pharmacist Department of Pharmacy, Taichung Veterans General Hospital, Taichung, Taiwan Taichung, Taiwan (Republic of China)
Background: Clopidogrel may be less effective in reducing the rate of cardiovascular events among persons who are CYP2C19 poor metabolizer. The CYP3A4 inhibition by calcium channel blockers (CCBs) may also attenuate the effectiveness of clopidogrel.
Objectives: The aim of this pharmacogenomic study was to investigate whether co-administration of CCBs individually or jointly attenuated the effectiveness of clopidogrel in patients with CYP2C19 poor metabolizer.
Methods: We constructed a retrospective cohort of patients who were first prescribed clopidogrel at discharge and underwent PCI with stenting. CYP2C19 genetic polymorphisms in 1,874 patients were identified by the Axiom Genome-Wide TWB 2.0 array plate. Concomitant use with CCBs was considered if the co-administration of the drug pair lasted for least 28 days. The population was divided into six categories by CYP2C19 phenotype: clopidogrel alone with extensive metabolizer (EM) (EM without CCBs), clopidogrel alone with intermediate metabolizer (IM) (IM without CCBs), clopidogrel alone with poor metabolizer (PM) (PM without CCBs), clopidogrel co-medication with EM(EM with CCBs), clopidogrel co-medication with IM(IM with CCBs), and clopidogrel co-medication with PM(PM with CCBs). We tracked the use of clopidogrel and CCBs and the rate of MACE (including myocardial infarction, ischaemic stroke, and revascularization). We used logistic regression for outcome analysis.
Results: We identified 1,874 eligible individuals who received clopidogrel and had the CYP2C19 phenotype information. Among the eligible subjects, 698 (37.2%) were on CCBs with clopidogrel. The mean age of patients was 63.3 years, 44.7% were 65 years of age or older, and 78.2% were male. Compared with EM without CCBs group, the risk of revascularization was no significant in IM and PM without CCBs groups. However, it significantly increased in EM, IM and PM with CCBs group. (odds ratio(OR):1.48, 95% confidence interval (CI):1.08–2.01; OR: 1.74, 95% CI :1.28–2.36; OR:2.19, 95% CI:1.38–3.47, respectively ). The risk of Myocardial infarction was also significantly increased in the group administered concurrent CCB therapy compared with no CCB, and when patients are CYP2C19 poor metabolizer, the odds ratio increase to 1.87 (95% CI: 1.21-2.90).
Conclusions: Clopidogrel–CCBs interaction are common. CYP2C19 polymorphisms also implicated in clopidogrel metabolism. Awareness of this drug-drug-gene interaction is important for optimizing the selection of concomitant therapies.
