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, MD
Research 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 ChB
Research Grants: Bayer, Eli Lilly, J&J, Sanofi-Aventis
Consulting Fees: Bayer, Eli Lilly, J&J, Sanofi-Aventis
No stock ownership

Background
Rivaroxaban
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
Xa
IIa
TF/VIIa
X IX
IXa
VIIIa
Va
II
Fibrin Fibrinogen
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 daily
15 mg for Cr Cl 30-49 ml/min
Atrial Fibrillation
Randomize
Double Blind /
Double Dummy
(n ~14,000)
Monthly Monitoring
Adherence 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 Size
Warfarin 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
Warfarin
Better
Enrollment
45 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
Study Conduct
Rivaroxaban Warfarin
Randomized, n
Lost to Follow-up, n
Premature Discontinuation, n (%)
Withdrew Consent, n
Median (25
th
, 75
th
) Exposure (days)
Median (25
th
, 75
th
) 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

83
1
13

83
1
13
Region (%)
North America
Latin America
Asia-Pacific
Central Europe
Western Europe

19
13
15
38
15

19
13
15
38
15
Creatinine Clearance (ml/min) (%)
30 - <50
50 - 80
> 80

21
47
32

21
48
31
Values are median (IQR)
Based on Intention-to-Treat Population
Baseline Demographics
Rivaroxaban
(N=7081)
Warfarin
(N=7090)
CHADS
2
Score (mean)
2 (%)
3 (%)
4 (%)
5 (%)
6 (%)
3.48
13
43
29
13
2
3.46
13
44
28
12
2
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 Results

Kenneth W. Mahaffey, MD
on Behalf of the ROCKET AF Investigators
Primary Efficacy Outcome
Stroke and non-CNS Embolism
Event Rates are per 100 patient-years
Based on Protocol Compliant on Treatment Population
0
1
2
3
4
5
6
0 120 240 360 480 600 720 840 960
No. at risk:
Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634
Warfarin 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
C
u
m
u
l
a
t
i
v
e

e
v
e
n
t

r
a
t
e

(
%
)

Rivaroxaban
Rivaroxaban Warfarin
Event
Rate
1.71 2.16
Rivaroxaban Warfarin
Event
Rate
Event
Rate
HR
(95% CI)
P-value
On
Treatment
N= 14,143
1.70 2.15
0.79
(0.65,0.95)
0.015
ITT
N= 14,171
2.12 2.42
0.88
(0.74,1.03)
0.117
Rivaroxaban
better
Warfarin
better
Primary Efficacy Outcome
Stroke and non-CNS Embolism
Event Rates are per 100 patient-years
Based 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

0.26
1.34
0.06

0.44
1.42
0.10

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

0.024
0.581
0.366
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
1.87
1.53
0.19
0.15
2.21
1.71
0.30
0.20
0.85 (0.70, 1.02)
0.89 (0.73, 1.10)
0.63 (0.36, 1.08)
0.75 (0.40, 1.41)
0.073
0.289
0.094
0.370
Event Rates are per 100 patient-years
Based 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

0.26
1.62
0.15

0.44
1.64
0.14

0.58 (0.38, 0.89)
0.99 (0.82, 1.20
1.05 (0.55, 2.01)

0.012
0.916
0.871
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
4.52
2.91
1.15
0.46
4.91
3.11
1.22
0.57
0.92 (0.82, 1.03)
0.94 (0.81, 1.08)
0.94 (0.75, 1.18)
0.80 (0.57, 1.12)
0.152
0.350
0.611
0.195
Key Secondary Efficacy Outcomes
Event Rates are per 100 patient-years
Based on Intention-to-Treat Population
Time in Therapeutic Range (TTR)
INR Data

INR range
Warfarin
Median (25
th
, 75
th
)
<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 included
Based on Safety Population
Primary Efficacy Outcome by Quartiles of cTTR
Stroke and non-CNS Embolism
Based on Rosendaal method with all INR values included
Based on Safety Population
Event Rates are per 100 patient-years
Rivaroxaban Warfarin
Center TTR
Events
%
Event
Rate
Events
%
Event
Rate
HR
(95% CI)
0.0 - 50.6% 2.6 1.8 3.7 2.5
0.71
(0.48, 1.03)
50.7 - 58.5% 3.0 1.9 3.5 2.2
0.83
(0.62, 1.29)
58.6 - 65.7% 3.1 1.9 3.5 2.1
0.92
(0.62, 1.28)
65.7 - 100.0% 2.2 1.3 3.0 1.8
0.77
(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-years
Based 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
3.60
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
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-years
Based 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 Event
Any Serious Adverse Event
AE leading to study drug discontinuation
82.4
37.3
15.7
82.2
38.2
15.2
Epistaxis
Peripheral edema
Dizziness
Nasopharyngitis
Cardiac failure
Bronchitis
Dyspnea
Diarrhea
10.1
6.1
6.1
5.9
5.6
5.6
5.3
5.3
8.6
6.2
6.3
6.4
5.9
5.9
5.5
5.6
ALT Elevation
>3 x ULN
>5 x ULN
>3 x ULN and T Bili > 2 x ULN

2.9
1.0
0.4

2.9
1.0
0.5
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
Sponsors
J & 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 Heart
Research Center
Shaun Goodman
Maggie Godin-Edgecomb
IDMC
Joe Alpert, Chair
Allen Skene, Co-chair
Gudrun Boysen
John Eikelboom
Peter Rothwell
CEC

Manesh Patel
Joni O'Briant
Lauren 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