Vorapaxar monotherapy for secondary stroke prevention: A call for randomized trial

Background and Purpose: Vorapaxar, a novel platelet thrombin protease-activated receptor 1 blocker, is currently approved for post-myocardial infarction and peripheral artery disease indications on top of clopidogrel or/and aspirin. We sought to summarize the conflicting stroke data after vorapaxar for justifying a secondary stroke prevention trial. Methods: Analyses of the stroke data after vorapaxar yielded from thrombin-receptor antagonist vorapaxar in acute coronary syndromes (TRACER) and TRA2P clinical trials, and affiliated Food and Drug Administration (FDA) reviews. Results: The stroke data are mixed, with catastrophic 2.5 excess of intracranial bleeding risks (HR = 2.52; 95% CI = 1.46–4.36, p <0.0001); trend to worsened second stroke rates (13.0% vs. 11.7%; HR = 1.03; 95% CI = 0.85–1.25, p = NS), but a hint towards less primary ischemic strokes in vorapaxar indicated population (HR = 0.57; 95% CI = 0.43 to 0.75; p <0.001). These conflicting data are not solely attributed to vorapaxar, but rather reflect unreasonably aggressive triple antiplatelet strategies utilized frequently in TRA2P and dominant in TRACER. Overall, the FDA-confirmed evidence advocates future vorapaxar secondary stroke prevention trial due to being first-in-class agent, unique pharmakynetics, and exhibiting very mild “comfort zone” antiplatelet profile. The three arm trial testing head-to-head monotherapy with vorapaxar (Zontivity®), versus clopidogrel (Plavix®), and versus extended-released dipyridamole with very low dose aspirin (Aggrenox®) is warranted. Conclusions: Vorapaxar may be superior to currently recommended antiplatelet strategies and should be tested as a monotherapy in a randomized outcome-driven secondary stroke prevention trial.