From the Klinik und Hochschulambulanz für Neurologie (L.S., T.B.B., M. Endres, C.H.N.), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humbold-Universität zu Berlin, and Berlin Institute of Health; Center for Stroke Research Berlin (L.S., T.B.B., I.G., J. Fiebach, M. Ebinger, M. Endres, C.H.N.), Charité-Universitätsmedizin; Berlin Institute of Health (L.S., T.B.B., M. Endres, C.H.N.), Germany; Hospices Civils de Lyon (F.B.), Service de Biostatistique; Université Lyon 1 and Centre National de la Recherche Scientifique (F.B.), UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne, France; Department of Neurology (J.V.), University Hospital Bern, Switzerland; Klinik und Poliklinik für Neurologie (M.J., B.C., G.T., C.G.), Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology (C.Z.S.), Aarhus University Hospital, Denmark; Department of Stroke Medicine (T.-H.C.), Université Claude Bernard Lyon 1, and Hospices Civils de Lyon, France; Department of Diagnostic and Interventional Neuroradiology (J. Fiehler), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Radiology (J.P., S.P.), Doctor Josep Trueta University Hospital, Department of Radiology (IDI) (J.P., S.P.), Girona Biomedical Research Institute (IDIBGI), Spain; Department of Neurology (V.T.), Austin Health, Heidelberg, Australia; Institute of Neuroscience and Psychology, University of Glasgow (K.M.), UK; Department of Stroke Medicine (N.N.), Université Claude Bernard Lyon 1, and Hospices Civils de Lyon, France; Department of Neurology (M. Ebinger), Medical Park Berlin Humboldtmühle; German Center for Cardiovascular Research (DZHK) (M. Endres, C.H.N.), Partner Site Berlin; German Center for Neurodegenerative Diseases (DZNE) (M. Endres, C.H.N.), Partner Site Berlin; ExcellenceCluster NeuroCure (M. Endres), Charité-Universitätsmedizin Berlin, Germany; Department of Neurology (R.L.), University Hospitals Leuven, Belgium; Department of Neurosciences (R.L.), Experimental Neurology, KU Leuven-University of Leuven; and VIB-KU Leuven Center for Brain and Disease Research (R.L.), Laboratory of Neurobiology, Leuven, Belgium.
Neurology. 2022 Jan 18;98(3):e302-e314. doi: 10.1212/WNL.0000000000013055. Epub 2021 Nov 15.
Cerebral microbleeds (CMBs) are common in patients with acute ischemic stroke and are associated with increased risk of intracerebral hemorrhage (ICH) after intravenous thrombolysis. Whether CMBs modify the treatment effect of thrombolysis is unknown.
We performed a prespecified analysis of the prospective randomized controlled multicenter Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial including patients with acute ischemic stroke with unknown time of symptom onset and diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch on MRI receiving alteplase or placebo. Patients were screened and enrolled between September 2012 and June 2017 (with final follow-up in September 2017). Patients were randomized to treatment with IV thrombolysis with alteplase at 0.9 mg/kg body weight or placebo. CMB status (presence, number, and distribution) was assessed after study completion by 3 raters blinded to clinical information following a standardized protocol. Outcome measures were excellent functional outcome at 90 days, defined by modified Rankin Scale (mRS) score ≤1, and symptomatic ICH according to National Institutes of Neurological Disease and Stroke trial criteria 22 to 36 hours after treatment.
