Rivaroxaban Once-daily oral direct factor Xa inhibition
        Compared with vitamin K antagonism for prevention
        ...
Study Organization
Steering
                      CEC
Committee
                   CEC PI                     Reviewers (t...
Risk Factors
                                                                                       • CHF                 ...
Statistical Methodologies
            Patient Populations

 Per Protocol
    All randomized patients excluding pre-defin...
Study Conduct
     Screened
      17,232

                                                   Rivaroxaban        Warfarin
 ...
Enrollment
                       45 countries, 1178 sites, 14,264 patients

                                             ...
Baseline Demographics
                                           Safety Population
                                       ...
TTR Data

 These data are for all warfarin patients and all INR values
  with imputation using the Rosendaal method.
 Ti...
Primary Efficacy Endpoint
 Per Protocol on Treatment Population


HR (95% CI)                      Warfarin
0.79 (0.66, 0....
Primary Efficacy Results by Cohort

                                           Rivaroxaban    Warfarin     Rivaroxaban vs....
Bleeding Outcomes
                      Safety on Treatment Population


                                          Rivarox...
Adverse Event Summary
Liver Enzymes
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AHA: ROCKET

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AHA: ROCKET

  1. 1. 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, MD on behalf of the ROCKET AF Investigators
  2. 2. Study Organization Steering CEC Committee CEC PI Reviewers (those with * were not active at end of trial) Diego Ardissino Ayrton Massaro Kenneth Mahaffey, MD Manesh Patel, MD Alvaro Avezum Bo Norrving IDMC Manesh Patel, MD Phil Aylward Martin Penicka SteeringCommittee CEC PL Executive Steering Committee Executive Jonathan Piccini, MD Willie Hester, MD * Christoph Bode Chair Dorairaj Prabhakaran Matthew Brennan, MD * Joni O'Briant Richard Becker Alpert Antonio Carolei Risto Roine Joe Rujuta Patel, MD * Ramon Corbalan Lead CEC Coord Scott D. Berkowitz Tan Ru San Pierluigi Tricoci, MD * Laszlo Csiba Günter Breithardt Co-chair Veronika Skvortsova Chiara Melloni, MD Lauren Price, RCIS Steering Committee Gabriel Steg Robert M. Califf Skene Anthony Dalby CoordinatingCenters Allen MD Coordinating CentersMatt Roe, IDMC CEC Sponsors Sponsors Rafael Diaz Keith Fox Vergara, MD * Jennifer Other CEC White WernerLauren Price, RCIS Harvey Coord Hacke Hans Diener Duke Clinical Research Institute Boysen Lawrence Wong Gudrun Diana McFarron, JonathanJeff Craig, MD * RN Johnson and Johnson Geoffrey Donnan Gorm Jensen Halperin Canadian Heart ResearchMichael Felker, MD * Institute Bayer HealthCare Shaun Goodman Gordon MacInnesGraeme Hankey John Eikelboom Raj Mehta, MD Hein Heidbuchel Kenneth Mahaffey Barbara Biedermann Dedrick Jordan, MD Dai-Yi Hu Christopher Nessel Chin, MD * Per Anton Sirnes Peter Rothwell Chee Tang Kurt Huber Robert Califf Daniel Robb Kociol, MD Singer Matyas Keltai Ken Mahaffey Matt Wilson, RN * Basil Lewis Manesh Patel Adriano Truffa, MD John Vavalle, MD Jose Lopez-Sandon Keith Fox Jean Louis Mas Bas Hamer
  3. 3. Risk Factors • CHF At least 3 Study Design • Hypertension required* • Age  75 • Diabetes OR Atrial Fibrillation • Stroke, TIA or Systemic embolus Randomize Rivaroxaban Double blind / Warfarin Double Dummy 20 mg daily (n ~ 14,000) INR target - 2.5 15 mg for Cr Cl 30-49 (2.0-3.0 inclusive) Monthly Monitoring Adherence to standard of care guidelines Primary Endpoint: Stroke or non-CNS Systemic Embolism Statistics: non-inferiority, >95% power, 2.3% warfarin event rate * 10% enrolled without stroke, TIA, systemic embolus and only 2 factors per protocol
