Vorapaxar (Zontivity) is a novel antiplatelet drug that antagonizes the protease-activated receptor 1 (PAR 1) on platelets leading to inhibition of platelet aggregation.1 Vorapaxar is indicated for patients with a history of myocardial infarction (MI) or peripheral artery disease (PAD) to reduce secondary cardiovascular events when used in combination with aspirin and/or P2Y12 inhibitors (e.g. clopidogrel, prasugrel).2 Some of the evidence for vorapaxar came from the TRA 2°P-TIMI 50 study, which evaluated the long term safety and efficacy of vorapaxar or placebo with aspirin and/or a P2Y12 inhibitor in patients with a history of MI, ischemic stroke, or PAD to prevent a secondary thrombotic event.3 The addition of vorapaxar reduced the risk of cardiovascular death, MI or stroke by 13% (NNT 83, p<0.001). However, it was also associated with an increased risk of moderate or severe bleeding (HR 1.66, NNH 59, p<0.001) and intracranial hemorrhage (NNH 200, p <0.001).3
Various treatments have been investigated to try to help mitigate the risk of recurrent cardiovascular complications in patients who had a prior MI; and while they reduce the risk, patients continue to be at a high risk for further events.4 It is unclear if continuing antiplatelet therapy with aspirin beyond 12 months results in additional benefit in patients with a history of a MI without conferring unnecessary harm.4,5 A subgroup analysis of the primary study sought to determine if long-term therapy with vorapaxar was beneficial in individuals with a prior MI compared to patients with the indication for enrollment of stroke or PAD.4
For purposes of the subgroup analysis, patients enrolled in the TRA 2°P-TIMI 50 who had a spontaneous MI within the past two weeks to twelve months were included. Exclusion criteria were: a planned revascularization, predisposition to bleeding, active abnormal bleeding within the past 30 days, active long term treatment with warfarin, or active hepatobillary disease. Patients received either vorapaxar 2.5 mg daily or placebo plus standard therapy. Standard therapy was defined as aspirin and/or a P2Y12 inhibitor (usually clopidogrel). The patients with a history of stroke were taken out of the study after 2 years due to a finding of an increased risk of intracranial hemorrhage. The primary endpoints of the study were a composite of cardiovascular death, MI, or stroke. Bleeding was evaluated using the GUSTO and TIMI classifications.4
The subgroup analysis included 17,779 patients (67% of the total trial participants) with a median follow-up of 30 months. Patient demographics were not significantly different between groups. Most patients were Caucasian, middle aged men, >60 kg who had a qualifying MI within three months prior to the study enrollment. Vorapaxar therapy resulted in a statistically significant reduction in the composite endpoint of CV death, MI, or stroke compared to placebo (HR 0.80; NNT 62.5; 95% CI, 0.72-0.89; p<0.0001). Vorapaxar also reduced the incidence of MI compared to placebo (5.7% vs. 7.0%, respectively, p = 0.0003). However, there was not a significant reduction in cardiovascular death (p= 0.12) or all-cause mortality (p= 0.35). The risk of CV death, stoke, or MI was not dependent on the timing of the qualifying MI prior to randomization. Risk of CV death, stroke, or MI was significantly reduced for the vorapaxar group when compared to placebo from randomization to day 360 and from day 360 to end of follow-up. More GUSTO moderate to severe bleeding and TIMI clinically significant bleeding occurred in the vorapaxar group, however there was no statistical difference in intracranial hemorrhage or fatal bleeding. When looking at the combined net clinical outcomes (clinical outcomes plus GUSTO severe/moderate bleeding), vorapaxar plus standard therapy was beneficial compared to placebo plus standard therapy (12.5% vs. 13.4%, respectively; p=0.038).4
Patient specific parameters also played a role ...