical considerations regarding stent implantation
..
In patients with ACS, ticagrelor (180 mg loading dose, 90 mg b.i.d.) on top of aspirin is recommended, regardless of initial
treatment strategy, including patients pre-treated with clopidogrel (which should be discontinued when ticagrelor is com- I B
c
menced) unless there are contraindications.
In patients with ACS undergoing PCI, prasugrel (60 mg loading dose, 10 mg o.d.) on top of aspirin is recommended for P2Y12 inhibi-
tor-naı̈ve patients with NSTE-ACS or initially conservatively managed STEMI if indication for PCI is established, or in STEMI patients I B
undergoing immediate coronary catheterization unless there is a high risk of life-threatening bleeding or other contraindications.c
Continued
250 ESC Guidelines
Pre-treatment with a P2Y12 inhibitor is generally recommended in patients in whom coronary anatomy is known and the
I A
decision to proceed to PCI is made, as well as in patients with STEMI.
Clopidogrel (600 mg loading dose, 75 mg o.d.) on top of aspirin is recommended in stable CAD patients undergoing
coronary stent implantation and in ACS patients who cannot receive ticagrelor or prasugrel, including those with prior I A
intracranial bleeding or indication for OAC.
Clopidogrel (300 mg loading dose in patients aged <_75, 75 mg o.d.) is recommended on top of aspirin in STEMI patients
I A
receiving thrombolysis.
In NSTE-ACS patients in whom coronary anatomy is not known, it is not recommended to administer prasugrel. III B
Routine platelet function testing to adjust antiplatelet therapy before or after elective stenting is not recommended. III A
In patients with ACS who were previously exposed to clopidogrel, switching from clopidogrel to ticagrelor is
recommended early after hospital admission at a loading dose of 180 mg irrespective of timing and loading dose of I B
clopidogrel, unless contraindications to ticagrelor exist.c
Dual antiplatelet therapy duration in patients with acute coronary syndrome treated with percutaneous coronary intervention
In patients with ACS treated with coronary stent implantation, DAPT with a P2Y12 inhibitor on top of aspirin is
recommended for 12 months unless there are contraindications such as excessive risk of bleeding (e.g. I A
PRECISE-DAPT >_25).
Dual antiplatelet therapy duration in patients with acute coronary syndrome undergoing medical therapy management
In patients with ACS who are managed with medical therapy alone and treated with DAPT, it is recommended to continue
I A
P2Y12 inhibitor therapy (either ticagrelor or clopidogrel) for 12 months.
Ticagrelor is recommended over clopidogrel, unless the bleeding risk outweighs the potential ischaemic benefit. I B
Dual antiplatelet therapy in patients undergoing elective cardiac and non-cardiac surgery
It is recommended to continue aspirin perioperatively if the bleeding risk allows, and to resume the recommended
I B
antiplatelet therapy as soon as possible post-operatively.
It is not recommended to discontinue DAPT within the first month of treatment in patients undergoing elective non-cardiac
III B
surgery.
Gender considerations
Similar type and duration of DAPT are recommended in male and female patients. I A
ACS = acute coronary syndrome; CAD = coronary artery disease; DAPT = dual antiplatelet therapy; NSTE-ACS = non-ST elevation acute coronary syndrome; OAC = oral
anticoagulant; PCI = percutaneous coronary intervention; PPI = proton pump inhibitor; PRECISE-DAPT = PREdicting bleeding Complications In patients undergoing Stent
implantation and subsEquent Dual Anti Platelet Therapy; STEMI = ST-elevation myocardial infarction; TIA = transient ischaemic attack.
a
Class of recommendation.
b
Level of evidence.
c
Contraindications for ticagrelor: previous intracranial haemorrhage or ongoing bleeds. Contraindications for prasugrel: previous intracranial haemorrhage, previous ischaemic
stroke or TIA, or ongoing bleeds; prasugrel is not recommended for patients >_75 years of age or with a body weight <60 kg.
d
While the evidence that a PPI does not increase the risk of cardiovascular events was generated with omeprazole, based on drug–drug interaction studies, omeprazole and
esomeprazole would appear to have the highest propensity for clinically relevant interactions, while pantoprazole and rabeprazole have the lowest.
ESC Guidelines 251
Pretreatment with P2Y12 inhibitors The occurrence of aconable bleeding while Metallic stent and DAPT duraon
when PCI is planned on DAPT should prompt reconsideraon of
type and duraon of DAPT regimen.
Switch between P2Y12 inhibitors
Liberal use of PPI to migate GI bleeding
risk The decision for DAPT duraon should be Risk scores to guide DAPT duraon
dynamic and reassessed during the course −PRECISE DAPT score
Elecve surgery requiring disconnuaon of the inially selected DAPT regimen.
−DAPT score
of the P2Y12 inhibitor aer 1 month
ACS ¼ acute coronary syndrome; APT ¼ anti-platelet therapy; CABG ¼ coronary artery bypass graft; DAPT ¼ dual antipla-
telet therapy; MI ¼ myocardial infarction; NSTE¼ Non-st-segment elevation; OAC ¼ oral anti-coagulant;PCI ¼ percuatenous
coronary intervention; PRECISE-DAPT ¼ PREdicting bleeding Complications In patients undergoing Stent implantation and
subsEquent Dual Anti Platelet Therapy; Stable CAD ¼ stable coronary artery disease.
..
12. Web addenda and Clinical ..
..
antiplatelet therapy in coronary artery disease in collabora-
tion with EACTS:
Cases companion document ..
.. Austria: Austrian Society of Cardiology, Franz Xaver Roithinger;
.. Azerbaijan: Azerbaijan Society of Cardiology, Farid Aliyev;
All Web figures, Web tables, and the Clinical Cases companion docu- ..
ment are available at the European Heart Journal online and also via .. Belarus: Belorussian Scientific Society of Cardiologists, Valeriy
.. Stelmashok; Belgium: Belgian Society of Cardiology, Walter
the ESC Web site at: www.escardio.org/guidelines ..
.. Desmet; Bulgaria: Bulgarian Society of Cardiology, Arman
.. Postadzhiyan; Cyprus: Cyprus Society of Cardiology, Georgios P.
..
13. Appendix .. Georghiou; Czech Republic: Czech Society of Cardiology, Zuzana
.. Motovska; Denmark: Danish Society of Cardiology, Erik Lerkevang
..
ESC Committee for Practice Guidelines (CPG): Stephan .. Grove; Estonia: Estonian Society of Cardiology, Toomas Marandi;
.. Finland: Finnish Cardiac Society, Tuomas Kiviniemi; The Former
Windecker (Chairperson) (Switzerland), Victor Aboyans (France), ..
Stefan Agewall (Norway), Emanuele Barbato (Italy), Héctor Bueno .. Yugoslav Republic of Macedonia: Macedonian Society of
.. Cardiology, Sasko Kedev; France: French Society of Cardiology,
(Spain), Antonio Coca (Spain), Jean-Philippe Collet (France), Ioan ..
Mircea Coman (Romania), Veronica Dean (France), Victoria Delgado .. Martine Gilard; Germany: German Cardiac Society, Steffen
..
(The Netherlands), Donna Fitzsimons (UK), Oliver Gaemperli .. Massberg; Greece: Hellenic Society of Cardiology, Dimitrios
(Switzerland), Gerhard Hindricks (Germany), Bernard Iung (France), .. Alexopoulos; Hungary: Hungarian Society of Cardiology, Robert
..
Peter Jüni (Canada), Hugo A. Katus (Germany), Juhani Knuuti .. Gabor Kiss; Iceland: Icelandic Society of Cardiology, Ingibjorg Jona
(Finland), Patrizio Lancellotti (Belgium), Christophe Leclercq .. Gudmundsdottir; Ireland: Irish Cardiac Society, Eugène P.
..
(France), Theresa McDonagh (UK), Massimo Francesco Piepoli .. McFadden; Israel: Israel Heart Society, Eli Lev; Italy: Italian
(Italy), Piotr Ponikowski (Poland), Dimitrios J. Richter (Greece), .. Federation of Cardiology, Leonardo De Luca; Kazakhstan:
..
Marco Roffi (Switzerland), Evgeny Shlyakhto (Russia), Iain A. Simpson .. Association of Cardiologists of Kazakhstan, Akhmetzhan Sugraliyev;
(UK), and Jose Luis Zamorano (Spain)
.. Kosovo: Kosovo Society of Cardiology, Edmond Haliti;
..
ESC National Cardiac Societies actively involved in the .. Kyrgyzstan: Kyrgyz Society of Cardiology, Erkin Mirrakhimov,
review process of the 2017 ESC focused update on dual
.. Latvia: Latvian Society of Cardiology, Gustavs Latkovskis;
ESC/EAS GUIDELINES
European Heart Journal (2019) 00, 178
doi:10.1093/eurheartj/ehz455
Document Reviewers: Christian Mueller (ESC Review Coordinator) (Switzerland), Heinz Drexel
(EAS Review Coordinator) (Austria), Victor Aboyans (France), Alberto Corsini1 (Italy), Wolfram Doehner
(Germany), Michel Farnier (France), Bruna Gigante (Sweden), Meral Kayikcioglu1 (Turkey),
Goran Krstacic (Croatia), Ekaterini Lambrinou (Cyprus), Basil S. Lewis (Israel), Josep Masip (Spain),
Philippe Moulin1 (France), Steffen Petersen (United Kingdom), Anna Sonia Petronio (Italy),
Massimo Francesco Piepoli (Italy), Xavier Pinto 1 (Spain), Lorenz Ra
€ ber (Switzerland), Kausik K. Ray1
1
For the Supplementary Data which include background information and detailed discussion of the data
that have provided the basis for the Guidelines see https://academic.oup.com/eurheartj/article-lookup/doi/
10.1093/eurheartj/ehz455#supplementary-data
...................................................................................................................................................................................................
Keywords Guidelines • dyslipidaemias • cholesterol • triglycerides • low-density lipoproteins • high-density lipopro-
teins • apolipoprotein B • lipoprotein(a) • lipoprotein remnants • total cardiovascular risk • treatment
(lifestyle) • treatment (drugs) • treatment (adherence) • very low-density lipoproteins • familial
hypercholesterolaemia
..
Table of contents .. 5.3.4 Lipoprotein(a) and risk of atherosclerosis . . . . . . . . . . . . . . . . 19
.. 5.4 Laboratory measurement of lipids and lipoproteins . . . . . . . . . . . 19
Abbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
.. 5.4.1 Lipoprotein measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
..