Of 503 patients enrolled in the WAKE-UP trial, 459 (91.3%; 288 [63%] men) were available for analysis. Ninety-eight (21.4%) had at least 1 CMB on baseline imaging; 45 (9.8%) had exactly 1 CMB; 37 (8.1%) had 2 to 4 CMBs; and 16 (3.5%) had ≥5 CMBs. Presence of CMBs was associated with a nonsignificant increased risk of symptomatic ICH (11.2% vs 4.2%; adjusted odds ratio [OR] 2.32, 95% confidence interval [CI] 0.99-5.43, = 0.052) but had no effect on functional outcome at 90 days (mRS score ≤1: 45.8% vs 50.7%; adjusted OR 0.99, 95% CI 0.59-1.64, = 0.955). Patients receiving alteplase had better functional outcome (mRS score ≤1: 54.6% vs 44.6%, adjusted OR 1.61, 95% CI 1.07-2.43, = 0.022) without evidence of heterogeneity in relation to CMB presence ( of the interactive term = 0.546). Results were similar for subpopulations with strictly lobar (presumed cerebral amyloid angiopathy related) or not strictly lobar CMB distribution.
In the randomized-controlled WAKE-UP trial, we saw no evidence of reduced treatment effect of alteplase in patients with acute ischemic stroke with ≥1 CMBs. Additional studies are needed to determine the treatment effect of alteplase and its benefit-harm ratio in patients with a larger number of CMBs.
ClinicalTrials.gov identifier NCT01525290; ClinicalTrialsRegister.EU identifier 2011-005906-32.
This study provides Class II evidence that for patients with acute ischemic stroke with unknown time of onset and diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch who received IV alteplase, CMBs are not significantly associated with functional outcome at 90 days.
脑微出血（CMB）在急性缺血性脑卒中患者中较为常见，并且与静脉溶栓后颅内出血（ICH）的风险增加相关。CMB 是否会影响溶栓治疗的效果尚不清楚。
我们对前瞻性随机对照多中心 Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke（WAKE-UP）试验进行了预设分析，该试验纳入了急性缺血性脑卒中且起病时间未知且磁共振弥散加权成像-液体衰减反转恢复不匹配的患者，这些患者接受阿替普酶或安慰剂治疗。患者于 2012 年 9 月至 2017 年 6 月间进行筛查和入组（最终随访时间为 2017 年 9 月）。患者被随机分配接受阿替普酶 0.9mg/kg 体重或安慰剂的静脉溶栓治疗。研究完成后，3 名评估者根据标准化方案，在不了解临床信息的情况下，对 CMB 状态（存在、数量和分布）进行评估。主要转归为治疗后 22 至 36 小时根据国立神经病学与卒中研究所试验标准评估的改良 Rankin 量表（mRS）评分≤1 的 90 天良好功能结局和症状性 ICH。
在 WAKE-UP 试验中，共纳入了 503 名患者，其中 459 名（91.3%；288 名男性）可进行分析。98 名（21.4%）患者基线影像上至少有 1 个 CMB；45 名（9.8%）患者存在 1 个 CMB；37 名（8.1%）患者有 2 至 4 个 CMB；16 名（3.5%）患者有≥5 个 CMB。CMB 的存在与症状性 ICH 的风险增加无显著相关性（11.2%比 4.2%；调整后的优势比[OR]2.32，95%置信区间[CI]0.99-5.43， = 0.052），但对 90 天的功能结局无影响（mRS 评分≤1：45.8%比 50.7%；调整后的 OR 0.99，95% CI 0.59-1.64， = 0.955）。接受阿替普酶治疗的患者功能结局更好（mRS 评分≤1：54.6%比 44.6%，调整后的 OR 1.61，95% CI 1.07-2.43， = 0.022），但与 CMB 存在与否之间没有证据表明存在异质性（交互项的 = 0.546）。在严格的脑叶（推测与脑淀粉样血管病相关）或非严格的脑叶 CMB 分布亚组中，结果相似。
在随机对照的 WAKE-UP 试验中，我们没有发现 CMB 数量≥1 的急性缺血性脑卒中患者中阿替普酶治疗效果降低的证据。需要进一步的研究来确定阿替普酶的治疗效果及其在 CMB 数量较多的患者中的获益-风险比。
本研究提供了 II 级证据，对于起病时间未知且磁共振弥散加权成像-液体衰减反转恢复不匹配的接受静脉阿替普酶治疗的急性缺血性脑卒中患者，CMB 与 90 天的功能结局无显著相关性。
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