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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.

SUBMITTER: Yi X

PROVIDER: S-EPMC6714622 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Concomitant Use of Proton-Pump Inhibitors and Clopidogrel Increases the Risk of Adverse Outcomes in Patients With Ischemic Stroke Carrying Reduced-Function CYP2C19*2.

Yi Xingyang X Han Zhao Z Zhou Qiang Q Cheng Wen W Lin Jing J Wang Chun C

Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis 20160916 1

<h4>Objective</h4>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.<h4>Methods</h4>We consecutively enrolled 523 patients with ischemic stroke receiving clopidogrel. Platelet aggregation was measured before and after 7 to 10 days of clopidogrel treatment ...[more]

PMID: 27637911

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Project description:Clopidogrel, one of the most commonly prescribed medications, is a prodrug requiring CYP450 biotransformation. Data suggest its pharmacologic effect varies based on CYP2C19 genotype, but there is uncertainty regarding the clinical risk imparted by specific genotypes.To define the risk of major adverse cardiovascular outcomes among carriers of 1 (? 26% prevalence in whites) and carriers of 2 (? 2% prevalence in whites) reduced-function CYP2C19 genetic variants in patients treated with clopidogrel.A literature search was conducted (January 2000-August 2010) in MEDLINE, Cochrane Database of Systematic Reviews, and EMBASE. Genetic studies were included in which clopidogrel was initiated in predominantly invasively managed patients in a manner consistent with the current guideline recommendations and in which clinical outcomes were ascertained.Investigators from 9 studies evaluating CYP2C19 genotype and clinical outcomes in patients treated with clopidogrel contributed the relevant hazard ratios (HRs) and 95% confidence intervals (CIs) for specific cardiovascular outcomes by genotype.Among 9685 patients (91.3% who underwent percutaneous coronary intervention and 54.5% who had an acute coronary syndrome), 863 experienced the composite end point of cardiovascular death, myocardial infarction, or stroke; and 84 patients had stent thrombosis among the 5894 evaluated for such. Overall, 71.5% were noncarriers, 26.3% had 1 reduced-function CYP2C19 allele, and 2.2% had 2 reduced-function CYP2C19 alleles. A significantly increased risk of the composite end point was evident in both carriers of 1 (HR, 1.55; 95% CI, 1.11-2.17; P = .01) and 2 (HR, 1.76; 95% CI, 1.24-2.50; P = .002) reduced-function CYP2C19 alleles, as compared with noncarriers. Similarly, there was a significantly increased risk of stent thrombosis in both carriers of 1 (HR, 2.67; 95% CI, 1.69-4.22; P < .0001) and 2 (HR, 3.97; 95% CI, 1.75-9.02; P = .001) CYP2C19 reduced-function alleles, as compared with noncarriers.Among patients treated with clopidogrel for percutaneous coronary intervention, carriage of even 1 reduced-function CYP2C19 allele appears to be associated with a significantly increased risk of major adverse cardiovascular events, particularly stent thrombosis.

Dataset Information

Concomitant Use of Proton-Pump Inhibitors and Clopidogrel Increases the Risk of Adverse Outcomes in Patients With Ischemic Stroke Carrying Reduced-Function CYP2C19*2.

Publications

Concomitant Use of Proton-Pump Inhibitors and Clopidogrel Increases the Risk of Adverse Outcomes in Patients With Ischemic Stroke Carrying Reduced-Function CYP2C19*2.

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