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CHEST Supplement

www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e531S

ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES

Background:The risk of stroke varies considerably across different groups of patients with atrialfibrillation (AF). Antithrombotic prophylaxis for stroke is associated with an increased risk ofbleeding. We provide recommendations for antithrombotic treatment based on net clinical ben-efit for patients with AF at varying levels of stroke risk and in a number of common clinicalscenarios.

Methods:We used the methods described in the Methodology for the Development of Antithrom-botic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Preven-tion of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based ClinicalPractice Guidelines article of this supplement.

Results:For patients with nonrheumatic AF, including those with paroxysmal AF, who are (1) atlow risk of stroke (eg, CHADS2[congestive heart failure, hypertension, age 75 years, diabetesmellitus, prior stroke or transient ischemic attack] score of 0), we suggest no therapy rather thanantithrombotic therapy, and for patients choosing antithrombotic therapy, we suggest aspirinrather than oral anticoagulation or combination therapy with aspirin and clopidogrel; (2) at inter-mediate risk of stroke (eg, CHADS2score of 1), we recommend oral anticoagulation rather thanno therapy, and we suggest oral anticoagulation rather than aspirin or combination therapy withaspirin and clopidogrel; and (3) at high risk of stroke (eg, CHADS2score of 2), we recommendoral anticoagulation rather than no therapy, aspirin, or combination therapy with aspirin andclopidogrel. Where we recommend or suggest in favor of oral anticoagulation, we suggest dabiga-tran 150 mg bid rather than adjusted-dose vitamin K antagonist therapy.Conclusions:Oral anticoagulation is the optimal choice of antithrombotic therapy for patients

with AF at high risk of stroke (CHADS2score of2). At lower levels of stroke risk, antithrombotictreatment decisions will require a more individualized approach.

CHEST 2012; 141(2)(Suppl):e531Se575S

Abbreviations: AAD5antiarrythmic drug; ACS5acute coronary syndrome; ACTIVE5Atrial Fibrillation Clopidogrel

Trial With Irbesartan for Prevention of Vascular Events; AF5atrial fibrillation; AFASAK5Atrial Fibrillation Aspirin andAnticoagulation; AFFIRM5Atrial Fibrillation Follow-up Investigation of Rhythm Management; CHADS25congestiveheart failure, hypertension, age 75 years, diabetes mellitus, prior stroke or transient ischemic attack; CHA2DS2-

VASc5congestive heart failure (or left ventricular systolic dysfunction), hypertension, age75 years, diabetes mellitus,prior stroke or transient ischemic attack, vascular disease, age 65 to 74 years, female sex; EAFT 5European AtrialFibrillation Trial; ESPS5European Stroke Prevention Study; INR5 international normalized ratio; LAA5 left atrialappendage; MI5myocardial infarction; PAF5paroxysmal atrial fibrillation; RCT5 randomized controlled trial;RE-LY5Randomized Evaluation of Long-Term Anticoagulation Therapy; SPAF5Stroke Prevention in Atrial Fibrilla-tion; TEE5 transesophageal echocardiography; TIA5 transient ischemic attack; VKA5vitamin K antagonist

Antithrombotic Therapy for Atrial Fibrillation

Antithrombotic Therapy and Prevention of Thrombosis,9th ed: American College of Chest Physicians

Evidence-Based Clinical Practice Guidelines

John J. You, MD; Daniel E. Singer, MD; Patricia A. Howard, PharmD;Deirdre A. Lane, PhD; Mark H. Eckman, MD; Margaret C. Fang, MD, MPH;Elaine M. Hylek, MD, MPH; Sam Schulman, MD, PhD; Alan S. Go, MD;Michael Hughes, PhD; Frederick A. Spencer, MD; Warren J. Manning, MD;

Jonathan L. Halperin, MD; and Gregory Y. H. Lip, MD

wnloaded From: http://journal.publications.chestnet.org/ on 02/25/2014
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e532S Antithrombotic Therapy for Atrial Fibrillation

oral anticoagulation(Grade 2B) or combinationtherapy with aspirin and clopidogrel (Grade 2B).

Remarks: Patients who place an exceptionally highvalue on stroke reduction and a low value on avoidingbleeding and the burden associated with antithrom-botic therapy are likely to choose antithrombotictherapy rather than no antithrombotic therapy. Other

factors that may influence the choices above are aconsideration of patient-specific bleeding risk andthe presence of additional risk factors for stroke,including age 65 to 74 years and female gender,

which have been more consistently validated, andvascular disease, which has been less well validated(see section 2.1.12). The presence of multiple non-CHADS2risk factors for stroke may favor oral anti-coagulation therapy.

2.1.9. For patients with AF, including those withparoxysmal AF, who are at intermediate risk ofstroke (eg, CHADS2 score1), we recommendoral anticoagulation rather than no therapy(Grade 1B). We suggest oral anticoagulationrather than aspirin (75 mg to 325 mg oncedaily) (Grade 2B) or combination therapy withaspirin and clopidogrel (Grade 2B). For patients

who are unsuitable for or choose not to take anoral anticoagulant (for reasons other than con-cerns about major bleeding), we suggest com-bination therapy with aspirin and clopidogrelrather than aspirin (75 mg to 325 mg once daily)(Grade 2B).

Remarks: Patients who place an exceptionally highvalue on stroke reduction and a low value on avoidingbleeding and the burden associated with anticoagu-lant therapy are likely to choose oral anticoagulationrather than antiplatelet therapy. Other factors thatmay influence the choice among antithrombotic ther-apies are a consideration of bleeding risk and thepresence of additional risk factors for stroke, includ-ing age 65 to 74 years and female gender, whichhave been more consistently validated, and vasculardisease, which has been less well validated (see sec-tion 2.1.12). The presence of multiple additional

non-CHADS2 risk factors for stroke may favor oralanticoagulation therapy.

2.1.10. For patients with AF, including thosewith paroxysmal AF, who are at high risk ofstroke (eg, CHADS2score2), we recommendoral anticoagulation rather than no therapy(Grade 1A), aspirin (75 mg to 325 mg once daily)(Grade 1B), or combination therapy with aspirinand clopidogrel (Grade 1B). For patients whoare unsuitable for or choose not to take an oralanticoagulant (for reasons other than concerns

Revision accepted August 31, 2011.Affiliations: From the Department of Medicine (Drs You,Schulman, and Spencer) and Department of Clinical Epidemi-ology and Biostatistics (Dr You), McMaster University, Hamilton,ON, Canada; Department of Medicine (Dr Singer), HarvardMedical School, and Clinical Epidemiology Unit (Dr Singer),General Medicine Division, Massachusetts General Hospital,Boston, MA; School of Pharmacy (Dr Howard), University ofKansas Medical Center, Kansas City, KS; University of BirminghamCentre for Cardiovascular Sciences (Drs Lane and Lip), CityHospital, Birmingham, England; Department of Clinical Medi-cine (Dr Eckman), Division of General Internal Medicine andCenter for Clinical Effectiveness, University of Cincinnati, Cin-

cinnati, OH; Department of Medicine (Dr Fang), Division ofHospital Medicine, University of California, San Francisco,San Francisco, CA; Boston University Medical Center ResearchUnit (Dr Hylek), Section of General Internal Medicine, Boston, MA;Comprehensive Clinical Research Unit (Dr Go), Division ofResearch, Kaiser Permanente Northern California, Oakland, CA;Decision Resources Inc (Dr Hughes), London, England; Sec-tion of Non-invasive Cardiac Imaging (Dr Manning), Beth IsraelDeaconess Medical Center, Boston, MA; and The Cardiovas-cular Institute (Dr Halperin), Mount Sinai Medical Center,New York, NY.Funding/Support: The Antithrombotic Therapy and Preventionof Thrombosis, 9th ed: American College of Chest PhysiciansEvidence-Based Clinical Practice Guidelines received support fromthe National Heart, Lung, and Blood Institute [R13 HL104758]and Bayer Schering Pharma AG. Support in the form of educa-

tional grants was also provided by Bristol-Myers Squibb; Pfizer,Inc; Canyon Pharmaceuticals; and sanofi-aventis US.Disclaimer: American College of Chest Physician guidelinesare intended for general information only, are not medical advice,and do not replace professional medical care and physicianadvice, which always should be sought for any medical condition.The complete disclaimer for this guideline can be accessed athttp://chestjournal.chestpubs.org/content/141/2_suppl/1S.Correspondence to: Gregory Y. H. Lip, MD, University ofBirmingham Centre for Cardiovascular Sciences, City Hospital,Birmingham, B18 7QH, England; e-mail:[email protected] 2012 American College of Chest Physicians.Reproductionof this article is prohibited without written permission from theAmerican College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).DOI: 10.1378/chest.11-2304

Summary of Recommendations

Note on Shaded Text: Throughout this guideline,shading is used within the summary of recommenda-tions sections to indicate recommendations that arenewly added or have been changed since the publica-tion of Antithrombotic and Thrombolytic Therapy:

American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).Recommendations that remain unchanged are notshaded.

2.1.8.For patients with AF, including those withparoxysmal AF, who are at low risk of stroke(eg, CHADS2 [congestive heart failure, hyper-tension, age 75 years, diabetes mellitus, priorstroke or transient ischemic attack] score0),

we suggest no therapy rather than antithrom-botic therapy (Grade 2B).For patients who dochoose antithrombotic therapy, we suggest aspi-rin (75 mg to 325 mg once daily) rather than

http://chestjournal.chestpubs.org/content/141/2_suppl/1Smailto:[email protected]://www.chestpubs.org/site/misc/reprints.xhtmlhttp://www.chestpubs.org/site/misc/reprints.xhtmlhttp://www.chestpubs.org/site/misc/reprints.xhtmlhttp://www.chestpubs.org/site/misc/reprints.xhtmlhttp://www.chestpubs.org/site/misc/reprints.xhtmlhttp://www.chestpubs.org/site/misc/reprints.xhtmlmailto:[email protected]://chestjournal.chestpubs.org/content/141/2_suppl/1S


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For patients with AF at low to intermediaterisk of stroke (eg, CHADS2 score of 0 or 1)during the first 12 months after placementof an intracoronary stent (bare metal or drugeluting), we suggest dual antiplatelet ther-apy rather than triple therapy (Grade 2C). At12 months after intracoronary stent place-ment, antithrombotic therapy is suggested as

for patients with AF and stable coronary arterydisease (see section 3.1).

