FA - Stroke Prevention in AF - Lip - Recomend X DR Medina - JAMA 2015

Clinical Review & Education
Review
Stroke Prevention in Atrial Fibrillation

A Systematic Review
Gregory Y. H. Lip, MD; Deirdre A. Lane, PhD
IMPORTANCE Atrial fibrillation (AF) is associated with an increase in mortality and morbidity,
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with a substantial increase in stroke and systemic thromboembolism. Strokes related to AF

are associated with higher mortality, greater disability, longer hospital stays, and lower
chance of being discharged home than strokes unrelated to AF.
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OBJECTIVE To provide an overview of current concepts and recent developments in stroke

prevention in AF, with suggestions for practical management.
EVIDENCE REVIEW A comprehensive structured literature search was performed using
MEDLINE for studies published through March 11, 2015, that reported on AF and stroke,
bleeding risk factors, and stroke prevention.
FINDINGS The risk of stroke in AF is reduced by anticoagulant therapy. Thromboprophylaxis
can be obtained with vitamin K antagonists (VKA, eg, warfarin) or a non-VKA oral
anticoagulant (NOAC). Major guidelines emphasize the important role of oral anticoagulation
(OAC) for effective stroke prevention in AF. Initially, clinicians should identify low-risk AF
patients who do not require antithrombotic therapy (ie, CHA2DS2-VASc score, 0 for men; 1 for
women). Subsequently, patients with at least 1 stroke risk factor (except when the only risk is
being a woman) should be offered OAC. A patients individual risk of bleeding from
antithrombotic therapy should be assessed, and modifiable risk factors for bleeding should
be addressed (blood pressure control, discontinuing unnecessary medications such as aspirin
or nonsteroidal anti-inflammatory drugs). The international normalized ratio should be tightly
controlled for patients receiving VKAs.
CONCLUSIONS AND RELEVANCE Stroke prevention is central to the management of AF,
irrespective of a rate or rhythm control strategy. Following the initial focus on identifying
low-risk patients, all others with 1 or more stroke risk factors should be offered OAC.
JAMA. 2015;313(19):1950-1962. doi:10.1001/jama.2015.4369
trial fibrillation (AF) increases the risk of morbidity and

mortality because of a substantially increased risk of
stroke and systemic thromboembolism. Overall, AF
increases the stroke risk 5-fold; the attributable risk of ischemic
stroke related to AF increases from 4.6% from the ages of 50
through 59 years to 20.2% from the ages of 80 through 89 years.1
Compared with non-AFrelated strokes, strokes related to AF are
associated with higher mortality, greater disability, longer hospital
stays, poorer functional outcome, and lower chance of being discharged home.2 Given the increasing prevalence and incidence of
AF, this arrhythmia confers a major public health and economic
burden on any health care system.
The risk of stroke in AF is reduced by antithrombotic therapy.3
Thromboprophylaxis can be obtained with vitamin K antagonists
(VKA, eg, warfarin) or a non-VKA oral anticoagulant (NOAC). All the
major guidelines emphasize the role of oral anticoagulation (OAC)
use for stroke prevention in AF.4,5
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Corresponding Author: Gregory Y.

H. Lip, MD, University of Birmingham
Centre for Cardiovascular Sciences,
City Hospital, Birmingham,
West Midlands B18 7QH, England
(g.y.h.lip@bham.ac.uk).
Section Editor: Mary McGrae
McDermott, MD, Senior Editor.
The objective of this article is to provide an overview of current concepts and recent developments in stroke prevention in patients with nonvalvular AF.
Search Strategy
A comprehensive structured literature search was performed
using MEDLINE for studies published through March 11, 2015, that
reported on AF and stroke or bleeding risk factors, as well as on
stroke prevention. The search terms included each of the following terms individually and in combination: atrial fibrillation,
thromboembolism, stroke risk, risk stratification, oral anticoagulation, warfarin, aspirin, and thromboprophylaxis. We focused on
primary published research articles and systematic reviews, as
well as on clinical trials complemented by large observational
cohorts.
JAMA May 19, 2015 Volume 313, Number 19 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
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Author Affiliations: University

of Birmingham Centre for
Cardiovascular Sciences,
City Hospital, Birmingham,
United Kingdom (Lip, Lane);
Aalborg Thrombosis Research Unit,
Department of Clinical Medicine,
Aalborg University, Aalborg,
Denmark (Lip).
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Review Clinical Review & Education
Risk Factors for Stroke
At a Glance
Atrial fibrillation can cause stroke by several mechanisms consistent with the Virchow triad for thrombogenesis (thrombus formation): (1) stasis in the left atrium causing flow abnormalities; (2) structural heart and vascular disease (eg, mitral stenosis; fulfilling the
abnormal vessel wall Virchow criterion); and (3) abnormal coagulation and fibrinolysis (eg, abnormal procoagulant hemostatic and
platelet factors; fulfilling the abnormal blood constituents criterion).6
The prothrombotic state in AF has recently been comprehensively
reviewed.6
The most common risk factors associated with stroke (eg, heart
failure, hypertension, diabetes, age, prior stroke) were initially identified from the non-VKA cohorts of randomized trials conducted 2
decades ago.2 Although these trials provided information on patients treated with placebo,
AF atrial fibrillation
they have been criticized for
CHADS2 congestive heart failure,
randomizing fewer than 10%
hypertension, age 75 years,
of patients screened and for
diabetes mellitus, stroke
not recording all the risk facCHA2DS2-VASc CHADS2 criteria plus
tors nor consistently definvascular disease, age 65-74 years, sex
ing them in the studies.7
category
Numerous systematic
HAS-BLED hypertension, abnormal
renal/liver function, stroke, bleeding
reviews have examined AFhistory or predisposition, labile
related stroke risk factors.8,9
international normalized ratio, elderly,
A study by the Stroke in AF
drugs/alcohol
Working Group 8 reported
HEMORR2HAGES hepatic or renal
that the strongest, most condisease, ethanol abuse, malignancy,
sistent independent risk facolder age, reduced platelet count or
function, rebleeding, hypertension,
tors for stroke were prior
anemia, genetic factors, excessive fall
stroke or transient ischemic
risk, and stroke
attack (TIA) (relative risk
INR international normalized ratio
[RR], 2.5; 95% CI, 1.8-3.5), inLAA left atrial appendage
creasing age (RR, 1.5 per
NOAC non-VKA oral anticoagulant
decade; 95% CI, 1.3-1.7),
OAC oral anticoagulation
a history of hypertension
(RR, 2.0; 95% CI, 1.6-2.5),
TIA transient ischemic attack
and diabetes mellitus (RR,
TTR time in therapeutic range
1.7; 95% CI, 1.4-2.0). In this
VKA vitamin K antagonists
systematic review, female
sex was inconsistently associated with stroke risk, and the evidence was inconclusive for heart failure or coronary artery disease
as independent predictors of AF-related stroke.
Other systematic reviews that included large observational
cohort studies also found evidence for vascular disease and
female sex 9 as risk factors for stroke. In a recent systematic
review and meta-analysis of 17 studies, there was a 1.31-fold (95%
CI, 1.18-1.46) elevated risk of stroke in women with AF.10 Even in
populations that were entirely anticoagulated, stroke rates were
higher in women, varying from 1.2% to 1.44% per patient-year for
men and 2.08% to 2.43% per patient-year for women. The risk of
stroke in women with AF is age dependent, with women younger
than 65 and having no other risk factors being at low risk.11,12 In
one European study involving AF patients younger than 65 years,
female sex did not emerge as an independent risk factor13; however, female sex appears to still confer some stroke risk, especially
in Asian cohorts.14,15
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The risk of stroke and mortality in AF is reduced by anticoagulant

