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 ChB on behalf of the ROCKET AF Investigators
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
Background Rivaroxaban TF/VIIa Direct, specific, competitive factor Xa inhibitor X IX Half-life 5-13 hours IXa VIIIa Clearance : Rivaroxaban Va 1/3 direct renal excretion 2/3 metabolism via CYP 450 Xa enzymes Oral, once daily dosing without need for coagulation II monitoring IIa Studied in >25,000 patients in post-op, DVT, PE and Fibrinogen Fibrin ACS patients Adapted from Weitz et al , 2005; 2008
Risk Factors Study Design • CHF • Hypertension At least 2 or • Age 75 3 required* • Diabetes OR Atrial Fibrillation • Stroke, TIA or Systemic embolus Rivaroxaban Randomize Warfarin Double Blind / Double Dummy 20 mg daily INR target - 2.5 (n ~ 14,000) 15 mg for Cr Cl 30-49 ml/min (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%
Statistical Methodologies Superiority Sample Size Non-inferiority Inferiority Warfarin event rate ~2.3 1.0 1.46 Type 1 error 0.05 (2-sided) Warfarin Rivaroxaban Better Better 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
Enrollment 45 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
Study Conduct Rivaroxaban Warfarin Randomized, n 7131 7133 Lost to Follow-up, n 18 18 Premature Discontinuation, n (%) 1693 (23.9%) 1589 (22.4%) Withdrew Consent, n 626 620 Median (25 th , 75 th ) Exposure (days) 589 (396, 805) 593 (404, 810) Median (25 th , 75 th ) Follow-up (days) 706 (522, 884) 708 (518, 886)
Baseline Demographics Rivaroxaban Warfarin (N=7090) (N=7081) Age (years) 73 (65, 78) 73 (65, 78) Female (%) 40 40 Race (%) White 83 83 Black 1 1 Asian 13 13 Region (%) North America 19 19 Latin America 13 13 Asia-Pacific 15 15 Central Europe 38 38 Western Europe 15 15 Creatinine Clearance (ml/min) (%) 30 - <50 21 21 50 - ≤80 48 47 > 80 31 32 Values are median (IQR) Based on Intention-to-Treat Population
Baseline Demographics Rivaroxaban Warfarin (N=7081) (N=7090) CHADS 2 Score (mean) 3.48 3.46 2 (%) 13 13 3 (%) 43 44 4 (%) 29 28 5 (%) 13 12 6 (%) 2 2 Prior VKA Use (%) 62 63 Congestive Heart Failure (%) 63 62 Hypertension (%) 90 91 Diabetes Mellitus (%) 40 39 Prior Stroke/TIA/Embolism (%) 55 55 Prior Myocardial Infarction (%) 17 18 Based on Intention-to-Treat Population
Trial Results Kenneth W. Mahaffey, MD on Behalf of the ROCKET AF Investigators
Time in Therapeutic Range (TTR) INR Data Warfarin Median (25 th , 75 th ) INR range 2.7 (0.0 – 9.0) <1.5 7.9 (3.5 – 14.0) 1.5 to <1.8 9.1 (5.3 – 13.6) 1.8 to <2.0 57.8 (43.0 – 70.5) 2.0 to 3.0 4.0 (1.9 – 6.5) >3.0 to 3.2 7.9 (3.3 – 13.8) >3.2 to 5.0 0.0 (0.0 – 0.5) >5.0 Based on Rosendaal method with all INR values included Based on Safety Population
Primary Efficacy Outcome Stroke and non-CNS Embolism 6 Rivaroxaban Warfarin Cumulative event rate (%) Warfarin 5 Event 1.71 2.16 Rate 4 Rivaroxaban 3 HR (95% CI): 0.79 (0.66, 0.96) 2 P-value Non-Inferiority: <0.001 1 0 0 120 240 360 480 600 720 840 960 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
Primary Efficacy Outcome Stroke and non-CNS Embolism Rivaroxaban Warfarin Event Event HR P-value Rate Rate (95% CI) On 0.79 1.70 2.15 0.015 Treatment (0.65,0.95) N= 14,143 0.88 ITT 2.12 2.42 0.117 (0.74,1.03) N= 14,171 Rivaroxaban Warfarin better better Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations
Key Secondary Efficacy Outcomes Rivaroxaban Warfarin Event Rate Event Rate HR (95% CI) P-value Vascular Death, 3.11 3.63 0.86 (0.74, 0.99) 0.034 Stroke, Embolism Stroke Type Hemorrhagic 0.26 0.44 0.59 (0.37, 0.93) 0.024 Ischemic 1.34 1.42 0.94 (0.75, 1.17) 0.581 Unknown Type 0.06 0.10 0.65 (0.25, 1.67) 0.366 Non-CNS Embolism 0.04 0.19 0.23 (0.09, 0.61) 0.003 Myocardial Infarction 0.91 1.12 0.81 (0.63, 1.06) 0.121 All Cause Mortality 1.87 2.21 0.85 (0.70, 1.02) 0.073 Vascular 1.53 1.71 0.89 (0.73, 1.10) 0.289 Non-vascular 0.19 0.30 0.63 (0.36, 1.08) 0.094 Unknown Cause 0.15 0.20 0.75 (0.40, 1.41) 0.370 Event Rates are per 100 patient-years Based on Safety on Treatment Population
Bleeding Outcomes Rivaroxaban Warfarin HR P- Event Rate Event Rate (95% CI) value Major and non-major 14.91 14.52 1.03 (0.96, 1.11) 0.442 Clinically Relevant Major 3.60 3.45 1.04 (0.90, 1.20) 0.576 Non-major Clinically 11.80 11.37 1.04 (0.96, 1.13) 0.345 Relevant Event Rates are per 100 patient-years Based on Safety on Treatment Population
Bleeding Outcomes Rivaroxaban Warfarin Event Rate Event Rate HR P- or N (Rate) or N (Rate) (95% CI) value Major 3.60 3.45 1.04 (0.90, 1.20) 0.576 >2 g/dL Hgb drop 2.77 2.26 1.22 (1.03, 1.44) 0.019 Transfusion 1.65 1.32 1.25 (1.01, 1.55) 0.044 Critical organ bleeding 0.82 1.18 0.69 (0.53, 0.91) 0.007 Bleeding causing death 0.24 0.48 0.50 (0.31, 0.79) 0.003 Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) 0.019 Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) 0.060 Intraventricular 2 (0.02) 4 (0.04) Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) 0.051 Subarachnoid 4 (0.04) 1 (0.01) Event Rates are per 100 patient-years Based on Safety on Treatment Population
Adverse Events and Liver Enzyme Data Rivaroxaban Warfarin (N=7111) (N=7125) Any Adverse Event 82.4 82.2 Any Serious Adverse Event 37.3 38.2 AE leading to study drug discontinuation 15.7 15.2 Epistaxis 10.1 8.6 Peripheral edema 6.1 6.2 Dizziness 6.1 6.3 Nasopharyngitis 5.9 6.4 Cardiac failure 5.6 5.9 Bronchitis 5.6 5.9 Dyspnea 5.3 5.5 Diarrhea 5.3 5.6 ALT Elevation >3 x ULN 2.9 2.9 >5 x ULN 1.7 1.7 >3 x ULN and T Bili > 2 x ULN 0.4 0.5 Values are N (%) Based on Safety Population
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.
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