Kenneth W. Mahaffey, MD and Keith AA Fox
Kenneth W. Mahaffey, MD and Keith AA Fox
Kenneth W. Mahaffey, MD and Keith AA Fox
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Rivaroxaban Once-daily oral direct factor Xa inhibition<br />
Compared with vitamin K antagonism for prevention<br />
of stroke <strong>and</strong> Embolism Trial in Atrial Fibrillation<br />
<strong>Kenneth</strong> W. <strong>Mahaffey</strong>, <strong>MD</strong> <strong>and</strong> <strong>Keith</strong> <strong>AA</strong> <strong>Fox</strong>, MB ChB<br />
on behalf of the ROCKET AF Investigators
Relevant Financial Relationships<br />
<strong>Kenneth</strong> W. <strong>Mahaffey</strong>, <strong>MD</strong><br />
Research Grants: AstraZeneca, Bayer, BI, BMS, Eli Lilly, J&J,<br />
Merck, Novartis, Portola, Regado, Sanofi-Aventis, The Medicines<br />
Company<br />
Consulting Fees: AstraZeneca, Bayer, BI, BMS, Eli Lilly, J&J,<br />
Merck, Novartis, Sanofi-Aventis<br />
No stock ownership<br />
http://www.dcri.duke.edu/research/coi.jsp<br />
<strong>Keith</strong> <strong>AA</strong> <strong>Fox</strong>, MB ChB<br />
Research Grants: Bayer, Eli Lilly, J&J, Sanofi-Aventis<br />
Consulting Fees: Bayer, Eli Lilly, J&J, Sanofi-Aventis<br />
No stock ownership
Background<br />
Rivaroxaban<br />
Direct, specific, competitive<br />
factor Xa inhibitor<br />
X<br />
TF/VIIa<br />
IX<br />
Half-life 5-13 hours<br />
Clearance :<br />
1/3 direct renal excretion<br />
VIIIa<br />
Va<br />
IXa<br />
Rivaroxaban<br />
2/3 metabolism via CYP 450<br />
enzymes<br />
Xa<br />
Oral, once daily dosing<br />
without need for coagulation<br />
monitoring<br />
Studied in >25,000 patients<br />
in post-op, DVT, PE <strong>and</strong><br />
ACS patients<br />
Fibrinogen<br />
II<br />
IIa<br />
Fibrin<br />
Adapted from Weitz et al, 2005; 2008
Study Design<br />
Atrial Fibrillation<br />
Risk Factors<br />
• CHF<br />
• Hypertension At least 2 or<br />
• Age ≥ 75 3 required*<br />
• Diabetes<br />
OR<br />
• Stroke, TIA or<br />
Systemic embolus<br />
Rivaroxaban<br />
20 mg daily<br />
15 mg for Cr Cl 30-49 ml/min<br />
R<strong>and</strong>omize<br />
Double Blind /<br />
Double Dummy<br />
(n ~ 14,000)<br />
Warfarin<br />
INR target - 2.5<br />
(2.0-3.0 inclusive)<br />
Monthly Monitoring<br />
Adherence to st<strong>and</strong>ard of care guidelines<br />
Primary Endpoint: Stroke or non-CNS Systemic Embolism<br />
* Enrollment of patients without prior Stroke, TIA or systemic embolism <strong>and</strong> only 2 factors capped at 10%
Statistical Methodologies<br />
Sample Size<br />
Warfarin event rate ~2.3<br />
Type 1 error 0.05 (2-sided)<br />
405 events; >95% power<br />
~14,000 patients<br />
Superiority<br />
Non-inferiority<br />
Inferiority<br />
Rivaroxaban<br />
Better<br />
Primary Efficacy Evaluation: Stroke or non-CNS<br />
Embolism<br />
Non-Inferiority: Protocol Compliant on treatment<br />
Superiority: On Treatment <strong>and</strong> then by Intention-to-Treat<br />
Primary Safety Evaluation: Major or non-Major Clinically<br />
Relevant Bleeding<br />
1.0 1.46<br />
Warfarin<br />
Better
Enrollment<br />
45 countries, 1178 sites, 14,264 patients<br />
Canada: 750<br />
United States: 1,932<br />
Mexico: 168<br />
Panama: 0<br />
Venezuela: 20<br />
Colombia: 268<br />
Peru: 84<br />
Brazil: 483<br />
Chile: 287<br />
Argentina: 569<br />
Pol<strong>and</strong>: 528<br />
Finl<strong>and</strong>: 16 Lithuania: 245<br />
