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G02-536 w_script.ppt 4/6/2017 3:55:16 PM Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke.

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Presentation on theme: "G02-536 w_script.ppt 4/6/2017 3:55:16 PM Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke."— Presentation transcript:

1 G w_script.ppt 4/6/2017 3:55:16 PM 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

2 Relevant Financial Relationships
G w_script.ppt 4/6/2017 3:55:16 PM 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

3 Background Rivaroxaban
G w_script.ppt 4/6/2017 3:55:16 PM Background Rivaroxaban TF/VIIa 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 X IX IXa VIIIa Rivaroxaban Va Xa II IIa Fibrinogen Fibrin Adapted from Weitz et al, 2005; 2008

4 Study Design Atrial Fibrillation Rivaroxaban Warfarin
G w_script.ppt 4/6/2017 3:55:16 PM Risk Factors CHF Hypertension Age  75 Diabetes OR Stroke, TIA or Systemic embolus Study Design At least 2 or 3 required* Atrial Fibrillation Rivaroxaban Randomize Double Blind / Double Dummy (n ~ 14,000) Warfarin 20 mg daily 15 mg for Cr Cl ml/min INR target - 2.5 ( 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 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

6 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 Denmark: 123 Russia: 1,292 Ukraine: 1,011 U.K.: 159 Canada: 750 Netherlands: 161 Belgium: 96 United States: 1,932 Korea: 204 France: 71 China: 496 Spain: 250 Taiwan: 159 Mexico: 168 Germany: 530 India: 269 Hong Kong: 73 Switzerland: 7 Thailand: 87 Philippines: 368 Austria: 32 Panama: 0 Malaysia: 51 Italy: 139 Venezuela: 20 Singapore: 44 Greece: 29 Colombia: 268 Turkey: 101 Peru: 84 Israel: 189 Australia: 242 Brazil: 483 South Africa: 247 Chile: 287 Argentina: 569 New Zealand: 116

7 Study Conduct Rivaroxaban Warfarin Randomized, n Lost to Follow-up, n
G w_script.ppt 4/6/2017 3:55:16 PM Study Conduct 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 1589 (22.4%) 620 593 (404, 810) 708 (518, 886)

8 Baseline Demographics
Rivaroxaban (N=7081) Warfarin (N=7090) Age (years) 73 (65, 78) Female (%) 40 Race (%) White Black Asian 83 1 13 Region (%) North America Latin America Asia-Pacific Central Europe Western Europe 19 15 38 Creatinine Clearance (ml/min) (%) <50 50 - ≤80 > 80 21 47 32 48 31 Values are median (IQR) Based on Intention-to-Treat Population

9 Baseline Demographics
Rivaroxaban (N=7081) Warfarin (N=7090) CHADS2 Score (mean) 2 (%) 3 (%) 4 (%) 5 (%) 6 (%) 3.48 13 43 29 2 3.46 44 28 12 Prior VKA Use (%) 62 63 Congestive Heart Failure (%) Hypertension (%) 90 91 Diabetes Mellitus (%) 40 39 Prior Stroke/TIA/Embolism (%) 55 Prior Myocardial Infarction (%) 17 18 Based on Intention-to-Treat Population

10 G w_script.ppt 4/6/2017 3:55:16 PM Trial Results Kenneth W. Mahaffey, MD on Behalf of the ROCKET AF Investigators

11 Primary Efficacy Outcome Stroke and non-CNS Embolism
Rivaroxaban Warfarin Event Rate 1.71 2.16 Warfarin Rivaroxaban Cumulative event rate (%) HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001 Days from Randomization No. at risk: Rivaroxaban Warfarin Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population

12 Primary Efficacy Outcome Stroke and non-CNS Embolism
Rivaroxaban Warfarin 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

13 Key Secondary Efficacy Outcomes
Rivaroxaban Warfarin 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 0.59 (0.37, 0.93) 0.94 (0.75, 1.17) 0.65 (0.25, 1.67) 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 0.85 (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 Key Secondary Efficacy Outcomes
Rivaroxaban Warfarin Event Rate HR (95% CI) P-value Vascular Death, Stroke, Embolism 4.51 4.81 0.94 (0.84, 1.05) 0.265 Stroke Type Hemorrhagic Ischemic Unknown Type 0.26 1.62 0.15 0.44 1.64 0.14 0.58 (0.38, 0.89) 0.99 (0.82, 1.20 1.05 (0.55, 2.01) 0.012 0.916 0.871 Non-CNS Embolism 0.16 0.21 0.74 (0.42, 1.32 0.308 Myocardial Infarction 1.02 1.11 0.91 (0.72, 1.16) 0.464 All Cause Mortality Vascular Non-vascular Unknown Cause 4.52 2.91 1.15 0.46 4.91 3.11 1.22 0.57 0.92 (0.82, 1.03) 0.94 (0.81, 1.08) 0.94 (0.75, 1.18) 0.80 (0.57, 1.12) 0.152 0.350 0.611 0.195 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 (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

16 G w_script.ppt 4/6/2017 3:55:16 PM Primary Efficacy Outcome by Quartiles of cTTR Stroke and non-CNS Embolism Rivaroxaban Warfarin Center TTR Events % Event Rate Events % Event Rate HR (95% CI) % 2.6 1.8 3.7 2.5 0.71 (0.48, 1.03) % 3.0 1.9 3.5 2.2 0.83 (0.62, 1.29) % 3.1 2.1 0.92 (0.62, 1.28) % 1.3 0.77 (0.49, 1.12) Based on Rosendaal method with all INR values included Based on Safety Population Event Rates are per 100 patient-years

17 Primary Safety Outcomes
G w_script.ppt 4/6/2017 3:55:16 PM Primary Safety Outcomes Rivaroxaban Warfarin 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

18 Primary Safety Outcomes
G w_script.ppt 4/6/2017 3:55:17 PM Primary Safety Outcomes Rivaroxaban Warfarin 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 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) 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 1 (0.01) Event Rates are per 100 patient-years Based on Safety on Treatment Population

19 Adverse Events and Liver Enzyme Data
G w_script.ppt 4/6/2017 3:55:17 PM Adverse Events and Liver Enzyme Data 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 5.9 5.6 5.3 8.6 6.2 6.3 6.4 5.5 ALT Elevation >3 x ULN >5 x ULN >3 x ULN and T Bili > 2 x ULN 2.9 1.0 0.4 0.5 Values are N (%) Based on Safety Population

20 Summary Efficacy: Safety: Conclusion:
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 Duke Clinical Research Institute
Study Organization Sponsors J & J and Bayer Christopher Nessel, Kimberly Schwabe, Scott Berkowitz, John Paolini IDMC Joe Alpert, Chair Allen Skene, Co-chair Gudrun Boysen John Eikelboom Peter Rothwell Executive Steering Committee 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 CEC Manesh Patel Joni O'Briant Lauren Price 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


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