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Canadian Journal of Cardiology

Canadian Cardiovascular Society Atrial Fibrillation Guidelines 2010: Prevention of Stroke and Systemic Thromboembolism in Atrial Fibrillation and Flutter

      Abstract

      The stroke rate in atrial fibrillation is 4.5% per year, with death or permanent disability in over half. The risk of stroke varies from under 1% to over 20% per year, related to the risk factors of congestive heart failure, hypertension, age, diabetes, and prior stroke or transient ischemic attack (TIA). Major bleeding with vitamin K antagonists varies from about 1% to over 12% per year and is related to a number of risk factors. The CHADS2 index and the HAS-BLED score are useful schemata for the prediction of stroke and bleeding risks.
      Vitamin K antagonists reduce the risk of stroke by 64%, aspirin reduces it by 19%, and vitamin K antagonists reduce the risk of stroke by 39% when directly compared with aspirin. Dabigatran is superior to warfarin for stroke prevention and causes no increase in major bleeding. We recommend that all patients with atrial fibrillation or atrial flutter, whether paroxysmal, persistent, or permanent, should be stratified for the risk of stroke and for the risk of bleeding and that most should receive antithrombotic therapy. We make detailed recommendations as to the preferred agents in various types of patients and for the management of antithrombotic therapies in the common clinical settings of cardioversion, concomitant coronary artery disease, surgical or diagnostic procedures with a risk of major bleeding, and the occurrence of stroke or major bleeding. Alternatives to antithrombotic therapies are briefly discussed.

      Résumé

      L'incidence annuelle de l'accident vasculaire cérébral (AVC) attribuable à la fibrillation auriculaire (FA) est de 4.5 %, causant la mort ou l'invalidité permanente dans plus de la moitié des cas. Cette incidence varie de moins de 1 % à plus de 20 % par année en fonction des facteurs de risque: insuffisance cardiaque, hypertension, âge, diabète et antécédents d'AVC ou d'ischémie cérébrale transitoire. Le risque d'hémorragie majeure sous traitement avec les antagonistes de la vitamine K varie entre 1 % et 12 % par année et s'avère lié à beaucoup d'autres facteurs. L'index de CHADS2 et le score HAS-BLED sont utiles pour la prédiction du risque d'AVC ou d'hémorragie. Le risque d'AVC est réduit de 64% avec le traitement aux antagonistes de la vitamine K et de 19% avec l'aspirine. Comparativement à l'aspirine, les antagonistes de la vitamine K réduisent ce risque de 39%. Le Dabigatran est supérieur à la warfarine pour la prévention du risque d'AVC sans augmentation du risque de saignement majeur. Nous recommandons que le risque d'AVC et de saignement majeur soit déterminé chez tous les patients avec FA ou flutter auriculaire (paroxystique, persistant ou permanent) et que la plupart reçoivent un traitement antithrombotique. Nos recommandations font état des agents antithrombotiques à favoriser dans les contextes cliniques de cardioversion, maladie cardiaque athérosclérotique concomitante, procédures diagnostiques ou chirurgicales avec risque d'hémorragie majeure associée, et en cas d'AVC ou de saignement majeur. Les alternatives au traitement antithrombotique sont brièvement discutées.

      Risk of Stroke

      Risk factors and risk estimation schemes

      In the 5 landmark randomized clinical trials of oral anticoagulants (OACs) among patients with nonvalvular atrial fibrillation (AF),
      Boston Area Anticoagulation Trial of Atrial Fibrillation Investigators
      The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation.
      • Connolly S.J.
      • Laupacis A.
      • Gent M.
      • et al.
      CAFA Study Coinvestigators
      Canadian Atrial Fibrillation Anticoagulation (CAFA) study.
      • Ezekowitz M.D.
      • Bridgers S.L.
      • James K.E.
      • et al.
      Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation.
      • Petersen P.
      • Boysen G.
      • Godtfredsen J.
      • et al.
      Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK study.
      • Petersen P.
      • Boysen G.
      Letter to editor.
      Stroke Prevention in Atrial Fibrillation Investigators
      Stroke Prevention in Atrial Fibrillation study: final results.
      most of whom had no previous stroke or TIA, control subjects had a mean 4.5% annual incidence of stroke (range, 3%-7%), over half of which resulted in death or permanent disability.
      Atrial Fibrillation Investigators
      Risk factors for stroke and efficiency of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials.
      The mean annual incidence of the composite of stroke or other systemic emboli was 5% (range, 3%-7.4%). These subjects had no contraindications to warfarin and no echocardiographic evidence of rheumatic valvular disease. The observed rates of stroke and other systemic embolism were similar to those reported in earlier cohorts
      • Wolf P.A.
      • Dawber T.R.
      • Thomas Jr, E.
      • et al.
      Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham Study.
      and likely are representative of individuals in the general population with AF and not receiving antithrombotic therapy. In the United States, the annual risk of stroke attributable to AF is 1.5% in the age group 50 to 59 years, rises to 23.5% in the age group 80 to 89 years, and overall is 15%.
      • Singer D.E.
      • Albers G.W.
      • Dalen J.E.
      • et al.
      Antithrombotic therapy in atrial fibrillation.
      An overview of the randomized control trials of warfarin therapy in AF
      Atrial Fibrillation Investigators
      Risk factors for stroke and efficiency of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials.
      determined that previous stroke or TIA, increasing age, history of hypertension, and diabetes were statistically significant multivariate predictors of stroke. Annual stroke risk ranged from 0 (patients younger than 60 years) to 1.3% (patients younger than 80 years with no other risk factors) and to 11.7% (patients with prior stroke or TIA). A recent systematic review
      The Stroke Risk in Atrial Fibrillation Working Group
      Independent predictors of stroke in patients with atrial fibrillation: a systematic review.
      examined the evidence identifying independent risk factors for stroke as reported in 7 studies selected according to rigourously defined criteria. The absolute annual risk of stroke varied 20 fold among patients grouped by various risk factors. Independent risk factors for stroke were the same as those previously identified
      Atrial Fibrillation Investigators
      Risk factors for stroke and efficiency of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials.
      : stroke or TIA (relative risk [RR] 2.5), age (RR 1.5/decade), history of hypertension (RR 2.0), and diabetes mellitus (RR 1.7). Female sex was an independent risk factor in 3 of 6 cohorts, but coronary artery disease and clinical congestive heart failure were not found to be independent risk factors in any of these studies. Even though congestive heart failure and reduced ejection fraction have been identified only as univariate risk factors,
      Atrial Fibrillation Investigators
      Risk factors for stroke and efficiency of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials.
      The Stroke Risk in Atrial Fibrillation Working Group
      Independent predictors of stroke in patients with atrial fibrillation: a systematic review.
      Stroke Prevention in Atrial Fibrillation Investigation
      Prevention of thromboembolism in atrial fibrillation: I. Clinical features of patients at risk.
      Stroke Prevention in Atrial Fibrillation Investigation
      Prevention of thromboembolism in atrial fibrillation: II. Echocardiographic features of patients at risk.
      they are included in current risk classification schemes.
      • Fuster V.
      • Rydén L.E.
      • Cannon A.S.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines.
      • Gage B.F.
      • Waterman A.D.
      • Shannon W.
      • et al.
      Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation.
      The review
      The Stroke Risk in Atrial Fibrillation Working Group
      Independent predictors of stroke in patients with atrial fibrillation: a systematic review.
      emphasized a variety of shortcomings of the studies, including inconsistencies in definitions of some of the risk factors, the use of antiplatelet therapies, and the stroke outcomes (ischemic strokes only, all strokes, strokes plus other systemic emboli, and strokes plus TIAs).
      The CHADS2 index
      • Gage B.F.
      • Waterman A.D.
      • Shannon W.
      • et al.
      Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation.
      (see Table 1 for the components of the acronym) assigns 1 point each for congestive heart failure, hypertension, age 75 years or older, and diabetes mellitus and 2 points for a history of stroke or TIA (Table 1). The scheme was validated and compared with 2 other schemes among 1733 Medicare beneficiaries aged 65 to 95 years who had been discharged from hospital with nonrheumatic AF and had not been prescribed warfarin. The CHADS2 index was the most accurate predictor of stroke, with the annual stroke rate increasing by about 2.0% for each 1-point increase in CHADS2 score (from 1.9% with a score of 0 to 18.2% with a score of 6). This scheme was also evaluated in comparison with several others among 2580 patients receiving aspirin in 6 prospective trials.
      • Gage B.F.
      • van Walraven C.
      • Pearce L.
      • et al.
      Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin.
      The CHADS2 index identified increments in stroke risk similar to those identified in the prior validation and was better than the other schema at discriminating medium- and high-risk patients. Although a recent systematic review
      Stroke Risk in Atrial Fibrillation Working Group
      Comparison of 12 risk stratification schemes to predict stroke in patients with nonvalvular atrial fibrillation.
      of 12 risk stratification schemes noted that none has been compared in a single cohort of adequate size and diversity, the CHADS2 index has appropriately become the favoured choice for determining risk of stroke and guiding choice of antithrombotic therapy.
      • Fuster V.
      • Rydén L.E.
      • Cannon A.S.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines.
      Table 1The CHADS2 score for estimating stroke risk in patients with atrial fibrillation according to the presence of major risk factors
      Data from Gage BF, et al.
      • Gage B.F.
      • Waterman A.D.
      • Shannon W.
      • et al.
      Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation.
      CHADS2 risk criteriaScore
      CCongestive heart failure1
      HHypertension1
      AAge >75 years1
      DDiabetes mellitus1
      S2(Prior) stroke or TIA2
      Adjusted stroke rate, %/y
      CHADS2 score(95% CI)
      01.9 (1.2-3.0)
      12.8 (2.0-3.8)
      24.0 (3.1-5.1)
      35.9 (4.6-7.3)
      48.5 (6.3-11.1)
      512.5 (8.2-17.5)
      618.2 (10.5-27.4)
      The European Society of Cardiology (ESC) has recently updated its guidelines for the management of AF
      • Camm A.J.
      • Kirchof P.
      • Lip G.Y.H.
      • et al.
      Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC)
      Guidelines for the management of atrial fibrillation.
      and has incorporated the new Birmingham 2009 schema (known by the acronym CHA2DS2-VASc) for the prediction of stroke risk.
      • Lip G.Y.H.
      • Nieuwlaat R.
      • Pisters R.
      • Lane D.R.
      • Crijns H.J.G.M.
      Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on Atrial Fibrillation.
      The schema was validated and compared with standard criteria in a subset of 1577 patients documented in the Euro Heart Survey on AF population. The schema is similar to the CHADS2, but gives 2 points for age of 75 years or older and 1 point for age between 65 and 74 years, 1 point for vascular disease (prior myocardial infarction, peripheral artery disease, or aortic plaque), and 1 point for female sex. The ESC recommends that the widely used and easily remembered CHADS2 be applied first; only if the score is under 2 should the new schema be applied to further grade risk of stroke in patients at low risk. The degree of risk can be refined, and if any of the additional risk factors embodied in the CHA2DS2-VASc are present, the score will be increased and may influence the physician to choose more potent antithrombotic management. Conversely, if the score remains at 0, the patient is clearly at very low risk of stroke and may not require any antithrombotic agent. The ESC recommends that a patient with a score of 0 according to the CHA2DS2-VASc schema should receive either aspirin or no antithrombotic therapy, with the latter preferred; a patient with a score of 1 should receive either aspirin or OAC, with the latter preferred; and a patient with a score of 2 should receive OAC. This new schema may eventually be useful for patient management, but for the present, the CCS recommends ongoing use of the CHADS2 schema.

