Platelet protease-activated receptor antagonism in cardiovascular medicine.
Ischemic heart disease remains the number one cause of death in the world despite advances in invasive and pharmacologic therapies. An ongoing area of research is the central role of platelets in atherothrombosis. Many therapeutic strategies have been developed over the last few decades affecting different platelet receptors to alter platelet-mediated thrombosis including targeting the receptors for thromboxane A(2), adenosine diphosphate, and fibrinogen. However, despite the use of pharmacologic agents directed at these pathways, residual morbidity and mortality still exist. Therefore, identifying agents that more favorably balance a reduction in ischemic events while minimizing bleeding events is an ongoing mission. Thrombin is known to be the most potent stimulant of platelet-mediated thrombosis whose action on the platelet is through a family of receptors known as the protease-activated receptors (PARs). Activation through the PAR-1 receptor, in particular, results in an early and intense response by the platelet to thrombin, and it is the primary thrombin receptor on platelets, thus making it a potentially desirable target for therapy. Most recently, two PAR-1 antagonists, atopaxar and vorapaxar, have been tested in clinical trials. Generally, the results show a reduction in ischemic event rates, but an increase in bleeding event rates. This article will summarize the current state of the literature and consider the role these drugs might play in the future for the prevention of ischemic heart disease events.
Gill Heart Institute, Division of Cardiovascular Medicine, University of Kentucky, Lexington, 40536, USA.
Matthew E
ME
Wiisanen
David J
DJ
Moliterno
D054058:Acute Coronary Syndrome / Q000188:drug therapy*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D003324:Coronary Artery Disease / Q000188:drug therapy*; D006470:Hemorrhage / Q000209:etiology; D006801:Humans; D007097:Imines / Q000627:therapeutic use*; D007783:Lactones / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000188:drug therapy*; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D013917:Thrombin / Q000378:metabolism; D016896:Treatment Outcome
C540445:E 5555; D007097:Imines; D007783:Lactones; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D013917:Thrombin; C530299:vorapaxar