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CLINICAL RESEARCH: ANTIPLATELET THERAPY

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

Benoît Labarthe, PharmD^_*, Pierre Théroux, MD, FACC^_*,_*, Michaël Angioï, MD, PhD and Marta Ghitescu^_*

^_* Department of Medicine, Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada
Département de Cardiologie, Hôpitaux de Brabois, Centre Hospitalier Universitaire de Nancy, Nancy, France

Manuscript received November 15, 2004; revised manuscript received February 3, 2005, accepted February 8, 2005.

^_* Reprint requests and correspondence: Dr. Pierre Théroux, Montreal Heart Institute, 5000 Belanger E, Montreal, Quebec, Canada H1T 1C8 (Email: pierre.theroux{at}ICM-MHI.org).

OBJECTIVES: 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.

Abbreviations and Acronyms   ADP = adenosine 5'-diphosphate   Agg6min = late aggregation   Aggmax = peak aggregation   ASA = acetylsalicylic acid   GP = glycoprotein   hirudin/PPACK = r-hirudin and D-phenylalanyl-prolyl-arginine chloromethyl ketone   PAC-1 = monoclonal antibody binding activated glycoprotein IIb/IIIa receptors   TRAP = thrombin receptor agonist peptide

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