Remarks: Patients who place an exceptionally highvalue on stroke reduction and a low value on avoid-ing bleeding and the burden associated with antico-agulant therapy are likely to choose triple therapyrather than dual antiplatelet therapy. Other factorsthat may influence this choice are a consideration ofbleeding risk and the presence of additional non-CHADS2risk factors for stroke (see section 2.1.12).

3.3. For patients with AF at intermediate to highrisk of stroke (eg, CHADS2score of 1 or greater)

who experience an acute coronary syndromeand do not undergo intracoronary stent place-ment, we suggest for the first 12 months,adjusted-dose VKA therapy (INR 2.0-3.0) plussingle antiplatelet therapy rather than dualantiplatelet therapy (eg, aspirin and clopidogrel)or triple therapy (eg, warfarin, aspirin, andclopidogrel) (Grade 2C).After the first 12 months,antithrombotic therapy is suggested as forpatients with AF and stable coronary arterydisease (see section 3.1).

For patients with AF at low risk of stroke(eg, CHADS2score of 0), we suggest dual anti-platelet therapy (eg, aspirin and clopidogrel)rather than adjusted-dose VKA therapy (INR2.0-3.0) plus single antiplatelet therapy ortriple therapy (eg, warfarin, aspirin, and clopid-ogrel) (Grade 2C). After the first 12 months,antithrombotic therapy is suggested as forpatients with AF and stable coronary arterydisease (see section 3.1).

Remarks: Patients who place an exceptionally highvalue on stroke reduction and a low value on avoidingbleeding and the burden associated with anticoagu-lant therapy are likely to choose adjusted-dose VKAtherapy plus single antiplatelet therapy rather thandual antiplatelet therapy. Other factors that mayinfluence this choice are a consideration of bleedingrisk and the presence of additional non-CHADS2riskfactors for stroke (see section 2.1.12).

3.4. For patients with AF being managed witha rhythm control strategy (pharmacologic or

about major bleeding), we recommend combi-nation therapy with aspirin and clopidogrelrather than aspirin (75 mg to 325 mg once daily)(Grade 1B).

2.1.11. For patients with AF, including thosewith paroxysmal AF, for recommendations infavor of oral anticoagulation (including 2.1.9,

2.1.10, and excluding 2.2, 3.1, 3.2, 3.3), wesuggest dabigatran 150 mg twice daily ratherthan adjusted-dose vitamin K antagonist (VKA)therapy (target INR range, 2.0-3.0) (Grade 2B).

Remarks:Dabigatran is excreted primarily by thekidney. It has not been studied and is contraindi-cated in patients with severe renal impairment (esti-mated creatinine clearance of 30 mL/min or less).Clinicians should be aware that there is no antidotefor dabigatran.

2.2.For patients with AF and mitral stenosis, we

recommend adjusted-dose VKA therapy (targetINR range, 2.0-3.0) rather than no therapy,aspirin (75 mg to 325 mg once daily), or combi-nation therapy with aspirin and clopidogrel (allGrade 1B). For patients with AF and mitral ste-nosis who are unsuitable for or choose not totake adjusted-dose VKA therapy (for reasonsother than concerns about major bleeding), werecommend combination therapy with aspirinand clopidogrel rather than aspirin (75 mg to325 mg once daily) alone (Grade 1B).

3.1. For patients with AF and stable coronaryartery disease (eg, no acute coronary syndromewithin the previous year) and who choose oralanticoagulation, we suggest adjusted-dose VKAtherapy alone (target international normal-ized ratio [INR] range, 2.0-3.0) rather thanthe combination of adjusted-dose VKA therapyand aspirin (Grade 2C).

3.2. For patients with AF at high risk of stroke(eg, CHADS2 score of 2 or greater) during thefirst month after placement of a bare-metal

stent or the first 3 to 6 months after place-ment of a drug-eluting stent, we suggest tripletherapy (eg, VKA therapy, aspirin, and clopid-ogrel) rather than dual antiplatelet therapy(eg, aspirin and clopidogrel) (Grade 2C). Afterthis initial period of triple therapy, we suggest a

VKA (INR 2.0-3.0) plus a single antiplatelet drugrather than VKA alone (Grade 2C). At 12 monthsafter intracoronary stent placement, antithrom-botic therapy is suggested as for patients with

AF and stable coronary artery disease (see sec-tion 3.1).



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(Grade 2C), but that initiation of anticoagulationmust not delay any emergency intervention(Grade 2C). After successful cardioversion tosinus rhythm, we suggest therapeutic antico-agulation for at least 4 weeks after successfulcardioversion to sinus rhythm rather than noanticoagulation, regardless of baseline strokerisk (Grade 2C). Decisions about anticoagulation

beyond 4 weeks should be made in accordancewith our risk-based recommendations for long-term antithrombotic therapy in section 2.1.

4.3. For patients with atrial flutter undergo-ing elective or urgent pharmacologic or elec-trical cardioversion, we suggest that the sameapproach to thromboprophylaxis be used asfor patients with atrial fibrillation undergoingcardioversion.

A

trial fibrillation (AF) is the most common sus-

tained cardiac arrhythmia. One in four individ-uals aged 40 years will develop AF during his orher lifetime, and it has been estimated that by the

year 2050, up to 16 million Americans will have AF.1,2Nonrheumatic AF is a strong, independent predictorof ischemic stroke associated with a fivefold increasein risk.3 Without thromboprophylaxis, the risk ofischemic stroke in patients with nonrheumatic AF,as seen in the control arms of the original trials ofantithrombotic therapy in AF, is 5% per year.4Overthe past 2 decades, considerable work has beendone to evaluate antithrombotic therapies to prevent

stroke in patients with AF, and the field continuesto evolve with the emergence of a new generation oforal anticoagulants.

This article begins with a discussion of themethods used to develop our recommendations forantithrombotic therapy in patients with AF. Next, weprovide our treatment recommendations, dividedinto the following sections:

1. Antithrombotic therapy in patients with AF ingeneral (includes patients with permanent, per-sistent, or paroxysmal AF [PAF])

2. Antithrombotic therapy in patients with AF inspecial situations:

Stable coronary artery disease Acute coronary syndrome (ACS) Intracoronary artery stent Acute ischemic stroke Management with a rhythm control strategy Chronic atrial flutter

3. Antithrombotic therapy for patients with AFundergoing cardioversion

catheter ablation), we suggest that antithrom-botic therapy decisions follow the general risk-based recommendations for patients with AF insection 2.1, regardless of the apparent persis-tence of normal sinus rhythm (Grade 2C).

3.5. For patients with atrial flutter, we sug-gest that antithrombotic therapy decisions

follow the same risk-based recommendations asfor AF.

4.1.1. For patients with AF of greater than 48 hor unknown duration undergoing elective electri-cal or pharmacologic cardioversion, we recom-mend therapeutic anticoagulation (adjusted-dose

VKA therapy, target INR range 2.0-3.0, low-molecular-weight heparin at full venous throm-boembolism treatment doses, or dabigatran)for at least 3 weeks before cardioversion ora transesophageal echocardiography (TEE)-

guided approach with abbreviated antico-agulation before cardioversion rather than noanticoagulation (Grade 1B). We recommendtherapeutic anticoagulation for at least 4 weeksafter successful cardioversion to sinus rhythmrather than no anticoagulation, regardless ofthe baseline risk of stroke (Grade 1B). Decisionsabout anticoagulation beyond 4 weeks shouldbe made in accordance with our risk-based rec-ommendations for long-term antithrombotictherapy in section 2.1.

4.1.2. For patients with AF of documentedduration of 48 h or less undergoing electivecardioversion (electrical or pharmacologic), wesuggest starting anticoagulation at presentation(low-molecular-weight heparin or unfraction-ated heparin at full venous thromboembolismtreatment doses) and proceeding to cardio-version rather than delaying cardioversion for3 weeks of therapeutic anticoagulation or aTEE-guided approach (Grade 2C). After suc-cessful cardioversion to sinus rhythm, we rec-ommend therapeutic anticoagulation for at least

4 weeks rather than no anticoagulation, regard-less of baseline stroke risk (Grade 2C). Decisionsabout long-term anticoagulation after cardio-version should be made in accordance withour risk-based recommendations for long-termantithrombotic therapy in section 2.1.

4.2. For patients with AF and hemodynamicinstability undergoing urgent cardioversion(electrical or pharmacologic), we suggest thattherapeutic-dose parenteral anticoagulationbe started before cardioversion, if possible



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frequent blood testing and clinic visits. For recommendationsabout patients with AF and stable coronary artery disease, intra-coronary stent placement, or recent ACS (sections 3.1-3.3), wealso considered the effect of different treatment options on theoutcome of nonfatal myocardial infarction (MI).

1.2 Patient Values and Preferences

In developing our treatment recommendations, we attemptedto account for patient values and preferences regarding these

health states. In this guideline, a systematic review of studiesassessing values and preferences related to antithrombotic therapyfound that values for health states and preferences for treatments

vary appreciably among individuals (MacLean et al9). The avail-able literature has several limitations. The studies eliciting prefer-ences were small and used different methods and tools, and mostincluded a sizeable proportion of participants who had previ-ously taken or were currently taking VKAs. Furthermore, thereare inconsistencies across studies that often are difficult to explain,leaving considerable uncertainty about average patient values.Nevertheless, to make our recommendations, we required an esti-mate of average patient values for the relevant outcomes so that

we could judge whether the trade-offs between benefit and harmwould favor one course of treatment over another.

