Kenneth W. Mahaffey, MD and Keith AA Fox, MB ChB on behalf of the - - PowerPoint PPT Presentation
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
Kenneth W. Mahaffey, MD and Keith AA Fox, MB ChB
Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention
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
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
X IX IXa VIIIa Va II Fibrin Fibrinogen
Adapted from Weitz et al, 2005; 2008
Rivaroxaban Warfarin
Primary Endpoint: Stroke or non-CNS Systemic Embolism
INR target - 2.5 (2.0-3.0 inclusive) 20 mg daily
15 mg for Cr Cl 30-49 ml/min
Randomize Double Blind / Double Dummy (n ~ 14,000)
Monthly Monitoring Adherence to standard of care guidelines
* Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%
Risk Factors
OR
Systemic embolus
At least 2 or 3 required*
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
1.0 1.46 Superiority Non-inferiority Inferiority
Rivaroxaban Better Warfarin Better
45 countries, 1178 sites, 14,264 patients
Canada: 750 United States: 1,932 Mexico: 168 Finland: 16 Lithuania: 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
Rivaroxaban Warfarin Randomized, n Lost to Follow-up, n Premature Discontinuation, n (%) Withdrew Consent, n Median (25th, 75th) Exposure (days) Median (25th, 75th) 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)
Rivaroxaban (N=7081)
Warfarin (N=7090) Age (years)
73 (65, 78)
73 (65, 78) Female (%)
40
40 Race (%) White Black Asian
83 1 13
83 1 13 Region (%) North America Latin America Asia-Pacific Central Europe Western Europe
19 13 15 38 15
19 13 15 38 15 Creatinine Clearance (ml/min) (%) 30 - <50 50 - ≤80 > 80
21 47 32
21 48 31
Values are median (IQR) Based on Intention-to-Treat Population
Rivaroxaban (N=7081) Warfarin (N=7090) CHADS2 Score (mean) 2 (%) 3 (%) 4 (%) 5 (%) 6 (%) 3.48 13 43 29 13 2 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
INR range Warfarin Median (25th, 75th) <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
Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population
1 2 3 4 5 6 120 240 360 480 600 720 840 960
Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634 Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655
Warfarin HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001 Days from Randomization Cumulative event rate (%) Rivaroxaban
Rivaroxaban Warfarin Event Rate 1.71 2.16
Rivaroxaban Warfarin Event Rate Event Rate HR (95% CI) P-value On Treatment
N= 14,143
1.70 2.15 0.79 (0.65,0.95) 0.015 ITT
N= 14,171
2.12 2.42 0.88 (0.74,1.03) 0.117
Rivaroxaban better Warfarin better
Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations
Rivaroxaban Warfarin Event Rate Event Rate HR (95% CI) P-value Vascular Death, Stroke, Embolism 3.11 3.63 0.86 (0.74, 0.99) 0.034 Stroke Type Hemorrhagic Ischemic Unknown Type 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
Rivaroxaban Warfarin Event Rate Event Rate HR (95% CI) P- value Major and non-major Clinically Relevant 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
Rivaroxaban Warfarin Event Rate
Event Rate
HR (95% CI) P- value Major >2 g/dL Hgb drop Transfusion Critical organ bleeding Bleeding causing death 3.60 2.77 1.65 0.82 0.24 3.45 2.26 1.32 1.18 0.48 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) 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
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 82.4 37.3 15.7 82.2 38.2 15.2 Epistaxis Peripheral edema Dizziness Nasopharyngitis Cardiac failure Bronchitis Dyspnea Diarrhea 10.1 6.1 6.1 5.9 5.6 5.6 5.3 5.3 8.6 6.2 6.3 6.4 5.9 5.9 5.5 5.6 ALT Elevation >3 x ULN >5 x ULN >3 x ULN and T Bili > 2 x ULN 2.9 1.7 0.4 2.9 1.7 0.5
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.