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Canadian Journal of Cardiology

Focused 2012 Update of the Canadian Cardiovascular Society Atrial Fibrillation Guidelines: Recommendations for Stroke Prevention and Rate/Rhythm Control

      Abstract

      The Canadian Cardiovascular Society (CCS) published the complete set of 2010 Atrial Fibrillation (AF) Guidelines in the January, 2011 issue of the Canadian Journal of Cardiology. During its deliberations, the CCS Guidelines Committee engaged to a timely review of future evidence, with periodic composition of focused updates to address clinically important advances. In 2011, results were published from 3 pivotal AF trials: the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF), the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study, and the Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS), comparing dronedarone with placebo in patients with permanent AF and additional cardiovascular disease risk-factor burden. Each of these large randomized trials provided clear results with major implications for AF management. Other important evidence that has emerged since the 2010 Guidelines includes findings about prediction instruments for AF-associated stroke and bleeding risk, stroke risk in paroxysmal-AF patients, risk-benefit considerations related to oral anticoagulation in patients with chronic kidney disease, and risk/benefit considerations in the use of antiplatelet agents, alone and in combination with each other or with oral anticoagulants, in AF patients. The Guidelines Committee judged that this extensive and important new evidence required focused updating of the 2010 Guidelines with respect to stroke prevention and rate/rhythm control. This report presents the details of the new recommendations, along with the background and rationale.

      Résumé

      La Société canadienne de cardiologie (SCC) a publié l'ensemble des lignes directrices de 2010 en matière de fibrillation auriculaire (FA) dans le numéro de janvier 2011 du Journal canadien de cardiologie. Au cours de ses discussions, le comité des lignes directrices de la SCC s'est engagé à revoir régulièrement les nouvelles données par la rédaction périodique de mises à jour ciblées portant sur les avancées cliniques importantes. En 2011, les résultats de 3 essais pivots sur la FA ont été publiés : le ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), l'étude ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) et le PALLAS (Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy), qui compare le dronédarone au placébo chez les patients ayant une FA permanente et des facteurs de risque cardiovasculaire additionnels. Chacun de ces essais hasardisés de grande envergure a fourni des résultats clairs sur les importantes conséquences de la prise en charge de la FA. Les autres données probantes importantes qui sont ressorties depuis la publication des lignes directrices 2010 incluaient les conclusions sur les outils de prédiction du risque d'accident vasculaire cérébral et d'hémorragie associé à la FA, du risque d'accident vasculaire cérébral chez les patients ayant une FA paroxystique, les considérations risques-avantages liés à l'anticoagulation orale chez les patients ayant une maladie rénale chronique (MRC) et les considérations risques-avantages de l'utilisation d'agents antiplaquettaires, seuls ou en combinaison avec d'autres agents antiplaquettaires ou agents anticoagulants oraux, chez les patients ayant une FA. Le comité des lignes directrices a estimé que ces nouvelles données probantes, importantes et exhaustives exigeaient une mise à jour ciblée des lignes directrices 2010 en ce qui a trait à la prévention des accidents vasculaires cérébraux, le maintien du rythme et la maîtrise de la fréquence. Ce rapport présente de manière détaillée les nouvelles recommandations, ainsi que leur fondement et leurs justifications.
      The development of the 2010 Canadian Cardiovascular Society (CCS) Atrial Fibrillation (AF) Guidelines included a commitment to a timely review of emerging evidence, with the periodic production of focused updates to address clinically important advances. In 2011, results were published from 3 pivotal AF trials: the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study, and the Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) trial, comparing dronedarone with placebo in patients with permanent AF and additional cardiovascular disease. Each of these 3 large randomized trials provided clear results with major implications for the management of AF. After reviewing these 3 trials and other emergent data, the CCS-AF Guidelines Committee has recommended important changes to the guidelines, specifically with respect to stroke prevention and rate and rhythm control. This focused update provides the details and rationale for the new recommendations.
      The present recommendations were developed with the same methods used for the initial guidelines.
      • Gillis A.M.
      • Skanes A.C.
      CCS Atrial Fibrillation Guidelines Committee
      Canadian Cardiovascular Society atrial fibrillation guidelines 2010: implementing GRADE and achieving consensus.
      The primary panel was reassembled and maintained a wide representation from primary and specialty care (internal medicine, cardiology, neurology, and emergency medicine). For continuity, the panel included many of the 2010 members. Conflict of interest declarations were updated and the primary panel included members without conflicts of interest on both the Stroke Prevention and Rate/Rhythm Control writing subgroups. Consistent with prior CCS AF guidelines, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was maintained in place of the American College of Cardiology/American Heart Association/Heart Rhythm Society grading system to evaluate evidence and strength of recommendations. Dissemination of the current update will follow the same multidimensional approach as the 2010 Guidelines, which resulted in over 10,000 downloads of manuscripts, slides, and the executive summary in the past year.

