Stroke Prevention in Atrial Fibrillation An Expert Commentary With Paulus Kirchhof , MD A Clinical Context Report

1. Stroke Prevention in Atrial FibrillationAn Expert Commentary With Paulus Kirchhof, MDA Clinical Context Report

2. Jointly Sponsored by: and Stroke Prevention in Atrial FibrillationExpert Commentary

3. Stroke Prevention in Atrial FibrillationExpert 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.

4. Stroke Prevention in Atrial FibrillationClinical 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.

5. Stroke Prevention in Atrial FibrillationClinical Context SeriesTarget 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.

6. Activity Learning Objective Upon successful completion of this educational program, participants should be able to: • Review the relevance and significance of the activity in the broader context of clinical care

7. CME Information: Physicians • Statement of Accreditation This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the University of Pennsylvania School of Medicine and MedPage Today. The University of Pennsylvania School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

8. CME Information • Credit Designation The University of Pennsylvania School of Medicine Office of CME designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits.™ Physicians should claim only the credit commensurate with the extent of their participation in the activity.

9. CME Information: Physicians • Credit for Family Physicians MedPage Today "News-Based CME" has been reviewed and is acceptable for up to 2098 Elective credits by the American Academy of Family Physicians. AAFP accreditation begins January 1, 2011. Term of approval is for one year from this date. Each article is approved for 1 Elective credit. Credit may be claimed for one year from the date of each article.

10. CE Information: Nurses • Statement of Accreditation • Projects In Knowledge, Inc. (PIK) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation • Projects In Knowledge is also an approved provider by the California Board of Registered Nursing, Provider Number CEP-15227 • This activity is approved for 0.75 nursing contact hours DISCLAIMER: Accreditation refers to educational content only and does not imply ANCC, CBRN, or PIK endorsement of any commercial product or service.

11. CE Information: Pharmacists • Projects In Knowledge® is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This program has been planned and implemented in accordance with the ACPE Criteria for Quality and Interpretive Guidelines. This activity is worth up to 0.75 contact hours (0.075 CEUs). The ACPE Universal Activity Number assigned to this knowledge-type activity is 0052-9999-11-2399-H04-P.

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

13. Disclosure Information 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. 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.

14. Disclosure Information Paulus Kirchhof, MD, 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

15. 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: 10.1093/europace/eur241.

16. 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

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

18. CHADS2 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: 2864-2870.

19. CHA2DS2-VASc Stroke Risk Score • 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 Source: CHEST 2010; 137(2): 263-272.

20. ATHENA Trial • 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 Source: Circulation 2009, 120; 1174-1180.

21. Early treatment of Atrial fibrillation for Stroke prevention Hypothesis: Adequateandearlycomprehensiverhythmcontroltherapycanprevent AF-relatedmajorcomplications (stroke, death, heartfailure) comparedtousualcare 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 www.easttrial.org

22. SPORTIF V Trial 3,922 patients with nonvalvular AF and risk factors for stroke (previous stroke, hypertension, or CHF) Randomized Double-blind to: • Ximelagatran (36 mg bid) • A novel, oral direct thrombin inhibitor ximelagatran • (n = 1,960) • Warfarin • Target INR 2.0-3.0 • (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 AHA 2003 Late Breaking Trials

23. 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

24. Primary Efficacy Outcome Stroke and non-CNS Embolism Warfarin Rivaroxaban Cumulative event rate (%) HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001 Days from Randomization No. at risk: Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634 Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655 Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population

25. ROCKET AF Summary 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

26. ARISTOTLE Data 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. Source: N Engl J Med 2011; 365: 981-992.

27. Summary At the end of this activity, participants should understand: • 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

28. Summary • 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

29. 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