therapy, whether with vitamin K antagonists (VKA, eg, warfarin)
or a non-VKA oral anticoagulant (NOAC).
As an initial step, clinicians should identify low-risk AF patients
who do not require antithrombotic therapy. Patients with at least
1 stroke risk factor (except when the only risk factor is being a
woman) should be offered OAC.
Clinicians also need to assess each patients individual risk of
bleeding with antithrombotic therapy and correct modifiable
bleeding risk factors: control blood pressure; remove unnecessary concomitant medication, such as aspirin, or NSAIDs; control
INR and avoid labile INRs; counsel patient to reduce alcohol
intake if excessive. Ultimately, the main priority is stroke
prevention.
In a recent systematic review, peripheral arterial disease was

significantly associated with AF-related stroke risk in all 10 observational studies, with a reported risk range of 1.3- to 2.5-fold.16
Complex aortic plaque on the descending aorta, as identified by
transesophageal echocardiography, was also a significant risk
factor.17 Prior myocardial infarction was validated as a significant
predictor of the primary end point in 5 of the 6 studies. There
may be ethnic differences evident for peripheral arterial disease
as a risk factor, with an RR of stroke approximately 1.22-fold
higher in European populations,18 but 1.80-fold higher in Far Eastern populations.19
Risk Stratification Schemes

The various stroke risk factors in AF have been used to formulate several stroke risk prediction tools,20-28 to help risk stratify patients with
AF (Table 1). The most common in use are the CHADS2 (congestive
heart failure; hypertension; age 75 years; diabetes mellitus,1 point
for each; stroke, 2 points) and CHA2DS2-VASc scores (see Table 3 for
definition). All the risk stratification schemes based on clinical risk
factors have weak or modest predictive value for identifying highrisk patients.2 However, the CHA2DS2-VASc score has particular value
in identifying low-risk patients who do not need antithrombotic
therapy.31,32 Hence, more recent guidelines have moved toward initial identification of low-risk patients first (because these patients
do not need any antithrombotic therapy), rather than focus on identifying high-risk patients.4
CHADS2
The CHADS2 score was formulated and initially validated in a registry of hospitalized patients with AF.22 The CHADS2 score is relatively simple for identifying high-risk patients (score >2), whereas
moderate risk was initially defined as a score of 1 to 2 and low risk as
a score of 0.22 The CHADS2 had various limitations, and does not include many of the commonly accepted stroke risk factors (eg, age
65-74 years, vascular disease, female sex, asymptomatic left ventricular diastolic dysfunction, etc). Furthermore, according to the
original validation study, those with a prior stroke and no other risk
factor (which represented the highest risk category) would only score
2 and would be classified as moderate risk.33
(Reprinted) JAMA May 19, 2015 Volume 313, Number 19
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Clinical Review & Education Review
Table 1. Risk Factors Included in Various Clinical Stroke Risk Stratification Schema and Guidelines
Risk Factors
Age, y
Other Factors
Female
Sex
Prior TE
Event
Hypertension
Heart
Failure
Diabetes
Mellitus
Vascular
Disease
Scheme
SPAF,20 1999
AFI,
21
1994
CHADS2,22 2001
Framingham,23
2003
65-75 >75
75
>75a
van Walraven,24
2003
Rietbrock,25 2008
CHA2DS2-VASc,26
2009
65-74 75
Many others
Proteinuria and eGFR; different weighting

for primary and secondary prevention
ACCP,29 2012
65-74 >75
CHADS2 score, 0, non-CHADS2 risk

factors (similar to CHA2DS2-VASc)
should be considered
ESC,4 2012
65-74 75
Based on CHA2DS2-VASc
27
QStroke,
2013
ATRIA,28 2013
Guidelines
CCS,30 2014
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65
AHA/ACC/HRS,5
2014
65-74 75
NICE,4 2014
65-74 75
Abbreviations: ACCP, American College of Chest Physicians; AFI, Atrial

Fibrillation Investigators; AHA/ACC/HRS, American Heart Association, American
College of Cardiology, and Heart Rhythm Society; CCS, Canadian Cardiovascular
Society; eGFR, estimated glomerular filtration rate; ESC, European Society of
Cardiology; NICE, National Institute for Health and Care Excellence; SPAF,
Stroke Prevention in Atrial Fibrillation; TE, thromboembolism. CHADS2:
C, congestive heart failure, H, hypertension, A, age 65 through 74 years,
D, diabetes, and S2, previous stroke, transient ischemic attack (TIA), or systemic
embolism; CHA2DS2-VASc: C, congestive heart failure, H, hypertension, A2, age
at least 75 years, D, diabetes, S2, previous stroke, TIA, or systemic embolism,
V, vascular disease, Sc, sex category female sex.
CHA2DS2-VASc
Other Risk Stratification Schemes
The CHA2DS2-VASc score (Table 2) was initially validated in the

