Safety and Efficacy of Vorapaxar in Secondary Prevention of Atherosclerotic Disease: A Meta-Analysis of Randomized Control Trials
Abstract
Objective: To study the cumulative evidence for vorapaxar use in patients with atherosclerotic cardiovascular disease.
Methods: A systematic review of randomized controlled trials in MEDLINE, EMBASE, EBSCO, CINAHL, Web of Science, and Cochrane databases comparing vorapaxar with placebo was performed. Pre-specified efficacy endpoints were all-cause mortality, cardiovascular mortality, myocardial infarction (MI), ischemic stroke, and repeat revascularization. The pre-specified safety endpoints were intracranial hemorrhage (ICH) and a composite of TIMI major and minor bleeding. Risk ratios were used as the metric of choice by applying random effects models.
Results: Five randomized controlled trials with 40,630 patients were included in the final analysis. Compared with placebo, vorapaxar led to a statistically non-significant reduction in risk of MI (RR 0.86; 95% CI 0.80–0.93, p = 0.427) and ischemic stroke (RR 0.84; 95% CI 0.72–0.97, p = 0.920). No differences were observed between vorapaxar and placebo with respect to all-cause mortality (RR 0.99; 95% CI 0.90–1.08, p = 0.620), cardiovascular mortality (RR 0.94; 95% CI 0.83–1.06, p = 0.351), repeat revascularization (RR 0.97; 95% CI 0.82–1.15, p = 0.236), and TIMI bleeding (RR 1.29; 95% CI 0.98–1.69, p = 0.126). Vorapaxar was associated with a statistically non-significant higher risk of ICH (RR 2.36; 95% CI 1.40–3.96, p = 0.137) compared with placebo.
Conclusion: Addition of vorapaxar to standard medical therapy in patients with atherosclerotic disease led to a statistically non-significant reduction in the risk of MI and ischemic stroke at the cost of a statistically non-significant increase in risk of ICH.
Keywords: Vorapaxar, Atherosclerotic vascular disease
Introduction
Atherothrombotic disease continues to be the leading cause of morbidity and mortality worldwide. Major guidelines recommend dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor (thienopyridines or ticagrelor) for secondary prevention after an acute myocardial infarction (AMI) or percutaneous coronary intervention (PCI) with stent implantation. However, a substantial residual cardiovascular (CV) risk remains despite use of current evidence-based antithrombotic therapy, which has prompted investigators to explore additional mechanisms of platelet activation and thrombus formation.
Thrombin is a potent stimulator of platelet activation and aggregation, primarily acting via protease-activated receptor-1 (PAR-1) on human platelets. Persistence of unsuppressed thrombin-mediated platelet activation after an index coronary event can therefore contribute to sustained thrombotic risk. Vorapaxar (SCH 530348, Merck) is a novel orally active and selective PAR-1 antagonist that offers a new strategy to further mitigate residual CV risk by complementing currently used targeted-drug therapy (Thromboxane- and P2Y12-inhibitor).
Extrapolating the results from the large, multicenter, randomized, phase 3 TRA 2P-TIMI 50 study, the Federal Drug Agency (FDA) has recently approved vorapaxar for use in addition to current standard antiplatelet therapy, including DAPT, for secondary prevention in stable patients after MI or peripheral arterial disease (PAD), and without history of stroke or transient ischemic attack (TIA). In the TRA 2P-TIMI 50 trial involving 26,449 patients, a significant improvement in the rate of the primary endpoint of cardiovascular death, AMI, stroke, or urgent revascularization was observed with additional vorapaxar therapy compared with placebo. On the other hand, the phase 3 TRACER trial randomizing more than 12,000 patients failed to demonstrate significant reduction in the pre-defined composite of cardiovascular mortality, MI, stroke, recurrent ischemia requiring hospitalization, or urgent PCI with the addition of vorapaxar to standard therapy. Furthermore, contrary to the findings elicited in phase 2 studies, a significantly higher risk of TIMI major and minor bleeding was observed in the vorapaxar arm in TRACER and TRA 2P-TIMI 50 trials. Thus, contradictory results reported by these major trials have raised questions over widespread adaptability of vorapaxar as part of triple antiplatelet therapy (TAPT) in actual clinical practice. Therefore, in the present meta-analysis, we aimed to specifically investigate the cumulative evidence for the safety and efficacy of vorapaxar in patients with atherosclerotic cardiovascular disease (ASCVD).