      Paroxysmal AF

      The Stroke Prevention in Atrial Fibrillation (SPAF) trial
      Stroke Prevention in Atrial Fibrillation Investigators
      Stroke Prevention in Atrial Fibrillation study: final results.
      found similar annual rates of ischemic stroke in patients with “recurrent” (3.2%) and “chronic” (3.3%) AF. A report from the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events-Warfarin (ACTIVE-W), based on 1202 patients with paroxysmal AF and 5495 with persistent or permanent AF, confirmed similar rates of thromboembolic events.
      • Hohnloser S.H.
      • Pajitnev D.
      • Pogue J.
      • et al.
      Incidence of stroke in paroxysmal versus sustained atrial fibrillation in patients taking oral anticaogulation or combined antiplatelet therapy: an ACTIVE W substudy.
      However, it is possible that the risk of stroke is less in patients whose episodes of AF are brief (<1 day) and self-terminating.
      • Hart R.G.
      • Pearce L.A.
      • Rothbart R.M.
      • et al.
      Stroke Prevention in Atrial Fibrillation Investigators
      Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy.
      The short-term risk of stroke appears to be higher in patients with recent-onset AF than in those with AF that first occurred more than 1 to 2 years ago.
      • Petersen P.
      • Godtfredsen J.
      Embolic complications in paroxysmal atrial fibrillation.
      • Wolf P.A.
      • Kannel W.B.
      • McGee D.L.
      • et al.
      Duration of atrial fibrillation and eminence of stroke: the Framingham Study.
      Among AF patients with prior stroke, the annual recurrence rate is about 12% without antithrombotic treatment.
      Atrial Fibrillation Investigators
      Risk factors for stroke and efficiency of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials.
      EAFT (European Atrial Fibrillation Trial) Study Group
      Secondary prevention in non-rheumatic atrial fibrillation after transient ischemic attack or minor stroke.
      Several case series reported recurrence rates of 0.1% to 1.3% per day during the first 2 weeks following a cardioembolic stroke.
      • Saxena R.
      • Lewis S.
      • Berge E.
      • Sandercock P.A.G.
      • Koustaal P.J.
      International Stroke Trial Collaborative Group
      Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the International Stroke Trial.

      Thyrotoxicosis and hypertrophic cardiomyopathy

      The risk of stroke in patients with thyrotoxic AF is substantial, although the mechanism and the relative role of congestive heart failure are uncertain. The risk of stroke is also substantial among patients with hypertrophic cardiomyopathy and AF. These risks have not been rigourously evaluated, and antithrombotic therapies for patients with AF and thyrotoxicosis or hypertrophic cardiomyopathy should be based on the presence of validated stroke risk factors.
      • Singer D.E.
      • Albers G.W.
      • Dalen J.E.
      • et al.
      Antithrombotic therapy in atrial fibrillation.
      • Fuster V.
      • Rydén L.E.
      • Cannon A.S.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines.
      • Camm A.J.
      • Kirchof P.
      • Lip G.Y.H.
      • et al.
      Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC)
      Guidelines for the management of atrial fibrillation.

      Atrial flutter

      There is a widespread perception that the risk of stroke is less with atrial flutter than with AF. However, a retrospective analysis of a large database of elderly hospitalized patients found little difference in the risk ratios for atrial flutter (1.4) and AF (1.6).
      • Biblo L.A.
      • Yuan Z.
      • Quan K.J.
      • Mackall J.A.
      • Rimm A.A.
      Risk of stroke in patients with atrial flutter.
      By 8 years of follow-up, more than half the patients with atrial flutter had developed AF, and these patients were more likely to experience a stroke. The development of AF was more likely among patients with congestive heart failure, rheumatic heart disease, hypertension, and diabetes mellitus.

      Trials of Antithrombotic Therapies

      Oral vitamin K antagonists and antiplatelet agents

      An overview
      Atrial Fibrillation Investigators
      Risk factors for stroke and efficiency of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials.
      of the initial 5 randomized trials of oral vitamin K antagonists compared with no treatment found the incidence of ischemic stroke was reduced from 4.5% per year to 1.4% per year (relative risk reduction [RRR] 68%; 95% CI, 50%-79%; P < .001). The rate of major hemorrhage with vitamin K antagonists was 1.3% per year vs 1% per year in controls. The most recent meta-analysis of such trials
      • Hart R.G.
      • Pearce L.A.
      • Aguilare M.I.
      Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation.
      included 1 additional trial (of secondary prevention of stroke) and calculated an RRR of 64% (95% CI, 49% to 74%) for the more clinically meaningful outcome of all stroke (ischemic or hemorrhagic; Fig. 1). The absolute risk reduction (ARR) was 2.7% per year in primary prevention trials and 8.4% per year in the only secondary prevention trial. There was an excess of 0.3% per year (P = not significant) of major extracranial hemorrhage with vitamin K antagonist therapy but a statistically significant ARR of mortality of about 1.6% per year.
      Figure thumbnail gr1
      Figure 1Randomized controlled trials (RCTs) of adjusted-dose warfarin (or other vitamin K antagonist in a small proportion of patients) vs placebo or no treatment. Point estimates of the relative risk reductions of stroke (ischemic plus hemorrhagic) with their associated 95% CIs are depicted for 5 trials of primary prevention and 1 of secondary prevention. The overall relative risk reduction is 64% (95% CI, 49%-74%). AFASAK, Atrial Fibrillation, ASpirin, AntiKoagulation; SPAF, Stroke Prevention in Atrial Fibrillation; BAATAF, Boston Area Anticoagulation Trial for Atrial Fibrillation; CAFA, Canadian Atrial Fibrillation; SPINAF, Stroke Prevention in Nonrheumatic Atrial Fibrillation; EAFT, European Atrial Fibrillation Trial.
      Reprinted from Hart RG et al
      • Hart R.G.
      • Pearce L.A.
      • Aguilare M.I.
      Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation.
      with permission from Ann Intern Med.
      The overview included trials of aspirin vs no treatment
      • Hart R.G.
      • Pearce L.A.
      • Aguilare M.I.
      Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation.
      and reported an RRR for all stroke of 19% (95% CI, 1% to 35%; Fig. 2), with an ARR of 0.8% per year in primary prevention trials and 2.5% per year in secondary prevention trials. There were no significant differences in major extracranial hemorrhage or mortality. An update of this overview
      • Hart R.G.
      • Pearce L.A.
      • Aguilar M.I.
      Adjusted-dose warfarin versus aspirin for preventing stroke in patients with atrial fibrillation.
      assessed trials of vitamin K antagonists vs aspirin and reported an RRR for all stroke of 39% (95% CI, 19%-53%) in favour of vitamin K antagonists (Fig. 3), equivalent to an ARR of about 0.9% per year for primary prevention and 7% per year for secondary prevention. There were no significant differences in major extracranial hemorrhage or mortality. The inclusion of 3 further trials comparing vitamin K antagonists with other antiplatelet agents did not importantly alter the findings.
      Figure thumbnail gr2
      Figure 2Randomized controlled trials (RCTs) of aspirin vs placebo or no treatment. Point estimates of the relative risk reductions of stroke (ischemic plus hemorrhagic) with their associated 95% CIs are depicted for 4 trials of primary prevention and 3 of secondary prevention. The overall relative risk reduction is 19% (95% CI, −1% to 35%). AFASAK, Atrial Fibrillation, ASpirin, AntiKoagulation; SPAF, Stroke Prevention in Atrial Fibrillation; EAFT, European Atrial Fibrillation Trial; ESPS, European Stroke Prevention Study; LASAF, Low-dose Aspirin, Stroke, Atrial Fibrillation; UK-TIA, United Kingdom Transient Ischemic Attack; JAST, Japan Atrial fibrillation Stroke Trial.
      Reprinted from Hart RG et al
      • Hart R.G.
      • Pearce L.A.
      • Aguilare M.I.
      Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation.
      with permission from Ann Intern Med.
      Figure thumbnail gr3
      Figure 3Randomized trials of adjusted-dose warfarin (or other vitamin K antagonist in a small proportion of patients) vs aspirin. Point estimates of the relative risk reductions of stroke (ischemic or hemorrhagic) with their associated 95% CIs are depicted for 7 trials of primary prevention and 1 of secondary prevention. The overall relative risk reduction is 39% (95% CI, 19%-53%). AFASAK, Atrial Fibrillation, ASpirin, AntiKoagulation; BAFTA, Birmingham Atrial Fibrillation Treatment of the Aged; Chinese ATAFS, Chinese Antithrombotic Therapy in Atrial Fibrillation; EAFT, European Atrial Fibrillation Trial; PATAF, Prevention of Arterial Thromboembolism in Atrial Fibrillation; SPAF, Stroke Prevention in Atrial Fibrillation.
      Reprinted from Hart RG et al
      • Hart R.G.
      • Pearce L.A.
      • Aguilar M.I.
      Adjusted-dose warfarin versus aspirin for preventing stroke in patients with atrial fibrillation.
      with permission from Ann Intern Med.
      Warfarin adjusted to an international normalized ratio (INR) of 2 to 3 has been compared with various regimens of lower-dose warfarin plus aspirin
      Stroke Prevention in Atrial Fibrillation Investigators
      Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study.
      and to warfarin at lower intensity and low fixed dose,
      • Gullov A.L.
      • Koefoed B.G.
      • Petersen P.
      • et al.
      Fixed minidose warfarin and aspirin alone and in combination vs. adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study.
      • Pengo V.
      • Zasso A.
      • Barbero F.
      • et al.
      Effectiveness of fixed minidose warfarin in the prevention of thromboembolism and vascular death in nonrheumatic atrial fibrillation.
      • Hellemons B.S.
      • Langenberg M.
      • Lodder J.
      • et al.
      Primary prevention of arterial thromboembolism in non-rheumatic atrial fibrillation in primary care: randomized controlled trial comparing two intensities of coumarin with aspirin.
      but none of these regimens was as effective. It had been expected that in patients suitable for warfarin therapy, the combination of aspirin plus clopidogrel might be noninferior to warfarin for the prevention of stroke, while offering the advantages of less bleeding and greater convenience. However, the ACTIVE-W trial
      • Connolly S.
      • Pogue J.
      • Hart R.
      • et al.
      ACTIVE Writing Group of the ACTIVE Investigators
      Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomized controlled trial.
      found the RR for the composite outcome of stroke, non–central nervous system embolus, myocardial infarction, and vascular death was 1.44 (95% CI, 1.18-1.76; P = .0003) for the combination of clopidogrel plus aspirin (75 mg and 75-100 mg/d) vs warfarin (INR 2-3). Somewhat surprisingly, the RR for major bleeding was 1.10 (95% CI, 0.83-1.45) with the combination.
      It had also been expected that in patients not suitable for warfarin therapy, the combination of aspirin and clopidogrel might be more effective than aspirin alone. The ACTIVE-A trial
      ACTIVE Investigators
      Effect of clopidogrel added to aspirin in patients with atrial fibrillation.
      did find that after a mean of 3.6 years, the risk of major vascular events was reduced by the combination (RR 0.89; 95% CI, 0.81-0.98; P = .01). However, major bleeding was increased by the combination (2.0% vs 1.3% per year; RR 1.57; 95% CI, 1.29-1.92; P < .01).

