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STATE-OF-THE-ART PAPER

Resistance to clopidogrel: A review of the evidence

Thuy Anh Nguyen, MSc, Pharm^_*, Jean G. Diodati, MD^,,|| and Chantal Pharand, PharmD^_*,,,_*

^_* Pharmacy Department, Hôpital du Sacré-Coeur de Montréal, Montreal, Canada
Service of Cardiology, Hôpital du Sacré-Coeur de Montréal, Montreal, Canada
Research Centre, Hôpital du Sacré-Coeur de Montréal, Montreal, Canada
Faculty of Pharmacy, Université de Montréal, Montreal, Canada.
^|| Faculty of Medicine, Université de Montréal, Montreal, Canada.

Manuscript received December 8, 2004; revised manuscript received January 19, 2005, accepted January 25, 2005.

^_* Reprint requests and correspondence: Dr. Chantal Pharand, Research Centre, Hôpital du Sacré-Coeur de Montréal, 5400, Gouin Boulevard West, Montreal, Quebec, Canada H4J 1C5. (Email: chantal.pharand{at}umontreal.ca).

Current available data show that about 4% to 30% of patients treated with conventional doses of clopidogrel do not display adequate antiplatelet response. Clopidogrel resistance is a widely used term that remains to be clearly defined. So far, it has been used to reflect failure of clopidogrel to achieve its antiaggregatory effect. The interpatient variability in clopidogrel response is multifactorial. It can be due to extrinsic or intrinsic mechanisms. Among extrinsic mechanisms are the possibility of clopidogrel underdosing in patients undergoing stenting or with acute coronary syndrome, and drug-drug interactions involving CYP3A4. Intrinsic mechanisms include genetic polymorphisms of the P2Y₁₂ receptor and of the CYP3As, accrued release of adenosine diphosphate, or up-regulation of other platelet activation pathways. Presently, there is no definite demonstration of an association between low responsiveness to clopidogrel and thrombotic events. The optimal level of clopidogrel-induced platelet inhibition, which will correlate quantitatively with clopidogrel’s ability to prevent atherothrombotic events is still lacking. Furthermore, because there is no single and validated platelet function assay to measure clopidogrel’s antiplatelet effect, it is not justified to routinely look for clopidogrel resistance in the clinical setting. This review discusses currently available evidence surrounding the variability in the antiplatelet response to clopidogrel.

Abbreviations and Acronyms   ACS = acute coronary syndromes   ADP = adenosine diphosphate   cAMP = cyclic adenosine monophosphate   CYP450 = cytochrome P450   GPIIb/IIIa = glycoprotein IIb/IIIa   PCI = percutaneous coronary intervention   PGE1 = prostaglandin E1   SAT = subacute stent thrombosis   VASP = vasodilator-stimulated phosphoprotein

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