C. Michael Gibson, M.S., M.D., Jessica Mega, M.P.H., M.D.,
& Eugene Braunwald, M.D.
on behalf of the ATLAS ACS 2 TIMI 51 Investigators
Anti-Xa Therapy to Lower
Cardiovascular Events in Addition to Standard Therapy in
Subjects with Acute Coronary Syndrome – Thrombolysis in
Myocardial Infarction 51 Trial (ATLAS-ACS 2 TIMI 51):
A Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of
Rivaroxaban in Subjects with Acute Coronary Syndrome
Funded by a Research Grant from Johnson and Johnson and Bayer to Brigham & Women’s
Hospital. Dr. Gibson has received honoraria & consulting fees from J&J and Bayer.
BACKGROUND: Thrombin In ACS
• There is excess thrombin generation that persists for 6
months following an index ACS event.1
• Thrombin is the most potent stimulant of platelet
aggregation.2
• Reduction of thrombin generation by warfarin reduces
recurrent MI by 44% in a meta-analysis of 10 ACS trials.3
• Rivaroxaban is a direct factor Xa inhibitor which blocks
initiation of the final common pathway leading to thrombin
generation.
• Based upon safety and efficacy in Phase II, 5.0 mg bid and
2.5 mg bid doses of Rivaroxaban were chosen for Phase III
evaluation in ATLAS TIMI 51.4
1. Merlini PA et al. Circulation. 1994;90:61-68. 2. Coughlin S. Thrombin signaling and protease-activated receptors. Nature 2000;407(6801):258-64. 3. Rothberg
MB et al Ann Intern Med. 2005 Aug 16;143(4):241-50. 4. Lancet. 2009;374(9683):29-38.
TRIAL ORGANIZATION
Trial Leadership: TIMI Study Group
Chairman: Eugene Braunwald, Principal Investigator: C. Michael Gibson
Investigator: Jessica Mega, Statisticians: Sabina Murphy, Charles Contant
Executive Committee
Jean-Pierre Bassand, Deepak Bhatt, Christoph Bode, Keith Fox, Marc Cohen,
Shinya Goto, David Schneider, Freek Verheugt
Sponsors: Johnson & Johnson and Bayer Health Care
J&J: Paul Burton, Peter DiBattiste, Alexei N. Plotnikov, Linda DeCaprio, Xiang Sun
Bayer: Nancy Cook Bruns, Scott Berkowitz, Frank Misselwitz
Data Safety Monitoring Board
Douglas Weaver (Chair) , Christian Hamm, Judith S. Hochman, Jeffrey Anderson,
Hiroyuki Daida, Statistician: Allan Skene
Recent ACS: STEMI, NSTEMI, UA
No increased bleeding risk, No warfarin, No ICH, No
prior stroke if on ASA + Thienopyridine
Stabilized 1-7 Days Post-Index Event
Stratified by Thienopyridine use at MD Discretion
Placebo
N=5,176
ASA + Thieno, n=4,821
ASA, n=355
+ ASA 75 to
100 mg/day
RIVAROXABAN
RIVAROXABAN
2.5 mg BID
5.0 mg BID
n=5,174
N=5,176
ASA + Thieno, n=4,825
ASA, n=349
ASA + Thieno, n=4,827
ASA, n=349
PRIMARY ENDPOINT:
EFFICACY: CV Death, MI, Stroke* (Ischemic + Hemg.)
