Atrial fibrillation, anticoagulation, fall risk, and outcomes in elderly patients

Transcription

1 Curriculum in Cardiology Atrial fibrillation, anticoagulation, fall risk, and outcomes in elderly patients Matthew B. Sellers, MD, a and L. Kristin Newby, MD, MHS a,b,c Durham, NC Atrial fibrillation (AF) affects 2.5 million patients in the United States. The incidence of this condition increases with age, such that approximately 5% of people N65 years of age have AF. Because of the lack of organized atrial contraction and thrombus formation in the left atrium, patients with AF are at increased risk of stroke. The estimated risk of stroke among all AF patients is 5% per year. Among patients without mitral stenosis, there is a graded relationship of stroke risk with the number of CHADS 2 risk factors. Warfarin is the recommended treatment for embolic stroke prophylaxis in AF in intermediate- to high-risk patients. However, elderly patients who are deemed to be at risk of falls are often not started on warfarin therapy secondary to a perceived higher risk of bleeding complications. These risks have been evaluated, but conclusive data regarding the riskbenefit trade-off are elusive. This review summarizes available data on the use of warfarin in elderly patients with AF, focusing on the risk of bleeding, and will specifically address the utility of falls risk assessment in the decision to initiate warfarin therapy for AF. (Am Heart J 2011;161:241-6.) Atrial fibrillation (AF) is the most common cardiac arrhythmia and currently affects nearly 2.5 million people in the United States. Approximately 5% of people N65 years of age carry this diagnosis 1 ; and with a growing geriatric population in the United States, this proportion is expected to increase by 2.5-fold over the next 50 years. 2 The risk of stroke in the setting of AF increases with age and may be as high as 23.5% in patients 80 to 90 years of age. 3 Furthermore, not only is AF associated with an increased risk of stroke; but the Framingham Study also demonstrated that mortality from AF-related strokes is almost double that of strokes unrelated to AF, and functional deficits after AF-related strokes were more likely to be severe. 4 Thus, anticoagulation therapy to prevent stroke is of paramount importance in patients at high risk for thromboembolic stroke. However, the bleeding risk associated with warfarin therapy has led physicians to be cautious in using (and, arguably, to underuse) warfarin in older patients, especially those perceived as being at risk for falls. 5,6 Some of these fears may stem from studies showing that antithrombotic therapy can double the risk of intracranial hemorrhage (ICH), especially fatal hemorrhagic events. 7-9 However, several other studies have called into question From the a Department of Medicine, Duke University Medical Center, Durham, NC, b Division of Cardiology, Duke University Medical Center, Durham, NC, and c The Duke Clinical Research Institute, Durham, NC. George J. Klein, MD served as guest editor for this article. Submitted April 2, 2010; accepted November 2, Reprint request: L. Kristin Newby, MD, MHS, Duke Clinical Research Institute, DUMC Box 17969, Durham, NC newby001@mc.duke.edu /$ - see front matter 2011, Mosby, Inc. All rights reserved. doi: /j.ahj the use of falls risk as a contraindication to antithrombotic therapy in the setting of AF for high-risk patients 10,11 ; indeed, there is little agreement on how to define or assess falls risk. Consequently, elderly patients who have the highest risk of stroke and of worse outcomes with stroke in the setting of AF 3,4 may be frequently undertreated despite a lack of evidence to support withholding therapy. This review summarizes some of the robust data behind the use of anticoagulants for stroke prevention in the setting of AF; the data behind adverse events, specifically hemorrhagic events, associated with the use of warfarin and aspirin; and what is presently known about the relationship of falls with bleeding in the context of the general risks and benefits of warfarin therapy in AF. No external sources of funding were used to support this work. The authors are solely responsible for the development of the concept for this review paper, as well as the drafting and editing of the paper and its final contents. Stroke prevention Multiple clinical trials and subsequent meta-analyses have demonstrated the benefit of aspirin compared with placebo, as well as warfarin compared with placebo, in reducing stroke risk among AF patients (Table I). In a pooled analysis of 3 randomized controlled trials (RCTs), the Atrial Fibrillation Investigators found that the relative risk reduction for aspirin versus placebo was 21% (95% CI 0%-38%, P =.05). 12 In addition, another meta-analysis of 6 RCTs of aspirin versus placebo for stroke prevention found that aspirin reduced stroke by 22% (95% CI 2%- 38%), with absolute risk reductions of 1.5% per year for

