Vorapaxar, a Platelet Thrombin Receptor
Antagonist, in Acute Coronary Syndromes
Kenneth W. Mahaffey, MD,
on behalf of the TRACER Investigators and Committees
Trial funded by Merck
Complete financial disclosures: www.DCRI.org
Background
Platelet
•
Vorapaxar
PAR-1
Thrombin
•
PAR-4
Clopidogrel
Prasugrel
Ticagrelor
Cangrelor
ADP
TBX A2
ASA
Anionic
phospholipid
surfaces
P2Y12
TBXA2-R
•
Vorapaxar:
 First-in-class
 Oral PAR-1
inhibitor
Metabolism:
 Primarily hepatic
via CYP 3A4
 Terminal half-life:
~126–269 hrs
Prior trials:
 No increase in
bleeding and
fewer MIs
GP IIb/IIIa
Chackalamannil S, J Med Chem, 2006
Trial Design
NSTE Acute Coronary
Syndromes
Key inclusion criteria
• Within 24 hrs of symptoms
•  biomarkers or ECG changes
• 1 other high-risk feature
Placebo
1:1
Randomized
Double-blind
Vorapaxar
Loading: 40 mg
Maintenance: 2.5 mg daily
Follow-up: 1, 4, 8, 12 months, then every 6 months
Standard of care based on practice guidelines
Efficacy Endpoints
Primary: CV death, MI, stroke, hospitalization for ischemia, urgent revascularization
Key Secondary: CV death, MI, stroke
Bleeding Endpoints: GUSTO moderate or severe and clinically significant TIMI bleeding
Statistical Considerations
•
•
•
Sample size
 Event-driven with estimated 15% reduction
 Power:
• 1900 primary endpoint events
>95%
• 1457 key secondary endpoint events
≥90%
 12,500 patients
Analysis
 Efficacy analyses: intention-to-treat
 Bleeding analyses: all subjects with ≥1 dose and on drug
 Hierarchical testing procedure to control overall
type 1 error
January 8, 2011: DSMB recommended to stop follow-up
in the trial
Enrollment
37 countries, 818 sites, 12,944 patients
Poland: 561
Norway: 251 Sweden: 346
Canada:
591
United States:
2772
Puerto Rico: 41
Colombia: 275
Peru: 11
Chile: 148
Denmark: 205
U.K.: 463
Netherlands: 471
Belgium: 153
Germany: 911
Portugal: 189
France: 441
Turkey: 164
Japan: 276
China: 219
South Korea: 127
Taiwan: 219
Spain: 379
Czech Rep: 496
Brazil: 284
Finland: 119
Hungary: 266
Switzerland:
211
Hong Kong: 17
Malaysia: 52
Singapore: 26
Austria: 319
Italy: 764
Argentina: 130
Israel: 410
South Africa: 207
Australia:
235
New Zealand: 195
Study Conduct
Placebo
(N=6471)
Vorapaxar
(N=6473)
30 (0.5)
27 (0.4)
1726 (27)
1818 (28)
Treatment duration (days)
393 (236, 588)
379 (231, 585)
Follow-up duration (days)
503 (348, 667)
500 (349, 668)
8 (0.1)
7 (0.1)
Did not receive treatment (%)
Discontinued treatment (%)
Lost to follow-up (%)
Median (IQR)
Baseline Demographics
Placebo
(N=6471)
Vorapaxar
(N=6473)
64 (58, 72)
64 (58, 71)
Female sex, %
28
28
Region of enrollment, %
North America
South America
Western Europe
Eastern Europe
Asia
Australia/New Zealand
26
7
45
12
7
3
26
7
45
12
7
3
Diabetes mellitus, %
31
32
Prior MI, %
29
29
Positive troponin or CK-MB, %
94
94
Antiplatelet agents, %
Aspirin
Thienopyridine
97
87
96
88
Age, yrs
Median (IQR)
Index Hospitalization Procedures
Placebo
(N=6471)
Vorapaxar
(N=6473)
Hospital presentation to randomization (hrs)
21 (12, 41)
21 (12, 41)
Symptom onset to randomization (hrs)
27 (8, 50)
27 (18, 49)
88
88
57
4 (2, 21)
58
46
58
4 (2, 21)
56
49
10
10
Cardiac catheterization, %
PCI, %
Loading dose of study drug to PCI (hrs)
Drug-eluting stent, %
Bare metal stent, %
CABG, %
Median (IQR)
Primary Endpoint
CV Death, MI, Stroke, Hospitalization for Ischemia, Urgent Revascularization
2-year KM rate
Placebo
Vorapaxar
19.9%
18.5%
HR (95% CI): 0.92 (0.85, 1.01)
P-value= 0.072
No. at risk
Placebo
Vorapaxar
6471 5844
6473 5897
5468
5570
5121
5199
3794
3881
2291
2318
795
832
Key Secondary Endpoint