1 Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 .. 5.4.2 Lipid measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
.. 5.4.3 Fasting or non-fasting? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
..
2.1 What is new in the 2019 Guidelines? . . . . . . . . . . . . . . . . . . . . . . . . . . 8 .. 5.5 Recommendations for measuring lipids and lipoproteins to
3 What is cardiovascular disease prevention? . . . . . . . . . . . . . . . . . . . . . . . . 8
.. estimate risk of atherosclerotic cardiovascular disease . . . . . . . . . . . . 20
..
3.1 Definition and rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 .. 6 Treatment targets and goals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
..
3.2 Development of the Joint Task Force Guidelines for the .. 7 Lifestyle modifications to improve the plasma lipid profile . . . . . . . . . . 22
management of dyslipidaemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 .. 7.1 Influence of lifestyle on total cholesterol and low-density
..
4 Total cardiovascular risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 .. lipoprotein cholesterol levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
4.1 Total cardiovascular risk estimation . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 .. 7.2 Influence of lifestyle on triglyceride levels . . . . . . . . . . . . . . . . . . . . . 24
..
4.1.1 Rationale for assessing total cardiovascular disease risk . . . . 11 .. 7.3 Influence of lifestyle on high-density lipoprotein cholesterol
4.1.2 How to use the risk estimation charts . . . . . . . . . . . . . . . . . . . . 14 .. levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
..
4.2 Risk levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 .. 7.4 Lifestyle recommendations to improve the plasma lipid
4.2.1 Role of non-invasive cardiovascular imaging .. profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
..
techniques in the assessment of total cardiovascular .. 7.4.1 Body weight and physical activity . . . . . . . . . . . . . . . . . . . . . . . . . 25
disease risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 .. 7.4.2 Dietary fat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
..
4.2.2 Risk-based intervention strategies . . . . . . . . . . . . . . . . . . . . . . . . 17 .. 7.4.3 Dietary carbohydrate and fibre . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5 Lipids and lipoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 .. 7.4.4 Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
..
5.1 Biological role of lipids and lipoproteins . . . . . . . . . . . . . . . . . . . . . . . 17 .. 7.4.5 Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5.2 Role of lipids and lipoproteins in the pathophysiology of .. 7.5 Dietary supplements and functional foods for the
..
atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 .. treatment of dyslipidaemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5.3 Evidence for the causal effects of lipids and lipoproteins on
.. 7.5.1 Phytosterols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
..
the risk of atherosclerotic cardiovascular disease . . . . . . . . . . . . . . . . . 18 .. 7.5.2 Monacolin and red yeast rice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5.3.1 Low-density lipoprotein cholesterol and risk of
.. 7.5.3 Dietary fibre . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
..
atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 .. 7.5.4 Soy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
5.3.2 Triglyceride-rich lipoproteins and risk of atherosclerosis . . 18
.. 7.5.5 Policosanol and berberine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
..
5.3.3 High-density lipoprotein cholesterol and risk of .. 7.5.6 n-3 unsaturated fatty acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
.
ESC/EAS Guidelines 3
..
9.10.3 Retinal vascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 ..
..
List of tables
9.10.4 Secondary prevention in patients with
.. Table 1 Classes of recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
abdominal aortic aneurysm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 .. Table 2 Levels of evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
9.10.5 Renovascular atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 ..
.. Table 3 New recommendations, and new and revised concepts . . . . . . 9
9.11 Other special populations at risk of atherosclerotic .. Table 4 Cardiovascular risk categories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
cardiovascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 ..
.. Table 5 Intervention strategies as a function of total cardiovascular
10 Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 ..
Evacetrapib in Patients at a High-Risk for ... eGFR Estimated glomerular filtration rate
Vascular Outcomes
.. EMA European Medicines Agency
..
ACCORD Action to Control Cardiovascular Risk in Diabetes .. EPA Eicosapentaenoic acid
ACS Acute coronary syndrome
.. ESC European Society of Cardiology
..
ALT Alanine aminotransferase .. EVOLVE EpanoVa fOr Lowering Very high
ANGPTL3 Angiopoietin-like protein 3
.. triglyceridEs
..
Apo Apolipoprotein .. EVOPACS EVOlocumab for early reduction of LDL-
..
both societies undertook a comprehensive review of the published .. The ESC CPG supervises and coordinates the preparation of new
evidence for management of a given condition according to ESC .. Guidelines. The Committee is also responsible for the endorsement
..
Committee for Practice Guidelines (CPG) policy. A critical evaluation .. process of these Guidelines. The ESC Guidelines undergo extensive
of diagnostic and therapeutic procedures was performed, including .. review by the CPG and external experts. After appropriate revisions
..
assessment of the riskbenefit ratio. The level of evidence and the .. the Guidelines are approved by all the experts involved in the Task
strength of the recommendation of particular management options
.. Force. The finalized document is approved by the CPG and EAS for
..
were weighed and graded according to predefined ESC scales, as out- .. publication in the European Heart Journal and Atherosclerosis
Wording to use
Classes of recommendations
Class II
Class III Evidence or general agreement that the Is not recommended ©ESC 2019
given treatment or procedure is not
useful/effective, and in some cases
may be harmful.
..
version of the Guidelines, which is freely available via the ESC and .. 2.1 What is new in the 2019 Guidelines?
EAS websites and hosted on their journals’ websites (EHJ and .. New recommendations, and new and revised concepts, are pre-
..
Atherosclerosis Journal). The National Cardiac Societies of the ESC .. sented in Table 3.
are encouraged to endorse, translate and implement all ESC ..
..
Guidelines. Implementation programmes are needed because it has ..
..
been shown that the outcome of disease may be favourably influ-
.. 3 What is cardiovascular disease
enced by the thorough application of clinical recommendations. ..
New recommendations
Cardiovascular imaging for assessment of ASCVD risk
Assessment of arterial (carotid and/or femoral) plaque burden on arterial ultrasonography should be considered as a risk modifier in individuals
at low or moderate risk.
PCSK9 inhibitors
New outcome study data of PCSK9 inhibitors are presented, and updated recommendations for their clinical use are provided.
Cost-effectiveness
The issue of cost-effectiveness of lipid-modifying interventions is updated in view of changes in the availability of generic products for statins and ezetimibe,
and of PCSK9 inhibitors.
ACS = acute coronary syndrome; ApoB = apolipoprotein B; ASCVD = atherosclerotic cardiovascular disease; CAC = coronary artery calcium; CHD = coronary heart disease;
of time. Total CVD risk expresses the combined effect of a number .. diagnostic tests, and methods of ascertainment, all of which can vary,
..
of risk factors on this risk estimate. In these Guidelines, we address .. resulting in very variable multipliers to convert fatal to total events. In
the lipid-related contribution to total CV risk and how to manage it
.. addition, total event charts, in contrast to those based on mortality,
..
at the clinical level. .. are more difficult to recalibrate to suit different populations. That said,
.. work is in progress to produce regional total event charts.
..
4.1.1 Rationale for assessing total cardiovascular disease .. The SCORE data indicate that the total CVD event risk is about
.. three times higher than the risk of fatal CVD for men, so a SCORE
risk ..
All current guidelines on the prevention of ASCVD in clinical practice .. risk of 5% translates into a CVD risk of 15% of total (fatal þ non-
..
recommend the assessment of total CVD risk. Prevention of ASCVD .. fatal) CVD endpoints; the multiplier is higher in women and lower in
in a given person should relate to his or her total CV risk: the higher .. older people.
..
the risk, the more intense the action should be. .. Clinicians often ask for thresholds to trigger certain interventions.
Many risk assessment systems are available and have been compre- ... This is problematic since risk is a continuum and there is no threshold
hensively reviewed (Supplementary Table 1 in the Supplementary .. at which, for example, a drug is automatically indicated. This is true
..
Data). Most guidelines use one of these risk assessment systems.68 .. for all continuous risk factors such as plasma cholesterol or systolic
Ideally, risk charts should be based on country-specific cohort data. .. BP (SBP). Therefore, the goals that are proposed in this document
..
These are not available for most countries. The SCORE (Systematic .. reflect this concept.
Coronary Risk Estimation) system can be recalibrated for use in dif- .. A particular problem relates to young people with high levels of risk
..
ferent populations by adjusting for secular changes in CVD mortality .. factors; a low absolute risk may conceal a very high relative risk requir-
and risk factor prevalence. Calibrated country-specific versions are .. ing at least intensive lifestyle advice. To motivate young people (i.e.
..
available for many European countries and can be found at http:// .. aged <40 years) not to delay changing their unhealthy lifestyle, an esti-
www.heartscore.org. These are now being updated to provide recali- .. mate of their relative risk—illustrating that lifestyle changes can reduce
..
brated, contemporaneous country-specific charts for all European .. relative risk substantially—may be helpful (Supplementary Figure 1).
countries. Other risk estimation systems—using both fatal and non-
.. Another approach to this problem is to use CV risk age. The risk
..
fatal events—can also be recalibrated, but the process is easier and .. age of a person with several CV risk factors is the age of a person
scientifically more robust for mortality than for total events. The
.. with the same level of risk but with ideal levels of risk factors. Thus, a
..
European Guidelines on CVD prevention in clinical practice (both .. high-risk 40-year-old would have a risk age >_65 years. Risk age can be
the 20129 and 201610 versions) recommend the use of the SCORE
.. estimated visually by looking at the SCORE chart (as illustrated in
..
system because it is based on large, representative European cohort .. Supplementary Figure 2). In this chart, the risk age of a person with risk
data sets and because it is relatively straightforward to recalibrate for
.. factors is defined as the age at which a person with ideal risk factor
..
individual countries. .. levels would reach the same risk level. Ideal risk factors are non-
.. smoking, total cholesterol (TC) <_4 mmol/L (<_155 mg/dL), and SBP
Persons with documented ASCVD, type 1 or type 2 DM (T1DM ..
and T2DM, respectively), very high levels of individual risk factors, or .. <_120 mmHg. Risk age is also automatically calculated as part of the
..
chronic kidney disease (CKD) are generally at very-high or high total .. latest revision of HeartScore (http://www.HeartScore.org).
CV risk. No risk estimation models are needed for such persons; .. Risk age has been shown to be independent of the CV endpoint
..
they all need active management of all risk factors. For other, appa- .. used,6,8 can be used in any population regardless of baseline risk or
rently healthy people, the use of a risk estimation system such as .. secular changes in mortality, and therefore avoids the need for
..