2 242 Sellers and Newby American Heart Journal February 2011 Table I. Relative risk reduction in meta-analysis of anticoagulation treatment Relative risk reduction No. of trials ASA versus placebo Warfarin versus placebo ASA versus warfarin Reference 3 21% (0%-38%) AF Investigators % (2%-38%) Hart et al % (48%-72%) Hart et al % (14%-52%) Hart et al 13 ASA, Acetylsalicylic acid. primary prevention and 2.5% per year for secondary prevention. 13 Even larger reductions have been demonstrated for warfarin relative to placebo. In 6 trials of warfarin versus placebo, adjusted-dose warfarin resulted in a risk reduction of 62% (95% CI 48%-72%). Finally, 5 RCTs showed that adjusted-dose warfarin compared with aspirin yielded a relative risk reduction of 36% (95% CI 14%-52%). 13 Patient risk in these warfarin versus aspirin trials was further stratified using the now-validated CHADS 2 criteria to determine which patients should be treated with aspirin and which should be treated more aggressively with vitamin K antagonists. Following from these clinical trials, the Seventh American College of Chest Physicians guidelines and the American College of Cardiology/American Heart Association/European Society of Cardiology guidelines for AF recommend either vitamin K antagonist or aspirin therapy for stroke reduction based on the CHADS 2 risk stratification scheme. 14,15 Hemorrhagic complications The relative benefit of warfarin compared with aspirin in preventing embolic stroke is known 12,13 ; however, warfarin therapy is not without risk. The association of hemorrhagic complications with warfarin use is well established, and elderly patients appear to be at higher risk. 9,16 In one analysis, when compared with patients b50 years of age, the unadjusted relative risk of patients 80 years of age having a life-threatening or fatal bleed on warfarin was 4.5 (95% CI ); after adjusting for intensity of anticoagulation, the increased risk remained (relative risk [RR] 4.6, 95% CI ). 16 Among patients treated with warfarin for deep venous thrombosis, age N65 years was an independent risk factor for bleeding (hazard ratio [HR] 1.3, 95% CI ) 9 ; and among patients 85 years of age compared with patients aged 70 to 74 years, the risk of ICH is substantially increased (adjusted odds ratio [OR] 2.5, 95% CI ). 17 Furthermore, among elderly patients who do have a severe hemorrhagic complication (such as an intracerebral hemorrhage), warfarin use appears to be associated with significantly higher mortality. In one prospective cohort, 3-month mortality after ICH among patients receiving warfarin at the time of an ICH was 52%, compared with 25.8% in patients not taking warfarin. Warfarin use was an independent predictor of death, with an OR of 2.2 (95% CI ) roughly a doubling in mortality in a dose-dependent manner. 8 In addition to fear of hemorrhagic complications, there may be other reasons physicians choose aspirin over warfarin therapy, such as warfarin's narrow therapeutic window, the atherosclerotic benefits of aspirin therapy, patient preference, and the lack of monitoring and ease of administration associated with aspirin. But as with all interventions, physicians must weigh the risks and benefits of treatment. Relationship of international normalized ratio with hemorrhage and stroke Warfarin monotherapy Recommendations for anticoagulation therapy in AF patients should consider the balance of stroke risk, bleeding risk, and other complications of warfarin therapy, all of which appear to be at least in part associated with the intensity of anticoagulation. Prothrombin time ratio is a strong predictor of bleeding risk in all age groups. 18 In addition, international normalized ratio (INR) may be associated with worse stroke outcomes. For example, in one study of AF patients taking warfarin who presented with stroke, patients with INR N2.0 had an increased risk of a severe stroke and an increased risk of death within 30 days relative to patients with an INR b2.0 (HR 3.4, 95% CI ). 19 It appears that an INR of 2.0 to 3.0 provides the best balance between bleeding risk and stroke prevention benefit. Fang et al 17 showed that, compared with an INR b2.0, an INR of 3.5 to 3.9 was associated with an increased risk of ICH (adjusted OR 4.6, 95% CI ), but an INR of 2.0 to 3.0 was not (adjusted OR 1.3, 95% CI ). In analyses from the SPORTIF III and SPORTIF V trials, rates of bleeding were higher among patients who had poor INR control compared with those with good control (goal INR ) 20 (Table II). In summary, there is a critical need for appropriate monitoring of INR in patients (particularly elderly patients) taking warfarin to limit hemorrhagic complica-

