title: Reduced clopidogrel metabolism in a multiethnic population: prevalence and rates of recurrent cerebrovascular events.
abstract: BACKGROUND
  Concern has recently been raised over the possibility of a reduced efficacy of clopidogrel because of genetic variations in cytochrome P450, family 2, subfamily C, polypeptide 19 (CYP2C19) metabolism. A black box warning from the US Food and Drug Administration recommends that all patients be tested. It has been estimated that approximately 3% (range 2-14%) of the population are poor metabolizers, but few data are available for cerebrovascular patients. The objective of this study is to evaluate the frequency and effects of variability in CYP2C19 metabolism in patients with cerebrovascular disease.
  
  
  METHODS
  A retrospective review of all patients with stroke and transient ischemic attack (TIA) tested for the clopidogrel CYP2C19 genotype was performed, with a collection of data including race/ethnicity, CYP2C19 status, and the presence of recurrent vascular events.
  
  
  RESULTS
  A total of 53 cerebrovascular patients were tested, consisting of 5.7% poor (n = 3), 26.4% intermediate (n = 14), 62.3% extensive (n = 33), 3.8% indeterminate (n = 2), and 1.9% "mixed ultra rapid and poor" (n = 1) metabolizers. Only 10 of 38 white patients (26.3%; 95% confidence interval [CI] 0.14-0.42) were intermediate or poor metabolizers, compared with 7 of 15 (46.7%; 95% CI 0.25-0.70) nonwhites. Of 43 patients treated with clopidogrel, 3 of 27 extensive metabolizers (11.1%; 95% CI 0.04-0.28) had recurrent cerebrovascular events compared with 33.3% of intermediate metabolizers (4/12; 95% CI 0.14-0.61) and 50% of poor metabolizers (1/2; 95% CI 0.09-0.90).
  
  
  CONCLUSIONS
  These data suggest that the proportion of poor/intermediate clopidogrel metabolizers in cerebrovascular patients is comparable to cardiovascular studies and these patients may have an increased risk of recurrent cerebrovascular events. Routine CYP2C19 testing may be warranted.
authors.affiliation: Department of Neurosciences, California Pacific Medical Center, CPMC Center for Stroke Research and Comprehensive Stroke Care Center, San Francisco, California; Department of Neurology, University of California, San Diego, San Diego, California.
authors.forename: Ilana
authors.initials: I
authors.lastname: Spokoyny
authors.affiliation: Department of Neurosciences, California Pacific Medical Center, CPMC Center for Stroke Research and Comprehensive Stroke Care Center, San Francisco, California. Electronic address: BarazaN@sutterhealth.org.
authors.forename: Nobl
authors.initials: N
authors.lastname: Barazangi
authors.affiliation: Department of Neurosciences, California Pacific Medical Center, CPMC Center for Stroke Research and Comprehensive Stroke Care Center, San Francisco, California; Department of Neurology, Methodist University Hospital, University of Tennessee, Memphis, Tennessee.
authors.forename: Victor
authors.initials: V
authors.lastname: Jaramillo
authors.affiliation: Department of Neurosciences, California Pacific Medical Center, CPMC Center for Stroke Research and Comprehensive Stroke Care Center, San Francisco, California.
authors.forename: Jack
authors.initials: J
authors.lastname: Rose
authors.affiliation: Department of Neurosciences, California Pacific Medical Center, CPMC Center for Stroke Research and Comprehensive Stroke Care Center, San Francisco, California.
authors.forename: Charlene
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Neurosciences, California Pacific Medical Center, CPMC Center for Stroke Research and Comprehensive Stroke Care Center, San Francisco, California.
authors.forename: Christine
authors.initials: C
authors.lastname: Wong
authors.affiliation: Department of Neurosciences, California Pacific Medical Center, CPMC Center for Stroke Research and Comprehensive Stroke Care Center, San Francisco, California.
authors.forename: David
authors.initials: D
authors.lastname: Tong
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D002561:Cerebrovascular Disorders / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D004351:Drug Resistance; D005006:Ethnicity; D006801:Humans; D002546:Ischemic Attack, Transient / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015995:Prevalence; D012008:Recurrence; D012189:Retrospective Studies; D020521:Stroke / Q000235:genetics / Q000378:metabolism; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine
keywords: Antiplatelet therapy; clopidogrel; drug metabolism; genetic testing; stroke; transient ischemic attack