Euro-Heart survey cohort.26 This score included various nonCHADS2 risk factors such as age from 65 to 74 years, female sex,
and vascular disease. For example, in contrast to CHADS2 the C in
CHA2DS2-VASc refers to congestive heart failure, including moderate to severe left ventricular dysfunction (ejection fraction, <40%)
and recent decompensated heart failure irrespective of ejection
fraction, thus including both heart failure with reduced ejection
fraction or heart failure with preserved ejection fraction.4 In the latter group, patients with cardiomyopathy (eg, restrictive or hypertrophic) could also be included under the C criterion, although
robust data are limited.
The CHA2DS2-VASc score has been validated in numerous
independent cohorts, including non-Western populations. In 2 Far
Eastern studies, the CHA2DS2-VASc but not the CHADS2 score
was significantly predictive of stroke.34,35 Most studies demonstrate that CHA2DS2-VASc is best at identifying truly low-risk
patients for whom the absolute risks of stroke or systemic embolism were less than 1% per year and was as good aspossibly
better thanthe older CHADS 2 score for predicting high-risk
patients. 31,32,36 The CHA 2 DS 2 -VASc score is now the recommended risk score by European,4 US,5 and National Institute for
Health and Care Excellence (NICE)4 guidelines.
Clinical stroke risk prediction scores such as CHADS 2 and

CHA 2 DS 2 -VASc are based on common risk factors in patients
with AF whom clinicians encounter in clinical practice. The
CHA2DS2-VASc score does not include other rare factors that have
been associated with stroke or systemic embolism in AF such as amyloid heart disease and end-stage renal failure. Large observational
cohorts have clarified the effect of severe renal impairment on stroke
and bleeding risks in AF, but renal impairment does not add predictive value to established scores, such as CHA2DS2-VASc.37
The other risk factor score schemes that have been developed, including the CHADS2 score,38 the Anticoagulation and
Risk Factors in Atrial Fibrillation (ATRIA) stroke score, 28 the
CHA2DS2-VASc score,39,40 and the Qstroke27 score, all have limitations. All the major guidelines have continued to emphasize the
use of the CHA2DS2-VASc score.
Most risk stratification schemes based on clinical criteria have
weak predictive value for high-risk patients who sustain events
(C statistic, approximately 0.6); thus, there has been much interest in the use of biomarkers to enhance the predictive value of
clinical risk scores. Such biomarkers can include blood markers
(eg, von Willebrand factor, D-dimer, natriuretic peptides),41-43
urine (eg, proteinuria, estimated glomerular filtration rate, or creatinine clearance),44 cardiac imaging (echocardiography, whether
Age and female sex combined are a single risk factor.
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Table 2. Summary of Guideline Recommendationsa

Stroke Risk Stratification
Treatment Recommendation
Comments
OAC
Warfarin or dabigatran
OAC
0 plus additional non-CHADS2 risk

factors (eg, age 65-74 y, woman,
and vascular disease)
OAC
No risk factors
No antithrombotic therapy
ACCP,29 2012
CHADS2 score
ESC,4 2012
Initial step: identify low risk patients
(CHA2DS2-VASc 0 in males,
1 in females)
Subsequent step: for patients

with 1 additional stroke risk factors
OAC is recommended for

CHA2DS2-VASc score 2
or should be considered for
CHA2DS2-VASc score of 1 in men
OAC refers to a VKA (eg, warfarin)

with TTR>70%, or a NOAC
(preferred); antiplatelet therapy
with aspirin-clopidogrel combination
therapy orless effectivelyaspirin
monotherapy is recommended only
when patients refuse any form of OAC
OAC
Warfarin or a NOAC, preferred
CCS,30 2014
Algorithm: identify those aged 65 y
and CHADS2 score risk factors
Algorithm: vascular disease
Aspirin
Algorithm: no risk factors,

ie, age <65 y with no CHADS2 risk
factors nor vascular disease
AHA/ACC/HRS,5 2014
CHA2DS2-VASc score
2
OAC
Nothing, aspirin, or OAC
OAC refers to warfarin or a NOAC

as an alternative
NICE,4 2014
Evaluative steps
Initial: identify low-risk patientsb
Subsequent: for AF patients

with 1 additional stroke risk
factors
Offer OAC (CHA2DS2-VASc 2)

or consider OAC (CHA2DS2-VASc score
of 1 in men)
transthoracic or transesophageal), or cerebral imaging (eg, computed tomography or magnetic resonance imaging), which would
provide additional refinement to clinical risk stratification for the
identification of high-risk individuals. The real practical value of
measuring various biomarkers for stroke-risk prediction would
require testing large cohorts of individuals who have not received
anticoagulation treatment rather than testing highly selected
cohorts of patients who have. Also, stroke risk scoring schemes
must have simplicity and ease of use, for rapid application in
everyday clinical practice. Although scoring systems incorporating complex multivariate analyses and modeling or addition of
biomarkers may offer some improved predictive value, the resultant scores are less practical for everyday clinical use because of
their complexity.
Any single stroke risk factor confers risk, and if left untreated,
patients with AF may be exposed to a fatal or disabling stroke.45
Stroke risk stratification schemes have been formulated with assumptions that risk factors carry equal weight, but they do not.15 With
the clinical practice change advocated by contemporary guidelines, the focus should be on the initial identification of truly lowjama.com
OAC refers to warfarin or a NOAC

as an alternative.
Aspirin monotherapy should not be
used for stroke prevention in AF.
Abbreviations: ACCP, American

College of Chest Physicians; AF, atrial
fibrillation; AHA/ACC/HRS, American
Heart Association, American College
of Cardiology, Heart Rhythm Society;
CCS, Canadian Cardiovascular
Society; European Society of
Cardiology; NICE, National Institute
for Health and Care Excellence;
NOAC, nonvitamin K antagonist oral
anticoagulant; OAC, oral
anticoagulant; TTR, time in
therapeutic range; VKA, vitamin K
antagonist.
a
See Table 1 footnotes for CHADS2

and CHA2DS2-VASc expansions.
Low-risk patients include men who

have a CHA2DS2-VASc score of 0
and women 1.
risk patients who do not need antithrombotic therapy. All other AF

patients who have 1 or more stroke risk factors can be offered stroke
prevention therapy.
Risk Factors for Bleeding

In addition to stroke risk assessment, it is important to evaluate
bleeding risk in AF patients, especially cases in which thromboprophylaxis is being considered.46 Various bleeding risk stratification
schemes have been proposed but until recently have not been widely
used due to complexity and overlaps with stroke risk.47 Of the various bleeding risk scores,48-53 only 3 have been derived and validated in AF populations: HEMORR2HAGES (hepatic or renal disease, ethanol abuse, malignancy, older age, reduced platelet count
or function, re-bleeding, hypertension, anemia, genetic factors, excessive fall risk, and stroke),50 HAS-BLED (hypertension, abnormal
renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio [INR], elderly, drugs/alcohol),52
and ATRIA.53
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Table 3. Assessment of Stroke and Bleeding Risk in Atrial Fibrillation