3 American Heart Journal Volume 161, Number 2 Sellers and Newby 243 Table II. Hemorrhagic complications in anticoagulation therapy Authors Anticoagulant Analysis Age, y Complication 95% CI/P value Fihn et al 16 Warfarin Age (>79 vs <51) >75 versus <51 RR (hemorrhage) 4.6% 1.2%-18.1% White et al 9 Warfarin Age (>65) >65 HR (hemorrhage) 1.3% 1.0%-1.7% Fang et al 17 Warfarin Age (>84 vs 70-74) >84 versus OR (ICH) 2.5% 1.3%-4.7% Hylek et al 19 Warfarin INR (>2 vs <2) (mean 78.3) HR (30-d mortality) 3.4% 1.1%-10.1% Fang et al 17 Warfarin INR ( ) >84 versus OR (ICH) 4.6% 2.3%-9.4% White et al 20 Warfarin INR 70.9 (mean) 3.85% versus 1.58% (hemorrhage) P <.01 Mant et al 21 ASA + warfarin ASA versus warfarin >75 (mean 81.5) RR (hemorrhage) 0.96% 0.53%-1.75% Adjusted for intensity of anticoagulation. Poor control (INR 2-3 <60% of time) versus good control (INR 2-3 >75% of time). tions. Anticoagulation clinics may provide one means of decreasing the rate of hemorrhagic complications from warfarin therapy. In one study, patients who were treated in an anticoagulation clinic were 59% less likely to experience a bleeding complication than patients receiving usual care (HR 0.41, 95% CI ). 22 Aspirin and warfarin treatment The balance of risk and benefit with combined use of aspirin and warfarin in patients with AF is also an important question, as many patients also have an indication for aspirin therapy. In the SPORTIF trials, there was no significant reduction in stroke, systemic embolism, or myocardial infarction with the use of warfarin plus aspirin; but major bleeding occurred significantly more often with the combined use of warfarin and aspirin (3.9% per year) compared with monotherapy with warfarin (2.3% per year, P b.01). 23 Aspirin monotherapy Because ICH is a major concern in elderly AF patients treated with warfarin therapy (as well as in others considered to be at high risk for ICH or other bleeding complications), one approach for physicians is to use aspirin monotherapy. As discussed previously, aspirin therapy does indeed decrease the risk of stroke in AF; however, aspirin is not as effective as warfarin. 12,13 Thus, electing to use aspirin instead of warfarin assumes that aspirin therapy offers a lower risk of ICH than warfarin therapy, which balances the lower efficacy for stroke prevention. However, among patients N75 years of age in the Birmingham Atrial Fibrillation Treatment of the Aged trial, there was no difference in the rates of ICH between aspirin- and warfarin-treated groups (RR 0.96, 95% CI ) with a goal INR of 2.0 to (Table II). However, the SPINAF II trial 24 (goal INR of 4.5) and the Japanese Nonvalvular Atrial Fibrillation Embolism Secondary Prevention trial 25 both found significantly higher rates of ICH among warfarin-treated patients than among those treated with aspirin. These mixed results do not necessarily support the decision to favor aspirin therapy over warfarin therapy when treating patients with AF who are at high risk for falls or hemorrhagic complications. Anticoagulation and risk of falls Although increasing age is consistently associated with increased bleeding risk in warfarin therapy, an evaluation that specifically focused on fall-related hemorrhagic events showed that warfarin treatment was not associated with an increased risk of bleeding complications. In this study, the cohort treated with warfarin (379 falls patients) exhibited a hemorrhagic event rate of 6%, compared with 11% among patients (2,256 falls) not treated with warfarin (P =.01). 26 However, these results were likely subject to selection bias because patients who are selected for warfarin therapy are less likely to be at risk for falls 5,6 and have fewer comorbid conditions, decreasing their risk of complications. In a large retrospective study of 1,245 Medicare patients, approximately 50% of whom were prescribed warfarin, patients at high risk of falls suffered ICH more than twice as often as other subjects. 