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.

背景与目的：随着基于传统危险因素的指南指导性二级预防方案的普及，缺血性卒中（ischemic stroke, IS）或短暂性脑缺血发作（transient ischemic attack, TIA）患者的卒中复发率已大幅降低，但仍存在残余复发风险。本研究旨在评估哪种IS亚型可从当前二级预防中获益最多，并探究不同IS病因分型患者残余复发风险的非传统危险因素。
方法：本研究纳入同时参与第三次中国卒中登记研究（Third China National Stroke Registry）生物标志物亚研究及影像学亚研究的IS/TIA患者。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、降压治疗及降糖治疗），对二级预防诊疗的执行情况进行评估。残余复发风险被定义为尽管严格遵循上述5项基于指南的二级预防策略，仍发生卒中复发的风险。采用Cox回归模型分析与卒中复发相关的危险因素。
结果：本研究共纳入9733例患者。随访3个月时，共计4186例（43.0%）患者坚持了全部5项二级预防策略，该群体的残余复发风险为5.1%。根据急性卒中治疗Org 10172试验（Trial of Org 10172 in Acute Stroke Treatment, TOAST）分型，心源性栓塞型卒中从当前二级预防中获益最为显著（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%）。即便坚持二级预防策略，高敏C反应蛋白、白细胞介素-6（interleukin-6, IL-6）水平升高及肾功能受损仍是LAA亚型患者残余复发风险的独立危险因素；而IL-6及氧化三甲胺（trimethylamine N-oxide）则与SAO亚型患者的残余复发风险显著相关。
结论：LAA与SAO亚型患者存在特异性的非传统危险因素，而炎症反应则是两类亚型患者残余复发风险的共同危险因素。