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PAR1 Inhibitors in ACS

Shinya Goto, MD, PhD

ACS is induced by a thrombus occluding a coronary arterial tree. Platelets and the coagulation cascade both play important roles in the development of symptomatic coronary arterial thrombosis. Although the prognosis of ACS has markedly improved (mostly because of the development of acute-phase reperfusion therapy with percutaneous coronary intervention and the use of strong antithrombotic and lipid-lowering drugs), there are still a substantial number of patients who suffer from thrombotic complications after ACS. Various receptors and activating signaling pathways in platelet cells are therapeutic targets in patients with ACS, and the current standard of care for these patients comprises aspirin (a specific inhibitor of platelet cyclooxygenase-1), and clopidogrel (a platelet P2Y12 adenosine diphosphate receptor antagonist). Of the platelet receptors, the thrombin receptor, namely protease-activated receptor-1 (PAR1), is considered to be an important potential target for future antiplatelet therapies to treat ACS. PAR1 may be a better target than the P2Y12 receptor with regard to preventing bleeding complications. Indeed, the excess bleeding complications that are induced by strong inhibition of the P2Y12 receptor are a problem with newly developed antiplatelet agents such as prasugrel. Although bleeding is also a problem with PAR1 inhibitors, the results of Phase II trials so far indicate that a better balance of thrombotic event rate reduction and the occurrence of bleeding complications can be achieved with PAR1 inhibition compared with P2Y12 receptor blockage. Further clarification of the efficacy and safety profiles of various PAR1 inhibitors in larger scale clinical trials is awaited. Acute Coronary Syndromes 2011;10(3):103–8.

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