Patients by Schema
Score
CHA2DS2-VASca
Congestive heart failure
Hypertension
Age 75 y
Diabetes mellitus
Stroke/TIA/TE
Vascular disease (prior MI, PAD, or aortic plaque)
Age 65-74 y
Sex category (ie, female sex)
Maximum score
HAS-BLEDb
Hypertension (systolic blood pressure >160 mm Hg)
Abnormal renal and liver function (1 point each)c
1 or 2
Stroke
Bleeding tendency/predispositionc
Labile INRs (eg, TTR<60%, applies only if the patient

is taking warfarin)c
Elderly (eg, age >65 y, frail condition)
Drugs or alcohol excess (1 point each)c
1 or 2
Maximum score
Abbreviations: INR, international normalized ratio; MI, myocardial infarction;

PAD, peripheral artery disease; TE, thromboembolism; TIA, transient ischemic
attack; TTR, time in therapeutic range.
a
CHA2DS2-VASc is used to initially identify low-risk patients (CHA2DS2-VASc,

0 in males, 1 in females) who do not need any antithrombotic therapy);
subsequently, stroke prevention is offered to those with at least 1 additional
stroke risk factor.
HAS-BLED categorizes those into low (score 0-2) or high (3) risk, where the
latter can be identified for more regular review and follow-up.
Abnormal renal function classified as the presence of long-term dialysis, renal

transplant, or serum creatinine of 2.3 mg/dL (200 mmol/L) or higher.
Abnormal liver function defined as chronic hepatic disease (eg, cirrhosis) or
biochemical evidence of significant hepatic derangement (eg, bilirubin 2 to 3
the upper limit of normal, in association with aspartate aminotransferase,
alanine aminotransferase, or alkaline phosphatase 3 the upper limit normal);
history of bleeding or predisposition (anemia); labile INR (ie, TTR<60%);
concomitant antiplatelet drugs or nonsteroidal anti-inflammatory drugs, or
alcohol excess.
Of the different scores, the simple HAS-BLED score (Table 3)

has been validated in multiple independent cohorts and outperforms other bleeding risk scores in the prediction of serious
bleeding.54-56 HAS-BLED has been validated in NOACs and in untreated and aspirin-treated patients,52,57 HAS-BLED is the only score
predictive of intracranial hemorrhage risk and also has been shown
to predict bleeding during bridging therapy58 and during percutaneous coronary intervention.59
A high HAS-BLED score is not a reason to withhold OAC, but it
can be used to highlight patients potential risk of bleeding and alert
physicians to schedule more regular follow-up visits and provide
straightforward warning about the necessity of avoiding falls and not
engaging in other high-risk activities. A high HAS-BLED score suggests the need to focus on correcting the potentially reversible factors that contribute to bleeding, which include uncontrolled hypertension, concomitant use of aspirin or nonsteroidal antiinflammatory drugs with OAC, excessive alcohol intake, and labile
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INRs. Use of a decision support tool that integrates patient-specific

stroke and bleeding risk would result in significant gains in qualityadjusted life expectancy.60
Falls are not an independent predictor of bleeding for those
who are taking OAC medication.61 A modeling exercise has suggested that a patient would need to fall 295 times a year for the
benefit of stroke prevention with OAC to outweigh the risk of
serious bleeding.62 Although a history of falls should not be a contraindication to OAC, AF patients who have actually sustained a
fall remain at high risk of thromboembolism and morbidity.63 Further investigation to ascertain the reasons for the fall and targeting interventions to reduce risk of fallsfor example, treatment
for correctable causes of falls (such as lowering blood pressure,
vertigo, etc), polypharmacy, and the need for walking aids
should be paramount. Nevertheless, treatment decisions should
be individualized.
Stroke and bleeding risk are closely related. Recent comparisons of HAS-BLED with the CHADS2 and CHA2DS2-VASc scores
showed an increase in bleeding rates among patients who have
higher HAS-BLED, CHADS2, and CHA2DS2-VASc scores, but this was
generally only significant for the HAS-BLED score; the latter score
was also superior to CHADS2 and CHA2DS2-VASc for bleeding risk
prediction.54,55 Other efforts have led to derivation and validation
of a composite stroke and bleeding risk score.64,65 Although there
was a marginal improvement in the C statistic for predicting highrisk patients (C for composite score, 0.728 [95% CI, 0.659-0.798]
compared with 0.706 [95% CI, 0.638-0.774] for HAS-BLED and
0.654 [95% CI, 0.574-0.733] for CHA2DS2-VASc scores), the discrimination compared with individual stroke and bleeding risk scores
was nonsignificant. Thus, stroke risk should be assessed using a validated stroke score scheme and bleeding risk with a specific bleeding risk score scheme.
Net Clinical Benefit of Oral Anticoagulants

Effective stroke prevention for patients with AF requires the use of
OACs, whether a VKA or a NOAC. NOACs fall into 2 broad classes,
the oral direct thrombin inhibitors (eg, dabigatran) and oral factor
Xa inhibitors (eg, rivaroxaban, apixaban, and edoxaban) (Table 4).
Stroke or systemic embolism is significantly reduced by VKAs
in patients with AF (RR reduction, 64%; 95% CI, 49%-74%).66
Vitamin K antagonists are associated with an absolute RR of 2.7%
per year (number needed to treat, 37) for embolism in patients
with no history of prior stroke (primary prevention) and 8.4% per
year (number needed to treat, 12) for patients with a history of
prior stroke (secondary prevention). Compared with the control
or placebo groups, the relative RR attributable to VKA is 26%
(95% CI, 3%-43%; absolute RR 1.6% per year) for all-cause
mortality.66
A meta-analysis examining the efficacy of aspirin compared
with either a control treatment or placebo for stroke or systemic
embolism or mortality in AF found no benefit.66 A 19% reduction
in stroke was observed with aspirin but that finding was attributable to the only positive study, the Stroke Prevention on Atrial
Fibrillation (SPAF-I) trial, which reported a 42% reduction in
stroke or systemic embolism with 325 mg/d of aspirin compared
with a control treatment. However, the SPAF-I trial had major
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Table 4. Optimal Selection of Oral Anticoagulation for Stroke Prevention in Atrial Fibrillation
VKA, Warfarin
Recurrent stroke or TIA despite
treatment VKAa
Moderate or severe renal impairmentb
Direct Thrombin Inhibitors
Factor X
Inhibitors
GI tract symptoms or dyspepsiac
Apixaban
75 mg dabigatran, 2/d (US);

