1. 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:

2. Background Vorapaxar: First-in-class Oral PAR-1 inhibitor Vorapaxar
Metabolism:
Primarily hepatic via CYP 3A4
Terminal half-life: ~126–269 hrs
Prior trials:
No increase in bleeding and fewer MIs
Platelet
Vorapaxar
Thrombin
PAR-1
PAR-4
Clopidogrel
Prasugrel
Ticagrelor
Cangrelor
Anionic
phospholipid
surfaces
I have simplified graphic and content.
I don't think we need P2Y 1 receptor. I would also leave out PAR-4.
ADP
P2Y12
TBXA2-R
TBX A2
GP IIb/IIIa
ASA
Chackalamannil S, J Med Chem, 2006

3. NSTE Acute Coronary Syndromes
Trial Design
NSTE Acute Coronary Syndromes
Key inclusion criteria
Within 24 hrs of symptoms
 biomarkers or ECG changes
1 other high-risk feature
1:1
Randomized
Double-blind
Placebo
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

4. 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

5. Enrollment 37 countries, 818 sites, 12,944 patients Poland: 561
Finland: 119
Norway: 251
Sweden: 346
Hungary: 266
Canada: 591
Denmark: 205
U.K.: 463
Turkey: 164
Netherlands: 471
United States: 2772
Belgium: 153
Japan: 276
China: 219
Germany: 911
South Korea: 127
Portugal: 189
France: 441
Taiwan: 219
Puerto Rico: 41
Spain: 379
Hong Kong: 17
Colombia: 275
Czech Rep: 496
Malaysia: 52
Switzerland: 211
Singapore: 26
Peru: 11
Brazil: 284
Australia: 235
Chile: 148
Austria: 319
Italy: 764
South Africa: 207
Argentina: 130
New Zealand: 195
Israel: 410

6. Study Conduct Placebo (N=6471) Vorapaxar (N=6473)
Did not receive treatment (%)
30 (0.5)
27 (0.4)
Discontinued treatment (%)
1726 (27)
1818 (28)
Treatment duration (days)
393 (236, 588)
379 (231, 585)
Follow-up duration (days)
503 (348, 667)
500 (349, 668)
Lost to follow-up (%)
8 (0.1)
7 (0.1)
Median (IQR)

7. Baseline Demographics
Placebo (N=6471)
Vorapaxar
(N=6473)
Age, yrs
64 (58, 72)
64 (58, 71)
Female sex, % 28
Region of enrollment, % North America South America Western Europe Eastern Europe Asia Australia/New Zealand
Diabetes mellitus, % 31 32
Prior MI, % 29
Positive troponin or CK-MB, % 94
Antiplatelet agents, % Aspirin Thienopyridine 97 87 96 88
Median (IQR)

8. 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)
Cardiac catheterization, % 88
PCI, % Loading dose of study drug to PCI (hrs)
Drug-eluting stent, % Bare metal stent, %
57 4 (2, 21)
58 46
58 4 (2, 21)
56 49
CABG, % 10
Median (IQR)

9. Primary Endpoint CV Death, MI, Stroke, Hospitalization for Ischemia, Urgent Revascularization
Placebo
Vorapaxar
2-year KM rate
 19.9%
 18.5%
HR (95% CI): 0.92 (0.85, 1.01)
P-value= 0.072
No. at risk Placebo Vorapaxar

10. Key Secondary Endpoint CV Death, MI, Stroke
Placebo
Vorapaxar
2-year KM rate
 16.4%
 14.7%
HR (95% CI): 0.89 (0.81, 0.98)
P-value= 0.018
No. at risk Placebo Vorapaxar

11. Selected Efficacy Outcomes
Placebo (N=6471)
Vorapaxar
(N=6473)
2-yr KM rate (%)
HR (95% CI)
P-value
Primary endpoint
19.9
18.5
0.92 (0.85–1.01)
0.072
CV death
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
1.07 (0.88–1.31)
0.49
Stent Thrombosis*
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

12. Bleeding Endpoints Placebo (N=6441) Vorapaxar (N=6446)
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)
GUSTO severe
1.6
2.9
1.66 (1.27–2.16)
TIMI major
2.5
4.0
1.53 (1.24–1.90)
Fatal
0.15
0.35
1.89 (0.80–4.45)
Intracranial hemorrhage
0.24
1.07
3.39 (1.78–6.45)
CABG-related TIMI major*
7.3
9.7
1.34 (0.92–1.95)
0.13
* data are proportions of patients

13. GUSTO Moderate/Severe
Bleeding Outcomes
GUSTO Moderate/Severe
ICH
Placebo
Vorapaxar
2-year KM rate
 5.2%
 7.2%
Placebo
Vorapaxar
2-year KM rate
 0.24%
 1.07%
No. at risk
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

14. GUSTO Moderate/Severe
Subgroups
GUSTO Moderate/Severe
Primary Endpoint
Placebo better
Vorapaxar better
Vorapaxar better
Placebo better

15. 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.

16. 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
Academic Research Organizations
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
F Verheugt (Chair), R Frye, J Hochman, P Steg, K Bailey, J Easton
CEC
A Johnson J O’ Briant M Smith P Tricoci
Core Lab ECG: P Armstrong, H Siha
Platelets: L Jennings, E Hord
Angio: M Gibson, A Chirlin

17. The full article is now available online at www.nejm.org