JAMA - Stroke Prevention in Atrial Fibrillation 2015

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Stroke Prevention in Atrial FibrillationA Systematic ReviewGregory Y. H. Lip, MD; Deirdre A. Lane, PhD

A trial fibrillation (AF) increases the risk of morbidity andmortality because of a substantially increased risk ofstroke and systemic thromboembolism. Overall, AF

increases the stroke risk 5-fold; the attributable risk of ischemicstroke related to AF increases from 4.6% from the ages of 50through 59 years to 20.2% from the ages of 80 through 89 years.1

Compared with non-AF–related strokes, strokes related to AF areassociated with higher mortality, greater disability, longer hospitalstays, poorer functional outcome, and lower chance of being dis-charged home.2 Given the increasing prevalence and incidence ofAF, this arrhythmia confers a major public health and economicburden 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 themajor guidelines emphasize the role of oral anticoagulation (OAC)use for stroke prevention in AF.4,5

The objective of this article is to provide an overview of cur-rent concepts and recent developments in stroke prevention in pa-tients with nonvalvular AF.

Search StrategyA comprehensive structured literature search was performedusing MEDLINE for studies published through March 11, 2015, thatreported on AF and stroke or bleeding risk factors, as well as onstroke prevention. The search terms included each of the follow-ing terms individually and in combination: atrial fibrillation,thromboembolism, stroke risk, risk stratification, oral anticoagula-tion, warfarin, aspirin, and thromboprophylaxis. We focused onprimary published research articles and systematic reviews, aswell as on clinical trials complemented by large observationalcohorts.

IMPORTANCE Atrial fibrillation (AF) is associated with an increase in mortality and morbidity,with a substantial increase in stroke and systemic thromboembolism. Strokes related to AFare associated with higher mortality, greater disability, longer hospital stays, and lowerchance of being discharged home than strokes unrelated to AF.

OBJECTIVE To provide an overview of current concepts and recent developments in strokeprevention in AF, with suggestions for practical management.

EVIDENCE REVIEW A comprehensive structured literature search was performed usingMEDLINE 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. Thromboprophylaxiscan be obtained with vitamin K antagonists (VKA, eg, warfarin) or a non-VKA oralanticoagulant (NOAC). Major guidelines emphasize the important role of oral anticoagulation(OAC) for effective stroke prevention in AF. Initially, clinicians should identify low-risk AFpatients who do not require antithrombotic therapy (ie, CHA2DS2-VASc score, 0 for men; 1 forwomen). Subsequently, patients with at least 1 stroke risk factor (except when the only risk isbeing a woman) should be offered OAC. A patient’s individual risk of bleeding fromantithrombotic therapy should be assessed, and modifiable risk factors for bleeding shouldbe addressed (blood pressure control, discontinuing unnecessary medications such as aspirinor nonsteroidal anti-inflammatory drugs). The international normalized ratio should be tightlycontrolled 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 identifyinglow-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

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Author Affiliations: Universityof Birmingham Centre forCardiovascular Sciences,City Hospital, Birmingham,United Kingdom (Lip, Lane);Aalborg Thrombosis Research Unit,Department of Clinical Medicine,Aalborg University, Aalborg,Denmark (Lip).

Corresponding Author: Gregory Y.H. Lip, MD, University of BirminghamCentre for Cardiovascular Sciences,City Hospital, Birmingham,West Midlands B18 7QH, England([email protected]).

Section Editor: Mary McGraeMcDermott, MD, Senior Editor.

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Risk Factors for Stroke

Atrial fibrillation can cause stroke by several mechanisms consis-tent with the Virchow triad for thrombogenesis (thrombus forma-tion): (1) stasis in the left atrium causing flow abnormalities; (2) struc-tural heart and vascular disease (eg, mitral stenosis; fulfilling theabnormal vessel wall Virchow criterion); and (3) abnormal coagula-tion and fibrinolysis (eg, abnormal procoagulant hemostatic andplatelet factors; fulfilling the abnormal blood constituents criterion).6

The prothrombotic state in AF has recently been comprehensivelyreviewed.6

The most common risk factors associated with stroke (eg, heartfailure, hypertension, diabetes, age, prior stroke) were initially iden-tified from the non-VKA cohorts of randomized trials conducted 2decades ago.2 Although these trials provided information on pa-

tients treated with placebo,they have been criticized forrandomizing fewer than 10%of patients screened and fornot recording all the risk fac-tors nor consistently defin-ing them in the studies.7

Numerous systematicreviews have examined AF-related stroke risk factors.8,9

A study by the Stroke in AFWorking Group8 reportedthat the strongest, most con-sistent independent risk fac-tors for stroke were priorstroke or transient ischemicattack (TIA) (relative risk[RR], 2.5; 95% CI, 1.8-3.5), in-creasing age (RR, 1.5 perdecade; 95% CI, 1.3-1.7),a history of hypertension(RR, 2.0; 95% CI, 1.6-2.5),and diabetes mellitus (RR,1.7; 95% CI, 1.4-2.0). In thissystematic review, female

sex was inconsistently associated with stroke risk, and the evi-dence was inconclusive for heart failure or coronary artery diseaseas independent predictors of AF-related stroke.