      Updated Guidelines for Stroke Prevention

      Predicting stroke risk

      The Congestive Heart Failure, Hypertension, Age > 75, Diabetes Mellitus, and Prior Stroke or Transient Ischemic Attack (CHADS2) index
      • Gage B.F.
      • Waterman A.D.
      • Shannon
      • et al.
      Validation of clinical classification schemes for predicting stroke Results from the National Registry of Atrial Fibrillation.
      assigns 1 point each for congestive heart failure, hypertension, age > 75, and diabetes, and 2 points for history of stroke or transient ischemic attack (TIA). It has been well validated, 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).
      • Gage B.F.
      • Waterman A.D.
      • Shannon
      • et al.
      Validation of clinical classification schemes for predicting stroke Results from the National Registry of Atrial Fibrillation.
      • Gage B.F.
      • van Walraven C.
      • Pearce L.
      • et al.
      Selecting patients with atrial fibrillation for anticoagulation Stroke risk stratification in patients taking aspirin.
      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 schemas assesses additional validation studies performed since publication of the risk schemas, including 6 validations of the CHADS2. A modified version of the CHADS2 schema
      • Rietbrock S.
      • Heeley E.
      • Plumb J.
      • Van Staa T.
      Chronic atrial fibrillation: incidence, prevalence, and prediction of stroke using the Congestive heart failure, Hypertension, Age > 75, Diabetes mellitus, and prior Stroke or transient ischemic attack (CHADS2) risk stratification scheme.
      gives increasing points to various age categories with up to 6 points for age ≥ 85 years, 6 points for stroke/TIA, 1 point for each of female sex and diabetes mellitus, but nothing for hypertension or heart failure. The modifications increased granularity for lower score groups and were associated with a slightly higher c-statistic than the standard CHADS2. The 2010 European Society of Cardiology (ESC) AF guidelines
      • Camm A.J.
      • et al.
      European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery
      Guidelines for the management of atrial fibrillation The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC) [erratum in 2011;32:1172].
      incorporated the Birmingham 2009 system (Congestive Heart Failure, Hypertension, Age ≥ 75 Years, Diabetes Mellitus, Stroke, Vascular Disease, Age 65 to 74 Years, Sex Category [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 CHA2DS2-VASc is similar to the CHADS2, but gives 2 points for age ≥ 75 years and 1 point each for age 65-74 years, vascular disease (prior myocardial infarction [MI], peripheral artery disease, or aortic plaque), and female sex. CHA2DS2-VASc was validated and compared with CHADS2 and other standard schemas in a subset of 1577 patients in the Euro Heart Survey on AF population. When patients with AF were categorized as low (score = 0), intermediate (score = 1), or high risk (score = 2), the c-statistic was 0.59 for CHADS2 and 0.61 for the CHA2DS2-VASc.
      • 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.
      Because the c-statistic ranges from values of 0.5 to 1, with 0.5 indicating no predictive value and 1 perfect prediction, both systems showed similar but weak predictive value. The 2010 ESC guidelines recommended that CHADS2 be applied first, with CHA2DS2-VASc applied only if the CHADS2 score is under 2, to refine the stroke-risk definition in lower-risk individuals. The 2010 CCS Guidelines,
      • Cairns J.A.
      • Connolly S.J.
      • McMurtry S.
      • et al.
      Canadian Cardiovascular Society atrial fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter.
      recommended that the CHADS2 schema be used for stroke risk prediction, in view of its simplicity, extensive validation, and wide use.
      Several large new validation studies of stroke-risk schemas have been considered in this 2012 CCS guidelines update. A 2008 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 had been compared in a single cohort of adequate size and diversity. Two subsequent studies validated and compared several stroke-prediction schemas in large populations of AF patients. Van Staa et al.
      • Van Staa T.P.
      • Setakis E.
      • Di Tanna G.L.
      • et al.
      A comparison of risk stratification schemes for stroke in 79,884 atrial fibrillation patients in general practice.
      analyzed several risk-prediction schemas in a 79,844-patient cohort from the UK General Practice Research Database and found that the c-statistics associated with the standard CHADS2, the modified CHADS2, and the CHA2DS2-VASc indicated very similar moderate predictive value. Olesen et al.
      • Olesen J.B.
      • Lip G.Y.H.
      • Hansen M.L.
      • et al.
      Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study.
      published a detailed comparison of CHADS2 and CHA2DS2-VASc schemas performance among all nonvalvular AF patients hospitalized in Denmark between 1997 and 2000. CHADS2 and CHA2DS2-VASc scores were evaluated in relation to rates of hospitalization or death due to thromboembolism at 1, 5, and 10 years. All 3 new risk-score components (age 65-74, vascular disease, and female sex) contributed significantly to risk prediction in univariate analysis, but female sex did not make a significant contribution in a multivariate model. The value of assigning a point for female sex continues to be debated.
      • Lane D.A.
      • Lip G.Y.H.
      Female gender is a risk factor for stroke in atrial fibrillation patients.
      The c-statistics were similar for both schemas when individual scores were used, but the CHA2DS2-VASc performed better when patients were categorized as low (score = 0), moderate (score = 1), or high (score ≥ 2) risk, principally because of more precise estimates of thromboembolic risk in patients with CHADS2 scores of 0 or 1.
      Whereas the stroke-risk for the CHADS2 = 0 group was 1.9% per year in the original validation,
      • Gage B.F.
      • Waterman A.D.
      • Shannon
      • et al.
      Validation of clinical classification schemes for predicting stroke Results from the National Registry of Atrial Fibrillation.
      subsequent validations found lower 1-year stroke-risks, between 0.5 and 1.7%.
      Stroke Risk in Atrial Fibrillation Working Group
      Comparison of 12 risk stratification schemes to predict stroke in patients with nonvalvular atrial fibrillation.
      • Van Staa T.P.
      • Setakis E.
      • Di Tanna G.L.
      • et al.
      A comparison of risk stratification schemes for stroke in 79,884 atrial fibrillation patients in general practice.
      • Olesen J.B.
      • Lip G.Y.H.
      • Hansen M.L.
      • et al.
      Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study.
      There is a large range of stroke-risk among patients with CHADS2 = 0, among whom appropriate therapy may range from oral anticoagulants (OACs) to acetylsalicylic acid (ASA) to no antithrombotic agent. Whereas about 20% of AF patients have a low-risk CHADS2 score (CHADS2 = 0),
      • Van Staa T.P.
      • Setakis E.
      • Di Tanna G.L.
      • et al.
      A comparison of risk stratification schemes for stroke in 79,884 atrial fibrillation patients in general practice.
      • Olesen J.B.
      • Lip G.Y.H.
      • Hansen M.L.
      • et al.
      Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study.
      the prevalence of CHA2DS2-VASc = 0 AF patients is about 8.5%
      • Van Staa T.P.
      • Setakis E.
      • Di Tanna G.L.
      • et al.
      A comparison of risk stratification schemes for stroke in 79,884 atrial fibrillation patients in general practice.
      • Olesen J.B.
      • Lip G.Y.H.
      • Hansen M.L.
      • et al.
      Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study.
      with a mean stroke-risk ≤ 0.5% per year. The principal value of CHA2DS2-VASc applies in these patients, most of whom do not require antithrombotic therapy. Patients with a CHADS2 ≥ 1 have a stroke-risk well over 2% per year and require OACs. Although most patients with a CHA2DS2-VASc score of 1 have sufficient risk to justify the use of OACs, a single CHA2DS2-VASc point based on vascular disease or female sex implies a stroke risk < 1.5% per year and ASA should be considered. Patients with a CHA2DS2-VASc ≥ 2 clearly have sufficient stroke risk to justify use of an OAC.
      There is extensive evidence that the stroke-risk of paroxysmal AF patients is similar to that among patients with persistent or permanent AF. Is there a threshold AF burden to require antithrombotic therapy? In the TRENDS study
      • Glotzer T.V.
      • Daoud E.G.
      • Wyse D.G.
      • et al.
      The relationship between daily atrial tachyarrhythmia burden from implantable device diagnostics and stroke risk The TRENDS study.
      patients with rhythm-monitoring pacemakers or implantable cardioverter defibrillators and ≥ 1 stroke-risk factor (mean CHADS2 = 2.2) were followed for a mean of 1.4 years. AF-burden was quantified as the longest total daily duration of atrial tachycardia (AT) (probable AF) during a 30-day monitoring period. The risk ratio (RR) for stroke/TIA/systemic thromboembolism (STE) with an AF-burden of < 5.5 hours of AT vs those with no AT was 0.98 (stroke/TIA incidence 1.1% per year). The RR for AF-burden ≥ 5.5 hours was 2.20 (stroke/TIA/STE incidence 2.4% per year). The Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) study
      • Healey J.S.
      • Connolly S.J.
      • Gold M.R.
      • et al.
      Subclinical atrial fibrillation and the risk of stroke.
      enrolled 2580 patients with age ≥ 65 years and hypertension followed for a mean of 2.8 years after implantation of first pacemaker or implantable cardioverter defibrillator. Device-detected AT (>190 beats per minute lasting > 6 minutes) occurred in 36%, and was associated with an increased risk of clinical AF (RR 5.56 vs patients without AT) and stroke/STE risk of 2.1% per year (RR 2.5 vs patients without AT). These 2 studies demonstrate a clear association between device-detected AT and stroke/STE. The ASSERT trial demonstrates that episodes as short as 6 minutes are markers for the development of clinical AF and for stroke/STE risk. However, the absolute stroke risk was lower in ASSERT patients than in clinical AF patients and there was typically a delay of many months between the appearance of device-detected AT and the occurrence of stroke/STE. In the absence of data from randomized trials of OAC in this population, it remains unclear if treatment of this very early phase of AF prevents stroke/STE.

