CYP2C19 Metabolizer Status and Clopidogrel Efficacy in the Secondary Prevention of Small Subcortical Strokes (SPS3) Study

Abstract

BackgroundThe role of the CYP2C19 genotype on clopidogrel efficacy has been studied widely, with data suggesting reduced clopidogrel efficacy in loss-of-function variant carriers taking clopidogrel after percutaneous coronary intervention; however, data are limited regarding the association between CYP2C19 genetic variants and outcomes in stroke patients. We investigated whether CYP2C19 metabolizer status affects the risk of recurrent stroke or major bleeding in subcortical stroke patients taking dual antiplatelet therapy with aspirin and clopidogrel.Methods and ResultsCYP2C19*2 and CYP2C19*17 were genotyped in 522 patients treated with dual antiplatelet therapy from the Secondary Prevention of Small Subcortical Strokes (SPS3) study. CYP2C19 metabolizer status was inferred from genotype, and associations with the risk of recurrent stroke and major bleeding were assessed in the overall cohort and by race/ethnic group with logistic regression modeling. In the overall cohort, there were no differences in outcomes by CYP2C19 metabolizer status (recurrent stroke, odds ratio 1.81 [95% CI 0.76 to 4.30]; major bleeding, odds ratio 0.67 [95% CI 0.22 to 2.03]). In white participants, those with CYP2C19 intermediate or poor metabolizer status had higher odds of recurrent stroke (odds ratio 5.19 [95% CI 1.08 to 24.90]) than those with extensive or ultrarapid metabolizer status, but there was no evidence of difference in major bleeding.ConclusionsThere were significant differences in recurrent stroke by CYP2C19 genotype-inferred metabolizer status in white subcortical stroke patients receiving dual antiplatelet therapy with aspirin and clopidogrel, consistent with cardiovascular studies on CYP2C19 and clopidogrel; however, the bleeding risk that led to early termination of the antiplatelet arm of the SPS3 trial does not appear to be explained by CYP2C19 genotype. This study was relatively underpowered; therefore, these findings should be interpreted with caution and warrant replication.Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306.

Association BetweenCYP2C19Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction Among Patients With Minor Stroke or Transient Ischemic Attack

“…No association between bleeding and carrier status was observed in either of the 2 studies. 23,24 The results from the clopidogrel-aspirin-treated group support both of their findings. Jia and colleagues 22 and Yang and colleagues.…”

“…[22][23][24] In a group of 176 white patients with small subcortical stroke who received clopidogrel and aspirin, CYP2C19*2 loss-of-function allele was associated with increased risk of stroke compared with extensive or ultrarapid (*17) metabolizer phenotypes. 23 No such association was observed in either African American or Spanish patients. Sun and colleagues 2 4 observed an increased risk of a composite of vascular events (including vascular death, nonfatal ischemic stroke, and nonfatal myocardial infarction) during 3-month follow-up in carriers compared with noncarriers of CYP2C19*2 or CYP2C19*3 alleles in a cohort of 625 consecutive patients with ischemic stroke receiving clopidogrel.…”

Investigating Real-World Clopidogrel Pharmacogenetics in Stroke Using a Bioresource Linked to Electronic Medical Records

“…Most of the patients included in the analysis were Chinese and only 386 patients (8% of the total 4,762) were of white origin and of these over 90% were from two studies using dual antiplatelet therapy. 22,24 Interestingly, the risk of vascular endpoints in relation to CYP2C19 genotype seems to be lower in studies in which the study protocol clearly included dual antiplatelet therapy for 90 days or longer than in studies using clopidogrel monotherapy. 13 Indeed, excluding the small number of individuals who were co-prescribed aspirin in our study further increased the HR (data not shown).…”

Influence of CYP2C19 genetic polymorphisms on clinical outcomes of intracranial aneurysms treated with stent-assisted coiling

“…Several studies have shown that carriers with CYP2C19 alleles *2 or *3 had significantly lower levels of the active metabolite of clopidogrel, and could be considered as risk predictors for clinical outcomes in ACS or patients with cerebrovascular ischemic stroke. McDonough et al 16 found that CYP2C19 IMs or PMs had higher residual platelet reactivity than EMs or UMs (ultrarapid metabolizers) during the follow-up period. Wallentin et al 17 also reported that carriers of the reduced function CYP2C19 allele variants showed a higher rate of clopidogrel resistance, and the occurrence of cardiovascular death, myocardial infarction or stroke, mainly within the first 30 days after the treatment for ACS.…”