      New non–vitamin-K-antagonist anticoagulants

      Ximelagatran is an oral direct thrombin inhibitor with predictable and stable pharmacokinetics and relatively low potential for interactions with other drugs and with foods. Coagulation monitoring and dose adjustments are not required. This agent was evaluated in 2 large trials employing noninferiority designs.
      Executive Steering Committee on behalf of the SPORTIF III Investigators
      Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin for the prevention of thromboembolism in patients with nonvalvular atrial fibrillation (SPORTIF III); a randomized trial.
      SPORTIF Executive Steering Committee for the SPORTIF V Investigators
      Ximelagatran vs. warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial.
      In both, it was concluded that ximelagatran was noninferior to warfarin. The incidence of major bleeding was similar with the 2 agents, but all bleeding was significantly less with ximelagatran. However, both studies found a 6-fold excess of patients with elevations of alanine aminotransferase to greater than 3 times the upper limit of normal, usually within the first 6 months. The Food and Drug Administration did not approve the new agent, having concluded that the more convenient dose and monitoring regimens and less total bleeding did not outweigh concerns about hepatic toxicity and the inappropriately large noninferiority margins.
      Dabigatran is an oral direct thrombin inhibitor that is licensed for use in Canada and the United States. It was compared with warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial,
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      in which 18,113 patients with AF (mean CHADS2= 2.1) were randomized to dabigatran 110 mg twice daily, dabigatran 150 mg twice daily, or warfarin (INR 2-3) and followed for a median of 2.0 years. The mean time in the therapeutic range for warfarin was 64%. Rates of discontinuation of therapy by 2 years were 16.6% for warfarin, 20.7% for dabigatran 110 mg, and 21.2% for dabigatran 150 mg. Approximately 20% of subjects were taking aspirin in addition to their study drug. The rates of the principal outcome of all stroke (ischemic or hemorrhagic) or non–central nervous system embolus were 1.69% per year with warfarin, 1.53% per year with dabigatran 110 mg (RR 0.91; 95% CI, 0.74-1.11; P < .001 for noninferiority), and 1.11% per year with dabigatran 150 mg (RR 0.66; 95% CI, 0.53-0.82; P < .001 for superiority; Fig. 4). The RR of stroke or systemic embolus for dabigatran 150 mg vs 110 mg was 0.73 (95% CI, 0.58-0.91; P = .005). The rates of major bleeding were 3.36% per year with warfarin, 2.71% per year with dabigatran 110 mg (RR vs warfarin 0.8, P = .003), and 3.11% per year with dabigatran 150 mg (RR vs warfarin 0.93, P = .31 and RR vs dabigatran 110 mg 1.16, P = .052). The rates of the net clinical benefit outcome (a composite of stroke, systemic embolism, pulmonary embolism, myocardial infarction, death, or major bleeding) were 7.64% per year with warfarin, 7.09% per year with dabigatran 110 mg (RR vs warfarin 0.92; 95% CI, 0.84-1.02), and 6.91% per year with dabigatran 150 mg (RR vs warfarin 0.91; 95% CI, 0.82-1.00). Hence, in this group of patients with clear indications for warfarin therapy, dabigatran 110 mg twice daily was associated with rates of stroke and systemic embolism similar to those associated with warfarin, but with a rate of major hemorrhage that was lower. Compared with warfarin, dabigatran 150 mg twice daily was associated with lower rates of stroke and systemic embolism and a similar rate of major hemorrhage. Compared with dabigatran 110 mg, the 150-mg dose was associated with lower rates of stroke and systemic embolus but a strong trend toward more major hemorrhage.
      Figure thumbnail gr4
      Figure 4Cumulative hazard rates (y-axis) vs time in years (x-axis) for the primary outcome of stroke (ischemic or hemorrhagic) or systemic embolism, according to treatment group (dabigatran 150 mg twice daily, dabigatran 110 mg twice daily, or warfarin [INR 2-3]). RR, relative risk.
      Reprinted from Connolly SJ, et al
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      with permission from N Engl J Med, © Massachusetts Medical Society.
      The data for the comparative beneficial and harmful effects of dabigatran vs warfarin among patients with AF are derived only from RE-LY and a relatively small pilot study (Prevention of Embolic and ThROmbotic events in patients with persistent atrial fibrillation).
      • Ezekowitz M.D.
      • Reilly P.A.
      • Nehmiz G.
      • et al.
      Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study).
      However, RE-LY enrolled over 18,000 patients. The recommendations made by previous national guidelines exercises have been based on a total of 2900 patients in the randomized trials of warfarin vs control, 3990 patients in the trials of aspirin vs control, and 3647 patients in the trials of warfarin vs aspirin. The results of RE-LY and studies of other newer anticoagulants, as they are published, must be taken into account in all subsequent guidelines exercises.
      Although dabigatran 110 mg twice daily was found to be as effective as warfarin and caused less major bleeding, and dabigatran 150 mg twice daily was found to be more effective than warfarin and with a similar risk of major bleeding, additional considerations are necessary in arriving at sensible recommendations for use. The subjects all had at least 1 risk factor for stroke (mean CHADS2 was 2.0), and patients with CrCl <30 mL per minute and any condition that increased the risk of bleeding were excluded. Dyspepsia was twice as common in the dabigatran groups, gastrointestinal bleeding was more common, and patients receiving dabigatran discontinued study therapy almost 50% more often in the first year of therapy than did those receiving warfarin. Although there was a trend to a reduction of the composite clinical outcome in the dabigatran groups, there was a trend to more frequent myocardial infarction with dabigatran, which was significant at the 150-mg dose. There was no hint of greater hepatic toxicity with dabigatran than with warfarin, but the total clinical experience extends to only a mean of 2 years, and careful long-term follow-up data are needed. Dabigatran tablets are much more costly than warfarin, but rigourous cost-effectiveness analyses will be needed to assess total costs.
      We recommend that when an OAC is indicated for stroke prevention, most patients should receive dabigatran in preference to warfarin. Possible exceptions would include patients with a propensity to dyspepsia, gastrointestinal bleeding, or both and those at substantial risk of coronary events (see more detailed discussion under the heading Coronary Artery Disease). The dose of 150 mg twice a day is preferable to 110 mg twice a day, except in patients of low body weight, decreased renal function, or at increased risk of major bleeding.
      Idraparinux is a specific inhibitor of activated factor X, which may be given in a fixed, weekly subcutaneous injection without coagulation monitoring. This agent was compared with vitamin K antagonists (INR 2-3) in the AMADEUS trial of 4576 patients.
      Amadeus Investigators
      Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomised, open-label, non-inferiority trial.
      The trial was stopped early because of excess clinically relevant bleeding with idraparinux (19.7% vs 11.3% per year, P < .0001), at which point idraparinux was noninferior for the principal outcome of all stroke or systemic embolism (hazard ratio 0.71; 95% CI, 0.39-1.30; P = .007). Elderly patients and those with renal insufficiency were more at risk of excess bleeding, but clearly at the dose regimen tested, idraparinux would not be a suitable alternative to vitamin K antagonist therapy in AF patients.
      There are several available oral, direct-acting factor Xa inhibitor drugs that have proven effective and safe in studies of deep venous thrombosis and offer promise in the setting of AF. In the Apixaban Versus ASA to Reduce the Rate Of Embolic Stroke (AVERROES) trial,
      A phase III study of apixaban in patients with atrial fibrillation (AVERROES).
      apixaban (5 mg twice a day) was compared with aspirin (81-324 mg daily) among patients with AF at more than very low risk of stroke in whom vitamin K antagonist therapy was unsuitable. The trial was terminated for early efficacy in 2010. In the Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation (ARISTOTLE) trial,
      Apixaban for the prevention of stroke in subjects with atrial fibrillation (ARISTOTLE).
      apixaban (5 mg twice a day) is being compared with warfarin (INR 2.5) among patients at somewhat higher risk of stroke. The expected enrollment is 15,000 patients, with completion in 2010. In the Rivaroxaban Once daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial,
      Randomized, double-blind study comparing once daily oral rivaroxaban with adjusted-dose oral warfarin for the prevention of stroke in subjects with non-valvular atrial fibrillation.
      which enrolled over 14,000 patients, rivaroxaban (20 mg/d) was compared to warfarin (INR 2.5) among patients with AF at risk of stroke and suitable for warfarin therapy. Rivaroxiban was noninferior to warfarin for the principal outcome of all stroke or systemic embolus.

      Atrial flutter

      Although there are no rigourous prospective data on the incidence of stroke among patients with atrial flutter, nor are there randomized trials of the value of anticoagulation, it is generally recommended that patients with atrial flutter be risk stratified and treated in the same manner as patients with AF.
      • Singer D.E.
      • Albers G.W.
      • Dalen J.E.
      • et al.
      Antithrombotic therapy in atrial fibrillation.
      • Fuster V.
      • Rydén L.E.
      • Cannon A.S.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines.