      Risk of hemorrhage

      The efficacy of antithrombotic therapy to prevent ischemic stroke must be balanced against the risk of major hemorrhage, particularly cerebral, which is often fatal. The bleeding risk depends on the specific antithrombotic agent and a variety of patient characteristics. Hemorrhagic risks increase as antithrombotic intensity increases from (1) ASA (75-325 mg/day) or clopidogrel (75 mg/day) alone, to (2) combination ASA plus clopidogrel, to (3) dabigatran 110 mg twice per day [bid], to (4) dabigatran 150 mg/day, rivaroxaban, and vitamin-K antagonists (VKAs), which carry similar risks. Apixaban appears to have a lower risk of major bleeding than VKAs. For VKAs, the bleeding risk depends upon the international normalized ratio (INR), the quality of monitoring, the duration of therapy (higher risk during initial few weeks of therapy), and the stability of dietary and other factors that may alter VKA potency. Bleeding risk is likely higher in common clinical practice than in the rigourous setting of a clinical trial or a dedicated, expert anticoagulation service.
      The 2010 ESC and CCS AF guidelines
      • Camm A.J.
      • et al.
      European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery
      Guidelines for the management of atrial fibrillation The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC) [erratum in 2011;32:1172].
      • Cairns J.A.
      • Connolly S.J.
      • McMurtry S.
      • et al.
      Canadian Cardiovascular Society atrial fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter.
      recommended the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly (> 65 Years), Drugs/Alcohol Concomitantly (HAS-BLED) score schema
      • Pisters R.
      • Lane D.A.
      • Nieuwlaat R.
      • et al.
      A novel user-friendly score (HAS-BLED) to assess one-year risk of major bleeding in atrial fibrillation patients: the Euro Heart Survey.
      for predicting bleeding risk. HAS-BLED 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. The HAS-BLED score allows clinicians to assign individualized patient risks of major bleeding from about 1% (score 0-1) to 12.5% (score 5). The HAS-BLED schema has been further validated in a large elderly, hospitalized population.
      • Olesen J.B.
      • Lip G.Y.H.
      • Hansen P.R.
      • et al.
      Bleeding risk in ‘real world’ patients with atrial fibrillation: comparison of two established bleeding prediction schemes in a nationwide cohort.
      The annual major bleeding rate was surprisingly high; 5.11% in the non-OAC group and 5.27% in the OAC group. The c-statistic associated with the 3-level grouping of patients was high (about 0.8).
      The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) score
      • Fang M.C.
      • Go A.S.
      • Chang Y.
      • et al.
      A new risk scheme to predict warfarin-associated hemorrhage The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study.
      assigns points to the following variables: anemia (3), severe renal disease (3), age ≥ 75 years (2), prior hemorrhage (1), and hypertension (1). The annual rates of major bleeding in the validation cohort were: 0.83% (0-3 points), 2.41% (4 points), and 5.32% (5-10 points). The c-statistics for continuous scores and for categories were 0.74 and 0.69 respectively, better than for 6 other published schemes. Surprisingly, no comparison was made to the HAS-BLED score. The HAS-BLED schema is simpler to remember and easier to use, and we suggest it as the best available for hemorrhage risk prediction over other more complicated (eg, Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older [Age > 75 Years], Reduced Platelet Count or Function, Rebleeding Risk, Hypertension [Uncontrolled], Anemia, Genetic Factors, Excessive Fall Risk, and Stroke [HEMORR2HAGES]) or less-validated (eg, ATRIA) schemas.
      The application of a bleeding risk schema is useful to ensure that important risk factors are systematically considered. The score can be useful in comparing the relative risks of stroke vs major bleeding with various antithrombotic therapies. Many of the factors that determine stroke risk are also predictors of bleeding, but stroke risks usually exceed those of major bleeding. Furthermore, 70% of strokes with AF are either fatal or leave severe residual deficits, whereas major bleeding is less often fatal and is less likely to leave significant residual effects in survivors. Patients at increased risk of major bleeding warrant extra caution and closer monitoring of antithrombotic therapy. Only when the stroke risk is low and the bleeding risk particularly high (eg, a young patient with AF and few or no stroke risk factors, but a high risk of major hemorrhage because of malignancy, prior major hemorrhage, or participation in contact sports) does the risk/benefit ratio favour no antithrombotic therapy. Patient preferences are of great importance in deciding on stroke prevention therapy in relation to benefits and risks.

      Newer OACs

      The limitations of warfarin as an OAC are well known. The degree of INR prolongation by a given dose of warfarin is unpredictable because of numerous factors affecting pharmacokinetics and pharmacodynamics. INR measurements are required at least monthly to maintain a safe/effective INR. Even with careful monitoring, it is difficult to achieve therapeutic range INRs > 65% of the time, and AF patients typically experience major bleeding at a rate of about 3.0 % per year.
      • Paikin J.S.
      • Eikelboom J.
      • Cairns J.A.
      • Hirsh J.
      New antithrombotic agents-insights from clinical trials.
      Several new OACs have been developed to obviate some of the problems associated with VKAs.
      • Paikin J.S.
      • Eikelboom J.
      • Cairns J.A.
      • Hirsh J.
      New antithrombotic agents-insights from clinical trials.
      Dabigatran, rivaroxaban, and apixaban have undergone extensive clinical evaluation and been found to be safe and efficacious.
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.V.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      They exert their anticoagulant effects by combining reversibly with either thrombin (dabigatran) or factor Xa (rivaroxaban and apixaban). Maximal blood levels and anticoagulant effects are observed quickly after oral intake. After drug discontinuation, anticoagulant effects diminish quickly because of short serum and receptor inhibition half-lives. Their absorption is largely unaffected by food or other medications, and their elimination kinetics are affected by few agents. Dose recommendations vary little among patients and anticoagulation monitoring is not required. Dose reductions are indicated for patients with reduced renal function, advanced age, or low body mass index. Two disadvantages are (1) clinically useful measurement of anticoagulant effect is challenging, and (2) no specific antidotes are yet available.