Other systematic reviews that included large observationalcohort studies also found evidence for vascular disease andfemale sex9 as risk factors for stroke. In a recent systematicreview 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 inpopulations that were entirely anticoagulated, stroke rates werehigher in women, varying from 1.2% to 1.44% per patient-year formen and 2.08% to 2.43% per patient-year for women. The risk ofstroke in women with AF is age dependent, with women youngerthan 65 and having no other risk factors being at low risk.11,12 Inone European study involving AF patients younger than 65 years,female sex did not emerge as an independent risk factor13; how-ever, female sex appears to still confer some stroke risk, especiallyin Asian cohorts.14,15

In a recent systematic review, peripheral arterial disease wassignificantly associated with AF-related stroke risk in all 10 obser-vational studies, with a reported risk range of 1.3- to 2.5-fold.16

Complex aortic plaque on the descending aorta, as identified bytransesophageal echocardiography, was also a significant riskfactor.17 Prior myocardial infarction was validated as a significantpredictor of the primary end point in 5 of the 6 studies. Theremay be ethnic differences evident for peripheral arterial diseaseas a risk factor, with an RR of stroke approximately 1.22-foldhigher in European populations,18 but 1.80-fold higher in Far East-ern populations.19

Risk Stratification SchemesThe various stroke risk factors in AF have been used to formulate sev-eral stroke risk prediction tools,20-28 to help risk stratify patients withAF (Table 1). The most common in use are the CHADS2 (congestiveheart failure; hypertension; age �75 years; diabetes mellitus,1 pointfor each; stroke, 2 points) and CHA2DS2-VASc scores (see Table 3 fordefinition). All the risk stratification schemes based on clinical riskfactors have weak or modest predictive value for identifying high-risk patients.2 However, the CHA2DS2-VASc score has particular valuein identifying low-risk patients who do not need antithrombotictherapy.31,32 Hence, more recent guidelines have moved toward ini-tial identification of low-risk patients first (because these patientsdo not need any antithrombotic therapy), rather than focus on iden-tifying high-risk patients.4

CHADS2

The CHADS2 score was formulated and initially validated in a regis-try of hospitalized patients with AF.22 The CHADS2 score is rela-tively simple for identifying high-risk patients (score >2), whereasmoderate risk was initially defined as a score of 1 to 2 and low risk asa score of 0.22 The CHADS2 had various limitations, and does not in-clude many of the commonly accepted stroke risk factors (eg, age65-74 years, vascular disease, female sex, asymptomatic left ven-tricular diastolic dysfunction, etc). Furthermore, according to theoriginal validation study, those with a prior stroke and no other riskfactor (which represented the highest risk category) would only score2 and would be classified as moderate risk.33

AF atrial fibrillation

CHADS2 congestive heart failure,hypertension, age �75 years,diabetes mellitus, stroke

CHA2DS2-VASc CHADS2 criteria plusvascular disease, age 65-74 years, sexcategory

HAS-BLED hypertension, abnormalrenal/liver function, stroke, bleedinghistory or predisposition, labileinternational normalized ratio, elderly,drugs/alcohol

HEMORR2HAGES hepatic or renaldisease, ethanol abuse, malignancy,older age, reduced platelet count orfunction, rebleeding, hypertension,anemia, genetic factors, excessive fallrisk, and stroke

INR international normalized ratio

LAA left atrial appendage

NOAC non-VKA oral anticoagulant

OAC oral anticoagulation

TIA transient ischemic attack

TTR time in therapeutic range

VKA vitamin K antagonists

At a Glance

• The risk of stroke and mortality in AF is reduced by anticoagulanttherapy, 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 patientswho do not require antithrombotic therapy. Patients with at least1 stroke risk factor (except when the only risk factor is being awoman) should be offered OAC.

• Clinicians also need to assess each patient’s individual risk ofbleeding with antithrombotic therapy and correct modifiablebleeding risk factors: control blood pressure; remove unneces-sary concomitant medication, such as aspirin, or NSAIDs; controlINR and avoid labile INRs; counsel patient to reduce alcoholintake if excessive. Ultimately, the main priority is strokeprevention.

Stroke Prevention in Atrial Fibrillation Review Clinical Review & Education

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CHA2DS2-VAScThe CHA2DS2-VASc score (Table 2) was initially validated in theEuro-Heart survey cohort.26 This score included various non-CHADS2 risk factors such as age from 65 to 74 years, female sex,and vascular disease. For example, in contrast to CHADS2 the C inCHA2DS2-VASc refers to congestive heart failure, including moder-ate to severe left ventricular dysfunction (ejection fraction, <40%)and recent decompensated heart failure irrespective of ejectionfraction, thus including both heart failure with reduced ejectionfraction or heart failure with preserved ejection fraction.4 In the lat-ter group, patients with cardiomyopathy (eg, restrictive or hyper-trophic) could also be included under the C criterion, althoughrobust data are limited.

The CHA2DS2-VASc score has been validated in numerousindependent cohorts, including non-Western populations. In 2 FarEastern studies, the CHA2DS2-VASc but not the CHADS2 scorewas significantly predictive of stroke.34,35 Most studies demon-strate that CHA2DS2-VASc is best at identifying “truly low-risk”patients for whom the absolute risks of stroke or systemic embo-lism were less than 1% per year and was as good as—possiblybetter than—the older CHADS2 score for predicting high-riskpatients.31,32,36 The CHA2DS2-VASc score is now the recom-mended risk score by European,4 US,5 and National Institute forHealth and Care Excellence (NICE)4 guidelines.

Other Risk Stratification SchemesClinical stroke risk prediction scores such as CHADS2 andCHA2DS2-VASc are based on common risk factors in patientswith AF whom clinicians encounter in clinical practice. TheCHA2DS2-VASc score does not include other rare factors that havebeen associated with stroke or systemic embolism in AF such as amy-loid heart disease and end-stage renal failure. Large observationalcohorts have clarified the effect of severe renal impairment on strokeand bleeding risks in AF, but renal impairment does not add predic-tive value to established scores, such as CHA2DS2-VASc.37

The other risk factor score schemes that have been devel-oped, including the CHADS2 score,38 the Anticoagulation andRisk Factors in Atrial Fibrillation (ATRIA) stroke score,28 theCHA2DS2-VASc score,39,40 and the Qstroke27 score, all have limi-tations. All the major guidelines have continued to emphasize theuse of the CHA2DS2-VASc score.

