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