      Efficacy and safety of new OACs in AF patients

      Dabigatran is approved in Canada, the USA, and Europe for the prevention of stroke and STE in AF and atrial flutter (AFL). 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.
      18,113 AF patients (mean CHADS2 = 2.1) were randomized to dabigatran (110 mg vs 150 mg twice daily, double-blind) or open-label warfarin and followed for a median of 2.0 years. The principal outcome rates (stroke or STE) were 1.69% per year with warfarin, 1.53% per year with dabigatran 110 mg (RR 0.91; 95% confidence interval [CI], 0.74-1.11), and 1.11% per year with dabigatran 150 mg (RR 0.66; 95% CI, 0.53-0.82; P < 0.001 vs warfarin). (Throughout this report, when RR is followed by a range, it indicates 95% CI). Major bleeding rates were 3.36% per year with warfarin, 2.71% with dabigatran 110 mg (RR vs warfarin 0.8; P = 0.003), and 3.11% with dabigatran 150 mg (RR vs warfarin 0.93; P = 0.31). Net clinical benefit rates (composite of stroke, STE, pulmonary embolism, MI, death, or major bleeding) were 7.64% per year with warfarin, 7.09% per year with dabigatran 110 mg (RR vs warfarin 0.92; 0.84-1.02), and 6.91% per year with dabigatran 150 mg (RR vs warfarin 0.91; 0.82-1.00). Patients taking dabigatran had more gastrointestinal (GI) bleeding, twice the likelihood of dyspepsia, and discontinued therapy almost 50% more often in the first year of therapy.
      Rivaroxaban is approved in Canada, the USA, and Europe for the prevention of stroke and STE in AF/AFL. The double-blind ROCKET-AF trial
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      randomized 14,264 AF patients (mean CHADS2 = 3.5) to rivaroxaban 20 mg once daily (15 mg once daily when CrCl was 30-49 mL/minute) or warfarin (median follow-up 1.9 years). Principal efficacy outcome rates (composite of stroke or STE were 2.2% per year with warfarin and 1.7% per year with rivaroxaban (RR vs warfarin 0.79; 0.66-0.96). In a secondary, intention-to-treat analysis, the respective rates were 2.4% vs 2.1% (RR 0.88; 0.75-1.03; P = 0.12 for superiority). Major bleeding rates were 3.4% per year with warfarin vs 3.6% with rivaroxaban (RR 1.04). There was significantly less intracranial, but more GI, bleeding with rivaroxaban. No net clinical benefit data were reported. MI rates were 1.12% per year with warfarin vs 0.91% per year with rivaroxaban (RR 0.81; P = 0.121). Adverse events occurred in 81.4% of rivaroxaban subjects vs 83.1% taking warfarin, with only epistaxis and hematuria significantly more common with rivaroxaban.
      Apixaban is not yet approved in Canada for stroke prevention in AF. In the ARISTOTLE trial,
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.V.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      18,113 AF-patients (mean CHADS2 = 2.1) were randomized (double-blind) to apixaban 5 mg twice daily (2.5 mg twice daily for 2 or more of: [1] age ≥ 80, [2] weight ≤ 60 kg, [3] serum creatinine ≥ 133 μmol/L) or to warfarin and followed for a median of 1.8 years. Principal outcome rates (stroke or STE) were 1.60% per year with warfarin vs 1.27% per year with apixaban (RR vs warfarin 0.79; 0.66-0.95; P < 0.01 for superiority). Major bleeding rates were 3.09% per year with warfarin vs 2.13% with apixaban (RR 0.69; P < 0.001), with substantial and statistically significant reductions in intracranial and GI bleeding. Net clinical benefit outcome rates (composite of stroke, STE, major bleeding, and all-cause mortality) were 4.11% per year with warfarin vs 3.17% per year with apixaban (RR 0.85; 0.78-0.92; P < 0.001). MI rates were 0.61% per year with warfarin vs 0.53% per year with apixaban (RR 0.88; P = 0.37). Overall adverse event rates were 81.5% (apixaban) vs 83.1% (warfarin), with no adverse event categories more frequent in patients taking apixaban.
      In the Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Strokes in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial,
      • Connolly S.J.
      • Eikelboom J.
      • Joyner C.
      • et al.
      Apixaban in patients with atrial fibrillation.
      5590 AF patients (mean CHADS2 = 2.0) unsuitable for warfarin therapy were randomized double-blind to apixaban 5 mg twice daily (2.5 mg twice daily in selected patients) or to the combination of ASA plus clopidogrel, and followed for a median of 1.1 years. The trial was stopped early because of marked outcome differences. Principal outcome rates (stroke or STE) were 3.7% per year with ASA/clopidogrel vs 1.6% per year with apixaban (RR vs ASA/clopidogrel 0.45; 0.32-0.62; P < 0.001). The rates of major bleeding were 1.2% per year with ASA/clopidogrel vs 1.4% with apixaban (RR 1.13; P < 0.57), with no significant differences in intracranial or GI bleeding.
      In summary, compared with warfarin, both dabigatran and apixaban are more efficacious than warfarin for the prevention of stroke and STE, while rivaroxaban is noninferior to warfarin. Apixaban causes less major bleeding than warfarin, while in comparison with warfarin there is no more major bleeding with either dabigatran 150 mg or rivaroxaban. There is significantly less intracranial bleeding with each of the new agents than with warfarin.
      The recommendations made by previous national guidelines exercises were based upon a total of 2900 patients in the randomized trials of warfarin vs control, 3990 patients in the trials of ASA vs control and 3647 patients in the trials of warfarin vs ASA. The 3 recent trials randomized over 50,000 subjects to 1 of the new agents vs warfarin, and 5500 to apixaban vs ASA/clopidogrel. The 5 major primary prevention trials of warfarin compared with control showed an absolute risk reduction (ARR) for stroke of 2.7% per year, and a number-needed-to-treat (NNT) of 37 to avoid 1 stroke during 1 year of treatment.
      • Hart R.G.
      • Pearce L.A.
      • Aguilare M.I.
      Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation.
      In RE-LY, the ARR for dabigatran vs warfarin was 0.58% per year (NNT = 172) and in ARISTOTLE the ARR for apixaban vs warfarin was 0.33% per year (NNT = 303). For intracranial hemorrhage, the ARRs are small (dabigatran ARR 0.44% per year, NNT = 227; rivaroxaban ARR 0.2% per year, NNT = 500; and apixaban ARR 0.47% per year, NNT = 213).
      Fig. 1)
      We recommend that all patients with AF or AFL (paroxysmal, persistent, or permanent), should be stratified using a predictive index for stroke risk (eg, CHADS2) and for the risk of bleeding (eg, HAS-BLED), and that most patients should receive either an OAC or ASA (Strong Recommendation, High-Quality Evidence).
      Figure thumbnail gr1
      Figure 1Summary of recommendations for antithrombotic agent use based on Congestive Heart Failure, Hypertension, Age > 75, Diabetes Mellitus, and Prior Stroke or Transient Ischemic Attack (CHADS2) score. Additional risk factors of age > 65, vascular disease, and female sex are integrated to increase granularity at low CHADS2 score (CHADS2 = 0). ASA, acetylsalicylic acid (aspirin); OAC, oral anticoagulant.
      We suggest, that when OAC therapy is indicated, most patients should receive dabigatran, rivaroxaban, or apixaban (once approved by Health Canada), in preference to warfarin (Conditional Recommendation, High-Quality Evidence).
      Values and preferences. This recommendation places a relatively high value on comparisons with warfarin showing that dabigatran and apixaban have greater efficacy and rivaroxaban has similar efficacy for stroke prevention; dabigatran and rivaroxaban have no more major bleeding and apixaban has less; all 3 new OACs have less intracranial hemorrhage and are much simpler to use. The recommendation places less value on the following features of warfarin: long experience with clinical use, availability of a specific antidote, and a simple and standardized test for intensity of anticoagulant effect. The preference for 1 of the new OACs over warfarin is less marked among patients already receiving warfarin with stable INRs and no bleeding complications.
      We recommend that patients at high risk of stroke (CHADS2 ≥ 2) should receive OAC therapy (Strong Recommendation, High-Quality Evidence).
      We recommend that most patients at intermediate risk of stroke (CHADS2 = 1) should receive OAC therapy (Strong Recommendation, High-Quality Evidence).
      We suggest, based on individual risk/benefit considerations, that ASA 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 OACs compared with ASA and less weight on the absolute increased risk for major hemorrhage with OACs compared with ASA.
      We suggest that patients at low risk of stroke (CHADS2 = 0) should have additional risk factors for stroke considered (including age 65-74 years, female sex, and presence of vascular disease) (Conditional Recommendation, Moderate-Quality Evidence).
      We suggest OAC therapy for patients at highest risk within this category (age greater than age 65 or the combination of female sex and vascular disease); ASA (75-325 mg/day) for patients at lower risk within this category (female sex or vascular disease); and no antithrombotic therapy for those patients at lowest risk in this category (no additional risk factors) (Conditional Recommendation, Low-Quality Evidence).
      Values and preferences. Among patients at higher risk, this recommendation places greater weight on the strokes prevented by OAC and ASA and less weight on the major bleeds caused. Among patients at lowest risk, this recommendation places greater weight on the inconvenience, costs, and risks (major hemorrhage) with OAC and ASA and relatively less weight on the strokes prevented.

      Elderly patients

      Advanced age (> 75 years) is a clear risk factor for both ischemic stroke and major hemorrhage. In the overall cohort of the RE-LY trial, there was no significant difference in major bleeding between warfarin and dabigatran 150 mg. There was a significant interaction between age and the choice of therapy.
      • Eikelboom J.W.
      • Wallentin L.
      • Connolly S.J.
      • et al.
      Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial.
      The efficacy of dabigatran was no different among patients aged ≥ 75 years and those < 75 years, but because 150 mg doses of dabigatran may cause more major bleeding among patients older than 75 years, it seems prudent to prescribe dabigatran at 110 mg. For both rivaroxaban and apixaban, efficacy against stroke/STE and safety for the avoidance of major hemorrhage is not significantly different between patients ≥ 75 years vs those < 75 years.
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.V.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.

