Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands.
Drugs. 2024 Oct;84(10):1275-1297. doi: 10.1007/s40265-024-02076-7. Epub 2024 Sep 5.
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.
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).
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.
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.
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.
PROSPERO identifier no. CRD42020220284.
氯吡格雷被广泛用于冠心病（CAD）、缺血性卒中和外周动脉疾病（PAD）患者的动脉血栓事件的二级预防。CYP2C19 在氯吡格雷转化为其活性代谢物中起着关键作用。氯吡格雷治疗的 CYP2C19 失活等位基因（LOF）携带者可能有更高的新动脉血栓事件风险。以前关于基因型指导治疗的研究主要在 CAD 中进行，结果不一。
同时研究 CYP2C19 基因型状态对最常见动脉粥样硬化疾病（CAD、卒中和 PAD）中动脉血栓事件发生率的影响。
对 Pubmed、EMBASE 和 MEDLINE 进行了全面检索，检索时间从建库到 2023 年 7 月 23 日。纳入了比较基因型指导与标准抗血栓治疗的随机对照试验（RCT），以及关于 CYP2C19 基因型状态与氯吡格雷治疗患者临床结局之间关联的队列研究和 RCT 的事后分析。主要疗效终点是主要不良心血管事件（MACE），安全性终点是主要出血。次要终点是心肌梗死、支架血栓形成和缺血性卒中等。
共确定了 44 项研究：11 项关于 CAD 的研究，29 项关于卒中和 4 项关于 PAD 的研究。在 CAD 中，与标准抗血栓治疗相比，基因型指导治疗显著降低了 MACE 的风险[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），但主要出血的发生率没有显著差异（RR 0.93，95% CI 0.70-1.23）。大多数 RCT 是在经皮冠状动脉介入治疗（PCI）后的患者中进行的（9/11）。在卒中患者中，与非携带者相比，LOF 携带者的 MACE（RR 1.61，95% CI 1.25-2.08）和复发性缺血性卒中（RR 1.89，95% CI 1.48-2.40）风险显著更高。在主要出血方面（RR 0.90，95% CI 0.43-1.89），未发现显著差异。在 EUCLID 试验中，6955 例接受氯吡格雷治疗的有症状 PAD 患者中，LOF 携带者和非携带者之间在 MACE 或主要出血方面无差异。在三项较小的关于接受经血管治疗后接受氯吡格雷治疗的 PAD 患者的研究中，CYP2C19 基因型状态与动脉血栓事件显著相关。
基因型指导治疗显著降低了 CAD 患者的动脉血栓事件发生率，尤其是在 PCI 后。在卒中史患者中，接受氯吡格雷治疗的 LOF 携带者发生 MACE 和复发性卒中等的风险更高。目前关于 PAD 中主要不良肢体事件的证据非常有限，无法得出有意义的结论。
PROSPERO 标识符编号 CRD42020220284。