10 The status of high risk for falls was based on documentation in the medical record; therefore, the definition of high risk was not standardized or defined in this retrospective study. Few studies have addressed the relationship of falls or predicted fall risk with bleeding in the setting of anticoagulation for AF. A meta-analysis of antithrombotic therapy in elderly patients at risk for falls concluded that the propensity for falling in elderly patients should not be an important factor when deciding whether or not a patient is a good candidate for anticoagulation for AF. 11 In this analysis, the quality-adjusted life expectancy was greatest for warfarin, followed by aspirin, followed by no therapy. This remained true unless the annual stroke risk was b2%. Considering these numbers, an elderly patient taking warfarin would have to fall approximately 300 times per year for the risk of bleeding complications from falling to outweigh the benefits for prevention of embolic stroke. However, the authors were not able to estimate similar rates for subdural and intracerebral hemorrhages because there were too few events. This of itself suggests that the risk of ICH among elderly patients at risk for falls is low. Finally, the stroke rate may have been overestimated, and complications underestimated, in the RCTs in the meta-analysis compared with clinical practice; and patients in the trials may have been monitored more intensely than is usual in clinical practice. 11

4 244 Sellers and Newby American Heart Journal February 2011 Figure 1 CHADS2 Score 0-1 CHADS2 Score Hazard Ratio (95% CI) Hazard ratio for out-of-hospital death, hospitalization for stroke, myocardial infarction or bleeding for warfarin treatment versus no warfarin treatment in atrial fibrillation patients according to CHADS2 risk score. Adapted from Gage et al. 10 In another assessment of falls risk and anticoagulation therapy for AF in 19,506 patients, after accounting for baseline factors associated with risk of ICH, neither warfarin nor aspirin treatment was associated with risk of ICH (HR 1.0, 95% CI for warfarin and HR 1.1, 95% CI for aspirin). 10 Importantly, in this study, the increased risk of stroke appeared to outweigh the risk of ICH. Among patients at high risk for falls, the HR for stroke was 1.3 (95% CI , P =.002) compared with patients who were not at high risk for falls. Furthermore, among patients at high risk for falls, the HR for stroke for each 1- point increase in CHADS 2 score was 1.42 (95% CI , P b.0001). The HR for the primary composite outcome of out-of-hospital death, hospitalization for stroke, myocardial infarction, and hemorrhage on warfarin compared with no warfarin was 0.98 (95% CI , P =.94) for a CHADS 2 score of 0 to 1 and 0.75 (95% CI , P =.004) for a CHADS 2 score of 2 to 6 (Figure 1). These results support the contention that patients at risk for falls but with concomitant increased stroke risk as manifested by a CHADS 2 score of 2 would benefit overall from anticoagulation, specifically, warfarin therapy, even in the setting of an increased risk of hemorrhage. 10 One underlying central limitation of the body of literature on falls risk in elderly patients is that there is no unifying definition of which patients are at risk of falls. Many of the documented trials rely on physician reporting of falls risk, reports that may be multifactorial and not necessarily based on actual risk of falling. This potentially introduces multiple confounders that may contribute to risk of ICH but are not related to the fall itself. Future directions The ACTIVE trials explored the role of clopidogrel (an irreversible inhibitor of the platelet P2Y12 receptor) plus aspirin versus aspirin alone in warfarin-intolerant patients (ACTIVE A) and clopidogrel plus aspirin versus warfarin (ACTIVE W) in AF patients who were able to take warfarin. 27 These trials included patients with AF at enrollment or 2 episodes of AF in the previous 6 months, in addition to 1 of the following risk factors for stroke: age N74 years, hypertension, previous stroke or transient ischemic attack, non central nervous system embolism, ejection fraction b45%, peripheral vascular disease, or age 55 to 74 years with diabetes or coronary artery disease. Warfarin was found to be superior to clopidogrel + aspirin in ACTIVE W 28 ; but clopidogrel + aspirin reduced risk of stroke and systemic embolism in patients intolerant of warfarin compared with aspirin alone, albeit at the expense of increased major bleeding that was most prominent in patients N65 years of age. 29 Thus, warfarin remains the cornerstone of treatment of most moderate- to high-risk patients with AF. However, several novel oral anticoagulants are expected to shift the balance of benefit and risk in anticoagulation for AF. In the RELY trial, the oral direct thrombin inhibitor dabigatran was compared at 2 doses with warfarin to a target INR of 2 to 3 in 18,113 patients with a mean age of 71.5 years. 