      Practical tip

      Among patients > 75 years and certainly those > 80 years, dose reduction of the new OACs, especially dabigatran, should be considered.
      As experience with the new OACs increases, a number of practical issues around their use will become clearer. Practical tips are provided to assist the practitioner in using new OACs where reasonable data exist to guide therapy. Further data are needed to guide bridging prior to and after surgical procedures, DC cardioversion, monitoring of anticoagulant effect, and reversal when bleeding occurs using new OACs. Likewise, advice for dose-reduction related to low body mass index and in the presence of hepatic dysfunction is needed.

      Coronary artery disease

      AF patients with concomitant coronary artery disease (CAD) present issues of concomitant antithrombotic therapy in the settings of primary prevention, stable CAD, acute coronary syndrome (ACS), or percutaneous coronary intervention (PCI). There is good randomized clinical trial (RCT) evidence
      • Becker R.C.
      • Meade T.W.
      • Berger P.B.
      • et al.
      The primary and secondary prevention of coronary artery disease.
      for the use of ASA, clopidogrel, combination ASA plus clopidogrel, and warfarin for patients with various manifestations of CAD. For primary prevention of coronary events, low-intensity warfarin (INR ≥ 1.5) is as effective as ASA. For secondary prevention post-MI, warfarin alone (INR 2.8–4.8) is at least as efficacious as ASA alone in preventing coronary events.
      • Becker R.C.
      • Meade T.W.
      • Berger P.B.
      • et al.
      The primary and secondary prevention of coronary artery disease.
      RCTs have shown the benefits of ASA plus clopidogrel for up to 1 year following an ACS (with or without PCI) and for PCI (both elective and post-ACS).
      • Becker R.C.
      • Meade T.W.
      • Berger P.B.
      • et al.
      The primary and secondary prevention of coronary artery disease.
      There has been no rigourous comparison of the combination of ASA and clopidogrel vs warfarin for patients post ACS, but RCTs have shown that ASA plus clopidogrel is more effective than warfarin (alone or in combination with ASA) post-PCI.
      No RCTs have specifically addressed antithrombotic management of patients with AF who also have CAD. For patients who require both OAC for stroke prophylaxis and antiplatelet therapy to prevent coronary events, so-called “triple therapy” (a combination of OAC, ASA, and a thienopyridene) is often prescribed, no studies have compared new OACs with placebo or ASA in primary CAD prevention, stable CAD, ACS, or PCI. However, from the trials of new OACs vs warfarin for AF, data are available on the comparative rates of coronary events overall and in subsets of CAD patients.
      The RE-LY trial initially reported a higher incidence of MI with dabigatran 150 mg dose vs warfarin (RR 1.38; 1.00-1.91; P = 0.048).
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      A recent meta-analysis incorporating the RE-LY data found a similar result but also noted a reduction in all-cause mortality associated with dabigatran.
      • Uchino K.
      • Hernandez A.V.
      Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials.
      An updated analysis of RE-LY
      • Hohnloser S.H.
      • Oldegren J.
      • Yang S.
      • et al.
      Myocardial ischemic events with atrial fibrillation treated with dabigatran or warfarin.
      found only a trend toward more frequent MIs on dabigatran (RR 1.27; 0.94-1.71; P = 0.12). Analysis of the composite outcomes of (1) MI, unstable angina, cardiac arrest, or cardiac death (RR 0.98; 0.85-1.12; P = 0.77), (2) composite cardiac events plus stroke and STE (RR 0.88; 0.78-0.98; P = 0.03), and (3) net clinical benefit (RR 0.90; 0.82-0.99; P = 0.02) favoured dabigatran over warfarin. When patients were categorized as having a baseline history of CAD and/or previous MI, there were no statistically significant interactions between allocated therapy and any of the major outcomes. In ROCKET-AF
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      , the MI RR for rivaroxaban vs warfarin was 0.81 (P = 0.121). In ARISTOTLE,
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.V.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      the MI RR for apixaban vs warfarin was 0.61 (P = 0.37). The available data from the RCTs of new OACs vs warfarin in AF do not suggest mitigation of the efficacies for the prevention of stroke in patients with CAD, nor does it suggest an excess of coronary events among those receiving any of the new OACs. Therefore, the qualifier that warfarin is preferred over dabigatran for patients at increased risk of coronary events presented in the 2010 CCS Guidelines, has been removed.
      There have been 3 recently published randomized phase II dose-finding trials of triple therapy (using 1 of the new OACs) vs ASA/clopidogrel,
      • Alexander J.H.
      • Becker R.C.
      • Bhatt D.L.
      • et al.
      Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial.
      • Mega J.L.
      • Braunwald E.
      • Mohanavelu S.
      • et al.
      Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial.
      • Oldgren J.
      • Budaj A.
      • Granger C.B.
      • et al.
      Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial.
      each of which found a substantial and significant increase in major bleeding rates with triple therapy. In none of the studies was there a significant reduction nor a suggestion of an increase in the principal coronary-ischemic outcome events. The patient cohorts in these studies were younger than the AF populations in studies comparing new OACs with warfarin and the patients did not have strong indications for anticoagulant therapy (eg, AF). A phase III study
      • Mega J.L.
      • Braunwald E.
      • Wiviott S.D.
      • et al.
      Rivaroxaban in patients with a recent acute coronary syndrome.
      of rivaroxaban “triple therapy” vs ASA plus clopidogrel found a statistically significant reduction of the primary composite outcome (cardiovascular death, MI, or stroke) but a significant increase of major bleeding. A similar phase III study of apixaban
      • Alexander J.H.
      • Lopes R.D.
      • Kilaru J.S.
      • et al.
      Apixaban with antiplatelet therapy after acute coronary syndrome.
      was stopped early because of high rates of major bleeding. The risk of major bleeding is definitely increased with the addition of any of the new OACs to antiplatelet therapy, as is observed with warfarin as part of “triple therapy.”
      In summary, no RCTs have directly addressed the management of patients with both AF and CAD. In the absence of RCTs, guidelines must be derived from reasonable extrapolations from the available RCTs in AF and CAD alone and from evidence of lesser quality among patients with both AF and CAD. The 2010 CCS Consensus recommended that warfarin be used in preference to dabigatran in those patients with AF and CAD requiring OAC therapy. The available evidence now suggests that 1 of the new OACs could be used in preference to warfarin when an OAC is indicated for the prevention of stroke in a patient with concomitant AF and CAD. Recommendations with respect to ACS and PCI remain unchanged. A full discussion can be found in the 2010 Guidelines.
      • Cairns J.A.
      • Connolly S.J.
      • McMurtry S.
      • et al.
      Canadian Cardiovascular Society atrial fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter.
      The issues regarding antithrombotic therapies for patients with CAD plus AF have been extensively discussed in recent evidence-based guidelines.
      • 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.
      • Singer D.E.
      • Albers G.W.
      • Dalen J.E.
      • et al.
      Antithrombotic therapy in atrial fibrillation.
      • 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.
      Fig. 2)
      We suggest that patients with AF/AFL who have stable CAD should receive antithrombotic therapy selected based upon their risk of stroke (ASA for most CHADS2 = 0 and OAC for most CHADS2 ≥ 1) (Conditional Recommendation, Moderate-Quality Evidence).
      Figure thumbnail gr2
      Figure 2A summary of our recommendations for antithrombotic management in settings of CAD. ACS, acute coronary syndrome; AF, atrial fibrillation; AFL, atrial flutter; ASA, acetylsalicylic acid (aspirin); CAD, coronary artery disease; CHADS2, Congestive Heart Failure, Hypertension, Age > 75, Diabetes Mellitus, and Prior Stroke or Transient Ischemic Attack; OAC, oral anticoagulant; PCI, percutaneous coronary intervention.
      We suggest that patients with AF/AFL who have experienced ACS or who have undergone PCI, should receive antithrombotic therapy selected based on 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 ASA plus clopidogrel plus OAC (Conditional Recommendation, Low-Quality Evidence).