Most risk stratification schemes based on clinical criteria haveweak predictive value for high-risk patients who sustain events(C statistic, approximately 0.6); thus, there has been much inter-est in the use of biomarkers to enhance the predictive value ofclinical 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 cre-atinine clearance),44 cardiac imaging (echocardiography, whether

Table 1. Risk Factors Included in Various Clinical Stroke Risk Stratification Schema and Guidelines

Risk Factors Other Factors

Age, yFemaleSex

Prior TEEvent

Hyper-tension

HeartFailure

DiabetesMellitus

VascularDisease

Scheme

SPAF,20 1999 >75a �a � � �

AFI,21 1994 65-75 >75 � � �

CHADS2,22 2001 ≥75 � � � �

Framingham,23

2003� � � � �

van Walraven,24

2003� � � �

Rietbrock,25 2008 � � � �

CHA2DS2-VASc,26

200965-74 ≥75 � � � � � �

QStroke,27 2013 � � � � � � � Many others

ATRIA,28 2013 � � � � � � � Proteinuria and eGFR; different weightingfor primary and secondary prevention

Guidelines

ACCP,29 2012 65-74 >75 � � � � � � CHADS2 score, 0, non-CHADS2 riskfactors (similar to CHA2DS2-VASc)should be considered

ESC,4 2012 65-74 ≥75 � � � � � � Based on CHA2DS2-VASc

CCS,30 2014 ≥65 � � � �

AHA/ACC/HRS,5

201465-74 ≥75 � � � � � � Based on CHA2DS2-VASc

NICE,4 2014 65-74 ≥75 � � � � � � Based on CHA2DS2-VASc

Abbreviations: ACCP, American College of Chest Physicians; AFI, AtrialFibrillation Investigators; AHA/ACC/HRS, American Heart Association, AmericanCollege of Cardiology, and Heart Rhythm Society; CCS, Canadian CardiovascularSociety; eGFR, estimated glomerular filtration rate; ESC, European Society ofCardiology; 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 systemicembolism; CHA2DS2-VASc: C, congestive heart failure, H, hypertension, A2, ageat least 75 years, D, diabetes, S2, previous stroke, TIA, or systemic embolism,V, vascular disease, Sc, sex category female sex.a Age and female sex combined are a single risk factor.

Clinical Review & Education Review Stroke Prevention in Atrial Fibrillation





transthoracic or transesophageal), or cerebral imaging (eg, com-puted tomography or magnetic resonance imaging), which wouldprovide additional refinement to clinical risk stratification for theidentification of high-risk individuals. The real practical value ofmeasuring various biomarkers for stroke-risk prediction wouldrequire testing large cohorts of individuals who have not receivedanticoagulation treatment rather than testing highly selectedcohorts of patients who have. Also, stroke risk scoring schemesmust have simplicity and ease of use, for rapid application ineveryday clinical practice. Although scoring systems incorporat-ing complex multivariate analyses and modeling or addition ofbiomarkers may offer some improved predictive value, the resul-tant scores are less practical for everyday clinical use because oftheir 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 as-sumptions that risk factors carry equal weight, but they do not.15 Withthe clinical practice change advocated by contemporary guide-lines, the focus should be on the initial identification of truly low-

risk patients who do not need antithrombotic therapy. All other AFpatients who have 1 or more stroke risk factors can be offered strokeprevention therapy.

Risk Factors for BleedingIn addition to stroke risk assessment, it is important to evaluatebleeding risk in AF patients, especially cases in which thrombopro-phylaxis is being considered.46 Various bleeding risk stratificationschemes have been proposed but until recently have not been widelyused due to complexity and overlaps with stroke risk.47 Of the vari-ous bleeding risk scores,48-53 only 3 have been derived and vali-dated in AF populations: HEMORR2HAGES (hepatic or renal dis-ease, ethanol abuse, malignancy, older age, reduced platelet countor function, re-bleeding, hypertension, anemia, genetic factors, ex-cessive fall risk, and stroke),50 HAS-BLED (hypertension, abnormalrenal/liver function, stroke, bleeding history or predisposition, la-bile international normalized ratio [INR], elderly, drugs/alcohol),52

and ATRIA.53

Table 2. Summary of Guideline Recommendationsa

Stroke Risk Stratification Treatment Recommendation CommentsACCP,29 2012

CHADS2 score

≥2 OAC Warfarin or dabigatran

1 OAC Warfarin or dabigatran

0 plus additional non-CHADS2 riskfactors (eg, age 65-74 y, woman,and vascular disease)

OAC Warfarin or dabigatran

No risk factors No antithrombotic therapy

ESC,4 2012

Initial step: identify ‘low risk’ patients(CHA2DS2-VASc 0 in males,1 in females)

No antithrombotic therapy

Subsequent step: for patientswith ≥1 additional stroke risk factors

OAC is recommended forCHA2DS2-VASc score ≥2or should be considered forCHA2DS2-VASc score of 1 in men

OAC refers to a VKA (eg, warfarin)with TTR>70%, or a NOAC(preferred); antiplatelet therapywith aspirin-clopidogrel combinationtherapy or—less effectively—aspirinmonotherapy is recommended onlywhen patients refuse any form of OAC

CCS,30 2014

Algorithm: identify those aged ≥65 yand CHADS2 score risk factors

OAC Warfarin or a NOAC, preferred

Algorithm: vascular disease Aspirin

Algorithm: no risk factors,ie, age <65 y with no CHADS2 riskfactors nor vascular disease

No antithrombotic therapy

AHA/ACC/HRS,5 2014

CHA2DS2-VASc score

≥2 OAC OAC refers to warfarin or a NOACas an alternative

1 Nothing, aspirin, or OAC

0 No antithrombotic therapy

NICE,4 2014

Evaluative steps

Initial: identify low-risk patientsb No antithrombotic therapy

Subsequent: for AF patientswith ≥1 additional stroke riskfactors

Offer OAC (CHA2DS2-VASc ≥2)or consider OAC (CHA2DS2-VASc scoreof 1 in men)

OAC refers to warfarin or a NOACas an alternative.Aspirin monotherapy should not beused for stroke prevention in AF.