  4. 4. Statistical Methodologies Patient Populations  Per Protocol  All randomized patients excluding pre-defined major protocol deviations including study drug compliance <60%  Safety Population  All randomized receiving at least one dose of study drug  ITT  All randomized patients followed to end of study (May 28, 2010)  On Treatment  On Treatment includes events on study drug or within 2 days of study drug discontinuation
  5. 5. Study Conduct Screened 17,232 Rivaroxaban Warfarin Randomized Lost to Follow-up 18 18 14,264 Rivaroxaban Warfarin Premature 1,499 1,451 7,131 7,133 Discontinuation Withdrew Consent 626 620 Data not used 50 43 Rivaroxaban Warfarin Total Per Protocol Population 6,958 7,004 13,962 (97.9%) Safety Population 7,061 7,082 14,143 (99.2%) ITT Population 7,081 7,090 14,171 (99.3%)
  6. 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 Hong Kong: 73 India: 269 Switzerland: 7 Thailand: 87 Philippines: 368 Austria: 32 Malaysia: 51 Panama: 0 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. 7. Baseline Demographics Safety Population Rivaroxaban (N=7111) Warfarin (N=7125) Age in Years 73 (65-78) 73 (65-78) Female 2819 (39.64) 2826 (39.66) White 5906 (83.05) 5952 (83.54) Black 94 (1.32) 85 (1.19) Asian 894 (12.57) 887 (12.45) Other 217 (3.05) 201 (2.82) Baseline Weight (kg)* 80.00 (69.00-92.70) 80.00 (69.00-92.00) Baseline Systolic Blood Pressure (mmHg)* 130.00 (120.00-140.00) 130.00 (120.00-140.00) Prior VKA Use 4431 (62.31) 4458 (62.57) No Prior VKA Use 2680 (37.69) 2667 (37.43) Creatinine Clearance Group (ml/min) <30 4 (0.06) 4 (0.06) 30-<50 1498 (21.09) 1472 (20.69) 50-≤80 3313 (46.64) 3410 (47.92) >80 2288 (32.21) 2230 (31.34) Congestive Heart Failure 4457 (62.69) 4437 (62.28) No Congestive Heart Failure 2653 (37.31) 2687 (37.72) Diabetes Mellitus 2869 (40.35) 2814 (39.49) No Diabetes Mellitus 4242 (59.65) 4311 (60.51) *Median (Q1-Q3) Hypertension 6419 (90.27) 6468 (90.78) No Hypertension 692 (9.73) 657 (9.22) Prior Stroke/TIA/Non-CNS Systemic Embolism 3905 (54.91) 3889 (54.58) No Prior Stroke/TIA/Non-CNS Systemic Embolism 3206 (45.09) 3236 (45.42) Prior Myocardial Infarction (MI) 1178 (16.57) 1282 (17.99) No Prior Myocardial Infarction (MI) 5933 (83.43) 5843 (82.01)
  8. 8. TTR Data  These data are for all warfarin patients and all INR values with imputation using the Rosendaal method.  Time in therapeutic range is being recalculated using the same approach as RELY (Wallentin, Lancet, 2010).
  9. 9. Primary Efficacy Endpoint Per Protocol on Treatment Population HR (95% CI) Warfarin 0.79 (0.66, 0.96) P-value non-inferiority <0.001 P-value superiority= 0.018 Rivaroxaban
  10. 10. Primary Efficacy Results by Cohort Rivaroxaban Warfarin Rivaroxaban vs. Warfarin P-value P-value Analysis Method Event Rate Event Rate Non-inferiority Superiority Per Protocol, 1.71 2.16 <0.001 0.018 on Treatment Safety, on Treatment 1.70 2.15 <0.001 0.015 ITT 2.12 2.42 <0.001 0.117 Rivaroxaban 1.0 Warfarin better better
  11. 11. Bleeding Outcomes Safety on Treatment Population Rivaroxaban Warfarin Rivaroxaban vs. Warfarin Event Event HR (95%) CI P-value Parameter Rate Rate Superiority 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 Hemoglobin Hematocrit 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 0.48 Death 0.24 0.50 (0.31, 0.79) 0.003 Non-major Clinically Relevant 11.80 11.37 1.04 (0.96, 1.13) 0.345 Minimal 2.35 2.03 1.16 (0.97, 1.39) 0.102
  12. 12. Adverse Event Summary
  13. 13. Liver Enzymes

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