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AHA: ROCKET
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. 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. 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. 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. 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%)
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. 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. 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. 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
