Kenneth W. Mahaffey, MD, on behalf of the TRACER Investigators and Committees

Vorapaxar, a Platelet Thrombin Receptor Antagonist, in Acute Coronary Syndromes

Trial funded by MerckComplete financial disclosures: www.DCRI.org

• 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

Background

Chackalamannil S, J Med Chem, 2006

Platelet

PAR-4

TBX A2TBXA2-R

Thrombin

Anionicphospholipidsurfaces

GP IIb/IIIa

ADP P2Y12

PAR-1

ClopidogrelPrasugrelTicagrelorCangrelor

ASA

Vorapaxar

Trial Design

1:1RandomizedDouble-blind

NSTE Acute Coronary Syndromes

Vorapaxar Loading: 40 mg

Maintenance: 2.5 mg daily

Placebo

Follow-up: 1, 4, 8, 12 months, then every 6 monthsStandard of care based on practice guidelines

Key inclusion criteria• Within 24 hrs of symptoms• biomarkers or ECG changes• 1 other high-risk feature

Efficacy Endpoints Primary: CV death, MI, stroke, hospitalization for ischemia, urgent revascularization Key Secondary: CV death, MI, strokeBleeding 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

Enrollment37 countries, 818 sites, 12,944 patients

Canada: 591

United States: 2772

Finland: 119

Denmark: 205

Hungary: 266

Netherlands: 471

Sweden: 346Norway: 251

U.K.: 463

Belgium: 153

France: 441Spain: 379

Austria: 319Italy: 764

Israel: 410

Poland: 561

Czech Rep: 496

Chile: 148

Peru: 11

Colombia: 275

Brazil: 284

Argentina: 130

South Africa: 207

China: 219South Korea: 127

Taiwan: 219

Malaysia: 52Singapore: 26

Australia: 235

Germany: 911Japan: 276

Turkey: 164

Hong Kong: 17

New Zealand: 195

Portugal: 189

Switzerland: 211

Puerto Rico: 41

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)

Baseline Demographics

Placebo(N=6471)

Vorapaxar(N=6473)

Age, yrs 64 (58, 72) 64 (58, 71)

Female sex, % 28 28

Region of enrollment, %North AmericaSouth AmericaWestern EuropeEastern EuropeAsiaAustralia/New Zealand

 267451273

 267

451273

Diabetes mellitus, % 31 32

Prior MI, % 29 29

Positive troponin or CK-MB, % 94 94

Antiplatelet agents, %AspirinThienopyridine

9787

9688

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)

Cardiac catheterization, % 88 88

PCI, %Loading dose of study drug to PCI (hrs)

Drug-eluting stent, %Bare metal stent, %

574 (2, 21)

5846

584 (2, 21)

5649

CABG, % 10 10

Median (IQR)

Primary EndpointCV Death, MI, Stroke, Hospitalization for Ischemia, Urgent Revascularization

No. at riskPlacebo 6471 5844 5468 5121 3794 2291 795Vorapaxar 6473 5897 5570 5199 3881 2318 832

HR (95% CI): 0.92 (0.85, 1.01)P-value= 0.072

Placebo Vorapaxar2-year KM rate  19.9%  18.5%

Key Secondary EndpointCV Death, MI, Stroke

No. at riskPlacebo 6471 5895 5575 5263 3922 2383 830Vorapaxar 6473 5949 5684 5356 4023 2427 868

HR (95% CI): 0.89 (0.81, 0.98)P-value= 0.018

Placebo Vorapaxar2-year KM rate  16.4%  14.7%

Selected Efficacy Outcomes Placebo

(N=6471)Vorapaxar(N=6473)

2-yrKM rate (%)

2-yrKM rate (%) HR (95% CI) P-value

Primary endpoint 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

ICH

Bleeding OutcomesGUSTO Moderate/Severe

No. at risk6441 5536 5137 4674 3393 1972 6506446 5529 5108 4598 3278 1883 625

HR (95% CI): 1.35 (1.16, 1.58)P-value <0.001

Placebo Vorapaxar

2-year KM rate  5.2%  7.2%

No. at risk6441 5673 5281 4823 3511 2038 6786446 5694 5272 4760 3411 1965 657

HR (95% CI): 3.39 (1.78, 6.45)P-value <0.001

Placebo Vorapaxar

2-year KM rate  0.24%  1.07%

SubgroupsGUSTO Moderate/Severe

Placebo better

Vorapaxar better

Primary Endpoint

Placebo better

Vorapaxar 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.

Executive CommitteeR Harrington (Chair), P Armstrong, P Aylward,

E Chen, K Mahaffey, D Moliterno, J Strony, F Van de Werf, L Wallentin, H White

Data & Safety Monitoring BoardF Verheugt (Chair), R Frye, J Hochman,

P Steg, K Bailey, J Easton

CECA Johnson J O’ BriantM Smith P Tricoci

Academic Research Organizations

DCRI: P Tricoci, T Rorick, S Leonardi, D Underwood, J Wrestler

CVC: P Armstrong, C SorochuckC5: A Lincoff, D Mason

Henry Ford: M Hudson, D SydlowskiThomas Jefferson: D Whellan,

B Gallagher Flinders: P Aylward, J Garrett

Green Lane: H White, S DouglasLeuven: P Sinnaeve, A Beernaert

SponsorMerck: E Chen, R Harmelin–Kadouri,

A Kilian, S Petrauskas, J Strony

Core LabECG: P Armstrong, H Siha

Platelets: L Jennings, E HordAngio: M Gibson, A Chirlin

Study Organization

Steering CommitteeG 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

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