110 mg dabigatran,
2/d (rest of world)
High risk of bleedingd

Preference for 1 dose per day
Rivaroxaban
Edoxaban
150 mg of dabigatran, 2/d
Abbreviations: GI, gastrointestinal; TIA, transient ischemic attack; VKA, vitamin K

antagonist.
a
Superior efficacy for preventing both stroke and hemorrhage.
For creatinine clearance of <15 mL/min use VKA.
internal heterogeneity for the aspirin effect. The study had 2

major groups: one group could not, or would not, take anticoagulation medicine. Of these, one subgroup of AF patients received
placebo and the other aspirin. For the group that could take anticoagulation medication, one subgroup received placebo; another,
aspirin; and a third group, warfarin. There was a significant, 94%
reduction in stroke risk attributable to aspirin compared with placebo in the anticoagulation-eligible group. In the group that could
not receive anticoagulation medication, there was no significant
difference in stroke rates between aspirin and placebo.67 Indeed,
aspirin is often considered for those deemed inappropriate for
anticoagulation. In the SPAF-I trial, aspirin did not reduce stroke
among those older than 75 years, nor did it prevent severe
strokes. In a meta-analysis of AF studies, the reduction of stroke
or vascular events using aspirin declined with age, whereas bleeding risk between it and warfarin was not markedly different.68
This was also evident from recent randomized trials and cohort
studies reporting that major bleeding and intracranial hemorrhage did not differ between aspirin and OAC use and that
adverse events occurred more frequently among very elderly
patients who were taking aspirin.
With VKAs, the quality of anticoagulation control is critical (as
reflected by the time in therapeutic range [TTR], with a target INR
of 2.0-3.0). Time in therapeutic ranges are closely related to efficacy and safety, with low rates of stroke and bleeding with high
TTRs. 69,70 With INRs persistently higher than 3.0, there is an
increase in bleeding, especially in elderly patients, whereas the
rate of thromboembolisms increase when INRs are less than 2.0.
Even at an average INR of 1.7, the risk of stroke already increases
2-fold. Thus, VKAs require regular anticoagulation monitoring and
are open to significant interpatient and intrapatient variability
due to interactions with diet, drugs, and alcohol, among other
factors.71
In more recent years, the availability of the NOACs has
changed the landscape of stroke prevention in AF. The NOACs
offer efficacy, safety, and convenience for stroke prevention compared with the VKAs. The various phase 3 trials comparing NOACs
against warfarin have been the subject of numerous reviews and
meta-analyses.
In a recent meta-analysis72 that included the RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy),
ROCKET-AF (Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibijama.com
Also has an increased risk of bleeding.
High risk of bleeding is defined by a HAS-BLED score of 3 or higher. Use agent

with the lowest incidence of bleeding, especially for GI tract bleeding.
Awaiting approval.
tion Compared With Vitamin K Antagonism for Prevention of

Stroke and Embolism Trial in Atrial Fibrillation), ARISTOTLE
(Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and
Embolism Trial in Atrial Fibrillation), and ENGAGE-AF TIMI 48
(Effective Anticoagulation with Factor Xa Next Generation in Atrial
FibrillationThrombolysis In Myocardial Infarction study 48) trials,
42 411 participants received a NOAC and 29 272 participants
received warfarin. NOACs significantly reduced stroke or systemic
embolism events by 19% compared with warfarin (RR, 0.81; 95%
CI, 0.73-0.91; P < .001) mainly related to a reduction in hemorrhagic stroke (RR, 0.49; 0.38-0.64; P < .001). NOACs also significantly reduced all-cause mortality (RR, 0.90; 0.85-0.95; P < .001)
and intracranial hemorrhage (RR, 0.48; 0.39-0.59; P < .001) but
increased gastrointestinal tract bleeding (RR, 1.25; 1.01-1.55;
P = .04). Low-dose NOACs had similar overall reductions in stroke
or systemic embolism events to warfarin (RR, 1.03; 0.84-1.27;
P = .74) and had a more favorable bleeding profile (RR, 0.65; 0.431.00; P = .05), with significantly more ischemic strokes (RR, 1.28;
1.02-1.60; P = .045).
With the availability of 4 different NOACs as well as the VKAs,
physicians now have a choice and can fit the drug to the patient. Various patient characteristics may influence the initial choice of one drug
over another (Table 4). In the absence of head-to-head clinical trials,
clinicians cannot directly compare one NOAC against another. Nevertheless, regulatory bodies and health economic analyses have performed indirect comparisons of one agent against another using warfarin as the comparator; such indirect comparisons (or network metaanalyses) should be interpreted with some caution given
heterogeneity in trial inclusion-exclusion criteria, quality of INR
control.73 Overall, there are few substantial differences in efficacy,
although 150 mg of dabigatran twice daily may offer the greatest potency by reducing both ischemic and hemorrhagic stroke, and it has
a similar risk of major bleeding as warfarin. For safety, the best bleeding profile is seen with 110 mg of dabigatran twice daily, apixaban,
and edoxaban.74-76
In some health care systems, there is a preference for a 3- to
6-month warfarin trial to determine if high TTRs (eg, >65%) can
be achieved. NOACs are only used if the TTRs remain poor
(<65%). This strategy may put patients at risk of stroke or systemic embolism because in the initial treatment stages, inadequate anticoagulation may result in an excess of thromboem(Reprinted) JAMA May 19, 2015 Volume 313, Number 19
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Table 5. Definition of the SAMe-TT2R2 Score, Used to Aid Initial Decision

