Jointly Sponsored by: and Stroke Prevention in Atrial Fibrillation Expert Commentary

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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Paulus Kirchhof, MD Chair in Cardiovascular Medicine University of Birmingham Birmingham, UK Professor, Cardiology and Angiology University of Müenster Müenster, Germany Discussant

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.

Disclosure Information Paulus Kirchhof, MD, has disclosed the following relevant financial relationships: has disclosed the following relevant financial relationships: Served as an advisor or consultant for: 3M Medica, AstraZeneca Pharmaceuticals LP, Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Inc, MEDA Pharmaceuticals, Inc, Medtronic, Inc, Merck & Co.,Otsuka Pharma, Pfizer/BMS, sanofi-aventis, SERVIER, Siemens, Takeda Pharmaceuticals North America, Inc. Received grants for clinical research from: 3M Medica/MEDA Pharmaceuticals, Inc, CV Therapeutics, Medtronic, Inc, Omron Healthcare, Inc, German Federal Ministry of Education and Research (BMBF), European Union, Fondation LeDucq, German Research Foundation (DFG), St. Jude Medical, sanofi-aventis

KEY Points of AFNET/EHRA Report Diagnose atrial fibrillation early enough to start therapy and prevent complications such as stroke Identify both conventional and emerging risk factors for atrial fibrillation and stroke Identify needs to start using newer anticoagulants in clinical practice as they enter the market Educate patients, physicians, payers, and healthcare organizations on the use of the newer drugs Source: Kirchhof P, et al “Comprehensive risk reduction in patients with atrial fibrillation: emerging diagnostic and therapeutic options -- a report from the 3rd Atrial Fibrillation Competence Network/European Heart Rhythm Association consensus conference” Europace 2011; DOI: /europace/eur241.

Burden of Atrial Fibrillation In an unselected population of 40 year olds, 25% will develop atrial fibrillation in their lifetime Every fourth to fifth stroke is related to atrial fibrillation Emerging data show that a portion of cryptogenic strokes are related to silent, undiagnosed paroxysmal atrial fibrillation

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

CHADS 2 Stroke Risk Score Total possible score of 6 Congestive heart failure – 1 point Hypertension – 1 point Age 75 or older – 1 point Diabetes – 1 point Previous stroke or transient ischemic attack – 2 points Source: JAMA 2001; 285:

CHA 2 DS 2 -VASc Stroke Risk Score Source: CHEST 2010; 137(2): Total possible score of 10 Hypertension – 1 point Age 75 or older – 2 points Age 65 to 74 – 1 point Diabetes – 1 point Previous stroke, transient ischemic attack, or thromboembolism – 2 points Vascular disease – 1 point Female gender – 1 point

ATHENA Trial Source: Circulation 2009, 120; Main results showed that dronedarone 400 bid significantly reduced cardiovascular hospitalization or all-cause death in patients with atrial fibrillation A post hoc analysis showed that dronedarone reduced the risk of stroke from 1.8% to 1.2% per year (HR 0.66, 95% CI 0.46 to 0.96) The effect was greater in patients with higher baseline stroke risk

Hypothesis: Adequate and early comprehensive rhythm control therapy can prevent AF-related major complications (stroke, death, heart failure) compared to usual care Primary outcome: composite of cardiovascular death, stroke, and heart failure or acute coronary syndrome measured as hospitalization Enrolment: Patients with recent-onset AF at risk for stroke or death E arly treatment of A trial fibrillation for St roke prevention

Ximelagatran (36 mg bid)  A novel, oral direct thrombin inhibitor ximelagatran (n = 1,960) Ximelagatran (36 mg bid)  A novel, oral direct thrombin inhibitor ximelagatran (n = 1,960) Warfarin  Target INR (n = 1,962) Warfarin  Target INR (n = 1,962) Endpoints (mean follow-up 20 months):  Primary – All strokes (ischemic or hemorrhagic) and systemic embolic events, based on an intention-to-treat analysis for non-inferiority  Secondary – Composite of death, stroke, systemic embolism, and MI; and safety variables, specifically bleeding and liver enzyme elevations Endpoints (mean follow-up 20 months):  Primary – All strokes (ischemic or hemorrhagic) and systemic embolic events, based on an intention-to-treat analysis for non-inferiority  Secondary – Composite of death, stroke, systemic embolism, and MI; and safety variables, specifically bleeding and liver enzyme elevations AHA 2003 Late Breaking Trials Randomized Double-blind to: 3,922 patients with nonvalvular AF and risk factors for stroke (previous stroke, hypertension, or CHF) SPORTIF V Trial

RE-LY Study Overview In a large, randomized trial, two doses of the direct thrombin inhibitor dabigatran were compared with warfarin in patients who had atrial fibrillation and were at risk for stroke At 2 years, the 110-mg dose of dabigatran was found to be noninferior, and the 150-mg dose superior, to warfarin with respect to the primary outcome of stroke or systemic embolism

Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population No. at risk: Rivaroxaban Warfarin Warfarin HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001 Days from Randomization Cumulative event rate (%) Rivaroxaban Warfarin Event Rate Primary Efficacy Outcome Stroke and non-CNS Embolism

Efficacy: – –Rivaroxaban was non-inferior to warfarin for prevention of stroke and non-CNS embolism – –Rivaroxaban was superior to warfarin while patients were taking study drug – –By intention-to-treat, rivaroxaban was non-inferior to warfarin but did not achieve superiority Safety: – –Similar rates of bleeding and adverse events – –Less ICH and fatal bleeding with rivaroxaban Conclusion: – –Rivaroxaban is a proven alternative to warfarin for moderate or high risk patients with AF ROCKET AF Summary

Treatment with apixaban as compared to warfarin in patients with AF and at least one additional risk factor for stroke: Reduces stroke and systemic embolism by 21% (p=0.01) Reduces major bleeding by 31% (p<0.001) Reduces mortality by 11% (p=0.047) with consistent effects across all major subgroups and with fewer study drug discontinuations on apixaban than on warfarin, consistent with good tolerability. ARISTOTLE Data Source: N Engl J Med 2011; 365:

In an unselected population of 40 year olds, 25% will develop atrial fibrillation in their lifetime Every fourth to fifth stroke is related to atrial fibrillation Risk factors for atrial fibrillation overlap with those for stroke in atrial fibrillation and include older age, previous stroke or TIA, hypertension, diabetes, and heart failure Summary At the end of this activity, participants should understand:

Newer anticoagulants are challenging warfarin and other vitamin K antagonists for the prevention of stroke in atrial fibrillation Dabigatran (Pradaxa), a direct thrombin inhibitor, has been approved for the prevention of stroke in this patient population Investigational oral direct factor Xa inhibitors, including rivaroxaban and apixaban, have been shown to be at least as effective as warfarin at preventing strokes; apixaban was superior in the ARISTOTLE trial Summary

The newer anticoagulants do not require regular testing of INR, as with the vitamin K antagonists Patients who are difficult to maintain in the therapeutic INR range may be good candidates for one of the newer agents The educational efforts surrounding vitamin K antagonists in past decades will need to be repeated for the newer agents Summary