Protease-activated receptor-1 antagonists in long-term antiplatelet therapy. Current state of evidence and future perspectives

• Vorapaxar is a potent, selective and competitive PAR-1 antagonist.
• Vorapaxar on top of standard antiplatelet therapy optimizes clinical outcomes in MI rates in patients with ACS or a history of MI.
• Vorapaxar on top of standard antiplatelet therapy reduces the risk of stent thrombosis in stable atherothrombotic patients.
• Vorapaxar on top of standard antiplatelet therapy reduces hospitalization need due to acute limb ischemia in PAD patients.
• PAR-1 blockade on top of standard antiplatelet therapy increases the risk of bleeding.

Atherothrombosis and its clinical manifestations are among the leading causes of death in the developed world. The current standard-of-care antiplatelet therapy for the treatment of such events comprises aspirin and a thienopyridine or ticagrelor. However, recurrent ischemic events due to residual cardiovascular risk are a common phenomenon in these patients. It is believed that this residual risk is caused, at least in part, by thrombin, which signals through protease-activated receptors (PARs) and especially PAR-1. Thus, PAR-1 antagonism could represent an effective approach in the treatment of atherothrombotic disease. In this context, two potent and selective agents have been developed, vorapaxar and atopaxar. However, only vorapaxar has completed phase 3 clinical trials. In the present review, the main pharmacodynamic and pharmacokinetic properties of the PAR-1 antagonists are briefly described and the latest clinical data on vorapaxar are presented.