SCORE, which estimates the 10 year cumulative risk of a first fatal .. recalibration.
atherosclerotic event, is recommended to estimate total CV risk, .. Lifetime risk is another approach to illustrate the impact of risk fac-
..
since many people have several risk factors that, in combination, may .. tors that may be useful in younger people.12 The greater the burden
result in high levels of total CV risk. .. of risk factors, the higher the lifetime risk. This approach produces
..
Risk estimates have been produced as charts for high- and low-risk .. higher risk figures for younger people because of their longer expo-
regions in Europe (Figures 1 and 2).11 All International Classification of .. sure times. Therefore, it is more useful as a way of illustrating risk
..
Diseases codes that are related to deaths from vascular origin caused .. than as a guide to treatment, because therapeutic trials have been
by atherosclerosis are included. The reasons for retaining a system
.. based on a fixed follow-up period and not on lifetime risk.
..
that estimates fatal as opposed to total fatal þ non-fatal events are .. Another problem relates to older people. In some age categories,
that non-fatal events are dependent on definition, developments in
.. the majority of people, especially males, will have estimated 10 year
12 ESC/EAS Guidelines
WOMEN MEN
180 7 8 8 9 11 12 13 15 15 17 20 23 23 26 30 34
160 5 6 6 7 9 9 10 11 12 14 16 18 18 21 24 27
140
65
4 4 5 5 7 7 8 9 9 11 12 14 14 16 19 22
120 3 3 4 4 5 5 6 7 7 8 10 11 11 13 15 17
Systolic blood pressure (mmHg)
180 4 4 5 5 7 8 9 10 10 11 13 15 16 19 22 25
160 3 3 3 4 5 6 6 7 7 8 10 11 12 14 16 19
60
140 2 2 2 3 4 4 4 5 5 6 7 8 9 10 12 14
120 1 1 2 2 3 3 3 3 4 4 5 6 6 7 9 10
180 2 2 3 3 5 5 6 7 6 7 9 10 11 13 16 18
160 1 2 2 2 3 3 4 4 4 5 6 7 8 9 11 13
55
140 1 1 1 1 2 2 2 3 3 3 4 5 5 6 7 9
120 1 1 1 1 1 1 2 2 2 2 3 3 4 4 5 6
180 1 1 2 2 3 3 4 4 4 5 6 7 8 9 11 13
160 1 1 1 1 2 2 2 3 2 3 3 4 5 6 7 9
50
140 0 0 1 1 1 1 1 2 2 2 2 3 3 4 5 6
120 0 0 0 0 1 1 1 1 1 1 1 2 2 2 3 4
180 0 0 1 1 1 1 2 2 2 2 2 3 4 4 5 7
160 0 0 0 0 1 1 1 1 1 1 1 2 2 2 3 4
140
40
0 0 0 0 0 0 0 1 0 1 1 1 1 1 2 2
120 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1
4 5 6 7 4 5 6 7 4 5 6 7 4 5 6 7
©ESC 2019
Total cholesterol (mmol/L)
Figure 1 Systematic Coronary Risk Estimation chart for European populations at high cardiovascular disease risk. The 10-year risk of fatal cardiovascular
disease in populations at high cardiovascular disease risk based on the following risk factors: age, gender, smoking, systolic blood pressure, and total choles-
terol. To convert the risk of fatal cardiovascular disease to risk of total (fatal þ non-fatal) cardiovascular disease, multiply by 3 in men and by 4 in women,
and slightly less in older people. Note: the Systematic Coronary Risk Estimation chart is for use in people without overt cardiovascular disease, diabetes
(type 1 and 2), chronic kidney disease, familial hypercholesterolaemia, or very high levels of individual risk factors because such people are already at high-
risk and need intensive risk factor management. Cholesterol: 1 mmol/L = 38.67 mg/dL. The SCORE risk charts presented above differ slightly from those in
the 2016 European Society of Cardiology/European Atherosclerosis Society Guidelines for the management of dyslipidaemias and the 2016 European
Guidelines on cardiovascular disease prevention in clinical practice, in that: (i) age has been extended from age 65 to 70; (ii) the interaction between age
and each of the other risk factors has been incorporated, thus reducing the overestimation of risk in older persons in the original Systematic Coronary
Risk Estimation charts; and (iii) the cholesterol band of 8 mmol/L has been removed, since such persons will qualify for further evaluation in any event.
SCORE = Systematic Coronary Risk Estimation.
ESC/EAS Guidelines 13
WOMEN MEN
180 4 4 5 5 7 7 8 9 8 9 10 12 12 14 16 18
160 3 3 4 4 5 6 6 7 6 7 8 9 9 11 12 14
140
65
2 3 3 3 4 4 5 5 5 5 6 7 7 8 9 11
120 2 2 2 2 3 3 3 4 3 4 5 5 5 6 7 8
Systolic blood pressure (mmHg)
180 2 3 3 3 4 5 5 6 5 6 7 8 8 10 11 13
160 2 2 2 2 3 3 4 4 4 4 5 5 6 7 8 9
60
140 1 1 1 2 2 2 3 3 3 3 3 4 4 5 6 7
120 1 1 1 1 2 2 2 2 2 2 2 3 3 4 4 5
180 1 1 2 2 3 3 3 4 3 4 4 5 6 7 8 9
160 1 1 1 1 2 2 2 3 2 2 3 3 4 4 5 6
55
140 1 1 1 1 1 1 1 2 1 2 2 2 3 3 3 4
120 0 0 0 1 1 1 1 1 1 1 1 2 2 2 2 3
180 1 1 1 1 2 2 2 3 2 2 3 3 4 5 5 6
160 0 0 1 1 1 1 1 2 1 1 2 2 2 3 3 4
50
140 0 0 0 0 1 1 1 1 1 1 1 1 1 2 2 3
120 0 0 0 0 0 0 0 1 0 1 1 1 1 1 1 2
180 0 0 0 0 1 1 1 1 1 1 1 1 2 2 3 3
160 0 0 0 0 0 0 0 1 0 0 1 1 1 1 1 2
140
40
0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1
120 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1
4 5 6 7 4 5 6 7 4 5 6 7 4 5 6 7
©ESC 2019
Total cholesterol (mmol/L)
Figure 2 Systematic Coronary Risk Estimation chart for European populations at low cardiovascular disease risk. The 10-year risk of fatal cardiovascular
disease in populations at low cardiovascular disease risk based on the following risk factors: age, gender, smoking, systolic blood pressure, and total choles-
terol. To convert the risk of fatal cardiovascular disease to risk of total (fatal þ non-fatal) cardiovascular disease, multiply by 3 in men and by 4 in women,
and slightly less in older people. Note: the Systematic Coronary Risk Estimation chart is for use in people without overt cardiovascular disease, diabetes
(type 1 and 2), chronic kidney disease, familial hypercholesterolaemia, or very high levels of individual risk factors because such people are already at high-
risk and need intensive risk factor management. Cholesterol: 1 mmol/L=38.67 mg/dL. The SCORE risk charts presented above differ slightly from those in
the 2016 European Society of Cardiology/European Atherosclerosis Society Guidelines for the management of dyslipidaemias and the 2016 European
Guidelines on cardiovascular disease prevention in clinical practice, in that: (i) age has been extended from age 65 to 70; (ii) the interaction between age
and each of the other risk factors has been incorporated, thus reducing the overestimation of risk in older persons in the original Systematic Coronary
Risk Estimation charts; and (iii) the cholesterol band of 8 mmol/L has been removed since such persons will qualify for further evaluation in any event.
SCORE = Systematic Coronary Risk Estimation.
14 ESC/EAS Guidelines
To estimate a person’s 10-year risk of CVD death, find the table for his/
her gender, smoking status, and age. Within the table, find the cell nearest
to the person’s BP and TC. Risk estimates will need to be adjusted
Box 4 Factors modifying Systematic Coronary Risk
Estimation risks
upwards as the person approaches the next age category.
Risk is initially assessed on the level of TC and systolic BP before treat- Social deprivation: the origin of many of the causes of CVD.
ment, if known. The longer the treatment and the more effective it is, the Obesity and central obesity as measured by the body mass index and
greater the reduction in risk, but in general it will not be more than about waist circumference, respectively.
one-third of the baseline risk. For example, for a person on antihyperten- Physical inactivity.
sive drug treatment in whom the pre-treatment BP is not known, if the Psychosocial stress including vital exhaustion.
total CV SCORE risk is 6%, then the pre-treatment total CV risk may Family history of premature CVD (men: <55 years and women: <60
have been 9%. years).
Low-risk persons should be offered advice to maintain their low-risk sta- Chronic immune-mediated inflammatory disorder.
tus. While no threshold is universally applicable, the intensity of advice
Major psychiatric disorders.
should increase with increasing risk.
Treatment for human immunodeficiency virus infection.
The charts may be used to give some indication of the effects of reducing
Atrial fibrillation.
risk factors, given that there is apparently a time lag before the risk
Left ventricular hypertrophy.
reduces. In general, people who stop smoking halve their cumulative risk
over a relatively short period of time. Chronic kidney disease.
Obstructive sleep apnoea syndrome.
BP = blood pressure; CV = cardiovascular; CVD = cardiovascular disease;
SCORE = Systematic Coronary Risk Estimation; TC = total cholesterol. Non-alcoholic fatty liver disease.
CVD = cardiovascular disease.
ESC/EAS Guidelines 15
A total CV risk estimate is part of a continuum. The cut-off points Low-risk Calculated SCORE <1% for 10-year risk of fatal CVD.
that are used to define high-risk are, in part, both arbitrary and based ASCVD = atherosclerotic cardiovascular disease; ACS = acute coronary syn-
drome; BP = blood pressure; CABG = coronary artery bypass graft surgery;
on the risk levels at which benefit is evident in clinical trials. In clinical CKD = chronic kidney disease; CT = computed tomography; CVD = cardiovas-
practice, consideration should be given to practical issues in relation cular disease; DM = diabetes mellitus; eGFR = estimated glomerular filtration
to the local healthcare systems. Not only should those at high risk be rate; FH = familial hypercholesterolaemia; LDL-C = low-density lipoprotein cho-
lesterol; MI = myocardial infarction; PCI = percutaneous coronary intervention;
identified and managed, but those at moderate risk should also SCORE = Systematic Coronary Risk Estimation; T1DM = type 1 DM; T2DM =
receive professional advice regarding lifestyle changes; in some cases, type 2 DM; TC = total cholesterol; TIA = transient ischaemic attack.
a
drug therapy will be needed to reduce atherosclerotic risk. Target organ damage is defined as microalbuminuria, retinopathy, or neuropathy.