SAFETY: TIMI major bleeding not associated with CABG
Event driven trial of 1,002 events in 15,342 patients**
* Stroke includes ischemic stroke, hemorrhagic stroke, and uncertain stroke
** 184 subjects were excluded from the efficacy analyses prior to unblinding
NATIONAL LEAD INVESTIGATORS
RUSSIA (1756)
M. Ruda
INDIA (1469)
V. Chopra
POLAND (1062)
M. Tendera
CHINA (901)
R. Gao
BULGARIA (792)
N. Gotcheva
UNITED STATES (684)
C.M. Gibson
UKRAINE (629)
A. Parkhomenko
BRAZIL (529)
J. Nicolau
ARGENTINA (404)
M. Amuchastegui
JAPAN (400)
S. Goto
NETHERLANDS (377)
T. Oude Ophuis
M. van Hessen
ISRAEL (353)
S. Meisel
GERMANY (332)
E. Giannitsis
ROMANIA (304)
D. Vinereanu
COLOMBIA (269)
R. Botero
MEXICO (254)
G. Llamas
AUSTRALIA (510)
P. Aylward
CZECH REPUBLIC (485)
P. Widimsky
HUNGARY (412)
R. Kiss
UNITED KINGDOM (254)
I. Squire
ITALY (235)
D. Ardissino
SPAIN (230)
A. Betriu
44 Countries
CHILE (213)
R. Corbalan
FRANCE (213)
G. Montalescot
CANADA (190)
M. Le May
P. Theroux
SLOVAKIA (178)
T. Duris
LITHUANIA (177)
B. Petrauskiene
TUNISIA (177)
H. Haouala
BELGIUM (173)
F. Van de Werf
EGYPT (159)
A. Mowafy
KOREA, REPUBLIC OF
(150)
K. Seung
SWEDEN (144)
M. Dellborg
THAILAND (140)
P. Sritara
766 Sites
TURKEY (119)
Z. Yigit
SERBIA (117)
Z. Vasiljevic
PORTUGAL (115)
J. Morais
LATVIA (100)
A. Erglis
DENMARK (99)
S. Eggert Jensen
NEW ZEALAND (98)
H. White
MALAYSIA (97)
K. Hian Sim
GREECE (69)
CROATIA (62)
M. Bergovec
MOROCCO (57)
PHILIPPINES (38)
BASELINE CHARACTERISTICS
Placebo
Rivaroxaban Rivaroxaban
2.5 mg BID
5.0 mg BID
Age, mean (SD)
61.5 (± 9.4)
61.8 (± 9.2)
61.9 (± 9.0)
Sex, male n (%)
75.0%
74.9%
74.2%
Prior MI, n (%)
27.3%
26.3%
27.1%
Diabetes, n (%)
31.8%
32.3%
31.8%
STEMI, n (%)
50.9%
50.3%
49.9%
NSTEMI, n (%)
25.6%
25.5%
25.8%
UA, n (%)
23.6%
24.2%
24.3%
PCI at Index Hosp, n (%)
59.9%
60.2%
60.0%
STATISTICAL ANALYSIS
The primary efficacy endpoint of CV death, MI and stroke* (ischemic +
hemorrhagic) was evaluated sequentially**:
• Pre-Specified Analysis: Rivaroxaban 2.5 + 5.0 mg BID doses pooled
together across both thienopyridine strata (all Rivaroxaban vs all
Placebo)
If p < 0.0499982 interim adjusted
• Rivaroxaban 2.5 mg BID and 5.0 mg BID doses separately across
both thienopyridine strata (p<0.05)
• The primary method of analysis was a log rank test stratified by thienopyridine
use in the mITT# population with confirmation in an ITT## analysis
* Stroke includes ischemic stroke, hemorrhagic stroke, and uncertain stroke
** Same testing procedure was conducted independently for ASA+Thienopyridine
# mITT, all randomized subjects and end point events, which are observed from randomization up to the earliest date of the
completion of the treatment period (i.e, global treatment end date), or 30 days after early discontinuation of the study drug or
30 days following randomization for those subjects who were randomly assigned to treatment but not treated
## ITT, all randomized subjects and end point events, which are observed from randomization up to the global treatment end
date
PRIMARY EFFICACY ENDPOINT:
CV Death / MI / Stroke* (Ischemic + Hemg.)
2 Yr KM Estimate
Estimated Cumulative Rate (%)
Placebo
No. at Risk
Placebo
Rivaroxaban
10.7%
8.9%
HR 0.84
(0.74-0.96)
ARR 1.7%
Rivaroxaban
(both doses)
mITT p = 0.008
ITT p = 0.002
NNT = 59
Months After Randomization
5113
4307
3470
2664
1831
1079
421
10229
8502
6753
5137
3554
2084
831
*: First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC across thienopyridine use strata
Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT
approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; ARR=Absolute Relative Reduction; NNT=Number needed to treat;
Rivaroxaban=Pooled Rivaroxaban 2.5 mg BID and 5 mg BID.
