Supplementary Material for: Anticoagulation and Risk of Stroke Recurrence in Patients with Embolic Stroke of Undetermined Source Having No Potential Source of Embolism

<b><i>Background:</i></b> This study aimed to determine whether use of oral anticoagulants (OACs) was associated with a reduced risk of recurrent stroke compared with use of antiplatelets (APs) in patients with embolic stroke of undetermined source (ESUS) having no potential source of embolism. <b><i>Methods:</i></b> Of 8,790 patients with acute ischemic stroke registered at 7 centers in the Fukuoka Stroke Registry from June 2007 to May 2017, we included 681 patients (mean age 69.7 [SD 14.1] years, 48.3% men) who experienced ESUS without a potential source of embolism and received OAC alone or AP alone. We estimated hazard ratios (HRs) and 95% confidential intervals (CIs) of recurrent ischemic stroke or any stroke after discharge using a Cox proportional hazards model and Fine and Gray model. <b><i>Results:</i></b> During a mean follow-up of 3.4 (SD 1.7) years, event rates of recurrent ischemic stroke were 4.4 per 100 person-years in 489 patients treated with AP and 2.0 per 100 person-years in 192 patients treated with OAC. OAC use was associated with a reduced risk of recurrent ischemic stroke, even after adjusting for potential confounding factors (multivariable-adjusted HR [95% CI], 0.42 [0.23–0.80]) and when additionally considering death as a competing risk (0.45 [0.24–0.85]). The reduced risk of recurrent ischemic stroke was still observed in patients treated with OAC (0.32 [0.15–0.67]) in reference to propensity score-matched patients treated with AP. These associations were maintained for all types of stroke, including ischemic and hemorrhagic stroke. <b><i>Conclusions:</i></b> This nonrandomized observational study suggests that anticoagulation therapy might be associated with a reduced risk of recurrent stroke compared with antiplatelet therapy in patients with ESUS in whom no potential source of embolism was identified. Further study should be performed in consideration of a potential source of embolism even in patients with ESUS.

<b><i>研究背景：</i></b> 本研究旨在明确在未发现潜在栓塞源的不明来源栓塞性卒中（embolic stroke of undetermined source, ESUS）患者中，与抗血小板药物（antiplatelets, APs）治疗相比，口服抗凝药（oral anticoagulants, OACs）治疗是否可降低卒中复发风险。<b><i>研究方法：</i></b> 2007年6月至2017年5月期间，于福冈卒中登记库（Fukuoka Stroke Registry）7个中心登记的8790例急性缺血性卒中患者中，本研究纳入了681例符合以下条件的患者：确诊为不明来源栓塞性卒中且未发现潜在栓塞源，仅接受口服抗凝药或仅接受抗血小板药物治疗；患者平均年龄为69.7岁（标准差14.1），男性占比48.3%。本研究采用Cox比例风险模型与Fine-Gray竞争风险模型，估算了患者出院后复发性缺血性卒中或任何类型卒中的风险比（hazard ratios, HRs）及95%置信区间（confidence intervals, CIs）。<b><i>研究结果：</i></b> 平均随访3.4年（标准差1.7）后，抗血小板药物治疗组（489例）的复发性缺血性卒中事件发生率为4.4例/100人年，口服抗凝药治疗组（192例）为2.0例/100人年。即使在校正潜在混杂因素后（多因素校正后的风险比[95%CI]为0.42[0.23~0.80]），且将死亡视为竞争风险时（0.45[0.24~0.85]），口服抗凝药治疗仍与复发性缺血性卒中风险降低相关。以倾向得分匹配后的抗血小板药物治疗患者为参照，口服抗凝药治疗患者的复发性缺血性卒中风险仍显著降低（0.32[0.15~0.67]）。上述关联在包括缺血性卒中与出血性卒中在内的所有卒中类型中均保持一致。<b><i>研究结论：</i></b> 本项非随机观察性研究表明，在未发现潜在栓塞源的不明来源栓塞性卒中患者中，与抗血小板治疗相比，抗凝治疗或可降低卒中复发风险。未来仍需开展进一步研究，即使在不明来源栓塞性卒中患者中也应考量潜在栓塞源的排查。