Making Between Vitamin K Antagonist (With Good Quality Anticoagulation
Control) and a NonVitamin K Antagonist Oral Anticoagulanta
Definitions
Points
Sex (female)
Age (<60 y)
Medical historyb
Treatment (interacting drugs, eg, amiodarone for

rhythm control)
Tobacco use (within 2 y)
Race (not white)
Maximum points
The SAMe-TT2R2 score is proposed as a means to help with decision making,

to identify those newly diagnosed nonanticoagulated AF patients who have a
probability of doing well while taking a vitamin K antagonist (VKA) (with
SAMe-TT2R2 score, 0-2) and achieve a time in therapeutic range (TTR) of at
least 65% or 70%. In contrast, a SAMe-TT2R2 score of more than 2 suggests
that such patients are unlikely to achieve a good TTR while taking a VKA, and a
non-VKA oral anticoagulant should be used upfront, without a trial of
warfarin period.
Two of the following: hypertension, diabetes mellitus, coronary artery disease

or myocardial infarctions, peripheral artery disease, congestive heart failure ,
previous stroke, pulmonary disease, or hepatic or renal disease.
bolic events (RR, 1.71; 95% CI, 1.39-2.12).77 Various clinical and
pharmacogenetic factors have been proposed as determinants of
warfarin dose or TTR.71,78 Recent randomized trials based on a
pharmacogenetic testing as a means of predicting the response
to warfarin have been disappointing.
Simple clinical risk factors have been incorporated into a
new score, the SAMe-TT2R2 score78 (Table 5), which has been
proposed as a means of identifying those newly diagnosed
patients with AF who have not been treated with anticoagulation
agents and who have a probability of doing well taking a VKA
(SAMe-TT2R2 score, 0-2) and achieve a TTR greater than 65% or
70%78,79 (Figure). In contrast, a SAMe-TT2R2 score higher than 2
suggests that such patients are unlikely to achieve a good TTR by
taking a VKA, so a NOAC should be used initially, without subjecting the patient to a trial of warfarin period. The SAMe-TT2R2
score has since been validated in independent studies to show it
can discern those likely to achieve poor TTRs. A high SAMe-TT2R2
score translates to a greater chance of labile INRs, thromboembolism, death, and bleeding.80-83 This approach has been recommended in a position document from the European Society of
Cardiology (ESC) Working Group on Thrombosis Anticoagulation
Task Force.71
Figure. Algorithm for Risk Stratification and Selection of Anticoagulation Therapy for Stroke Prevention in Atrial Fibrillation
Patient with newly diagnosed
atrial fibrillation
Calculate CHA2DS2-VASc score

to determine stroke risk
High stroke risk?

Male, CHA2DS2-VASc score 1
Female, CHA2DS2-VASc score 2
No
(Low stroke
risk)
Yes a
(High stroke
risk)
Calculate SAMe TT2R2 score to determine

initial anticoagulation treatmenta
No
(Score 0-2)
SAMe TT2R2 score >2?
Yes
(Score >2)
Vitamin K antagonist (VKA) therapy

(eg, warfarin)
Monitor anticoagulation control (goal:

time in therapeutic range [TTR] >70%)
Inadequate anticoagulation control?

TTR <65%
OR
within past 6 mo
INR >5 twice
or
INR >8 once
or
INR <2 twice
No
Yes
Non-VKA-oral anticoagulant therapy

(oral direct thrombin inhibitors or oral
factor Xa inhibitors)
Continue VKA therapy with regular

monitoring
See Table 1 footnotes for abbreviation expansions; SAMe-TT2R2 is explained in

Table 5.
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Consider NOAC or VKA. If considering VKA, calculate SAMe-TT2R2 first before

deciding on optimal OAC therapy.
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Net Clinical Benefit

When making decisions about thromboprophylaxis, an important
consideration is to balance ischemic stroke prevention against the
potential risk of serious bleeding. The net clinical benefit of antithrombotic therapy can be determined in many ways, eg, by balancing the reduction in ischemic stroke against the risk of serious
bleeding (ie, intracranial hemorrhage) weighted 1.5-fold.84 Other
complex weighted formulae for net clinical benefit have been proposed, but none are perfect.
Recent studies have found a positive net clinical benefit (balancing ischemic stroke reduction against the risk of intracranial
hemorrhage weighted 1.5-fold) for OAC in patients with AF and at
least 1 additional stroke risk factor.85,86 With the NOACs, the net
clinical benefit was also generally positive for dabigatran and
apixaban with CHA2DS2-VASc score of 1, and for all NOACs with
CHA2DS2-VASc score of at least 2,87 and in a modeling analysis,
could translate to an additional 65 000 cardiovascular events
and deaths prevented in Europe.88 The threshold for initiating
OAC treatment has been calculated as a stroke rate of 0.9% per
year, based on the balance of ischemic stroke reduction vs intracranial hemorrhage with the availability of new safer OAC
agents.89
Guidelines for AF Treatment