      Stroke prevention in non-valvular AF in patients with chronic kidney disease

      Chronic kidney disease (CKD) commonly afflicts patients with AF,
      • Baber U.
      • Howard V.J.
      • Halperin J.L.
      • et al.
      Association of chronic kidney disease with atrial fibrillation among adults in the United States: REasons for Geographic and Racial Differences in Stroke (REGARDS) study.
      • Iguchi Y.
      • Kimura K.
      • Kobayashi K.
      • et al.
      Relation of atrial fibrillation to glomerular filtration rate.
      • Jonsson K.M.
      • Wieloch M.
      • Sterner G.
      • et al.
      Glomerular filtration rate in patients with atrial fibrillation on warfarin treatment: a subgroup analysis from the auricula registry in sweden.
      and can influence drug metabolism,
      • Harder S.
      Renal profiles of anticoagulants.
      rates of bleeding,
      • Lip G.Y.
      • Frison L.
      • Halperin J.L.
      • Lane D.A.
      Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score.
      and rates of stroke.
      • Nakagawa K.
      • Hirai T.
      • Takashima S.
      • et al.
      Chronic kidney disease and CHADS(2) score independently predict cardiovascular events and mortality in patients with nonvalvular atrial fibrillation.
      Management of AF-patients therefore requires accurate assessments of renal function and recognition of comorbid CKD to make safe and effective therapeutic choices. More detailed discussion of assessment of estimated glomerular filtration rate (eGFR), the effect of CKD on rates of stroke and hemorrhage, and therapies for stroke prevention in AF is in the Supplementary Material.

      Clinical trials

      Clinical trials of antiplatelet agents or OACs in AF have not systematically enroled patients with severe CKD (glomerular filtration rate [GFR] < 30 mL/minute) (see Supplemental Table S1). Data from RCTs of stroke/STE prevention (Table 1) support OAC use in patients with mild to moderate CKD, but there are no RCT data in patients with severe CKD (GFR < 30 mL/minute).
      Table 1Therapeutic choices in patients with chronic kidney disease and stroke risk factors (CHADS2 ≥ 1)
      GFRWarfarinDabigatranRivaroxabanApixaban
      Not yet approved by Health Canada.
      GFR ≥ 60 mL/minDose adjusted for INR 2.0-3.0
      • Hart R.G.
      • Pearce L.A.
      • Asinger R.W.
      • Herzog C.A.
      Warfarin in atrial fibrillation patients with moderate chronic kidney disease.
      150 mg bid or 110 mg bid
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      20 mg daily
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      5 mg bid
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.V.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      GFR 50-59 mL/minDose adjusted for INR 2.0-3.0
      • Hart R.G.
      • Pearce L.A.
      • Asinger R.W.
      • Herzog C.A.
      Warfarin in atrial fibrillation patients with moderate chronic kidney disease.
      150 mg bid or 110 mg bid
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      20 mg daily
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      5 mg bid
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.V.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      GFR 30-49 mL/minDose adjusted for INR 2.0-3.0
      • Hart R.G.
      • Pearce L.A.
      • Asinger R.W.
      • Herzog C.A.
      Warfarin in atrial fibrillation patients with moderate chronic kidney disease.
      150 mg bid or 110 mg bid
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      15 mg daily
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      5 mg bid (for GFR > 25 mL/min only)
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.V.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.


      Consider 2.5 mg bid
      Consider Apixaban 2.5 mg po bid if GFR ≤ 25 mL/min, especially if age > 80 or body weight < 60 kg.20
      GFR 15-29 mL/min (not on dialysis)No RCT data
      Dose adjusted warfarin has been used, but observational data regarding safety and efficacy is conflicting (see text).
      No RCT data
      Modelling studies suggest that dabigatran 75 mg bid might be safe for patients with GFR 15-29 mL/min, but this has not been validated in a prospective cohort.18
      No RCT data
      No published studies support a dose for this level of renal function; product monographs suggest the drug is contraindicated for this level of renal function.
      5 mg bid (for GFR > 25 mL/min only)
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.V.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.


      Consider 2.5 mg bid
      Consider Apixaban 2.5 mg po bid if GFR ≤ 25 mL/min, especially if age > 80 or body weight < 60 kg.20
      GFR < 15 mL/min (on dialysis)No RCT data
      Dose adjusted warfarin has been used, but observational data regarding safety and efficacy is conflicting (see text).
      No RCT data
      No published studies support a dose for this level of renal function; product monographs suggest the drug is contraindicated for this level of renal function.
      No RCT data
      No published studies support a dose for this level of renal function; product monographs suggest the drug is contraindicated for this level of renal function.
      No RCT data
      bid, twice daily; CHADS2, Congestive Heart Failure, Hypertension, Age > 75, Diabetes Mellitus, and Prior Stroke or Transient Ischemic Attack score; GFR, glomerular filtration rate; INR, international normalized ratio; RCT, randomized clinical trial.
      low asterisk Not yet approved by Health Canada.
      Consider Apixaban 2.5 mg po bid if GFR ≤ 25 mL/min, especially if age > 80 or body weight < 60 kg.
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.V.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      Dose adjusted warfarin has been used, but observational data regarding safety and efficacy is conflicting (see text).
      § Modelling studies suggest that dabigatran 75 mg bid might be safe for patients with GFR 15-29 mL/min, but this has not been validated in a prospective cohort.
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      No published studies support a dose for this level of renal function; product monographs suggest the drug is contraindicated for this level of renal function.

