title: Concomitant Use of Proton-Pump Inhibitors and Clopidogrel Increases the Risk of Adverse Outcomes in Patients With Ischemic Stroke Carrying Reduced-Function CYP2C19*2.
abstract: OBJECTIVE
  Conflicting data exist as to whether proton-pump inhibitors (PPIs) diminish the efficacy of clopidogrel. The aim of this study was to investigate the association between cytochrome P450 ( CYP) genetic variants and clinical adverse outcomes of concomitant use of PPIs and clopidogrel by patients.
  
  
  METHODS
  We consecutively enrolled 523 patients with ischemic stroke receiving clopidogrel. Platelet aggregation was measured before and after 7 to 10 days of clopidogrel treatment. Single-nucleotide polymorphisms of CYP3A4, CYP3A5, CYP2C19*2, and CYP2C19*3 were examined using mass spectrometry. The primary outcome was a composite of recurrent ischemic stroke (RIS), myocardial infarction (MI), and vascular death that occurred during the 1-year follow-up period. The safety outcome was hemorrhagic episodes that occurred during the 1-year follow-up period.
  
  
  RESULTS
  This study comprised a total of 523 patients with IS, 96.3% (155/161) patients treated with PPIs and 95.9% (347/362) in patients treated without PPIs completed 1-year follow-up. The primary outcome was observed in 69 (13.7%) patients (56 RIS, 7 MI, and 6 died). There was no significant difference in the frequencies of primary outcome and safety outcome between patients treated with or without PPIs. The frequency of primary outcome was significantly higher in patients carrying CYP2C19*2 AG/AA genotype receiving PPIs compared with the same genotype in those not receiving PPIs. The PPIs used in patients carrying CYP2C19*2 AG/AA was independently associated with the primary outcome after adjusting for other risk factors.
  
  
  CONCLUSIONS
  The concomitant use of PPIs and clopidogrel may be associated with an increased risk of RIS, MI, or vascular death in patients with IS carrying reduced-function CYP2C19*2.
authors.affiliation: 1 Department of Neurology, People's Hospital of Deyang City, Deyang, Sichuan, China.
authors.forename: Xingyang
authors.initials: X
authors.lastname: Yi
authors.affiliation: 2 Department of Neurology, Second Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Han
authors.affiliation: 3 Department of Neurology, Third Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: 1 Department of Neurology, People's Hospital of Deyang City, Deyang, Sichuan, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Cheng
authors.affiliation: 3 Department of Neurology, Third Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lin
authors.affiliation: 1 Department of Neurology, People's Hospital of Deyang City, Deyang, Sichuan, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Wang
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D012307:Risk Factors; D020521:Stroke / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D054328:Proton Pump Inhibitors; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine
keywords: clopidogrel; cohort study; cytochrome P450 enzymes; ischemic stroke; proton-pump inhibitor; single-nucleotide polymorphism