Polygenic Risk Score for the Efficacy of Clopidogrel in Patients With Minor Stroke or Transient Ischemic Attack: A Post Hoc Analysis of the CHANCE Trial.

IF 8.9 1区医学 Q1 CLINICAL NEUROLOGY Stroke Pub Date : 2025-04-01 Epub Date: 2025-03-07 DOI:10.1161/STROKEAHA.124.049140

Xin Qiu, Yingyu Jiang, Hong-Qiu Gu, Yong Jiang, Xinying Huang, Xia Meng, Yongjun Wang, Zixiao Li

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Abstract

Background: Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is recommended for secondary prevention in patients with a minor stroke or transient ischemic attack. However, the effectiveness of DAPT can be significantly influenced by genetic variations. This study aimed to estimate the impact of multiple single-nucleotide polymorphisms across various genes on DAPT efficacy using polygenic risk score (PRS).

Methods: In this post hoc analysis, we included 2905 patients from the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events), which enrolled a total of 5170 patients in China between October 2009 and July 2012. The primary outcome was new stroke within 90 days. Sixteen single-nucleotide polymorphisms across 7 genes involved in clopidogrel metabolism were selected for PRS development. PRS were calculated by summing single-nucleotide polymorphisms from each individual. The Cox proportional-hazards regression model was utilized to estimate the hazard ratio (HR) and 95% CIs of PRS. The predictive value of PRS was estimated by C statistic and compared with a previously validated model.

Results: The elevated PRSs were associated with an increased risk of new stroke within 90 days (P_trend=0.01). The efficacy of DAPT versus aspirin alone in preventing 1-year composite vascular events was significantly different between patients with low (adjusted HR, 0.47 [95% CI, 0.31-0.71]) and high PRSs (adjusted HR, 0.84 [95% CI, 0.60-1.18]; P_interaction=0.03). In patients receiving DAPT, higher PRSs were associated with increased risk of new stroke and composite vascular events at 90 days (adjusted HR per SD increase was 1.51 [95% CI, 1.15-1.99]) and at 1 year (adjusted HR per SD increase was 1.34 [95% CI, 1.08-1.67]). The C statistic for predicting 90-day new stroke using the PRS developed in this study was 0.57 (95% CI, 0.52-0.62), compared with 0.52 (95% CI, 0.48-0.55) for the ABCD-GENE score.

Conclusions: Using PRS integrating multiple genes may enhance the precision of secondary prevention strategies for patients with minor stroke or transient ischemic attack in the short and long term.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00979589.

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氯吡格雷对轻度中风或短暂性脑缺血发作患者疗效的多基因风险评分：CHANCE试验的事后分析

背景：氯吡格雷和阿司匹林双重抗血小板治疗（DAPT）被推荐用于轻度卒中或短暂性脑缺血发作患者的二级预防。然而，DAPT的有效性会受到遗传变异的显著影响。本研究旨在利用多基因风险评分（PRS）评估不同基因间的多个单核苷酸多态性对DAPT疗效的影响。方法：在这项事后分析中，我们纳入了来自CHANCE试验（氯吡格雷在高风险急性非致残性脑血管事件患者中的应用）的2905例患者，该试验于2009年10月至2012年7月在中国共纳入了5170例患者。主要结果为90天内新发卒中。我们选择了涉及氯吡格雷代谢的7个基因中的16个单核苷酸多态性用于PRS的发育。PRS通过汇总每个个体的单核苷酸多态性来计算。采用Cox比例风险回归模型估计PRS的风险比（HR）和95% ci。通过C统计量估计PRS的预测值，并与先前验证的模型进行比较。结果：PRSs升高与90天内新发卒中风险增加相关（p趋势=0.01）。低（校正HR， 0.47 [95% CI, 0.31-0.71]）和高（校正HR， 0.84 [95% CI, 0.60-1.18]）患者之间DAPT与阿司匹林单独预防1年复合血管事件的疗效有显著差异；Pinteraction = 0.03)。在接受DAPT的患者中，较高的PRSs与90天内新发卒中和复合血管事件的风险增加相关（调整后HR / SD增加1.51 [95% CI, 1.15-1.99]）和1年（调整后HR / SD增加1.34 [95% CI, 1.08-1.67]）。使用本研究开发的PRS预测90天新卒中的C统计量为0.57 (95% CI, 0.52-0.62)，而ABCD-GENE评分为0.52 （95% CI, 0.48-0.55）。结论：整合多基因的PRS可提高轻度脑卒中或短暂性脑缺血发作患者短期和长期二级预防策略的准确性。注册：网址：https://www.clinicaltrials.gov；唯一标识符：NCT00979589。

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来源期刊

Stroke 医学-临床神经学

CiteScore

13.40

自引率

6.00%

发文量

2021

审稿时长

3 months

期刊介绍： Stroke is a monthly publication that collates reports of clinical and basic investigation of any aspect of the cerebral circulation and its diseases. The publication covers a wide range of disciplines including anesthesiology, critical care medicine, epidemiology, internal medicine, neurology, neuro-ophthalmology, neuropathology, neuropsychology, neurosurgery, nuclear medicine, nursing, radiology, rehabilitation, speech pathology, vascular physiology, and vascular surgery. The audience of Stroke includes neurologists, basic scientists, cardiologists, vascular surgeons, internists, interventionalists, neurosurgeons, nurses, and physiatrists. Stroke is indexed in Biological Abstracts, BIOSIS, CAB Abstracts, Chemical Abstracts, CINAHL, Current Contents, Embase, MEDLINE, and Science Citation Index Expanded.