Methods
We followed the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) statement for reporting systematic reviews and meta-analyses of randomized controlled trials (RCTs) for the protocol of our meta-analysis. We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and the clinical trial registries maintained at clinicaltrials.gov for RCTs evaluating the safety and efficacy of vorapaxar. The following search terms were used: vorapaxar, SCH530348, protease-activated receptor-1 inhibitor or PAR-1 antagonist, coronary artery disease (CAD), and atherosclerotic cardiovascular disease. Pertinent trials were also searched in major national/international cardiology meetings (American College of Cardiology, American Heart Association, European Society of Cardiology, Transcatheter Cardiovascular Therapeutics). References of original and review articles were crosschecked. We manually searched references of identified studies. The search period took place from January 1, 2002, to March 31, 2016. No language restrictions were applied. Prospective RCTs were selected if they met the following criteria: (i) study population of patients with ASCVD; (ii) assignment of participants to vorapaxar or a placebo group; and (iii) provide data on outcomes for vorapaxar and placebo arms. Non-RCTs were excluded.
Two reviewers independently screened the titles and abstracts for relevance. The manuscripts of selected titles/abstracts were reviewed for inclusion or exclusion using the above-mentioned selection criteria. Two reviewers independently determined the articles to be included and excluded, and data from the relevant articles were extracted using pre-defined extraction forms. Any disagreements in data extraction were discussed until consensus was reached. Key study and patient characteristics were extracted, including the following outcomes, reported at the longest available follow-up according to intention-to-treat principles. Pre-specified efficacy endpoints were all-cause mortality, cardiovascular mortality, myocardial infarction, ischemic stroke, repeat revascularization, and target vessel revascularization (TVR). The pre-specified safety endpoints were intracranial hemorrhage (ICH) and composite of Thrombolysis In Myocardial Infarction (TIMI) major and minor bleeding.
The statistical analysis was performed according to the recommendations from the Cochrane Collaboration using Review Manager Version 5.1. A random-effects model with inverse variance weighting was used to calculate odds ratio (OR) and 95% confidence interval, associated with vorapaxar versus placebo for the above endpoints. Forest plot was used to observe the overall effect of studies. Heterogeneity between studies was assessed using Cochrane’s Q test and I2 statistic, which denotes the percentage of total variation across studies that is a result of heterogeneity rather than chance. Heterogeneity was considered significant if the p value was less than 0.05. Publication bias was assessed by Begg’s test and Egger’s regression test.
Results
A total of 188 publications were found at initial search and after abstract and manuscript evaluation, five studies including 40,630 patients were selected for final analysis. Baseline characteristics of the studies included in the current analysis have been summarized.
Clinical outcomes with the addition of vorapaxar versus placebo to standard-of-care practices showed that compared with placebo, vorapaxar led to a statistically non-significant reduction in risk of myocardial infarction (RR 0.86; 95% CI 0.80–0.93, p = 0.427) and ischemic stroke (RR 0.84; 95% CI 0.72–0.97, p = 0.920). Vorapaxar was associated with a statistically non-significant higher risk of intracranial hemorrhage.
Discussion
Vorapaxar, as a selective PAR-1 antagonist, represents a novel approach to reduce residual thrombotic risk in patients with atherosclerotic cardiovascular disease by inhibiting thrombin-mediated platelet activation. Despite promising results in early phase studies, large phase 3 trials have shown conflicting evidence regarding its efficacy and safety profile. The TRA 2P-TIMI 50 trial demonstrated a significant reduction in composite cardiovascular endpoints with vorapaxar, leading to FDA approval for secondary prevention in selected stable patients. However, the TRACER trial did not show significant benefits and reported increased bleeding risks. This meta-analysis consolidates evidence from five randomized controlled trials and suggests that vorapaxar may reduce the risk of myocardial infarction and ischemic stroke, although these reductions were not statistically significant. Additionally, there is a trend toward increased risk of intracranial hemorrhage, also not statistically significant. These findings highlight the need for careful patient selection and risk-benefit assessment when considering vorapaxar as an adjunct to standard antiplatelet therapy.
Conclusion
The addition of vorapaxar to standard medical therapy in patients with atherosclerotic disease leads to a statistically non-significant reduction in the risk of myocardial infarction and ischemic stroke, accompanied by a statistically non-significant increase in the risk of intracranial hemorrhage. Further studies are warranted MK-5348 to better define the patient populations who may benefit most from vorapaxar while minimizing bleeding risks.