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Guide For The Treatment of

Symptomatic Heart Failure with
Reduced and Preserved Ejection
A.A. Sg. Mas Meiswaryasti Putra, MD
Faculty Of Medicine Mataram University
Mataram General Hospital
The Burden of Heart Failure


21 MILLION adults worldwide In 2012, the overall worldwide
are living with heart failure cost of heart failure was nearly
This number is expected to $108 BILLION.6
50% of heart failure patients die
within 5 years from diagnosis.5


Heart failure is the NUMBER 1 majority of HF patients has 3 or
cause of hospitalisation for more comorbidities 3
patients aged >65 years.4

1. Mozaffarian D et al. Circulation. 2015;131(4):e29-e322.

2. Mosterd A et al. Heart. 2007;93(9):1137-1146.
4. Cowie MR et al. Oxford PharmaGenesis; 2014. Accessed February 18, 2015.
5. Fauci AS et al. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008.
6. Cook C et al. Int J Cardiol. 2014;171(3):368-376.
Definition of Heart Failure
Heart failure can be defined as an abnormality of cardiac structure or function
leading to failure of the heart to deliver oxygen at a rate commensurate with
the requirements of the metabolizing tissues, despite normal filling pressures
(or only at the expense of increased filling pressures).1

TERMINOLOGY used to describe HF2

Related to EF* : HFrEF (reduced ejection fraction: EF<40%)

HFmEF (mildly impaired EF: EF 40-49%
HFpEF (preserved ejection fraction: EF ≥50%)*
Related to time-course: New onset, transient, chronic
Related to progression: Acute, stable, worsening
Related to location : Left heart, right heart, combined

* There is no consensus concerning the cut-off for preserved EF2

1. McMurray et al. Eur Heart J 2012;33:1787–847

2. Dickstein K et al. Eur Heart J 2008;29:2388–442
Definition of Heart Failure According to Ejection
Fraction by ESC 2016 Heart Failure Guidelines1
Types of heart failure by LVEF criteria: reduced (HFrEF), mid-range (HFmrEF) and preserved (HFpEF) ejection fraction


Symptoms ± * *
* Symptoms ± Signs Symptoms ± Signs

LVEF <40% LVEF 40-49% LVEF ≥50%

1. Elevated levels of natriuretic 1. Elevated levels of natriuretic

** **
peptides peptides
2. At least one criterion: 2. At least one criterion:
a. Relevant structural heart a. Relevant structural heart
disease (LVH and/or LAE), disease (LVH and/or LAE),
b. diastolic dysfunction b. diastolic dysfunction

HFmrEF = heart failure with mid-range ejection fraction LAE LVEF = left atrial enlargement
HFpEF = heart failure with preserved ejection fraction LVH = left ventricular ejection fraction
HFrEF = heart failure with reduced ejection fraction = left ventricular hypertrophy

* Signs may not be present in the early stages of HF (especially in HFpEF) and in patients treated with diuretics
**B-type natriuretic peptide (BNP) >35 pg/ml and/or N-terminal pro-B type natriuretic peptide (NT-proBNP) >125 pg/mL

1. Ponikowski P, Voors AA, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016;37:2129-200
Common Causes and Risk Factors for HF

Other heart Rhythm High blood Poor blood supply to lungs

disorders disorders
Heart muscle Heart Lung disease,
defects problems problems asthma,
Coronary heart bronchitis,
Valve defects High blood
disease obstructed
pressure in lungs
Heart airways
failure Diabete Kidney
Failure to take s disease
preventive Other medical Obesity
medication Lifestyle
Diet (excessive Alcohol or Side effects of disordered
salt or fluid intake) drug misuse medications
Infections breathing
Chagas disease Rheumatic fever disorders
Graph according to references 1

“Many cases of heart failure can be regarded as the end stage of other
“Many people have existing illnesses that
underlying illnesses and could be prevented if patients with these
place them at risk of heart failure.”1
illnesses were identified and treated appropriately at an earlier stage.”1

1. Ponikowski P, Anker SD, AlHabib KF, et al. Heart failure: preventing disease and death worldwide. ESC Heart Failure 2014;1:4-25
Models Explaining The Pathogenesis of Heart
1940s through the 1960s 1970s and 1980s
Cardiorenal model Cardiocirculatory model • Symptom relief
• Diuretics • Inotropes
• Digitalis • Vasodilators

