Matching the Evaluation of the Clinical Efficacy of Clopidogrel to Platelet Function Tests Relevant to the Biological Properties of the Drug

Abstract

ObjectivesThis study aimed to explore platelet function tests relevant to the biological effects of clopidogrel that could help the clinical monitoring of drug efficacy.BackgroundClopidogrel selectively inhibits the P2Y12receptor, the major role of which is stabilization of aggregation, whereas initiation of aggregation depends on activity of both P2Y1and P2Y12receptors.MethodsTests used were peak aggregation (Aggmax) and late aggregation (Agg6min), and disaggregation, relating to P2Y1and P2Y12activity, respectively; and monoclonal antibody binding activated glycoprotein (GP) IIb/IIIa receptors (PAC-1) and P-selectin, measuring activation and secretion. A first study compared hirudin/PPACK (r-hirudin and D-phenylalanyl-prolyl-arginine chloromethyl ketone) with citrate as blood anticoagulant (16 patients), and a second control study compared the effects of clopidogrel, aspirin, or both (20 normal controls).ResultsClopidogrel similarly inhibited adenosine 5′-diphosphate (ADP)-induced Aggmaxwith either anticoagulant, but significantly more Agg6min(75% vs. 31%), P-selectin (72% vs. 53%), and PAC-1 (62% vs. 24%) in hirudin/PPACK. In the control study, it inhibited Aggmaxby 22%, and Agg6min, P-selectin, and PAC-1, by 69%, 66%, and 55%, respectively (all p < 0.05). Disaggregation at six min reached 62% with clopidogrel, but was virtually absent with placebo and aspirin. Non-responsiveness as evaluated by inhibition of Aggmaxin citrate was diagnosed in 35% of patients; in half this rate by Agg6min, P-selectin, and PAC-1; and in 6% to 12% with the latter tests performed in hirudin/PPACK.ConclusionsThe evaluation of clopidogrel responsiveness by platelet function tests is largely influenced by the choice of blood preservative and functional tests. Measures of aggregation stabilization, and of consequent secretion and activation, identified most patients as responders, contrasting with measures of peak aggregation, by likely reflecting better the interactions clopidogrel and the P2Y12receptor