As described by Guyatt et al10in this guideline, to obtain ourestimates of average patient values, we have used ratings of keyhealth states from participating guideline panelists informed byour systematic review of the relevant literature. The results of thepanelist value rating exercise suggest that on average, patients

would find a typical nonfatal stroke (ischemic or hemorrhagic)approximately three times as aversive as a nonfatal major extra-cranial bleed (typically a GI bleed) and a typical nonfatal MI asaversive as a nonfatal major extracranial bleed.

With the exception of the choice between VKA therapy andno therapy, the choice of one antithrombotic treatment overanother for long-term stroke prevention in AF will not lead todifferences in all-cause mortality (section 2). Thus, for thesechoices that are not expected to result in a difference in mor-tality, for every 1,000 patients treated for 1 year, if the number ofnonfatal strokes prevented is less than one-third of the number ofnonfatal major extracranial bleeds caused by a given antithrom-botic therapy, we have recommended against that intervention.If the number of nonfatal strokes prevented is appreciably morethan one-third of the number of nonfatal major extracranialbleeding events that result from a given antithrombotic therapy,

we have recommended in favor.Making these trade-offs requires not only estimates regarding

average patient values for the relevant outcomes but also best esti-mates of (1) the effect of a given treatment on these outcomesagainst a given comparator (ie, relative risk) and (2) the absoluteevent rates for these outcomes in untreated patients (or, for PICOquestions of a treatment vs an active comparator, the absoluteevent rates in patients receiving the active comparator). In the

following section, we present the methods used to obtain theseestimates for our guidelines.

1.3 Estimating the Magnitude of Treatment Effect

For each clinical question, we extracted data regarding thepreviously discussed outcomes from the relevant clinical trials.

When there were multiple randomized controlled trials (RCTs)addressing the same clinical question, we conducted meta-analyses using random-effects models and the Mantel-Haenszelmethod to obtain pooled estimates of treatment effect, expressedas relative risk. For studies that did not report the proportionof strokes that were fatal and nonfatal, we used all available datain the published report to obtain a best estimate of the effect of

The article ends with a discussion of practicalissues in the use of adjusted-dose vitamin K antago-nist (VKA) therapy in patients with AF and sugges-tions for future research.

Table 1 specifies the clinical question beingaddressed in this article (in PICO [population, inter-

vention, comparator, outcomes] format) and the typesof studies used. This article does not give recommen-

dations for antithrombotic therapy in patients withAF around the time of surgical or invasive proce-dures (see Douketis et al5), at the time of presen-tation with acute stroke (see Lansberg et al6), or inpatients with AF who have prosthetic heart valves (see

Whitlock et al7). This article does not give recom-mendations for patients with AF who are pregnant.For general recommendations on antithrombotic ther-apy during pregnancy (ie, not specific to AF), seeBates et al.8 Finally, the recommendations in thisarticle apply to patients with persistent and perma-nent AF and to patients with PAF but do not apply to

patients with a single, transient, self-limited episodeof AF associated with acute illness.

1.0Methods

To inform our guideline development, we searched for relevantarticles published since the last literature search performed forthe Antithrombotic and Thrombolytic Therapy: American Collegeof Chest Physicians Evidence-Based Clinical Practice Guidelines(8th Edition). Specifically, for literature regarding the assess-ment of stroke risk in patients with AF, we searched Medline forarticles published from January 1, 2005, to October 2009 usingthe search terms atrial fibrillation, atrial flutter, risk assess-ment, risk factors, risk stratification, stroke, and thrombo-embolism. For literature regarding prevention of stroke andthromboembolism in patients with AF, we searched Medlinefor articles published from January 1, 2005, to October 2009using the search terms coumarins, warfarin, dicumarol,phenprocoumon, acenocoumarol, fondaparinux, idraparinux,aspirin, triflusal, indobufen, dabigatran, ximelagatran,rivaroxaban, apixaban, ticlopidine, clopidogrel, catheterablation, watchman, PLAATO, cardioversion, atrial fibril-lation, and atrial flutter.

1.1 Outcomes of Interest

The outcomes most relevant to patients with AF include death,

nonfatal stroke, systemic embolism, nonfatal major extracranialbleeding, and the burden and lifestyle limitations associated withoutpatient antithrombotic therapy. To facilitate decision-making,the term stroke in this article includes ischemic stroke and intra-cranial hemorrhage (intracerebral, subdural, and subarachnoidhemorrhage). Although there may be some differences in theimpact of these intracranial events (eg, subdural hemorrhage) onquality of life, we judged that on average, the impact would besimilar. We also explicitly considered that outpatient antithrom-botic therapy was associated with a burden to the patient, whichin some cases, such as aspirin, is a requirement to take a dailymedication, or in other cases, such as adjusted-dose VKA therapy,is not only a requirement to take a daily medication but also arequirement to limit ones lifestyle, restrict ones diet, and undergo



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tic plaque in the descending aorta seen on transesophageal echo-cardiography [TEE] or a history of peripheral arterial disease)independently predicts stroke risk among patients with AF.21-23

1.4.3 Stroke Risk Stratification Schema:Many risk stratifi-cation schema, which use various combinations of the risk fac-tors discussed previously, have been developed to aid cliniciansin the assessment of stroke risk in patients with nonrheumaticAF (Table S13).12Despite substantial efforts in this field overthe past several decades, all available schema have only modest

ability to predict stroke in patients with AF, with C statistics typi-cally between 0.55 and 0.70.4,24-43(A C statistic of 0.50 indicatesa model that does not discriminate better than chance alone, anda C statistic of 1.00 indicates perfect discrimination.)

The CHADS2score is the most validated risk scheme, havingbeen independently tested in at least 10 separate cohorts after itsoriginal derivation.24,32,35-46The CHADS2score gives a single pointfor each of congestive heart failure (originally defined as a recentexacerbation of congestive heart failure), hypertension (defined asa history of hypertension, rather than a presence of elevated BP),age 75 years, and diabetes mellitus and two points for priorstroke or TIA (Table 2).30

Despite its widespread adoption and ease of use, the CHADS2score has limitations. First, congestive heart failure is not a consis-

tently demonstrated independent predictor of stroke. Second, therisk associated with a history of hypertension may differ amongpatients with well-treated vs poorly treated hypertension.46-48Third, in most studies, the CHADS2score has only a modest abilityto predict stroke in patients with AF (C statistic, 0.56-0.70).24,32,35-46Finally, the threshold of stroke risk at which treatment withoral anticoagulation will be preferred is likely to decrease withthe emergence of new oral anticoagulants that do not require reg-ular monitoring of the international normalized ratio (INR) andthat may be associated with greater reductions in stroke andless risk of bleeding compared with adjusted-dose VKA therapy.49Thus, stroke risk stratification schema will need to evolve to moreaccurately identify patients who are at sufficiently low risk ofstroke and can be treated with aspirin or no antithrombotic ther-apy, whereas all other patients with AF can be considered fororal anticoagulation.

The CHA2DS2-VASc (congestive heart failure [or left ventric-ular systolic dysfunction], hypertension, age ,75 years; diabetesmellitus, prior stroke or transient ischemic attack, vascular disease,age 65 to 74 years, female sex) score is a new risk scheme thatcombines the CHADS2score with additional moderate risk fac-tors, which were also included in the 2006 American Collegeof Cardiology/American Heart Association/European Society ofCardiology and National Institute for Health and Clinical Excel-lence AF practice guidelines.29,50Specifically, the CHA2DS2-VAScscore assigns points as in the original CHADS2 score (Table 2)

with the exception of age75 years, which is assigned two points.It also assigns a single point for each of the following additional

treatment on nonfatal stroke by assuming a case fatali ty rate of50% for hemorrhagic stroke and 25% for ischemic stroke basedon population-based stroke registry data and the case fatalityrates observed in the RCTs of patients with AF that reportedsuch data.11 For nonfatal major extracranial bleeding, we acceptedthe definition of major bleeding from the individual studies, and

when the proportion of major extracranial bleeds that were fatalvs nonfatal was not reported, we applied the average case fatalityrate for major extracranial bleeding reported across the relevantclinical trials (15%). For the outcome of systemic embolism,

we used the total number of events (fatal and nonfatal) becausesystemic embolism was an infrequent event and typically notreported as fatal vs nonfatal.

1.4 Deriving Baseline Risk of Stroke in Patients With AF

The risk of stroke varies considerably across different groupsof patients with AF.12Simple validated tools for the assessment ofstroke risk in patients with AF help in identifying those who aremore likely to benefit than be harmed from antithrombotic therapy.

1.4.1 Pattern of AF:Guidelines have categorized the pat-tern of AF into (1) PAF, in which recurrent episodes terminatespontaneously within 7 days and usually in ,48 h; (2) persistentAF, in which the episode of AF does not self-terminate within

7 days or is terminated by cardioversion; and (3) permanent AF,in which AF is present for some time and cardioversion eitherhas failed or has not been attempted.13

For patients with PAF, periods of sinus rhythm theoreticallyshould lessen the risk of stroke, yet transitions from AF to sinusrhythm may acutely heighten risk in a manner similar to theincrease in risk caused by cardioversion. Although some studiessuggest that PAF is associated with a lower risk of stroke thanpersistent or permanent AF, patients with PAF generally are

younger and have a lower prevalence of other stroke risk factors,and clinical trial data suggest that PAF confers a relative risk ofstroke similar to persistent or permanent AF when controlling forassociated stroke risk factors.14-17 Pending further evidence, itseems reasonable to treat patients with PAF in a manner similar

to those with persistent and permanent AF; thus, our risk-basedtreatment recommendations apply to patients with PAF and per-sistent and permanent AF.