1990s up till now • Prevention of

Neurohormonal model disease
• ACEIs progression
• BBs
• MRAs • Mortality reduction

Cardiorenal model1-4

• HF viewed as a problem of excessive salt and water retention caused by abnormalities of renal blood flow
• ® provided rational basis for use of digitalis and diuretics aimed at improving renal function

Cardiocirculatory or hemodynamic model1-4

• HF as a result of abnormalities of the pumping capacity of the heart (® reduced cardiac output) and excessive peripheral vasoconstriction
• ® provided rational basis for use of inotropes, vasodilators to augment cardiac output

Neurohormonal model1-4

• activation of several neurohormonal systems explaining the progression of the disease and exerting direct toxic effects on the myocardium
• ® provided rational basis for use of neurohormonal antagonists (ACEIs, BBs, MRAs)

1. Packer M. How Should Physicians View Heart Failure? The Philosophical and Physiological Evolution of Three Conceptual Models of the Disease. Am J Cardiol 1993;71;3C-11C
2. Mann DL. Mechanisms and Models in Heart Failure. A Combinatorial Approach. Circulation 1999;100:999-1008
3. Mann DL, Bristow MR. Mechanisms and Models in Heart Failure. The Biomechanical Model and Beyond. Circulation 2005;111:2837-49
4. Pepper GS, Ree RW. Sympathetic Activation in Heart Failure and Its Treatment With β-Blockade. Arch Intern Med 1999;159:225-34
Neurohormonal and Compensatory Mechanisms
in the Pathophysiology of Heart Failure1
Poor ventricular function / myocardial damage
(e.g. post myocardial infarction, dilated cardiomyopathy)

Heart failure

Decreased stroke volume and cardiac output

Neurohormonal response

Activation of sympathetic system Renin angiotensin aldosterone system

• Vasoconstriction: increased sympathetic tone, angiotensin II, endothelins, impaired nitric oxide release
• Sodium and fluid retention: increased vasopressin and aldosterone

Further stress on ventricular wall and dilatation (remodeling)

leading to worsening of ventricular function

Further heart failure

1. Jackson G, Gibbs CR, Davies MK, Lip GYH. ABC of heart failure. Pathophysiology. BMJ 2000;320:167-70
ACCF/AHA Stages of Heart Failure Classification3
Comparison of ACCF/AHA stages of HF classification and NYHA functional classification3

ACCF/AHA Stages of Heart Failure (HF) NYHA Functional Classification

A At high risk for HF but without structural heart

disease or symptoms of HF

B Structural heart disease but without signs or I

No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF.
symptoms of HF

No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF.
C Structural heart disease with prior or current
symptoms of HF
II Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in
symptoms of HF.

III Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes
symptoms of HF.

Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest.

Refractory HF requiring specialized interventions Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest.

ACCF = American College of Cardiology Foundation HF = Heart failure

AHA = American Heart Association NYHA = New York Heart Association

3. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure. Circulation 2013;128:e240-e327
Symptoms and signs of HF

The diagnosis of HF can be difficult, especially in the early stages

Symptoms Signs

Typical More specific

Breathlessness Elevated jugular venous pressure

Orthopnoea Hepatojugular reflux

Paroxysmal nocturnal dyspnoea Third heart sound (gallop rhythm)

Reduced exercise tolerance Laterally displaced apical impulse

Fatigue, tiredness, increased time to recover

Cardiac murmur
after exercise McMurray et al. Eur Heart J 2012;33:1787–847

Ankle swelling

McMurray et al. Eur Heart J 2012;33:1787–847

Principles of diagnosis of HF

All diagnostic steps are equally important

Ø Consider: Medical history, signs, symptoms

Ø Confirm: Natriuretic peptides, Echocardiography
Ø Assess clinical phenotype: HFrEF vs. HFpEF
Ø Assess etiology: Angiography, cMRI, Biopsy
Ø Risk stratification
Ø Workup for targeted therapies

Presented by BM Pieske during HF SUMMIT 2015

Algorithm for the diagnosis of heart failure1
Outpatient with heart failure
symptoms or signs

ECG and chest radiograph

BNP, or NT-proBNP, or MR-proANP

ECG normal and BNP <35 pg/mL, or NT- ECG abnormal, BNP ≥35 pg/mL, or NT-proBNP
proBNP <125 pg/mL ≥125 pg/mL