When the only available oral anticoagulants were the VKAs, the
focus was to identify high-risk patients to be targeted for this
inconvenient drug, VKA (eg, warfarin), given the need for anticoagulation monitoring and other restrictions necessary with VKA
use. Also, older guidelines, such as the 2006 ACC/AHA/ESC joint
guidelines had divided patients using the CHADS2 score into low-,
moderate-, and high-risk strata, for which low-risk patients were
recommended aspirin; moderate-risk patients, aspirin or warfarin;
and high-risk patients, warfarin.90 Such an approach did not work
well, and numerous studies have shown that high-risk patients
were undertreated, with OAC being used in approximately 50%
of patients and with regional differences evident.91 Also, stroke
risk is a continuum, and any 1 risk factor can confer risk if left
untreated, exposing the patient with AF to a fatal or disabling
stroke.45
In 2010, and in a focused update in 2012, the ESC guidelines advocated a change in clinical practice highlighting the need to identify the low-risk patients (age <65 years and lone AF, including women) who do not need any antithrombotic therapy. Patients with 1 or
more stroke risk factors should be offered OAC, with a preference
for NOACs. If VKAs are used, a TTR higher than 70% was recommended. Only if patients refuse any form of OAC, then antiplatelet
therapy with aspirin-clopidogrel combination therapy (if not at an
unduly high bleeding risk) orless effectivelyaspirin monotherapy, may be considered. The HAS-BLED score is recommended for bleeding risk assessment.
In 2012, the American College of Chest Physicians (ACCP) published its consensus guidelines on antithrombotic therapy in
AF patients.29 This was based on the CHADS2 score, where OAC
was recommended for those with CHADS2 score of 1 or higher. In
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patients with a CHADS2 score of 0, additional non-CHADS2 risk factors should be considered, including age from 65 through 74 years,
female sex, and vascular disease, whereby the presence of multiple
non-CHADS2 risk factors would merit OAC treatment.
In 2014, the new AHA/ACC/HRS guidelines5 for AF advocated
use of the CHA2DS2-VASc score for stroke risk stratification, but in
a categorical approach whereby OAC was recommended for a
CHA2DS2-VASc score of 2 or higher, and no therapy for a score of
0; however, for CHA2DS2-VASc score of 1, the recommendation
was no therapy, aspirin or OAC. Oral anticoagulants could be
either NOACs or VKAs. The value of the US guidelines approach
for CHA2DS2-VASc score of 1 was recently tested in a nationwide
cohort study of 12 935 men with AF and a CHA2DS2-VASc score of
1 but were not receiving antithrombotic therapy, where the
annual stroke rate overall was 2.75%. 92 The risk of ischemic
stroke ranged from 1.96% per year for AF patients with vascular
disease to 3.50% per year for those aged 65 through 74 years.
For women with AF and a CHA2DS2-VASc score of 2 (ie, 1 additional risk factor), the annual stroke rate was 2.55%, with the risk
of ischemic stroke increasing from 1.91% per year for patients
with hypertension to 3.34% per year for those aged 65 through
74 years. Similar findings were observed from the Danish nationwide cohort study, where event rates in nontreated AF patients
with 1 additional stroke risk factor increased stroke by 3.01-fold
and death by 3.12-fold, at 1 year follow-up.93 Thus, OAC should
still be considered for AF patients with 1 additional stroke risk factor given their high risk of ischemic stroke and death.
In 2014, NICE published its new AF guidelines.4 In contrast to
some guidelines, the NICE guidelines are based on systematic reviews, evidence appraisal and cost-effectiveness. NICE guidelines
advocate use of the CHA2DS2-VASc and HAS-BLED scores for stroke
and bleeding risk assessment, respectively. The recommendations
are to initially identify low-risk patients who do not need any antithrombotic therapy. Patients with a CHA2DS2-VASc score 2 or higher
should be offered OAC, while men with a score of 1 should be considered for OAC. If VKAs are used, a TTR of higher than 65% was recommended. The guidelines clearly state that aspirin should not be
used for stroke prevention in AF, due to its minimal efficacy, poor
safety, and lack of cost-effectiveness.
The Canadian Cardiovascular Society (CCS) published its
focused update in 2014, proposing a simplified algorithm-based
approach to stroke risk stratification.30 The first step in the algorithm is to identify those aged 65 years or older who should be
offered OAC. The second step is to identify those younger than
65 years with CHADS2 risk factors who should have OAC. Next,
those younger than 65 years who have a CHADS2 score of 0 with
arterial disease, ie, coronary, aortic or peripheral are recommended aspirin alone. Finally, those patients younger than 65
years with no CHADS2 risk factors nor vascular disease are recommended no antithrombotic therapy.30 This approach was tested
in a nationwide cohort study, in which the overall rate of the combined end point of ischemic stroke, systemic embolism , or TIA
was 4.32 per 100 person-years at 1 year, among the patients who
would have had an indication for OAC therapy according to ESC
guidelines but were not recommended for OAC according to the
2014 CCS algorithm; also, the subgroup of patients with prior vascular disease and a CHADS2 score of 0 (ie, only recommended
aspirin treatment according to CCS algorithm) had an event rate
1957
of 4.84 per 100-person-years at 1-year follow-up.94 Thus, based

on the 2014 CCS algorithm, the subgroup not recommended for
OAC were not low risk and use of the ESC guideline approach
offered additional refinement of stroke risk stratification in such
patients.
In summary, stroke risk stratification and treatment decisions
can now be simplified, notwithstanding the various approaches advocated in guidelines. The initial step is to identify the low-risk patients who do not need any antithrombotic therapy, given their low
absolute risk of stroke. Low-risk patients are those aged younger than
65 years with no stroke risk factors (a CHA2DS2-VASc score of 0 for
males or 1 for females). Subsequently, patients with at least 1 additional stroke risk factor can be offered effective stroke prevention,
which is OAC, either NOAC or VKA (Figure). Thus, this includes male
AF patients with a CHA2DS2-VASc score of 1 and a score of 2 or higher
for everyone else, irrespective of other risk stratification enhancements. In terms of clinical application and practicality, such an approach makes clinical decision making very simple and practical, without the necessity for complex investigations that may delay
treatment decisions.
Does use of risk scores in guidelines to aid treatment decisions improve outcomes? As mentioned above, use of the
CHA2DS2-VASc score enables refinement of stroke risk stratification and enables identification of those AF patients still at appreciable stroke risk who were previously considered at low risk
when using other risk schemes.31,45,94-96 The net clinical benefit is
also positive for patients with a CHA 2 DS 2 -VASc score of 1 or
higher, whether from real-world cohorts or modeling analyses
with the NOACs.85-87 Indeed, modeling analyses show that use of
the ESC guidelines would translate to a reduction in additional
thromboembolic, mortality, and bleeding events in Europe
and Asia, compared with older guideline strategies.88,97 Finally,
guideline adherent treatment is associated with improved efficacy and safety outcomes, whether from observational98,99 or
trial-based100 cohorts.
Specific Considerations
1958
Acute Coronary Syndrome and Percutaneous Coronary

