High loading dose of clopidogrel is unable to satisfactorily inhibit platelet reactivity in patients with glycoprotein IIIA gene polymorphism: a genetic substudy of PRAGUE-8 trial

The study aimed to assess the impact of nine polymorphisms of genes encoding platelet receptors, enzymes, and hemostatic factors on clopidogrel efficacy to inhibit platelet reactivity in patients with stable coronary artery disease undergoing elective coronary angiography either with or without ad hoc percutaneous coronary intervention. The study was performed as a genetic substudy of the PRAGUE-8 trial. Ninety-five patients pretreated with 600 mg clopidogrel at least 6 h prior to coronary angiography were tested. Baseline platelet reactivity to ADP was assessed before the drug was administered. Clopidogrel efficacy was tested again at 12 and 28h after administration. Polymorphisms of platelet receptors, glycoprotein (GP) la (807C/T), GPVI (13254C/T), GPIIIa (PIA1/PIA2), PAR-1 (IVSn-14A/T), P2Y(12) (32C/T), P2Y(12) (H(1)/H(2)) haplotype, gene variations of cyclooxygenase-1, Leiden, and factor 11 mutations were studied. Flow cytometric tests of vasodilator-stimulated phosphoprotein phosphorylation states were used as a measure of drug efficacy. None of the gene polymorphisms influenced baseline ADP-induced platelet reactivity significantly. Twenty-eight hours after drug administration, differences in suppression of ADP-induced platelet reactivity were observed between polymorphism-positive and polymorph ism-negative patients. Inhibition of platelet reactivity, after 600 mg of clopidogrel, was significantly less in carriers of PIA2 (P = 0.009) for mean decrease in platelet reactivity index. The proportion of clopidogrel nonresponders (platelet reactivity index >50%) was apparently higher in PIA2 carriers in comparison with PIA1/PIA1 patients (54 vs. 24%, P = 0.082). A 600 mg loading dose of clopidogrel failed to acceptably inhibit platelet reactivity in patients who were positive for the PIA2 polymorphism. Blood Coagul Fibrinolysis 20:257-262 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.