CYP2C19 metabolizer status and clopidogrel efficacy in the Secondary Prevention of Small Subcortical Strokes (SPS3) study

Caitrin W McDonough, Leslie A McClure, Braxton D Mitchell, Yan Gong, Richard B Horenstein, Joshua P Lewis, Thalia S Field, Robert L Talbert, Oscar R Benavente, Julie A Johnson, Alan R Shuldiner, Caitrin W McDonough, Leslie A McClure, Braxton D Mitchell, Yan Gong, Richard B Horenstein, Joshua P Lewis, Thalia S Field, Robert L Talbert, Oscar R Benavente, Julie A Johnson, Alan R Shuldiner

Abstract

Background: The 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 results: CYP2C19*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.

Conclusions: There 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 registration: URL: www.clinicaltrials.gov. Unique identifier: NCT00059306.

Keywords: CYP2C19; clopidogrel; pharmacogenomics; stroke prevention; subcortical stroke.

© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1
Figure 1
Odds ratios for recurrent stroke in the CYP2C19IM/PM phenotype compared with the EM/UM phenotype in genetically defined white, black, and Hispanic participants. All odds ratios were adjusted for age and sex. The odds ratio for Hispanic participants was not estimable because of 0 events in IM/PM participants. EM indicates extensive metabolizer; IM, intermediate metabolizer; n/a, not estimable; PM, poor metabolizer; UM, ultrarapid metabolizer.

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