Abbreviations: ACCP, AmericanCollege of Chest Physicians; AF, atrialfibrillation; AHA/ACC/HRS, AmericanHeart Association, American Collegeof Cardiology, Heart Rhythm Society;CCS, Canadian CardiovascularSociety; European Society ofCardiology; NICE, National Institutefor Health and Care Excellence;NOAC, nonvitamin K antagonist oralanticoagulant; OAC, oralanticoagulant; TTR, time intherapeutic range; VKA, vitamin Kantagonist.a See Table 1 footnotes for CHADS2

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

have a CHA2DS2-VASc score of 0and women 1.






Of the different scores, the simple HAS-BLED score (Table 3)has been validated in multiple independent cohorts and outper-forms other bleeding risk scores in the prediction of seriousbleeding.54-56 HAS-BLED has been validated in NOACs and in un-treated and aspirin-treated patients,52,57 HAS-BLED is the only scorepredictive of intracranial hemorrhage risk and also has been shownto predict bleeding during bridging therapy58 and during percuta-neous coronary intervention.59

A high HAS-BLED score is not a reason to withhold OAC, but itcan be used to highlight patients’ potential risk of bleeding and alertphysicians to schedule more regular follow-up visits and providestraightforward warning about the necessity of avoiding falls and notengaging in other high-risk activities. A high HAS-BLED score sug-gests the need to focus on correcting the potentially reversible fac-tors that contribute to bleeding, which include uncontrolled hyper-tension, concomitant use of aspirin or nonsteroidal anti-inflammatory drugs with OAC, excessive alcohol intake, and labile

INRs. Use of a decision support tool that integrates patient-specificstroke and bleeding risk would result in significant gains in quality-adjusted life expectancy.60

Falls are not an independent predictor of bleeding for thosewho are taking OAC medication.61 A modeling exercise has sug-gested that a patient would need to fall 295 times a year for thebenefit of stroke prevention with OAC to outweigh the risk ofserious bleeding.62 Although a history of falls should not be a con-traindication to OAC, AF patients who have actually sustained afall remain at high risk of thromboembolism and morbidity.63 Fur-ther investigation to ascertain the reasons for the fall and target-ing interventions to reduce risk of falls—for example, treatmentfor correctable causes of falls (such as lowering blood pressure,vertigo, etc), polypharmacy, and the need for walking aids—should be paramount. Nevertheless, treatment decisions shouldbe individualized.

Stroke and bleeding risk are closely related. Recent compari-sons of HAS-BLED with the CHADS2 and CHA2DS2-VASc scoresshowed an increase in bleeding rates among patients who havehigher HAS-BLED, CHADS2, and CHA2DS2-VASc scores, but this wasgenerally only significant for the HAS-BLED score; the latter scorewas also superior to CHADS2 and CHA2DS2-VASc for bleeding riskprediction.54,55 Other efforts have led to derivation and validationof a composite stroke and bleeding risk score.64,65 Although therewas a marginal improvement in the C statistic for predicting high-risk 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 and0.654 [95% CI, 0.574-0.733] for CHA2DS2-VASc scores), the dis-crimination compared with individual stroke and bleeding risk scoreswas nonsignificant. Thus, stroke risk should be assessed using a vali-dated stroke score scheme and bleeding risk with a specific bleed-ing risk score scheme.

Net Clinical Benefit of Oral AnticoagulantsEffective stroke prevention for patients with AF requires the use ofOACs, whether a VKA or a NOAC. NOACs fall into 2 broad classes,the oral direct thrombin inhibitors (eg, dabigatran) and oral factorXa inhibitors (eg, rivaroxaban, apixaban, and edoxaban) (Table 4).

Stroke or systemic embolism is significantly reduced by VKAsin 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 patientswith no history of prior stroke (primary prevention) and 8.4% peryear (number needed to treat, 12) for patients with a history ofprior stroke (secondary prevention). Compared with the controlor placebo groups, the relative RR attributable to VKA is 26%(95% CI, 3%-43%; absolute RR 1.6% per year) for all-causemortality.66

A meta-analysis examining the efficacy of aspirin comparedwith either a control treatment or placebo for stroke or systemicembolism or mortality in AF found no benefit.66 A 19% reductionin stroke was observed with aspirin but that finding was attribut-able to the only positive study, the Stroke Prevention on AtrialFibrillation (SPAF-I) trial, which reported a 42% reduction instroke or systemic embolism with 325 mg/d of aspirin comparedwith a control treatment. However, the SPAF-I trial had major

Table 3. Assessment of Stroke and Bleeding Risk in Atrial FibrillationPatients by Schema

ScoreCHA2DS2-VASca

Congestive heart failure 1

Hypertension 1

Age ≥75 y 2

Diabetes mellitus 1

Stroke/TIA/TE 2

Vascular disease (prior MI, PAD, or aortic plaque) 1

Age 65-74 y 1

Sex category (ie, female sex) 1

Maximum score 9

HAS-BLEDb

Hypertension (systolic blood pressure >160 mm Hg) 1

Abnormal renal and liver function (1 point each)c 1 or 2

Stroke 1

Bleeding tendency/predispositionc 1

Labile INRs (eg, TTR<60%, applies only if the patientis taking warfarin)c

1

Elderly (eg, age >65 y, frail condition) 1

Drugs or alcohol excess (1 point each)c 1 or 2

Maximum score 9

Abbreviations: INR, international normalized ratio; MI, myocardial infarction;PAD, peripheral artery disease; TE, thromboembolism; TIA, transient ischemicattack; 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 additionalstroke risk factor.

b HAS-BLED categorizes those into low (score 0-2) or high (�3) risk, where thelatter can be identified for more regular review and follow-up.

c Abnormal renal function classified as the presence of long-term dialysis, renaltransplant, or serum creatinine of 2.3 mg/dL (200 mmol/L) or higher.Abnormal liver function defined as chronic hepatic disease (eg, cirrhosis) orbiochemical 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, oralcohol excess.






