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 Merck Complete 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 A2 TBXA2-R

Thrombin

Anionic phospholipid surfaces

GP IIb/IIIa

ADP P2Y12

PAR-1

Clopidogrel Prasugrel Ticagrelor Cangrelor

ASA

Vorapaxar

Trial Design

1:1 Randomized Double-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 months Standard of care based on practice guidelines

Key inclusion criteria •  Within 24 hrs of symptoms •  á !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, 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

Canada: 591

United States: 2772

Finland: 119

Denmark: 205

Hungary: 266

Netherlands: 471

Sweden: 346 Norway: 251

U.K.: 463

Belgium: 153

France: 441 Spain: 379

Austria: 319 Italy: 764

Israel: 410

Poland: 561

Czech Rep: 496

Chile: 148

Peru: 11

Colombia: 275

Brazil: 284

Argentina: 130

South Africa: 207

China: 219 South Korea: 127

Taiwan: 219

Malaysia: 52 Singapore: 26

Australia: 235

Germany: 911 Japan: 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 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

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, %

57 4 (2, 21)

58 46

58 4 (2, 21)

56 49

CABG, % 10 10

Median (IQR)

0%

5%

10%

15%

20%

0 1 4 8 12 18 24

Even

t Rat

e

Months from Randomization

Placebo

Vorapaxar

Primary Endpoint CV Death, MI, Stroke, Hospitalization for Ischemia, Urgent Revascularization

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

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

Placebo Vorapaxar 2-year KM rate 19.9% 18.5%

0%

5%

10%

15%

20%

0 1 4 8 12 18 24

Even

t Rat

e

Months from Randomization

Placebo

Vorapaxar

Key Secondary Endpoint CV Death, MI, Stroke

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

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

Placebo Vorapaxar 2-year KM rate 16.4% 14.7%

Selected Efficacy Outcomes Placebo

(N=6471) Vorapaxar (N=6473)

2-yr KM rate (%)

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 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 Outcomes GUSTO Moderate/Severe

No. at risk 6441 5536 5137 4674 3393 1972 650 6446 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 risk 6441 5673 5281 4823 3511 2038 678 6446 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%

0%24180 12841

2%

4%

6%

8%

Even

t Rat

e

Months from Randomization

Placebo

Vorapaxar

24180 12841

Placebo

Vorapaxar

Months from Randomization

0%

1%

2%

Subgroups GUSTO Moderate/Severe

Placebo better

Vorapaxar better

Primary Endpoint   P-­value   Interaction       0.46             0.29

    0.62

    0.13

    0.31

    0.35

 

10.25 2Placebo better

Vorapaxar better

  P-­value

  Interaction

Overall  

Age   0.14

     <75  years  

Sex   0.85

     Female  

     Male  

Region   0.87

     North  America  

     South  America  

     West  Europe  

     East  Europe  

     Asia  

     Australia  

Thienopyridine   0.044

     Yes  

     No  

Aspirin  dose   0.079

     >100  mg  

Troponin  or  CKMB   0.48

     Pos  

     Neg  

0.5 1 4

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 Committee R 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 Board F Verheugt (Chair), R Frye, J Hochman,

P Steg, K Bailey, J Easton

CEC A Johnson J O’ Briant M Smith P Tricoci

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

Sponsor Merck: E Chen, R Harmelin–Kadouri,

A Kilian, S Petrauskas, J Strony

Core Lab ECG: P Armstrong, H Siha

Platelets: L Jennings, E Hord Angio: M Gibson, A Chirlin

Study Organization

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

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