Intervention
Many patients with AF have associated coronary artery disease.
Some may present with an acute coronary syndrome (ACS), be undergoing percutaneous coronary intervention, or both. Such patients are at high risk, so management is complex, having to use OAC
plus antiplatelet therapy to balance between stroke prevention, recurrent cardiac ischemia, stent thrombosis, and risk of serious bleeding (especially intracranial hemorrhage).105,106 Observational and trial
data have recently been reviewed by a European consensus group,107
which recommends an initial period of triple therapy (OAC, aspirin,
clopidogrel) followed by OAC plus a single antiplatelet drug
(preferably clopidogrel). After 1 year, the patients can receive OAC
alone. In some patients at low thrombotic risk or high-bleeding risk,
the initial triple therapy period could be substituted with OAC plus
clopidogrel. In guidelines in which OAC is mentioned, this could refer to a NOAC or well-managed VKA (with TTR >70%). Thirdgeneration drug eluting stents are also the preferred option, and with
improvements in stent technology, the period during which additional dual antiplatelet drugs are needed can be shortened.
Bridging
Bridging refers to the use of a short-acting anticoagulants, eg,
low-molecular-weight heparin, during the interruption of a
longer-acting oral agent. Bridging anticoagulation is often used
during anticoagulation interruptions for operative procedures
and is associated with a higher risk of bleeding and adverse
events. Indeed, observational and trial data do not support the
use of routine bridging given the higher bleeding risks and no difference in thromboembolism when compared with an uninterrupted OAC strategy; thus, the latter approach is used for most
procedures.108 However, bridging may perhaps be considered for
some very high-risk subgroups (eg, prosthetic mechanical heart
valves); thus, risk stratification is important.109 NOACs may be
beneficial based on promising data from post hoc analysis from
randomized trials.110 Nevertheless, the use of NOACs requires
understanding of their pharmacology, given their fast onset and
offset of action, as well as the effect of renal function.
Chronic Renal Failure
Left Atrial Appendage Occlusion
Atrial fibrillation patients with renal impairment represent a highrisk group, demonstrating a greater risk of stroke, myocardial infarction, and major bleeding.101 Approximately 20% of AF patients show
a significant reduction in renal function over 2 years, and even normal or mild renal impairment at baseline did not preclude some patients from progressing to severe renal impairment.102
Patients with severe renal impairment were largely excluded
from randomized trials, and all NOACs do have some degree of renal excretion (the highest being with dabigatran, whereby the drug
is also removed by hemodialysis). Initial observational studies were
conflicting suggesting that stroke prevention with warfarin was offset by a high rate of major bleeding, especially in patients requiring
dialysis.103 The most recent data from the Swedish AF cohort study37
suggests that warfarin is still associated with a positive net clinical
benefit, balancing stroke reduction against bleeding risk, but emphasizes the importance of a high TTR to minimize adverse effects.
Similar data have been published from the Danish nationwide cohort study.104
The concept of left atrial appendage (LAA) occlusion arises because most atrial thrombi arise from the LAA, in patients with AF.
Thus, over the last decade, the LAA has been removed during cardiac surgery, or more recently subject to percutaneous occlusion with
a variety of devices. For example, the WATCHMAN device has been
tested in a randomized trial (PROTECT-AF),111 which showed that the
LAA occlusion device was noninferior for safety and efficacy to standard therapy (warfarin). There was an initial excess of complications (eg, pericardial tamponade) in the device intervention group
than in the control group (7.4 vs 4.4 per 100 patient-years; RR, 1.69,
95% CI, 1.01-3.19), but as operators became more experienced this
diminished, as has been seen in subsequent registries. These findings were reinforced in the PREVAIL trial,112 which showed that LAA
occlusion was noninferior to warfarin for ischemic stroke prevention or systemic embolism at more than 7 days after the procedure.
Other methods of LAA occlusion are also available, but randomized trials are lacking. A recent position document from the European
Heart Rhythm Association comprehensively reviews the literature
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and suggests practical points for its use.113 For now, LAA occlusion
may be considered in patients with a high stroke risk and contraindications for long- term OAC.4
Cardioversion
Cardioversion of AF requires OAC for a minimum of 3 weeks
before cardioversion, and OAC continued during and after cardioversion. Recent data on the NOACs may support their use to facilitate cardioversion and may be associated with less delay to the
procedure, in contrast to using VKAs for which delays or cancellations were common pending a therapeutic INR.114-116 Irrespective
of apparent successful rhythm control (whether by cardioversion
or ablation), patients should continue taking OAC in the presence
of stroke risk factors. Rhythm control should not be performed as
a basis to stop OAC.
Patient Values and Preferences

Increasing awareness is evident on the importance of patient attitudes and preferences in deciding on managing strategies for AF, as
ARTICLE INFORMATION
Conflict of Interest Disclosures: Both authors
have completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr Lip
reported that he has served as a consultant for
Bayer Healthcare, Merck, AstraZeneca, sanofiaventis, Bristol-Myers Squibb/Pfizer, and
Boehringer Ingelheim, and has been on the speaker
bureaus for Bayer, Bristol-Myers Squibb/Pfizer,
Boehringer Ingelheim, and sanofi-aventis. Dr Lane
reported that she has received an investigator
initiated educational grants from Bayer Healthcare
and Boehringer Ingelheim and has been on the
speakers bureau for Boehringer Ingelheim, Bayer,
and Bristol-Myers Squibb/Pfizer.
Submissions:We encourage authors to submit
papers for consideration as a Review. Please
contact Mary McGrae McDermott, MD, at
mdm608@northwestern.edu.
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Clinical Review & Education

Stroke Prevention in Atrial Fibrillation

Author Audio Interview at

with a substantial increase in stroke and systemic thromboembolism. Strokes related to AF

OBJECTIVE To provide an overview of current concepts and recent developments in stroke

trial fibrillation (AF) increases the risk of morbidity and

Corresponding Author: Gregory Y.

JAMA May 19, 2015 Volume 313, Number 19 (Reprinted)

Copyright 2015 American Medical Association. All rights reserved.

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Author Affiliations: University

Stroke Prevention in Atrial Fibrillation

Review Clinical Review & Education

Risk Factors for Stroke

The risk of stroke and mortality in AF is reduced by anticoagulant

In a recent systematic review, peripheral arterial disease was

Risk Stratification Schemes

Copyright 2015 American Medical Association. All rights reserved.

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Clinical Review & Education Review

Stroke Prevention in Atrial Fibrillation

Proteinuria and eGFR; different weighting

CHADS2 score, 0, non-CHADS2 risk

Abbreviations: ACCP, American College of Chest Physicians; AFI, Atrial

Other Risk Stratification Schemes

The CHA2DS2-VASc score (Table 2) was initially validated in the

Clinical stroke risk prediction scores such as CHADS 2 and

Age and female sex combined are a single risk factor.

JAMA May 19, 2015 Volume 313, Number 19 (Reprinted)

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Stroke Prevention in Atrial Fibrillation

Review Clinical Review & Education

Table 2. Summary of Guideline Recommendationsa

0 plus additional non-CHADS2 risk

Subsequent step: for patients

OAC is recommended for

OAC refers to a VKA (eg, warfarin)

Warfarin or a NOAC, preferred

Algorithm: no risk factors,

Nothing, aspirin, or OAC

OAC refers to warfarin or a NOAC

Subsequent: for AF patients

Offer OAC (CHA2DS2-VASc 2)

OAC refers to warfarin or a NOAC

Abbreviations: ACCP, American

See Table 1 footnotes for CHADS2

Low-risk patients include men who

risk patients who do not need antithrombotic therapy. All other AF

Risk Factors for Bleeding

Copyright 2015 American Medical Association. All rights reserved.

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Clinical Review & Education Review

Stroke Prevention in Atrial Fibrillation

Table 3. Assessment of Stroke and Bleeding Risk in Atrial Fibrillation

Vascular disease (prior MI, PAD, or aortic plaque)

Sex category (ie, female sex)

Abnormal renal and liver function (1 point each)c

Labile INRs (eg, TTR<60%, applies only if the patient

Elderly (eg, age >65 y, frail condition)

Drugs or alcohol excess (1 point each)c

Abbreviations: INR, international normalized ratio; MI, myocardial infarction;

CHA2DS2-VASc is used to initially identify low-risk patients (CHA2DS2-VASc,