internal heterogeneity for the aspirin effect. The study had 2major groups: one group could not, or would not, take anticoagu-lation medicine. Of these, one subgroup of AF patients receivedplacebo and the other aspirin. For the group that could take anti-coagulation 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 pla-cebo in the anticoagulation-eligible group. In the group that couldnot receive anticoagulation medication, there was no significantdifference in stroke rates between aspirin and placebo.67 Indeed,aspirin is often considered for those deemed inappropriate foranticoagulation. In the SPAF-I trial, aspirin did not reduce strokeamong those older than 75 years, nor did it prevent severestrokes. In a meta-analysis of AF studies, the reduction of strokeor vascular events using aspirin declined with age, whereas bleed-ing risk between it and warfarin was not markedly different.68

This was also evident from recent randomized trials and cohortstudies reporting that major bleeding and intracranial hemor-rhage did not differ between aspirin and OAC use and thatadverse events occurred more frequently among very elderlypatients who were taking aspirin.

With VKAs, the quality of anticoagulation control is critical (asreflected by the time in therapeutic range [TTR], with a target INRof 2.0-3.0). Time in therapeutic ranges are closely related to effi-cacy and safety, with low rates of stroke and bleeding with highTTRs.69,70 With INRs persistently higher than 3.0, there is anincrease in bleeding, especially in elderly patients, whereas therate of thromboembolisms increase when INRs are less than 2.0.Even at an average INR of 1.7, the risk of stroke already increases2-fold. Thus, VKAs require regular anticoagulation monitoring andare open to significant interpatient and intrapatient variabilitydue to interactions with diet, drugs, and alcohol, among otherfactors.71

In more recent years, the availability of the NOACs haschanged the landscape of stroke prevention in AF. The NOACsoffer efficacy, safety, and convenience for stroke prevention com-pared with the VKAs. The various phase 3 trials comparing NOACsagainst warfarin have been the subject of numerous reviews andmeta-analyses.

In a recent meta-analysis72 that included the RE-LY (Random-ized Evaluation of Long-term Anticoagulation Therapy),ROCKET-AF (Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibi-

tion Compared With Vitamin K Antagonism for Prevention ofStroke and Embolism Trial in Atrial Fibrillation), ARISTOTLE(Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Com-pared With Vitamin K Antagonism for Prevention of Stroke andEmbolism Trial in Atrial Fibrillation), and ENGAGE-AF TIMI 48(Effective Anticoagulation with Factor Xa Next Generation in AtrialFibrillation–Thrombolysis In Myocardial Infarction study 48) trials,42 411 participants received a NOAC and 29 272 participantsreceived warfarin. NOACs significantly reduced stroke or systemicembolism events by 19% compared with warfarin (RR, 0.81; 95%CI, 0.73-0.91; P < .001) mainly related to a reduction in hemor-rhagic stroke (RR, 0.49; 0.38-0.64; P < .001). NOACs also signifi-cantly 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) butincreased gastrointestinal tract bleeding (RR, 1.25; 1.01-1.55;P = .04). Low-dose NOACs had similar overall reductions in strokeor systemic embolism events to warfarin (RR, 1.03; 0.84-1.27;P = .74) and had a more favorable bleeding profile (RR, 0.65; 0.43-1.00; 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. Vari-ous patient characteristics may influence the initial choice of one drugover another (Table 4). In the absence of head-to-head clinical trials,clinicians cannot directly compare one NOAC against another. Nev-ertheless, regulatory bodies and health economic analyses have per-formed indirect comparisons of one agent against another using war-farin as the comparator; such indirect comparisons (or network meta-analyses) should be interpreted with some caution givenheterogeneity in trial inclusion-exclusion criteria, quality of INRcontrol.73 Overall, there are few substantial differences in efficacy,although 150 mg of dabigatran twice daily may offer the greatest po-tency by reducing both ischemic and hemorrhagic stroke, and it hasa similar risk of major bleeding as warfarin. For safety, the best bleed-ing 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- to6-month warfarin trial to determine if high TTRs (eg, >65%) canbe achieved. NOACs are only used if the TTRs remain poor(<65%). This strategy may put patients at risk of stroke or sys-temic embolism because in the initial treatment stages, inad-equate anticoagulation may result in an excess of thromboem-

Table 4. Optimal Selection of Oral Anticoagulation for Stroke Prevention in Atrial Fibrillation

VKA, Warfarin Direct Thrombin InhibitorsFactor XInhibitors Rivaroxaban Apixaban Edoxaban

Recurrent stroke or TIA despitetreatment VKAa 150 mg of dabigatran, 2/d

Moderate or severe renal impairmentb � � �

GI tract symptoms or dyspepsiac � �

High risk of bleedingd75 mg dabigatran, 2/d (US);110 mg dabigatran,2/d (rest of world)

� �e

Preference for 1 dose per day � � �

Abbreviations: GI, gastrointestinal; TIA, transient ischemic attack; VKA, vitamin Kantagonist.a Superior efficacy for preventing both stroke and hemorrhage.b For creatinine clearance of <15 mL/min use VKA.

c Also has an increased risk of bleeding.d 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.e Awaiting approval.






bolic events (RR, 1.71; 95% CI, 1.39-2.12).77 Various clinical andpharmacogenetic factors have been proposed as determinants ofwarfarin dose or TTR.71,78 Recent randomized trials based on apharmacogenetic testing as a means of predicting the responseto warfarin have been disappointing.

