Vorapaxar for secondary stroke prevention: perspectives and obstacles

Vorapaxar, a novel antiplatelet thrombin protease-activated receptor 1 (PAR-1) inhibitor, has been evaluated in the successful TRA2P trial and failed TRACER trial. The drug is currently approved for post myocardial infarction and peripheral artery disease indications on top of clopidogrel and/or aspirin. The stroke data after vorapaxar are mixed, dominated with heavy excess of intracranial bleeding risks and slightly worsened second stroke rates, but show less primary ischemic strokes. Fortunately, these conflicting data do not belong purely to vorapaxar per se but rather, reflect unreasonably aggressive strategies, including predominantly triple antiplatelet therapy, utilized in both Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients with Arteriosclerosis (TRA2P) and especially in Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes (TRACER). The FDA-confirmed evidence strongly suggests that unique pharmacokinetics and a very mild "comfort zone" antiplatelet profile makes vorapaxar a good candidate for improved secondary stroke prevention. The outcome-driven, randomized trial should test head-to-head monotherapy with vorapaxar (Zontivity®) versus clopidogrel (Plavix®) and versus dipyridamole with very low dose aspirin (Aggrenox®). The advantages and potential pitfalls of such a trial are discussed in this article.