1.4.2 Independent Risk Factors for Stroke in Patients With AF:Two recent systematic reviews have identified clinical and echo-cardiographic factors that are independently associated with anincreased risk of stroke in patients with AF. 18,19The individualstudies from these systematic reviews, in addition to articlesidentified in an updated literature search performed for thisguideline, are summarized in Tables S1 through S12 (tables thatcontain an S before the number denote supplementary tablesnot contained in the body of the article and available instead in anonline data supplement; see the Acknowledgments for moreinformation). In terms of clinical applicability, the most consistentlyidentified risk factors for ischemic stroke among patients withAF are a history of ischemic stroke or transient ischemic attack(TIA)the strongest dichotomous predictor of stroke riskolderage, hypertension, and diabetes. Although impaired left ventricularsystolic function is a risk factor for stroke in AF, there are conflictingdata about whether a history of congestive heart failure per se raisesthe risk of ischemic stroke in AF. Although age thresholds oftenare used in stroke risk schemes, stroke risk in AF increases contin-uously with age, appreciably rising from age 65 years onward.20There is moderate-quality evidence that women face a higher riskof stroke than men.18A history of coronary artery disease has notconsistently been found to be an independent risk factor for strokein patients with AF.18However, there is low-quality evidence thatthe presence of atherosclerotic vascular disease (eg, complex aor-

Table 2[Section 1.4.3] CHADS2Score30forAssessment of Stroke Risk in Patients With

Nonrheumatic AF

Risk Factor Points

Recent Congestive heart failure exacerbation 1History of Hypertension 1Age75 y 1Diabetes mellitus 1Prior history of Stroke or transient ischemic attack 2

CHADS25congestive heart failure, hypertension, age 75 years,diabetes mellitus, prior stroke or transient ischemic attack. See Table 1legend for expansion of other abbreviation.



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score of 1.5, and a substantial majority (78%) of patients in thecohort had a CHADS2score of1.44Although CHADS2-specificrates of all-cause mortality are not available from this cohort, therisk of death is expected to be lower in low-risk patients with aCHADS2score of 0 because of their younger age, lower preva-lence of vascular risk factors, and lower rates of fatal ischemicstroke.

1.6 Deriving Baseline Risk of Nonfatal Major

Extracranial BleedingTo develop our recommendations, we also required estimates

of the baseline risk of nonfatal major extracranial bleeding inpatients with AF. We obtained this estimate from observationalstudies of VKA therapy in cohorts that included exclusively orpredominantly patients with AF (median rate of 1.3% per yearacross these studies).44,53,54To estimate the baseline risk of non-fatal major extracranial bleeding off VKA therapy, we used thismedian rate of bleeding on VKA therapy from the observa-tional studies (1.3% per year) and divided by the pooled relativerisk (2.58) of nonfatal major extracranial bleeding associated with

VKA therapy, as obtained from RCTs of VKA therapy vs no therapy.Therefore, our estimate of the baseline risk of nonfatal majorextracranial bleeding off therapy was 0.5% per year.

2.0Antithrombotic Therapy forPatients With AF in General

Over the past 2 decades, numerous RCTs haveinvestigated antithrombotic therapies to reduce therisk of thromboembolism, principally ischemic stroke,in patients with AF. In this section, we summarize theevidence and give treatment recommendations for

VKA therapy, antiplatelet monotherapy (eg, aspirin),dual antiplatelet therapy with aspirin and clopid-

ogrel, and new oral anticoagulants (eg, dabigatran) inpatients with AF.

2.1 Patients With Nonrheumatic AF

2.1.1 VKAs vs No Therapy:Six RCTs that enrolleda total of 2,584 patients and address the primary pre-

vention (Atrial Fibrillation Aspirin and Anticoagulation[AFASAK] 1, Boston Area Anticoagulation Trial forAtrial Fibrillation [BAATAF], Canadian Atrial Fibril-lation Anticoagulation [CAFA], Stroke Prevention inAtrial Fibrillation [SPAF] I, Stroke Prevention in

Nonrheumatic Atrial Fibrillation [SPINAF]) and sec-ondary prevention (European Atrial Fibrillation Trial[EAFT]) of stroke in patients with AF provide high-quality evidence that VKA therapy reduces therisk of death by one-fourth and the risk of nonfatalstroke by two-thirds compared with no therapy(Table 3).55-61For patients with a CHADS2score of 0,the studies provide moderate-quality evidence that

VKA therapy increases the risk of nonfatal majorextracranial bleeding due to imprecision of the esti-mate (wide CIs). The studies provide high-qualityevidence for patients with higher CHADS2 scores.

risk factors: female sex, age 65 to 74 years, and vascular disease(defined as a history of MI, peripheral arterial disease, or complexaortic plaque). The CHA2DS2-VASc score has been evaluated inat least five separate cohorts since its original description. Withthe exception of a recent study by Olesen et al,24all other studieshave found that the predictive ability of CHA2DS2-VASc is similarto that of the CHADS2score (C statistics of each risk score is0.6across the various studies) and not statistically significantly greaterthan that of CHADS2.36,40-43Because the CHADS2score has beenextensively validated and is easy for clinicians to remember and

use, we use the CHADS2score as the principal approach for ourrisk-based treatment recommendations.

1.4.4 Estimating the Baseline Risk of Nonfatal Stroke byCHADS2Score:To develop our recommendations, we requiredestimates of the absolute rate of nonfatal stroke (ischemic or hem-orrhagic) for patients according to their underlying risk of stroke,as characterized by their CHADS2score. Ideally, we would obtainthese estimates of baseline risk from published annual rates ofstroke, by CHADS2score, among untreated patients. However,such data are not available.

Therefore, to obtain estimates of annual stroke risk, we usedpooled data from aspirin-treated patients enrolled in six clinicaltrials of antithrombotic therapy for stroke prevention in AF.37This

published report presented data regarding ischemic stroke rates(fatal and nonfatal combined) on aspirin, stratified by CHADS2score. We used the following calculations to estimate the annualrisk of nonfatal stroke (ie, ischemic and hemorrhagic) on aspirin:(1) multiplication of reported rates of ischemic stroke by 1.08 toaccount for additional hemorrhagic strokes on aspirin therapy(based on the observed ratio of ischemic:hemorrhagic strokes inaspirin arms of RCTs in patients with AF) and (2) an estimationthat 50% and 25% of hemorrhagic and ischemic strokes, respec-tively, were fatal.

Depending on the clinical question being addressed by a par-ticular recommendation, we adjusted these absolute rates ofnonfatal stroke on aspirin to reflect the clinical scenario beingaddressed. For the recommendation addressing VKA therapy

vs no treatment, for example, to estimate absolute rates of non-fatal stroke on no treatment, we increased our estimates of therate of nonfatal stroke on aspirin by 21% to account for the esti-mated efficacy of aspirin in preventing stroke in AF). We there-fore used the following absolute rates of nonfatal stroke inuntreated patients to develop our recommendations: 0.8%, 2.2%,4.5%, and 9.6% per year for patients with CHADS2scores of 0, 1,2, and 3 to 6, respectively.

We have chosen to base our treatment recommendations onabsolute rates of stroke derived from clinical trials, recognizingthat these data have important limitations. Less than 10% ofpatients screened were enrolled in these historical trials, there

was limited racial and ethnic diversity, and there is some evi-dence suggesting that stroke rates may now be lower than atthe time these RCTs were conducted 2 decades ago possibly

because of improved treatment of cardiovascular risk factors, suchas hypertension.51,52 However, despite these limitations, theseclinical trial-based data regarding stroke events were systemati-cally and prospectively collected, and they remain the best avail-able source of stroke rates stratified by CHADS2score.

1.5 Deriving Baseline Risk of Death in Patients With AF

We used data from an observational health plan databasestudy of 11,526 patients with nonvalvular AF (the Anticoagula-tion and Risk Factors in Atrial Fibrillation [ATRIA] Study) toobtain an estimate of the risk of all-cause mortality in patients

with AF not treated with warfarin (53 deaths per 1,000 patient-years). Untreated patients in this cohort had a mean CHADS2



9/45


Table3

[Sections2.1.1,2.1.8,2.1.9,2.1.10]

ShouldVKAsRatherThanNoTherapyBeUsedinPatientsWithAF?a

QualityAssessment

SummaryofFin

dings

RiskofBias

Inconsistency

Indirectness

Imprecision

Publ

ication

B

ias

StudyEventRates(%)

EstimationofAbso

luteEffects

1yTimeFrame

No.of

Studies

WithNo

Therapy

WithVKA

RelativeEffect

(95%CI)

WithNoTherapy

WithVKA(95%CI)

Qualityof

Evidence

Death(criticaloutcome)meanfollow-up1.7y

6RCTs

Noserious

limitations

Noserious

inconsistency

Noserious

indirectness

Noserious

imprecision

Undetected

136/1,425(9.5)

103/1,429(7.2)

RR0.72

(0.55-0.94)

53per1,000b

15fewerdeaths

p

er1,000c

(

from3fewer

t

o24fewer)

High

Nonfatalstroke(criticaloutcome)meanfollow-up1.7y;ischemicstrokeandin

tracranialhemorrhaged

6RCTs

Noserious

limitations

Noserious

inconsistency

Noserious

Indirectness

Noserious

imprecision

Undetected

108/1,425e(7.6)

36/1,429f(

2.5)

RR0.34

(0.23-0.49)

CHADS20points

High

8per1,000g

5fewerstrokes

p

er1,000(from

4

fewerto

6

fewer)

CHADS21point

22per1,000

15fewerstrokes

p

er1,000(from

1

1fewerto

1

7fewer)

CHADS22points

45per1,000

30fewerstrokes

p

er1,000(from

2

3fewerto

3

5fewer)

CHADS23-6po

ints

96per1,000

63fewerstrokes

p

er1,000(from

4

9fewerto

7

4fewer)

