Supplementary Material for: White Matter Hyperintensities Improve Ischemic Stroke Recurrence Prediction

Background: Nearly one in 5 patients with ischemic stroke will invariably experience a second stroke within 5 years. Stroke risk stratification schemes based solely on clinical variables perform only modestly in non-atrial fibrillation (AF) patients and improvement of these schemes will enhance their clinical utility. Cerebral white matter hyperintensities are associated with an increased risk of incident ischemic stroke in the general population, whereas their association with the risk of ischemic stroke recurrence is more ambiguous. In a non-AF stroke cohort, we investigated the association between cerebral white matter hyperintensities and the risk of recurrent ischemic stroke, and we evaluated the predictive performance of the CHA2DS2VASc score and the Essen Stroke Risk Score (clinical scores) when augmented with information on white matter hyperintensities. Methods: In a registry-based, observational cohort study, we included 832 patients (mean age 59.6 (SD 13.9); 42.0% females) with incident ischemic stroke and no AF. We assessed the severity of white matter hyperintensities using MRI. Hazard ratios stratified by the white matter hyperintensities score and adjusted for the components of the CHA2DS2VASc score were calculated based on the Cox proportional hazards analysis. Recalibrated clinical scores were calculated by adding one point to the score for the presence of moderate to severe white matter hyperintensities. The discriminatory performance of the scores was assessed with the C-statistic. Results: White matter hyperintensities were significantly associated with the risk of recurrent ischemic stroke after adjusting for clinical risk factors. The hazard ratios ranged from 1.65 (95% CI 0.70-3.86) for mild changes to 5.28 (95% CI 1.98-14.07) for the most severe changes. C-statistics for the prediction of recurrent ischemic stroke were 0.59 (95% CI 0.51-0.65) for the CHA2DS2VASc score and 0.60 (95% CI 0.53-0.68) for the Essen Stroke Risk Score. The recalibrated clinical scores showed improved C-statistics: the recalibrated CHA2DS2VASc score 0.62 (95% CI 0.54-0.70; p = 0.024) and the recalibrated Essen Stroke Risk Score 0.63 (95% CI 0.56-0.71; p = 0.031). C-statistics of the white matter hyperintensities score were 0.62 (95% CI 0.52-0.68) to 0.65 (95% CI 0.58-0.73).Conclusions: An increasing burden of white matter hyperintensities was independently associated with recurrent ischemic stroke in a cohort of non-AF ischemic stroke patients. Recalibration of the CHA2DS2VASc score and the Essen Stroke Risk Score with one point for the presence of moderate to severe white matter hyperintensities led to improved discriminatory performance in ischemic stroke recurrence prediction. Risk scores based on white matter hyperintensities alone were at least as accurate as the established clinical risk scores in the prediction of ischemic stroke recurrence.

背景：每5名缺血性脑卒中患者中，近1人会在5年内复发脑卒中。仅基于临床变量的脑卒中风险分层方案在非心房颤动（atrial fibrillation, AF）患者中仅表现中等，对这类方案的优化可提升其临床应用价值。脑白质高信号（cerebral white matter hyperintensities）与普通人群首发缺血性脑卒中的风险升高存在关联，但其与缺血性脑卒中复发风险的关联则更为模糊。本研究在非房颤脑卒中队列中，探讨了脑白质高信号与缺血性脑卒中复发风险的关联，并评估了纳入脑白质高信号信息后，CHA₂DS₂-VASc评分与Essen脑卒中风险评分的预测性能。方法：本研究为一项基于登记队列的观察性研究，共纳入832例首发缺血性脑卒中且无房颤的患者（平均年龄59.6岁，标准差13.9；女性占比42.0%）。采用磁共振成像（magnetic resonance imaging, MRI）评估脑白质高信号的严重程度。基于Cox比例风险回归分析，计算经脑白质高信号评分分层、且校正CHA₂DS₂-VASc评分各组分的风险比。对于存在中重度脑白质高信号的患者，在原有临床评分基础上加1分，以此计算重新校准后的临床评分。采用C统计量（C-statistic）评估各评分的区分性能。结果：在校正临床风险因素后，脑白质高信号与缺血性脑卒中复发风险显著相关。风险比范围从轻度改变的1.65（95%置信区间0.70~3.86）至最严重改变的5.28（95%置信区间1.98~14.07）。CHA₂DS₂-VASc评分预测缺血性脑卒中复发的C统计量为0.59（95%置信区间0.51~0.65），Essen脑卒中风险评分为0.60（95%置信区间0.53~0.68）。重新校准后的临床评分展现出更优的区分性能：校正后的CHA₂DS₂-VASc评分为0.62（95%置信区间0.54~0.70；p=0.024），校正后的Essen脑卒中风险评分为0.63（95%置信区间0.56~0.71；p=0.031）。脑白质高信号评分的C统计量范围为0.62（95%置信区间0.52~0.68）至0.65（95%置信区间0.58~0.73）。结论：在非房颤缺血性脑卒中患者队列中，脑白质高信号负荷的升高与缺血性脑卒中复发独立相关。针对存在中重度脑白质高信号的患者，为CHA₂DS₂-VASc评分与Essen脑卒中风险评分各加1分进行重新校准后，二者在缺血性脑卒中复发预测中的区分性能得到提升。仅基于脑白质高信号的风险评分，在缺血性脑卒中复发预测中的准确性至少与已确立的临床风险评分相当。