      Risk of Hemorrhage

      The efficacy of any antithrombotic therapy for the prevention of ischemic stroke must be balanced against the risk of major hemorrhage, particularly cerebral hemorrhage, which is often fatal. In each of the initial randomized trials of antithrombotic therapies, the principal outcome was the composite of ischemic stroke or systemic embolus. Although hemorrhage and the subsets of intracranial and intracerebral hemorrhage were generally reported, the net benefit for major clinical outcomes was not always clear. More recent trials and overviews have focused on the principal outcome of all stroke (ischemic plus hemorrhagic) or systemic embolus, a more meaningful outcome for patients and treating physicians. The incidence of extracranial major hemorrhage (usually without long-term sequellae among survivors) can be subjectively compared to the reduced incidence of all stroke in order to reach conclusions about the net patient benefits of antithrombotic therapies.
      The risk of hemorrhage depends on the specific antithrombotic agent (including dose and monitoring) and on a variety of patient characteristics. The risks of hemorrhage are lowest with either aspirin (75-325 mg/d) or clopidogrel (75 mg/d) alone, higher when they are combined, higher still with dabigatran 110 mg twice a day, and highest with dabigatran 150 mg per day and vitamin K antagonists, which carry similar risks. When vitamin K antagonists are used, the bleeding risk depends on the INR, the quality of monitoring, the duration of therapy (the risk is higher during the initial few weeks of therapy), and the stability of dietary and other factors that may alter the INR at a given dose of the chosen agent. The risk of bleeding is likely to be higher in common clinical practice than in the rigourous setting of a clinical trial or a dedicated, expert anticoagulation service.
      For most patients who are candidates for warfarin, an INR range of 2.0 to 3.0 with a target of 2.5 appears optimal.
      • Singer D.E.
      • Albers G.W.
      • Dalen J.E.
      • et al.
      Antithrombotic therapy in atrial fibrillation.
      • Fuster V.
      • Rydén L.E.
      • Cannon A.S.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines.
      In a large cohort of patients, the risk of ischemic stroke, severity of stroke, and mortality rose sharply when INR fell to 1.5 to 1.9, but the risk of intracranial hemorrhage did not rise until INR values exceeded 3.9.
      • Hylek E.M.
      • Go A.S.
      • Chang Y.
      • et al.
      Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation.
      A recent meta-analysis
      • Oake N.
      • Fergusson D.A.
      • Forster A.J.
      • van Walraven C.
      Frequency of adverse events in patients with poor anticoagulation: a meta-analysis.
      of studies that assigned hemorrhagic and thromboembolic events in patients taking anticoagulants to discrete INR ranges found that 44% of hemorrhages occurred when INRs were above the therapeutic range, 48% of thromboembolic events took place when INRs were below it, and the mean proportion of events that occurred when the patient's INR was outside the therapeutic range was higher in the studies of shorter follow-up. Patients with a previous TIA or minor stroke may benefit from a somewhat higher INR of 2.0 to 3.5, with a target of 3.0.
      • Fuster V.
      • Rydén L.E.
      • Cannon A.S.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines.
      • Camm A.J.
      • Kirchof P.
      • Lip G.Y.H.
      • et al.
      Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC)
      Guidelines for the management of atrial fibrillation.
      European Atrial Fibrillation Trial Study Group
      Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia.
      Patients at higher risk of cerebral hemorrhage, particularly those older than 75 years, may benefit from a somewhat lower INR range of 1.6 to 2.5, with a target of 2.0,
      • Fuster V.
      • Rydén L.E.
      • Cannon A.S.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines.
      although protection against ischemic stroke drops off sharply when INRs fall below this target.
      The HEMORR2HAGES scheme
      • Gage B.F.
      • Yan Y.
      • Milligan P.E.
      • et al.
      Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF).
      was developed from 3 previously published prediction rules, a recent systematic review, and a formal literature search. The scheme allotted 2 points for a previously documented episode of bleeding and 1 point each for hepatic or renal disease, ethanol abuse, malignancy, age >75 years, reduced platelet count or function, rebleeding risk, hypertension (uncontrolled), anemia, genetic factors (CYP 2C19 SNPs), excessive falls (including neuropsychiatric disease), and stroke. When compared with the 3 earlier prediction rules in a population of elderly patients with AF
      • Gage B.F.
      • Yan Y.
      • Milligan P.E.
      • et al.
      Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF).
      who were receiving warfarin, aspirin, or no antithrombotic therapy, the new scheme provided good discrimination among patients with an annual risk of hospitalization for hemorrhage while receiving warfarin, which ranged from 1.9% to 12.3%.
      The new ESC guidelines for management of AF
      • Pisters R.
      • Lane D.A.
      • Nieuwlaat R.
      • et al.
      A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.
      suggest the use of a new schema for the prediction of bleeding risk (Table 2). It is based on the presence of hypertension, abnormal liver or renal function, history of stroke or bleeding, labile INRs, elderly age (>65 years), and concomitant use of drugs that promote bleeding or excess alcohol use (HAS-BLED is the acronym)
      • Pisters R.
      • Lane D.A.
      • Nieuwlaat R.
      • et al.
      A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.
      and was derived from the Euro Heart Survey on AF. The proposed schema relies on fewer and more readily obtained risk factors than earlier schemata do and performs at least as well as the HEMOR2RHAGES schema in the prediction of bleeding events. Documentation of a HAS-BLED score allows the clinician to assign the patient a risk of major bleeding ranging from about 1% (score 0-1) to 12.5% (score 5) and can be useful in decisions about the relative risks of stroke vs major bleeding with various antithrombotic therapies. Patients at high risk of major bleeding warrant caution in the use of antithrombotic therapies and closer monitoring and follow-up. We suggest the use of this new schema as a simpler alternative to the HEMOR2RHAGES schema.
      Table 2The HAS-BLED score for estimating the risk of major bleeding among AF patients
      Data from Pisters R, et al.
      • Pisters R.
      • Lane D.A.
      • Nieuwlaat R.
      • et al.
      A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.
      Clinical characteristicScore
      Hypertension1
      Abnormal renal or liver function (1 point each)1 or 2
      Stroke1
      Bleeding1
      Labile INRs1
      Elderly (eg, age >65 yr)1
      Drugs or alcohol (1 point each)1 or 2
      Risk factor scoreMajor bleeds (%/y)
      01.13
      11.02
      21.88
      33.74
      48.70
      512.50
      We recommend that all patients with AF or AFL (paroxysmal, persistent, or permanent) should be stratified using a predictive index for stroke (eg, CHADS2) and for the risk of bleeding (eg, HAS-BLED) and that most patients should receive antithrombotic therapy (Strong Recommendation, High-Quality Evidence).
      We recommend that patients at very low risk of stroke (CHADS2 = 0) should receive aspirin (75-325 mg/d) (Strong Recommendation, High-Quality Evidence).
      We recommend that patients at low risk of stroke (CHADS2 = 1) should receive OAC therapy (either warfarin [INR 2 to 3] or Dabigatran) (Strong Recommendation, High-Quality Evidence). We suggest, based on individual risk-benefit considerations, that aspirin is a reasonable alternative for some (Conditional Recommendation, Moderate-Quality Evidence).

      Values and preferences

      This recommendation places relatively greater weight on the absolute reduction of stroke risk with both warfarin and dabigatran compared with aspirin and less weight on the absolute increased risk for major hemorrhage with an OAC compared with aspirin.
      We recommend that patients at moderate risk of stroke (CHADS2 ≥2 should receive OAC therapy (either warfarin [INR 2-3] or Dabigatran) (Strong Recommendation, High-Quality Evidence).
      We suggest that when OAC therapy is indicated, most patients should receive dabigatran in preference to warfarin. In general, the dose of dabigatran 150 mg by mouth twice a day is preferable to a dose of 110 mg by mouth twice a day (exceptions discussed in text) (Conditional Recommendation, High-Quality Evidence).

      Values and preferences

      This recommendation places a relatively high value on the greater efficacy of dabigatran during a relatively short time of follow-up, particularly among patients who have not previously received an OAC; the lower incidence of intracranial hemorrhage; and its ease of use—and less value on the long safety experience with warfarin.
      Figure 5 is a flow chart outlining our recommendations for the choice of antithrombotic therapy.
      Figure thumbnail gr5
      Figure 5A summary of our recommendations for thromboembolic management guided by the CHADS2 score. See Table 1, Table 2 for definitions of CHADS2 and HAS-BLED. OAC, oral anticoagulant.
      Recent practice guidelines
      • Singer D.E.
      • Albers G.W.
      • Dalen J.E.
      • et al.
      Antithrombotic therapy in atrial fibrillation.
      • Fuster V.
      • Rydén L.E.
      • Cannon A.S.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines.
      stress the importance of appropriate antithrombotic therapy for AF, and yet practice surveys indicate that rates of compliance range from rather low
      • Waldo A.L.
      • Becker R.C.
      • Tapson V.F.
      • Colgan K.J.
      Hospitalized patients with atrial fibrillation and a high risk of stroke are not being provided with adequate anticoagulation.
      • Rowan S.B.
      • Bailey D.N.
      • Bublitz C.E.
      • Anderson R.J.
      Trends in anticoagulation for atrial fibrillation in the U.S.: an analysis of the national ambulatory medical care survey database.
      • Glazer N.L.
      • Dublin S.
      • Smith N.L.
      • et al.
      Newly detected atrial fibrillation and compliance with antithrombotic guidelines.
      • Simpson S.R.
      • Wilson C.
      • Hannaford P.C.
      • Williams D.
      Evidence for age and sex differences in the secondary prevention of stroke in Scottish primary care.
      • Hylek E.M.
      • D'Antonio J.
      • Evans-Molina C.
      • et al.
      Translating the results of randomized trials into clinical practice: the challenge of warfarin candidacy among hospitalized elderly patients with atrial fibrillation.
      to reasonably high.
      • Nieuwlaat R.
      • Capucci A.
      • Lip G.Y.H.
      • et al.
      Antithrombotic treatment in real-life atrial fibrillation patients: a report from the Euro Heart Survey on Atrial Fibrillation.

      Selected Clinical Settings

      Elderly patients

      Advanced age (>75 years) has been consistently noted as a risk factor for both ischemic stroke and major hemorrhage, particularly intracranial. Hylek et al
      • Hylek E.M.
      • Evans-Molina C.
      • Shea C.
      • Henault L.E.
      • Regan S.
      Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation.
      reported a series of 472 patients aged ≥65 years (153 patients aged ≥80 years), with electrocardiogram-verified AF, newly started on warfarin at the study institution, and managed by the on-site anticoagulation clinic. Anticoagulation control was very good, with 56% of person-time within the INR range of 2.0 to 3.0, 29% below 2.0, 11% within 3.0 to <4.0, and only 2% ≥4.0. Even within this optimized setting, the rate of major hemorrhage (100% follow-up) was 7.2 per 100 patient-years (intracranial hemorrhage 2.5 per 100 patient-years). The incidence of major hemorrhage was 13.1% for patients aged ≥80 years vs 4.75% for those <80 years. The risk during the first 90 days of therapy was 3 times that of the remainder of the year. The risk of major hemorrhage was increased 20 times among patients with an INR > 4.0. Most of the intracranial bleeds occurred in patients aged ≥75 years. The rate of major hemorrhage was higher in patients with higher CHADS2 scores. In contrast, the Birmingham Atrial Fibrillation Treatment of the Aged study
      • Mant J.
      • Hobbs R.
      • Roalfe A.
      • et al.
      BAFTA investigators
      Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomized controlled trial.
      found that in patients aged >75 years, warfarin was more efficacious than aspirin in preventing all strokes (ischemic plus hemorrhagic) and did not cause more major extracranial hemorrhage (1.4% per year with warfarin vs 1.6% per year with aspirin). The lower bleeding risk may be attributable to more restrictive patient selection for a clinical trial than for the Hylek survey and to the fact that 40% of them had been taking warfarin safely prior to entering the trial. A more recent cohort study found an annual incidence of major extracranial bleeding of 1.3% with careful INR management.
      • Poli D.
      • Antonucci E.
      • Grifoni E.
      • et al.
      Bleeding risk during oral anticoagulation in patients older than 80 years.
      These observations point to the challenges in choosing the optimal antithrombotic therapy for very elderly patients in order to ensure a favourable risk-benefit ratio.
      • Wyse D.G.
      Bleeding while starting anticoagulation for thromboembolism prophylaxis in elderly patients with atrial fibrillation.
      For those with no stroke risk factors other than age ≥75 years, some guidelines have recommended consideration of aspirin in preference to warfarin.
      • Fuster V.
      • Rydén L.E.
      • Cannon A.S.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines.
      Nevertheless, ischemic stroke, with its dire consequences, is relatively frequent, and the competing risk of intracranial hemorrhage with warfarin may be acceptable. If warfarin is to be used, great care must be taken to rigourously maintain the selected therapeutic INR with frequent monitoring in the first 3 months and more often than the “standard” monthly interval subsequently.