30 In this trial, low-dose dabigatran (110 mg twice daily) was noninferior to warfarin in preventing stroke or systemic embolism and exhibited a better bleeding profile than warfarin, with 2.7% of patients assigned to dabigatran experiencing a major hemorrhage (RR 0.80, 95% CI ). Highdose dabigatran (150 mg twice daily) was superior to warfarin in preventing stroke or systemic embolism (RR 0.66, 95% CI ), with similar rates of major bleeding (RR 0.93, 95% CI ). Importantly, both the high- and low-dose dabigatran groups had significantly lower rates of ICH compared with the warfarin group: 27 (0.23% per year) intracranial bleeds in the lowdose group, 36 (0.30% per year) in the high-dose group, and 87 (0.74% per year) in the warfarin group (RR 0.31, 95% CI , low-dose vs warfarin; RR 0.40, 95% CI , high-dose vs warfarin). Dabigatran was recently approved by the US Food and Drug Administration for the prevention of stroke and embolism in AF and will be available in 2 doses: a 75-mg, twice-daily dose intended for patients with severe renal dysfunction and a 150-mg, twice-daily dose. 31,32 In addition, at the 2010 European Society of Cardiology scientific sessions, results were presented from an RCT examining apixaban (an oral competitive factor Xa antagonist) compared with aspirin in warfarin-intolerant patients. 33 The study identified a N50% reduction in thromboembolic complications in apixaban-treated patients with an acceptable bleeding risk, which resulted in early termination of the trial by the data monitoring committee. Full publication of the results is pending. The ongoing ROCKET AF trial is comparing the efficacy and safety of rivaroxaban (another oral factor Xa

5 American Heart Journal Volume 161, Number 2 Sellers and Newby 245 inhibitor) versus warfarin in a superiority trial in patients with moderate to high CHADS 2 scores 34 ; and the ARISTOTLE trial is assessing the efficacy and safety of apixaban compared with warfarin across the spectrum of CHADS 2 risk scores in an ongoing noninferiority trial. 35 The results of both trials are expected within the year and may provide additional alternatives to warfarin anticoagulation with lower bleeding risk that may be particularly beneficial in elderly patients. Finally, pharmacogenetic guidance of warfarin dosing may improve the safety of warfarin use. Trials completed to date have been small and have not shown benefit on intermediate end points or bleeding, 36 but larger RCTs are ongoing. Conclusions The population of elderly patients with AF presents challenges with regard to the decision to provide anticoagulation treatment as well as which therapy, aspirin or warfarin, to choose. A higher likelihood of drug-drug interactions with warfarin, more adverse effects, and more comorbidities are at play in making these decisions. However, the available data suggest that physicians' decisions are guided more by their concerns over bleeding than an evaluation of the patient's risk for stroke; in many cases, their concerns regarding bleeding appear to be overemphasized in the equation. Overall, warfarin appears to be generally underused in the treatment of elderly AF patients despite fairly clear evidence that it reduces embolic and ischemic events, benefits that outweigh bleeding risk. We conclude that the risk of falling in the elderly population should not be an absolute or relative contraindication to the initiation of warfarin therapy, but that physicians should use their clinical judgment, weighing the evidence for risk and benefit with each case they are presented, including consideration of newer anticoagulants as they become clinically available. References 1. Feinberg WM, Blackshear JL, Laupacis A, et al. