Funding: The TRACER trial was funded by Merck & Co., Inc.

1. Association of Aspirin Dose and Vorapaxar Safety and Efficacy in Non–ST-Segment Elevation Acute Coronary Syndrome Patients in TRACER Kenneth W. Mahaffey, Zhen Huang, Pierluigi Tricoci, Frans Van de Werf, Harvey D. White, Paul W. Armstrong, Claes Held, Sergio Leonardi, Philip E. Aylward, David J. Moliterno, Lars Wallentin, Edmond Chen, John Strony, Robert A. Harrington Funding: The TRACER trial was funded by Merck & Co., Inc.

2. Trial Design NSTE Acute Coronary Syndromes • Key inclusion criteria • Within 24 hrs of symptoms • biomarkers or ECG changes • 1 other high-risk feature N=12,944 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

3. Background *Mahaffey, Circulation, 2011 • When added to standard of care in patients with NSTE ACS and high use of aspirin (ASA) 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 • Results from PLATO suggested a potential relationship between ASA dose and clinical outcomes with ticagrelor.*

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

5. Study Aims • To describe the dosing of ASA in a global population of patients with ACS • To explore the association between ASA dosing and clinical outcomes • To assess whether the observed effect of vorapaxar in TRACER was modified by concomitant exposure of ASA during the trial

6. Methods • Efficacy analyses included all randomized participants through last study visit • Safety analyses were performed on all randomized patients who received at least one dose of and while on study drug • Landmark analyses: • 30 days, 31–180 days, 181–365 days • Covariates included ASA dosing, region, randomized treatment, randomized treatment and ASA dose interaction, randomized treatment and region interaction, and baseline characteristics

7. Baseline Characteristics

8. ASA Dosing by Region Baseline and Hospital Discharge Western Europe: AUS, BEL, DEN, FIN, FRA, GER, ISR, ITA, NET, NOR, POR, SAF, SPA, SWE, SWI, UK Eastern Europe: CZE, HUN, POL, TUR

9. Baseline ASA Dose Efficacy Outcomes Efficacy endpoints: randomization to last visit *Values in italics are adjusted HRs (95% CIs) and P-values for baseline covariates Vorapaxar better Placebo better

10. Baseline ASA Dose Safety Outcomes Vorapaxar better Placebo better Bleeding endpoints: first dose to last does *Values in italics are adjusted HRs (95% CIs) and P-values for baseline covariates

11. Discharge ASA Dose Efficacy Outcomes Vorapaxar better Placebo better Event accrual period: discharge to last visit Population: randomized subjects who didn’t experience efficacy endpoint events during index hospitalization

12. Landmark Analyses Vorapaxar, ASA Discharge Dose, and Region Interaction

13. Limitations • The trial was not designed to be powered to look specifically at subgroups, including those defined by ASA dosing. • This is a post-hoc, ongoing, exploratory analysis evaluating the complex issue of post-randomization events, randomized treatment effect, and outcomes. • Confounders or biases may not be recognized or accounted for in the landmark analyses.

14. Conclusions • In TRACER, most patients were treated with low-dose ASA. • Substantial differences in baseline demographics in patients treated with low-dose compared with high-dose ASA. • Patients treated with higher ASA dose tended to have higher efficacy and safety event rates. • Overall, the effects of vorapaxar across ASA dose groups appear consistent. • Additional analyses need to explore drivers of choice of ASA dose and associations with outcomes.