      Cardioversion

      Although the randomized trials have shown no improvement in major outcomes, including thromboembolism, with a rhythm control strategy vs rate control, individual patients may gain symptomatic benefit and even long-term freedom from AF after electrical or pharmacologic cardioversion. The strongest predictor of initial and persistent success with cardioversion is short duration of the AF before cardioversion. In general, it may be expected that AF occurring in conjunction with surgery (see accompanying article titled “Prevention and Treatment of Atrial Fibrillation Following Cardiac Surgery”
      • Mitchell L.B.
      CCS Atrial Fibrillation Guidelines Committee
      Canadian Cardiovascular Society Atrial Fibrillation Guidelines 2010: prevention and treatment of atrial fibrillation following cardiac surgery.
      ), viral illness, alcohol excess, or in association with thyrotoxicosis or pulmonary embolus has a high likelihood of reversion with persistence of sinus rhythm if there has been resolution of the precipitating cause. Successful and sustained reversion to sinus rhythm is associated with relatively young age and freedom from underlying heart disease. Some patients have intolerable symptoms and poor exercise tolerance during AF and may prefer attempted rhythm control to rate control. The rate of initial success in restoring sinus rhythm is high, but in the contemporary Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, vigorous efforts to establish and sustain sinus rhythm resulted in prevalences of only 82.5%, 73.3%, and 62.6% at 1, 3, and 5 years, respectively.
      • Wyse D.G.
      • Waldo A.L.
      • DiMarco J.P.
      • et al.
      A comparison of rate control and rhythm control in patients with atrial fibrillation.

      Stroke risk with cardioversion

      Cardioversion is appropriate for selected patients with AF or AFL,
      • Mitchell L.B.
      CCS Atrial Fibrillation Guidelines Committee
      Canadian Cardiovascular Society Atrial Fibrillation Guidelines 2010: prevention and treatment of atrial fibrillation following cardiac surgery.
      • Wyse D.G.
      • Waldo A.L.
      • DiMarco J.P.
      • et al.
      A comparison of rate control and rhythm control in patients with atrial fibrillation.
      necessitating consideration of the possibility of associated thromboembolism. A well-designed prospective cohort study reported a reduction of postcardioversion systemic embolism of from 5.3% to 0.8% among anticoagulated patients.
      • Bjerkelund C.J.
      • Orning O.M.
      The efficacy of anticoagulant therapy in preventing embolism related to DC electrical conversion of atrial fibrillation.
      These observations have been supported by several published case series.
      • Fuster V.
      • Rydén L.E.
      • Cannon A.S.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines.
      Two more-recent studies reported remarkably similar incidences of cerebral embolization among patients receiving OAC in the setting of electrical cardioversion.
      • Klein A.L.
      • Grimm R.A.
      • Murray R.D.
      • et al.
      Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation.
      • Seidel K.
      • Ramekaen M.
      • Drogemuller A.
      • et al.
      Embolic events in patients with atrial fibrillation and effective anticoagulation: value of transesophageal echocardiography to guide direct-current cardioversion: final results of the Ludwigschafen Observational Cardioversion Study.
      It is generally believed that a newly formed thrombus will become organized and adherent to the left atrial wall within 2 weeks of formation. Transesophageal echocardiography (TEE) reveals that in the majority of patients, thrombus resolves, rather than simply becoming firmly adherent to the wall of the left atrium or left atrial appendage.
      • Collins L.J.
      • Silverman D.I.
      • Douglas P.S.
      • Manning W.J.
      Cardioversion of nonrheumatic atrial fibrillation: reduced thromboembolic complications with 4 weeks of precardioversion anticoagulation are related to atrial thrombus resolution.
      Accordingly, it is generally recommended that documented systemic anticoagulation at therapeutic levels be instituted at least 3 weeks before cardioversion.
      • Singer D.E.
      • Albers G.W.
      • Dalen J.E.
      • et al.
      Antithrombotic therapy in atrial fibrillation.
      • Fuster V.
      • Rydén L.E.
      • Cannon A.S.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines.
      An analysis that pooled data from 32 studies found that 98% of thromboembolic events occurred within 10 days of cardioversion of AF or flutter.
      • Berger M.
      • Schweitzer P.
      Timing of thromboembolic events after electrical cardioversion of atrial fibrillation or flutter: a retrospective analysis.
      However, evidence exists that even after successful electrical cardioversion, atrial contraction may not normalize for weeks when AF has been present for some time,
      • Manning W.J.
      • Silverman D.I.
      • Keightly C.S.
      • et al.
      Transesophageal echocardiographically facilitated early cardioversion from atrial fibrillation using short-term anticoagulation: final results of a prospective 4.5 year study.
      • Padraig G.O.
      • Puleo P.R.
      • Bolli R.
      • et al.
      Return of atrial mechanical function following electrical cardioversion of atrial dysrhythmias.
      and therefore maintenance of anticoagulation for at least 4 weeks after cardioversion seems prudent.
      • Singer D.E.
      • Albers G.W.
      • Dalen J.E.
      • et al.
      Antithrombotic therapy in atrial fibrillation.
      • Fuster V.
      • Rydén L.E.
      • Cannon A.S.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines.
      If AF or AFL persists or recurs after attempted cardioversion, or if symptoms suggest that the presenting AF or AFL has been recurrent, antithrombotic therapy should be continued indefinitely with either aspirin or OAC as appropriate. If normal sinus rhythm is achieved and sustained for 4 weeks, the need for ongoing antithrombotic therapy depends on the risk of stroke, and in difficult cases, the practitioner may require expert consultative advice. There is no evidence that the incidence of thromboembolism is less with pharmacologic than with electrical cardioversion,
      • Lown B.
      Electrical reversion of cardiac arrhythmias.
      • Goldman M.
      The management of chronic atrial fibrillation: indications and method of conversion to sinus rhythm.
      and accordingly, it is generally recommended that anticoagulant management should not differ.
      • Fuster V.
      • Rydén L.E.
      • Cannon A.S.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines.
      New-onset AF is generally not thought to warrant anticoagulation if cardioversion is undertaken within 48 hours of its onset, based on case series showing an incidence of thromboembolism <1%
      • Singer D.E.
      • Albers G.W.
      • Dalen J.E.
      • et al.
      Antithrombotic therapy in atrial fibrillation.
      • Fuster V.
      • Rydén L.E.
      • Cannon A.S.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines.
      • Weigner M.J.
      • Caulfield T.A.
      • Danias P.G.
      • et al.
      Risk for clinical thromboembolism associated with conversion to sinus rhythm in patients with atrial fibrillation lasting less than 48 hours.
      • Gallagher M.M.
      • Hennessy B.J.
      • Edvardsson N.
      • et al.
      Embolic complications of direct current cardioversion of atrial arrhythmias: association with low intensity of anticoagulation at the time of cardioversion.
      without OAC. Even when the duration of the current episode of AF is <48 hours, if the patient is at particularly high risk of stroke (eg, mechanical valve, rheumatic heart disease, recent stroke, or TIA), it would be appropriate to delay cardioversion to allow the patient to receive OAC for 3 weeks before the procedure and to continue indefinitely. Following attempted cardioversion, if AF persists or recurs or if symptoms suggest the presenting AF or AFL has been recurrent, antithrombotic therapy (OAC or aspirin) should be commenced and continued indefinitely. If normal sinus rhythm is achieved and sustained, the need for ongoing antithrombotic therapy depends on the risk of stroke. (See accompanying article titled “Management of Recent-Onset Atrial Fibrillation and Flutter in the Emergency Department.”
      • Stiell I.G.
      • Macle L.
      CCS Atrial Fibrillation Guidelines Committee
      Canadian Cardiovascular Society Atrial Fibrillation Guidelines 2010: management of recent-onset atrial fibrillation and flutter in the emergency department.
      )

      Atrial flutter

      Retrospective studies of patients with atrial flutter undergoing cardioversion suggest that the risk of thromboembolism may not be importantly different from that for patients with AF.
      • Weigner M.J.
      • Caulfield T.A.
      • Danias P.G.
      • et al.
      Risk for clinical thromboembolism associated with conversion to sinus rhythm in patients with atrial fibrillation lasting less than 48 hours.
      • Gallagher M.M.
      • Hennessy B.J.
      • Edvardsson N.
      • et al.
      Embolic complications of direct current cardioversion of atrial arrhythmias: association with low intensity of anticoagulation at the time of cardioversion.
      Case series note a very low incidence of thromboemboli when patients with atrial flutter are adequately anticoagulated prior to cardioversion.
      • Gallagher M.M.
      • Hennessy B.J.
      • Edvardsson N.
      • et al.
      Embolic complications of direct current cardioversion of atrial arrhythmias: association with low intensity of anticoagulation at the time of cardioversion.
      • Stiell I.G.
      • Macle L.
      CCS Atrial Fibrillation Guidelines Committee
      Canadian Cardiovascular Society Atrial Fibrillation Guidelines 2010: management of recent-onset atrial fibrillation and flutter in the emergency department.
      • Elhendy A.
      • Gentile F.
      • Khandheria B.K.
      • et al.
      Thromboembolic complications after electrical cardioversion in patients with atrial flutter.
      It is generally recommended that patients with atrial flutter who are to be cardioverted receive an anticoagulant regimen identical to that for patients with AF.
      • Singer D.E.
      • Albers G.W.
      • Dalen J.E.
      • et al.
      Antithrombotic therapy in atrial fibrillation.
      • Fuster V.
      • Rydén L.E.
      • Cannon A.S.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines.
      • Camm A.J.
      • Kirchof P.
      • Lip G.Y.H.
      • et al.
      Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC)
      Guidelines for the management of atrial fibrillation.

      Emergency cardioversion

      Emergency cardioversion may be required because of ischemia or hemodynamic compromise in some situations and should not be delayed, even if the AF has been present for more than 48 hours and the patient is not already anticoagulated. In such a situation, concomitant anticoagulation with unfractionated heparin (UFH) or low molecular weight heparin (LMWH) may offer some benefit, but there are no published evaluations. (See accompanying article titled “Management of Recent-Onset Atrial Fibrillation and Flutter in the Emergency Department.”
      • Stiell I.G.
      • Macle L.
      CCS Atrial Fibrillation Guidelines Committee
      Canadian Cardiovascular Society Atrial Fibrillation Guidelines 2010: management of recent-onset atrial fibrillation and flutter in the emergency department.
      )
      We recommend that hemodynamically stable patients with AF or AFL of ≥48 hours or uncertain duration for whom electrical or pharmacologic cardioversion is planned should receive therapeutic OAC therapy (warfarin [INR 2-3] or dabigatran) for 3 weeks before and at least 4 weeks post-cardioversion.
      Following attempted cardioversion,
       If AF or AFL persists or recurs or if symptoms suggest that the presenting AF or AFL has been recurrent, the patient should have antithrombotic therapy continued indefinitely (using either OAC or aspirin, as appropriate).
       If sinus rhythm is achieved and sustained for 4 weeks, the need for ongoing antithrombotic therapy should be determined on the basis of the risk of stroke, and in selected cases expert consultation may be required (Strong Recommendation, Moderate-Quality Evidence).
      We recommend that hemodynamically stable patients with AF or AFL of known duration 48 hours may undergo cardioversion without prior or subsequent anticoagulation. However, if the patient is at particularly high risk of stroke (eg, mechanical valve, rheumatic heart disease, recent stroke, or TIA), cardioversion should be delayed, and the patient should receive OAC for 3 weeks before and at least 4 weeks post-cardioversion.
      Following attempted cardioversion,
       If AF or AFL persists or recurs or if symptoms suggest that the presenting AF or AFL has been recurrent, antithrombotic therapy (OAC or aspirin, as appropriate) should be commenced and continued indefinitely.
       If normal sinus rhythm is achieved and sustained for 4 weeks, the need for ongoing antithrombotic therapyshould be determined on the basis of the risk of stroke according to CHADS2 score, and in selected cases expert consultation may be required (Strong Recommendation, Moderate-Quality Evidence).
      We suggest that hemodynamically unstable patients with AF or AFL who require emergency cardioversion be managed as follows:
       If the AF or AFL is of known duration 48 hours, the patient may generally undergo cardioversion without prior anticoagulation. However, if the patient is at particularly high risk of stroke (eg, mechanical valve, rheumatic heart disease, recent stroke, or TIA), the patient should receive IV UFH or LMWH before cardioversion if possible, or immediately thereafter if even a brief delay is unacceptable, and then be converted to OAC for at least 4 weeks post-cardioversion.
       If the AF or AFL is of ≥48 hours or of uncertain duration, we suggest the patient receive intravenous UFH or LMWH before cardioversion if possible, or immediately thereafter if even a brief delay is unacceptable. Such a patient should then be converted to OAC for at least 4 weeks post-cardioversion.
      Following attempted cardioversion, the guidelines for subsequent antithrombotic therapy are identical to those for the management of hemodynamically stable patients undergoing cardioversion (Conditional Recommendation, Low-Quality Evidence).
      Figure 6 is a flow chart outlining our recommendations for antithrombotic therapy in conjunction with cardioversion.
      Figure thumbnail gr6
      Figure 6A summary of our recommended strategies for antithrombotic therapy in conjunction with cardioversion. CHADS2, please see ; INR, international normalized ratio; NSR, normal sinus rhythm; OAC, oral anticoagulant; TEE, transesophageal echocardiography; TIA, transient ischemic attack.

