title: Matching the evaluation of the clinical efficacy of clopidogrel to platelet function tests relevant to the biological properties of the drug.
abstract: OBJECTIVE
  This study aimed to explore platelet function tests relevant to the biological effects of clopidogrel that could help the clinical monitoring of drug efficacy.
  
  
  BACKGROUND
  Clopidogrel selectively inhibits the P2Y12 receptor, the major role of which is stabilization of aggregation, whereas initiation of aggregation depends on activity of both P2Y1 and P2Y12 receptors.
  
  
  METHODS
  Tests used were peak aggregation (Agg(max)) and late aggregation (Agg(6min)), and disaggregation, relating to P2Y1 and P2Y12 activity, 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).
  
  
  RESULTS
  Clopidogrel similarly inhibited adenosine 5'-diphosphate (ADP)-induced Agg(max) with either anticoagulant, but significantly more Agg(6min) (75% vs. 31%), P-selectin (72% vs. 53%), and PAC-1 (62% vs. 24%) in hirudin/PPACK. In the control study, it inhibited Agg(max) by 22%, and Agg(6min), 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 Agg(max) in citrate was diagnosed in 35% of patients; in half this rate by Agg(6min), P-selectin, and PAC-1; and in 6% to 12% with the latter tests performed in hirudin/PPACK.
  
  
  CONCLUSIONS
  The 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 P2Y12 receptor.
authors.affiliation: Department of Medicine, Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada.
authors.forename: Benoît
authors.initials: B
authors.lastname: Labarthe
authors.forename: Pierre
authors.initials: P
authors.lastname: Théroux
authors.forename: Michaël
authors.initials: M
authors.lastname: Angioï
authors.forename: Marta
authors.initials: M
authors.lastname: Ghitescu
mesh_terms: D000368:Aged; D000787:Angina Pectoris / Q000188:drug therapy*; D000925:Anticoagulants / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects*; D016022:Case-Control Studies; D000077144:Clopidogrel; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010979:Platelet Function Tests; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin