Introduction: Active metabolite of clopidogrel blocks P2Y12 receptor and consequently reduces cardiovascular events (CVEs) in stroke patients. Since CYP2C19 is the major enzyme involved in the generation of active metabolite, several large-scale studies of the patients who mostly underwent percutaneous coronary intervention have indicated that the genotypes of CYP2C19 are associated with recurrent CVEs. However, reliable prospective data regarding this association in stroke patients are sparse.
Methods: A multicenter, prospective cohort study of stable stroke patients receiving long-term clopidogrel therapy (for at least 28 days before enrollment) for the secondary prevention of CVEs was conducted at 14 hospitals in Japan. Between September 2010 and March 2012, 511 patients were enrolled and underwent CYP2C19 genotyping to identify loss-of-function polymorphisms (*2 and *3). On-treatment platelet reactivity was assessed by ADP-induced platelet aggregation and vasodilator-stimulated phosphoprotein (VASP) index. We followed all patients for 2 years to evaluate the association of CYP2C19 polymorphisms with the composite outcome including cardiac death, stroke, myocardial infarction and cerebral/carotid vascularization.
Results: Median follow-up period was 728 days. Of 511 patients, 243 (48%) and 76 (15%) patients were classified as intermediate (IM:*1/*2 or *1/*3) and poor (PM:*2/*2, *2/*3, or *3/*3) metabolizers, respectively. The prevalence of IM/PM was substantially higher than that of studies on Caucasian populations. On-treatment platelet reactivity (mean±SD) assessed by ADP-induced platelet aggregation (52±18% in extensive metabolizer [EM:*1/*1], 60±16% in IM, and 69±71% in PM) or VASP index (43±15% in EM, 52±16% in IM, and 67±14% in PM) was significantly different among the groups (p<0.0001). However, there was no significant difference in the incidence of the composite outcome among the groups (EM vs IM; hazard ratio [HR] 0.99 [95% CI 0.48—2.04], p=0.97, vs PM; HR 0.80 [0.26—2.51], p=0.70).
Conclusions: Despite the significant association of CYP2C19 polymorphisms with on-treatment platelet reactivity, these parameters did not predict the recurrence of CVEs in stroke patients with long-term clopidogrel therapy.