16 ESC/EAS Guidelines
Table 5 Intervention strategies as a function of total cardiovascular risk and untreated low-density lipoprotein choles-
terol levels
Total CV risk Untreated LDL-C levels
(SCORE) %
........................................................................................................................................................................
<1.4 mmol/L 1.4 to <1.8 1.8 to <2.6 2.6 to <3.0 3.0 to <4.9 4.9 mmol/L
(55 mg/dL) mmol/L (55 mmol/L (70 mmol/L (100 mmol/L (116 to (190 mg/dL)
to <70 mg/dL) to <100 mg/dL) to <116 mg/dL) <190 mg/dL)
Primary <1, low-risk Lifestyle Lifestyle advice Lifestyle advice Lifestyle advice Lifestyle inter- Lifestyle inter-
prevention advice vention, con- vention and
sider adding concomitant
drug if drug
uncontrolled intervention
Classa/Levelb I/C I/C I/C I/C IIa/A IIa/A
1 to <5, or Lifestyle Lifestyle advice Lifestyle advice Lifestyle inter- Lifestyle inter- Lifestyle inter-
moderate risk advice vention, con- vention, con- vention and
(see Table 4) sider adding sider adding concomitant
drug if drug if drug
uncontrolled uncontrolled intervention
Classa/Levelb I/C I/C IIa/A IIa/A IIa/A IIa/A
5 to <10, or Lifestyle Lifestyle advice Lifestyle inter- Lifestyle inter- Lifestyle inter- Lifestyle inter-
high-risk advice vention, con- vention and con- vention and vention and
(see Table 4) sider adding comitant drug concomitant concomitant
drug if intervention drug drug
uncontrolled intervention intervention
Classa/Levelb IIa/A IIa/A IIa/A I/A I/A I/A
10, or at Lifestyle Lifestyle inter- Lifestyle inter- Lifestyle inter- Lifestyle inter- Lifestyle inter-
very-high advice vention, con- vention and vention and con- vention and vention and
risk due sider adding concomitant comitant drug concomitant concomitant
to a risk condi- drug if drug intervention drug drug
tion uncontrolled intervention intervention intervention
(see Table 4)
Classa/Levelb IIa/B IIa/A I/A I/A I/A I/A
Secondary Very-high-risk Lifestyle inter- Lifestyle inter- Lifestyle inter- Lifestyle inter- Lifestyle inter- Lifestyle inter-
prevention vention, con- vention and vention and vention and con- vention and vention and
sider adding concomitant concomitant comitant drug concomitant concomitant
drug if drug drug intervention drug drug
uncontrolled intervention intervention intervention intervention
Classa/Levelb IIa/A I/A I/A I/A I/A I/A
CV = cardiovascular; LDL-C = low-density lipoprotein cholesterol; SCORE = Systematic Coronary Risk Estimation.
a
Class of recommendation.
b
Level of evidence.
ESC/EAS Guidelines 17
follow-up period was low (1.54.9%).26 In contrast, the rates of .. reduction is proportional to the absolute reduction in LDL-C and the
..
ASCVD and coronary heart disease (CHD) events in individuals with .. absolute reduction in LDL-C resulting from a particular drug regimen
a CAC score >100 Agatston were 18.9 and 12.7 per 1000 person-
.. depends only on baseline LDL-C, at any given level of baseline risk the
..
years, respectively.18 Compared with a strategy of treating all .. higher the initial LDL-C level the greater the absolute reduction in
patients, the use of CAC score to guide long-term statin therapy has
.. risk. Advice on individual drug treatments is given in section 8.
been shown to be cost-effective.27 Note that CAC score is often
very low in patients younger than 45 years of age with severe familial Recommendations for cardiovascular disease risk
..
lipoproteins retained in the arterial wall provoke a complex process .. between the absolute changes in plasma LDL-C and the risk of
that leads to lipid deposition and the initiation of an atheroma.43 .. ASCVD.34,4550 The remarkable consistency among these studies, in
..
Continued exposure to ApoB-containing lipoproteins leads to .. addition to biological and experimental evidence, provides compel-
additional particles being retained over time in the artery wall, and to .. ling evidence that LDL-C is causally associated with the risk of
..
the growth and progression of atherosclerotic plaques. On average, .. ASCVD, and that lowering LDL-C reduces the risk of ASCVD pro-
people with higher concentrations of plasma ApoB-containing lipo- .. portionally to the absolute achieved reduction in LDL-C.2,51
..
proteins will retain more particles and accumulate lipids faster, result- .. Furthermore, Mendelian randomization studies have demon-
ing in more rapid growth and the progression of atherosclerotic .. strated that long-term exposure to lower LDL-C levels is associated
..
plaques. .. with a much lower risk of CV events as compared with shorter-term
Because atherosclerotic plaques grow over time as additional .. exposure to lower LDL-C (as achieved, for example, in randomized
..
ApoB-containing lipoprotein particles are retained, the size of the .. trials).48,52 These data provide strong support for the concept that
total atherosclerotic plaque burden is likely to be determined by
.. LDL particles have both a causal and cumulative effect on the risk of
..
both the concentration of circulating LDL-C and other ApoB-con- .. ASCVD. Therefore, the effect of LDL-C on the risk of ASCVD
taining lipoproteins, and by the total duration of exposure to these
.. appears to be determined by both the absolute magnitude and the
..
lipoproteins. Therefore, a person’s total atherosclerotic plaque bur- .. total duration of exposure to LDL-C.2
den is likely to be proportional to the cumulative exposure to these
.. The clinical benefit of lowering LDL-C is determined by the reduc-
..
lipoproteins.44 .. tion in circulating LDL particles as estimated by ApoB, which is usually
Eventually, the increase of the atherosclerotic plaque burden along
.. mirrored by a reduction of cholesterol carried by those particles.2,53
..
with changes in the composition of the plaque reaches a critical point .. Therefore, the clinical benefit of therapies that lower LDL-C by
..
at which disruption of a plaque can result, with the formation of an .. reducing LDL particle mass will be proportional to the absolute
overlying thrombus that acutely obstructs blood flow resulting in .. reduction in LDL-C, because—on average—the reduction in LDL-C
..
unstable angina, myocardial infarction (MI), or death. Therefore, the .. and LDL particles will be concordant.34,50,54,55 In contrast, the clinical
risk of experiencing an acute ASCVD event rises rapidly as more .. benefit of therapies that lower LDL-C by a mechanism that may dra-
..
ApoB-containing lipoproteins become retained and the atherosclerotic .. matically modify their composition may not be proportional to the
plaque burden increases. This provides the rationale for encouraging a .. observed absolute reduction in LDL-C, but instead would be
..
healthy lifestyle to maintain low levels of ApoB-containing lipoproteins .. expected to be proportional to the absolute change in LDL particle
throughout life to slow the progression of atherosclerosis; it also .. concentration as measured by a reduction in ApoB.2,53
..
explains the motivation to recommend treatment to lower LDL-C and ..
other ApoB-containing lipoproteins, for both the primary prevention ..
.. 5.3.2 Triglyceride-rich lipoproteins and risk of
of ASCVD and the secondary prevention of recurrent CV events.44 ..
.. atherosclerosis
.. TG-rich VLDL particles and their remnants carry most of the circulat-
5.3 Evidence for the causal effects of ..
.. ing TGs. Therefore, the plasma TG concentration reflects the con-
lipids and lipoproteins on the risk of .. centration of circulating ApoB-containing TG-rich lipoproteins.
..
atherosclerotic cardiovascular disease .. Elevated plasma TG levels are associated with an increasing risk of
5.3.1 Low-density lipoprotein cholesterol and risk of .. ASCVD, but this association becomes null after adjusting for non-
..
atherosclerosis .. HDL-C, an estimate of the total concentration of all ApoB-containing
Plasma LDL-C is a measure of the cholesterol mass carried by LDL .. lipoproteins.45 Similarly, lowering TG with fibrates reduces the risk of
..
particles, by far the most numerous of the ApoB-containing lipopro- .. CV events by the same amount as LDL-C-lowering therapies when
teins, and is an estimate of the concentration of circulating LDL.
.. measured per unit change of non-HDL-C,50 suggesting that the effect
..
Numerous epidemiological studies, Mendelian randomization studies, .. of plasma TGs on ASCVD is mediated by changes in the concentra-
and RCTs have consistently demonstrated a log-linear relationship
.. tion of TG-rich lipoproteins as estimated by non-HDL-C.
ESC/EAS Guidelines 19
..
Mendelian randomization studies also suggest that the association .. plasminogen, and it has pro-inflammatory effects most likely related
between plasma TGs and the risk of CHD may be causal; however, .. to the oxidized phospholipid load carried by Lp(a).71
..
this evidence must be interpreted with caution because nearly all var- .. Higher plasma Lp(a) concentrations are associated with an
iants associated with TGs are also associated with HDL-C, LDL-C, or .. increased risk of ASCVD, but it appears to be a much weaker risk fac-
..
Lp(a).5659 A recent Mendelian randomization study demonstrated .. tor for most people than LDL-C.72,73 In contrast, Mendelian random-
that TG-lowering lipoprotein lipase (LPL) variants and LDL-C-lower- .. ization studies have consistently demonstrated that lifelong exposure
..
ing LDL receptor variants had the same effect on the risk of ASCVD .. to higher Lp(a) levels is strongly and causally associated with an
..
5.4.2 Lipid measurements .. needed to establish a reliable and reproducible method for the quan-
In clinical practice, the concentration of plasma lipoproteins is not .. tification of Lp(a) mass or particle number.92
..
usually measured directly but is instead estimated by measuring their ..
cholesterol content. TC in humans is distributed primarily among ..
.. 5.4.3 Fasting or non-fasting?
three major lipoprotein classes: VLDL, LDL, and HDL. Smaller .. Traditionally, blood sampling for lipid analyses has been recom-
amounts of cholesterol are also contained in two minor lipoprotein
..
.. mended in the fasting state. Recent systematic studies comparing fast-
classes: IDL and Lp(a). A standard serum lipid profile measures the .. ing and non-fasting samples have suggested that the difference is
..
20% of patients there may be discordance between measured LDL-C ..
..
6 Treatment targets and goals
and ApoB levels.85,109
..