      Transesophageal echocardiography guidance

      The potential role of TEE to rule out the presence of atrial thrombi and the avoidance of anticoagulation was studied in several case series. An overview of these studies
      • Elhendy A.
      • Gentile F.
      • Khandheria B.K.
      • et al.
      Thromboembolic complications after electrical cardioversion in patients with atrial flutter.
      reported that patients with no atrial thrombus who then underwent electrical cardioversion had an unacceptably high incidence of embolization by comparison with anticoagulated patients in separate case series. It is generally accepted that the absence of thrombi on TEE does not eliminate the requirement for a period of 4 weeks of anticoagulation following cardioversion.
      The Assessment of Cardioversion Utilizing Echocardiography (ACUTE) was a multicentre randomized prospective of trial of 1222 patients with AF of more than 2 days' duration.
      • Klein A.L.
      • Grimm R.A.
      • Murray R.D.
      • et al.
      Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation.
      Patients were assigned to therapy guided by TEE findings or to conventional management. Patients assigned to TEE were anticoagulated at therapeutic levels (typically with UFH intravenously for 24 hours or warfarin [INR = 2-3] for 5 days) prior to attempted cardioversion. If TEE showed no thrombus, the patient underwent cardioversion and continued on anticoagulant therapy for 4 weeks. If thrombus was detected, warfarin was given for 3 weeks, TEE was repeated, and if the thrombus had resolved, cardioversion was performed and warfarin continued for 4 weeks. If thrombus was still detected after 3 weeks of anticoagulation, no cardioversion was attempted, but warfarin was continued for 4 weeks further. The patients randomized to no TEE received warfarin for 3 weeks precardioversion and a further 4 weeks post-cardioversion. There was no significant difference between the TEE and the no-TEE groups in the rate of embolic events or prevalence of sinus rhythm. The TEE group had fewer total hemorrhagic events, most of them minor. Right or left heart thrombi were identified in 13.8% of patients who underwent TEE. Of those patients with thrombi detected, 88.2% had a thrombus in the left atrial appendage. Among those patients with atrial thrombi detected, the value of repeat TEE after the initial 3 weeks of anticoagulation is uncertain.
      • Moreyra E.
      • Finkelhor R.S.
      • Debul R.D.
      Limitations of transesophageal echocardiography in the risk assessment of patients before nonanticoagulated cardioversion from atrial fibrillation and flutter: an analysis of pooled trials.
      The investigators subsequently reported the results of a small randomized controlled trial which found no difference in safety outcomes between UFH and enoxaparin for the acute anticoagulation phase.
      • Klein A.L.
      • Jasper S.E.
      • Katz J.F.
      • et al.
      The use of enoxaparin compared to unfractionated heparin for short-term antithrombotic therapy in atrial fibrillation patients undergoing transoesophageal echocardiography-guided cardioversion: Assessment of Cardioversion Using Transoesophageal Echocardiography (ACUTE) II randomized multicentre study.
      In centres where TEE is readily available and the interpretations reliable, a TEE-guided management strategy may safely shorten the time to cardioversion by comparison with standard anticoagulant regimens. The cost-effectiveness of such an approach depends very much on local and national patterns of practice and cost structures.
      We suggest that hemodynamically stable patients with AF or AFL of ≥48 hours or of unknown duration may undergo cardioversion guided by TEE (following the protocol from the Assessment of Cardioversion Utilizing Echocardiography trial as detailed in the text) (Conditional Recommendation, High-Quality Evidence).

      Coronary Artery Disease

      The clinician managing a patient with AF must often deal with concomitant coronary artery disease in the settings of primary prevention, stable coronary artery disease, an acute coronary syndrome (ACS), or percutaneous coronary intervention (PCI). There is good evidence for the use of aspirin for primary prevention,
      • Berger J.S.
      • Roncaglioni M.C.
      • Avanzini F.
      • et al.
      Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials.
      • Sanmuganathan P.S.
      • Ghaharamani P.
      • Jackson P.R.
      • et al.
      Aspirin for the primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials.
      for aspirin or clopidogrel for stable coronary artery disease,
      CAPRIE Steering Committee
      A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
      for aspirin supplemented by clopidogrel for up to 1 year following an ACS (with or without PCI
      • Yusuf S.
      • Zhao F.
      • Mehta S.
      • et al.
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      • Sabatine M.S.
      • Cannon C.P.
      • Gibson C.M.
      • et al.
      Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation.
      • Chen Z.M.
      • Jiang L.X.
      • Chen Y.P.
      • et al.
      Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial.
      • Mehta S.R.
      • Yusuf S.
      • Peters R.J.
      • et al.
      Effects of pretreatment with clopidogrel and aspirin followed by long-tern therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.
      • Rubboli A.
      • Milandri M.
      • Castelvetri C.
      • et al.
      Meta-analysis of trials comparing oral anticoagulation and aspirin versus dual antiplatelet therapy after coronary stenting: clues for the management of patients with an indication for long-term anticoagulation undergoing coronary stenting.
      • Leon M.B.
      • Baim D.S.
      • Popma J.J.
      • et al.
      A clinical trial comparing three antithrombotic-drug regimens after coronary stenting.
      • Bertrand M.E.
      • Rupprecht H.J.
      • Urban P.
      • Gershlick A.H.
      Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS).
      • Steinhubl S.R.
      • Berger P.B.
      • Mann J.T.
      • et al.
      Early and sustained dual antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial.
      • Becker R.C.
      • Meade T.W.
      • Berger P.B.
      • et al.
      The primary and secondary prevention of coronary artery disease.
      • King S.B.
      • Smith S.C.
      • Hirshfeld J.W.
      • et al.
      2007 focused update of the ACC/AHA/SCAI guideline update for percutaneous coronary intervention.
      ) and for PCI (both elective
      • Bertrand M.E.
      • Rupprecht H.J.
      • Urban P.
      • Gershlick A.H.
      Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS).
      • Steinhubl S.R.
      • Berger P.B.
      • Mann J.T.
      • et al.
      Early and sustained dual antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial.
      and post-ACS
      • Mehta S.R.
      • Yusuf S.
      • Peters R.J.
      • et al.
      Effects of pretreatment with clopidogrel and aspirin followed by long-tern therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.
      ). Warfarin alone or in combination with aspirin is less effective than aspirin plus clopidogrel for patients post-PCI.
      • Rubboli A.
      • Milandri M.
      • Castelvetri C.
      • et al.
      Meta-analysis of trials comparing oral anticoagulation and aspirin versus dual antiplatelet therapy after coronary stenting: clues for the management of patients with an indication for long-term anticoagulation undergoing coronary stenting.
      • Leon M.B.
      • Baim D.S.
      • Popma J.J.
      • et al.
      A clinical trial comparing three antithrombotic-drug regimens after coronary stenting.
      There is considerable evidence from randomized controlled trials, that for primary prevention among patients at high risk of coronary events, low-intensity warfarin (INR 1.5) is as effective as aspirin for the prevention of coronary events,
      Medical Research Council's General Practice Research Framework
      Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk.
      and for secondary prevention following myocardial infarction, warfarin alone (INR 2.8-4.8)
      • Smith P.
      • Arneson H.
      • Holme I.
      The effect of warfarin on mortality and reinfection after myocardial infarction.
      or warfarin (INR 2-2.5) plus aspirin (75-100 mg)
      • Hurlen N.
      • Abdelnoor M.
      • Smith P.
      • et al.
      Warfarin, aspirin or both after myocardial infarction.
      • Fiore L.D.
      • Ezekowitz M.D.
      • Brophy M.T.
      • et al.
      Department of Veterans Affairs Cooperative Studies Program Clinical Trial comparing combined warfarin and aspirin with aspirin alone in survivors of myocardial infarction: primary results of the CHAMP study.
      is at least as efficacious as aspirin alone in reducing subsequent coronary events.
      • Anand S.S.
      • Yusuf S.
      Oral anticoagulants in patients with coronary artery disease.
      There has been no rigourous comparison of warfarin vs the combination of aspirin and clopidogrel.
      The benefits of antithrombotic therapies for the primary prevention of coronary events must be balanced against the risks of major bleeding attributable to both aspirin and vitamin K antagonists. Although viewpoints vary, once the annual risk of a coronary event exceeds 1% to 1.5%, antithrombotic therapy is likely to confer more benefit than harm.
      • Sanmuganathan P.S.
      • Ghaharamani P.
      • Jackson P.R.
      • et al.
      Aspirin for the primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials.
      • Becker R.C.
      • Meade T.W.
      • Berger P.B.
      • et al.
      The primary and secondary prevention of coronary artery disease.
      Among patients with known coronary artery disease, ACS, or recent PCI, the benefits of appropriate antithrombotic therapy strongly outweigh the harms. Both aspirin and warfarin are appropriate for the primary prevention of coronary events in those patients at higher risk and for secondary prevention in most patients with known coronary artery disease. Accordingly, when such patients also have AF or AFL, it seems reasonable to choose the most appropriate antithrombotic therapy for the prevention of stroke with the expectation that the chosen therapy will also be protective against coronary events. For primary prevention of coronary events and for stable coronary artery disease, when the risk of stroke is very low (CHADS2 = 0), aspirin would be appropriate because of its lower bleeding risk and greater ease of administration. When the risk of stroke is higher (CHADS2 ≥1), warfarin would be appropriate, instead of aspirin.
      In the setting of elective PCI, aspirin plus clopidogrel are required for optimal prophylaxis against stent thrombosis. If the patient also has AF with a risk of stroke that is very low to low (CHADS2 ≤1), then aspirin plus clopidogrel would be appropriate for a minimum of 1 month for a bare metal stent, 3 months for a sirolimus drug-eluting stent, or 6 months for a paclitaxel drug-eluting stent; subsequently, CHADS2 = 0 patients might continue on aspirin alone, and CHADS2 = 1 patient might stay on aspirin plus clopidogrel or be switched to warfarin. If the risk of stroke is higher (CHADS2 ≥ 2), OAC is required for adequate stroke prophylaxis. Hence, for optimal prophylaxis against both stroke and coronary events, a period of therapy with a combination of aspirin, clopidogrel, and OAC (“triple antithrombotic therapy”) may be required, even though the risk of bleeding is considerably increased by this combination.
      • Lip G.Y.H.
      • Huber K.
      • Andreotti F.
      • et al.
      Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting.
      Whereas the optimal duration of dual antiplatelet therapy post-PCI for patients without AF is up to 12 months, the duration of triple therapy in patients with AF is uncertain and should be decided on the basis of balancing the likely risks of a stent-related event vs the risk of bleeding. Those patients at particularly high risk of bleeding should be considered for the use of a bare metal stent rather than a drug-eluting stent, with the triple therapy continued for only 1 month.
      Following an episode of ACS, aspirin plus clopidogrel appear optimal for up to 1 year. If the patient also has AF with a risk of stroke that is very low to low (CHADS2 ≤1), then aspirin plus clopidogrel would be appropriate for up to 1 year; subsequently, CHADS2 = 0 patients might continue on aspirin alone, and CHADS2 = 1 patients might stay on aspirin plus clopidogrel or be switched to warfarin. If the risk of stroke is higher (CHADS2 ≥2), warfarin is required for adequate stroke prophylaxis. Hence, for optimal prophylaxis against both stroke and coronary events, a period of therapy with combination aspirin, clopidogrel, and warfarin may be required, as for the patients with elective PCI. Whereas the optimal duration of dual antiplatelet therapy post-ACS for patients without AF is up to 12 months, the duration of triple therapy in patients with AF should be decided based on balancing the likely risks of a stent-related event vs the risk of bleeding. There are no randomized trials to guide the decisions, but it might be reasonable to prescribe 1 month of triple therapy, followed by up to 1 year of a combination of warfarin plus clopidogrel or warfarin plus aspirin, followed by warfarin alone as suggested in other guidelines.
      • Anand S.S.
      • Yusuf S.
      Oral anticoagulants in patients with coronary artery disease.
      The issues regarding antithrombotic therapies for patients with coronary artery disease plus AF have been extensively evaluated in recent evidence-based guidelines.
      • Singer D.E.
      • Albers G.W.
      • Dalen J.E.
      • et al.
      Antithrombotic therapy in atrial fibrillation.
      • Fuster V.
      • Rydén L.E.
      • Cannon A.S.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines.
      • Steinhubl S.R.
      • Berger P.B.
      • Mann J.T.
      • et al.
      Early and sustained dual antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial.
      • King S.B.
      • Smith S.C.
      • Hirshfeld J.W.
      • et al.
      2007 focused update of the ACC/AHA/SCAI guideline update for percutaneous coronary intervention.
      • Lip G.Y.H.
      • Huber K.
      • Andreotti F.
      • et al.
      Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting.
      In the RE-LY trial, although the net clinical benefit outcome (a composite of stroke, systemic embolism, pulmonary embolism, myocardial infarction, death, or major bleeding) was in favour of dabigatran 150 mg (hazard ratio 0.91; 95% CI, 0.82-1.00; P = .04), there was a higher incidence of myocardial infarction with dabigatran (hazard ratio 1.38; 95% CI, 1.00-1.91; P = .048). There has not yet been a trial of dabigatran to evaluate the agent for the primary or secondary prevention of coronary events. Given the known benefits of warfarin for the reduction of coronary events, which can be substantial in those patients at higher risk, when OAC is indicated to prevent stroke in those who have AF and are also at high risk of a coronary event (eg, those without evidence of coronary artery disease whose Framingham risk is ≥2% per year, those with stable coronary artery disease with high risk features, and those with or ACS in recent months), it seems prudent to recommend warfarin in preference to dabigatran.
      We suggest that patients with AF or AFL who have stable coronary artery disease should receive antithrombotic therapy selected on the basis of their risk of stroke (aspirin for CHADS2 = 0 and OAC for CHADS2 ≥1). Warfarin is preferred over dabigatran for those at high risk of coronary events (Conditional Recommendation, Moderate-Quality Evidence).
      We suggest that patients with AF or AFL who have experienced ACS or who have undergone PCI should receive antithrombotic therapy selected on the basis of a balanced assessment of their risks of stroke, of recurrent coronary artery events, and of hemorrhage associated with the use of combinations of antithrombotic therapies, which in patients at higher risk of stroke may include aspirin plus clopidogrel plus OAC (Conditional Recommendation, Low-Quality Evidence).
      Figure 7 is a flow chart outlining our recommendations for the management of antithrombotic therapy in the setting of coronary artery disease.
      Figure thumbnail gr7
      Figure 7A summary of our recommendations for antithrombotic management in settings of coronary artery disease. ACS, acute coronary syndrome; CAD, coronary artery disease; CHADS2, see ; OAC, oral anticoagulant; PCI, percutaneous coronary intervention.

