Objective: To investigate the association between protease-activated receptors-1 (PAR-1) gene F2R polymorphisms and efficacy of clopidogrel for minor stroke or transient ischemic attack (TIA).

Methods: Three single-nucleotide polymorphisms (CYP2C19*2 [681G>A, rs4244285], CYP2C19*3 [636G>A, rs4986893] and F2R [IVSn-14 A/T, rs168753] were genotyped among 2,924 patients randomized to clopidogrel plus aspirin (n=1461) or aspirin alone (n=1463). The primary efficacy outcome was new stroke (ischemic or hemorrhagic) and the safety outcome was any bleeding.

Results: Overall, 859(29.4%) were AA homozygotes, 1479(50.6%) were AT heterozygotes and 586(20.0%) were TT homozygotes for F2R IVSn -14 polymorphisms; 1716 (58.7%) were carriers of at least one CYP2C19 loss-of-function allele (*2 or *3). Compared with aspirin alone, patients with clopidogrel-aspirin treatment had a low risk of new stroke in patients with AT genotype (7.6% vs. 11.3%; hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.44-0.89) and TT genotype (5.8% vs. 11.6%; HR, 0.46; 95% CI, 0.25-0.82) but not in carriers of the AA genotype (10.8% vs. 11.6%; HR, 0.95; 95% CI, 0.63-1.44) (p=0.03 for interaction). The association between F2R IVSn -14 A/T polymorphism and clopidogrel response was present regardless of the carrier status of the CYP2C19 loss-of-function alleles. The F2R IVSn -14 genotypes were not associated with the risk of any bleeding for clopidogrel-aspirin treatment (P=0.66 for interaction).

Conclusions: Among patients with minor ischemic stroke or TIA who were receiving clopidogrel and aspirin, those carrying F2R IVSn -14 T allele had a lower rate of recurrent stroke than those who were not.

Clinicaltrials.gov Identifier: NCT00979589.

Supplemental Data corresponding to research paper 'F2R Polymorphisms and Clopidogrel Efficacy and Safety in Patients with Minor Stroke or TIA'

It contains supplemental figures and supplemental tables for this paper.

• Figure e-1. PAR-1 pathway and clopidogrel action
• Figure e-2. Flow diagram of participants in the genetic substudy for F2R IVSn -14 A/T
• Table e-1. Baseline differences between individuals with and without genetic data
• Table e-2. Event rate and effect of clopidogrel-aspirin vs. aspirin in patients with genotype data and in the parent trial.
• Table e-3. Baseline characteristics between treatment groups for each genotype of the F2R IVSn -14 A/T polymorphism.
• Table e-4. Baseline characteristics among groups stratified by CYP2C19 Loss-of-function allele carrier status and F2R IVSn -14 A/T genotype
• Table e-5. Baseline characteristics between treatment groups stratified by CYP2C19 Loss-of-function allele carrier status and F2R IVSn -14 A/T genotype.
• Table e-6. Effect of clopidogrel-aspirin as compared with aspirin on clinical outcome stratified by CYP2C19 loss-of-function allele carrier status.
• Table e-7. Rate of bleeding and effect of clopidogrel-aspirin vs. aspirin in carriers of both CYP2C19 Loss-of-function alleles and at least one T allele of F2R IVSn -14 A/T