      Observational studies

      Observational studies of warfarin for stroke prevention in AF patients with CKD have provided inconsistent results. An observational study of 399 patients with CKD and AF, including 93 patients on dialysis and 132 with an eGFR of < 15 mL/minute per 1.73m2, suggested a significantly lower rate of stroke with warfarin vs no warfarin and no significant increase in hemorrhage.
      • Lai H.M.
      • Aronow W.S.
      • Kalen P.
      • et al.
      Incidence of thromboembolic stroke and of major bleeding in patients with atrial fibrillation and chronic kidney disease treated with and without warfarin.
      Two other small observational studies did not identify benefit with warfarin in dialysis patients with AF.
      • To A.C.
      • Yehia M.
      • Collins J.F.
      Atrial fibrillation in haemodialysis patients: do the guidelines for anticoagulation apply?.
      • Genovesi S.
      • Vincenti A.
      • Rossi E.
      • et al.
      Atrial fibrillation and morbidity and mortality in a cohort of long-term hemodialysis patients.
      Some reports suggest that in AF patients on dialysis, warfarin use is associated with harm. In an observational study of 2188 dialysis patients, warfarin use was associated with increased stroke risk, especially in those > 75 years old (RR 2.17; 1.04-4.53).
      • Wizemann V.
      • Tong L.
      • Satayathum S.
      • et al.
      Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy.
      Another study in 1671 dialysis patients found a similarly increased rate of both ischemic (5.8% warfarin use vs 2.3% nonuse) and hemorrhagic stroke (1.2% warfarin use vs 0.5% nonuse).
      • Chan K.E.
      • Lazarus J.M.
      • Thadhani R.
      • Hakim R.M.
      Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation.
      A large retrospective cohort study evaluated 41,425 patients with incident hemodialysis but not necessarily AF, and found increased mortality with warfarin (RR 1.27; 1.18-1.37), clopidogrel (RR 1.24; 1.13-1.35), and ASA (RR 1.06; 1.01-1.11).
      • Chan K.E.
      • Lazarus J.M.
      • Thadhani R.
      • Hakim R.M.
      Anticoagulant and antiplatelet usage associates with mortality among hemodialysis patients.
      Although observational studies are prone to confounders and bias, the findings are disconcerting and highlight an urgent need for RCTs of antithrombotic therapies for stroke prevention in patients with severe CKD and also AF. The Kidney Disease: Improving Global Outcomes authors have advised that, pending further data, “routine anticoagulation of dialysis-dependent CKD patients with AF for primary prevention of stroke is not indicated.”
      • Herzog C.A.
      • Asinger R.W.
      • Berger A.K.
      • et al.
      Cardiovascular disease in chronic kidney disease A clinical update from kidney disease: improving global outcomes (KDIGO).
      We recommend that patients with AF who are receiving OAC:
      Have their renal function assessed at least annually by measuring serum creatinine and calculating eGFR (Strong Recommendation, Moderate-Quality Evidence).
      Be regularly considered for the need for alteration of OAC drug and/or dose changes based on eGFR (Strong Recommendation, Moderate-Quality Evidence).
      For antithrombotic therapy of CKD patients, therapy should relate to eGFR as follows:
      eGFR > 30 mL per minute: We recommend that such patients receive antithrombotic therapy according to their CHADS2 score as detailed in recommendations for patients for patients with normal renal function (Strong Recommendation, High-Quality Evidence).
      eGFR 15-30 mL per minute and not on dialysis: We suggest that such patients receive antithrombotic therapy according to their CHADS2 score as for patients with normal renal function. The preferred agent for these patients is warfarin (Conditional Recommendation, Low-Quality Evidence).
      Values and preferences. This recommendation places a relatively higher value on prevention of ischemic stroke than on bleeding complications associated with antithrombotic therapy, as well as the limited data available for new OACs in CKD patients. No therapy may be appropriate for some patients with eGFR 15-30 mL per minute (not on dialysis), with a stronger preference for avoiding bleeding complications than preventing ischemic stroke.
      eGFR < 15mL per minute (on dialysis): We suggest that such patients not routinely receive either OAC (Conditional Recommendation, Low-Quality Evidence) or ASA for stroke prevention in AF (Conditional Recommendation, Low-Quality Evidence).
      Values and preferences. This recommendation places a relatively higher weight on observational data linking warfarin and ASA use with mortality in patients on dialysis, and relatively lower weight on the potential for these agents to prevent ischemic stroke. Therapy with OACs or antiplatelet drugs may be appropriate for some patients with eGFR < 15 mL per minute (on dialysis) in whom there is a stronger preference for avoiding ischemic stroke.

      Practical tip

      Patients with eGFR 30-50 mL per minute need more frequent measures of eGFR and may need OAC dose reductions with conditions that may transiently reduce eGFR. This is especially true in the elderly (age older than 75 years) as bleeding risk increases with age.
      • Eikelboom J.W.
      • Wallentin L.
      • Connolly S.J.
      • et al.
      Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial.

      Updated Guidelines for Rate/Rhythm Control

      Updated risk/benefit assessment for dronedarone

      The “A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death From Any Cause in Patients With Atrial Fibrillation/Atrial Flutter” (ATHENA) trial evaluated the safety and efficacy of dronedarone therapy in 4628 higher risk patients with AF or AFL (paroxysmal or persistent with sinus rhythm restoration planned).
      • Hohnloser S.H.
      • Crijns H.J.
      • van Eickels M.
      • et al.
      Effect of dronedarone on cardiovascular events in atrial fibrillation.
      After a mean follow-up of 21 ± 5 months, there was a reduction in the primary outcome variable (death or first cardiovascular hospitalization) from 39.4% (placebo group) to 31.9% (dronedarone group; RR 0.76; 0.69-0.84; P < 0.001). There was also a statistically significant reduction in cardiovascular mortality (RR 0.71; 0.51-0.98; P = 0.03) and death from cardiac arrhythmia (RR 0.55; 0.34-0.88; P = 0.01). In a post hoc analysis there was a statistically significant reduction in stroke (RR 0.66; 0.46-0.96, P = 0.03).
      • Connolly S.J.
      • Crijns H.J.
      • Torp-Pedersen C.
      • et al.
      Analysis of stroke in ATHENA: a placebo-controlled, double-blind, parallel-arm trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular hospitalization or death from any cause in patients with atrial fibrillation/atrial flutter.
      There were 473 patients in ATHENA that developed permanent AF: these patients had a similar response to dronedarone therapy as the overall study population with respect to the primary outcome.
      • Nieuwlaat R.
      • Hohnloser S.H.
      • Connolly S.J.
      Effects of dronedarone in patients with permanent atrial fibrillation during the ATHENA study [abstract].
      The latter observation led to the hypothesis that dronedarone has beneficial effects independent of AF prevention perhaps mediated by ventricular rate-slowing, blood pressure lowering, adrenergic blockade, and/or ventricular fibrillation prevention. This hypothesis was tested in the PALLAS trial; a double-blind, placebo-controlled, parallel group RCT involving higher risk permanent AF patients.
      • Connolly S.J.
      • Camm A.J.
      • Halperin J.L.
      • et al.
      Dronedarone in high-risk permanent atrial fibrillation.
      The PALLAS trial intended to enrol 10,800 patients during a 2-year period with 1 additional year of follow-up. The trial was prematurely terminated for safety reasons after enrolment of 3236 patients. PALLAS had 2 coprimary outcomes; the composite of stroke, MI, STE, or death from cardiovascular causes (termed the first coprimary outcome) and the composite of death or first unplanned cardiovascular hospitalization (the second coprimary outcome). After a median follow-up of 3.5 months, there were increases in the first coprimary outcome from 1.2% in the placebo group to 2.7% in the dronedarone group (RR 2.29; 1.34-3.94, P = 0.002) and in the second coprimary outcome from 4.1% (placebo group) to 7.8% (dronedarone group; RR 1.95; 1.45-2.62; P < 0.001). The composites included statistically significant increases in first unplanned cardiovascular hospitalization (RR 1.97; 1.44-2.70; P < 0.001), first unplanned heart failure hospitalization (RR 1.97; 1.44-2.70; P < 0.001), death from any cause (RR 1.81; 1.10-2.99; P = 0.05), stroke (RR 2.32; 1.11-4.88; P = 0.02), and a statistically nonsignificant increase in ACS (RR 1.89; 0.80-4.45; P = 0.14). There was also a statistically significant increase in any reported liver function abnormality from 1.7% in the placebo group to 3.8% in the dronedarone group (P < 0.001). Acute liver injury has also been reported in the postmarket release experience with the drug.
      • Joghetaei N.
      • Weirich G.
      • Huber W.
      • Buchler P.
      • Estner H.
      Acute liver failure associated with dronedarone.
      The results of PALLAS thus stand in stark distinction to those of ATHENA. The mechanism for this dichotomy has not been determined. Working on the premise that both results are valid for their respective populations, considerations of potential mechanisms for this dichotomy have focused on differences between the 2 study populations. One clear difference is that ATHENA enroled patients with paroxysmal or persistent AF/AFL while PALLAS enroled patients with permanent AF/AFL. Accordingly, dronedarone should not be used in patients with permanent AF/AFL for the purpose of rate control. This is a change from the 2010 version of the guidelines in which dronedarone was listed as a second-line choice for rate control (see Fig. 3 for an updated rate-control guideline schema).
      Figure thumbnail gr3
      Figure 3Summary of recommendations for choice of rate-control agents for various conditions. CAD, coronary artery disease; CCB, calcium channel blocking agents; Rx, therapy.
      PALLAS patients were also significantly older, with a higher proportion of males and a higher prevalence of CAD compared with ATHENA. Of particular note, PALLAS patients were more likely to have symptomatic congestive heart failure (54% vs 21%), a left ventricular ejection fraction ≤ 0.40 (21% vs less than 12%), and were more likely to be receiving concomitant therapy with digoxin (33% vs 14%). Considering the magnitude of each of these differences, and the prior results of the Antiarrhythmic Trial With Dronedarone in Moderate to Severe Congestive Heart Failure Evaluating Morbidity Decrease (ANDROMEDA) showing increased mortality in patients with severe heart failure and left ventricular dysfunction,
      • Kober L.
      • Torp-Pedersen C.
      • McMurray J.J.
      • et al.
      Increased mortality after dronedarone therapy for severe heart failure.
      dronedarone should not be used in patients with a history of heart failure symptoms or a left ventricular ejection fraction < 0.40. PALLAS showed that dronedarone significantly increases serum digoxin concentrations and data to be published soon will demonstrate a particular increase in harm from the interaction of dronedarone and digoxin. There are 3 new recommendations that were not a part of the 2010 version of the guidelines.
      • Gillis A.M.
      • Verma A.
      • Talajic M.
      • et al.
      Canadian Cardiovascular Society atrial fibrillation guidelines 2010: rate and rhythm management.
      (See Figure 4, Figure 5 for updated rhythm-control drug recommendations).
      Figure thumbnail gr4
      Figure 4Summary of recommendations for choice of rhythm-control therapy in patients with normal systolic left ventricular function and no history of congestive heart failure. AV, atrioventricular; CAD, coronary artery disease; CHF, congestive heart failure; Hx, history; VT, ventricular tachycardia.
      Figure thumbnail gr5
      Figure 5Summary of recommendations for choice of rhythm-control therapy in patients with a history of congestive heart failure (current or remote) or left ventricular systolic dysfunction. CHF, congestive heart failure; EF, ejection fraction; Hx, history; VT, ventricular tachycardia.
      We recommend that dronedarone not be used in patients with permanent AF nor for the sole purpose of rate control (Strong Recommendation, High-Quality Evidence).
      We recommend dronedarone not be used in patients with a history of heart failure or a left ventricular ejection fraction ≤ 0.40 (Strong Recommendation, Moderate-Quality Evidence).
      We suggest dronedarone be used with caution in patients taking digoxin (Conditional Recommendation, Moderate-Quality Evidence).
      Values and preferences. These recommendations recognize that the mechanism(s) for the differences between the results of the ATHENA and the PALLAS trials have not yet been determined. These recommendations are based on the known differences between the 2 patient populations and are also informed by the results of the ANDROMEDA trial.
      Based on this new evidence, it has become clear that dronedarone, like all antiarrhythmic drugs, has important risks and limitations. These risks and limitations are important determinants in choosing an agent and are highlighted throughout the guidelines. For example, flecainide and propafenone should be avoided in patients with atherosclerotic heart disease and heart failure. Sotalol is used with caution in patients at risk of QT-interval prolongation and torsades de pointes, and amiodarone is used with caution because of its risk of long-term noncardiac side effects. Like the other available agents, dronedarone remains a useful antiarrhythmic drug option for appropriately chosen AF patients. These considerations are reflected in the Practical Tip below and are summarized in Figure 4, Figure 5.

