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

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. Background. Platelet. Vorapaxar : First-in-class

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

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  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: www.DCRI.org

  2. Background Platelet • 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 Vorapaxar PAR-1 Thrombin PAR-4 Clopidogrel Prasugrel Ticagrelor Cangrelor Anionic phospholipid surfaces ADP P2Y12 TBXA2-R TBX A2 GP IIb/IIIa ASA Chackalamannil S, J Med Chem, 2006

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

  6. Study Conduct Median (IQR)

  7. Baseline Demographics Median (IQR)

  8. Index Hospitalization Procedures Median (IQR)

  9. Primary EndpointCV 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

  10. Key Secondary EndpointCV Death, MI, Stroke No. atrisk 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

  11. Selected Efficacy Outcomes *ARC definite or probable; data are proportions of patients

  12. Bleeding Endpoints * data are proportions of patients

  13. Bleeding Outcomes GUSTO Moderate/Severe ICH 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. atrisk 6441 5536 5137 4674 3393 1972 650 6446 5529 5108 4598 3278 1883 625 No. atrisk 6441 5673 5281 4823 3511 2038 678 6446 5694 5272 4760 3411 1965 657

  14. Subgroups GUSTO Moderate/Severe Primary Endpoint Vorapaxarbetter Placebo better Vorapaxarbetter 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 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 SorochuckC5: A Lincoff, D MasonHenry Ford: M Hudson, D SydlowskiThomas Jefferson: D Whellan, B Gallagher Flinders: P Aylward, J GarrettGreen 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’ BriantM Smith P Tricoci Core LabECG: 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

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