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, MB ChB
on behalf of the ROCKET AF Investigators
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
TF/VIIa
X
IX
 Half-life 5-13 hours
VIIIa
 Clearance :
Rivaroxaban
Va
 1/3 direct renal excretion
 2/3 metabolism via CYP 450
enzymes
Xa
 Oral, once daily dosing
without need for coagulation
monitoring
 Studied in >25,000 patients
in post-op, DVT, PE and
ACS patients
IXa
II
IIa
Fibrinogen
Fibrin
Adapted from Weitz et al, 2005; 2008
Risk Factors
Study Design
Atrial Fibrillation
Rivaroxaban
20 mg daily
15 mg for Cr Cl 30-49 ml/min
Randomize
Double Blind /
Double Dummy
(n ~ 14,000)
• CHF
• Hypertension
At least 2 or
3 required*
• Age  75
• Diabetes
OR
• Stroke, TIA or
Systemic embolus
Warfarin
INR target - 2.5
(2.0-3.0 inclusive)
Monthly Monitoring
Adherence to standard of care guidelines
Primary Endpoint: Stroke or non-CNS Systemic Embolism
* Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%
Statistical Methodologies
Superiority
 Sample Size
 Warfarin event rate ~2.3
 Type 1 error 0.05 (2-sided)
 405 events; >95% power
Non-inferiority
Inferiority
1.0
Rivaroxaban
Better
1.46
Warfarin
Better
 ~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
Enrollment
45 countries, 1178 sites, 14,264 patients
Canada: 750
United States: 1,932
Mexico: 168
Panama: 0
Venezuela: 20
Colombia: 268
Peru: 84
Brazil: 483
Chile: 287
Argentina: 569
Poland: 528
Finland: 16
Lithuania: 245
Sweden: 28
Hungary: 237
Norway: 49
Romania: 783
Czech Rep: 598
Bulgaria: 678
Russia: 1,292
Denmark: 123
Ukraine: 1,011
U.K.: 159
Netherlands: 161
Belgium: 96
Korea: 204
China: 496
France: 71
Taiwan: 159
Spain: 250
Germany: 530
Hong Kong: 73
India: 269
Switzerland: 7
Thailand: 87
Philippines: 368
Austria: 32
Malaysia: 51
Italy: 139
Singapore: 44
Greece: 29
Turkey: 101
Israel: 189
Australia: 242
South Africa: 247
New Zealand: 116
Study Conduct
Rivaroxaban
Warfarin
7131
7133
18
18
1693 (23.9%)
1589 (22.4%)
626
620
589 (396, 805)
593 (404, 810)
Median (25th, 75th) Follow-up (days) 706 (522, 884)
708 (518, 886)
Randomized, n
Lost to Follow-up, n
Premature Discontinuation, n (%)
Withdrew Consent, n
Median (25th, 75th) Exposure (days)
Baseline Demographics
Age (years)
Female (%)
Rivaroxaban
(N=7081)
73 (65, 78)
40
Warfarin
(N=7090)
73 (65, 78)
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)
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
CHADS2 Score (mean)
2 (%)
3 (%)
4 (%)
5 (%)
6 (%)
Based on Intention-to-Treat Population
Trial Results
Kenneth W. Mahaffey, MD
on Behalf of the ROCKET AF Investigators
Primary Efficacy Outcome
Stroke and non-CNS Embolism
Cumulative event rate (%)
6
5
Event
Rate
Rivaroxaban
Warfarin
1.71
2.16
Warfarin
4
Rivaroxaban
3
HR (95% CI): 0.79 (0.66, 0.96)
2
P-value Non-Inferiority: <0.001
1
0
0
No. at risk:
Rivaroxaban 6958
Warfarin
7004
120
240
360
480
600
720
840
960
Days from Randomization
6211
6327
5786
5911
5468
5542
Event Rates are per 100 patient-years
Based on Protocol Compliant on Treatment Population
4406
4461
3407
3478
2472
2539
1496
1538
634
655
Primary Efficacy Outcome
Stroke and non-CNS Embolism
Rivaroxaban Warfarin
Event
Event
Rate
Rate
On
Treatment
N= 14,171
Rivaroxaban
better
P-value
1.70
2.15
0.79
(0.65,0.95)
0.015
2.12
2.42
0.88
(0.74,1.03)
0.117
N= 14,143
ITT
HR
(95% CI)
Warfarin
better
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
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
Vascular Death,
Stroke, Embolism
Event Rates are per 100 patient-years
Based on Safety on Treatment Population
Key Secondary Efficacy Outcomes
Rivaroxaban
Warfarin
Event Rate
Event Rate
HR (95% CI)
P-value
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
Vascular Death,
Stroke, Embolism
Event Rates are per 100 patient-years
Based on Intention-to-Treat Population
Time in Therapeutic Range (TTR)
INR Data
Warfarin
INR range
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 included
Based on Safety Population
Primary Efficacy Outcome by Quartiles of cTTR
Stroke and non-CNS Embolism
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)
Based on Rosendaal method with all INR values included
Based on Safety Population
Event Rates are per 100 patient-years
Primary Safety Outcomes
Rivaroxaban
Warfarin
Event Rate
Event Rate
HR
(95% CI)
Pvalue
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
Major and non-major
Clinically Relevant
Event Rates are per 100 patient-years
Based on Safety on Treatment Population
Primary Safety Outcomes
Rivaroxaban
Warfarin
Event Rate
or N (Rate)
Event Rate
or N (Rate)
HR
(95% CI)
Pvalue
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
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)
Major
>2 g/dL Hgb drop
Transfusion (> 2 units)
Critical organ bleeding
Bleeding causing death
Intracranial Hemorrhage
Event Rates are per 100 patient-years
Based on Safety on Treatment Population
Adverse Events and Liver Enzyme Data
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
Values are N (%)
Based on Safety Population
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
IDMC
Sponsors
J & J and Bayer
Christopher Nessel, Kimberly Schwabe,
Scott Berkowitz, John Paolini
Executive Steering
Committee
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
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
Joe Alpert, Chair
Allen Skene, Co-chair
Gudrun Boysen
John Eikelboom
Peter Rothwell
CEC
Manesh Patel
Joni O'Briant
Lauren Price