Simple clinical risk factors have been incorporated into anew score, the SAMe-TT2R2 score78 (Table 5), which has beenproposed as a means of identifying those newly diagnosedpatients with AF who have not been treated with anticoagulationagents and who have a probability of doing well taking a VKA(SAMe-TT2R2 score, 0-2) and achieve a TTR greater than 65% or70%78,79 (Figure). In contrast, a SAMe-TT2R2 score higher than 2suggests that such patients are unlikely to achieve a good TTR bytaking a VKA, so a NOAC should be used initially, without subject-ing the patient to a “trial of warfarin” period. The SAMe-TT2R2

score has since been validated in independent studies to show itcan discern those likely to achieve poor TTRs. A high SAMe-TT2R2

score translates to a greater chance of labile INRs, thromboembo-lism, death, and bleeding.80-83 This approach has been recom-mended in a position document from the European Society ofCardiology (ESC) Working Group on Thrombosis AnticoagulationTask Force.71

Table 5. Definition of the SAMe-TT2R2 Score, Used to Aid Initial DecisionMaking Between Vitamin K Antagonist (With Good Quality AnticoagulationControl) and a Non–Vitamin K Antagonist Oral Anticoagulanta

Definitions PointsSex (female) 1

Age (<60 y) 1

Medical historyb 1

Treatment (interacting drugs, eg, amiodarone forrhythm control)

1

Tobacco use (within 2 y) 2

Race (not white) 2

Maximum points 8

a The SAMe-TT2R2 score is proposed as a means to help with decision making,to identify those newly diagnosed nonanticoagulated AF patients who have aprobability of doing well while taking a vitamin K antagonist (VKA) (withSAMe-TT2R2 score, 0-2) and achieve a time in therapeutic range (TTR) of atleast 65% or 70%. In contrast, a SAMe-TT2R2 score of more than 2 suggeststhat such patients are unlikely to achieve a good TTR while taking a VKA, and anon-VKA oral anticoagulant should be used upfront, without a “trial ofwarfarin” period.

b Two of the following: hypertension, diabetes mellitus, coronary artery diseaseor myocardial infarctions, peripheral artery disease, congestive heart failure ,previous stroke, pulmonary disease, or hepatic or renal disease.

Figure. Algorithm for Risk Stratification and Selection of Anticoagulation Therapy for Stroke Prevention in Atrial Fibrillation

No Yes a

(Low strokerisk)

(High strokerisk)

No Yes(Score 0-2) (Score >2)

Patient with newly diagnosedatrial fibrillation

High stroke risk?Male, CHA2DS2-VASc score ≥1 Female, CHA2DS2-VASc score ≥2

Calculate CHA2DS2-VASc scoreto determine stroke risk

No antithrombotic therapy Calculate SAMe TT2R2 score to determineinitial anticoagulation treatmenta

SAMe TT2R2 score >2?

Continue VKA therapy with regularmonitoring

Vitamin K antagonist (VKA) therapy(eg, warfarin)

Monitor anticoagulation control (goal:time in therapeutic range [TTR] >70%)

No Yes

Non-VKA-oral anticoagulant therapy(oral direct thrombin inhibitors or oralfactor Xa inhibitors)

Inadequate anticoagulation control?TTR <65%

ORwithin past 6 mo

INR >5 twiceor

INR >8 onceor

INR <2 twice

See Table 1 footnotes for abbreviation expansions; SAMe-TT2R2 is explained inTable 5.

a Consider NOAC or VKA. If considering VKA, calculate SAMe-TT2R2 first beforedeciding on optimal OAC therapy.






Net Clinical Benefit

When making decisions about thromboprophylaxis, an importantconsideration is to balance ischemic stroke prevention against thepotential risk of serious bleeding. The net clinical benefit of anti-thrombotic therapy can be determined in many ways, eg, by bal-ancing the reduction in ischemic stroke against the risk of seriousbleeding (ie, intracranial hemorrhage) weighted 1.5-fold.84 Othercomplex weighted formulae for net clinical benefit have been pro-posed, but none are perfect.

Recent studies have found a positive net clinical benefit (bal-ancing ischemic stroke reduction against the risk of intracranialhemorrhage weighted 1.5-fold) for OAC in patients with AF and atleast 1 additional stroke risk factor.85,86 With the NOACs, the netclinical benefit was also generally positive for dabigatran andapixaban with CHA2DS2-VASc score of 1, and for all NOACs withCHA2DS2-VASc score of at least 2,87 and in a modeling analysis,could translate to an additional 65 000 cardiovascular eventsand deaths prevented in Europe.88 The threshold for initiatingOAC treatment has been calculated as a stroke rate of 0.9% peryear, based on the balance of ischemic stroke reduction vs intra-cranial hemorrhage with the availability of new safer OACagents.89

Guidelines for AF TreatmentWhen the only available oral anticoagulants were the VKAs, thefocus was to identify high-risk patients to be targeted for thisinconvenient drug, VKA (eg, warfarin), given the need for antico-agulation monitoring and other restrictions necessary with VKAuse. Also, older guidelines, such as the 2006 ACC/AHA/ESC jointguidelines had divided patients using the CHADS2 score into low-,moderate-, and high-risk strata, for which low-risk patients wererecommended aspirin; moderate-risk patients, aspirin or warfarin;and high-risk patients, warfarin.90 Such an approach did not workwell, and numerous studies have shown that high-risk patientswere undertreated, with OAC being used in approximately 50%of patients and with regional differences evident.91 Also, strokerisk is a continuum, and any 1 risk factor can confer risk if leftuntreated, exposing the patient with AF to a fatal or disablingstroke.45

In 2010, and in a focused update in 2012, the ESC guidelines ad-vocated a change in clinical practice highlighting the need to iden-tify the low-risk patients (age <65 years and lone AF, including wom-en) who do not need any antithrombotic therapy. Patients with 1 ormore stroke risk factors should be offered OAC, with a preferencefor NOACs. If VKAs are used, a TTR higher than 70% was recom-mended. Only if patients refuse any form of OAC, then antiplatelettherapy with aspirin-clopidogrel combination therapy (if not at anunduly high bleeding risk) or—less effectively—aspirin mono-therapy, may be considered. The HAS-BLED score is recom-mended for bleeding risk assessment.

