Abstract
Atherothrombotic disease is a leading public health problem. Although current antiplatelet agents, such as aspirin and adenosine diphosphate (ADP)-receptor antagonists, reduce the morbidity and mortality associated with atherothrombotic disease, the residual risk for ischemic events remains substantial. The high residual risk despite dual antiplatelet therapy can be attributed to the fact that platelets possess multiple pathways of activation that are not all inhibited by aspirin and ADP-receptor antagonists. Among these, binding of thrombin to the proteinase-activated receptor 1 (PAR1) is the most potent platelet activation pathway. In addition, the PAR1 pathway does not appear to be essential for initiating hemostasis. Inhibition of the PAR1 receptor thus offers a possible new therapeutic approach with a potentially improved benefit-to-risk profile for treatment of patients with atherothrombotic disease. Preclinical and clinical studies have confirmed that SCH 530348, a potent, orally active thrombin-receptor antagonist selective for PAR1, does not increase bleeding liability when added to dual antiplatelet therapy. Currently, two large ongoing phase 3 clinical trials are evaluating the efficacy and safety of SCH 530348 in combination with the standard of care in patients with acute coronary syndromes as well as for secondary prevention in patients with previous history of atherothrombotic disease.
