Influence of smoking on CYP2C19 genetic variants and clopidogrel efficacy in patients with minor stroke or transient ischaemic attack

Background and purpose: Studies suggest that smoking affects clopidogrel efficacy. However, whether it influences the association between CYP2C19 genetic variants and clopidogrel efficacy is not clear.

Methods: In total, 2961 patients from the CHANCE trial were involved in this substudy and were successfully genotyped for two single-nucleotide polymorphisms of CYP2C19 (*2 and *3). The Cox proportional risk regression model was used to evaluate the interactions between CYP2C19*2 and CYP2C19*3 carrier status and clopidogrel efficacy stratified by smoking status.

Results: There were marginal significant interactions between CYP2C19*2 and CYP2C19*3 allele carrier status and antiplatelet treatment regimen for the risk of recurrent stroke and composite events (P = 0.054, P = 0.051, respectively) amongst smokers, but not in non-smokers. Amongst smokers, clopidogrel plus aspirin decreased the recurrence rate of stroke compared with aspirin alone in non-carriers (3.8% vs. 11.8%, hazard ratio 0.32, 95% confidence interval 0.15-0.65, P = 0.002), but not in carriers. Similar results were also found for the recurrence rate of composite events in smokers. No significant difference was found for hemorrhage events in any group.

Conclusions: Amongst patients with minor stroke or transient ischaemic attack, marginal significant interactions between CYP2C19*2 and CYP2C19*3 allele carrier status and clopidogrel efficacy were found in smokers but not in non-smokers. Amongst smokers, clopidogrel plus aspirin might decrease the recurrence rate of stroke in non-carriers of *2 and *3 alleles of CYP2C19 compared with aspirin alone. However, caution should be taken to interpret our findings in view of several limitations in our study.