STENT THROMBOSIS*
ARC Definite, Probable, Possible
Estimated Cumulative incidence (%)
2 Yr KM Estimate
Placebo
2.9%
2.3%
HR 0.69
Rivaroxaban
(both doses)
ARC Definite/probable: HR=0.65, mITT p=0.017, ITT p=0.012
(0.51- 0.93)
mITT p = 0.016
ITT p = 0.008
Months After Randomization
* End point events are as adjudicated by the CEC across thienopyridine use strata
Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT
approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; Rivaroxaban=Pooled Rivaroxaban 2.5 mg BID and 5 mg BID.
PRIMARY EFFICACY ENDPOINT: 5.0 mg BID
CV Death / MI / Stroke* (Ischemic + Hemg.)
Estimated Cumulative incidence (%)
Placebo
10.7%
10
8.8%
HR 0.85
mITT
p=0.028
5
Rivaroxaban
5 mg BID
ITT
P=0.010
0
0
12
24
Months
Rivaroxaban at 5 mg PO BID was associated with a numerical but not statistically significant reduction in mortality.
* First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC
Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT
approach; Stratified log-rank p-values are provided for both mITT and ITT approaches.
PRIMARY EFFICACY ENDPOINT*: 2.5 mg PO BID
CV Death / MI / Stroke*
All Cause Death
Cardiovascular Death
5%
5%
Estimated Cumulative incidence (%)
12%
HR 0.84
HR 0.66
Placebo
10.7%
mITT
p=0.020
4.1%
mITT
p=0.002
9.1%
ITT
p=0.007
HR 0.68
Placebo
Placebo
mITT
p=0.002
4.5%
ITT
p=0.004
ITT
p=0.005
2.9%
2.7%
0
Rivaroxaban
2.5 mg BID
Rivaroxaban
2.5 mg BID
Rivaroxaban
2.5 mg BID
NNT = 63
NNT = 71
NNT = 63
12
Months
24
0
12
Months
24
0
12
Months
24
* First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC across thienopyridine use strata
Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT
approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; NNT=Number needed to treat.
PRIMARY EFFICACY ENDPOINTS: 2.5 mg PO BID
In Patients Treated with ASA + Thienopyridine
CV Death / MI / Stroke*
Estimated Cumulative incidence (%)
12%
HR 0.85
All Cause Death
Cardiovascular Death
5%
5%
HR 0.62
Placebo
mITT
p=0.039
mITT
p<0.001
10.4%
HR 0.64
Placebo
4.2%
Placebo
mITT
p<0.001
4.5%
9.0%
ITT
p=0.011
ITT
p<0.001
ITT
p<0.001
2.7%
2.5%
0
Rivaroxaban
2.5 mg BID
Rivaroxaban
2.5 mg BID
Rivaroxaban
2.5 mg BID
NNT = 71
NNT = 59
NNT = 56
12
Months
24
0
12
Months
24
0
12
Months
*: First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC
Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT
approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; NNT=Number needed to treat.