Sweden: 28<br />
Hungary: 237<br />
Norway: 49 Romania: 783<br />
Czech Rep: 598<br />
Bulgaria: 678<br />
Denmark: 123<br />
Russia: 1,292<br />
Ukraine: 1,011<br />
U.K.: 159<br />
Netherl<strong>and</strong>s: 161<br />
Belgium: 96<br />
Korea: 204<br />
France: 71<br />
China: 496<br />
Spain: 250<br />
Taiwan: 159<br />
Germany: 530<br />
India: 269<br />
Hong Kong: 73<br />
Switzerl<strong>and</strong>: 7<br />
Thail<strong>and</strong>: 87 Philippines: 368<br />
Austria: 32<br />
Malaysia: 51<br />
Italy: 139<br />
Singapore: 44<br />
Greece: 29<br />
Turkey: 101<br />
Israel: 189<br />
Australia: 242<br />
South Africa: 247<br />
New Zeal<strong>and</strong>: 116
Study Conduct<br />
Rivaroxaban<br />
Warfarin<br />
R<strong>and</strong>omized, n<br />
Lost to Follow-up, n<br />
Premature Discontinuation, n (%)<br />
Withdrew Consent, n<br />
Median (25 th , 75 th ) Exposure (days)<br />
Median (25 th , 75 th ) Follow-up (days)<br />
7131<br />
18<br />
1693 (23.9%)<br />
626<br />
589 (396, 805)<br />
706 (522, 884)<br />
7133<br />
18<br />
1589 (22.4%)<br />
620<br />
593 (404, 810)<br />
708 (518, 886)
Baseline Demographics<br />
Rivaroxaban<br />
(N=7081)<br />
Warfarin<br />
(N=7090)<br />
Age (years) 73 (65, 78) 73 (65, 78)<br />
Female (%) 40 40<br />
Race (%)<br />
White<br />
Black<br />
Asian<br />
Region (%)<br />
North America<br />
Latin America<br />
Asia-Pacific<br />
Central Europe<br />
Western Europe<br />
Creatinine Clearance (ml/min) (%)<br />
30 - 80<br />
Values are median (IQR)<br />
Based on Intention-to-Treat Population<br />
83<br />
1<br />
13<br />
19<br />
13<br />
15<br />
38<br />
15<br />
21<br />
47<br />
32<br />
83<br />
1<br />
13<br />
19<br />
13<br />
15<br />
38<br />
15<br />
21<br />
48<br />
31
Baseline Demographics<br />
CHADS 2 Score (mean)<br />
2 (%)<br />
3 (%)<br />
4 (%)<br />
5 (%)<br />
6 (%)<br />
Rivaroxaban<br />
(N=7081)<br />
3.48<br />
13<br />
43<br />
29<br />
13<br />
2<br />
Warfarin<br />
(N=7090)<br />
3.46<br />
13<br />
44<br />
28<br />
12<br />
2<br />
Prior VKA Use (%) 62 63<br />
Congestive Heart Failure (%) 63 62<br />
Hypertension (%) 90 91<br />
Diabetes Mellitus (%) 40 39<br />
Prior Stroke/TIA/Embolism (%) 55 55<br />
Prior Myocardial Infarction (%) 17 18<br />
Based on Intention-to-Treat Population
Trial Results<br />
<strong>Kenneth</strong> W. <strong>Mahaffey</strong>, <strong>MD</strong><br />
on Behalf of the ROCKET AF Investigators
Cumulative event rate (%)<br />
6<br />
5<br />
4<br />
3<br />
2<br />
1<br />
Primary Efficacy Outcome<br />
Stroke <strong>and</strong> non-CNS Embolism<br />
Event<br />
Rate<br />
Rivaroxaban<br />
Warfarin<br />
1.71 2.16<br />
Warfarin<br />
Rivaroxaban<br />
HR (95% CI): 0.79 (0.66, 0.96)<br />
P-value Non-Inferiority:
Primary Efficacy Outcome<br />
Stroke <strong>and</strong> non-CNS Embolism<br />
On<br />
Treatment<br />
N= 14,143<br />
Rivaroxaban<br />
Event<br />
Rate<br />
Warfarin<br />
Event<br />
Rate<br />
1.70 2.15<br />
HR<br />
(95% CI)<br />
0.79<br />
(0.65,0.95)<br />
P-value<br />
0.015<br />
ITT<br />
N= 14,171<br />
2.12 2.42<br />
0.88<br />
(0.74,1.03)<br />
0.117<br />
Rivaroxaban<br />
better<br />
Warfarin<br />
better<br />
Event Rates are per 100 patient-years<br />
Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations
Key Secondary Efficacy Outcomes<br />
Rivaroxaban<br />
Warfarin<br />
Vascular Death,<br />
