Abstract T P341: Impact Of Cytochrome P450 2C19 Polymorphism On High On-treatment Platelet Reactivity In Stroke Patients Treated With Clopidogrel
BACKGROUND: Clopidogrel is one of the most commonly used anti-platelet drugs. Recent reports suggested the association of allelic variants of the genes modulating metabolic activation (CYP2C19 and paraoxonase-1) and bioavailability (ABCB1) of clopidogrel with high on-treatment platelet reactivity (HTPR), possibly resulting in the recurrence of thrombotic events. However, these studies mostly examined patients with coronary heart disease and the impact of these polymorphisms in stroke patients is largely unknown.
METHODS: We conducted a multicenter, prospective cohort study of 518 Japanese patients from 14 hospitals who were administrated clopidogrel. Residual platelet reactivity was determined by a change in light transmission induced by platelet aggregation in platelet-rich plasma after adding ADP. The vasodilator-stimulated phosphoprotein (VASP) index was also measured using flow cytometry. We investigated the association of polymorphisms of aforementioned enzymes with HTPR.
RESULTS: In terms of CYP2C19 loss-of-function polymorphisms (*2 and *3), the prevalence of intermediate (IM: *1*2 or *1*3) or poor (PM: *2*2, *2*3, or *3*3) metabolizer was much higher (IM: 47% or PM: 15%) in Japanese than in Caucasian populations. Residual platelet reactivity was significantly higher in PM and IM groups than that in the wild-type extensive metabolizer (EM: *1*1) group assessed by 5 μM ADP-induced platelet aggregation (PM: 69.4% ± 17.1%, IM: 59.7% ± 16.2%, EM: 51.5% ± 17.5%, p < 0.0001) and VASP index (PM: 66.6% ± 14.1%, IM: 52.4% ± 16.0%, EM: 42.9% ± 15.0%, p < 0.0001). Furthermore, HTPR determined by both assays was associated with the ABCB1 polymorphism (rs1045642) but not with the paraoxonase-1 Q192R mutation.
CONCLUSIONS: Our results indicate that both CYP2C19 and ABCB1 polymorphisms significantly contribute to HTPR in stroke patients treated with clopidogrel. At present, we are monitoring these patients for a two-year period to determine whether these genetic variants and HTPR affect the recurrence of thrombotic events.
Author Disclosures: T. Tanaka: None. S. Miyata: Honoraria; Modest; Daiich-Sankyo. H. Yamamoto: None. T. Miyata: Research Grant; Significant; Taisho Pharmaceutical Co., Ltd.. Honoraria; Modest; Alexion, Sysmex, Bayer, Daiichi-Sankyo, Mitsubishi Chemical Medience. K. Nagatsuka: Honoraria; Modest; Sanofi.
- © 2014 by American Heart Association, Inc.