In 2012, the American College of Chest Physicians (ACCP) pub-lished its consensus guidelines on antithrombotic therapy inAF patients.29 This was based on the CHADS2 score, where OACwas recommended for those with CHADS2 score of 1 or higher. In

patients with a CHADS2 score of 0, additional non-CHADS2 risk fac-tors should be considered, including age from 65 through 74 years,female sex, and vascular disease, whereby the presence of multiplenon-CHADS2 risk factors would merit OAC treatment.

In 2014, the new AHA/ACC/HRS guidelines5 for AF advocateduse of the CHA2DS2-VASc score for stroke risk stratification, but ina categorical approach whereby OAC was recommended for aCHA2DS2-VASc score of 2 or higher, and no therapy for a score of0; however, for CHA2DS2-VASc score of 1, the recommendationwas “no therapy, aspirin or OAC.” Oral anticoagulants could beeither NOACs or VKAs. The value of the US guidelines approachfor CHA2DS2-VASc score of 1 was recently tested in a nationwidecohort study of 12 935 men with AF and a CHA2DS2-VASc score of1 but were not receiving antithrombotic therapy, where theannual stroke rate overall was 2.75%.92 The risk of ischemicstroke ranged from 1.96% per year for AF patients with vasculardisease 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 addi-tional risk factor), the annual stroke rate was 2.55%, with the riskof ischemic stroke increasing from 1.91% per year for patientswith hypertension to 3.34% per year for those aged 65 through74 years. Similar findings were observed from the Danish nation-wide cohort study, where event rates in nontreated AF patientswith 1 additional stroke risk factor increased stroke by 3.01-foldand death by 3.12-fold, at 1 year follow-up.93 Thus, OAC shouldstill be considered for AF patients with 1 additional stroke risk fac-tor given their high risk of ischemic stroke and death.

In 2014, NICE published its new AF guidelines.4 In contrast tosome guidelines, the NICE guidelines are based on systematic re-views, evidence appraisal and cost-effectiveness. NICE guidelinesadvocate use of the CHA2DS2-VASc and HAS-BLED scores for strokeand bleeding risk assessment, respectively. The recommendationsare to initially identify low-risk patients who do not need any anti-thrombotic therapy. Patients with a CHA2DS2-VASc score 2 or highershould be offered OAC, while men with a score of 1 should be con-sidered for OAC. If VKAs are used, a TTR of higher than 65% was rec-ommended. The guidelines clearly state that aspirin should not beused for stroke prevention in AF, due to its minimal efficacy, poorsafety, and lack of cost-effectiveness.

The Canadian Cardiovascular Society (CCS) published itsfocused update in 2014, proposing a simplified algorithm-basedapproach to stroke risk stratification.30 The first step in the algo-rithm is to identify those aged 65 years or older who should beoffered OAC. The second step is to identify those younger than65 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 recom-mended aspirin alone. Finally, those patients younger than 65years with no CHADS2 risk factors nor vascular disease are recom-mended “no antithrombotic therapy.”30 This approach was testedin a nationwide cohort study, in which the overall rate of the com-bined end point of ischemic stroke, systemic embolism , or TIAwas 4.32 per 100 person-years at 1 year, among the patients whowould have had an indication for OAC therapy according to ESCguidelines but were not recommended for OAC according to the2014 CCS algorithm; also, the subgroup of patients with prior vas-cular disease and a CHADS2 score of 0 (ie, only recommendedaspirin treatment according to CCS algorithm) had an event rate






of 4.84 per 100-person-years at 1-year follow-up.94 Thus, basedon the 2014 CCS algorithm, the subgroup not recommended forOAC were not low risk and use of the ESC guideline approachoffered additional refinement of stroke risk stratification in suchpatients.

In summary, stroke risk stratification and treatment decisionscan now be simplified, notwithstanding the various approaches ad-vocated in guidelines. The initial step is to identify the low-risk pa-tients who do not need any antithrombotic therapy, given their lowabsolute risk of stroke. Low-risk patients are those aged younger than65 years with no stroke risk factors (a CHA2DS2-VASc score of 0 formales or 1 for females). Subsequently, patients with at least 1 addi-tional stroke risk factor can be offered effective stroke prevention,which is OAC, either NOAC or VKA (Figure). Thus, this includes maleAF patients with a CHA2DS2-VASc score of 1 and a score of 2 or higherfor everyone else, irrespective of other risk stratification enhance-ments. In terms of clinical application and practicality, such an ap-proach makes clinical decision making very simple and practical, with-out the necessity for complex investigations that may delaytreatment decisions.

Does use of risk scores in guidelines to aid treatment deci-sions improve outcomes? As mentioned above, use of theCHA2DS2-VASc score enables refinement of stroke risk stratifica-tion and enables identification of those AF patients still at appre-ciable stroke risk who were previously considered at low riskwhen using other risk schemes.31,45,94-96 The net clinical benefit isalso positive for patients with a CHA2DS2-VASc score of 1 orhigher, whether from real-world cohorts or modeling analyseswith the NOACs.85-87 Indeed, modeling analyses show that use ofthe ESC guidelines would translate to a reduction in additionalthromboembolic, mortality, and bleeding events in Europeand Asia, compared with older guideline strategies.88,97 Finally,guideline adherent treatment is associated with improved effi-cacy and safety outcomes, whether from observational98,99 ortrial-based100 cohorts.