CV Death, MI, Stroke
2-year KM rate
Placebo
Vorapaxar
16.4%
14.7%
HR (95% CI): 0.89 (0.81, 0.98)
P-value= 0.018
No. at risk
Placebo
Vorapaxar
6471 5895
6473 5949
5575
5684
5263
5356
3922
4023
2383
2427
830
868
Selected Efficacy Outcomes
Placebo
(N=6471)
Vorapaxar
(N=6473)
2-yr
2-yr
KM rate (%) KM rate (%)
Primary endpoint
HR (95% CI)
P-value
19.9
18.5
0.92 (0.85–1.01)
0.072
CV death
3.8
3.8
1.00 (0.83–1.22)
0.96
MI
12.5
11.1
0.88 (0.79–0.98)
0.021
Stroke
2.1
1.9
0.93 (0.70–1.23)
0.61
Hospitalization for
ischemia
1.5
1.6
1.14 (0.83–1.58)
0.42
Urgent
revascularization
3.5
3.8
1.07 (0.88–1.31)
0.49
Stent Thrombosis*
1.5
1.7
1.12 (0.78–1.62)
0.54
All-cause mortality
6.1
6.5
1.05 (0.90–1.23)
0.52
*ARC definite or probable; data are proportions of patients
Bleeding Endpoints
Placebo
(N=6441)
Vorapaxar
(N=6446)
2-yr
KM rate (%)
2-yr
KM rate (%)
HR (95% CI)
P-value
GUSTO
moderate or severe
5.2
7.2
1.35 (1.16–1.58)
<0.001
Clinically significant
TIMI
14.6
20.2
1.43 (1.31–1.57)
<0.001
GUSTO severe
1.6
2.9
1.66 (1.27–2.16)
<0.001
TIMI major
2.5
4.0
1.53 (1.24–1.90)
<0.001
Fatal
0.15
0.35
1.89 (0.80–4.45)
0.15
Intracranial hemorrhage
0.24
1.07
3.39 (1.78–6.45)
<0.001
CABG-related
TIMI major*
7.3
9.7
1.34 (0.92–1.95)
0.13
* data are proportions of patients
Bleeding Outcomes
GUSTO Moderate/Severe
Placebo
Vorapaxar
5.2%
7.2%
2-year KM rate
ICH
2-year KM rate
Placebo
Vorapaxar
0.24%
1.07%
HR (95% CI): 3.39 (1.78, 6.45)
P-value <0.001
HR (95% CI): 1.35 (1.16, 1.58)
P-value <0.001
No. at risk
6441 5536 5137 4674
6446 5529 5108 4598
3393
3278
1972
1883
650
625
No. at risk
6441 5673 5281 4823
6446 5694 5272 4760
3511
3411
2038
1965
678
657
Subgroups
GUSTO Moderate/Severe
Vorapaxar
better
Placebo
better
Primary Endpoint
Vorapaxar
better
Placebo
better
Summary
When added to standard of care in patients with NSTE ACS and
high use of aspirin and P2Y12 inhibition, vorapaxar:
•
Did not significantly reduce the composite of CV death,
MI, stroke, hospitalization for ischemia, or urgent
revascularization
•
Reduced CV death, MI, or stroke
•
Significantly increased bleeding, including major bleeding
and intracranial hemorrhage
Whether PAR-1 blockade improves outcomes with different
medication strategies or in other patient populations with coronary
artery disease requires further study.
Study Organization
Executive Committee
Academic Research
Organizations
R Harrington (Chair), P Armstrong, P Aylward,
E Chen, K Mahaffey, D Moliterno, J Strony,
F Van de Werf, L Wallentin, H White
DCRI: P Tricoci, T Rorick, S Leonardi,
D Underwood, J Wrestler
CVC: P Armstrong, C Sorochuck
C5: A Lincoff, D Mason
Henry Ford: M Hudson, D Sydlowski
Thomas Jefferson: D Whellan,
B Gallagher
Flinders: P Aylward, J Garrett
Green Lane: H White, S Douglas
Leuven: P Sinnaeve, A Beernaert
Steering Committee
G Ambrosio, A Betriu, C Bode, A Cequier,
T Cheem, M Chen, J Cornel, A Dalby,
R Diaz, A Erkan, P Grande, C Held, K Huber,
M Hudson, Y Huo, D Isaza, J Jukema, M Laine,
B Lewis, A Lincoff, J Lixin, G Montalescot,
J Nicolau, J Nordrehaug, P Ofner, H Ogawa,
S Park, M Pfisterer, J Prieto, L Providencia,
W Ruzyllo, P Sinnaeve, R Storey, P Tricoci,
M Valgimigli, D Whellan, P Widimsky,
L Wong, T Yamaguchi
Sponsor
Merck: E Chen, R Harmelin–Kadouri,
A Kilian, S Petrauskas, J Strony
Data & Safety Monitoring Board
CEC
Core Lab
F Verheugt (Chair), R Frye, J Hochman,
P Steg, K Bailey, J Easton
A Johnson
J O’ Briant
M Smith
P Tricoci
ECG: P Armstrong, H Siha
Platelets: L Jennings, E Hord
Angio: M Gibson, A Chirlin
The full article is now available
online at www.nejm.org