F2R Polymorphisms and Clopidogrel Efficacy and Safety in Patients With Minor Stroke or TIA

Neurology. 2021 Jan 5;96(1):e1-e9. doi: 10.1212/WNL.0000000000011078. Epub 2020 Oct 22.


Objective: To investigate the association between protease-activated receptor-1 (PAR-1) gene F2R polymorphisms and efficacy of clopidogrel for minor stroke or 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 = 1,461) or aspirin alone (n = 1,463). 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, 1,479 (50.6%) were AT heterozygotes, and 586 (20.0%) were TT homozygotes for F2R IVSn-14 polymorphisms; 1,716 (58.7%) were carriers of at least 1 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 the F2R IVSn-14 T allele had a lower rate of recurrent stroke than those who were not.

Clinicaltrialsgov identifier: NCT00979589.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Clopidogrel / therapeutic use*
  • Double-Blind Method
  • Female
  • Genotype
  • Humans
  • Ischemic Attack, Transient / drug therapy*
  • Ischemic Attack, Transient / genetics
  • Male
  • Middle Aged
  • Platelet Aggregation Inhibitors / therapeutic use*
  • Polymorphism, Single Nucleotide
  • Receptor, PAR-1 / genetics*
  • Recurrence
  • Stroke / drug therapy*
  • Stroke / genetics
  • Treatment Outcome


  • Platelet Aggregation Inhibitors
  • Receptor, PAR-1
  • Clopidogrel

Associated data

  • ClinicalTrials.gov/NCT00979589