Burke Kerry Anne, Mirza Selman, Wright Stuart, Greaves Nicholas S, Newman William G, McDermott John H
Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK
Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, UK.
BMJ Open. 2025 May 6;15(5):e088456. doi: 10.1136/bmjopen-2024-088456.
Patients with chronic limb-threatening ischaemia (CLTI) are often prescribed clopidogrel in order to reduce their risk of major adverse limb and cardiovascular events. Clopidogrel is metabolised by the CYP2C19 enzyme and genetic variations in are common. These variants can influence an individual's ability to metabolise clopidogrel to its active metabolite. Few studies have investigated the relationship between patient genotype and outcomes in vascular surgery. This work aims to establish the relationship between patient genotype and outcomes after revascularisation in patients with CLTI who are prescribed clopidogrel. It will consider whether pharmacogenetics can be used to ensure patients are prescribed effective medications to optimise their outcomes.
This is an observational cohort study of patients undergoing lower limb surgical, endovascular or hybrid revascularisation for CLTI at Manchester University NHS Foundation Trust. Patients taking clopidogrel post-procedure, as well as those prescribed a non-clopidogrel based medication regimen, will be recruited prior to or shortly after revascularisation. Patients will undergo genotyping and will be followed up using online records. The study has 90% power to detect 114 amputations with a target sample size of 483 participants. The primary outcomes are risk of amputation at 1 year and a composite endpoint for the risk of major adverse limb events (MALE) or death from any cause at 1 year. Secondary outcomes are risk of MALE at 1 year, risk of major adverse cardiovascular events (MACE) or death from any cause at 1 year, death within 30 days of revascularisation, minor re-interventions at 1 year, total number of re-interventions at 1 year and rate of systemic or gastrointestinal bleed at 1 year.Risk of amputation, MALE and MACE will be analysed using Cox models. All remaining outcomes will be analysed using negative binomial models. Potential competing events for the risk of amputation will be investigated as part of a sensitivity analysis. Patients given a non-clopidogrel-based medication will be compared as an additional analysis.
Manchester University Research Ethics Committee approval obtained as part of the Implementing Pharmacogenetics to Improve Prescribing (IPTIP) trial process (IRAS 305751). The results of the study will be published in a peer-reviewed journal and presented at international conferences.
This work is a sub-protocol for the IPTIP study which is registered as ISRCTN14050335.
慢性肢体威胁性缺血（CLTI）患者常被处方氯吡格雷，以降低发生严重肢体和心血管不良事件的风险。氯吡格雷由CYP2C19酶代谢，该基因存在常见变异。这些变异会影响个体将氯吡格雷代谢为其活性代谢物的能力。很少有研究调查患者基因型与血管外科手术结局之间的关系。这项工作旨在确定接受氯吡格雷治疗的CLTI患者血管再通术后患者基因型与结局之间的关系。它将探讨药物遗传学是否可用于确保为患者处方有效药物以优化其结局。
这是一项观察性队列研究，研究对象为在曼彻斯特大学国民保健服务基金会信托医院接受下肢手术、血管腔内或混合血管再通术治疗CLTI的患者。血管再通术前或术后不久将招募术后服用氯吡格雷的患者以及接受非氯吡格雷药物治疗方案的患者。患者将接受基因分型，并通过在线记录进行随访。该研究有90%的把握度检测到114例截肢病例，目标样本量为483名参与者。主要结局为1年时的截肢风险以及1年时严重肢体不良事件（MALE）风险或任何原因导致的死亡的复合终点。次要结局为1年时的MALE风险、1年时严重心血管不良事件（MACE）风险或任何原因导致的死亡、血管再通术后30天内的死亡、1年时的小的再次干预、1年时的再次干预总数以及1年时的全身或胃肠道出血率。截肢风险、MALE和MACE将使用Cox模型进行分析。所有其余结局将使用负二项式模型进行分析。作为敏感性分析的一部分，将调查截肢风险的潜在竞争事件。作为额外分析，将对接受非氯吡格雷药物治疗的患者进行比较。
作为实施药物遗传学改善处方（IPTIP）试验过程的一部分，已获得曼彻斯特大学研究伦理委员会的批准（IRAS 305751）。研究结果将发表在同行评审期刊上，并在国际会议上展示。
这项工作是IPTIP研究的子方案，该研究已注册为ISRCTN14050335。