No cardiac dysfunction Cardiac dysfunction confirmed as

Other causes of increase in NPs cause of symptoms and signs

Heart failure unlikely Start heart failure treatment

1. Metra M, Teerlink JR. Heart failure. Seminar. Lancet 2017;390:1981-95

2. Ponikowski P, Voors AA, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016;37:2129-200
3. McMurray JJV, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur Heart J 2012;33:1787-847
Diagnosing HF

The diagnosis of HFpEF is more difficult than the diagnosis of HFrEF

The diagnosis of HFrEF requires three conditions to be satisfied

1. Symptoms typical of HF

2. Signs typical of HF

3. Reduced LVEF

The diagnosis of HFpEF requires four conditions to be satisfied

1. Symptoms typical of HF
2. Signs typical of HF
3. Normal or only mildly reduced LVEF and LV not dilated
4. Relevant structural heart disease (LV hypertrophy/LA enlargement) and/or diastolic

McMurray et al. Eur Heart J 2012;33:1787–847

HFA/ESC diagnostic recommendations HFpEF
Symptoms or signs of HF

Normal or mildly reduced LV systolic function (LVEF >50% and LVEDVI <97 mL/m2)

Evidence of abnormal LV relaxation, filling, diastolic distensibility, and diastolic stiffness

Invasive hemodynamic EIEʹ >15 15 >EIE′ >8 NT-proBNP >220 pg/mL or BNP >200
measurements pg/mL
mPCW >12 mmHg
or LVEDP >16 mmHg
or t >48 ms
or b >0.27

EIE′ >8
NT-proBNP Echo – blood flow Doppler
>220 pg/mL or EIA>50 yr <0.5 and DT>50 yr >280 ms
BNP >200 pg/mL or Ard–Ad >30 ms
or LAVI >40 mL/m2
or LVMI >122 g/m2(♀); >149 g/m2 (♂) or atrial fibrillation

Paulus et al. Eur Heart J 2007;28:2539–50
Particular Relevance of BNP

• diagnosis
• staging
• risk stratification
• monitor/titrate therapy
• admission/discharge decisions:
> rule out symptomatic LV dysfunction

A normal natriuretic peptide level in an untreated patient virtually

excludes significant cardiac disease
Consider different cut-off values in various clinical situations

Presented by K Dickstein during HF SUMMIT 2015

There are many treatment objectives for chronic HF

Objectives of treatment for chronic HF

1. Prognosis • reduce mortality

2. Morbidity • relieve symptoms and signs
• improve QoL
• eliminate edema and fluid retention
• increase exercise capacity
• reduce fatigue and breathlessness
• reduce the need for hospitalization
• provide end of life care
3. Prevention • occurrence of myocardial damage
• progression of myocardial damage
• remodelling of the myocardium
• reoccurrence of symptoms and fluid
• hospitalization
Neurohormonal antagonists are the backbone of
medical treatment of HF3
Three neurohumoral antagonists*

u an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB),

u a beta-blocker (BB), and
u a mineralocorticoid receptor antagonist (MRA)
− have been shown to improve survival in patients with HFrEF
− are recommended for every patient with HFrEF unless contraindicated or not
tolerated.1, 2

There is consensus that

u ACEIs and BBs are complementary and

u should both be started together as soon as possible after diagnosis of HFrEF is made.1, 2

*A new compound (LCZ696; angiotensin receptor neprilysin inhibitor = ARNI) that combines the moieties of an ARB (valsartan) and a neprilysin (NEP) inhibitor (sacubitril) has recently been
shown to be superior to an ACEI (enalapril) in reducing the risk of death and of hospitalization for HF in a single trial with strict inclusion/exclusion criteria. Sacubitril/valsartan is therefore
recommended to replace ACEIs in ambulatory HFrEF patients who remain symptomatic despite optimal therapy and who fit these trial criteria.2,3

1. McMurray JJV, Adamopoulos S, Anker SD, et al. for the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the ESC. Developed in
collaboration with the HFA of the ESC. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur Heart J 2012;33:1787-1847
2. Ponikowski P, Voors AA, Anker SD, et al. for the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC).
Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart
failure. Eur Heart J 2016;37:2129-2200
3. Metra M, Teerlink JR. Heart failure. Seminar. Lancet 2017;390:1981-95
Treatment options for HFpEF
Improving prognosis
‘No treatment has yet been shown, convincingly, to reduce morbidity and mortality in
patients with HFpEF.’ (ESC Guidelines 2012)

