title: CYP2C19 metabolizer status and clopidogrel efficacy in the Secondary Prevention of Small Subcortical Strokes (SPS3) study.
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.
  
  
  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.
  
  
  BACKGROUND
  URL: www.clinicaltrials.gov. Unique identifier: NCT00059306.
authors.affiliation: Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL (C.W.M.D., Y.G., J.A.J.).
authors.forename: Caitrin W
authors.initials: CW
authors.lastname: McDonough
authors.affiliation: Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, AL (L.A.M.C.).
authors.forename: Leslie A
authors.initials: LA
authors.lastname: McClure
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD (B.D.M., R.B.H., J.P.L., A.R.S.) Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD (B.D.M., R.B.H., J.P.L., A.R.S.) Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, MD (B.D.M., A.R.S.).
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.affiliation: Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL (C.W.M.D., Y.G., J.A.J.).
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD (B.D.M., R.B.H., J.P.L., A.R.S.) Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD (B.D.M., R.B.H., J.P.L., A.R.S.).
authors.forename: Richard B
authors.initials: RB
authors.lastname: Horenstein
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD (B.D.M., R.B.H., J.P.L., A.R.S.) Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD (B.D.M., R.B.H., J.P.L., A.R.S.).
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Lewis
authors.affiliation: Department of Neurology, University of British Columbia, Vancouver, British Columbia, Canada (T.S.F., O.R.B.).
authors.forename: Thalia S
authors.initials: TS
authors.lastname: Field
authors.affiliation: College of Pharmacy, University of Texas at Austin, TX (R.L.T.).
authors.forename: Robert L
authors.initials: RL
authors.lastname: Talbert
authors.affiliation: Department of Neurology, University of British Columbia, Vancouver, British Columbia, Canada (T.S.F., O.R.B.).
authors.forename: Oscar R
authors.initials: OR
authors.lastname: Benavente
authors.affiliation: Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL (C.W.M.D., Y.G., J.A.J.) Division of Cardiovascular Medicine, College of Medicine, University of Florida, Gainesville, FL (J.A.J.).
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
authors.affiliation: Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD (B.D.M., R.B.H., J.P.L., A.R.S.) Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD (B.D.M., R.B.H., J.P.L., A.R.S.) Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, MD (B.D.M., A.R.S.).
authors.forename: Alan R
authors.initials: AR
authors.lastname: Shuldiner
mesh_terms: D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D012008:Recurrence; D055502:Secondary Prevention / Q000379:methods*; D020521:Stroke / Q000453:epidemiology / Q000235:genetics / Q000517:prevention & control*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine
keywords: CYP2C19; clopidogrel; pharmacogenomics; stroke prevention; subcortical stroke