title: Vorapaxar: The Current Role and Future Directions of a Novel Protease-Activated Receptor Antagonist for Risk Reduction in Atherosclerotic Disease.
abstract: BACKGROUND
  Despite the current standard of care, patients with cardiovascular disease remain at a high risk for recurrent events. Inhibition of thrombin-mediated platelet activation through protease-activated receptor-1 antagonism may provide reductions in atherosclerotic disease beyond those achievable with the current standard of care.
  
  
  OBJECTIVE
  Our primary objective is to evaluate the clinical literature regarding the role of vorapaxar (Zontivity™) in the reduction of cardiovascular events in patients with a history of myocardial infarction and peripheral artery disease. In particular, we focus on the potential future directions for protease-activating receptor antagonists in the treatment of a broad range of atherosclerotic diseases.
  
  
  METHODS
  A literature search of PubMed and EBSCO was conducted to identify randomized clinical trials from August 2005 to June 2016 using the search terms: 'vorapaxar', 'SCH 530348', 'protease-activated receptor-1 antagonist', and 'Zontivity™'. Bibliographies were searched and additional resources were obtained.
  
  
  RESULTS
  Vorapaxar is a first-in-class, protease-activated receptor-1 antagonist. The Thrombin Receptor Antagonist for Clinical Event Reduction (TRACER) trial did not demonstrate a significant reduction in a broad primary composite endpoint. However, the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P-TIMI 50) trial examined a more traditional composite endpoint and found a significant benefit with vorapaxar. Vorapaxar significantly increased bleeding compared with standard care. Ongoing trials will help define the role of vorapaxar in patients with peripheral arterial disease, patients with diabetes mellitus, and other important subgroups. The use of multivariate modeling may enable the identification of subgroups with maximal benefit and minimal harm from vorapaxar.
  
  
  CONCLUSIONS
  Vorapaxar provides clinicians with a novel mechanism of action to further reduce the burden of ischemic heart disease. Identification of patients with a high ischemic risk and low bleeding risk would enable clinicians to maximize the utility of this unique agent.
authors.affiliation: Pharmaceutical Sciences Department, School of Pharmacy, Cedarville University, 251 North Main Street, Cedarville, OH, 45314, USA. rgryka@cedarville.edu.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Gryka
authors.affiliation: Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Cedarville, OH, USA.
authors.forename: Leo F
authors.initials: LF
authors.lastname: Buckley
authors.affiliation: Center for Pharmacy Care, Duquesne University, Pittsburgh, PA, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Anderson
mesh_terms: D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000494:pharmacology* / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use*; D044462:Receptors, Proteinase-Activated / Q000037:antagonists & inhibitors*; D040242:Risk Reduction Behavior
chemical_list: D007783:Lactones; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D044462:Receptors, Proteinase-Activated; C530299:vorapaxar