Considering the potential inaccuracy of LDL-C in dyslipidaemia, .. In previous EAS/ESC Guidelines for the management of dyslipidae-
among patients with DM or high TG levels, and in patients with very .. mias1,113 and other major guidelines on the treatment of blood cho-
..
low LDL-C levels, measurement of both ApoB and non-HDL-C is .. lesterol to reduce atherosclerotic CV risk in adults,40,114 the
recommended as part of routine lipid analysis for risk evaluation in .. importance of LDL-C lowering to prevent ASCVD is strongly
..
patients with elevated plasma TGs. Because ApoB provides an accu- .. emphasized. The European Task Force felt that limiting the current
TC is to be used for the estimation of total CV risk by means of the SCORE system. I C
HDL-C analysis is recommended to further refine risk estimation using the online SCORE system. I C
LDL-C analysis is recommended as the primary lipid analysis method for screening, diagnosis, and management. I C
TG analysis is recommended as part of the routine lipid analysis process. I C
Non-HDL-C evaluation is recommended for risk assessment, particularly in people with high TG levels, DM, obesity, or
I C
very low LDL-C levels.
ApoB analysis is recommended for risk assessment, particularly in people with high TG levels, DM, obesity, metabolic syn-
drome, or very low LDL-C levels. It can be used as an alternative to LDL-C, if available, as the primary measurement for
I C
screening, diagnosis, and management, and may be preferred over non-HDL-C in people with high TG levels, DM, obesity,
or very low LDL-C levels.
Lp(a) measurement should be considered at least once in each adult person’s lifetime to identify those with very high
inherited Lp(a) levels >180 mg/dL (>430 nmol/L) who may have a lifetime risk of ASCVD equivalent to the risk associated IIa C
with heterozygous familial hypercholesterolaemia.
Lp(a) should be considered in selected patients with a family history of premature CVD, and for reclassification in people
IIa C
who are borderline between moderate and high-risk.
Apo = apolipoprotein; ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; CVD = cardiovascular disease; DM = diabetes mellitus; HDL-C = high-density lip-
oprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein(a); SCORE = Systematic Coronary Risk Estimation; TC = total cholesterol; TG =
triglyceride.
22 ESC/EAS Guidelines
treatment, although this consensus opinion has not been fully tested.
.. Secondary goals have also been defined by inference for non-
..
For all these reasons, the European Task Force retains a goal .. HDL-C and for ApoB; they receive a moderate grading, as they have
approach to lipid management and treatment goals are tailored to ... not been extensively studied in RCTs. The specific goal for non-
..
the total CV risk level. There is also evidence suggesting that lowering .. HDL-C should be 0.8 mmol/L (30 mg/dL) higher than the corre-
of LDL-C beyond the goals that were set in the previous EAS/ESC .. sponding LDL-C goal; the adjustment of lipid-lowering therapy in
..
Guidelines is associated with fewer ASCVD events.34,116,117 .. accordance with these secondary goals may be considered in patients
Therefore, it seems appropriate to reduce LDL-C to as low a level as .. at very high CV risk after achievement of an LDL-C goal, although the
..
In secondary prevention for patients at very-high risk,c an LDL-C reduction of >_50% from baselined and an LDL-C goal of
I A
<1.4 mmol/L (<55 mg/dL) are recommended.3335,119,120
In primary prevention for individuals at very-high risk but without FH,c an LDL-C reduction of >_50% from baselined and
I C
an LDL-C goal of <1.4 mmol/L (<55 mg/dL) are recommended.3436
In primary prevention for individuals with FH at very-high risk, an LDL-C reduction of >_50% from baseline and an LDL-C
IIa C
goal of <1.4 mmol/L (<55 mg/dL) should be considered.
For patients with ASCVD who experience a second vascular event within 2 years (not necessarily of the same type as the
first event) while taking maximally tolerated statin-based therapy, an LDL-C goal of <1.0 mmol/L (<40 mg/dL) may be IIb B
considered.119,120
In patients at high risk,c an LDL-C reduction of >_50% from baselined and an LDL-C goal of <1.8 mmol/L (<70 mg/dL) are
I A
recommended.34,35
In individuals at moderate risk,c an LDL-C goal of <2.6 mmol/L (<100 mg/dL) should be considered.34 IIa A
c 36
In individuals at low risk, an LDL-C goal <3.0 mmol/L (<116 mg/dL) may be considered. IIb A
ASCVD = atherosclerotic cardiovascular disease; FH = familial hypercholesterolaemia; LDL-C = low-density lipoprotein cholesterol.
a
Class of recommendation.
b
Level of evidence.
c
For definitions see Table 4.
d
The term ‘baseline’ refers to the LDL-C level in a person not taking any LDL-C-lowering medication. In people who are taking LDL-C-lowering medication(s), the projected
baseline (untreated) LDL-C levels should be estimated, based on the average LDL-C-lowering efficacy of the given medication or combination of medications.
ESC/EAS Guidelines 23
Table 8 summarizes the currently available evidence on the influen- .. ranges from 0.26.5% of the total energy intake in different popula-
..
ces of lifestyle changes and functional foods on lipoproteins, indicat- .. tions.165 Unsaturated fat-rich oils from safflower, sunflower,
ing the magnitudes of the effects and the levels of evidence in relation
.. rapeseed, flaxseed, corn, olives, or soybean were shown to reduce
..
to the impacts on the specific lipoprotein class; for the reasons out- .. LDL-C levels (-0.42 to -0.20 mmol/L) when used in substitution of
lined above, the levels of evidence are not based on RCTs with
.. SFA-rich foods like butter or lard.166 The effects of carbohydrate
..
ASCVD endpoints. Moreover, within the Guidelines on the manage- .. consumption on LDL-C are described in section 7.4.3.
ment of dyslipidaemias, information on the potential to improve
.. Body weight reduction also influences TC and LDL-C levels, but
..
plasma lipoprotein profiles by dietary means is clinically relevant, .. the magnitude of the effect is small: in obese people, a decrease in
..
even in the absence of a clear demonstration of CV benefits. .. LDL-C concentration of 0.2 mmol/L (8 mg/dL) is observed for every
.. 10 kg of weight loss.147,167 The reduction of LDL-C levels induced by
..
7.1 Influence of lifestyle on total .. regular physical exercise is even smaller.151,168 The benefits of weight
cholesterol and low-density lipoprotein ... reduction and physical exercise on the CV risk profile likely impact
.. on other risk factors, especially hypertension and diabetes.
cholesterol levels ..
.. Table 9 summarizes the possible choices of foods to lower TC and
Saturated fatty acids (SFAs) are the dietary factor with the greatest .. LDL-C levels. Given the cultural diversity of the European popula-
impact on LDL-C levels (0.020.04 mmol/L or 0.81.6 mg/dL of ..
.. tions, they should be translated into practical behaviours, considering
LDL-C increase for every additional 1% energy coming from satu- .. local habits and socio-economic factors.
rated fat).164 Quantitatively, dietary trans fatty acids have a similar ele- ..
..
vating effect on LDL-C to that of SFAs; however, while SFAs increase ..
HDL-C levels, trans fats decrease them.137 Trans unsaturated fatty .. 7.2 Influence of lifestyle on triglyceride
..
acids can be found in limited amounts (usually <5% of total fat) in .. levels
dairy products and in meats from ruminants. ‘Partially hydrogenated
.. Weight reduction improves insulin sensitivity and decreases TG lev-
..
fatty acids’ of industrial origin represent the major source of trans .. els. Regular physical exercise reduces plasma TG levels over and
fatty acids in the diet; the average consumption of trans fatty acids
.. above the effect of weight reduction.151,168,169 Alcohol intake has a
ESC/EAS Guidelines 25
Table 9 Food choices to lower low-density lipoprotein cholesterol and improve the overall lipoprotein profile
To be preferred To be used in moderation To be chosen occasionally in
limited amounts
Cereals Wholegrains Refined bread, rice, and pasta, bis- Pastries, muffins, pies, croissants
cuits, corn flakes
Vegetables Raw and cooked vegetables Potatoes Vegetables prepared in butter or
..
major impact on TG levels, particularly in individuals with HTG.153,170 .. particularly to people at increased CV risk, may also be able to mod-
The detrimental effects of a high-carbohydrate diet on TGs occur .. ify plasma TG and HDL-C levels (Table 9). This section focuses on
..
mainly when refined carbohydrate-rich foods are consumed, while .. dietary and other lifestyle factors that may be implemented to
they are much less prominent if the diet is based largely on fibre-rich, .. improve the overall lipoprotein profile.
..
low-glycaemic index foods. This applies particularly to people with ..
DM or MetS.171,172 ..
.. 7.4.1 Body weight and physical activity
Habitual consumption of significant amounts (>10% energy) of .. Since overweight, obesity, and—in particular—abdominal adiposity
dietary fructose contributes to TG elevation, particularly in people ..
.. often contribute to dyslipidaemia, caloric intake should be reduced
with HTG or abdominal obesity. These effects are dose-dependent; .. and energy expenditure increased in those with excessive weight
with a habitual fructose consumption between 1520% of total ..
.. and/or abdominal adiposity.
energy intake, plasma TG increases by as much as 3040%. Sucrose, .. In the case of excess weight, body weight reduction, even if modest
a disaccharide containing glucose and fructose, represents an impor-
..
.. (510% of basal body weight), improves lipid abnormalities and
tant source of fructose in the diet.159,173,174 .. favourably affects the other CV risk factors often present in dyslipidae-
..
.. mic individuals.148 While the beneficial effects of weight reduction on
7.3 Influence of lifestyle on high-density .. metabolic and surrogate markers have been demonstrated, the bene-
..
lipoprotein cholesterol levels .. fits of weight loss on mortality and CV outcome are less clear.175
Weight reduction increases HDL-C levels; a 0.01 mmol/L (0.4 mg/ .. Weight reduction can be achieved by decreasing the consumption
..
dL) increase is observed for every kilogram decrease in body weight .. of energy-dense foods, inducing a caloric deficit of 300500 kcal/day.
when weight reduction has stabilized. Aerobic physical activity, such
.. The intervention should combine diet and exercise; this approach
..
as 2530 km of brisk walking per week (or any equivalent activity), .. also leads to the greatest improvement in physical performance and
may increase HDL-C levels by 0.080.15 mmol/L (3.16 mg/dL).169
.. quality of life, and mitigates reductions in muscle and bone mass, par-
..
Smoking cessation may also contribute to HDL-C elevation, provided .. ticularly in older people.176 It is always appropriate to advise people
that weight gain is prevented.163
.. with dyslipidaemia to engage in regular physical exercise of moderate
..