Stroke, Embolism<br />
Stroke Type<br />
Hemorrhagic<br />
Ischemic<br />
Unknown Type<br />
Event Rate Event Rate HR (95% CI) P-value<br />
3.11 3.63 0.86 (0.74, 0.99) 0.034<br />
0.26<br />
1.34<br />
0.06<br />
0.44<br />
1.42<br />
0.10<br />
0.59 (0.37, 0.93)<br />
0.94 (0.75, 1.17)<br />
0.65 (0.25, 1.67)<br />
0.024<br />
0.581<br />
0.366<br />
Non-CNS Embolism 0.04 0.19 0.23 (0.09, 0.61) 0.003<br />
Myocardial Infarction 0.91 1.12 0.81 (0.63, 1.06) 0.121<br />
All Cause Mortality<br />
Vascular<br />
Non-vascular<br />
Unknown Cause<br />
1.87<br />
1.53<br />
0.19<br />
0.15<br />
2.21<br />
1.71<br />
0.30<br />
0.20<br />
0.85 (0.70, 1.02)<br />
0.89 (0.73, 1.10)<br />
0.63 (0.36, 1.08)<br />
0.75 (0.40, 1.41)<br />
0.073<br />
0.289<br />
0.094<br />
0.370<br />
Event Rates are per 100 patient-years<br />
Based on Safety on Treatment Population
Key Secondary Efficacy Outcomes<br />
Rivaroxaban<br />
Warfarin<br />
Vascular Death,<br />
Stroke, Embolism<br />
Stroke Type<br />
Hemorrhagic<br />
Ischemic<br />
Unknown Type<br />
Event Rate Event Rate HR (95% CI) P-value<br />
4.51 4.81 0.94 (0.84, 1.05) 0.265<br />
0.26<br />
1.62<br />
0.15<br />
0.44<br />
1.64<br />
0.14<br />
0.58 (0.38, 0.89)<br />
0.99 (0.82, 1.20<br />
1.05 (0.55, 2.01)<br />
0.012<br />
0.916<br />
0.871<br />
Non-CNS Embolism 0.16 0.21 0.74 (0.42, 1.32 0.308<br />
Myocardial Infarction 1.02 1.11 0.91 (0.72, 1.16) 0.464<br />
All Cause Mortality<br />
Vascular<br />
Non-vascular<br />
Unknown Cause<br />
4.52<br />
2.91<br />
1.15<br />
0.46<br />
4.91<br />
3.11<br />
1.22<br />
0.57<br />
0.92 (0.82, 1.03)<br />
0.94 (0.81, 1.08)<br />
0.94 (0.75, 1.18)<br />
0.80 (0.57, 1.12)<br />
0.152<br />
0.350<br />
0.611<br />
0.195<br />
Event Rates are per 100 patient-years<br />
Based on Intention-to-Treat Population
Time in Therapeutic Range (TTR)<br />
INR Data<br />
Warfarin<br />
INR range Median (25 th , 75 th )<br />
5.0 0.0 (0.0 – 0.5)<br />
Based on Rosendaal method with all INR values included<br />
Based on Safety Population
Primary Efficacy Outcome by Quartiles of cTTR<br />
Stroke <strong>and</strong> non-CNS Embolism<br />
Center TTR<br />
Rivaroxaban<br />
Events<br />
%<br />
Event<br />
Rate<br />
Events<br />
%<br />
Warfarin<br />
Event<br />
Rate<br />
0.0 - 50.6% 2.6 1.8 3.7 2.5<br />
50.7 - 58.5% 3.0 1.9 3.5 2.2<br />
58.6 - 65.7% 3.1 1.9 3.5 2.1<br />
65.7 - 100.0% 2.2 1.3 3.0 1.8<br />
HR<br />
(95% CI)<br />
0.71<br />
(0.48, 1.03)<br />
0.83<br />
(0.62, 1.29)<br />
0.92<br />
(0.62, 1.28)<br />
0.77<br />
(0.49, 1.12)<br />
Based on Rosendaal method with all INR values included<br />
Based on Safety Population<br />
Event Rates are per 100 patient-years
Primary Safety Outcomes<br />
Major <strong>and</strong> non-major<br />
Clinically Relevant<br />
Rivaroxaban<br />
Event Rate<br />
Warfarin<br />
Event Rate<br />
HR<br />
(95% CI)<br />
P-<br />
value<br />
14.91 14.52 1.03 (0.96, 1.11) 0.442<br />
Major 3.60 3.45 1.04 (0.90, 1.20) 0.576<br />
Non-major Clinically<br />
Relevant<br />
11.80 11.37 1.04 (0.96, 1.13) 0.345<br />
Event Rates are per 100 patient-years<br />
Based on Safety on Treatment Population
Major<br />
>2 g/dL Hgb drop<br />
Transfusion (> 2 units)<br />
Critical organ bleeding<br />
Bleeding causing death<br />
Primary Safety Outcomes<br />
Rivaroxaban<br />
Event Rate<br />
or N (Rate)<br />
3.60<br />
2.77<br />
1.65<br />
0.82<br />
0.24<br />
Warfarin<br />
