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Kenneth W. Mahaffey, MD, on behalf of the TRACER Investigators and Committees Vorapaxar, a Platelet Thrombin Receptor Antagonist, in Acute Coronary Syndromes.

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Presentation on theme: "Kenneth W. Mahaffey, MD, on behalf of the TRACER Investigators and Committees Vorapaxar, a Platelet Thrombin Receptor Antagonist, in Acute Coronary Syndromes."— Presentation transcript:

1 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:

2 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 A 2 TBXA 2 -R Thrombin Anionic phospholipid surfaces GP IIb/IIIa ADP P2Y 12 PAR-1 Clopidogrel Prasugrel Ticagrelor Cangrelor ASA Vorapaxar

3 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  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

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 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

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, yrs64 (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, %3132 Prior MI, %29 Positive troponin or CK-MB, %94 Antiplatelet agents, % Aspirin Thienopyridine Median (IQR)

8 Index Hospitalization Procedures Placebo (N=6471) Vorapaxar (N=6473) Hospital presentation to randomization (hrs) 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) (2, 21) CABG, %10 Median (IQR)

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

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

11 Selected Efficacy Outcomes Placebo (N=6471) Vorapaxar (N=6473) 2-yr KM rate (%) HR (95% CI)P-value Primary endpoint (0.85–1.01)0.072 CV death (0.83–1.22)0.96 MI (0.79–0.98)0.021 Stroke (0.70–1.23)0.61 Hospitalization for ischemia (0.83–1.58)0.42 Urgent revascularization (0.88–1.31)0.49 Stent Thrombosis* (0.78–1.62)0.54 All-cause mortality (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 (1.16–1.58)<0.001 Clinically significant TIMI (1.31–1.57)<0.001 GUSTO severe (1.27–2.16)<0.001 TIMI major (1.24–1.90)<0.001 Fatal (0.80–4.45)0.15 Intracranial hemorrhage (1.78–6.45)<0.001 CABG-related TIMI major* (0.92–1.95)0.13 * data are proportions of patients

13 ICH Bleeding Outcomes GUSTO Moderate/Severe No. at risk HR (95% CI): 1.35 (1.16, 1.58) P-value <0.001 PlaceboVorapaxar 2-year KM rate 5.2% 7.2% No. at risk HR (95% CI): 3.39 (1.78, 6.45) P-value <0.001 PlaceboVorapaxar 2-year KM rate 0.24% 1.07%

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

15 Summary When added to standard of care in patients with NSTE ACS and high use of aspirin and P2Y 12 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 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

17 The full article is now available online at


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