Prasugrel for arterial coronary thrombosis

Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndrome undergoing percutaneous coronary intervention. Clopidogrel, in combination with aspirin, is associated with improvement in long-term vascular clinical outcomes in these patients and is currently the antiplatelet standard of care. However, a significant number of patients still experience secondary ischemic thrombotic events due to potential insufficient platelet inhibition or noncompliance. Therefore, the development of better and safer antiplatelet agents is of the utmost priority. Indeed, oral antiplatelet agents, such as aspirin in the ISIS-2 study and clopidogrel in the COMMIT mega trial, in moderate doses are among the very few classes of drugs that reduce absolute mortality in patients after acute vascular thrombotic events. Prasugrel (CS-747; LY-640315), an experimental third-generation oral thienopyridine, is a specific, irreversible antagonist of the platelet adenosine diphosphate P2Y₁₂ receptor. Preclinical and early phase clinical studies have shown that prasugrel has greater antiplatelet potency, lower variability in platelet response and faster onset of inhibition than dopidogrel. However, the doses of the drug chosen for further prasugrel developments are much higher (about 2.5-2.7 times higher) than those of conventional dopidogrel regimen(s). The recent TRITON trial assessed head-to-head prasugrel versus dopidogrel, both in addition to aspirin, and led to numerous controversies with regard to the fairness of the trial design, interpretation of its results, and the suitability of the high maintenance pra-sugrel dose for chronic preventive human use. We critically review various aspects of prasugrel development, focusing on the discrepancies between the official interpretation of the results and actual findings. We conclude that the benefits of prasugrel are exaggerated and that the risks are underestimated. Very careful maintenance dose selection and a flawless long-term safety profile for the new agents will become the keys to the success of future oral antiplatelet drug development.