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 Direct, specific, competitive factor Xa inhibitor X TF/VIIa IX Half-life 5-13 hours Clearance : 1/3 direct renal excretion VIIIa Va IXa 2/3 metabolism via CYP 450 enzymes Xa Oral, once daily dosing without need for coagulation monitoring Studied in >25,000 patients in post-op, DVT, PE and ACS patients Fibrinogen II IIa Fibrin Adapted from Weitz et al, 2005; 2008
Study Design Atrial Fibrillation Risk Factors CHF Hypertension At least 2 or Age 75 3 required* Diabetes OR Stroke, TIA or Systemic embolus 20 mg daily 15 mg for Cr Cl 30-49 ml/min Randomize Double Blind / Double Dummy (n ~ 14,000) 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%
Statistical Methodologies Sample Size event rate ~2.3 Type 1 error 0.05 (2-sided) 405 events; >95% power Superiority Non-inferiority Inferiority Better 1.0 1.46 Better ~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 Canada: 750 United States: 1,932 Mexico: 168 Panama: 0 Venezuela: 20 Colombia: 268 Peru: 84 Brazil: 483 Chile: 287 Argentina: 569 Poland: 528 Finland: 16 Lithuania: 245 Sweden: 28 Hungary: 237 Norway: 49 Romania: 783 Czech Rep: 598 Bulgaria: 678 Denmark: 123 Russia: 1,292 Ukraine: 1,011 U.K.: 159 Netherlands: 161 Belgium: 96 Korea: 204 France: 71 China: 496 Spain: 250 Taiwan: 159 Germany: 530 India: 269 Hong Kong: 73 Switzerland: 7 Thailand: 87 Philippines: 368 Austria: 32 Malaysia: 51 Italy: 139 Singapore: 44 Greece: 29 Turkey: 101 Israel: 189 Australia: 242 South Africa: 247 New Zealand: 116
Study Conduct 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) 7131 18 1693 (23.9%) 626 589 (396, 805) 706 (522, 884) 7133 18 1589 (22.4%) 620 593 (404, 810) 708 (518, 886)
Baseline Demographics (N=7081) (N=7090) Age (years) 73 (65, 78) 73 (65, 78) Female (%) 40 40 Race (%) White Black Asian Region (%) North America Latin America Asia-Pacific Central Europe Western Europe Creatinine Clearance (ml/min) (%) 30 - <50 50-80 > 80 Values are median (IQR) Based on Intention-to-Treat Population 83 1 13 19 13 15 38 15 21 47 32 83 1 13 19 13 15 38 15 21 48 31
Baseline Demographics CHADS 2 Score (mean) 2 (%) 3 (%) 4 (%) 5 (%) 6 (%) (N=7081) 3.48 13 43 29 13 2 (N=7090) 3.46 13 44 28 12 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 INR range Median (25 th, 75 th ) <1.5 2.7 (0.0 9.0) 1.5 to <1.8 7.9 (3.5 14.0) 1.8 to <2.0 9.1 (5.3 13.6) 2.0 to 3.0 57.8 (43.0 70.5) >3.0 to 3.2 4.0 (1.9 6.5) >3.2 to 5.0 7.9 (3.3 13.8) >5.0 0.0 (0.0 0.5) Based on Rosendaal method with all INR values included Based on Safety Population
Cumulative event rate (%) 6 5 4 3 2 1 Primary Efficacy Outcome Stroke and non-cns Embolism Event Rate 1.71 2.16 HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001 0 0 120 240 360 480 600 720 840 960 No. at risk: 6958 6211 5786 5468 4406 3407 2472 1496 634 7004 6327 5911 5542 4461 3478 2539 1538 655 Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population Days from Randomization
Primary Efficacy Outcome Stroke and non-cns Embolism On Treatment N= 14,143 Event Rate Event Rate 1.70 2.15 HR (95% CI) 0.79 (0.65,0.95) P-value 0.015 ITT N= 14,171 2.12 2.42 0.88 (0.74,1.03) 0.117 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 Vascular Death, Stroke, Embolism Stroke Type Hemorrhagic Ischemic Unknown Type Event Rate Event Rate HR (95% CI) P-value 3.11 3.63 0.86 (0.74, 0.99) 0.034 0.26 1.34 0.06 0.44 1.42 0.10 0.59 (0.37, 0.93) 0.94 (0.75, 1.17) 0.65 (0.25, 1.67) 0.024 0.581 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 Vascular Non-vascular Unknown Cause 1.87 1.53 0.19 0.15 2.21 1.71 0.30 0.20 0.85 (0.70, 1.02) 0.89 (0.73, 1.10) 0.63 (0.36, 1.08) 0.75 (0.40, 1.41) 0.073 0.289 0.094 0.370 Event Rates are per 100 patient-years Based on Safety on Treatment Population
Bleeding Outcomes Major and non-major Clinically Relevant Event Rate Event Rate HR (95% CI) P- value 14.91 14.52 1.03 (0.96, 1.11) 0.442 Major 3.60 3.45 1.04 (0.90, 1.20) 0.576 Non-major Clinically Relevant 11.80 11.37 1.04 (0.96, 1.13) 0.345 Event Rates are per 100 patient-years Based on Safety on Treatment Population
Major >2 g/dl Hgb drop Transfusion Critical organ bleeding Bleeding causing death Bleeding Outcomes Event Rate or N (Rate) 3.60 2.77 1.65 0.82 0.24 Event Rate or N (Rate) 3.45 2.26 1.32 1.18 0.48 HR (95% CI) 1.04 (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) P- value 0.576 0.019 0.044 0.007 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 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 Values are N (%) Based on Safety Population (N=7111) 82.4 37.3 15.7 10.1 6.1 6.1 5.9 5.6 5.6 5.3 5.3 2.9 1.7 0.4 (N=7125) 82.2 38.2 15.2 8.6 6.2 6.3 6.4 5.9 5.9 5.5 5.6 2.9 1.7 0.5
Efficacy: Summary was non-inferior to warfarin for prevention of stroke and non-cns embolism. 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: is a proven alternative to warfarin for moderate or high risk patients with AF.