Vorapaxar is a first-in-class protease-activated receptor-1 antagonist indicated for secondary prevention in stable patients with previous myocardial infarction (MI) or peripheral artery disease and no cerebrovascular disease. Vorapaxar is not recommended for initiation in the acute phase of acute coronary syndromes (ACS) because of an unfavorable balance between bleeding and efficacy when started in that setting. The aim of this analysis was to investigate outcomes in patients who experienced a new ACS while receiving vorapaxar for long-term secondary prevention. Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic ischemic Events–Thrombolysis In Myocardial Infarction 50 was a randomized, double-blind, placebo-controlled trial of vorapaxar (n = 26,449). We evaluated bleeding and ischemic events during the acute care of patients with a new ACS during the trial. During a median follow-up of 30 months, 799 patients (8.9%) randomized to vorapaxar and 913 (10.0%) to placebo had a new ACS event (p = 0.003); 87% and 86%, respectively, were on study therapy at the time of the event. In a landmark analysis through 7 days after ACS, the rates of Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe bleeding were 0.8% versus 0.8% (hazard ratio [HR] 0.99, 95% CI 0.33 to 2.94) and GUSTO moderate/severe bleeding were 2.5% versus 1.6% (HR 1.59, 95% CI 0.78 to 3.24) with vorapaxar versus placebo. The effect of vorapaxar on cardiovascular death, MI, or stroke (2.4% vs 4.4%; HR 0.54, 95% CI 0.31 to 0.93; p = 0.027) was consistent with the overall trial result. In conclusion, in patients who experience a new ACS event while receiving vorapaxar for secondary prevention, continuing therapy was associated with favorable efficacy without excess severe bleeding during the period of acute ACS management.
Thrombin, a serine protease critical to atherothrombosis, activates human platelets through interaction with the protease-activated receptor-1. Vorapaxar is a first-in-class oral protease-activated receptor-1 antagonist that is approved in the United States for secondary prevention of atherothrombosis in stable patients with previous myocardial infarction (MI) or peripheral artery disease (PAD) without a history of stroke or transient ischemic attack. Although vorapaxar was shown to be efficacious and to improve net clinical outcomes when started in stable patients with a history of atherothrombotic disease, it is not recommended for initiation in the acute phase of an acute coronary syndrome (ACS) because of an unfavorable balance between bleeding risk and efficacy when started in that setting. As such, there may be uncertainty for clinicians regarding the continued administration of vorapaxar in patients who experience a new ACS event while receiving vorapaxar for long-term secondary prevention. To address this question, we investigated the 7-day (perihospital) outcomes of patients who developed a new ACS while receiving vorapaxar or placebo in the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic ischemic Events (TRA 2°P)–Thrombolysis In Myocardial Infarction (TIMI) 50 trial. Our focus was on the incidence of serious bleeding with continued administration of vorapaxar in this setting with a concurrent exploratory evaluation of efficacy.
Methods
TRA 2°P-TIMI 50 was a multinational, randomized, double-blind, placebo-controlled trial of vorapaxar for the secondary prevention of ischemic events in 26,449 patients with stable atherothrombotic disease. Because vorapaxar is contraindicated in patients with a history of stroke or transient ischemic attack, this analysis was restricted to the 20,170 patients who qualified for the trial on the basis of previous MI or PAD absent a history of cerebrovascular disease (Food and Drug Administration approval population). Patients who qualified for the trial on the basis of a history of MI had a history of spontaneous MI within the 2 weeks to 12 months previous to enrollment, and those with symptomatic PAD had a history of intermittent claudication, in conjunction with either an ankle–brachial index of <0.85 or previous revascularization for limb ischemia. Details of the full eligibility criteria have been reported.
For the purpose of this analysis, we identified patients who experienced a new ACS event, either unstable angina or MI, during their participation in the trial. The trial protocol stipulated that the study drug should be continued through all such ischemic events, including in patients undergoing invasive procedures. There were no restrictions placed on the use of concomitant parenteral or oral anticoagulant or antiplatelet therapies in this setting. Concomitant antiplatelet medications were to be recorded in the case report form by the investigator.
The primary focus of this post hoc analysis was serious bleeding that might occur in the setting of a new presentation with ACS and the addition of standard antithrombotic therapies to vorapaxar. The principal safety end point for this analysis was severe bleeding according to the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) bleeding classification system during the 7-day period after presentation with a new ACS event. This period was selected to be inclusive of the average duration of in-hospital acute management of ACS. In addition, fatal bleeding, intracranial hemorrhage, and GUSTO moderate and severe bleeding are reported. Efficacy was evaluated for consistency with the overall trial result. The primary efficacy end point for this analysis was the composite of cardiovascular (CV) death, MI, or stroke during the 7 days after presentation with a new ACS. A Clinical Events Committee blinded to the randomized treatment allocation adjudicated all end points for the present analysis using predefined standard definitions.
We compared the baseline characteristics of patients allocated to vorapaxar versus placebo using the chi-square test for categorical variables and Wilcoxon rank-sum testing for continuous variables. Landmark analyses were performed establishing time zero as the time and date of the recorded onset of a first new ACS. Event rates presented are Kaplan–Meier estimates of the cumulative incidence at 7 days after the new ACS. Outcomes between vorapaxar and placebo were analyzed using Cox regression in a landmark analysis starting from the first new ACS event through 7 days.
