High on-clopidogrel platelet reactivity: Genotyping Can help to optimize antiplatelet treatment (original) (raw)

2011, Thrombosis Research

Clopidogrel is a thienopyridine prodrug that must be converted into an active metabolite to target the platelet ADP P2Y 12 receptor. The pharmacodynamic response to clopidogrel exhibits considerable interindividual variability, part of which is dependent on genetic factors. About 20% of patients have decreased biological responsiveness to clopidogrel with a higher risk of cardiovascular events [1]. Two genetic factors that contribute to limit the efficacy of clopidogrel have been identified in healthy volunteers. One is the gain-of-function polymorphism (H2 allele) of the P2Y 12 gene, the clopidogrel active metabolite target, which was associated with increased ADP-induced platelet aggregation ex vivo in healthy volunteers [2]. Furthermore, the H2 allele was found more frequent in arteritic patients enrolled in the PALLAS study compared to controls. This association remained significant in multivariate regression analysis (OR, 2.3; CI, 1.4 to 3.9; P = 0.002) after adjustment for diabetes, smoking, hypertension, hypercholesterolemia, and other selected platelet receptor gene polymorphisms [3]. Finally, homozygosity for the H2 allele was associated with a poor response to clopidogrel in a small subset of healthy volunteers [4] and in patients treated with aspirin and clopidogrel after percutaneous coronary intervention [5]. The other factor is a loss-of-function polymorphism of cytochrome P450 2 C19 (CYP2C19*2), involved in the conversion of clopidogrel into its pharmacologically active metabolite [6]. Carriers of at least one CYP2C19*2 allele have a 30% to 35% decrease in clopidogrel exposure [7] and have significantly increased rates of death, recurrent infarction, and other cardiac events such as stent thrombosis [7-9]. Here, we describe the clinical management of two patients with suspected genetic resistance to clopidogrel.