Kenneth W. Mahaffey, MD and Keith AA Fox, MB ChB

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

Relevant Financial Relationships

Kenneth W. Mahaffey, MDResearch 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

http://www.dcri.duke.edu/research/coi.jsp

Keith AA Fox, MB ChBResearch Grants: Bayer, Eli Lilly, J&J, Sanofi-Aventis

Consulting Fees: Bayer, Eli Lilly, J&J, Sanofi-Aventis

No stock ownership

BackgroundRivaroxaban

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

Rivaroxaban

XaXa

IIaIIa

TF/VIIaTF/VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

Adapted from Weitz et al, 2005; 2008

Rivaroxaban Warfarin

Primary Endpoint: Stroke or non-CNS Systemic Embolism

INR target - 2.5 (2.0-3.0 inclusive)

20 mg daily15 mg for Cr Cl 30-49 ml/min

Atrial Fibrillation

RandomizeDouble Blind / Double Dummy

(n ~ 14,000)

Monthly MonitoringAdherence to standard of care guidelines

Study Design

* Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

Risk Factors• CHF • Hypertension • Age 75 • Diabetes OR• Stroke, TIA or Systemic embolus

At least 2 or 3 required*

Statistical Methodologies

Sample SizeWarfarin 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

WarfarinBetter

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: 28Norway: 49 Romania: 783

U.K.: 159

Belgium: 96

Switzerland: 7

France: 71Spain: 250Germany: 530

Austria: 32Italy: 139

Greece: 29Turkey: 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: 73Thailand: 87 Philippines: 368

Malaysia: 51

Singapore: 44

Australia: 242

New Zealand: 116

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

18

1589 (22.4%)

620

593 (404, 810)

708 (518, 886)

Rivaroxaban (N=7081)

Warfarin(N=7090)

Age (years) 73 (65, 78) 73 (65, 78)

Female (%) 40 40

Race (%) White Black Asian

831

13

831

13

Region (%) North America Latin America Asia-Pacific Central Europe Western Europe

1913153815

1913153815

Creatinine Clearance (ml/min) (%) 30 - <50 50 - ≤80 > 80

214732

214831

Values are median (IQR)Based on Intention-to-Treat Population

Baseline Demographics

Rivaroxaban (N=7081)

Warfarin (N=7090)

CHADS2 Score (mean) 2 (%)

3 (%)

4 (%)

5 (%)

6 (%)

3.48134329132

3.46134428122

Prior VKA Use (%) 62 63

Congestive Heart Failure (%) 63 62

Hypertension (%) 90 91

Diabetes Mellitus (%) 40 39

Prior Stroke/TIA/Embolism (%) 55 55

Prior Myocardial Infarction (%) 17 18

Based on Intention-to-Treat Population

Baseline Demographics

Trial ResultsKenneth W. Mahaffey, MD on Behalf of the ROCKET AF Investigators

Primary Efficacy OutcomeStroke and non-CNS Embolism

Event Rates are per 100 patient-yearsBased on Protocol Compliant on Treatment Population

No. at risk:Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655

Warfarin

HR (95% CI): 0.79 (0.66, 0.96)

P-value Non-Inferiority: <0.001

Days from Randomization

Cu

mu

lati

ve e

ven

t ra

te (

%)

Rivaroxaban

Rivaroxaban Warfarin

Event Rate

1.71 2.16

  Rivaroxaban Warfarin    Event Rate

Event Rate

HR(95% CI) P-value

On TreatmentN= 14,143

1.70 2.15 0.79 (0.65,0.95)  0.015

ITTN= 14,171

2.12 2.42 0.88 (0.74,1.03)  0.117

Rivaroxabanbetter

Warfarinbetter

Primary Efficacy OutcomeStroke and non-CNS Embolism

Event Rates are per 100 patient-yearsBased on Safety on Treatment or Intention-to-Treat thru Site Notification populations

Key Secondary Efficacy Outcomes

Rivaroxaban Warfarin

Event Rate 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

0.261.340.06

0.441.420.10

0.59 (0.37, 0.93)0.94 (0.75, 1.17)0.65 (0.25, 1.67)

0.0240.5810.366

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

1.871.530.190.15

2.211.710.300.20

0.85 (0.70, 1.02)0.89 (0.73, 1.10)0.63 (0.36, 1.08)0.75 (0.40, 1.41)

0.0730.2890.0940.370

Event Rates are per 100 patient-yearsBased on Safety on Treatment Population

Rivaroxaban Warfarin

Event Rate 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

0.261.620.15

0.441.640.14

0.58 (0.38, 0.89)0.99 (0.82, 1.201.05 (0.55, 2.01)

0.0120.9160.871

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

4.522.911.150.46

4.913.111.220.57

0.92 (0.82, 1.03)0.94 (0.81, 1.08)0.94 (0.75, 1.18)0.80 (0.57, 1.12)

0.1520.3500.6110.195

Key Secondary Efficacy Outcomes

Event Rates are per 100 patient-yearsBased on Intention-to-Treat Population

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 includedBased on Safety Population

Primary Efficacy Outcome by Quartiles of cTTRStroke and non-CNS Embolism

Based on Rosendaal method with all INR values includedBased on Safety PopulationEvent Rates are per 100 patient-years

Rivaroxaban Warfarin

Center TTREvents

%Event Rate

Events %

Event Rate

HR(95% CI)

0.0 - 50.6% 2.6 1.8 3.7 2.50.71

(0.48, 1.03)

50.7 - 58.5% 3.0 1.9 3.5 2.20.83

(0.62, 1.29)

58.6 - 65.7% 3.1 1.9 3.5 2.10.92

(0.62, 1.28)

65.7 - 100.0% 2.2 1.3 3.0 1.80.77

(0.49, 1.12)

Primary Safety Outcomes

Rivaroxaban Warfarin

Event Rate 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-yearsBased on Safety on Treatment Population

Rivaroxaban Warfarin

Event Rate or N (Rate)

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

3.602.771.650.820.24

3.452.261.321.180.48

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)

0.5760.0190.0440.0070.003

Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) 0.019

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 4 (0.04) 1 (0.01)

Event Rates are per 100 patient-yearsBased on Safety on Treatment Population

Primary Safety Outcomes

Adverse Events and Liver Enzyme Data

Values are N (%)Based on Safety Population

Rivaroxaban (N=7111)

Warfarin (N=7125)

Any Adverse EventAny Serious Adverse EventAE leading to study drug discontinuation

82.437.315.7

82.238.215.2

EpistaxisPeripheral edemaDizzinessNasopharyngitisCardiac failureBronchitisDyspneaDiarrhea

10.16.16.15.95.65.65.35.3

8.66.26.36.45.95.95.55.6

ALT Elevation >3 x ULN >5 x ULN >3 x ULN and T Bili > 2 x ULN

2.91.00.4

2.91.00.5

Summary

Efficacy:

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.

Study Organization

Executive Steering Committee

SponsorsJ & J and Bayer

Christopher Nessel, Kimberly Schwabe, Scott Berkowitz, John Paolini

Duke Clinical Research Institute

Jonathan Piccini, Karen Hannan, Jyotsna Garg, Lisa

Eskenazi, Angela Kaiser, Patricia Stone

Canadian HeartResearch Center

Shaun GoodmanMaggie Godin-Edgecomb

IDMC

Joe Alpert, ChairAllen Skene, Co-chair

Gudrun Boysen John Eikelboom

Peter Rothwell

CEC

Manesh PatelJoni O'BriantLauren Price

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