.. intensity for >_30 min/day, even if they are not overweight.168
7.4 Lifestyle recommendations to ..
..
improve the plasma lipid profile .. 7.4.2 Dietary fat
..
LDL-C lowering represents the primary target for reducing CV risk .. Avoiding any consumption of trans fat is a key measure of the dietary
and therefore deserves special emphasis in the evaluation of lifestyle
.. prevention of CVD. The trans fatty acids produced in the partial hydro-
..
measures. The diet recommended to the general population, and . genation of vegetable oils account for 80% of total intake. Thanks to
26 ESC/EAS Guidelines
..
efforts made in different parts of the world, the intake of trans fatty .. 7.4.5 Smoking
acids has decreased substantially over the past 1015 years. .. Smoking cessation has clear benefits regarding overall CV risk, and
..
As for saturated fat, its consumption should be <10% of the total .. specifically on HDL-C levels.163
caloric intake and should be further reduced (<7% of energy) in the ..
..
presence of hypercholesterolaemia. For most individuals, a wide .. 7.5 Dietary supplements and functional
range of total fat intakes is acceptable, and will depend upon individ- ..
.. foods for the treatment of dyslipidaemias
ual preferences and characteristics. However, fat intakes >3540% .. Nutritional evaluation of functional foods includes not only the
..
plasma cholesterol concentrations who do not qualify for treatment .. 8 Drugs for treatment of
with statins in view of their global CV risk. However, there is a clear ..
.. dyslipidaemias
need for better regulation of RYR supplements. Information regard- ..
ing the precise composition of these products, the quantities of their ..
.. 8.1 Statins
components, and their purity should be implemented.185 .. 8.1.1 Mechanism of action
..
.. Statins reduce the synthesis of cholesterol in the liver by competi-
..
slightly, increased frequency of muscle symptoms in statin- .. have yielded conflicting findings and there is a need for further explo-
..
allocated groups.239,240 The Anglo-Scandinavian Cardiac .. ration of the risk of haemorrhagic stroke in particular types of
Outcomes Trial Lipid-Lowering Arm (ASCOT-LLA) study .. patients. Note, however, that the overall benefit on other stroke sub-
..
addressed this issue by comparing the incidence of four different .. types greatly outweighs this small (and uncertain) hazard.34,36
adverse events, including muscle-related symptoms, during both
..
..
the blinded, placebo-controlled trial and its open-label extension .. 8.1.4.5 Adverse effects on kidney function. There is no clear evidence
study.238 They concluded that a nocebo effect (i.e. one caused by
.. that statins have a clinically significant beneficial or adverse effect on
..
..
8.2 Cholesterol absorption inhibitors .. although significant and in line with the CTT expectations.268
8.2.1 Mechanism of action
.. Therefore, the study supports the proposition that LDL-C lowering
..
Ezetimibe inhibits intestinal uptake of dietary and biliary cholesterol .. by means other than statins is beneficial and safe. The beneficial effect
.. of ezetimibe is also supported by genetic studies of mutations in
at the level of the brush border of the intestine [by interacting with ..
the Niemann-Pick C1-like protein 1 (NPC1L1)] without affecting the .. NPC1L1; naturally occurring mutations that inactivate the protein
.. were found to be associated with reduced plasma LDL-C and
absorption of fat-soluble nutrients. By inhibiting cholesterol absorp- ..
tion, ezetimibe reduces the amount of cholesterol delivered to the .. reduced risk for CAD.55,269,270
..
performed before many of the modern treatment options were .. majority of patients, including those with HeFH and, albeit to a lower
available.276278 .. level, those with HoFH with residual LDLR expression. Receptor-
..
.. deficient HoFH responds poorly to the therapy.285
..
8.3.4 Adverse effects and interactions ..
Gastrointestinal (GI) adverse effects (most commonly flatulence, .. 8.4.2.2 Triglycerides and high-density lipoprotein cholesterol. These
.
constipation, dyspepsia, and nausea) are often present with these .. highly efficacious LDL-lowering agents also lower TG levels, and
.
drugs, even at low doses, which limits their practical use. These .. increase those of HDL-C and ApoA-I as a function of the dosing regi-
..
The ODYSSEY Outcomes trial randomized 18 924 patients after .. Lomitapide is an MTP inhibitor designed for o.d. oral treatment of
hospitalization for acute MI or unstable angina, treated with statins, .. HoFH. In an open-label, single-arm titration study evaluating lomita-
..
and with LDL-C >_1.8 mmol/L (>_70 mg/dL), non-HDL cholesterol .. pide as adjunct therapy to statins, with or without apheresis and a
>_2.6 mmol/L (>_100 mg/dL), or ApoB >_80 mg/dL, to receive injec- .. low-fat diet,301 LDL-C was reduced by 50% from baseline at 26
..
tions of alirocumab or matching placebo. Allocation to alirocumab .. weeks and by 44% at 56 weeks. Lomitapide was also shown to
reduced the mean baseline LDL-C from 2.38 mmol/L (92 mg/dL) to .. decrease the frequency of apheresis in HoFH patients. It should be
..
1.24 mmol/L (48 mg/dL) at 12 months. There was a 15% relative .. noted that the drug’s effect on CV outcomes has not yet been
..
TG-lowering effects of fibrates have been reported to be markedly .. As a class, fibrates have been reported to raise both serum creati-
less (5 and 20%, respectively) in long-term intervention trials in .. nine and homocysteine levels in both short- and long-term studies.
..
people with T2DM but without elevated levels of TGs.306,307 .. The increase of serum creatinine by fibrate therapy seems to be fully
.. reversible when the drug is stopped. Data from meta-analyses sug-
..
.. gest that a reduction of calculated glomerular filtration rate (GFR)
8.7.3 Effect on cardiovascular morbidity and mortality .. does not reflect any adverse effects on kidney function.315 Fibrates
..
The clinical effects of fibrates have been primarily illustrated by six .. are associated with a slightly increased risk of pancreatitis.321 The
..
ASCVD outcomes in people with elevated serum TGs; the trial .. which raises HDL-C levels by 130% and lowers LDL-C by 37%, was
enrolled 8000 patients on statin therapy, with LDL-C levels .. studied in the ACCELERATE trial,63 which was terminated due to
..
between 1.02.6 mmol/L (41100 mg/dL) and various CV risk fac- .. futility. Recently, anacetrapib, which raises HDL-C and ApoA-I levels
tors, including persistent elevated TGs between 1.75.6 mmol/L .. (by 104 and 36%, respectively), and lowers LDL-C and ApoB (by 17
..
(150499 mg/dL), and either established ASCVD or DM, and at least .. and 18%, respectively), was studied in the REVEAL trial. Anacetrapib
one other CV risk factor. Use of high doses (2 g b.i.d.) of EPA as com- .. reduced major coronary events by 9% over a median of 4.1 years.64
..
pared with placebo (mineral oil) resulted in a 25% relative risk .. The magnitude of the relative risk reduction appeared to be consis-
It is recommended that a high-intensity statin is prescribed up to the highest tolerated dose to reach the goals set for the
I A
specific level of risk.32,34,38
If the goalsc are not achieved with the maximum tolerated dose of a statin, combination with ezetimibe is
I B
recommended.33
For primary prevention patients at very-high risk, but without FH, if the LDL-C goal is not achieved on a maximum toler-
IIb C
ated dose of a statin and ezetimibe, a combination with a PCSK9 inhibitor may be considered.
For secondary prevention, patients at very-high risk not achieving their goalc on a maximum tolerated dose of a statin and
I A
ezetimibe, a combination with a PCSK9 inhibitor is recommended.119,120
For very-high-risk FH patients (that is, with ASCVD or with another major risk factor) who do not achieve their goalc on
I C
a maximum tolerated dose of a statin and ezetimibe, a combination with a PCSK9 inhibitor is recommended.
If a statin-based regimen is not tolerated at any dosage (even after rechallenge), ezetimibe should be considered.197,265,353 IIa C
If a statin-based regimen is not tolerated at any dosage (even after rechallenge), a PCSK9 inhibitor added to ezetimibe
IIb C
may also be considered.197,265,353
If the goalc is not achieved, statin combination with a bile acid sequestrant may be considered. IIb C
ASCVD = atherosclerotic cardiovascular disease; FH = familial hypercholesterolaemia; LDL-C = low-density lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin/
kexin type 9.
a
Class of recommendation.
b
Level of evidence.
c
For definitions see Table 7.
36 ESC/EAS Guidelines
©ESC 2019
Absolute risk reduction
Figure 3 Expected clinical benefits of low-density lipoprotein cholesterol-lowering therapies. The expected clinical benefits of treatment to lower low-
density lipoprotein cholesterol for any person can be estimated; it depends on the intensity of therapy, the baseline low-density lipoprotein cholesterol
level, the expected absolute achieved reduction in low-density lipoprotein cholesterol, and the baseline estimated risk of atherosclerotic cardiovascular
disease. The intensity of therapy should be selected to achieve the recommended proportional reduction in low-density lipoprotein cholesterol based on
the person’s estimated risk of atherosclerotic cardiovascular disease. Multiplying the proportional reduction in low-density lipoprotein cholesterol by a
person’s baseline low-density lipoprotein cholesterol level estimates the expected absolute reduction in low-density lipoprotein cholesterol that is likely
to be achieved with that therapy. Because each 1.0 mmol/L absolute reduction in low-density lipoprotein cholesterol is associated with a 20% reduction in
the risk of cardiovascular events, larger absolute reductions in low-density lipoprotein cholesterol lead to larger proportional reductions in risk.
Multiplying the proportional reduction in risk expected for the achieved absolute reduction in low-density lipoprotein cholesterol by a person’s estimated
baseline risk of atherosclerotic cardiovascular disease determines the expected absolute risk reduction for that person. LDL-C = low-density lipoprotein
cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9.
ESC/EAS Guidelines 37
Risk modifiers
imaging (subclinical atherosclerosis)
Risk Reclassification?
