Limitations of current therapies to prevent thrombosis: a need for novel strategies.

Bleeding limits the benefit of current anti-platelet drugs for preventing heart attacks and stroke. Aspirin and clopidogrel, the two most widely prescribed anti-platelet drugs, are metabolized to active compounds that covalently and irreversibly modify their respective therapeutic targets (COX1 and P2Y12). The enduring effects of aspirin and clopidogrel are of concern in patients receiving anti-platelet therapy who require emergency surgery as this places them at greater risk of haemorrhage. As clopidogrel must be activated by cytochrome P450 metabolism, recent pharmacogenomic studies have revealed that patients lacking a functional allele of CYP2C19 derive no therapeutic benefit from the drug. Prasugrel, a second generation thienopyridine, whose bioconversion is not affected by CYP genetic polymorphism, demonstrates improved clinical benefit, but with increased bleeding risk. Anti-platelet drugs currently in cardiovascular trials that may have reduced bleeding risk include reversible P2Y12 antagonists (cangrelor, ticagrelor, and elinogrel), a PAR1 antagonist (SCH 530 348) and an EP3 antagonist (DG-041). The platelet EP3 receptor for prostaglandin E(2) is an attractive therapeutic target as EP3 antagonists may selectively avert thrombosis over atherosclerotic plaques without affecting bleeding risk.