Supplementary Material for: Nontraditional Risk Factors for Residual Recurrence Risk in Patients with Ischemic Stroke of Different Etiologies

Background and Objective: With the popularization of guideline-based secondary prevention based on traditional risk factors, rates of stroke recurrence reduced greatly after ischemic stroke (IS) or transient ischemic attack (TIA), but the residual risk still exists. We aim to evaluate which IS subtype benefits the most from the current secondary prevention and to evaluate nontraditional risk factors for residual recurrence risk of different IS etiologies. Methods: The study included IS/TIA patients who participated in both biomarker substudy and imaging substudy of the Third China National Stroke Registry. We used 5 guideline-recommended interventions (antiplatelet, statins, anticoagulant, antihypertensive, and antidiabetic therapies) to document the performance of secondary prevention care. Residual risk was defined as the risk of stroke recurrence despite adherence to these 5 guideline-based secondary prevention strategies. Risk factors associated with stroke recurrence were analyzed by using Cox regression models. Results: In total, 9,733 patients were included in this study. At 3 months, 4,186 (43.0%) patients adhered to 5 secondary prevention strategies, and the residual risk of recurrence was 5.1%. According to Trial of Org 10172 in Acute Stroke Treatment subtypes, cardioembolism benefited the most from current secondary prevention (relative risk reduction: 65.2%), followed by large-artery atherosclerosis (LAA) (29.0%) and small-artery occlusion (SAO) (20.0%). Despite adhering to secondary prevention strategies, high sensitivity C-reactive protein, interleukin-6 (IL-6) levels, and impaired renal function were independent risk factors for the residual recurrence risk of LAA subtype, while IL-6 and trimethylamine N-oxide significantly contributed to the residual risk of SAO subtype. Conclusions: LAA and SAO subtypes own the specific nontraditional risk factors while inflammation is a common risk factor for residual recurrence risk of both.

背景与研究目的：随着基于传统风险因素的指南推荐二级预防的普及，缺血性脑卒中（ischemic stroke, IS）或短暂性脑缺血发作（transient ischemic attack, TIA）患者的脑卒中复发率已大幅降低，但仍存在残余复发风险。本研究旨在评估不同缺血性脑卒中亚型在当前二级预防方案中的获益程度，并探究不同病因亚型缺血性脑卒中残余复发风险的非传统危险因素。研究方法：本研究纳入同时参与第三次中国脑卒中登记研究（Third China National Stroke Registry）生物标志物亚研究与影像学亚研究的缺血性脑卒中/短暂性脑缺血发作患者。我们采用5项指南推荐的干预措施（抗血小板治疗、他汀类药物治疗、抗凝治疗、降压治疗与降糖治疗）来评估二级预防诊疗的落实情况。残余复发风险定义为：即便严格遵循上述5项基于指南的二级预防策略，仍发生脑卒中复发的风险。采用Cox回归模型分析与脑卒中复发相关的危险因素。研究结果：本研究共纳入9733例患者。随访至3个月时，4186例（43.0%）患者严格落实了5项二级预防策略，其残余复发风险为5.1%。根据急性脑卒中治疗ORG 10172试验（Trial of Org 10172 in Acute Stroke Treatment, TOAST）分型，心源性栓塞型卒中获益最为显著（相对风险降低率：65.2%），其次为大动脉粥样硬化型（large-artery atherosclerosis, LAA，29.0%）与小动脉闭塞型（small-artery occlusion, SAO，20.0%）。即便落实了二级预防策略，高敏C反应蛋白、白细胞介素-6（interleukin-6, IL-6）水平升高与肾功能受损均为大动脉粥样硬化型卒中残余复发风险的独立危险因素；而白细胞介素-6与氧化三甲胺（trimethylamine N-oxide）为小动脉闭塞型卒中残余复发风险的显著独立危险因素。研究结论：大动脉粥样硬化型与小动脉闭塞型卒中存在各自特异性的非传统危险因素，而炎症反应则是两类亚型残余复发风险的共同危险因素。