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Kenneth W. Mahaffey, MD and Keith AA Fox, MB ChB on behalf of the ROCKET AF Investigators Rivaroxaban Once-daily oral direct factor Xa inhibition Compared.

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Presentation on theme: "Kenneth W. Mahaffey, MD and Keith AA Fox, MB ChB on behalf of the ROCKET AF Investigators Rivaroxaban Once-daily oral direct factor Xa inhibition Compared."— Presentation transcript:

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

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  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 Background Rivaroxaban  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 Rivaroxaban Xa IIa TF/VIIa XIX IXa VIIIa Va II FibrinFibrinogen Adapted from Weitz et al, 2005; 2008

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

5 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 Superiority Non-inferiority Inferiority Rivaroxaban Better Warfarin Better

6 Enrollment 45 countries, 1178 sites, 14,264 patients Canada: 750 United States: 1,932 Mexico: 168 Finland: 16Lithuania: 245 Denmark: 123 Hungary: 237 Netherlands: 161 Ukraine: 1,011 Bulgaria: 678 Sweden: 28 Norway: 49 Romania: 783 U.K.: 159 Belgium: 96 Switzerland: 7 France: 71 Spain: 250 Germany: 530 Austria: 32 Italy: 139 Greece: 29 Turkey: 101 Israel: 189 Poland: 528 Czech Rep: 598 Panama: 0 Chile: 287 Peru: 84 Colombia: 268 Brazil: 483 Venezuela: 20 Argentina: 569 South Africa: 247 Russia: 1,292 China: 496 India: 269 Korea: 204 Taiwan: 159 Hong Kong: 73 Thailand: 87 Philippines: 368 Malaysia: 51 Singapore: 44 Australia: 242 New Zealand: 116

7 Study Conduct RivaroxabanWarfarin Randomized, n Lost to Follow-up, n Premature Discontinuation, n (%) Withdrew Consent, n Median (25 th, 75 th ) Exposure (days) Median (25 th, 75 th ) Follow-up (days) (23.9%) (396, 805) 706 (522, 884) (22.4%) (404, 810) 708 (518, 886)

8 Rivaroxaban (N=7081) Warfarin (N=7090) Age (years) 73 (65, 78) Female (%) 40 Race (%) White Black Asian Region (%) North America Latin America Asia-Pacific Central Europe Western Europe Creatinine Clearance (ml/min) (%) 30 - < ≤80 > Values are median (IQR) Based on Intention-to-Treat Population Baseline Demographics

9 Rivaroxaban (N=7081) Warfarin (N=7090) CHADS 2 Score (mean) 2 (%) 3 (%) 4 (%) 5 (%) 6 (%) Prior VKA Use (%) 6263 Congestive Heart Failure (%) 6362 Hypertension (%) 9091 Diabetes Mellitus (%) 4039 Prior Stroke/TIA/Embolism (%) 55 Prior Myocardial Infarction (%) 1718 Based on Intention-to-Treat Population Baseline Demographics

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

11 Primary Efficacy Outcome Stroke and non-CNS 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

12 RivaroxabanWarfarin Event Rate HR (95% CI) P-value On Treatment N= 14, (0.65,0.95) ITT N= 14, (0.74,1.03) Rivaroxaban better Warfarin better Primary Efficacy Outcome Stroke and non-CNS Embolism 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 RivaroxabanWarfarin Event Rate HR (95% CI)P-value Vascular Death, Stroke, Embolism (0.74, 0.99)0.034 Stroke Type Hemorrhagic Ischemic Unknown Type (0.37, 0.93) 0.94 (0.75, 1.17) 0.65 (0.25, 1.67) Non-CNS Embolism (0.09, 0.61)0.003 Myocardial Infarction (0.63, 1.06)0.121 All Cause Mortality Vascular Non-vascular Unknown Cause (0.70, 1.02) 0.89 (0.73, 1.10) 0.63 (0.36, 1.08) 0.75 (0.40, 1.41) Event Rates are per 100 patient-years Based on Safety on Treatment Population

14 RivaroxabanWarfarin Event Rate HR (95% CI)P-value Vascular Death, Stroke, Embolism (0.84, 1.05)0.265 Stroke Type Hemorrhagic Ischemic Unknown Type (0.38, 0.89) 0.99 (0.82, (0.55, 2.01) Non-CNS Embolism (0.42, Myocardial Infarction (0.72, 1.16)0.464 All Cause Mortality Vascular Non-vascular Unknown Cause (0.82, 1.03) 0.94 (0.81, 1.08) 0.94 (0.75, 1.18) 0.80 (0.57, 1.12) 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 INR range Warfarin Median (25 th, 75 th ) < (0.0 – 9.0) 1.5 to < (3.5 – 14.0) 1.8 to < (5.3 – 13.6) 2.0 to (43.0 – 70.5) >3.0 to (1.9 – 6.5) >3.2 to (3.3 – 13.8) > (0.0 – 0.5) Based on Rosendaal method with all INR values included Based on Safety Population

16 Primary Efficacy Outcome by Quartiles of cTTR Stroke and non-CNS Embolism Based on Rosendaal method with all INR values included Based on Safety Population Event Rates are per 100 patient-years RivaroxabanWarfarin Center TTR Events % Event Rate Events % Event Rate HR (95% CI) % (0.48, 1.03) % (0.62, 1.29) % (0.62, 1.28) % (0.49, 1.12)

17 Primary Safety Outcomes RivaroxabanWarfarin Event Rate HR (95% CI) P- value Major and non-major Clinically Relevant (0.96, 1.11)0.442 Major (0.90, 1.20)0.576 Non-major Clinically Relevant (0.96, 1.13)0.345 Event Rates are per 100 patient-years Based on Safety on Treatment Population

18 RivaroxabanWarfarin Event Rate or N (Rate) HR (95% CI) P- value Major >2 g/dL Hgb drop Transfusion (> 2 units) Critical organ bleeding Bleeding causing death (0.90, 1.20) 1.22 (1.03, 1.44) 1.25 (1.01, 1.55) 0.69 (0.53, 0.91) 0.50 (0.31, 0.79) Intracranial Hemorrhage55 (0.49)84 (0.74)0.67 (0.47, 0.94)0.019 Intraparenchymal37 (0.33)56 (0.49)0.67 (0.44, 1.02)0.060 Intraventricular2 (0.02)4 (0.04) Subdural14 (0.13)27 (0.27)0.53 (0.28, 1.00)0.051 Subarachnoid4 (0.04)1 (0.01) Event Rates are per 100 patient-years Based on Safety on Treatment Population Primary Safety Outcomes

19 Adverse Events and Liver Enzyme Data Values are N (%) Based on Safety Population Rivaroxaban (N=7111) Warfarin (N=7125) Any Adverse Event Any Serious Adverse Event AE leading to study drug discontinuation Epistaxis Peripheral edema Dizziness Nasopharyngitis Cardiac failure Bronchitis Dyspnea Diarrhea ALT Elevation >3 x ULN >5 x ULN >3 x ULN and T Bili > 2 x ULN

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 Executive Steering Committee Sponsors J & J and Bayer Christopher Nessel, Kimberly Schwabe, Scott Berkowitz, John Paolini 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 IDMC Joe Alpert, Chair Allen Skene, Co-chair Gudrun Boysen John Eikelboom Peter Rothwell CEC Manesh Patel Joni O'Briant Lauren Price 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


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