Efficacy and Safety of Vorapaxar in Patients With Prior Ischemic Stroke

Abstract

Protease-activated receptor-1 is the predominant receptor for thrombin on human platelets. Vorapaxar is a potent antagonist of protease-activated receptor-1 that inhibits thrombinmediated platelet activation. 4 Phase 2 trials of vorapaxar suggested efficacy with acceptable safety in patients with acute ischemic stroke. 4,5 We previously reported the efficacy and safety of vorapaxar among a broad group of patients with prior atherothrombosis who enrolled in the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Background and Purpose-Vorapaxar is an antiplatelet agent that antagonizes thrombin-mediated activation of the proteaseactivated receptor-1 on platelets. We tested the efficacy and safety of vorapaxar in a prespecified analysis in the stroke subcohort from a multinational, randomized, placebo-controlled trial. Methods-We randomly assigned patients with prior atherothrombosis (myocardial infarction, peripheral artery disease, or ischemic stroke) to receive vorapaxar (2.5 mg daily) or placebo added to standard antiplatelet therapy. Patients who qualified with stroke (N=4883) had a history of ischemic stroke in the prior 2 weeks to 12 months. The primary end point was the composite of cardiovascular death, myocardial infarction, or any stroke. Results-The qualifying stroke was classified as large vessel in 35%, small vessel in 47%, and other/unknown in 18%. In the stroke cohort, cardiovascular death, myocardial infarction, or stroke through 3 years was not reduced with vorapaxar versus placebo (13.0% vs 11.7%; hazard ratio, 1.03; 95% confidence interval, 0.85-1.25), including recurrent ischemic stroke (hazard ratio, 0.99; 95% confidence interval, 0.78-1.25). There were no significant differences in the effect of vorapaxar based on the type or timing of the qualifying stroke. Intracranial hemorrhage at 3 years was increased with vorapaxar (2.5% vs 1.0%; hazard ratio, 2.52; 95% confidence interval, 1.46-4.36). Conclusions-In

Parmodulins inhibit thrombus formation without inducing endothelial injury caused by vorapaxar

“…These concentrations are in the range of predicted plasma concentrations achieved with the dosing regimens used in the TRACER and TRA-2P studies. 17,18 Similarly, atopaxar, SCH79797, and BMS-200261 all induced apoptosis in endothelial cells (supplemental Figure 5). In contrast, no significant increase in apoptosis was observed when endothelial cells were incubated with parmodulin 2 at concentrations as high as 30 mM (Figure 6A-B) or hirudin (not shown).…”

“…[17][18][19][20] We therefore studied parmodulin 2 in assays of both thrombosis and hemostasis. ] i flux was evaluated in COS-7 transfected with (B) wild-type (WT) PAR1, (C) WT PAR4, (D) the DH8 PAR1 mutant, (E) a chimeric PAR1 in which il2 was replaced with il2 of PAR4, and (F) a chimeric PAR1 in which il3 was replaced with il3 of PAR4.…”

“…Vorapaxar has been evaluated in 2 large, randomized phase 3 clinical studies in the settings of acute coronary syndromes (TRACER) 17 and in secondary prevention of atherothrombotic events (TRA-2P). 18 Its use was associated with decreased cardiovascular death or ischemic events in the secondary prevention trial. 18 However, vorapaxar recipients had a significantly increased incidence of major bleeding, including intracranial hemorrhage, in both studies.…”

“…18 Its use was associated with decreased cardiovascular death or ischemic events in the secondary prevention trial. 18 However, vorapaxar recipients had a significantly increased incidence of major bleeding, including intracranial hemorrhage, in both studies. Meta-analyses of clinical trials evaluating vorapaxar and a second orthosteric PAR1 antagonist, atopaxar, confirm an association of these inhibitors with bleeding risk.…”

Bleeding in continuous flow left ventricular assist device recipients: an acquired vasculopathy?

“…For example, use of voraxapar, a PAR-1 blocker, in lieu of aspirin as an antiplatelet agent; though the observed increased risk of intracranial hemorrhage noted in patients with a history of stroke and treated with voraxapar is concerning (29). A more intriguing option is the use of a direct thrombin inhibitor such as dabigatran instead of warfarin.…”