Y N
Define treatment goal Lifestyle advice /
See Table 7 Lifestyle intervention
Y N
Follow-up
Annually, or more frequently Add ezetimibe
if indicated
Y N
• Secondary prevention (very-high-risk)
Follow-up
• Primary prevention: patients with
Annually, or more frequently Add PCSK9 inhibitor
FH and another major risk factor
if indicated
(very-high risk)
B Treatment goal
for LDL-C • SCORE <1%
• SCORE ≥1% and <5%
• Young patients (T1DM <35 years;
T2DM <50 years) with DM duration
3.0 mmol/L
(116 mg/dL)
Low <10 years without other risk factors
1.8 mmol/L
(70 mg/dL)
High • ASCVD (clinical/imaging)
• SCORE ≥10%
& ≥50% • FH with ASCVD or with another
reduction major risk factor
• Severe CKD (eGFR <30 mL/min)
from • DM & target organ damage: ≥3
1.4 mmol/L
baseline Very High major risk factors; or early onset of
(55 mg/dL) T1DM of long duration (>20 years)
©ESC 2019
Figure 4 (A) Treatment algorithm for pharmacological low-density lipoprotein cholesterol lowering. (B) Treatment goals for low-density lipoprotein
cholesterol across categories of total cardiovascular disease risk. ASCVD = atherosclerotic cardiovascular disease; BP = blood pressure; CKD = chronic
kidney disease; CV = cardiovascular; DM = diabetes mellitus; eGFR = estimated glomerular filtration rate; FH = familial hypercholesterolaemia; LDL-C =
low-density lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9; SCORE = Systematic Coronary Risk Estimation; T1DM =
type 1 DM; T2DM = type 2 DM; TC = total cholesterol.
38 ESC/EAS Guidelines
..
outcomes.354 Recently, the REDUCE-IT trial194 demonstrated that in .. among these, FH is the most common and is strongly related to CVD
statin-treated patients with high CV risk with fasting TG levels .. (Table 11). In general, in a patient with dyslipidaemia, the pattern of
..
between 135499 mg/dL (1.521.63 mmol/L), high-dose icosapent .. inheritance commonly does not suggest that there is a major single
ethyl, a highly purified and stable EPA (2 g) taken b.i.d., significantly .. gene (monogenic) disorder causing the abnormality; rather, it stems
..
reduced the risk of ischaemic events, including CV death, by about .. from the inheritance of more than one gene variant affecting lipopro-
one-quarter over a median follow-up of 4.9 years. In addition, the .. tein metabolism that, on its own, might have relatively little effect, but
..
VITAL trial showed that n-3 fatty acids at the lower dose of 1 g/day .. in combination with another or others has a greater influence on TC,
Table 12 Dutch Lipid Clinic Network diagnostic criteria for familial hypercholesterolaemia
Criteria Points
1) Family history
First-degree relative with known premature (men aged <55 years; women <60 years) coronary or vascular disease, 1
or first-degree relative with known LDL-C above the 95th percentile
First-degree relative with tendinous xanthomata and/or arcus cornealis, or children aged <18 years with LDL-C above the 95th percentile 2
2) Clinical history
Patient with premature (men aged <55 years; women <60 years) CAD 2
Patient with premature (men aged <55 years; women <60 years) cerebral or peripheral vascular disease 1
a
3) Physical examination
Tendinous xanthomata 6
Arcus cornealis before age 45 years 4
4) LDL-C levels (without treatment)
LDL-C >_8.5 mmol/L (>_325 mg/dL) 8
LDL-C 6.58.4 mmol/L (251325 mg/dL) 5
LDL-C 5.06.4 mmol/L (191250 mg/dL) 3
LDL-C 4.04.9 mmol/L (155190 mg/dL) 1
5) DNA analysis
Functional mutation in the LDLR, apoB, or PCSK9 genes 8
Choose only one score per group, the highest applicable; diagnosis is based on the total number of points obtained
A ‘definite’ FH diagnosis requires >8 points
A ‘probable’ FH diagnosis requires 68 points
A ‘possible’ FH diagnosis requires 35 points
CAD = coronary artery disease; FH = familial hypercholesterolaemia; LDL-C = low-density lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9.
a
Exclusive of each other (i.e. maximum 6 points if both are present).
40 ESC/EAS Guidelines
FH is a monogenic disease caused by loss-of-function mutations in Recommendations for the detection and treatment of
the LDLR or apoB genes, or a gain-of-function mutation in the PCSK9 patients with heterozygous familial hypercholesterolaemia
gene; around 95% of FH cases are caused by mutations in LDLR. More
Recommendations Classa Levelb
than 1000 different mutations that cause FH have been identified in
LDLR. The different mutations cause reduced function or complete It is recommended that a diagnosis of FH is
loss-of-function, the latter being associated with more severe hyper- considered in patients with CHD aged <55
cholesterolaemia and CVD. years for men and <60 years for women, in
..
undertaken. Restriction of calories and fat content (1015% recom- .. vascular events, major coronary events, coronary revascularization,
mended) in the diet, and alcohol abstinence are obligatory. Fibrate ther- .. and stroke were similar in women and men.35
..
apy (fenofibrate) should be initiated, with n-3 fatty acids (24 g/day) as ..
adjunct therapy. Lomitapide may also be considered in severe cases.37 In
..
.. 9.2.2 Non-statin lipid-lowering drugs
patients with DM, insulin therapy should be initiated to achieve good gly- ..
caemic control. In general, a sharp decrease of TG values is seen within
.. Definitive evidence of the cardioprotective effects of non-statin drugs
.. that lower LDL-C is now available, and the beneficial effects are simi-
25 days. In the acute setting, plasmapheresis is able to rapidly lower ..
the associated absolute increase in risk for a given increment in TC is .. 9.4 Diabetes and metabolic syndrome
..
larger with increasing age.217 .. The number of people with DM will increase from 415 million
..
.. today up to 550 million by 2030, but the situation may get even
9.3.1 Effects of statins in primary and secondary
.. worse.399 Despite significant advantages in the management strat-
..
prevention .. egies that lessen atherosclerotic CVD risk factors, CVD has remained
The use of statin therapy declines with increasing age, reflecting dif-
.. the leading cause of morbidity and mortality in patients with T2DM.
..
ferences in both prescription and compliance.395,396 This trend is .. The good news is that fatal CVD outcomes have declined significantly
Recommendations for the treatment of dyslipidaemias in older people (aged >65 years)
Treatment with statins is recommended for older people with ASCVD in the same way as for younger patients.217 I A
217
Treatment with statins is recommended for primary prevention, according to the level of risk, in older people aged <_75 years. I A
Initiation of statin treatment for primary prevention in older people aged >75 years may be considered, if at high-risk or above.217 IIb B
It is recommended that the statin is started at a low dose if there is significant renal impairment and/or the potential for drug
I C
interactions, and then titrated upwards to achieve LDL-C treatment goals.
..
the clearance of both TRLs and remnants, resulting in prolonged .. Ezetimibe lowers LDL-C by 24% and, when added to statin ther-
residence times of these particles in the circulation.413,414 In fact, .. apy, decreases the risk of major vascular events.33 The relative risk
..
the defective catabolism of TRLs seems to be a more important .. reduction in major vascular events is proportional to the absolute
contributor to the elevation of plasma TGs than the increased .. degree of LDL-C lowering and consistent with the relationship seen
..
production rate leading to an excess of remnant particles. .. for statins. The subset of patients with DM in IMPROVE-IT had, as
Together, TRL remnants, small dense LDL, and small dense HDL .. expected, a higher rate of major vascular events than patients with-
..
comprise the atherogenic lipid profile, which is also characterized .. out DM (46 vs. 31% 7 year KaplanMeier rate in the placebo arm).
..
9.5 Patients with acute coronary .. pronounced (46% relative risk reduction) in a post hoc analysis includ-
.. ing 865 ST-elevation MI (STEMI) patients undergoing reperfusion by
syndromes and patients undergoing ..
.. primary PCI.443 Based on current evidence, we recommend the initia-
percutaneous coronary intervention .. tion of high-intensity statin therapy during the first 14 days of hospi-
Patients who present with ACS are at increased risk of experiencing ..
.. talization for the index ACS.438442 Moreover, pre-treatment (or
recurrent CV events. For these patients, lipid management should be .. loading dose for patients already on a statin) with a high-intensity sta-
undertaken in the context of a comprehensive global risk reduction ..
.. tin should be considered in ACS patients with planned invasive
maximally tolerated statin dose and ezetimibe prior to the event, Recommendations for lipid-lowering therapy in very-
the addition of a PCSK9 inhibitor early after the event (during high-risk patients with acute coronary syndromes
the hospitalization for the ACS event if possible) should be
Recommendations Classa Levelb
considered.
In all ACS patients without any contraindica-
9.5.1.4 n-3 polyunsaturated fatty acids. Oral supplementation with tion or definite history of intolerance, it is rec-
highly purified n-3 PUFAs reduced mortality in survivors of MI in one ommended that high-dose statin therapy is I A
..
9.6 Stroke .. hospitalizations,218,471 as well as a small reduction in MI, was
Stroke has a heterogeneous aetiology, including cardiac throm-
.. observed in a pooled analysis of the Controlled Rosuvastatin
..
boembolism [often associated with atrial fibrillation, but also of .. Multinational Trial in Heart Failure (CORONA) and GISSI-HF tri-
.. als.472 Based on current evidence, routine administration of statins in
uncertain source (embolic stroke of undetermined source)], carotid ..
artery and proximal aortic atherosclerosis and thromboembolism, .. patients with HF without other indications for their use (e.g. CAD) is
.. not recommended. Because there is no evidence of harm in patients
small-vessel CVD, and intracranial haemorrhage (including intracere- ..
bral and subarachnoid haemorrhage). Dyslipidaemia may play a varia- .. on statin treatment after the occurrence of HF, there is no need for
..
Recommendations for lipid-lowering therapy in patients with HF .. whether statin therapy is effective in more advanced CKD, particularly
and valvular diseases are shown below. .. dialysis patients. By combining data from the three CKD trials with
..
.. other trials in the existing database, the CTT investigators found that,
Recommendations for the treatment of dyslipidaemias .. even after adjusting for the smaller LDL-C reductions achieved among
in chronic heart failure or valvular heart diseases ..
.. patients with more advanced CKD and for differences in outcome defi-
.. nitions between dialysis trials, there was a trend towards smaller relative
Recommendations Classa Levelb ..
.. reductions per mmol/L reduction in LDL-C in major atherosclerotic
..
9.10.2 Carotid artery disease .. 9.11 Other special populations at risk of
While there are currently no randomized studies that have assessed ..
.. atherosclerotic cardiovascular disease
whether lipid-lowering treatments reduce the incidence of CV events .. In general, the effects of lowering LDL-C are determined by the abso-
in patients enrolled on the basis of carotid atherosclerotic disease ..
.. lute risk of ASCVD and the achieved reduction in LDL-C, so it is
and without previous CV events, lipid-lowering therapy had .. important to identify and treat all those at increased risk of ASCVD.
reduced stroke in numerous studies. In a meta-analysis of RCTs ..
