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 28 h after administration. Polymorphisms of platelet receptors, glycoprotein (GP) Ia (807C/T), GPVI (13254C/T), GPIIIa (PlA1/PlA2), PAR-1 (IVSn-14A/T), P2Y12 (32C/T), P2Y12 (H1/H2) haplotype, gene variations of cyclooxygenase-1, Leiden, and factor II 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 polymorphism-negative patients. Inhibition of platelet reactivity, after 600 mg of clopidogrel, was significantly less in carriers of PlA2 (P=0.009) for mean decrease in platelet reactivity index. The proportion of clopidogrel nonresponders (platelet reactivity index >50%) was apparently higher in PlA2 carriers in comparison with PlA1/PlA1 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 PlA2 polymorphism.
Motovska
Zuzana
Z
Third Medical Faculty of Charles University, University Hospital Kralovske Vinohrady, Prague, Czech Republic. zuzana.motovska@iex.cz
Widimsky
Petr
P
Kvasnicka
Jan
J
Petr
Robert
R
Bilkova
Dana
D
Hajkova
Jaroslava
J
Marinov
Iuri
I
Simek
Stanislav
S
Kala
Petr
P
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000368:Aged; D016824:Antigens, Human Platelet / Q000235:genetics; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation / Q000187:drug effects* / Q000235:genetics; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D020641:Polymorphism, Single Nucleotide; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013997:Time Factors
D016824:Antigens, Human Platelet; C061248:ITGB3 protein, human; D039661:Integrin beta3; D010975:Platelet Aggregation Inhibitors; C083451:human platelet antigen 1b; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D013988:Ticlopidine