24
PRIMARY EFFICACY SUBGROUP RESULTS (mITT)
HR (95% CI)
Pinteraction
Overall
0.84 (0.74 0.96)
ASA
ASA + thienopyridine
0.69 (0.45 -1.05)
0.86 (0.75 -0.98)
0.34
<65 Years
65 Years
0.83 (0.70 - 0.99)
0.94
STEMI
NSTEMI
UA
0.85 (0.70 - 1.03)
0.85 (0.68 - 1.06)
0.82 (0.62 - 1.07)
0.96
Male
Female
0.87 (0.75 - 1.01)
0.40
Weight <60 kg
Weight 60 to <90 kg
Weight 90 kg
0.83 (0.56 - 1.25)
Prior MI
No Prior MI
0.83 (0.68 - 1.01)
Diabetes Mellitus
No Diabetes Mellitus
0.96 (0.77 - 1.20)
Creatinine Cl <50mL /min
Creatinine Cl >50 mL /min
0.88 (0.62 - 1.26)
North America
South America
Western Europe
Eastern Europe
Asia
Other
0.57 (0.33 - 0.97)
0.84 (0.70 - 1.01)
0.77 (0.60 - 0.99)
0.98
0.85 (0.72 - 0.99)
0.83 (0.64 - 1.08)
0.80
0.85 (0.72 - 1.01)
0.14
0.78 (0.67 - 0.92)
0.82
0.84 (0.73 - 0.96)
0.89 (0.59 - 1.34)
0.90 (0.59 - 1.37)
0.83 (0.69 - 1.00)
0.86 (0.63 - 1.17)
0.92 (0.60 - 1.39)
0.5
0.8
Rivaroxaban Better
1.0
1.25
2.0
Placebo Better
0.80
SAFETY ENDPOINTS
Treatment-Emergent Non CABG TIMI Major Bleeding*
Analysis
2 Yr KM Estimate
Placebo
2.5 mg
Rivaroxaban
5.0 mg
Rivaroxaban
0.6%
1.8%
2.4%
HR 3.46
HR 4.47
p<0.001
p<0.001
Post-Treatment Ischemic Events#
1-10 Days After Last
Dose
1.8%
1.4%
2.2%
p=NS
p=NS
Liver Function Test (ALT > 3xULN) ##
Treatment-Emergent
1.6%
1.3%
1.4%
p=NS
p=NS
There was no excess of either combined ALT > 3x ULN and Total Bilirubin > 2x ULN cases
among patients treated with Rivaroxaban, or SAEs.
*: First occurrence of Non-CABG TIMI major bleeding events occurred between first dose to 2 days post last dose as adjudicated by the CEC across thienopyridine use
strata; Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine are provided; Stratified log-rank p-values
are provided; #: Raw percentage for CV death/MI/stroke (ischemic, hemorrhagic, uncertain) ; ##: Raw percentage of subjects with abnormal value measured between first
dose to 2 days post last dose among subjects with normal baseline measurement.
TREATMENT-EMERGENT
FATAL BLEEDS AND ICH
1.2
1
0.8
0.6
p=NS for Riva
vs Placebo
0.7
p=0.044 for
2.5 mg vs 5.0 mg
0.4
0.4
0.2
0
p=0.009 Riva
Vs Placebo
Placebo
2.5 mg Rivaroxaban
5.0 mg Rivaroxaban
0.2
0.4
p=NS for Riva
vs Placebo
0.2
0.2
0.1*
0.1 0.1
n=9 n=6 n=15
n=5 n=14 n=18
n=4 n=5 n=8
Fatal
ICH
Fatal ICH
*Among patients treated with aspirin + thienopyridine, there was an increase in fatal bleeding among patients treated with
5.0 mg of Rivaroxaban (15/5110) vs 2.5 mg of Rivaroxaban (5/5115) (p=0.02)
SUMMARY- SAFETY
• There was a dose dependent increase in bleeding
associated with rivaroxaban (2.5 mg ↓ 5.0 mg).
• Although ICH was increased with rivaroxaban,
there was no excess risk of fatal ICH or fatal
bleeding associated with rivaroxaban compared to
placebo.
• No evidence of drug induced liver injury or
rebound (post-treatment) ischemic events
SUMMARY-EFFICACY
• The primary efficacy endpoint of CV death, MI
and stroke was reduced when added to standard
therapy for both rivaroxaban doses combined,
and for the 2.5 and 5.0 mg BID doses separately
• CV and all cause death were reduced for both
rivaroxaban doses combined, and for the 2.5 mg
BID dose in both mITT and ITT analyses
SUMMARY-EFFICACY (cont.)
• When 2.5 mg PO BID of rivaroxaban was added
to ASA + thienopyridine, cardiovascular death
was reduced by 38% and all cause death by 36%
• One death prevented if 56 patients treated for two
years with 2.5 mg BID of Rivaroxaban