Impact of CYP2C19 Genotype Status on Clinical Outcomes in Patients with Symptomatic Coronary Artery Disease, Stroke, and Peripheral Arterial Disease: A Systematic Review and Meta-Analysis.

IF 13 1区 医学 Q1 PHARMACOLOGY & PHARMACY
Drugs Pub Date : 2024-10-01 Epub Date: 2024-09-05 DOI:10.1007/s40265-024-02076-7
Dominique P M S M Maas, Loes H Willems, Josephine Kranendonk, Cornelis Kramers, Michiel C Warlé
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引用次数: 0

Abstract

Background: Clopidogrel is widely used for the secondary prevention of atherothrombotic events in patients with coronary artery disease (CAD), ischemic stroke, and peripheral arterial disease (PAD). CYP2C19 plays a pivotal role in the conversion of clopidogrel to its active metabolite. Clopidogrel-treated carriers of a CYP2C19 loss-of-function allele (LOF) may have a higher risk of new atherothrombotic events. Previous studies on genotype-guided treatment were mainly performed in CAD and showed mixed results.

Purpose: To simultaneously investigate the impact of CYP2C19 genotype status on the rate of atherothrombotic events in the most common types of atherosclerotic disease (CAD, stroke, PAD).

Methods: A comprehensive search in Pubmed, EMBASE, and MEDLINE from their inception to July 23rd 2023 was performed. Randomized controlled trials (RCTs) comparing genotype-guided and standard antithrombotic treatment, and cohort studies and post hoc analyses of RCTs concerning the association between CYP2C19 genotype status and clinical outcomes in clopidogrel-treated patients were included. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the safety end point major bleeding. Secondary endpoints were myocardial infarction, stent thrombosis, and ischemic stroke.

Results: Forty-four studies were identified: 11 studies on CAD, 29 studies on stroke, and 4 studies on PAD. In CAD, genotype-guided therapy significantly reduced the risk of MACE [risk ratio (RR) 0.60, 95% confidence interval (CI) 0.43-0.83], myocardial infarction (RR 0.53, 95% CI 0.42-0.68), and stent thrombosis (RR 0.64, 95% CI 0.43-0.94), compared with standard antithrombotic treatment. The rate of major bleeding did not differ significantly (RR 0.93, 95% CI 0.70-1.23). Most RCTs were performed in patients after percutaneous coronary intervention (9/11). In stroke, LOF carriers had a significantly higher risk of MACE (RR 1.61, 95% CI 1.25-2.08) and recurrent ischemic stroke (RR 1.89, 95% CI 1.48-2.40) compared with non-carriers. No significant differences were found in major bleeding (RR 0.90, 95% CI 0.43-1.89). In the 6955 patients with symptomatic PAD treated with clopidogrel in the EUCLID trial, no differences in MACE or major bleeding were found between LOF carriers and non-carriers. In three smaller studies on patients with PAD treated with clopidogrel after endovascular therapy, CYP2C19 genotype status was significantly associated with atherothrombotic events.

Conclusions: Genotype-guided treatment significantly decreased the rate of atherothrombotic events in patients with CAD, especially after PCI. In patients with history of stroke, LOF carriers treated with clopidogrel had a higher risk of MACE and recurrent stroke. The available evidence in PAD with regard to major adverse limb events is too limited to draw meaningful conclusions.

Registration: PROSPERO identifier no. CRD42020220284.

Abstract Image

CYP2C19 基因型状态对无症状冠心病、中风和外周动脉疾病患者临床结局的影响:系统回顾与元分析》。
背景:氯吡格雷被广泛用于冠状动脉疾病(CAD)、缺血性中风和外周动脉疾病(PAD)患者动脉粥样硬化血栓事件的二级预防。CYP2C19 在将氯吡格雷转化为其活性代谢物的过程中起着关键作用。接受氯吡格雷治疗的 CYP2C19 功能缺失等位基因(LOF)携带者发生新的动脉粥样硬化血栓事件的风险可能更高。目的:同时研究 CYP2C19 基因型状态对最常见类型的动脉粥样硬化疾病(CAD、中风、PAD)的动脉粥样硬化血栓事件发生率的影响:方法:在Pubmed、EMBASE和MEDLINE上进行了从开始到2023年7月23日的全面检索。研究纳入了基因型指导抗血栓治疗与标准抗血栓治疗的随机对照试验(RCT),以及有关氯吡格雷治疗患者的CYP2C19基因型状态与临床结果之间关系的队列研究和RCT的事后分析。主要疗效终点为主要不良心血管事件(MACE),安全性终点为大出血。次要终点为心肌梗死、支架血栓和缺血性中风:结果:共确定了 44 项研究:结果:共确定了 44 项研究:11 项关于 CAD 的研究、29 项关于中风的研究和 4 项关于 PAD 的研究。与标准抗血栓治疗相比,基因型指导下的 CAD 治疗可显著降低 MACE(风险比 (RR):0.60,95% 置信区间 (CI):0.43-0.83)、心肌梗死(RR:0.53,95% CI:0.42-0.68)和支架血栓形成(RR:0.64,95% CI:0.43-0.94)的风险。大出血率没有显著差异(RR 0.93,95% CI 0.70-1.23)。大多数研究都是针对经皮冠状动脉介入治疗(9/11)后的患者。在中风方面,LOF 携带者与非携带者相比,发生 MACE(RR 1.61,95% CI 1.25-2.08)和复发性缺血性中风(RR 1.89,95% CI 1.48-2.40)的风险明显更高。在大出血方面没有发现明显差异(RR 0.90,95% CI 0.43-1.89)。在EUCLID试验中,6955名症状性PAD患者接受了氯吡格雷治疗,在MACE或大出血方面,LOF携带者与非携带者之间没有发现差异。在对接受血管内治疗后使用氯吡格雷治疗的PAD患者进行的三项较小规模研究中,CYP2C19基因型状态与动脉粥样硬化血栓事件显著相关:结论:基因型指导下的治疗可明显降低 CAD 患者的动脉粥样硬化血栓事件发生率,尤其是在 PCI 治疗后。在有中风史的患者中,接受氯吡格雷治疗的LOF携带者发生MACE和复发性中风的风险较高。在PAD患者中,关于肢体主要不良事件的现有证据非常有限,无法得出有意义的结论:注册:PROSPERO 识别码编号CRD42020220284。
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来源期刊
Drugs
Drugs 医学-毒理学
CiteScore
22.70
自引率
0.90%
发文量
134
审稿时长
3-8 weeks
期刊介绍: Drugs is a journal that aims to enhance pharmacotherapy by publishing review and original research articles on key aspects of clinical pharmacology and therapeutics. The journal includes: Leading/current opinion articles providing an overview of contentious or emerging issues. Definitive reviews of drugs and drug classes, and their place in disease management. Therapy in Practice articles including recommendations for specific clinical situations. High-quality, well designed, original clinical research. Adis Drug Evaluations reviewing the properties and place in therapy of both newer and established drugs. AdisInsight Reports summarising development at first global approval. Moreover, the journal offers additional digital features such as animated abstracts, video abstracts, instructional videos, and podcasts to increase visibility and educational value. Plain language summaries accompany articles to assist readers with some knowledge of the field in understanding important medical advances.
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