Stroke Prevention in Atrial Fibrillation An Expert Commentary With Freek W.A. Verheugt, MD, FACC, FESC A Clinical Conte

1. Stroke Prevention in Atrial FibrillationAn Expert Commentary With Freek W.A. Verheugt, MD, FACC, FESCA 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 educational grants from Bristol-Myers Squibb, Pfizer and 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 0.5 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 0.5 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 0.5 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 0.5 contact hours (0.05 CEUs). The ACPE Universal Activity Number assigned to this knowledge-type activity is 0052-9999-11-2433-H04-P.

12. Discussant Freek W.A. Verheugt, MD, FACC, FESC Professor of Cardiology Chairman, Department of Cardiology Onze Lieve Vrouwe Gasthuis Amsterdam, The Netherlands

13. Disclosure Information Freek W.A. Verheugt, MD, FACC, FESC has disclosed the following relevant financial relationship:
 Served on the Speakers Bureau for Bayer HealthCare Pharmaceuticals

14. Disclosure Information Michael Mullen, MD, Clinical Instructor of Vascular Neurology, University of Pennsylvania; Chris Kaiser; 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.

15. Primary Event Rate Per Year: Warfarin vs. Aspirin • Patients <75 years – 1.3% vs. 1.9% • Patients >75 years – 3.6% vs. 4.8% Data from the SPAF-II (Stroke Prevention in Atrial Fibrillation II) study. Source: Lancet 1994; 343(8899): 687-691.

16. Annual Event Risk Per Year • Warfarin: 3.93% • Aspirin Plus Clopidogrel: 5.60% • The relative risk for a vascular event was 1.44 for those on clopidogrel plus aspirin compared with those on warfarin Data from the ACTIVE W (Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events) trial. Source: Lancet 2006; 367(9526): 1903-1912.

17. Three Major Trials of New Afib Drugs • RE-LY trial • Twice-daily dabigatran (Pradaxa), an oral direct thrombin inhibitor • Found superior to warfarin • ROCKET-AF • Once-daily rivaroxaban (Xarelto), an oral direct factor Xa inhibitor • Found noninferior to warfarin • ARISTOTLE • Twice-daily apixaban(Elquis), an oral direct factor Xainhibitor • Found superior to warfarin

18. Approval of New Afib Drugs • Dabigatran • Approved in Europe, the U.S., and Canada for thromboembolic prevention in patients with atrial fibrillation and those undergoing knee or hip replacement surgery • Rivaroxaban • Approved in Europe, the U.S. and Canada for prevention of deep vein thrombosis in patients undergoing knee or hip replacement surgery • Apixaban • Approved in Europe for thromboembolic prevention in patients undergoing knee or hip replacement surgery

19. Cost of Warfarin Versus Dabigatran • Warfarin per year: $109 retail ($0.30/day), $1,700 INR monitoring • Dabigatranper year: $2,737 retail ($7.50/day)1 • Turakhia, et al. found dabigatran cost-effective in those over 65 years at risk for stroke with an estimated cost of $45,372 per QALY. That analysis was based on the cost of high-dose dabigatran being $13 per dose2 Sources: 1. BOLT International Market Research. 2. Ann Intern Med 2011; 154(1): 1-11.

20. Warfarin Patients in Optimal Therapeutic Range • RE-LY: 66%1 • ROCKET-AF: 54%2 • ARISTOTLE: 62%3 Sources: 1. N Engl J Med 2009; 361: 1139-1151. 2. N Engl J Med 2011; 365: 883-891. 3. N Engl J Med 2011; 365: 981-992.

21. Shortcomings of Warfarin • Interacts with some foods • Interacts with many commonly-used medications • Has to be monitored via blood draws to maintain effective therapeutic range • Onset of clotting mechanism takes about a day • Risk of hemorrhage

22. Summary At the end of this activity, participants should understand: • Warfarin maintenance has challenges • A newer class of oral anticoagulants, including dabigatran, rivaroxaban, and apixaban, will challenge the dominance of warfarin • These novel agents have proven either noninferior or superior to warfarin in large clinical trials • It’s currently unknown how quickly these new drugs will be adopted