Event Rate<br />
or N (Rate)<br />
3.45<br />
2.26<br />
1.32<br />
1.18<br />
0.48<br />
HR<br />
(95% CI)<br />
1.04 (0.90, 1.20)<br />
1.22 (1.03, 1.44)<br />
1.25 (1.01, 1.55)<br />
0.69 (0.53, 0.91)<br />
0.50 (0.31, 0.79)<br />
P-<br />
value<br />
0.576<br />
0.019<br />
0.044<br />
0.007<br />
0.003<br />
Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) 0.019<br />
Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) 0.060<br />
Intraventricular 2 (0.02) 4 (0.04)<br />
Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) 0.051<br />
Subarachnoid 4 (0.04) 1 (0.01)<br />
Event Rates are per 100 patient-years<br />
Based on Safety on Treatment Population
Adverse Events <strong>and</strong> Liver Enzyme Data<br />
Any Adverse Event<br />
Any Serious Adverse Event<br />
AE leading to study drug discontinuation<br />
Epistaxis<br />
Peripheral edema<br />
Dizziness<br />
Nasopharyngitis<br />
Cardiac failure<br />
Bronchitis<br />
Dyspnea<br />
Diarrhea<br />
ALT Elevation<br />
>3 x ULN<br />
>5 x ULN<br />
>3 x ULN <strong>and</strong> T Bili > 2 x ULN<br />
Values are N (%)<br />
Based on Safety Population<br />
Rivaroxaban<br />
(N=7111)<br />
82.4<br />
37.3<br />
15.7<br />
10.1<br />
6.1<br />
6.1<br />
5.9<br />
5.6<br />
5.6<br />
5.3<br />
5.3<br />
2.9<br />
1.0<br />
0.4<br />
Warfarin<br />
(N=7125)<br />
82.2<br />
38.2<br />
15.2<br />
8.6<br />
6.2<br />
6.3<br />
6.4<br />
5.9<br />
5.9<br />
5.5<br />
5.6<br />
2.9<br />
1.0<br />
0.5
Efficacy:<br />
Summary<br />
Rivaroxaban was non-inferior to warfarin for prevention of<br />
stroke <strong>and</strong> non-CNS embolism.<br />
Rivaroxaban was superior to warfarin while patients were<br />
taking study drug.<br />
By intention-to-treat, rivaroxaban was non-inferior to warfarin<br />
but did not achieve superiority.<br />
Safety:<br />
Similar rates of bleeding <strong>and</strong> adverse events.<br />
Less ICH <strong>and</strong> fatal bleeding with rivaroxaban.<br />
Conclusion:<br />
Rivaroxaban is a proven alternative to warfarin for moderate or<br />
high risk patients with AF.
Study Organization<br />
Sponsors<br />
J & J <strong>and</strong> Bayer<br />
Christopher Nessel, Kimberly Schwabe,<br />
Scott Berkowitz, John Paolini<br />
Steering Committee<br />
Diego Ardissino, Alvaro Avezum, Phil<br />
Aylward, Barbara Biedermann,<br />
Christoph Bode, Antonio Carolei,<br />
Ramon Corbalan, Laszlo Csiba,<br />
Anthony Dalby, Rafael Diaz, Hans<br />
Diener, Geoffrey Donnan, Shaun<br />
Goodman, Bas Hamer, Hein<br />
Heidbuchel, Dai-Yi Hu, Kurt Huber,<br />
Gorm Jensen, Matyas Keltai, Basil<br />
Lewis, Jose Lopez-S<strong>and</strong>on, Jean<br />
Louis Mas, Ayrton Massaro, Gordon<br />
MacInnes, Bo Norrving, Martin<br />
Penicka, Dorairaj Prabhakaran, Risto<br />
Roine, Tan Ru San, Per Anton Sirnes,<br />
Veronika Skvortsova, Gabriel Steg,<br />
Harvey White, Lawrence Wong<br />
Executive Steering<br />
Committee<br />
Duke Clinical Research<br />
Institute<br />
Jonathan Piccini, Karen<br />
Hannan, Jyotsna Garg, Lisa<br />
Eskenazi, Angela Kaiser,<br />
Patricia Stone<br />
Canadian Heart<br />
Research Center<br />
Shaun Goodman<br />
Maggie Godin-Edgecomb<br />
IDMC<br />
Joe Alpert, Chair<br />
Allen Skene, Co-chair<br />
Gudrun Boysen<br />
John Eikelboom<br />
Peter Rothwell<br />
CEC<br />
Manesh Patel<br />
Joni O'Briant<br />
Lauren Price
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