Galinovic Ivana, Fiebach Jochen B, Boutitie Florent, Cheng Bastian, Cho Tae-Hee, Ebinger Martin, Endres Matthias, Enzinger Christian, Fiehler Jens, Ford Ian, Gregori Johannes, Günther Matthias, Lemmens Robin, Muir Keith W, Nighoghossian N, Roy Pascal, Simonsen Claus Z, Thijs Vincent N, Wouters Anke, Gerloff Christian, Thomalla Götz, Pedraza Salvador
From the Center for Stroke Research Berlin (I.G., J.B.F.), Charité-Universitätsmedizin Berlin, Germany; Service de Biostatistique (F.B., P.R.), Hospices Civils de Lyon, France; Department of Neurology (B.C., C.G., G.T.), University Medical Center Hamburg-Eppendorf, France; Department of Stroke Medicine (T.-H.C.), Université Claude Bernard Lyon 1, Hospices Civils de Lyon, France; Neurologie der Rehaklinik Medical Park Humboldtmühle (M. Ebinger), Berlin; Klinik und Hochschulambulanz für Neurologie (M. Endres), Charité-Universitätsmedizin Berlin; Center for Stroke Research Berlin (M. Endres); German Center for Neurodegenerative Diseases (DZNE), partner site Berlin (M. Endres); German Centre for Cardiovascular Research (DZHK), partner site Berlin (M. Endres); German Center for Mental Health (DZPG), partner site Berlin (M. Endres), Germany; Department of Neurology (C.E.), Medical University of Graz, Austria; Department of Diagnostic and Interventional Neuroradiology (J.F.), Universitätsklinikum Hamburg-Eppendorf, Germany; Robertson Centre for Biostatistics (I.F.), University of Glasgow, Scotland; mediri GmbH (J.G.); Fraunhofer Institute for Digital Medicine MEVIS (M.G.), Bremen, Germany; Department of Neurosciences (R.L., A.W.), Experimental Neurology, KU Leuven-University of Leuven, Belgium; School of Psychology & Neuroscience (K.W.M.), University of Glasgow, Scotland; Department of Stroke Medicine (N.N.), Université Claude Bernard Lyon 1, and Hospices Civils de Lyon, France; Department of Neurology (C.Z.S.), Aarhus University Hospital, Denmark; Florey Institute of Neuroscience and Mental Health (V.N.T.), Heidelberg, Australia; and Institut d'Investigació Biomèdica de Girona (S.P.), Hospital Universitari Doctor Josep Trueta, Girona, Spain.
Neurology. 2025 Jan 28;104(2):e209871. doi: 10.1212/WNL.0000000000209871. Epub 2024 Dec 20.
Data from randomized trials on the treatment effect of pure thrombolysis in patients with vessel occlusion are lacking. We examined data from a corresponding subsample of patients from the multicenter, randomized, placebo-controlled WAKE-UP trial to determine whether MRI-guided IV thrombolysis with alteplase in unknown-onset ischemic stroke benefits patients presenting with vessel occlusion.
Patients with an acute ischemic lesion visible on MRI diffusion-weighted imaging but no marked parenchymal hyperintensity on fluid-attenuated inversion recovery images were randomized to treatment with IV alteplase or placebo. The primary end point was a favorable outcome defined by a modified Rankin Scale score of 0-1 at 90 days after stroke. We investigated the interaction between vessel status and treatment effect using an unconditional logistic regression model. Treatment effects (adjusted odds ratio [aOR]) and their 95% CI were compared in patients with and without any vessel occlusion (AVO) and large vessel occlusion (LVO).
185 patients (mean age 64.5 years, 46% female, median NIH Stroke Scale score 9, median time between last seen well and MRI 10.26 hours) received treatment and presented with an occlusion. 98 (20%) had LVO (defined as occlusion of the internal carotid artery, middle cerebral artery trunk, or combination). A favorable outcome was observed in 30 of 94 patients with AVO (31.9%) in the alteplase group and in 18 of 91 (19.8%) in the placebo group (aOR 2.04, 95% CI 1.00-4.18). In the subgroup of patients with LVO, a favorable outcome was observed in 16 of 53 (30.2%) in the alteplase group and in 7 of 44 (15.9%) in the placebo group (aOR 2.08, 95% CI 0.71-6.10). Treatment with alteplase was associated with higher odds of favorable outcomes with no heterogeneity of treatment effect between patients with AVO and patent vessel ( = 0.56), or between patients with and without LVO ( = 0.69).
Although the WAKE-UP study was not powered to demonstrate treatment efficacy in patient subpopulations, this subgroup analysis points to a benefit of MRI-guided thrombolysis in patients with unknown-onset ischemic stroke, independent of vessel occlusion.
Registered at ClinicalTrials.gov with unique identifier NCT01525290 (clinicaltrials.gov/study/NCT01525290). The study was first posted on February 2, 2012; the first patient was enrolled on September 24, 2012.
This study provides Class II evidence that for patients with unknown-onset ischemic stroke with AVO, MRI-guided treatment with IV tissue plasminogen activator improves outcomes.
关于血管闭塞患者单纯溶栓治疗效果的随机试验数据尚缺。我们研究了多中心、随机、安慰剂对照的WAKE-UP试验中相应患者亚组的数据，以确定在不明发病时间的缺血性卒中患者中，磁共振成像（MRI）引导下静脉注射阿替普酶溶栓是否对存在血管闭塞的患者有益。
MRI弥散加权成像上可见急性缺血性病灶但液体衰减反转恢复序列图像上无明显实质高信号的患者被随机分为静脉注射阿替普酶治疗组或安慰剂组。主要终点为卒中后90天改良Rankin量表评分为0 - 1分所定义的良好预后。我们使用无条件逻辑回归模型研究血管状态与治疗效果之间的相互作用。比较有或无任何血管闭塞（AVO）及大血管闭塞（LVO）患者的治疗效果（调整优势比[aOR]）及其95%置信区间。
185例患者（平均年龄64.5岁，46%为女性，美国国立卫生研究院卒中量表评分中位数为9，最后一次正常状态至MRI检查的时间中位数为10.26小时）接受治疗并存在血管闭塞。98例（20%）有LVO（定义为颈内动脉、大脑中动脉主干闭塞或两者合并）。阿替普酶组94例AVO患者中有30例（31.9%）获得良好预后，安慰剂组91例中有18例（19.8%）获得良好预后（aOR 2.04，95%置信区间1.00 - 4.18）。在LVO亚组患者中，阿替普酶组53例中有16例（30.2%）获得良好预后，安慰剂组44例中有7例（15.9%）获得良好预后（aOR 2.08，95%置信区间0.71 - 6.10）。阿替普酶治疗与良好预后的较高几率相关，AVO患者与血管通畅患者之间（P = 0.56）或有与无LVO患者之间（P = 0.69）治疗效果无异质性。
尽管WAKE-UP研究的样本量不足以证明在患者亚组中的治疗效果，但该亚组分析表明，在不明发病时间的缺血性卒中患者中，MRI引导下溶栓有益，且与血管闭塞无关。
在ClinicalTrials.gov注册，唯一标识符为NCT01525290（clinicaltrials.gov/study/NCT01525290）。该研究于2012年2月2日首次发布；首例患者于2012年9月24日入组。
本研究提供II类证据，即对于存在AVO的不明发病时间的缺血性卒中患者，MRI引导下静脉注射组织型纤溶酶原激活剂可改善预后。
