Background:

Clopidogrel, an antiplatelet prodrug, is widely used for prevention of the recurrent cardiovascular events. CYP2C19 is one of the crucial enzymes for the activation of clopidogrel. Recent studies, mostly done in cardiovascular patients, showed association of the CYP2C19 genotypes with recurrent cardiovascular events. However, prospective data on the impact of the genetic variants in stroke patients are limited.

Methods:

Five hundred and eighteen Japanese non-acute stroke patients treated with clopidogrel were registered at 14 institutions. Three CYP2C19 variants (CYP2C19*2, *3, *17) were genotyped and the patients were classified into three clopidogrel metabolizer groups inferred from the CYP2C19 genotypes: extensive (EM: *1/*1), intermediate (IM: *1/*2 or *1/*3), and poor (PM: *2/*2, *2/*3, or *3/*3). The CYP2C19*17 carriers were excluded from the analysis. The antiplatelet effects of clopidogrel were assessed by Adenosine diphosphate (ADP) -induced platelet aggregation and vasodilator-stimulated phosphoprotein (VASP) phosphorylation, expressed as VASP index. The endpoint was the composite incidence of stroke, transient ischemic attack, myocardial infarction, revascularization, other thromboembolic disease, or cardiovascular death during 2 years of follow-up.

Inclusion Criteria:

• Patients who had received long-term clopidogrel therapy (once a day for at least one month) with a minimum one-month interval between enrollment and the last cerebral ischemic or TIA event.
• Males and females aged 20 years or older who were prescribed clopidogrel for the secondary prevention of cerebral infarction or transient ischemic attack and who were willing and able to give written informed consent.

Exclusion Criteria:

• Malignancies
• Congenital bleeding tendency
• Atrial fibrillation
• Concomitant use of an oral anticoagulant agent
• a platelet count of < 100 x 109/L or > 450 x 109/L within 3 months of enrollment
• Modified rankin scale > 4

Patients were recruited at each institution between October 2009 and March 2012. The investigators enrolled males and females aged 20 years or older who had experienced cerebral infarction or transient ischemic attack (TIA) (except for cardiogenic embolism) in the prior 3 years but not in the last one month, who received long-term clopidogrel therapy (75 mg once a day) for the secondary prevention (for at least one month), and who were willing and able to give written informed consent.