Kenneth W. Mahaffey, MD and Keith AA Fox, MB ChB

Transcription

1 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

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 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

4 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 ml/min Randomize Double Blind / Double Dummy (n ~ 14,000) INR target ( 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 Statistical Methodologies Sample Size event rate ~2.3 Type 1 error 0.05 (2-sided) 405 events; >95% power Superiority Non-inferiority Inferiority Better 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

6 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

7 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) (23.9%) (396, 805) 706 (522, 884) (22.4%) (404, 810) 708 (518, 886)

8 Baseline Demographics (N=7081) (N=7090) Age (years) 73 (65, 78) 73 (65, 78) Female (%) 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

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

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

11 Time in Therapeutic Range (TTR) INR Data INR range Median (25 th, 75 th ) < ( ) 1.5 to < ( ) 1.8 to < ( ) 2.0 to ( ) >3.0 to ( ) >3.2 to ( ) > ( ) Based on Rosendaal method with all INR values included Based on Safety Population

12 Cumulative event rate (%) Primary Efficacy Outcome Stroke and non-cns Embolism Event Rate HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: < No. at risk: Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population Days from Randomization

13 Primary Efficacy Outcome Stroke and non-cns Embolism On Treatment N= 14,143 Event Rate Event Rate HR (95% CI) 0.79 (0.65,0.95) P-value ITT N= 14, (0.74,1.03) better better Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations

14 Key Secondary Efficacy Outcomes Vascular Death, Stroke, Embolism Stroke Type Hemorrhagic Ischemic Unknown Type Event Rate Event Rate HR (95% CI) P-value (0.74, 0.99) (0.37, 0.93) 0.94 (0.75, 1.17) 0.65 (0.25, 1.67) Non-CNS Embolism (0.09, 0.61) Myocardial Infarction (0.63, 1.06) 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

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

16 Major >2 g/dl Hgb drop Transfusion Critical organ bleeding Bleeding causing death Bleeding Outcomes Event Rate or N (Rate) Event Rate or N (Rate) 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 Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) Intraventricular 2 (0.02) 4 (0.04) Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) Subarachnoid 4 (0.04) 1 (0.01) Event Rates are per 100 patient-years Based on Safety on Treatment Population

17 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) (N=7125)

18 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.