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Kenneth W. Mahaffey, MD and Keith AA Fox, MB ChB on behalf of the ROCKET AF Investigators

R ivaroxaban O nce-daily oral direct factor Xa inhibition C ompared with vitamin K antagonism for prevention of stroke and E mbolism T rial in A trial F ibrillation . Kenneth W. Mahaffey, MD and Keith AA Fox, MB ChB on behalf of the ROCKET AF Investigators.

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Kenneth W. Mahaffey, MD and Keith AA Fox, MB ChB on behalf of the ROCKET AF Investigators

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  1. Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation Kenneth W. Mahaffey, MD and Keith AA Fox, MB ChBon behalf of the ROCKET AF Investigators

  2. Relevant Financial Relationships • Kenneth W. Mahaffey, MD • Research Grants: AstraZeneca, Bayer, BI, BMS, Eli Lilly, J&J, Merck, Novartis, Portola, Regado, Sanofi-Aventis, The Medicines Company • Consulting Fees: AstraZeneca, Bayer, BI, BMS, Eli Lilly, J&J, Merck, Novartis, Sanofi-Aventis • No stock ownership • http://www.dcri.duke.edu/research/coi.jsp • Keith AA Fox, MB ChB • Research Grants: Bayer, Eli Lilly, J&J, Sanofi-Aventis • Consulting Fees: Bayer, Eli Lilly, J&J, Sanofi-Aventis • No stock ownership

  3. BackgroundRivaroxaban TF/VIIa • Direct, specific, competitive factor Xa inhibitor • Half-life 5-13 hours • Clearance : • 1/3 direct renal excretion • 2/3 metabolism via CYP 450 enzymes • Oral, once daily dosing without need for coagulation monitoring • Studied in >25,000 patients in post-op, DVT, PE and ACS patients X IX IXa VIIIa Rivaroxaban Va Xa II IIa Fibrinogen Fibrin Adapted from Weitz et al, 2005; 2008

  4. Risk Factors • CHF • Hypertension • Age  75 • Diabetes • OR • Stroke, TIA or Systemic embolus Study Design At least 2 or 3 required* Atrial Fibrillation Rivaroxaban Warfarin Randomize Double Blind / Double Dummy (n ~ 14,000) 20 mg daily 15 mg for Cr Cl 30-49 ml/min INR target - 2.5 (2.0-3.0 inclusive) Monthly Monitoring Adherence to standard of care guidelines Primary Endpoint: Stroke or non-CNS Systemic Embolism * Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

  5. Superiority Non-inferiority Inferiority 1.0 1.46 Warfarin Better Rivaroxaban Better Statistical Methodologies • Sample Size • Warfarin event rate ~2.3 • Type 1 error 0.05 (2-sided) • 405 events; >95% power • ~14,000 patients • Primary Efficacy Evaluation: Stroke or non-CNS Embolism • Non-Inferiority: Protocol Compliant on treatment • Superiority: On Treatment and then by Intention-to-Treat • Primary Safety Evaluation: Major or non-Major Clinically Relevant Bleeding

  6. Enrollment45 countries, 1178 sites, 14,264 patients Poland: 528 Finland: 16 Lithuania: 245 Sweden: 28 Hungary: 237 Norway: 49 Romania: 783 Czech Rep: 598 Bulgaria: 678 Russia: 1,292 Denmark: 123 Ukraine: 1,011 U.K.: 159 Canada: 750 Netherlands: 161 Belgium: 96 Korea: 204 United States: 1,932 China: 496 France: 71 Taiwan: 159 Spain: 250 Mexico: 168 Germany: 530 Hong Kong: 73 India: 269 Switzerland: 7 Thailand: 87 Philippines: 368 Austria: 32 Malaysia: 51 Panama: 0 Italy: 139 Singapore: 44 Venezuela: 20 Greece: 29 Colombia: 268 Turkey: 101 Peru: 84 Israel: 189 Australia: 242 Brazil: 483 South Africa: 247 Chile: 287 Argentina: 569 New Zealand: 116

  7. Study Conduct

  8. Baseline Demographics Values are median (IQR) Based on Intention-to-Treat Population

  9. Baseline Demographics Based on Intention-to-Treat Population

  10. Trial ResultsKenneth W. Mahaffey, MD on Behalf of the ROCKET AF Investigators

  11. Primary Efficacy OutcomeStroke 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

  12. Primary Efficacy OutcomeStroke and non-CNS Embolism Rivaroxaban better Warfarinbetter Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations

  13. Key Secondary Efficacy Outcomes Event Rates are per 100 patient-years Based on Safety on Treatment Population

  14. Key Secondary Efficacy Outcomes Event Rates are per 100 patient-years Based on Intention-to-Treat Population

  15. Time in Therapeutic Range (TTR)INR Data Based on Rosendaal method with all INR values included Based on Safety Population

  16. Primary Efficacy Outcome by Quartiles of cTTRStroke and non-CNS Embolism Based on Rosendaal method with all INR values included Based on Safety Population Event Rates are per 100 patient-years

  17. Primary Safety Outcomes Event Rates are per 100 patient-years Based on Safety on Treatment Population

  18. Primary Safety Outcomes Event Rates are per 100 patient-years Based on Safety on Treatment Population

  19. Adverse Events and Liver Enzyme Data Values are N (%) Based on Safety Population

  20. 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.

  21. Study Organization IDMC Joe Alpert, ChairAllen Skene, Co-chairGudrun Boysen John Eikelboom Peter Rothwell SponsorsJ & J and Bayer Christopher Nessel, Kimberly Schwabe, Scott Berkowitz, John Paolini Executive Steering Committee Steering Committee Diego Ardissino, Alvaro Avezum, Phil Aylward, Barbara Biedermann, Christoph Bode, Antonio Carolei, Ramon Corbalan, Laszlo Csiba, Anthony Dalby, Rafael Diaz, Hans Diener, Geoffrey Donnan, Shaun Goodman, Bas Hamer, Hein Heidbuchel, Dai-Yi Hu, Kurt Huber, Gorm Jensen, Matyas Keltai, Basil Lewis, Jose Lopez-Sandon, Jean Louis Mas, Ayrton Massaro, Gordon MacInnes, Bo Norrving, Martin Penicka, Dorairaj Prabhakaran, Risto Roine, Tan Ru San, Per Anton Sirnes, Veronika Skvortsova, Gabriel Steg, Harvey White, Lawrence Wong CEC Manesh Patel Joni O'Briant Lauren Price Duke Clinical Research Institute Jonathan Piccini, Karen Hannan, Jyotsna Garg, Lisa Eskenazi, Angela Kaiser, Patricia Stone Canadian Heart Research Center Shaun Goodman Maggie Godin-Edgecomb

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