STUDY Study drug Endpoint Outcome Publication
Yusuf S et al
CHARM- CV death or HF
Candesartan 3023 Lancet 2003
Preserved hospitalization
Cleland JG et al
Death or HF end-point
PEP-CHF Perindopril 850 Eur Heart J 2006
hospitalization not met

Death or HF Massie BN et al NEJM

I-Preserve Irbesartan 4128 hospitalization 2008

McMurray et al. Eur Heart J 2012;33:1787–847

Yusuf S et al. Lancet 2003;362:777
Cleland JG et al. Eur Heart J 2006;27:2338
Massie BM et al. NEJM 2008;359:2456
Comorbidities in HF

Comorbidities impact prognosis in patients with HF1,2

Why comorbidities are relevant in HF1:

• Comorbidities may affect the use of
treatments for HF
COPD Iron deficiency • Drugs used to treat comorbidities may
cause worsening of HF
Comorbidities in
• Drugs used to treat HF and
patients with HF Depression comorbidities may interact and
Hypertension Sleep disturbance reduce patient adherence
Angina Cancer
• Most comorbidities are associated
with worse clinical status and are
Diabetes mellitus predictors of poor prognosis in HF
Renal Anaemia
dysfunction Cachexia

1. McMurray et al. Eur Heart J 2012;33:1787–847

2. Ennezat et al. Nephrol Dial Transplant 2011;26:3908-13
Holistic management of HF
ESC Guidelines 2012
Management programmes for patients with HFrEF & HFpEF
• Should employ a multidisciplinary approach
• Should target high-risk symptomatic patients
• Should include competent and professionally educated staff

• Optimized medical and device management
• Adequate patient education, with special emphasis on adherence and self-care
• Patient involvement in symptom monitoring and flexible diuretic use
• Follow-up after discharge
• Increased access to healthcare
• Facilitated access to care during episodes of decompensation
• Assessment of (and appropriate intervention in response to) an unexplained increase in weight,
nutritional status, functional status, quality of life, and laboratory findings
• Access to advanced treatment options
• Provision of psychosocial support to patients and family and/or caregivers McMurray et al. Eur Heart J 2012;33:1787–847

McMurray et al. Eur Heart J 2012;33:1787–847

ESC Recommendations for Exercise

RECOMMENDATIONS CLASS LEVEL • Services, such as cardiac rehabilitation

and palliative care, must be integrated
It is recommended that regular I A into the overall provision for patients with
aerobic exercise is encouraged in HF
patients with heart failure to
• Multidisciplinary management
improve functional capacity and
programmes are vital, designed to
improve outcomes through structured
follow-up with patient education,
It is recommended that patients I A
optimization of medical treatment,
with heart failure are enrolled in a
psychosocial support, and improved
multidisciplinary care management
access to care.
programme to reduce the risk of
heart failure hospitalization

McMurray et al. Eur Heart J 2012;33:1787–847

Personalised medicine in HF
Personalisation for patients with HF will surely improve in the
future, but also today one does not fit all
Personalisation by traditional biomarkers:
• Echo
• Blood Pressure
• Laboratory examinations (renal function, electrolytes, hemoglobin, glycemia)

Other more recent biomarkers

How can we improve the personalisation of treatment in the future
• Genetics
• Pharmacogenomics
• Gene therapy

Presented by A. Maggioni during HF SUMMIT 2015


Summary: HF Guidelines
• ACE-inhibitors, beta-blockers and mineralocorticoid receptor antagonists
form the cornerstone of HF therapy, given their mortality benefit. Incremental
addition of treatments is recommended as HF progresses: Adding therapies
is adding life.

• HFrEF and HFpEF differently respond to treatment. Treatment in HFpEF is

aimed to improve signs and symptoms, as no treatment has yet been shown
to improve prognosis in HFpEF.

• HF care is already somewhat personalised, since management is guided by

traditional biomarkers (echo, ECG, blood pressure, laboratory examinations).
In the future, genetics, pharmacogenomics and gene therapy may yield more
targeted treatment strategies.

• The ESC guidelines also recommend regular aerobic exercise and enrolment
in care-management programmes.