Are we making efficient use of clopidogrel?

This editorial refers to “Limited early antiplatelet effect of 300 mg clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions”1 by Lepäntalo et al. on page 476 Blood platelets play a major role in the occurrence of thrombotic complications after percutaneous coronary interventions (PCI). Introduction of the thienopyridine drug ticlopidine as an adjunctive antiplatelet therapy has considerably improved the outcome of patients who undergo PCI.1 Thienopyridines act via blockade of one (P2Y12) of the three adenosine 5 \(^{{^}}\) -diphosphate (ADP) receptors, reducing ADP-induced platelet activation and aggregation.2 Concerns about the side effects of ticlopidine, especially severe neutropenia and thrombotic thrombocytopenic purpura, were a major reason for the rapid replacement of this drug with clopidogrel. Another important limitation of ticlopidine is its delayed onset of action, with maximum inhibition of ADP-induced platelet aggregation achieved only several days after administration. Rapid inhibition of platelet aggregation is crucial for the prevention of post-interventional ischaemic complications, as demonstrated by the use of glycoprotein IIb/IIIa inhibitors during coronary artery stenting. Clopidogrel, a newer thienopyridine derivative, has advantages over ticlopidine such as its better safety profile and quicker onset of action. Clopidogrel is not active in vitro and its hepatic biotransformation by cytochrome P450 (CYP) 3A43 produces as yet ill-defined active metabolite(s) with antiaggregatory effects.4 Depending on the dose used, the maximal effect of clopidogrel is achieved within a few hours (⁠ \(>\) 300 mg)5 to several days (75 mg).4 The inhibition of aggregation lasts 8–10 days, which corresponds to platelet life span. Apart from the dose-dependence of the onset of the full action of clopidogrel, its efficacy is affected by a relevant interindividual variability in platelet response.6,7 Therefore, investigations on optimal dosing and timing of the administration of clopidogrel and factors underlying interindividual variability, as well as ways to overcome it, are of paramount importance in the current era of an explosive increase of the number of PCIs performed, especially after the tremendous success demonstrated with drug-eluting stents.