The goals of platelet inhibition in acute coronary syndromes

Satellite Session, The goals of platelet inhibition in acute coronary, 219003.

Austria, Vienna, 3 September 2007:

Platelet activation and aggregation play important roles in the pathogenesis of cardiac ischemic events after either spontaneous plaque disruption in acute coronary syndromes or mechanical disruption of coronary artery plaques caused by percutaneous coronary intervention (PCI), which could be considered an artificially induced acute coronary syndrome.

Standard therapy for the prevention of thrombotic events after acute coronary syndromes and coronary stenting involves dual antiplatelet therapy with aspirin plus a thienopyridine, already established in European and American guidelines years ago. Thienopyridines, like clopidogrel and prasugrel, block platelet activation and aggregation by inhibiting the P2Y12 ADP receptor. Most clinical trials supporting the use of thienopyridines plus aspirin in PCI compared with aspirin alone were originally conducted with ticlopidine. However, clopidogrel has largely replaced ticlopidine for use in PCI because of better tolerability and a lower risk of hematologic abnormalities compared with ticlopidine.

Despite the widespread use of clopidogrel in patients undergoing PCI with currently available thienopyridines, several important issues remain. Data from the Clopidogrel to Reduce Events During Observation (CREDO) trial suggest that most of the acute effect seen in reducing periprocedural events with clopidogrel was limited to patients who received the drug at least 6 hours, and perhaps as many as 15 hours, before the procedure.

As irreversible inhibitors of platelet function, the effects of thienopyridines are long-lasting, and therefore seem to carry a more or less inherent risk of bleeding complications, also resulting in a reluctance in current clinical practice to give these agents before determining whether a patient is likely to need coronary bypass surgery or using it over very long periods. This balance in efficacy/side-effects may be especially important for patients that receive a drug-eluting stent, which may require prolonged powerful antiplateletherapy to avoid the recently reported very late (>1 year after drug eluting stent implantation) stent thrombosis, a serious an possibly life threatening conditition.

Finally, a significant variability in the response to clopidogrel among healthy subjects and patients undergoing PCI or suffering from ACS has been observed, with some individuals having minimal inhibition of ADP-induced platelet aggregation.This concept of clopidogrel resistance led to the concern that some patients may not be adequately protected from the intense platelet activation and aggregation that occur after ACS with or without PCI and are therefore at increased risk for thrombotic events. Because of all of these issues, an improved antiplatelet regimen for the treatment of ACS and to support PCI still seems desirable.

Promising results with Prasugrel (CS-747, LY640315) a novel thienopyridine antiplatelet agent that has been shown in preclinical studies and in the JUMBO TIMI 26 trial to be possibly more potent and to have a more rapid onset of action than clopidogrel.

Conclusion:

The currently most used thienopyridine antiplatelet agent clopidogrel is an important component of the adjunctive therapy in ACS and PCI with (drug eluting) stenting. However since on one hand not all thrombotic complications are avoided and on the other hand still bleeding complications do occur, there seems to be room for improvement with new and hopefully better (thienopyridine) antiplatelet agents, especially since patients with drug eluting stents implanted may require prolonged treatment with this class of drugs.