Vanderbilt University School of Medicine, 1161 21st Ave S # D3300, Nashville, TN 37232, United States; Surgical Outcomes Center for Kids, Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, TN, United States.
Vanderbilt University School of Medicine, 1161 21st Ave S # D3300, Nashville, TN 37232, United States.
J Stroke Cerebrovasc Dis. 2021 Feb;30(2):105464. doi: 10.1016/j.jstrokecerebrovasdis.2020.105464. Epub 2020 Nov 24.
Intracranial atherosclerotic disease (ICAD) is responsible for 8-10% of acute ischemic strokes, and resistance to antiplatelet therapy is prevalent. CYP2C19 gene loss-of-function (up to 45% of patients) causes clopidogrel resistance. For patients with asymptomatic ICAD and ICAD characterized by transient ischemic attack (TIA), this study measures the effect of CYP2C19 loss-of-function on ischemic stroke risk during clopidogrel therapy.
From a deidentified database of medical records, patients were selected with ICD-9/10 code for ICAD, availability of CYP2C19 genotype, clopidogrel exposure, and established patient care. Dual-antiplatelet therapy patients were included. Patients with prior ischemic stroke, other neurovascular condition, intracranial angioplasty/stenting, or observation time <1 month were excluded. Time-to-event analysis using Cox regression was conducted to model first-time ischemic stroke events based on CYP2C19 loss-of-function allele and adjusted for age, gender, race, length of aspirin, length of concurrent antiplatelet/anticoagulant treatment, diabetes, coagulopathy, hypertension, heart disease, atrial fibrillation, and lipid disorder. Subset analyses were performed for asymptomatic and post-TIA subtypes of ICAD.
A total of 337 patients were included (median age 68, 58% male, 88% Caucasian, 26% CYP2C19 loss-of-function). A total of 161 (47.8%) patients had TIA at time of ICAD diagnosis, while 176 (52.2%) were asymptomatic. First-time ischemic stroke was observed among 20 (12.4%) post-TIA ICAD patients and 17 (9.7%) asymptomatic ICAD patients. Median observation time was 2.82 [IQR 1.13-5.17] years. CYP2C19 loss-of-function allele was associated with ischemic stroke event (HR 2.2, 95% CI 1.1-4.3, p=0.020) after adjustment. Post-TIA ICAD patients had a higher risk of ischemic stroke from CYP2C19 loss-of-function (HR 3.4, 95% CI 1.4-8.2, p=0.006).
CYP2C19 loss-of-function was associated with 3-fold increased risk of first-time ischemic stroke for ICAD patients treated with clopidogrel after TIA. This effect was not observed for asymptomatic ICAD. CYP2C19-guided antiplatelet selection may improve stroke prevention in ICAD after TIA.
颅内动脉粥样硬化性疾病（ICAD）占急性缺血性中风的 8-10%，抗血小板治疗抵抗较为常见。CYP2C19 基因失功能（高达 45%的患者）导致氯吡格雷抵抗。对于无症状性 ICAD 和以短暂性脑缺血发作（TIA）为特征的 ICAD 患者，本研究旨在测量 CYP2C19 失功能对氯吡格雷治疗期间缺血性中风风险的影响。
从医疗记录的 ICD-9/10 代码选择具有 ICAD、CYP2C19 基因型、氯吡格雷暴露和既定患者护理的患者。纳入双重抗血小板治疗患者。排除有既往缺血性中风、其他神经血管疾病、颅内血管成形术/支架置入术或观察时间<1 个月的患者。使用 Cox 回归进行时间事件分析，根据 CYP2C19 失功能等位基因建立首次缺血性中风事件模型，并调整年龄、性别、种族、阿司匹林使用时间、同时使用抗血小板/抗凝药物的时间、糖尿病、凝血障碍、高血压、心脏病、心房颤动和血脂异常。对无症状和 TIA 后 ICAD 亚型进行亚组分析。
共纳入 337 例患者（中位年龄 68 岁，58%为男性，88%为白种人，26%为 CYP2C19 失功能）。161 例（47.8%）患者在 ICAD 诊断时患有 TIA，176 例（52.2%）为无症状。在 20 例 TIA 后 ICAD 患者和 17 例无症状 ICAD 患者中观察到首次缺血性中风。中位观察时间为 2.82[IQR 1.13-5.17]年。CYP2C19 失功能等位基因与调整后的缺血性中风事件相关（HR 2.2，95%CI 1.1-4.3，p=0.020）。TIA 后 ICAD 患者 CYP2C19 失功能与缺血性中风风险增加（HR 3.4，95%CI 1.4-8.2，p=0.006）相关。
TIA 后接受氯吡格雷治疗的 ICAD 患者，CYP2C19 失功能与首次缺血性中风风险增加 3 倍相关。这种作用在无症状性 ICAD 中未观察到。CYP2C19 指导的抗血小板药物选择可能会改善 TIA 后 ICAD 的卒中预防。
