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 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

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

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 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

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 Region of enrollment, % North America South America Western Europe Eastern Europe Asia Australia/New Zealand   26 7 45 12 7 3 Diabetes mellitus, % 31 32 Prior MI, % 29 Positive troponin or CK-MB, % 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 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)

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 6471 5844 5468 5121 3794 2291 795 Vorapaxar 6473 5897 5570 5199 3881 2318 832

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 6471 5895 5575 5263 3922 2383 830 Vorapaxar 6473 5949 5684 5356 4023 2427 868

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

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

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 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 HR (95% CI): 1.35 (1.16, 1.58) P-value <0.001 No. at risk 6441 5536 5137 4674 3393 1972 650 6446 5529 5108 4598 3278 1883 625

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

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