Methods

The TRACER trial’s primary results and design have been published. In brief, 12,944 participants with non–ST-segment elevation acute coronary syndrome were recruited from >800 centers in 37 countries. Participants were randomly assigned in a double-blind fashion to either placebo or vorapaxar administered as a 40-mg loading dose followed by a 2.5-mg/day maintenance dose. The study was planned to continue until all participants had been treated for at least 1 year. Concomitant medications, including antiplatelet therapies, and management strategies were left to the discretion of the treating physician.

After discharge from the index hospitalization, participants were to be followed-up at 30 days, 4 months, 8 months, 12 months, and then every 6 months until the end of the study. At each visit, standard electronic case report form instruments were used to collect information about clinical end points, adverse events, procedures, and medications, including ASA use and dose.

The TRACER trial was funded by Merck & Co., Inc. The Duke Clinical Research Institute (Durham, North Carolina) maintained a copy of the full trial data set and performed the analyses for this manuscript independent of the sponsor. An international executive committee, including representatives from the sponsor, designed the trial and was responsible for overseeing study conduct, which conformed to the Declaration of Helsinki, and reporting of results. Ethics committees or institutional review boards approved the study. All participants provided written informed consent.

Values are provided as n (%) or median with interquartile range as appropriate. ASA-dose groups were defined as follows and were reported as the total dose per day: low dose (≤100 mg), medium dose (>100 mg and <300 mg), and high dose (≥300 mg). For analyses evaluating outcomes associated with postbaseline ASA use, dosing was collapsed into 2 categories because few participants used a medium dose after baseline: low dose (<300 mg) and high dose (≥300 mg). The Jonckheere-Terpstra method was used to test the ordered differences in dose levels between the 2 groups.

The efficacy and safety outcomes were the same as evaluated in the main trial : the primary efficacy outcome was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or urgent revascularization, and the key secondary outcome was the composite of cardiovascular death, myocardial infarction, or stroke. Safety outcomes included Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe bleeding and Thrombolysis In Myocardial Infarction major bleeding. Efficacy analyses were performed on the intention-to-treat population, defined as all randomized participants. Also, efficacy analyses included all events from randomization to the last follow-up visit. Safety analyses included all randomized participants who received at least 1 dose of assigned study drug. Also, safety analyses included all events from randomization to the last dose of study drug. The following regions were defined in the main trial’s statistical analysis plan based on clinically and geographically meaningful regions and were also used for these analyses: North America, Latin America, Western Europe, Eastern Europe, Asia, and Australia and New Zealand.

The associations between (1) baseline and discharge ASA dose and (2) clinical efficacy and safety outcomes were evaluated. ASA use was reported as the percentage of participants taking ASA (≥5 days in a month), and the median dose during each month after randomization was calculated while participants were taking the randomized treatment. The dose of concomitant medication was only available for the time during which a participant was taking the randomized study drug.

Landmark analysis of efficacy and safety end points was performed for the following time periods: 0 to 30, 31 to 180, and 181 to 365 days. The population for each period comprised participants who survived without experiencing any efficacy or safety end point events during the previous period and who were taking ASA at the beginning of their current period. Adjustment was performed for the following covariates: ASA dose, region, study drug assignment, study drug assignment and ASA-dose interaction, study drug assignment and region interaction, and baseline characteristics, including thienopyridine use.

All analyses were performed using SAS, version 9.2 (SAS Institute, Cary, North Carolina), and report nominal significance levels without adjustment for multiplicity.

Results

Overall, 96.7% (vorapaxar 96.4% and placebo 96.9%) of participants were treated with ASA at baseline. Table 1 lists the proportion of participants treated with various dosing categories of ASA. Most participants were treated with low-dose ASA, and few participants were treated with medium-dose ASA. A greater proportion of participants were treated with low-dose ASA at discharge compared with baseline. This is partially reflective of the higher dose given to participants when they arrived at the hospital.

Table 2 lists baseline demographics by ASA dose. Overall, participant features were generally balanced across ASA doses except for region. Table 3 lists ASA dose by region. Participants in North America were more often treated with higher doses of ASA compared with other regions at baseline and at discharge. Of the 12,253 participants taking ASA during the trial, 10,320 (84.2%) did not change dose during follow-up. Of the 1,933 participants who took ASA and changed dose during the trial, 556 (29%) changed dose during the index hospitalization. The remainder changed dose at a median (interquartile range) of 20 days (1 to 116) after discharge. Few participants (n = 439) changed ASA dose more than once.

Figure 1 shows the primary and secondary end point composite event rates and unadjusted and adjusted hazard ratios for vorapaxar compared with placebo by baseline ASA dose. Participants treated with ≥300 mg ASA had higher event rates compared with participants treated with ≤100 mg ASA. There were no statistically significant interactions between vorapaxar effect and ASA dose. The unadjusted and adjusted hazard ratios in participants treated with ≤100 versus ≥300 mg of ASA suggested a trend toward a greater treatment effect associated with vorapaxar compared with placebo in the low-dose ASA group.

Baseline ASA dose efficacy outcomes. Efficacy end points: randomization to last visit. ^∗ Values in italics are adjusted HRs (95% CIs) and p values for baseline covariates. CI = confidence interval; HR = hazard ratio.

