Vorapaxar for secondary stroke prevention: perspectives and obstacles

Abstract

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.

Keywords:

• vorapaxar
• stroke
• prevention
• cerebrvascular disease
• efficacy
• bleeding
• clinical trials

Key issues

• Secondary stroke prevention represents a growing but still unmet and unsolved urgent need.

• Vorapaxar, is a first-in-class antiplatelet PAR-receptor antagonist currently approved for post-myocardial infarction and peripheral artery disease indications.

• There is some intriguing evidence that vorapaxar may benefit patients post stroke, although the antiplatelet strategies should be more delicate.

• Monotherapy with vorapaxar should be tested against current options in a randomized outcome-driven stroke prevention trial.

Financial & competing interests disclosure

VL Serebruany is listed as an inventor for the issued US patent “Treating vascular events with statins by inhibiting PAR-1 and PAR-4” (7,842,716) assigned to HeartDrug™ Research; and “Method for treatment of platelet activity with E5555” (USN 61/080,791); assigned to Eisai and HeartDrug™. He received compensation for the issued U.S. Patent 11/996,380 “Use of PAR-1/PAR-4 inhibitors for treating and preventing vascular diseases” on prasugrel assigned to Lilly. Part of this work was supported by the “Brain Pool” program funded by the Korean Ministry of Science and Technology to VL Serebruany.MH Kim, SD Fortmann and DF Hanley have nothing to disclose. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.