1. 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 Association of Aspirin Dose and Vorapaxar Safety and Efficacy in Non–ST-Segment Elevation Acute Coronary Syndrome Patients in TRACER Funding: The TRACER trial was funded by Merck & Co., Inc.

2. Trial Design N=12,944 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

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

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

7. Baseline Characteristics Low Dose (≤100 mg) Medium Dose (100–300 mg) High Dose (≥300 mg) Overall n (%)7523 (60%)1049 (8%)3943 (32%) Age Median (Q1, Q3)64 (58, 72)63 (57, 70) Age <7581%85%86% Age ≥7519%15%14% Female sex28% DM30%34% MI30%27%29% PCI24%22%26% + Troponin or CKMB93%94%95% CrCl: <30 ml/min2% 1% CrCl: 30–60 ml/min13%12%11%

8. ASA Dosing by Region Baseline and Hospital Discharge Region North America (3404) Latin America (848) Western Europe (5839) Eastern Europe (1487) Asia/ Pacific (936) Australia/ New Zealand (430) N326081356641448908422 Baseline Dose (mg) ≤100 19%53%46%42%53%35% >100 and <300 10%27%14%4%15%3% ≥300 71%20%40%53%32%62% N292777851171341811394 Discharge Dose (mg) ≤100 38%80%92%90%93%86% >100 and <300 2%18%7%2%4%9% ≥300 60%2%1%8%3%5% 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 Patients with Event 2-year Event RateHR (95% CI)* P-value for Interaction Primary efficacy endpoint event 0.065 0.140 ≤100 mg 120218.45% 0.89 (0.80, 1.00) 0.90 (0.80, 1.04) >100 and <300 mg 18319.13% 0.74 (0.55, 0.99) 0.82 (0.60, 1.11) ≥300 mg 67520.27% 1.05 (0.90, 1.22) 1.05 (0.90, 1.23) Key secondary endpoint event 0.140 0.424 ≤100 mg 97915.03% 0.86 (0.75, 0.97) 0.87 (0.76, 0.99) >100 and <300 mg 15315.96% 0.75 (0.55, 1.04) 0.84(0.60, 1.17) ≥300 mg 54516.41% 1.02 (0.86, 1.20) 0.99 (0.83, 1.18) Placebo better Vorapaxar better

10. Baseline ASA Dose Safety Outcomes Patients with Event 2-year Event RateHR (95% CI)* P-value for Interaction GUSTO Severe Bleeding 0.915 0.954 ≤100 mg 1372.26% 1.61 (1.15, 2.28) 1.63 (1.15, 2.33) >100 and <300 mg 151.64% 1.52 (0.54, 4.26) 1.94 (0.64, 5.92) ≥300 mg 682.24% 1.83 (1.11, 3.00) 1.88 (1.10, 3.18) TIMI Major Bleeding 0.242 0.426 ≤100 mg 1963.12% 1.33 (1.00, 1.76) 1.36 (1.02, 1.82) >100 and <300 mg 192.13% 1.75 (0.69, 4.44) 1.79 (0.68, 4.68) ≥300 mg 1143.68% 1.99 (1.35, 2.94) 1.93 (1.29, 2.89) Bleeding endpoints: first dose to last does *Values in italics are adjusted HRs (95% CIs) and P-values for baseline covariates Placebo better Vorapaxar better

11. Discharge ASA Dose Efficacy Outcomes Event accrual period: discharge to last visit Population: randomized subjects who didn’t experience efficacy endpoint events during index hospitalization Endpoints Post Discharge Total Patients Event Rate at 2 Years HR (95% CI) P-value for Interaction Vorapaxar* Dose VorapaxarPlacebo Primary efficacy endpoint0.849 ≥300 mg189617.2%19.2%0.94 (0.75, 1.19) <300 mg891913.1%13.8%0.92 (0.81, 1.05) Key secondary efficacy endpoint 0.493 ≥300 mg190111.4%15.1%0.79 (0.60, 1.05) <300 mg89499.7%10.7%0.89 (0.77, 1.03) Placebo better Vorapaxar better

12. Landmark Analyses Vorapaxar, ASA Discharge Dose, and Region Interaction HR (95% CI): Vorapaxar vs Placebo 0–30 Days31–180 Days181–365 Days Primary efficacy endpoint ASA ≥300 mg1.13 (0.89, 1.44)0.87 (0.56, 1.36)0.92 (0.45, 1.89) ASA <300 mg0.79 (0.70, 0.93)0.98 (0.80, 1.19)1.01 (0.77, 1.34) Key secondary efficacy endpoint ASA ≥300 mg1.12 (0.87, 1.46)0.56 (0.33, 0.96)0.89 (0.37, 2.16) ASA <300 mg0.79 (0.66, 0.94)0.95 (0.69,.132)0.79 (0.66, 0.94)

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. 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. Conclusions