Nonfatalmajorextracranialbleeds(importantoutcome)meanfollow-up1.7y

6RCTs

Noserious

limitations

Noserious

inconsistency

Noserious

indirectness

Noserious

imprecision

Undetected

7/1,425(0.5)

23/1,429(1.6)

RR2.58

(1.12-5.97)

5per1,000h

8m

orebleeds

p

er1,000(from

1

moreto

2

5more)

Highi

Systemicembo

lism(importantoutcome)meanfollow-up1

.7y

6RCTs

Noserious

limitations

Noserious

inconsistency

Noserious

Indirectness

Imprecisej

Undetected

10/1,425(0.7)

4/1,429(0.3)

RR0.42

(0.15-1.20)

4per1,000k

2fewersystemic

e

mboliper1,000

(

from3fewer

t

o1more)

Moderate

(Continued)



10/45


11/45


2.1.2 implies that adjusted-dose warfarin is far supe-rior to aspirin for the prevention of stroke in patients

with AF but is likely to be associated with a greaterrisk of bleeding complications. Direct evidenceregarding this clinical question comes from 11 RCTs(total of 6,526 patients) comparing adjusted-dose

VKA therapy to antiplatelet monotherapy (AFASAK 1,AFASAK 2, Birmingham Atrial Fibrillation Treat-

ment of the Aged [BAFTA], EAFT, National Studyfor Prevention of Embolism in Atrial Fibrillation[NASPEAF], Primary Prevention of Arterial Throm-boembolism in Nonrheumatic AF in Primary CareTrial [PATAF], Studio Italiano Fibrillazione Atriale[SIFA], SPAF II, SPAF III, Vemmos et al,69and War-farin vs Aspirin for Stroke Prevention in Octogenar-ians With AF [WASPO]) (Table 5).55,60,70-77Antiplatelettherapy was typically with aspirin 75 to 325 mg/d,but in the SIFA and NASPEAF studies, it was withindobufen and triflusal, respectively.72,74In SPAF IIIand one of the two antiplatelet arms of AFASAK II,

aspirin was given in combination with fixed mini-dose (ineffective) warfarin.70,76

These trials provide high-quality evidence thatadjusted-dose VKA therapy reduces by one-half therisk of nonfatal stroke compared with antiplateletmonotherapy. These trials suggest that VKA therapyincreases the risk of nonfatal major extracranialbleeding by about 50% compared with aspirin (pooledrisk ratio, 1.42; 95% CI, 0.89-2.29), but the qualityof evidence was rated down to moderate because ofimprecision. Indirect evidence from RCTs of adjusted-dose VKA therapy vs aspirin in other populations

suggest that VKA therapy is likely associated with atrue twofold to 2.5-fold increase in major bleedingrisk.78,79 For the outcomes of death and systemicembolism, pooled estimates of treatment effect fromtrials of VKA therapy in patients with AF were impre-cise, leaving uncertainty about the impact of VKAtherapy on these outcomes compared with antiplate-let monotherapy.

2.1.4 VKAs vs Dual Antiplatelet Therapy WithAspirin and Clopidogrel: The Atrial FibrillationClopidogrel Trial With Irbesartan for Prevention of

Vascular Events (ACTIVE) W trial assessed dualantiplatelet therapy with aspirin and clopidogrel as apotential alternative to VKA therapy (INR 2.0-3.0).80The trial was stopped early because of findings ofsuperiority of VKA therapy (for their primary out-come of stroke, systemic embolism, MI, or vasculardeath) and did not find evidence of a difference inthe risk of major bleeding (Table 6). Most patients(77%) were receiving VKA therapy before randomi-zation, raising some concerns about generalizabilityof these findings to patients with AF who are beingnewly started on VKA therapy (ie, by enrolling mostly

The studies also provide moderate-quality evidencethat VKA therapy reduces the risk of systemic embo-lism (rated down for imprecision).

2.1.2 Antiplatelet Monotherapy (Aspirin) vs NoTherapy:Several RCTs of antiplatelet monotherapy

vs no therapy in patients with AF have shown thatantiplatelet therapy leads to, at best, a modest reduc-

tion in the risk of nonfatal stroke. Antiplatelet mono-therapy in these trials was either with aspirin alone(AFASAK 1; SPAF I; EAFT; United Kingdom Tran-sient Ischaemic Attack Aspirin trial [UK-TIA]; Low-Dose Aspirin, Stroke, Atrial Fibrillation [LASAF];European Stroke Prevention Study [ESPS]-2; andJapan Atrial Fibrillation Stroke Trial [JAST]), aspirinin combination with fixed (ineffective) minidose

warfarin (Swedish Atrial Fibrillation Trial [SAFT]),or dipyridamole (ESPS-2).55,58,60,62-66Aspirin dosingin these trials typically ranged from 50 to 325 mg/d.In the LASAF, JAST, and SAFT trials, aspirin was

compared with a no-treatment control arm, whereas inthe remaining trials, comparison was to placebo.63,64,66ESPS-2 and UK-TIA were stroke prevention trialsconducted primarily in non-AF populations, and onlythe data from the subset of patients with AF are con-sidered here.62,65

Pooled data from these trials provide moderate-quality evidence (rated down for imprecision) thatantiplatelet monotherapy is associated with a 21%relative reduction in risk of nonfatal stroke com-pared with no treatment (Table 4). Although our con-fidence in the benefits of aspirin therapy is moderate,

our confidence in its bleeding risk is high. Althoughthe trials of antiplatelet monotherapy in patientswith AF were underpowered to precisely estimatethe risk of nonfatal major extracranial bleeding, trialsof aspirin for the primary and secondary preventionof cardiovascular disease have conclusively demon-strated that aspirin is associated with an increasedrisk of major hemorrhage. An individual patient datameta-analysis combining data from six cardiovas-cular primary prevention trials (95,000 subjects) anda meta-analysis of 60 cardiovascular secondary pre-

vention trials (94,000 subjects) found that aspirin

is associated with a significant 50% to 60% relativeincrease, respectively, in the risk of major extracra-nial bleeding.67,68 For the outcomes of death andsystemic embolism, pooled estimates of treatmenteffect from trials of antiplatelet monotherapy inpatients with AF were imprecise, leaving uncer-tainty about the impact of antiplatelet monotherapyon these outcomes when compared with no treat-ment (Table 4).

2.1.3 VKAs vs Antiplatelet Monotherapy (Aspirin):The evidence summarized in sections 2.1.1 and



12/45


(Continued)

Table4[Section

2.1.2,2.1.8]ShouldAntiplatelet(A

spirin)MonotherapyRatherThanN

oTherapyBeUsedinPatientsWithAF?a,b

QualityAssessment

SummaryofFindings

No.of

Studies

RiskofBias

Inconsistency

Indirectness

Imprecision

Publication

Bias

StudyEventRates(%)

RelativeEffect

(95%CI)

EstimationofAb

soluteEffects

1yTimeFrame

Qualityof

Evidence

WithNo

Therapy

With

Antiplatelet

WithNo

Therapy

WithAntiplatelet

(95%CI)


6RCTs

Noserious

limitations

Noserious

inconsistency

Noserious

indirectness

Imprecisec

Und

etected

231/2,152(10.7)

215/2,246(9.6

)

RR0.89

(0.75-1.05)

53per1,000d

6few

erdeaths

per1,000(from

13

fewerto3more)

Moderate


tracranialhemorrhagee

8RCTs

Noserious

limitations

Noserious

inconsistency

Noserious

indirectness

Imprecisef

Und

etected

197/2,274g(8.7)

174/2,498h(7.

0)

RR0.79

(0.65-0.96)

CHADS20po

ints

Moderate

8per1,000i

2few

erstrokes

per1,000(from0

few

erto3fewer)

CHADS21po

int

22per1,000

5few

erstrokes

per1,000(from1

few

erto8fewer)

CHADS22po

ints

45per1,000

9few

erstrokes

per1,000(from2

few

erto16fewer)

CHADS23-6p

oints

96per1,000

20fewerstrokes

per1,000(from4

few

erto34fewer)

Nonfatalma

jorextracranialbleeds(importantoutcome)j

60RCTs

Noserious

limitations

Noserious

inconsistency

Noserious

indirectness

Noserious

imprecision

Und

etected

333/47,168(0.7)

535/47,158(1.1)

RR1.60

(1.40-1.80)

5per1,000k

3morebleeds

per1,000(from2

mo

reto4more)

High



13/45
http://www.chestpubs.org/


14/45


Table5[Sections2.1.3,2.1.8,2.1.9,2.1.1

0]ShouldVKAsRatherThanAspirinBeUsedinPatientsWithAF?a

QualityAssessment

SummaryofFindings

No.of

Studies

RiskofBias

Inconsistency

Indirectness

Imprecision

Publication

Bia

s

StudyEventRates(%)

RelativeEffect

(95%CI)

EstimationofAbsoluteEffects

1-yTimeFr

ame

Qualityof

Evidence

WithASA

WithVKA

WithASA

WithVKA(95%CI)


10RCTs

Noserious

limitations

Noserious

inconsistency

Noserious

indirectness

Impreciseb

Undetected

351/3,020(11.6)

327/2,835(11.5)

RR0.97

(0.85-1.12)

47per1,000c1fewerd

eathper1,000

(from7

fewerto

6more

)

Moderate


tracranialhemorrhaged

11RCTs

Noserious

limitations

Noserious

inconsistency

Noserious

indirectness

Noserious

imprecision

Undetected

209/3,356e(6.2)

94/3,170f(

3.0)

RR0.48

(0.33-0.70)

CHADS20points

High

6per1,000g

3fewerstrokesper1,000

(from2

fewerto

4fewer)

CHADS21p

oint

17per1,000


(from5

fewerto

11fewer)

CHADS22p

oints

36per1,000


(from1

1fewerto

24fewer)

CHADS23-6

points

76per1,000


(from2

3fewerto

51fewer)

Nonfatalmajorextracranialbleeds(importantoutcome)meanfollow-up1.8y

11RCTs

Noserious

limitations

Noserious

inconsistency

Noserious

indirectness

Impreciseh

Undetected

45/3,356(1.3)

64/3,170(2.0)

RR1.42

(0.89-2.29)

8per1,000i

3morebleedsper1,000

(from1

fewerto

10mor

e)

Moderate

Systemicembo

lism(importantoutcome)meanfollow-up1

.8y

11RCTs

Noserious

limitations

Noserious

inconsistency

Noserious

indirectness

Imprecisej

Undetected

20/3,356(0.6)

13/3,170(0.4)

RR0.81

(0.40-1.64)

3per1,000k

1fewersystemic

embolismper1,000

(from2

fewer

to2more)

Moderate

(Continued)



15/45


16/45


(Continued)

Table6[Sections2.1.4,2.1.9,2.1.10]ShouldV

KAsRatherThanAspirinPlusClopidogrelBeUsedinPatientsWithAF?