Specific ConsiderationsChronic Renal FailureAtrial fibrillation patients with renal impairment represent a high-risk group, demonstrating a greater risk of stroke, myocardial infarc-tion, and major bleeding.101 Approximately 20% of AF patients showa significant reduction in renal function over 2 years, and even nor-mal or mild renal impairment at baseline did not preclude some pa-tients from progressing to severe renal impairment.102

Patients with severe renal impairment were largely excludedfrom randomized trials, and all NOACs do have some degree of re-nal excretion (the highest being with dabigatran, whereby the drugis also removed by hemodialysis). Initial observational studies wereconflicting suggesting that stroke prevention with warfarin was off-set by a high rate of major bleeding, especially in patients requiringdialysis.103 The most recent data from the Swedish AF cohort study37

suggests that warfarin is still associated with a positive net clinicalbenefit, balancing stroke reduction against bleeding risk, but em-phasizes the importance of a high TTR to minimize adverse effects.Similar data have been published from the Danish nationwide co-hort study.104

Acute Coronary Syndrome and Percutaneous CoronaryInterventionMany patients with AF have associated coronary artery disease.Some may present with an acute coronary syndrome (ACS), be un-dergoing percutaneous coronary intervention, or both. Such pa-tients are at high risk, so management is complex, having to use OACplus antiplatelet therapy to balance between stroke prevention, re-current cardiac ischemia, stent thrombosis, and risk of serious bleed-ing (especially intracranial hemorrhage).105,106 Observational and trialdata 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 OACalone. In some patients at low thrombotic risk or high-bleeding risk,the initial triple therapy period could be substituted with OAC plusclopidogrel. In guidelines in which OAC is mentioned, this could re-fer to a NOAC or well-managed VKA (with TTR >70%). Third-generation drug eluting stents are also the preferred option, and withimprovements in stent technology, the period during which addi-tional dual antiplatelet drugs are needed can be shortened.

BridgingBridging refers to the use of a short-acting anticoagulants, eg,low-molecular-weight heparin, during the interruption of alonger-acting oral agent. Bridging anticoagulation is often usedduring anticoagulation interruptions for operative proceduresand is associated with a higher risk of bleeding and adverseevents. Indeed, observational and trial data do not support theuse of routine bridging given the higher bleeding risks and no dif-ference in thromboembolism when compared with an uninter-rupted OAC strategy; thus, the latter approach is used for mostprocedures.108 However, bridging may perhaps be considered forsome very high-risk subgroups (eg, prosthetic mechanical heartvalves); thus, risk stratification is important.109 NOACs may bebeneficial based on promising data from post hoc analysis fromrandomized trials.110 Nevertheless, the use of NOACs requiresunderstanding of their pharmacology, given their fast onset andoffset of action, as well as the effect of renal function.

Left Atrial Appendage OcclusionThe concept of left atrial appendage (LAA) occlusion arises be-cause most atrial thrombi arise from the LAA, in patients with AF.Thus, over the last decade, the LAA has been removed during car-diac surgery, or more recently subject to percutaneous occlusion witha variety of devices. For example, the WATCHMAN device has beentested in a randomized trial (PROTECT-AF),111 which showed that theLAA occlusion device was noninferior for safety and efficacy to stan-dard therapy (warfarin). There was an initial excess of complica-tions (eg, pericardial tamponade) in the device intervention groupthan 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 thisdiminished, as has been seen in subsequent registries. These find-ings were reinforced in the PREVAIL trial,112 which showed that LAAocclusion was noninferior to warfarin for ischemic stroke preven-tion or systemic embolism at more than 7 days after the procedure.Other methods of LAA occlusion are also available, but random-ized trials are lacking. A recent position document from the EuropeanHeart Rhythm Association comprehensively reviews the literature






and suggests practical points for its use.113 For now, LAA occlusionmay be considered in patients with a high stroke risk and contrain-dications for long- term OAC.4

CardioversionCardioversion of AF requires OAC for a minimum of 3 weeksbefore cardioversion, and OAC continued during and after cardio-version. Recent data on the NOACs may support their use to facili-tate cardioversion and may be associated with less delay to theprocedure, in contrast to using VKAs for which delays or cancella-tions were common pending a therapeutic INR.114-116 Irrespectiveof apparent successful rhythm control (whether by cardioversionor ablation), patients should continue taking OAC in the presenceof stroke risk factors. Rhythm control should not be performed asa basis to stop OAC.

Patient Values and PreferencesIncreasing awareness is evident on the importance of patient atti-tudes and preferences in deciding on managing strategies for AF, as

well as treatment adherence.117 Particularly with NOACs (with theirshort half-life), poor adherence can be associated with a greater riskof stroke and mortality.118 Simply to avoid 1 stroke, patients are evenprepared to sustain 4 major bleeding events.119 In contrast, physi-cians are more concerned with avoiding major bleeding, even at theexpense of patients sustaining strokes.120,121

ConclusionsSubstantial recent advances are evident in the area of stroke pre-vention in AF. Treatment has changed greatly, recognizing that strokeprevention is the cornerstone of AF management. Indeed, follow-ing the initial identification of low-risk patients using the CHA2DS2-VASc score, physicians can then offer effective thromboprophy-laxis (which is OAC) to patients with at least 1 additional stroke riskfactor. Clinicians should not offer aspirin for stroke prevention in AF.With this approach, clinicians can improve AF patient outcomes andreduce the huge burden of AF-related stroke.

ARTICLE INFORMATION

Conflict of Interest Disclosures: Both authorshave completed and submitted the ICMJE Form forDisclosure of Potential Conflicts of Interest. Dr Lipreported that he has served as a consultant forBayer Healthcare, Merck, AstraZeneca, sanofi-aventis, Bristol-Myers Squibb/Pfizer, andBoehringer Ingelheim, and has been on the speakerbureaus for Bayer, Bristol-Myers Squibb/Pfizer,Boehringer Ingelheim, and sanofi-aventis. Dr Lanereported that she has received an investigatorinitiated educational grants from Bayer Healthcareand Boehringer Ingelheim and has been on thespeakers bureau for Boehringer Ingelheim, Bayer,and Bristol-Myers Squibb/Pfizer.

Submissions:We encourage authors to submitpapers for consideration as a Review. Pleasecontact Mary McGrae McDermott, MD, [email protected].

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JAMA - Stroke Prevention in Atrial Fibrillation 2015

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