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995;155: Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285: Garwood CL, Corbett TL. Use of anticoagulation in elderly patients with atrial fibrillation who are at risk for falls. Ann Pharmacother 2008;42: Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996;27: Dharmarajan TS, Varma S, Akkaladevi S, et al. To anticoagulate or not to anticoagulate? A common dilemma for the provider: physicians' opinion poll based on a case study of an older long-term care facility resident with dementia and atrial fibrillation. J Am Med Dir Assoc 2006;7: Man-Son-Hing M, Laupacis A. Anticoagulant-related bleeding in older persons with atrial fibrillation: physicians' fears often unfounded. Arch Intern Med 2003;163: He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials. JAMA 1998; 280: Rosand J, Eckman MH, Knudsen KA, et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med 2004;164: White RH, Beyth RJ, Zhou H, et al. Major bleeding after hospitalization for deep-venous thrombosis. Am J Med 1999;107: Gage BF, Birman-Deych E, Kerzner R, et al. Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. Am J Med 2005;118: Man-Son-Hing M, Nichol G, Lau A, et al. Choosing antithrombotic therapy for elderly patients with atrial fibrillation who are at risk for falls. Arch Intern Med 1999;159: The efficacy of aspirin in patients with atrial fibrillation. Analysis of pooled data from 3 randomized trials. The Atrial Fibrillation Investigators. Arch Intern Med 1997;157: Hart RG, Benavente O, McBride R, et al. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999;131: Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 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 (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:e Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:429S-56S. 16. Fihn SD, Callahan CM, Martin DC, et al. The risk for and severity of bleeding complications in elderly patients treated with warfarin. The National Consortium of Anticoagulation Clinics. Ann Intern Med 1996;124: Fang MC, Chang Y, Hylek EM, et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med 2004;141: Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system bleeding during antithrombotic therapy: recent data and ideas. Stroke 2005;36: Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349: White HD, Gruber M, Feyzi J, et al. Comparison of outcomes among patients randomized to warfarin therapy according to anticoagulant control: results from SPORTIF III and V. Arch Intern Med 2007;167: Mant J, Hobbs FD, Fletcher K, et al. 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 randomised controlled trial. Lancet 2007;370: Nichol MB, Knight TK, Dow T, et al. Quality of anticoagulation monitoring in nonvalvular atrial fibrillation patients: comparison of anticoagulation clinic versus usual care. Ann Pharmacother 2008;42:

6 246 Sellers and Newby American Heart Journal February Flaker GC, Gruber M, Connolly SJ, et al. Risks and benefits of combining aspirin with anticoagulant therapy in patients with atrial fibrillation: an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) trials. Am Heart J 2006;152: SPAF II Investigators. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 1994;343: Yamaguchi T. Optimal intensity of warfarin therapy for secondary prevention of stroke in patients with nonvalvular atrial fibrillation : a multicenter, prospective, randomized trial. Japanese Nonvalvular Atrial Fibrillation-Embolism Secondary Prevention Cooperative Study Group. Stroke 2000;31: Bond AJ, Molnar FJ, Li M, et al. The risk of hemorrhagic complications in hospital in-patients who fall while receiving antithrombotic therapy. Thromb J 2005;3: Connolly SJ, Yusuf S, Budaj A, et al. Rationale and design of ACTIVE: the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events. Am Heart J 2006;151: 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 randomised controlled trial. Lancet 2006;367: Connolly SJ, Pogue J, Hart RG, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009;360: Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361: U.S. Food and Drug Administration Web site. FDA news release. FDA approves Pradaxa to prevent stroke in people with atrial fibrillation (October 19, 2010). Available at: Events/Newsroom/PressAnnouncements/ucm htm (accessed October 22, 2010). 32. Wood S, O'Riordan M. FDA approves dabigatran for stroke prevention, embolism in AF patients. October 20, Available at: (accessed October 22, 2010). 33. Eikelboom JW, O'Donnell M, Yusuf S, et al. Rationale and design of AVERROES: apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment. Am Heart J 2010;159: e Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J 2010;159: e Lopes RD, Alexander JH, Al-Khatib SM, et al. Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J 2010;159: Kangelaris KN, Bent S, Nussbaum RL, Garcia DA, Tice JA. Genetic testing before anticoagulation? A systematic review of pharmacogenetic dosing of warfarin. J Gen Intern Med 2009;24: