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Kenneth W. Mahaffey, MD and Keith AA Fox, MD
on behalf of the ROCKET AF Investigators
Rivaroxaban Once-daily oral direct factor Xa inhibition
Compared with vitamin K antagonism for prevention
of stroke and Embolism Trial in Atrial Fibrillation
Study Organization
Executive Steering Committee
SponsorsIDMC CECCoordinating CentersSteering Committee Sponsors
Johnson and Johnson
Bayer HealthCare
Coordinating Centers
Duke Clinical Research Institute
Canadian Heart Research Institute
Steering
Committee
Diego Ardissino
Alvaro Avezum
Phil Aylward
Christoph Bode
Antonio Carolei
Ramon Corbalan
Laszlo Csiba
Anthony Dalby
Rafael Diaz
Hans Diener
Geoffrey Donnan
Shaun Goodman
Hein Heidbuchel
Dai-Yi Hu
Kurt Huber
Matyas Keltai
Basil Lewis
Jose Lopez-Sandon
Jean Louis Mas
Ayrton Massaro
Bo Norrving
Martin Penicka
Dorairaj Prabhakaran
Risto Roine
Tan Ru San
Veronika Skvortsova
Gabriel Steg
Harvey White
Lawrence Wong
Gorm Jensen
Gordon MacInnes
Barbara Biedermann
Per Anton Sirnes
Robert Califf
Ken Mahaffey
Manesh Patel
Keith Fox
Bas Hamer
IDMC
Chair
Joe Alpert
Co-chair
Allen Skene
Gudrun Boysen
John Eikelboom
Peter Rothwell
CEC
CEC PI
Manesh Patel, MD
CEC PL
Joni O'Briant
Lead CEC Coord
Lauren Price, RCIS
Other CEC Coord
Diana McFarron, RN
Reviewers (those with * were not active at end of trial)
Kenneth Mahaffey, MD
Manesh Patel, MD
Jonathan Piccini, MD
Willie Hester, MD *
Matthew Brennan, MD *
Rujuta Patel, MD *
Pierluigi Tricoci, MD *
Chiara Melloni, MD
Matt Roe, MD
Jennifer Vergara, MD *
Lauren Price, RCIS
Jeff Craig, MD *
Michael Felker, MD *
Raj Mehta, MD
Dedrick Jordan, MD
Chee Tang Chin, MD *
Robb Kociol, MD
Matt Wilson, RN *
Adriano Truffa, MD
John Vavalle, MD
Executive Steering Committee
Richard Becker
Scott D. Berkowitz
Günter Breithardt
Robert M. Califf
Keith Fox
Werner Hacke
Jonathan Halperin
Graeme Hankey
Kenneth Mahaffey
Christopher Nessel
Daniel Singer
Rivaroxaban Warfarin
Primary Endpoint: Stroke or non-CNS Systemic Embolism
Statistics: non-inferiority, >95% power, 2.3% warfarin event rate
INR target - 2.5
(2.0-3.0 inclusive)
20 mg daily
15 mg for Cr Cl 30-49
Atrial Fibrillation
Randomize
Double blind /
Double Dummy
(n ~ 14,000)
Monthly Monitoring
Adherence to standard of care guidelines
Study Design
Risk Factors• CHF • Hypertension • Age 75 • Diabetes OR• Stroke, TIA or Systemic embolus
At least 3
required*
* 10% enrolled without stroke, TIA, systemic embolus and only 2 factors per protocol
Statistical MethodologiesPatient 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
Study Conduct
Screened
17,232
Randomized
14,264
Rivaroxaban
7,131
Warfarin
7,133
Rivaroxaban Warfarin
Lost to Follow-up 18 18
Premature
Discontinuation
1,499 1,451
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%)
Enrollment45 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
Baseline DemographicsSafety Population
Rivaroxaban (N=7111) Warfarin (N=7125)
Age in Years 73 (65-78) 73 (65-78)
Female 2819 (39.64) 2826 (39.66)
White
Black
Asian
Other
5906 (83.05)
94 (1.32)
894 (12.57)
217 (3.05)
5952 (83.54)
85 (1.19)
887 (12.45)
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
No Prior VKA Use
4431 (62.31)
2680 (37.69)
4458 (62.57)
2667 (37.43)
Creatinine Clearance Group (ml/min)
<30
30-<50
50-≤80
>80
4 (0.06)
1498 (21.09)
3313 (46.64)
2288 (32.21)
4 (0.06)
1472 (20.69)
3410 (47.92)
2230 (31.34)
Congestive Heart Failure
No Congestive Heart Failure
4457 (62.69)
2653 (37.31)
4437 (62.28)
2687 (37.72)
Diabetes Mellitus
No Diabetes Mellitus
2869 (40.35)
4242 (59.65)
2814 (39.49)
4311 (60.51)
Hypertension
No Hypertension
6419 (90.27)
692 (9.73)
6468 (90.78)
657 (9.22)
Prior Stroke/TIA/Non-CNS Systemic Embolism
No Prior Stroke/TIA/Non-CNS Systemic Embolism
3905 (54.91)
3206 (45.09)
3889 (54.58)
3236 (45.42)
Prior Myocardial Infarction (MI)
No Prior Myocardial Infarction (MI)
1178 (16.57)
5933 (83.43)
1282 (17.99)
5843 (82.01)*Me
dia
n (
Q1
-Q3
)
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).
Primary Efficacy EndpointPer Protocol on Treatment Population
Warfarin
Rivaroxaban
HR (95% CI)
0.79 (0.66, 0.96)
P-value non-inferiority <0.001
P-value superiority= 0.018
Primary Efficacy Results by Cohort
Rivaroxaban Warfarin
Analysis Method Event Rate Event RateP-value
Non-inferiority
P-value
Superiority
1.0Rivaroxaban
better
Warfarin
better
Per Protocol,
on Treatment1.71 2.16 <0.001 0.018
Safety, on Treatment 1.70 2.15 <0.001 0.015
ITT 2.12 2.42 <0.001 0.117
Rivaroxaban vs. Warfarin
Bleeding OutcomesSafety on Treatment Population
Rivaroxaban vs. WarfarinRivaroxaban Warfarin
ParameterEvent
Rate
Event
Rate
HR (95%) CI P-value
Superiority
Major and non-major Clinically Relevant 14.91 14.52 1.03 (0.96, 1.11) 0.442
Major
Hemoglobin Hematocrit Drop
Transfusion
Critical Organ Bleeding
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
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
Adverse Event Summary
Liver Enzymes