The primary safety analysis was restricted to patients who received at least one dose of study drug and included events through 60 days after premature cessation of study therapy or 30 days after a final visit at the conclusion of the trial. In addition, we performed an “on-treatment” sensitivity analysis restricted to those patients who were continuing study drug during the management of the new ACS event. To minimize bias, the efficacy analysis included all patients from the intention-to-treat population who experienced a new ACS event, regardless of whether they were still taking the study drug at the time of the event.
Results
During a median follow-up of 30 months, a total of 1,712 patients developed a new ACS event, including 799 patients (Kaplan Meier estimate 8.9%) randomized to vorapaxar and 913 patients (Kaplan Meier estimate 10.0%) randomized to placebo (hazard ratio [HR] 0.87, 95% CI 0.79 to 0.95; p = 0.003). Of the 1,712 total new ACS events, 57% (n = 970) were MIs, 27% (n = 470) were unstable angina leading to urgent coronary revascularization, and 16% (n = 272) were unstable angina requiring hospitalization. Of the 970 MIs, 78% (n = 754) were spontaneous (type 1 MI), 9% (n = 88) were demand-type (type 2 MI), and 12% (n = 113) were related to stent thrombosis (type 4b). Of the type 1 MIs, 200 were ST-elevation MIs and 554 were non-ST elevation MIs.
The baseline characteristics of these patients stratified by their allocation to vorapaxar or placebo are listed in Table 1 . Among the 1,712 subjects in this analysis, 86% in the placebo group and 86% in the vorapaxar group qualified for the trial on the basis of a previous MI. Eighty-six percent of patients in the placebo arm and 87% in the vorapaxar arm were on treatment at the time of ACS, with 79% in each arm continuing study drug through at least 7 days from the presentation with ACS. Eighty-six percent of patients allocated to placebo and 83% of patients allocated to vorapaxar had undergone previous coronary revascularization. Of patients in the placebo group, 22% had undergone previous coronary artery bypass grafting and 80% had undergone previous percutaneous coronary intervention, compared with 20% and 75%, respectively, of patients in the vorapaxar group. No significant differences were observed between patients receiving vorapaxar versus placebo with respect to aspirin, thienopyridine, or glycoprotein IIb/IIIa receptor antagonist use at the time of the new ACS event ( Table 2 ).
| Placebo N = 913 n (%) | Vorapaxar N = 799 n (%) | p-value | |
|---|---|---|---|
| Demographic information | |||
| Age in years, median (25 th -75 th IQR) | 60 (52-68) | 61 (52-69) | 0.29 |
| Female sex | 224 (24.5%) | 207 (25.9%) | 0.51 |
| White race | 799 (87.5%) | 699 (87.5%) | 0.99 |
| Qualifying type of atherosclerosis | |||
| Myocardial infarction (MI) | 785 (86.0%) | 687 (86.0%) | 0.99 |
| Peripheral arterial disease (PAD) | 128 (14.0%) | 112 (14.0%) | 0.99 |
| Past medical history | |||
| Diabetes mellitus | 316 (34.6%) | 256 (32.0%) | 0.26 |
| Hypertension | 697 (76.4%) | 602 (75.3%) | 0.60 |
| Hyperlipidemia | 824 (90.3%) | 720 (90.1%) | 0.92 |
| Heart Failure | 133 (14.6%) | 126 (15.8%) | 0.49 |
| Peripheral arterial disease | 246 (26.9%) | 217 (27.2%) | 0.92 |
| Current smoker | 208 (22.8%) | 182 (22.8%) | 0.99 |
| Previous coronary revascularization | 786 (86.1%) | 660 (82.6%) | 0.047 |
| Prior coronary artery bypass grafting | 202 (22.1%) | 159 (19.9%) | 0.26 |
| Prior percutaneous coronary intervention | 726 (79.5%) | 601 (75.2%) | 0.03 |
| eGFR <60 ml/min/1.73 m 2 | 164 (18.1%) | 160 (20.2%) | 0.28 |
| Use of antiplatelet agents at randomization | |||
| Aspirin | 877 (96.1%) | 770 (96.4%) | 0.74 |
| Thienopyridine | 720 (78.9%) | 632 (79.1%) | 0.90 |
| On study drug at time of ACS | 781 (85.5%) | 693 (86.7%) | 0.77 |
| Placebo N = 913 n (%) | Vorapaxar N = 799 n (%) | p-value | |
|---|---|---|---|
| Concomitant antiplatelet treatment | |||
| Aspirin | 877 (96.1%) | 770 (96.4%) | 0.74 |
| Thienopyridine | 743 (81.4%) | 642 (80.4%) | 0.59 |
| Glycoprotein IIb/IIIa receptor inhibitor | 71 (7.8%) | 46 (5.8%) | 0.10 |
| Fibrinolytic agent | 16 (1.8%) | 11 (1.4%) | 0.53 |
| Coronary revascularization performed | 542 (59.4%) | 460 (57.6%) | 0.45 |
| Percutaneous coronary intervention | 473 (51.8%) | 402 (50.3%) | 0.54 |
| Coronary artery bypass grafting | 72 (7.9%) | 68 (8.5%) | 0.64 |
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