Supplementary Material for: IV-Thrombolysis for Acute Ischemic Stroke with Unknown Onset in Patients on Oral Anticoagulation

Abstract
Introduction
IV-thrombolysis is established in the unknown or extended time window based on multimodal imaging. Further, increasing evidence exists regarding IV-thrombolysis in patients on oral anticoagulation including direct oral anticoagulants (DOAC). However, data on IV-thrombolysis in ischemic stroke patients on oral anticoagulation with unknown time of stroke onset is sparse.

Methods
This study bases on the longitudinal cohort study Stroke Research Consortium in Northern Bavaria (STAMINA; ClinicalTrials.gov Identifier: NCT04357899). Acute ischemic stroke patients treated with iv-thrombolysis (IVT) in the unknown or extended time window from January 2015 to December 2019 were included. Patient selection based on multimodal CT or MRI. Patients on oral anticoagulation (vitamin-K antagonist (VKA) or DOAC within 48 hours) were eligible for IV-thrombolysis based on INR-measurement (VKA) or plasma levels (DOAC) according to an institutional protocol. Primary outcomes were the incidence of any and symptomatic intracranial hemorrhage.

Results
Of 170 ischemic stroke patients treated with IV-thrombolysis in the unknown or extended time window, 151 had no oral anticoagulation at stroke onset and 19 were on oral anticoagulation (6 on vitamin-K antagonist (VKA) and 13 on direct oral anticoagulant (DOAC)). The risk of symptomatic ICH according to ECASS II criteria was similar between the patients with and without oral anticoagulation (1 (5.3%) vs. 4 (2.7%); p=0.453). After adjustment for confounding factors pre-medication with oral anticoagulation was not associated with symptomatic ICH (aOR 1.02 (0.09 – 11.02); p=0.988).

Conclusion
IV-thrombolysis for ischemic stroke with unknown onset appeared safe in selected patients on oral anticoagulation with both DOAC and VKA.

摘要
引言
基于多模态成像，静脉溶栓（intravenous thrombolysis，IVT）已被应用于未知发病时间或延长时间窗的卒中患者中。此外，越来越多的证据支持口服抗凝治疗（包括直接口服抗凝剂（direct oral anticoagulants，DOAC））患者接受静脉溶栓治疗。然而，针对发病时间未知且接受口服抗凝治疗的缺血性卒中患者行静脉溶栓的相关研究数据仍较为匮乏。
方法
本研究依托北巴伐利亚卒中研究联盟（STAMINA）的纵向队列研究（临床试验注册平台（ClinicalTrials.gov）注册号：NCT04357899）。研究纳入2015年1月至2019年12月期间，于未知发病时间或延长时间窗内接受静脉溶栓（intravenous thrombolysis，IVT）治疗的急性缺血性卒中患者。患者入选基于多模态计算机断层扫描（CT）或磁共振成像（MRI）检查结果。根据本机构的试验方案，对于卒中发病48小时内接受口服抗凝治疗的患者（维生素K拮抗剂（vitamin K antagonist，VKA）或直接口服抗凝剂（DOAC）），可通过检测国际标准化比值（INR，针对VKA使用者）或血浆药物浓度（针对DOAC使用者）评估其是否符合静脉溶栓治疗的入选标准。本研究的主要结局指标为任意类型颅内出血及症状性颅内出血（symptomatic intracranial hemorrhage）的发生率。
结果
在170例于未知发病时间或延长时间窗内接受静脉溶栓治疗的缺血性卒中患者中，151例患者卒中发病时未接受口服抗凝治疗，19例患者发病时接受口服抗凝治疗，其中6例使用维生素K拮抗剂（VKA），13例使用直接口服抗凝剂（DOAC）。依据欧洲急性卒中协作研究II（European Cooperative Acute Stroke Study II，ECASS II）标准评估，口服抗凝治疗组与非口服抗凝治疗组患者的症状性颅内出血风险无显著差异（分别为1例（5.3%）与4例（2.7%）；p=0.453）。在校正混杂因素后，院前口服抗凝治疗与症状性颅内出血无显著相关性（校正优势比（aOR）1.02，95%置信区间：0.09~11.02；p=0.988）。
结论
针对发病时间未知的缺血性卒中患者，在经过筛选的口服抗凝治疗（包括DOAC与VKA）人群中实施静脉溶栓治疗似乎具有安全性。