Figure 2 shows GUSTO severe and Thrombolysis In Myocardial Infarction major bleeding outcomes and unadjusted and adjusted hazard ratios for vorapaxar compared with placebo by baseline ASA dose. Compared with participants treated with ≤100 mg of ASA, participants treated with ≥300 mg ASA had similar GUSTO severe bleeding event rates and slightly higher Thrombolysis In Myocardial Infarction major bleeding rates. There were no statistically significant interactions between study treatment effect on bleeding and ASA dose. The unadjusted and adjusted hazard ratios in participants treated with ≤100 versus ≥300 mg of ASA suggested a trend toward more prominent bleeding risk associated with vorapaxar compared with placebo.

Baseline ASA dose safety outcomes. Bleeding end points: first dose to last dose. ^∗ Values in italics are adjusted HRs (95% CIs) and p values for baseline covariates. CI = confidence interval; HR = hazard ratio; TIMI = Thrombolysis In Myocardial Infarction.

Figures 3 and 4 show the primary efficacy and safety end points by discharge ASA dose. Because the proportion of participants discharged on medium-dose ASA was small, the categories of ASA dose were revised to <300 mg and ≥300 mg. The results are consistent with those observed for baseline ASA.

Discharge ASA dose efficacy outcomes. Event accrual period: discharge to last visit. Population: randomized participants who did not experience efficacy endpoint events during index hospitalization. CI = confidence interval; HR = hazard ratio.

Discharge ASA dose safety outcomes. CI = confidence interval; HR = hazard ratio; TIMI = Thrombolysis In Myocardial Infarction.

A series of analyses showing adjusted hazard ratios for vorapaxar versus placebo for efficacy and safety outcomes for baseline and discharge ASA dosing are listed in Tables 4 and 5 . The adjusted hazard ratios showed trends suggesting that in participants treated with higher-dose ASA, vorapaxar was associated with trends toward lesser efficacy in reducing cardiovascular outcomes compared with placebo. No statistically significant p values were observed for analyses evaluating the interaction among vorapaxar × ASA dose × region or among vorapaxar × ASA dose × thienopyridine use for any of the safety or efficacy end points evaluated (data not shown).

Table 4

Efficacy and bleeding end points after randomization by region and by dose at baseline

ASA Dose at Baseline (mg)	Total Participants	Event Rate at 2 yrs (%)		HR (95% CI) for Vorapaxar vs Placebo	p Value for Interaction Vorapaxar × Dose Within a Region
		Vorapaxar	Placebo
Primary efficacy end point event	12,944	18.5	19.9	0.92 (0.85–1.01)
North America	3,404	22.1	24.7	0.95 (0.81–1.11)
≤100	951	23.90	23.50	0.80 (0.58–1.10)	0.175
>100 and <300	163	14.60	38.20	0.66 (0.29–1.48)
≥300	2,146	22.20	24.90	1.05 (0.85–1.28)
ROW	9,540	16.8	17.9	0.92 (0.82–1.02)
≤100	6,572	16.80	18.50	0.92 (0.81–1.04)	0.474
>100 and <300	886	15.90	19.00	0.85 (0.59–1.20)
≥300	1,797	16.30	14.60	1.08 (0.83–1.41)
Key secondary efficacy end point event	12,944	14.7	16.4	0.89 (0.81–0.98)
North America	3,404	16.9	20.9	0.85 (0.71–1.02)
≤100	951	18.20	21.20	0.70 (0.49–0.99)	0.249
>100 and <300	163	14.60	33.90	0.74 (0.31–1.77)
≥300	2,146	16.90	20.40	0.94 (0.75–1.19)
ROW	9,540	13.6	14.7	0.91 (0.81–1.03)
≤100	6,572	13.40	15.10	0.90 (0.78–1.04)	0.417
>100 and <300	886	13.10	15.70	0.82 (0.56–1.22)
≥300	1,797	14.00	12.30	1.10 (0.82–1.46)
GUSTO moderate or severe bleeding	12,877	7.2	5.2	1.35 (1.16–1.58)
North America	3,387	9.7	7.1	1.26 (0.97–1.66)
≤100	945	9.50	8.30	1.10 (0.68–1.78)	0.436
>100 and <300	162	6.80	3.10	Cannot converge because of small number of events
≥300	2,137	10.00	6.40	1.42 (0.99–2.04)
ROW	9,500	6.2	4.6	1.37 (1.13–1.67)
≤100	6,546	6.20	5.00	1.27 (1.01–1.60)	0.342
>100 and <300	883	5.20	2.40	1.88 (0.80–4.40)
≥300	1,791	6.10	4.10	1.70 (1.08–2.69)
TIMI major bleeding	12,877	4.0	2.5	1.53 (1.24–1.90)
North America	3,387	5.3	2.5	2.27 (1.45–3.55)
≤100	945	4.50	1.80	2.85 (1.13–7.20)	0.467
>100 and <300	162	2.10	0.00	Cannot converge because of small number of events
≥300	2,137	5.70	2.80	2.13 (1.23–3.70)
ROW	9,500	3.5	2.5	1.36 (1.05–1.77)
≤100	6,546	3.50	2.70	1.26 (0.92–1.71)	0.252
>100 and <300	883	3.00	1.70	1.72 (0.62–4.81)
≥300	1,791	3.60	2.10	2.03 (1.10–3.74)

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