.. There are a few specific groups of patients in whom an underlying dis-
enrolling >90 000 patients, statin therapy did lead to a 21% reduction .. ease confers such increased risk, and in addition in whom the stand-
..
Statins have been shown to reduce C-reactive protein secretion .. applies to tests of possible toxicity, such as ALT and CK.
by hepatocytes,539 and a series of clinical trials and post hoc analyses .. Recommendations stem from consensus rather than evidence-based
..
have found that beneficial outcomes after statin therapy relate both .. medicine.
to a reduction in cholesterol levels and reduced inflammation.540544 .. Response to therapy can be assessed at 68 weeks from initiation
..
The Justification for the Use of Statins in Prevention: an Intervention .. of therapy, but response to lifestyle may take longer. Standard prac-
Trial Evaluating Rosuvastatin (JUPITER) trial542 demonstrated that in .. tice for subsequent follow-up monitoring is 612 months, but such
..
primary prevention for individuals with chronically elevated C-reac- .. monitoring intervals are arbitrary. As a minimum, LDL-C should be
Table 13 Summary of recommendations for monitoring lipids and enzymes in patients, before and on lipid-lowering
therapy
Testing lipids
How often should lipids be tested?
•Before starting lipid-lowering drug treatment, at least two measurements should be made, with an interval of 112 weeks, with the exception of condi-
tions where prompt drug treatment is suggested, such as ACS and very high-risk patients.
ACS = acute coronary syndrome; ALT = alanine aminotransferase; CK = creatine kinase; ULN = upper limit of normal.
54 ESC/EAS Guidelines
..
increasing obesity, and diabetes560563 are the main contributors. .. in CV risk factors, primarily reductions in plasma cholesterol, BP
CVD cost the European Union about e210 billion in 2015, one-half .. levels, and smoking.560563,567 Lifestyle changes at the population
..
of which was in healthcare costs (8% of total healthcare expendi- .. level may be more cost-effective than lifestyle and drug interven-
ture), and the other half in productivity losses and informal care.558 .. tions at the individual level, particularly when targeted to popula-
..
In these Guidelines, the Joint Task Force recommends a range of .. tions at increased risk. Awareness and knowledge of how lifestyle
actions to reduce CVD by targeting plasma lipids, ranging from .. risk factors lead to CVD has increased in recent decades.
..
population-wide initiatives to promote healthy lifestyles to individual- .. Moreover, legislation promoting a healthy lifestyle, such as
Socioeconomic factors ..
.. cost-effectiveness are greater among people at higher ASCVD risk
.. (Figure 6).36,233 Consequently, increased efforts and higher-intensity
..
.. interventions should be aimed at individuals and populations at higher
.. ASCVD risk.
Figure 5 Health impact pyramid.
..
..
ESC/EAS Guidelines 55
©ESC 2019
LDL cholesterol reduction (mmol/L)
with statin treatment
Figure 6 Absolute reductions in major vascular events with statin therapy.233 LDL = low-density lipoprotein. Reproduced from The Lancet, 388/10059,
Collins et al., ‘Interpretation of the evidence for the efficacy and safety of statin therapy’, 2532-2561, 2016, with permission from Elsevier.
Prevention of CVD by lifestyle changes, medication, or both is cost-effective in many scenarios, including population-based approaches and actions directed
at individuals at increased CVD risk.
Cost-effectiveness depends on several factors, including baseline CVD risk and LDL levels, cost of treatment, and uptake of preventive strategies.
Interventions to prevent CVD are more cost-effective among individuals and populations at higher CVD risk.
Cost-effectiveness analyses are importantly informed by assumptions about long-term disease prognosis and treatment effects. Strengthening of the evidence
to inform these assumptions is encouraged.
CVD = cardiovascular disease; LDL = low-density lipoprotein.
Cost-effectiveness requires evidence for effects of interventions on health and healthcare over a long time period; modelling techniques fill gaps. More data
are needed from RCTs and observational studies.
Direct evidence of effects of lipid-modifying treatments on overall mortality, particularly among people at low-to-moderate CVD risk, older people, and for
newer interventions, is lacking. Long-term post-trial follow-up in RCTs should be encouraged.
The cost-effectiveness of using lifetime CVD risk and more precise CVD risk scores to target interventions needs further investigation.
CVD = cardiovascular disease; RCT = randomized controlled trial.
56 ESC/EAS Guidelines
..
13 Strategies to encourage ..
..
(3) Use of cardiac imaging for risk stratification. CAC score
assessment with CT may be helpful in reaching decisions about
adoption of healthy lifestyle ..
.. treatment in people who are at moderate risk of ASCVD.
changes and adherence to lipid- .. Obtaining such a score may assist in discussions about treatment
..
modifying therapies .. strategies in patients where the LDL-C goal is not achieved with
.. lifestyle intervention alone and there is a question of whether to
..
Helping patients to change to healthier lifestyle habits is most effec- .. institute LDL-C-lowering treatment. Assessment of arterial (caro-
• Prospective studies are needed to investigate the incremental value of reclassifying total CV risk and defining eligibility for lipid-lowering therapy based on
CAC scores in individuals at moderate or high-risk.
• Outcome-based comparisons of CAC scores vs. assessment of arterial (carotid or femoral) plaque burden by ultrasonography for CV risk reclassification
in people at moderate or high-risk are needed.
• Although calibrated country-specific versions of the SCORE system are available for many European countries, risk charts based on country-specific
cohort data are missing for most countries. Regional total event charts (vs. mortality-only charts) are needed.
• Total CV risk estimation by means of the SCORE system and, accordingly, recommendations on eligibility for statins as well as treatment goals are based
on TC, whereas LDL-C is the primary lipid analysis method for screening, diagnosis, and management.
• There are no outcome-based comparisons of LDL-C vs. ApoB as primary measurement methods for screening, diagnosis, and management.
• Against a background of genetic and randomized clinical trial evidence showing no significant effect of increasing HDL levels on the risk of CVD events,
the clinical impact of therapies altering the function of HDL particles is unknown. More evidence is needed regarding the apparently adverse association
of extremely high levels of HDL-C with clinical outcomes.
• Dedicated studies assessing outcomes with specific Lp(a)-lowering therapies are warranted.
• More evidence is needed for PCSK9 inhibitors in specific populations, including patients with severe CKD and on dialysis, patients with HIV infection, in
children and adolescents with FH, after heart transplantation, and during pregnancy.
• The effects of PCSK9 inhibition on specific body compartments (as with siRNA or antisense) or only within plasma (as with monoclonal antibodies)
remain to be established.
• How early should a PCSK9 inhibitor be initiated in patients with ACS or stroke? In view of evidence of sustained clinical benefit associated with the early
initiation of statin treatment in the acute phase of ACS or stroke, the optimal timing of PCSK9 inhibitor treatment in ACS and stroke patients remains to
be addressed in outcome studies.
• Whether very low LDL-C levels achieved with the combination of statin, ezetimibe, and PCSK9 inhibitor reduce the need for further PCI remains to be
addressed in outcome studies.
• In patients with chronic HF, a small benefit of n-3 PUFAs has been shown in one RCT and merits further investigation.
• What is the optimal screening programme for detecting FH?
• In view of limited access to genetic testing in several environments, more evidence is needed regarding outcomes with only clinical vs. genetic screening
and diagnosis of FH.
• More RCT evidence is required to support the use of statin-based treatment in older people (aged >_75 years, but particularly in those aged >_80 years).
• More RCT evidence is needed for statin treatment in kidney transplant recipients.
• There are no data on the effects of statins, ezetimibe, or fibrates on CV events in dyslipidaemic HIV-infected patients.
• More evidence is needed regarding attainment of recommended LDL goals among very high-risk patients in real-world practice in the era of increasingly
prescribed combination therapies for LDL lowering.
58 ESC/EAS Guidelines
16 ‘What to do’ and ‘what not to do’ messages from the Guidelines
For FH patients with ASCVD who are at very-high risk, treatment to achieve a >_50% reduction from baseline and an LDL-C
I C
<1.4 mmol/L (<55 mg/dL) is recommended. If goals cannot be achieved, a drug combination is recommended.
Treatment with a PCSK9 inhibitor is recommended in very-high risk FH patients if the treatment goal is not achieved on a maxi-
I C
mal tolerated statin plus ezetimibe.
In children, testing for FH is recommended from the age of 5 years, or earlier if HoFH is suspected. I C
Treatment of dyslipidaemias in older people
ACS = acute coronary syndrome(s); Apo = apolipoprotein; ASCVD = atherosclerotic cardiovascular disease; CAD = coronary artery disease; CHD = coronary heart disease;
CIID = chronic immune-mediated inflammatory diseases; CKD = chronic kidney disease; CV = cardiovascular; CVD = cardiovascular disease; DM = diabetes mellitus; FH = fam-
ilial hypercholesterolaemia; HDL-C = high-density lipoprotein cholesterol; HeFH = heterozygous FH; HF = heart failure; HoFH = homozygous FH; HTG = hypertriglyceridae-
mia; LDL-C = low-density lipoprotein cholesterol; MetS = metabolic syndrome; PAD = peripheral arterial disease; PCSK9 = proprotein convertase subtilisin/kexin type 9;
SCORE = Systematic Coronary Risk Estimation; SMI = severe mental illness; TC = total cholesterol; TG = triglycerides; TIA = transient ischaemic event; T1DM = type 1 DM;
T2DM = type 2 DM.
a
Class of recommendation.
b
Level of evidence.
60 ESC/EAS Guidelines
..
17 Supplementary data ..
..
Colin Baigent (United Kingdom), Jean-Philippe Collet (France),
Veronica Dean (France), Victoria Delgado (Netherlands), Donna
Supplementary Data with additional Supplementary Tables, Boxes,
..
.. Fitzsimons (United Kingdom), Chris P. Gale (United Kingdom),
and text complementing the full text—as well as sections on other .. Diederick E. Grobbee (Netherlands), Sigrun Halvorsen (Norway),
features of a healthy diet contributing to cardiovascular disease pre-
..
.. Gerhard Hindricks (Germany), Bernard Iung (France), Peter Jüni
vention, chronic immune-mediated inflammatory diseases, HIV .. (Canada), Hugo A. Katus (Germany), Ulf Landmesser (Germany),
..
patients, severe mental illness, and adhering to medications along .. Christophe Leclercq (France), Maddalena Lettino (Italy), Basil S.