      Practical tip

      Dronedarone is a reasonable choice for rhythm control in selected patients with AF. Typically, these would be patients with nonpermanent (predominantly paroxysmal) AF with minimal structural heart disease. Consideration should be given to monitoring for liver enzyme elevations within 6 months of initiating therapy with dronedarone.

      Updated choices for rate control

      It is generally assumed that “uncontrolled AF” is undesirable, because it may lead to worsened symptoms and an increased risk of heart failure. Atrioventricular nodal blocking drugs are administered on the assumption that a slower ventricular response leads to improved subjective and objective outcomes. The 2010 Guidelines emphasize the lack of evidence for this concept, and the revised resting ventricular rate target for AF patients is now set at 100 beats per minute or less.
      • Gillis A.M.
      • Verma A.
      • Talajic M.
      • et al.
      Canadian Cardiovascular Society atrial fibrillation guidelines 2010: rate and rhythm management.
      Either β-blocking drugs or nondihydropyridine calcium channel-blocking drugs (diltiazem, verapamil) can be used to achieve ventricular rate control. Although some new data have become available, there remains insufficient evidence to routinely recommend 1 agent over another. β-blockers are generally more “effective” at slowing ventricular rates both at rest and during exercise than calcium channel blockers, but their use is associated with a higher risk of adverse effects, primarily fatigue and exercise intolerance.
      • Dorian P.
      • Connors S.P.
      Pharmacological and nonpharmacological methods for rate control.
      • Groenveld H.F.
      • Crijns H.J.
      • Van den Berg M.P.
      • et al.
      The effect of rate control on quality of life in patients with permanent atrial fibrillation: data from the Race II (Rate Control Efficacy in Permanent Atrial Fibrillation II) study.
      • Boriani G.
      • Biffi M.
      • Diemberger I.
      • Martignani C.
      • Branzi A.
      Rate control in atrial fibrillation: choice of treatment and assessment of efficacy.
      In a combined analysis of randomized trials of β-blockers and calcium channel blockers vs placebo or digoxin or for rate control in AF, β-blocker use did not improve exercise tolerance during AF in any study, and led to a reduction in maximum exercise capacity in a minority of studies.
      • Boriani G.
      • Biffi M.
      • Diemberger I.
      • Martignani C.
      • Branzi A.
      Rate control in atrial fibrillation: choice of treatment and assessment of efficacy.
      Conversely, rate-slowing calcium channel blockers did not reduce exercise tolerance in any of the studies, and resulted in improved exercise tolerance in a substantial proportion.
      An additional consideration in selection of drugs for rate control is the Canadian Hypertension Education Program recommendation not to use β-blockers as initial antihypertensive therapy in patients older than 60 years.
      • Rabi D.M.
      • Daskalopoulou S.S.
      • Padwal R.S.
      • et al.
      The 2011 Canadian Hypertension Education Program recommendations for the management of hypertension: blood pressure measurement, diagnosis, assessment of risk, and therapy [in English, French].
      Because 60%-80% of patients with AF have hypertension as a cause or comorbidity, it seems reasonable to use a long-acting, rate-slowing calcium channel blocker for both hypertension and rate control, adding other agents (eg, an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, or diuretic) if necessary to achieve recommended blood pressure targets.

      Supplementary material

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      Linked Article

      • Erratum
        Canadian Journal of CardiologyVol. 28Issue 3
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          In March/April 2012 issue, there was an error in the article “Focused 2012 Update of the Canadian Cardiovascular Society Atrial Fibrillation Guidelines: Recommendations for Stroke Prevention and Rate/Rhythm Control” by Skanes et al. (Can J Cardiol 2012;28:125-36). On page 129, in the second and fourth paragraphs, information provided about AVERROES trial was incorrect. The AVERROES trial included 5599 patients and compared apixaban to ASA only, not apixaban to ASA plus clopidogrel. The corrected paragraphs appear below with changes in bold.
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