      Invasive Procedures

      When a patient receiving an OAC or antiplatelet agent is to undergo a surgical or diagnostic procedure that has a risk of major bleeding, the risk of a thromboembolic event occurring while the antithrombotic agent is reduced or stopped must be weighed against the goal of a reduced risk of major bleeding.
      • Kearon C.
      • Hirsh J.
      Management of anticoagulation before and after elective surgery.
      • Douketis J.D.
      • Berger P.B.
      • Dunn A.S.
      • et al.
      The perioperative management of antithrombotic therapy.
      We suggest that such patients be stratified as to their risk of stroke, which can range from <1% to >20% per year. If there is a very low to moderate risk of stroke (CHADS2 ≤ 2), the antithrombotic agent should be discontinued before the procedure (aspirin or clopidogrel for 7-10 days, warfarin for 5 days if the INR was in the range of 2-3, and dabigatran for 2 days). Once postprocedure hemostasis is established (about 24 hours), the antithrombotic therapy should be reinstated. If the risk of bleeding from the procedure is low, the clinician might choose to continue the antithrombotic agent uninterrupted.
      On the other hand, if there is a particularly high risk of stroke (eg, prosthetic valve, recent stroke or TIA, rheumatic valve disease, CHADS2 ≥ 3) or of other thromboembolism (eg, Fontan procedure), some form of antithrombotic therapy should be continued until as close to the time of the procedure as is judged to be safe in terms of the risk and consequences of procedural bleeding, and it should be reinstated as soon as hemostasis is established post-procedure. Consideration should be given to the risk of major bleeding from the procedure in determining the antithrombotic regimen. It is likely that most potentially hemorrhagic dental procedures, if undertaken with appropriate surgical skill and the use of hemostatic mouthwash, can be done without discontinuing warfarin, provided the preoperative INR is under 3.0.
      • Patatanian E.
      • Fugate S.E.
      Hemostatic mouthwashes in anticoagulated patients undergoing dental extraction.
      Cataract extraction and minor dermatologic procedures may also be done without interrupting warfarin.
      • Douketis J.D.
      • Berger P.B.
      • Dunn A.S.
      • et al.
      The perioperative management of antithrombotic therapy.
      A randomized controlled trial is currently underway by a group of Canadian investigators who are comparing the strategies of uninterrupted warfarin vs bridging UFH or LMWH in the mangement of patients having a cardiac arrhythmia device implanted.
      • Birnie D.
      • Healey J.S.
      • Krahn A.
      • et al.
      Bridge or continue Coumadin for device surgery: a randomized controlled trial rationale and design.
      We suggest that patients with AF or AFL who are receiving aspirin, clopidogrel, or OAC and are scheduled for a surgical or diagnostic procedure carrying a risk of major bleeding be stratified by their risk of stroke:
      If there is a very low to moderate risk of stroke (CHADS2 ≤2), patients should have their antithrombotic agent discontinued before the procedure (aspirin or clopidogrel for 7-10 days, warfarin for 5 days if the INR was in the range of 2-3, and dabigatran for 2 days). Once postprocedure hemostasis is established (about 24 hours), the antithrombotic therapy should be reinstated (Conditional Recommendation, Low-Quality Evidence).
      If there is a particularly high risk of stroke (eg, mechanical valve, recent stroke or TIA, rheumatic valve disease, CHADS2 ≥3) or of other thromboembolism (eg, Fontan procedure), further consideration should be given to the risk of major bleeding from the procedure:
      If there is an acceptable perioperative bleeding risk (ie, risk of stroke outweighs risk of bleeding), patients should have OAC therapy continued perioperatively or have their OAC discontinued before the procedure and be bridged with LMWH or UFH perioperatively (Conditional Recommendation, Low-Quality Evidence).
      If there is a substantial risk of major and potentially problematic bleeding (ie, risk of bleeding and risk of stroke are both substantial), patients should have their OAC discontinued before the procedure, with LMWH or UFH bridging until 12 to 24 hours preprocedure. Once postprocedure hemostasis is established (about 24 hours), the OAC should be reinstated with LMWH or UFH bridging (Conditional Recommendation, Low-Quality Evidence).
      Figure 8 is a flow chart outlining our recommendations for the management of antithrombotic therapy in patients undergoing invasive procedures.
      Figure thumbnail gr8
      Figure 8A summary of our recommendations for management of antithrombotic therapies in patients undergoing surgical or diagnostic procedures with a risk of major bleeding. AF, atrial fibrillation; CHADS2, see ; INR, international normalized ratio; LMWH, low molecular weight heparin; OAC, oral anticoagulant; TIA, transient ischemic attack; UFH, ultrafractionated heparin.

