Association Of CYP2C19 Polymorphisms With The Clinical Efficacy Of Clopidogrel Therapy In Patients Undergoing Carotid Artery Stenting

Background and purpose: Carotid artery atherosclerotic stenosis is an important risk factor for ischemic stroke.Approximately 25% of ischemic stroke cases are due to focal atherosclerosis and consecutive narrowing(stenosis)of the internal carotid artery.Carotid artery stenting(CAS)is a most commonly used option for treating carotid atherosclerotic stenosis in China,because it possesses the advantages of noninvasiveness and easy recovery.After CAS,patients must be administered a long-term regimen of clopidogrel for antiplatelet therapy.Clopidogrel is a prodrug that requires hepatic cytochrome P450(CYP)for its conversion into an active metabolite to play the role of inhibiting platelet aggregation.The CYP2C19 loss-of-function(LOF)alleles(*2 and *3)reduce the level of the active metabolite of clopidogrel in the blood,which contributes to a decrease in the function of clopidogrel,resulting in inhibiting platelet aggregation.Furthermore,the frequencies of CYP2C19 LOF alleles(*2 and *3)was highest in Asian population.However,it is not yet clear whether the CYP2C19 LOF alleles(*2 and *3)have an impact on the clinical efficacy of clopidogrel therapy after CAS in Chinese population.In this study,we selected patients with CYP2C19 LOF alleles who had undergone CAS for enrollment to determine the relationship between CYP2C19 gene polymorphisms and the clinical efficacy of clopidogrel therapy after CAS.The findings of this study could provide guidance for the development of clinical personalized antiplatelet therapy after CAS.Methods and Results: From November 2012 to June 2014,959 ischemic stroke patients underwent CYP2C19 genotype screening at our hospital.The frequencies of all the genotype were: *1/*1 was 38.79%(n=372),*1/*2 was 42.44%(n=407),*1/*3 was 6.25%(n=60),*2/*2 was 9.18%(n=88),*2/*3 was 2.82%(n=27),*3/*3 was 0.52%(n=5).According to the differences in their CYP2C19 genotypes,the 241 patients undergoing CAS were divided into the following 5 groups(none of the patients had the *3/*3 genotype): *1/*1(n=89),*1/*2(n=116),*1/*3(n=16),*2/*2(n=16),and *2/*3(n=4).No differences were observed in the baseline characteristics among the 5 groups.We included age,sex,smoking,hypertension,hyperlipidemia,and diabetes in multivariate Cox regression analysis to identify independent correlates of the primary end-points.The results showed that the CYP2C19 LOF alleles(*2 and *3)were risk factors for post-CAS prognosis(relative risk,2.411;95% CI,1.050 to 5.537;P=0.038).Based on the results obtained using the Cox regression model,we explored the respective effects of the different CYP2C19 genotypes on the clinical prognosis of the patients treated with clopidogrel after CAS.The follow-up time was 1 year.The primary clinical end-points were ischemic events,and the secondary clinical end-point was bleeding events.Within the 1 year follow-up,the patients carrying CYP2C19(*2 and *3)alleles were more likely to have ischemic events compare to the patients carrying none(hazard ratio,2.131;95%CI of ratio,1.067 to 4.255;P=0.032),and the CYP2C19*2 allele and CYP2C19*3 allele had the same effect on end point(hazard ratio,0.4708;95%CI of ratio,0.1562 to 1.419;P=0.1808).Conclusion: CYP2C19 loss-of-functional alleles(*2 and *3)have a significant impact on the prognosis of patients with clopidogrel therapy after carotid artery stenting,and the influence of the CYP2C19*2 and *3 allele on it does not differ.