QualityAssessment

SummaryofFindings

No.of

Studies

RiskofBias

Inconsistency

Indirectness

Imprecision

Pub

lication

Bias

StudyEventRates(%)

RelativeEffect

(95%CI)


1-yTimeF

rame

Qualityof

Evidence

With

ASA1C

lopid

WithVKA

With

ASA1C

lopid

WithVKA(95%CI)

Death(criticaloutcome)medianfollow-up1.3y

1RCT

Noserious

limitationsa

Noserious

inconsistency

Noserious

indirectness

Impreciseb

Und

etected

159/3,335(4.8)

158/3,371(4.7

)

RR0.98

(0.79-1.22)

46per1,000c

1fewerdeath

per1,000(from

10fewerto

10more)

Moderate

Nonfatalstroke(criticaloutcome)m

edianfollow-up1.3y;ischemicstrokeandintracranialhemorrhaged

1RCT

Noserious

limitationsa

Noserious

inconsistency

Noserious

indirectness

Noserious

imprecision

Und

etected

72/3,335e(2.2)

41/3,371f(1.2

)

RR0.56

(0.39-0.82)

CHADS20

points

High

5per1,000g

2fewerstrokes

per1,000(from1

fe

werto3fewer)

CHADS21

point

13per1,000

6fewerstrokes

per1,000(from2

fe

werto8fewer)

CHADS22

points

26per1,000

11fewerstrokes

per1,000(from5

fe

werto16fewer)

CHADS23-6points

55per1,000

24fewerstrokes

per1,000(from10

fe

werto34fewer)

Nonfatalmajorextracranialbleeds(importantoutcome)medianfollow-up1.3yh

1RCT

Noserious

limitationsa

Noserious

inconsistency

Noserious

indirectness

(77%of

patients

were

receiving

VKAat

studyentry)

Imprecisei

Und

etected

85/3,335(2.5)

78/3,371(2.3

)

RR0.91

(0.67-1.23)

12per1,000j

1fewerbleeds

per1,000(from4

fe

werto3more)

Moderate



17/45


18/45


results of a three-arm RCT of 18,113 patients withAF in which dabigatran 110 mg bid, and dabiga-tran 150 mg bid, were compared with open-label,adjusted-dose warfarin (target INR 2.0-3.0).84Basedon best estimates of the proportion of strokes andmajor extracranial bleeds that were nonfatal (thepublished report did not present the number orproportion of fatal and nonfatal events), dabigatran

at a dose of 150 mg bid is associated with a statisti-cally significant one-third reduction in nonfatal stroke,

with no evidence of a difference in the risk of nonfa-tal major extracranial bleeding compared with war-farin. Moreover, the data raised the possibility thatdabigatran 150 mg bid may reduce all-cause mortalitycompared with warfarin (relative risk, 0.89; 95% CI,0.79-1.01) (Table 9). In contrast, dabigatran at a doseof 110 mg bid was not associated with a significantdifference in the risk of death, nonfatal stroke, nonfa-tal major extracranial bleeding, or systemic embolism(Table 10).

ROCKET-AF (Rivaroxaban Once Daily Oral directFactor Xa inhibition Compared with Vitamin K Antago-nism for Prevention of Stroke and Embolism Trialin Atrial Fibrillation) was a double-blind, double-dummy RCT comparing rivaroxaban 20 mg oncedaily to adjusted-dose warfarin (INR 2.0-3.0) in14,264 patients with AF at increased risk of stroke(mean CHADS2score of 3.5).85In the intention-to-treat analysis, rivaroxaban was noninferior to warfarinfor the primary end point of stroke (ischemic or hem-orrhagic) or systemic embolism but was not superiorto warfarin (hazard ratio, 0.88; 95% CI, 0.74-1.03).

The trial did not find evidence of a difference inmajor bleeding between rivaroxaban and warfarin(hazard ratio, 1.04; 95% CI, 0.90-1.20). Major GIbleeding was more common with rivaroxaban than

with warfarin (3.2% and 2.2%, respectively, P,.001).Mortality was not significantly different betweenrivaroxaban and warfarin.

The Apixaban vs Acetylsalicylic Acid to PreventStrokes (AVERROES) RCT compared apixaban 5 mgbid to aspirin in 5,599 patients with AF who weredemonstrated or expected to be unsuitable candi-dates for adjusted-dose VKA therapy.86The trial was

stopped early for benefit and was consistent withthe trials of VKA therapy vs aspirin (section 2.1.3),reporting that apixaban reduces by one-half theoccurrence of the primary outcome of stroke andsystemic embolism compared with aspirin (hazardratio, 0.45; 95% CI, 0.32-0.62). The trial failed todemonstrate or exclude a difference in the risk ofmajor extracranial bleeding with apixaban compared

with aspirin (hazard ratio, 1.23; 95% CI, 0.74-2.05),and the results were consistent with those of earliertrials of VKA therapy vs aspirin (section 2.1.3), whichsuggest an increase in the risk of major extracranial

prior users of VKA therapy, the study sample may bemore representative of patients in whom VKA therapyis well tolerated). In prespecified subgroup analyses,the investigators did not find evidence of a differencein the effect of VKA therapy on primary outcomein patients who were and were not receiving VKAtherapy at study entry. However, there was a signifi-cant difference (interaction P5 .03) in the effect on

major bleeding, depending on whether patients wereprior users of VKA therapy. For patients who werenot receiving VKA therapy at study entry, VKA therapy

was associated with a nonsignificant trend toward a69% relative increase in major bleeding compared

with dual antiplatelet therapy, whereas in patientsalready receiving VKA therapy at study entry, VKAtherapy was associated with a nonsignificant trendtoward a 24% relative decrease in major bleedingcompared with dual antiplatelet therapy.

2.1.5 Dual Antiplatelet Therapy With Aspirin

and Clopidogrel vs Aspirin Alone: The ACTIVE Astudy compared combination aspirin and clopid-ogrel therapy with aspirin alone.81The trial enrolled7,554 patients considered unsuitable for VKA therapy(approximately one-half because of a physicians judg-ment that VKA was inappropriate, one-fourth becauseof a specific risk of bleeding, and one-fourth becauseof the patients preference not to take a VKA as thesole reason) and found that combination therapy ismore effective in reducing the risk of nonfatal strokein patients with AF but also increases the risk of non-fatal major extracranial bleeds compared with treat-

ment with aspirin alone (Table 7).2.1.6 New Oral Anticoagulants vs VKAs: Anti-

thrombotic therapy for AF is evolving rapidly becauseof the development of new oral anticoagulants thatdirectly target different parts of the coagulation path-

way, have a more predictable anticoagulant effect,and do not require INR monitoring. Included in thisnew group of drugs are direct thrombin inhibitors(eg, dabigatran) and direct factor Xa inhibitors (apixa-ban, rivaroxaban, edoxaban). Results of large phase 3clinical trials of these agents in patients with AFhave been recently published or will be reported

soon (Table 8). Although ximelagatran is no longerapproved for use by regulatory agencies because ofconcerns about severe liver toxicity, the Stroke Pre-

vention Using an Oral Thrombin Inhibitor in PatientsWith AF (SPORTIF) III and V trials were a proof ofprinciple that a direct thrombin inhibitor can achievesimilar protection against stroke compared with war-farin (ie, findings met the investigators prespecifiednoninferiority criterion) with no evidence of increasedbleeding risk.82,83

The Randomized Evaluation of Long-Term Anti-coagulation Therapy (RE-LY) trial reported the



19/45


(Continued)

Table7[Sectio

ns2.1.5,2.1.8,2.1.9,2.1.10]ShouldAspirinPlusClopidogrelRatherT

hanAspirinBeUsedinPatientsWithAF?

QualityAssessment

SummaryofFindings

RiskofBias

Inconsistency

Indirectness

Imprecision

Publication

B

ias

StudyEventRates(%)

RelativeEffect

(95%CI)


1-yTimeFrame

No.of

Studies

WithASA

With

ASA/Clopid

WithASA

WithASA/Clopid

(95%CI)

Qualityof

Evidence


1RCT

Noserious

limitations

Noserious

inconsistency

Noserious

indirectness

Imprecisea

Undetected

841/3,782(22.2)

825/3,772(21.9)

RR0.98

(0.90-1.07)

47per1,000b

1fewerdeath

per1,000(from5

fe

werto3more)

Moderate


edianfollow-up3.6y;ischemicstrokeandintracranialhemorrhagec

1RCT

Noserious

limitations

Noserious

inconsistency

Noserious

indirectness

Noserious

imprecision

Undetected

315/3,782d(

8.3)

226/3,772e(6.0)

RR0.72

(0.61-0.85)

CHADS20

points

High

6per1,000f

2fewerstrokes

per1,000(from1

fe

werto2fewer)

CHADS21point

17per1,000

5fewerstrokes

per1,000(from3

fe

werto7fewer)

CHADS22

points

36per1,000

10fewerstrokes

per1,000(from5

fe

werto14fewer)

CHADS23-6points

76per1,000

21fewerstrokes

per1,000(from11

fewerto30fewer)

Nonfatalmajorextracranialbleeds(importantoutcome)medianfollow-up3.6yg

1RCT

Noserious

limitations

Noserious

inconsistency

Noserious

indirectness

Noserious

imprecision

Undetected

112/3,782(3.0)

167/3772(4.4)

RR1.50

(1.18-1.89)

8per1,000h

4morebleeds

per1,000(from1

m

oreto7more)

High



20/45


21/45


dabigatran over adjusted-dose VKA therapy in sec-tion 2.1.11.

