Department of Pharmacy, University of Rajshahi, Rajshahi, 6205, Bangladesh.
Department of Medicine, Faridpur Medical College Hospital, Faridpur, Bangladesh.
Int J Clin Pharm. 2021 Oct;43(5):1360-1369. doi: 10.1007/s11096-021-01261-y. Epub 2021 Mar 28.
Background Efficacy of clopidogrel may be diminished due to either co-administration of proton pump inhibitors or carrying CYP2C19 loss-of-function alleles. However, patients may be at greater risk of major adverse cardiovascular events if taking clopidogrel together with proton pump inhibitors and also inherited the CYP2C19 loss-of-function alleles which may cause further reduction of clopidogrel efficacy. This is due to the cumulative effects of drug-drug interactions and drug-gene interactions collectively referred to as multifactorial drug-gene interactions. Aim of the review The aim of this analysis was to estimate aggregated risk of major adverse cardiovascular events for either coronary heart disease or stroke patients with multifactorial drug-gene interactions versus clopidogrel alone with or without drug-gene interactions. Methods Literatures were searched using different resources based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analysis was performed using RevMan software following either fixed/random effects model based on the levels of heterogeneity. A p value < 0.05 (2-sided) was considered statistically significant. Results In total, five studies consisting 8,802 patients of coronary artery diseases or stroke were included in this meta-analysis in which 3,767 were prescribed clopidogrel alone, 1,931 were concomitantly taking clopidogrel and PPIs, 2,146 were carrying CYP2C19 loss-of-function alleles and 958 were taking both clopidogrel and proton pump inhibitors while also carrying CYP2C19 loss-of-function alleles. It was found that patients with multifactorial drug-gene interactions were associated with significantly increased risk of major adverse cardiovascular events compared to those taking clopidogrel alone without CYP2C19 loss-of-function alleles (12% vs. 5.8%; RR 1.73; 95% CI 1.12-2.67; p = 0.01). Patients with multifactorial drug-gene interactions were also associated with significantly increased risk of major adverse cardiovascular events compared to drug-gene interactions (RR 1.63; 95% CI 1.31-2.03; p < 0.0001). Patients taking clopidogrel with proton pump inhibitors were also associated with 35% significantly increased risk of major adverse cardiovascular events compared to those taking only clopidogrel (RR 1.35; 95% CI 1.11-1.65; p = 0.003). Conclusion Patients inheriting CYP2C19 loss-of-function alleles have significantly increased risk of major adverse cardiovascular events when taking clopidogrel and proton pump inhibitors concurrently.
背景 由于质子泵抑制剂的联合用药或 CYP2C19 失活等位基因的携带，氯吡格雷的疗效可能会降低。然而，如果患者同时服用氯吡格雷和质子泵抑制剂，并遗传了 CYP2C19 失活等位基因，这可能会导致氯吡格雷疗效进一步降低，那么他们发生主要不良心血管事件的风险可能会更高。这是由于药物-药物相互作用和药物-基因相互作用的累积效应，统称为多因素药物-基因相互作用。
目的 本分析的目的是评估患有多因素药物-基因相互作用的冠心病或中风患者与单独使用氯吡格雷（无论是否存在药物-基因相互作用）相比，发生主要不良心血管事件的风险。
方法 根据系统评价和荟萃分析的首选报告项目，使用不同资源进行文献检索。根据异质性水平，使用 RevMan 软件进行荟萃分析，采用固定/随机效应模型。p 值<0.05（双侧）被认为具有统计学意义。
结果 共纳入了五项研究，包括 8802 例冠心病或中风患者，这些研究均进行了荟萃分析，其中 3767 例患者单独服用氯吡格雷，1931 例患者同时服用氯吡格雷和质子泵抑制剂，2146 例患者携带 CYP2C19 失活等位基因，958 例患者同时服用氯吡格雷和质子泵抑制剂并携带 CYP2C19 失活等位基因。结果发现，与未携带 CYP2C19 失活等位基因且单独服用氯吡格雷的患者相比，同时患有多因素药物-基因相互作用的患者发生主要不良心血管事件的风险显著增加（12%比 5.8%；RR 1.73；95%CI 1.12-2.67；p=0.01）。与药物-基因相互作用相比，患有多因素药物-基因相互作用的患者发生主要不良心血管事件的风险也显著增加（RR 1.63；95%CI 1.31-2.03；p<0.0001）。与单独服用氯吡格雷相比，同时服用氯吡格雷和质子泵抑制剂的患者发生主要不良心血管事件的风险也显著增加 35%（RR 1.35；95%CI 1.11-1.65；p=0.003）。
结论 当携带 CYP2C19 失活等位基因的患者同时服用氯吡格雷和质子泵抑制剂时，发生主要不良心血管事件的风险显著增加。
