title: Vorapaxar: a novel protease-activated receptor-1 inhibitor.
abstract: BACKGROUND
  Platelet activation and reactivity are pivotal for both acute and chronic atherothrombotic event occurrences.
  
  
  METHODS
  Only 20% relative risk (∼ 2% absolute risk) reduction associated with newer P2Y(12) receptor blocker therapy such as prasugrel and ticagrelor compared with clopidogrel indicates that dual antiplatelet therapy may be associated with a ceiling effect in attenuating platelet-mediated ischemic event occurrence and that residual ischemic event occurrences are mediated by other pathways that are unblocked by current antiplatelet therapy. Therefore, inhibition of the thrombin-protease-activated receptor (PAR)-1 interaction may provide additional benefits in attenuating ischemic event occurrence in selected patients. There are two major PAR-1 blockers are under investigations - vorapaxar and atopaxar. In preclinical and Phase I - II studies, inhibition of thrombin-mediated platelet activation by a PAR-1 inhibitor, in general, has added to the antithrombotic efficacy of aspirin and clopidogrel without increasing bleeding. However, intracranial hemorrhage in patients with a history of stroke associated with vorapaxar and hepatic toxicity associated with atopaxar are important concerns.
  
  
  CONCLUSIONS
  At this time, the specific role of PAR-1 inhibitor in the settings of percutaneous coronary intervention and acute coronary syndrome, both during the acute setting and as a long-term therapeutic agent, is not clear. Although the PAR-1 inhibitors are associated with less bleeding, its effectiveness as an antithrombotic agent and also side effects are major concerns. Future large-scale trials with goals addressing these concerns are needed to define the specific role of PAR-1 receptor inhibitor.
authors.affiliation: Sinai Center for Thrombosis Research, 2401 W. Belvedere Ave, Baltimore, MD 21215, USA. PGURBEL@LIFEBRIDGEHEALTH.ORG
authors.forename: Paul A
authors.initials: PA
authors.lastname: Gurbel
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Jeong
authors.forename: Udaya S
authors.initials: US
authors.lastname: Tantry
mesh_terms: D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D007783:Lactones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D058990:Molecular Targeted Therapy; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D007783:Lactones; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; C530299:vorapaxar