The data from RE-LY do not directly address theuse of dabigatran in patients with AF and mitral ste-nosis (patients with hemodynamically relevant val-

vular disease were excluded from this study), or inpatients with AF in other special situations (sections 2.2and 3.0). Therefore, we have not extrapolated thedata from RE-LY to these clinical situations and haveinstead restricted those recommendations for oralanticoagulation to adjusted-dose VKA therapy. Thereis direct evidence from RE-LY regarding the use ofdabigatran in patients with AF undergoing cardiover-sion, and these data are summarized in section 4.1.1.

2.1.8 Recommendations for Patients With AF atLow Risk of Stroke (eg, CHADS2Score of 0):Patients

at sufficiently low risk of ischemic stroke may optfor no treatment rather than antithrombotic therapy

with either aspirin or an oral anticoagulant. Forinstance, for every 1,000 patients at low risk of stroke

with a CHADS2score of 0, VKA therapy comparedwith no treatment is anticipated to result in five fewernonfatal strokes at the expense of eight more nonfatalmajor extracranial bleeds and the additional burdenof adjusted-dose VKA treatment (Table 3). Although

VKA therapy is expected to reduce all-cause mortalityin patients with AF in general, it is likely that thismortality benefit does not extend to low-risk patients.

The absolute reduction in fatal ischemic stroke withVKA therapy will be far fewer such patients, whereastheir absolute increase in fatal intracranial hemor-rhage will be similar to those with higher CHADS2scores.51

For patients with a CHADS2score of 0, treatmentwith aspirin for 1 year may result in the prevention oftwo nonfatal strokes per 1,000 patients (moderate-quality evidence due to imprecision) at the expenseof three additional nonfatal major extracranial bleedsper 1,000 patients compared with no treatment(Table 4). If stroke rates are truly declining over time,

bleeding with oral anticoagulation compared withaspirin.

ARISTOTLE (Apixaban for the Prevention ofStroke in Subjects With Atrial Fibrillation) was adouble-blind, double-dummy RCT comparing apixaban

5 mg bid to warfarin (INR 2.0-3.0) in 18,201 patientswith AF (mean CHADS2score of 2.1).87Apixabanreduced by 21% the risk of the primary outcome ofstroke (ischemic or hemorrhagic) or systemic embo-lism (hazard ratio, 0.79; 95% CI, 0.66-0.95) andreduced by 31% the risk of major bleeding (hazardratio, 0.69; 95% CI, 0.60-0.80) compared with warfa-rin. There was no evidence of a difference in majorGI bleeding between apixaban and warfarin (hazardratio, 0.89; 95% CI, 0.70-1.15). All-cause mortality

was lower with apixaban compared with warfarin(hazard ratio, 0.89; 95% CI, 0.80-0.998). In all three

recently completed trials of novel anticoagulantsvs warfarin (RE-LY, ROCKET-AF, and ARISTOTLE),the rate of intracranial hemorrhage (including bothhemorrhagic stroke and other intracranial bleeds)

was lower in patients assigned to the novel anticoag-ulant than in patients assigned to warfarin.84,85,87,88

2.1.7 General Approach to RecommendationsAbout New Oral Anticoagulants in This Article:Ourguideline panel elected to make recommendationsonly for those drugs that have received regulatoryapproval for use in AF (ie, dabigatran).89 Although

based on the results of a single trial, there is evidencefrom RE-LY that dabigatran is no worse than VKAtherapy with respect to nonfatal major extracranialbleeding and that it is similar or superior to warfarin

with respect to nonfatal stroke, systemic embolism,and all-cause mortality in patients with nonvalvularAF (section 2.1.6).Therefore, for patients with non-rheumatic AF, wherever we recommend (or suggest)

VKA therapy, we also recommend (or suggest) theuse of dabigatran, and in these situations, our rec-ommendations simply refer to oral anticoagulation.88

We address the specific question of whether to use

Table 8[Section 2.1.6] Phase 3 RCTs of New Oral Anticoagulants in Patients With AF

Trial Intervention Comparator Status

SPORTIF III Ximelagatran Warfarin (INR, 2.0-3.0) Published82,83SPORTIF VRE-LY Dabigatran (150 or 110 mg bid) Warfarin (INR, 2.0-3.0) Published84AVERROES Apixaban (5 mg bid) Aspirin (81-324 mg daily) Published86ROCKET-AF Rivaroxaban (20 mg once daily) Warfarin (INR, 2.0-3.0) Published85ARISTOTLE Apixaban (5 mg bid) Warfarin (INR, 2.0-3.0) Published87

ENGAGE-AF TIMI 48 Edoxaban (high- and low-dose regimens) Warfarin (INR, 2.0-3.0) Currently recruitingARISTOTLE5Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; AVERROES5Apixaban versus Acetylsalicylic Acid toPrevent Strokes; ENGAGE-AF TIMI 485Effective Anticoagulation With Factor xA Next Generation in Atrial Fibrillation-Thrombolysis InMyocardial Infarction Study 48; INR5 international normalized ratio; RE-LY5Randomized Evaluation of Long-Term Anticoagulation Therapy;ROCKET-AF5Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke andEmbolism Trial in Atrial Fibrillation; SPORTIF5Stroke Prevention Using an Oral Thrombin Inhibitor in Patients With AF.



22/45


(Continued)

Table9[Section2.1.6,2.1.11]ShouldDabigatran150mgbidRatherThanVKAsbeUsedinPatientsWithAF?

QualityAssessment

SummaryofFindings

RiskofBias

Inconsistency

Indirectness

Imprecision

Publication

B

ias

StudyEventRates(%)

RelativeEffect

(95%CI)

EstimationofAb

soluteEffects

1-yTimeFrame

No.of

Studies

WithVKA

WithDabi

150mg

WithVKA

W

ithDabigatran

150(95%CI)

Qualityof

Evidence


1RCT

Noserious

limitations

Noserious

inconsistency

Noserious

indirectness

Serious

imprecisiona

Undetected

487/6,022(8.1)

438/6,076(7.2

)

RR0.89

(0.79-1.01)

38per1,000b

4fewerdeaths

per1,000(from8

fewerto0more)

Moderate



1RCT

Noserious

limitations

Noserious

inconsistency

Noserious

indirectness

Noserious

imprecision

Undetected

149/6,022d(

2.5)

101/6,076e(1.7)

RR0.67

(0.52-0.86)

CHADS20

points

High

3per1,000f

1fewerstrokes

per1,000(from0

fewerto1fewer)

CHADS21point

8per1,000

3fewerstrokes

per1,000(from1

fewerto4fewer)

CHADS22

points

17per1,000

6fewerstrokes

per1,000(from2

fewerto8fewer)

CHADS23-6points

36per1,000

12f

ewerstrokes

per1,000(from5

fewerto17fewer)


1RCT

Noserious

limitations

Noserious

inconsistency

Noserious

indirectness

Imprecisea

Undetected

264/6,022(4.4)

286/6076(4.7)

RR1.07

(0.91-1.26)

13per1,000h

1m

orebleed

per1,000(from1

fewerto3more)

Moderate

Systemicembolism(importantoutcome)medianfollow-up2.0y

1RCT

Noserious

limitations

Noserious

inconsistency

Noserious

indirectness

Imprecisea

Undetected

14/6,022(0.2)

12/6076(0.2)

RR0.85

(0.39-1.84)

2per1,000i

0fewersystemic

emboliper1,000

(from1fewer

to2more)

Moderate



23/45


24/45


(Continued)

Table10[Section2.1.6,2.1.11]ShouldDa

bigatran110mgbidRatherThanV

KAsBeUsedinPatientsWithAF?

QualityAssessment

SummaryofFindings

RiskofBias

Inconsistency

Indirectness

Imprecision

Publication

Bias

StudyEventRates(%)

RelativeEffect

(95%CI)


1-yTimeFrame

No.of

Studies

WithVKA

WithDabi

110mg

WithVKA

W

ithDabigatran

110(95%CI)

Qualityof

Evidence


1RCT

Noserious

limitations

Noserious

inconsistency

Noserious

indirectness

Imprecisea

Unde

tected

487/6,022(8.1)

446/6,015(7.4)

RR0.92

(0.81-1.04)

38per1,000b

3fewerdeaths

per1,000(from7

fe

werto2more)

Moderate



1RCT

Noserious

limitations

Noserious

inconsistency

Noserious

indirectness

Imprecisea

Unde

tected

149/6,022d(

2.5)

132/6,015e(2.2

)

RR0.89

(0.70-1.12)

CHADS20

points

Moderate

3per1,000f

0fewerstrokes

per1,000(from1

fe

werto0more)

CHADS21point

8per1,000

1fewerstrokes

per1,000(from2

fe

werto1more)

CHADS22

points

17per1,000

2fewerstrokes

per1,000(from5

fe

werto2more)

CHADS23-

6points

36per1,000

4fewerstrokes

per1,000(from11

fe

werto4more)


1RCT

Noserious

limitations

Noserious

inconsistency

Noserious

indirectness

Imprecisea

Unde

tected

264/6,022(4.4)

250/6,015(4.2)

RR0.95

(0.80-1.12)

13per1,000h

1fewerbleeds

per1,000(from3

fe

werto2more)

Moderate



25/45


26/45


no reduction in all-cause mortality. However, becauseabsolute rates of stroke may have fallen over thepast 2 decades, we may be overestimating the abso-lute reduction in nonfatal stroke achieved with VKAtherapy. Moreover, the true extent of bleeding risk

with VKA therapy compared with aspirin therapy isunclear because the pooled estimate of the relativerisk of bleeding from the relevant RCTs is imprecise

(Table 5). The limited ability of CHADS2to accu-rately predict stroke risk (C statistic, 0.6-0.7), theconsiderable variability in patient values and pref-erences, and the burden and lifestyle limitationsassociated with adjusted-dose VKA therapy, intro-duce further uncertainty.

