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.

Trial Design

N=12,9441:1

RandomizedDouble-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 monthsStandard 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, strokeBleeding Endpoints: GUSTO moderate or severe and clinically significant TIMI bleeding

Background

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.*

*Mahaffey, Circulation, 2011

SubgroupsGUSTO Moderate/Severe

Placebo better

Vorapaxar better

Primary Endpoint

Placebo better

Vorapaxar better

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

• 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

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) 63 (57, 70)

Age <75 81% 85% 86%

Age ≥75 19% 15% 14%

Female sex 28% 28% 28%

DM 30% 34% 34%

MI 30% 27% 29%

PCI 24% 22% 26%

+ Troponin or CKMB 93% 94% 95%

CrCl: <30 ml/min 2% 2% 1%

CrCl: 30–60 ml/min 13% 12% 11%

ASA Dosing by RegionBaseline and Hospital Discharge

Region

North America(3404)

Latin America

(848)

Western Europe(5839)

Eastern Europe(1487)

Asia/Pacific(936)

 Australia/New

Zealand(430)

N 3260 813 5664 1448 908 422

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%

N 2927 778 5117 1341 811 394

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, UKEastern Europe: CZE, HUN, POL, TUR

Baseline ASA DoseEfficacy 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 Rate HR (95% CI)*

P-value for Interaction

Primary efficacyendpoint event

0.0650.140

≤100 mg 1202 18.45% 0.89 (0.80, 1.00)0.90 (0.80, 1.04)

>100 and <300 mg 183 19.13% 0.74 (0.55, 0.99)0.82 (0.60, 1.11)

≥300 mg 675 20.27%1.05 (0.90, 1.22)1.05 (0.90, 1.23)

Key secondary endpoint event

0.1400.424

≤100 mg 979 15.03% 0.86 (0.75, 0.97)0.87 (0.76, 0.99)

>100 and <300 mg 153 15.96%0.75 (0.55, 1.04)0.84(0.60, 1.17)

≥300 mg 545 16.41%1.02 (0.86, 1.20)0.99 (0.83, 1.18)

Placebo better

Vorapaxar better

Baseline ASA DoseSafety Outcomes

Patients with Event

2-yearEvent Rate HR (95% CI)*

P-value for Interaction

GUSTO Severe Bleeding 0.9150.954

≤100 mg 137 2.26% 1.61 (1.15, 2.28)1.63 (1.15, 2.33)

>100 and <300 mg 15 1.64%1.52 (0.54, 4.26)1.94 (0.64, 5.92)

≥300 mg 68 2.24%1.83 (1.11, 3.00)1.88 (1.10, 3.18)

TIMI Major Bleeding 0.2420.426

≤100 mg 196 3.12%1.33 (1.00, 1.76)1.36 (1.02, 1.82)

>100 and <300 mg 19 2.13%1.75 (0.69, 4.44)1.79 (0.68, 4.68)

≥300 mg 114 3.68%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

Discharge ASA Dose Efficacy Outcomes

Event accrual period: discharge to last visitPopulation: randomized subjects who didn’t experience efficacy endpoint events during index hospitalization

Endpoints Post DischargeTotal

Patients

Event Rate at 2 Years

HR (95% CI)

P-value for Interaction Vorapaxar*

DoseVorapaxar Placebo

Primary efficacy endpoint 0.849

≥300 mg 1896 17.2% 19.2% 0.94 (0.75, 1.19)

<300 mg 8919 13.1% 13.8% 0.92 (0.81, 1.05)

Key secondary efficacy endpoint         0.493

≥300 mg 1901 11.4% 15.1% 0.79 (0.60, 1.05)

<300 mg 8949 9.7% 10.7% 0.89 (0.77, 1.03) Placebo better

Vorapaxar better

Landmark AnalysesVorapaxar, ASA Discharge Dose, and Region Interaction

HR (95% CI): Vorapaxar vs Placebo 0–30 Days 31–180 Days 181–365 Days

Primary efficacy endpoint      

ASA ≥300 mg 1.13 (0.89, 1.44) 0.87 (0.56, 1.36) 0.92 (0.45, 1.89)

ASA <300 mg 0.79 (0.70, 0.93) 0.98 (0.80, 1.19) 1.01 (0.77, 1.34)Key secondary efficacy endpoint      

ASA ≥300 mg 1.12 (0.87, 1.46) 0.56 (0.33, 0.96) 0.89 (0.37, 2.16)

ASA <300 mg 0.79 (0.66, 0.94) 0.95 (0.69, .132) 0.79 (0.66, 0.94)

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.

• 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