Stroke Prevention in Atrial Fibrillation An Expert Commentary With Michael D. Ezekowitz, MD, PhD A Clinical Context Report

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Supported in part by an educational grant from Ortho-McNeil, Division of Ortho-McNeil- Janssen Pharmaceuticals, Inc., administered by Ortho-McNeil Janssen Scientific Affairs, LLC. Stroke Prevention in Atrial Fibrillation Expert Commentary

Stroke Prevention in Atrial Fibrillation Clinical Context Series The goal of this series is to provide up-to- date information and multiple perspectives on the pathogenesis, symptoms, risk factors, and complications of stroke prevention in atrial fibrillation as well as current and emerging treatments and best practices in the management of stroke prevention in atrial fibrillation.

Stroke Prevention in Atrial Fibrillation Clinical Context Series Target Audience Electrophysiologists, cardiologists, primary care physicians, nurses, nurse practitioners, physician assistants, pharmacists, and other healthcare professionals involved in the management of stroke prevention in atrial fibrillation.

Activity Learning Objective

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Michael D. Ezekowitz, MD, PhD Professor of Medicine Cardiovascular Medicine Mainline Healthcare Interventional Cardiology Wynnewood, Pennsylvania Discussant

Disclosure Information Michael D. Ezekowitz, MD, PhD, has disclosed the following relevant financial relationships: has disclosed the following relevant financial relationships: Served as a consultant for: – –ARYx Therapeutics – –AstraZeneca Pharmaceuticals – –Boehringer Ingelheim Pharmaceuticals, Inc. – –Bristol-Myers Squibb – –Daiichi-Sankyo – –Eisai Inc. – –Gilead Science, Inc. – –Johnson & Johnson – –Medtronic, Inc. – –Merck & Co., Inc. – –Pfizer Inc. – –Portola Pharmaceuticals – –Sanofi

Disclosure Information and have disclosed that they have no relevant financial relationships or conflicts of interest with commercial interests related directly or indirectly to this educational activity. Michael Mullen, MD, Clinical Instructor of Vascular Neurology, University of Pennsylvania; Todd Neale; and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner, have disclosed that they have no relevant financial relationships or conflicts of interest with commercial interests related directly or indirectly to this educational activity. and have no relevant financial relationships or conflicts of interest with commercial interests related directly or indirectly to this educational activity. The staff of The University of Pennsylvania School of Medicine Office of CME, MedPage Today, and Projects In Knowledge have no relevant financial relationships or conflicts of interest with commercial interests related directly or indirectly to this educational activity.

Risk Factors for Stroke in Atrial Fibrillation Previous stroke or TIA Older age Hypertension Diabetes Heart failure Female gender Vascular disease

Completed Studies: Warfarin vs. Placebo 100%50%0%-50%-100% Warfarin betterWarfarin worse Risk Reduction AFASAK : Peterson, et al Lancet 1989; 1: 175 BAATAF : Investigators NEJM 1990; 323: 1505 SPAF: Investigators Stroke 1990; 21: 538 SPINAF : Ezekowitz, et al NEJM 1992; 327: # EventsPt-yrs DOUBLE BLIND OPEN LABEL Warfarin Era

Source: Connolly S, et al ”Dabigatran versus wafarin in patients with atrial fibrillation” N Engl J Med 2009: 361.c & N Engl J Med 2010: 363. Modern Era: RE-LY 150 mg BID

Source: Connolly S, et al ”Dabigatran versus wafarin in patients with atrial fibrillation” N Engl J Med 2009: 361.c & N Engl J Med 2010: 363. Granger, et al N Engl J Med 2011 Modern Era: ARISTOTLE

Stroke/Systemic Embolism Hemorrhagic Stroke Myocardial Infarction Safety Outcomes ICH Major Bleeding Efficacy Outcomes Rivaroxiban betterWarfarin better Rivaroxaban versus WARFARIN (ROCKET-AF)

Patient Populations Lacking Data With New Anticoagulants Patients with mechanical heart valves Patients with poor renal function Children

Reduction in Intracranial Hemorrhage Versus Placebo Dabigatran 150 mg BID – 0.30% versus 0.74% (RR 0.40, P<0.001) Apixaban 5 mg BID – 0.33% versus 0.80% (HR 0.42, P<0.001) Rivaroxaban 20 mg – 0.5% versus 0.7% (HR 0.67, P=0.02) Sources: N Engl J Med 2009; 361: ; N Engl J Med 2011; 365: ; N Engl J Med 2011; 365:

Mortality Reductions Versus Placebo Dabigatran 150 mg BID – 3.64% versus 4.13% (RR 0.88, P=0.051) Apixaban 5 mg BID – 3.52% versus 3.94% (HR 0.89, P=0.047) Rivaroxaban 20 mg – 4.5% versus 4.9% (HR 0.92, P=0.15) Sources: N Engl J Med 2009; 361: ; N Engl J Med 2011; 365: ; N Engl J Med 2011; 365:

Strokes associated with afib tend to be severe, killing about 20% of patients in a month 60% of survivors are severely disabled Afib-related strokes tend to become more common as the population ages Summary At the end of this activity, participants should understand:

Dabigatran (Pradaxa) is a direct thrombin inhibitor, and apixaban and rivaroxaban (both not yet approved) are direct factor Xa inhibitors All have been shown to as effective (rivaroxaban) or better (dabigatran and apixaban) than warfarin at preventing strokes It is unclear whether the different mechanisms of action will be important in differentiating between the new anticoagulants Summary

Warfarin will remain relevant, as some patient populations – including those with mechanical heart valves – have not been included in the trials of new anticoagulants Patients who are well controlled on warfarin might want to keep taking it because it is inexpensive Conversely, the reduction in intracranial bleeding with the newer anticoagulants might argue for switching patients who are well controlled on warfarin Summary

Patients must be committed to taking the new anticoagulants and to the twice-daily regimen Emphasis must be placed on minimizing temporary and permanent discontinuation of the novel anticoagulants Much of the bleeding risk with the new anticoagulants comes from extracranial bleeds, which are more tolerable than intracranial hemorrhages Summary