Compared with combination therapy with aspirinand clopidogrel, VKA therapy is expected to resultin six fewer nonfatal strokes per 1,000 patients overa 1-year period, anywhere from four fewer to threemore nonfatal major extracranial bleeds, and noreduction in all-cause mortality (Table 6). Uncertainty

regarding the small net clinical benefit at a CHADS2score of 1 arises as a result of the limitations of theCHADS2score in estimating stroke risk and the pos-sibility of declining absolute stroke rates over time.Uncertainty regarding the value of the small netbenefit arises from the variability in patient valuesand preferences and the burden and lifestyle limita-tions associated with adjusted-dose VKA therapy.

For patients at intermediate risk of stroke with aCHADS2 score of 1 who are unsuitable for or choosenot to take an oral anticoagulant for reasons otherthan concerns about major bleeding (eg, difficulty

maintaining a stable INR, lifestyle limitations ofregular INR monitoring, dietary restrictions thatare too burdensome, or costs of new anticoagulantdrugs that are too high), combination therapy withaspirin and clopidogrel provides additional benefit ofstroke reduction at the cost of additional bleeding(ACTIVE A trial) (Table 7). Patients opting for com-bination antiplatelet therapy rather than treatment

with an oral anticoagulant should be informed thatthey are choosing an inferior treatment with regardto stroke prevention.

Recommendation

2.1.9. For patients with AF, including those withparoxysmal AF, who are at intermediate risk ofstroke (eg, CHADS2score51), we recommendoral anticoagulation rather than no therapy(Grade 1B).We suggest oral anticoagulationrather than aspirin (75 mg to 325 mg once daily)(Grade 2B) or combination therapy with aspirinand clopidogrel (Grade 2B). For patients whoare unsuitable for or choose not to take an oralanticoagulant (for reasons other than concerns

then the already small benefits of antithrombotictherapy (number needed to treat for 1 year to preventone nonfatal stroke of 500 for aspirin and 200 for

VKA therapy) will be even smaller.For patients who do choose antithrombotic therapy,

the potential choices are aspirin, dual antiplatelettherapy with aspirin and clopidogrel, or oral antico-agulation. For every 1,000 patients with a CHADS2

score of 0, treatment for 1 year with adjusted-doseVKA therapy or with combination aspirin and clopid-ogrel therapy compared with aspirin is anticipated toresult in small reductions in nonfatal stroke and anincrease in nonfatal major extracranial bleeding suchthat the net benefits of either VKA therapy or dualantiplatelet therapy with aspirin and clopidogrel wouldbe small, particularly given the possibility of decliningstroke rates over time (Tables 5, 7).

Recommendation

2.1.8. For patients with AF, including those withparoxysmal AF, who are at low risk of stroke(eg, CHADS2score50), we suggest no therapyrather than antithrombotic therapy (Grade 2B).For patients who do choose antithrombotictherapy, we suggest aspirin (75 mg to 325 mgonce daily) rather than oral anticoagulation(Grade 2B) or combination therapy with aspirinand clopidogrel (Grade 2B).

Remarks:Patients who place an exceptionally highvalue on stroke reduction and a low value on avoid-ing bleeding and the burden associated with anti-

thrombotic therapy are likely to choose antithrombotictherapy rather than no antithrombotic therapy. Otherfactors that may influence the choices above are aconsideration of patient-specific bleeding risk andthe presence of additional risk factors for stroke,including age 65 to 74 years and female sex, whichhave been more consistently validated, and vascu-lar disease, which has been less well validated (seesection 2.1.12). The presence of multiple non-CHADS2risk factors for stroke may favor oral anti-coagulation therapy.

2.1.9 Recommendations for Patients With AF atIntermediate Risk of Stroke (eg, CHADS2Score of 1):For patients at intermediate risk of stroke witha CHADS2 score of 1, compared with no therapy,1 year of VKA therapy is expected to result in15 fewer deaths and 15 fewer nonfatal strokesper 1,000 patients at the cost of eight more nonfatalmajor extracranial bleeds (Table 3). Regarding thechoice between VKA therapy and aspirin, VKA therapyis anticipated to prevent nine nonfatal strokes forevery 1,000 patients treated for 1 year compared withaspirin but will result in three additional bleeds and



27/45


stroke (eg, CHADS2score2), we recommendoral anticoagulation rather than no therapy(Grade 1A),aspirin (75 mg to 325 mg once daily)(Grade 1B), or combination therapy with aspirinand clopidogrel (Grade 1B). For patients whoare unsuitable for or choose not to take an oralanticoagulant (for reasons other than concernsabout major bleeding), we recommend combi-

nation therapy with aspirin and clopidogrelrather than aspirin (75 mg to 325 mg once daily)(Grade 1B).

2.1.11 Recommendation Regarding Dabigatranvs Adjusted-Dose VKA Therapy: The RE-LY trialshowed that dabigatran, at the higher dose of 150 mgbid, leads to reductions in nonfatal stroke, probablereductions in all-cause mortality, and no apparentincrease in the risk of nonfatal major extracranialbleeding compared with VKA therapy (Table 9),

whereas there was no evidence that dabigatran

110 mg bid leads to a significant reduction in relevantoutcomes compared with VKA therapy (Table 10). Inthe United States, the Food and Drug Administra-tion approved the use of dabigatran for the preven-tion of thromboembolism in patients with AF at adose of 150 mg bid but not at a dose of 110 mg bid.However, the Food and Drug Administration didapprove, based on pharmacokinetic considerationsrather than direct evidence from RCTs in AF popula-tions, a dose of 75 mg bid for patients with severerenal insufficiency (defined as a creatinine clearance15-30 mL/min).89

For the question of whether to use dabigatranvs adjusted-dose VKA therapy, the evidence suggestsnet clinical benefit at the 150-mg dose. At the timeof this writing, however, knowledge regarding theefficacy and safety of the new oral anticoagulantsfor patients with AF is still limited to one large ran-domized trial per agent. Uncommon but seriousadverse effects may emerge with large-scale use ofthe drugs. Performance in usual clinical care maydeteriorate because of less-restricted patient selec-tion and suboptimal adherence to the unmonitoreddrug. For patients who do experience bleeding com-

plications, clinicians need to be aware that there isno antidote to reverse the anticoagulant effects ofdabigatran.90Given these concerns, it would be rea-sonable for VKA-experienced patients who are wellcontrolled (ie, INR within therapeutic range a highproportion of the time) to continue on VKA therapyif they are satisfied with it and are tolerating it wellrather than switching to dabigatran.

There is evidence from meta-analyses of RCTs92

that home monitoring of VKA therapy reduces throm-boembolic events by 42% compared with usualmonitoring (see also Holbrook et al91), which is

about major bleeding), we suggest combinationtherapy with aspirin and clopidogrel rather thanaspirin (75 mg to 325 mg once daily) (Grade 2B).

Remarks:Patients who place an exceptionally highvalue on stroke reduction and a low value on avoidingbleeding and the burden associated with anticoag-ulant therapy are likely to choose oral anticoagula-

tion rather than antiplatelet therapy. Other factorsthat may influence the choice among antithrombotictherapies are a consideration of bleeding risk andthe presence of additional risk factors for stroke,including age 65 to 74 years and female gender, whichhave been more consistently validated, and vasculardisease, which has been less well validated (see sec-tion 2.1.12). The presence of multiple non-CHADS2risk factors for stroke may favor oral anticoagulationtherapy.

2.1.10 Recommendations for Patients With AF atHigh Risk of Stroke (eg, CHADS

2

Score of 2, WhichIncludes Prior Ischemic Stroke or TIA): Patients athigh risk of ischemic stroke, which includes patients

with a history of ischemic stroke or TIA, can antici-pate large benefits (ie, 15 fewer deaths and 30 fewernonfatal strokes per 1,000 patients during 1 year of

VKA therapy) with anticoagulation (Table 3).For every 1,000 patients with a CHADS2score of

2 treated for 1 year with VKA therapy rather thanaspirin, we anticipate 19 fewer nonfatal strokes atthe expense of three more nonfatal major extracra-nial bleeds (Table 5). For every 1,000 such patientstreated with VKA rather than combination therapy

with aspirin and clopidogrel, we anticipate 11 fewerstrokes and anywhere between four fewer to threemore nonfatal major extracranial bleeds (Table 6).There is therefore a substantial net clinical benefit

with oral anticoagulation.For patients at high risk of ischemic stroke with a

CHADS2score of 2 who are unsuitable for or whochoose not to take an oral anticoagulant for reasonsother than concerns about major bleeding (eg, diffi-culty maintaining a stable INR, lifestyle limitations ofregular INR monitoring, dietary restrictions that aretoo burdensome, or costs of new anticoagulant drugsthat are too high), aspirin and clopidogrel therapy

will result in a substantial reduction in stroke com-pared with aspirin alone (ACTIVE A trial) (Table 7).Patients opting for combination antiplatelet therapyrather than treatment with an oral anticoagulantshould be informed that they are choosing an inferiortreatment with regard to stroke prevention.

Recommendation

2.1.10. For patients with AF, including thosewith paroxysmal AF, who are at high risk of



28/45


bleeding risk because there are insufficient datato estimate reliably the absolute bleeding rates forpatients in different categories of bleeding riskon different antithro

ac por fa aticoagulantes

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