      Stroke Management in Patients With AF

      Among AF patients experiencing a stroke, the high rate of recurrence suggested that there was some urgency in initiating anticoagulation after the occurrence of embolic stroke. The International Stroke Trial Collaborative Group randomized 18,451 patients with ischemic stroke within 24 hours of onset to subcutaneous unfractionated heparin (5000 IU twice a day or 12,500 IU twice a day), aspirin 300 mg per day, both, or neither and maintained for 14 days or until prior hospital discharge.
      • Saxena R.
      • Lewis S.
      • Berge E.
      • Sandercock P.A.G.
      • Koustaal P.J.
      International Stroke Trial Collaborative Group
      Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the International Stroke Trial.
      CT scan was performed to exclude intracranial hemorrhage when possible and was mandatory in comatose patients. Among the 3169 patients with AF, both doses of heparin were significantly more effective for the prevention of recurrent stroke of ischemic or unknown type but resulted in significantly more symptomatic intracranial hemorrhage. There was no significant difference among the regimens in the rate of the composite outcome of recurrent stroke or symptomatic intracranial hemorrhage or in the rate of all-cause mortality. Patients with AF had a higher mortality than did patients without AF (16.9% vs 7.5%), probably because of greater mean age and larger cerebral infarcts. The rate of recurrence, within 14 days, of stroke of ischemic or unknown type was 3.9% among patients with AF, considerably lower than that reported in earlier studies but still higher than in patients without AF in this study. The results indicate that heparin is not indicated in the acute management of embolic stroke among patients with AF. Published guidelines for the management of stroke in a patient with AF
      • Albers G.W.
      • Amarenco P.
      • Easton J.D.
      • Sacco R.L.
      • Teal P.
      Antithrombotic and thrombolytic therapy for ischemic stroke.
      • Broderick J.
      • Connolly S.
      • Feldman E.
      • et al.
      Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update.
      • Adams H.P.
      • del Zoppo G.
      • Alberts M.J.
      • et al.
      Guidelines for the early management of adults with ischemic stroke.
      are based on extrapolations from clinical trials
      • Birnie D.
      • Healey J.S.
      • Krahn A.
      • et al.
      Bridge or continue Coumadin for device surgery: a randomized controlled trial rationale and design.
      • Chen Z.M.
      • Sandercock P.
      • Pan H.C.
      • et al.
      Indications for early aspirin use in acute ischemic stroke: a combined analysis of 40,000 randomized patients from the Chinese Acute Stroke Trial and the International Stroke Trial: indications for early aspirin.
      and include recommendations for the use of intravenous rtPA for selected patients within 3 hours of onset. Patients who receive rtPA should not receive any antiplatelet or anticoagulant therapy for at least 24 hours subsequently. If there is no evidence of hemorrhage on urgent CT scan, and yet the patient is not to receive fibrinolytic therapy, the patient should begin aspirin 325 mg per day immediately thereafter, with conversion to OAC after 14 days, or sooner if the infarct size is small and the patient is normotensive. If the clinical and computed tomography picture are consistent with a TIA, then immediate heparin therapy may be acceptable. If stroke occurs in a patient with AF or AFL who is already receiving anticoagulation, the drug should be stopped and intracranial hemorrhage should be excluded. If intracranial hemorrhage is present, the anticoagulation should be reversed, and subsequent decisions to resume anticoagulation should be made after reassessment of the risks of embolism and the risks of recurrent intracranial hemorrhage. For those without intracranial hemorrhage, it would be reasonable to start aspirin 325 mg per day when the INR falls below 1.5 and to restart the anticoagulant at day 14, or sooner if the infarct is small and the patient is normotensive.
      • Albers G.W.
      • Amarenco P.
      • Easton J.D.
      • Sacco R.L.
      • Teal P.
      Antithrombotic and thrombolytic therapy for ischemic stroke.
      • Broderick J.
      • Connolly S.
      • Feldman E.
      • et al.
      Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update.
      If warfarin is chosen as the anticoagulant, meticulous attention should be given to maintenance of the INR in the range of 2 to 3. A double-blind randomized trial
      • Berge E.
      • Abdelnoor M.
      • Nakstad P.H.
      • Sandset P.M.
      HAEST Study Group
      Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study.
      of LMWH vs aspirin (160 mg/d) among patients with acute ischemic stroke and AF showed a trend to more recurrent ischemic stroke in the LMWH group (odds ratio 1.13; 95% CI, 0.57-2.24), supporting the strategy of early administration of aspirin to such patients in preference to heparin.
      We recommend that patients with AF or AFL who experience a stroke be managed acutely according to the published guidelines of the American Heart and American Stroke Associations
      • Adams H.P.
      • del Zoppo G.
      • Alberts M.J.
      • et al.
      Guidelines for the early management of adults with ischemic stroke.
      (Strong Recommendation, Moderate-Quality Evidence).

      Hemorrhage on OAC Therapy

      The major determinants of OAC-induced bleeding are the INR, patient characteristics, and the concomitant use of drugs that interfere with hemostasis. The acute management of hemorrhage in a patient receiving OAC requires a graded response according to published guidelines,
      • Schulman S.
      • Beyth R.J.
      • Kearon C.
      • Levine M.N.
      Hemorrhagic complications of anticoagulant and thrombolytic treatment.
      beginning with the immediate measurement of the INR, stopping the OAC, and assessment of the severity of hemorrhage. If there is major bleeding, vitamin K may be given intravenously, and if the bleeding is life threatening, vitamin K should be accompanied by fresh frozen plasma, prothrombin complex concentrate, or recombinant factor VIIa. If the INR is elevated and no explanatory pathology is found, it may be appropriate to restart the OAC, attempting to maintain the INR in the usual therapeutic range with intensified monitoring and attention to patient factors that can increase the INR in the setting of a given dose of OAC. If the bleeding is not life threatening and occurs with an INR in the therapeutic range, once pathology is ruled out and if the CHADS2 score is ≥2, it may be appropriate to reinstitute the OAC, attempting to maintain a therapeutic INR.
      We suggest that patients with AF or AFL who experience hemorrhage while on OAC therapy be managed according to the practice guidelines of the American College of Chest Physicians
      • Schulman S.
      • Beyth R.J.
      • Kearon C.
      • Levine M.N.
      Hemorrhagic complications of anticoagulant and thrombolytic treatment.
      (Conditional Recommendation, Low-Quality Evidence).

      Pharmacogenomics

      Eventually, pharmacogenomic algorithms may allow more rapid and safe determinations of initial warfarin dosage, particularly among patients whose warfarin requirements are particularly low or high.
      International Warfarin Pharmacogenetics Consortium
      Estimation of the warfarin dose with clinical and pharmacogenetic data.
      For the present, routine genetic testing is not advised in the management of therapy with a vitamin K antagonist.

      Alternatives to Antithrombotic Therapies

      Rhythm control and stroke risk

      An overview
      • de Denus S.
      • Sanoski C.A.
      • Carlsson J.
      • Opolski G.
      • Spinler S.A.
      Rate vs. rhythm control in patients with atrial fibrillation: a meta-analysis.
      of the 5 trials that compared the strategies of rhythm vs rate control in AF found a mortality of 13.0% with rate control vs 14.6% with rhythm control (odds ratio 0.87, P = .09). The rates of ischemic stroke and major hemorrhage were similar. The AFFIRM trial
      • Wyse D.G.
      • Waldo A.L.
      • DiMarco J.P.
      • et al.
      A comparison of rate control and rhythm control in patients with atrial fibrillation.
      is by far the largest, mandated anticoagulation (INR 2.0-3.0) in the rate-control group (85% maintained warfarin) and strongly encouraged in the rhythm-control group, while allowing cessation at the physician's discretion if sustained sinus rhythm was achieved (70% maintained warfarin). Ischemic stroke occurred at an annual rate of about 1% in each group, and in most instances the patient was either off warfarin or the INR was <2.0. The authors concluded that continuous anticoagulation is warranted in all patients with AF and 1 or more risk factors for stroke, whether or not sinus rhythm appears to be restored and maintained, and this approach is recommended by consensus groups.
      • Singer D.E.
      • Albers G.W.
      • Dalen J.E.
      • et al.
      Antithrombotic therapy in atrial fibrillation.
      • Fuster V.
      • Rydén L.E.
      • Cannon A.S.
      • et al.
      ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines.
      Left atrial radiofrequency ablation is increasingly used as a rhythm control approach to treat AF, raising questions about the role of long-term OAC therapy in such patients.
      • Verma A.
      • Macle L.
      • Cox J.L.
      • Skanes A.C.
      CCS Atrial Fibrillation Guidelines Committee
      Canadian Cardiovascular Society Atrial Fibrillation Guidelines 2010: catheter ablation for atrial fibrillation/atrial flutter.
      The issues are the risk of dislodgement of left atrium thrombus during the ablation procedure, bleeding in association with the invasive procedure, creation of thrombogenic areas of left atrium endothelial damage, and the risk of embolization during long-term follow-up. Recommendations are generally weak and based on evidence of low or very low quality.
      • Verma A.
      • Macle L.
      • Cox J.L.
      • Skanes A.C.
      CCS Atrial Fibrillation Guidelines Committee
      Canadian Cardiovascular Society Atrial Fibrillation Guidelines 2010: catheter ablation for atrial fibrillation/atrial flutter.
      TEE is advised immediately preprocedure to ensure there is no important left atrium thrombus. In general, the procedure is performed with the patient adequately anticoagulated, either by sustaining the preprocedure warfarin (usually allowing the INR to fall to the lower end of the therapeutic range) or with use of bridging LMWH both before and after the procedure. In the latter case, UFH is given with access to the left atrium. The UFH or LMWH are discontinued at the completion of the procedure, and the sheath is removed when the ACT returns to a safe level. Parenteral anticoagulation is reinitiated within hours of the sheath removal and maintained until therapeutic anticoagulation is reestablished with warfarin or dabigatran, which is continued for at least 3 months. Long-term OAC should continue if AF recurs. In the presence of sustained normal sinus rhythm, OAC should be discontinued only if the long-term risk of stroke is low (CHADS2 score <2). (See further details in the accompanying article titled “Catheter Ablation of Atrial Fibrillation and Flutter.”
      • Verma A.
      • Macle L.
      • Cox J.L.
      • Skanes A.C.
      CCS Atrial Fibrillation Guidelines Committee
      Canadian Cardiovascular Society Atrial Fibrillation Guidelines 2010: catheter ablation for atrial fibrillation/atrial flutter.
      )

      Left atrial appendage-directed interventions

      A range of surgical procedures focused on curing AF have been developed and reported during the past 20 years.
      • Calkins H.
      • Brugada J.
      • Packer D.
      • et al.
      HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendation for personnel, policy, procedures and follow-up.
      Left atrial appendage removal or occlusion may be done in an attempt to lower the risk of thromboembolism as part of a Cox Maze procedure or as an adjunct to another cardiac surgical procedure. Only case series are available in the literature, with levels of success very specific to individual centres and the indications uncertain. The long-term risk of stroke after such procedures appears to be low, but the requirement for long-term OAC is unclear, and advice should be provided by the expert centre conducting the arrhythmia surgery. A Canadian collaborative group is currently conducting a pilot study evaluating left atrial appendage occlusion in conjunction with various cardiac surgical procedures (clinicaltrials.gov, NCT00908700). (See detailed discussion in the accompanying article titled “Surgical Therapy for Atrial Fibrillation.”
      • Pagé P.
      CCS Atrial Fibrillation Guidelines Committee
      Canadian Cardiovascular Society Atrial Fibrillation Guidelines 2010: surgical therapy.
      )
      Percutaneous closure of the left atrial appendage was evaluated in a randomized, noninferiority comparison of conventional warfarin vs the Watchman occluding device and subsequent discontinuation of warfarin.
      • Holmes D.R.
      • Reddy V.
      • Turi Z.G.
      • et al.
      Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomized non-inferiority trial.
      The composite primary outcome (any stroke, cardiovascular or unexplained death, or systemic embolism) at a mean of 18 months was nonsignificantly less in the Watchman group (RR = 0.62; 95% CI, 0.35-1.25), and the device was concluded to be noninferior to conventional warfarin therapy. However, there were relatively few events, the follow-up was short, there are substantial learning curve considerations, and the antithrombotic regimen used with the device was complex and changing. Additional, adequately powered studies, particularly in patients at higher risk of stroke, are needed for adequate assessment of this new technique.

      Acknowledgements

      The authors are grateful to Grant Stotts, MD, FRCPC, for advice and liaison with the Canadian Stroke Network and to Marie-Josee Martin and Jody McCombe for final transcription of the manuscript. Administrative and technical support was provided by the Canadian Cardiovascular Society .

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