Safety and efficacy of sonothrombolysis for acute ischaemic stroke: a multicentre, double-blind, phase 3, randomised controlled trial
Safety and efficacy of sonothrombolysis for acute ischaemic stroke: a multicentre, double-blind, phase 3, randomised controlled trial
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DOI：
10.1016/s1474-4422(19)30026-2
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发表时间：
2019-04-01
期刊：
影响因子：
48
通讯作者：
Schellinger, Peter D.
中科院分区：
文献类型：
--
作者：
Alexandrov, Andrei, V;Kohrmann, Martin;Schellinger, Peter D.
背景：脉冲波超声可增加颅内血栓对阿替普酶（重组组织型纤溶酶原激活剂）的暴露，可能促进早期再灌注。我们的目的是确定是否一种新的操作员独立的经颅超声设备提供低功率高频超声可以改善功能的结果与阿替普酶治疗急性缺血性stroke.Methods后，我们做了一个多中心，双盲，3期，随机对照试验（CLOTBUST-ER）在76个医疗中心在14个国家。我们纳入了在北美症状发作3 h内和在所有其他国家症状发作4.5 h内接受静脉溶栓（阿替普酶推注）的急性缺血性卒中（美国国立卫生研究院卒中量表评分>= 10）患者。通过交互式网络响应系统将参与者随机分配（1：1）到主动超声（2 MHz脉冲波超声120分钟[超声溶栓];干预组）或假超声（对照组）。使用独立于操作员的器械进行超声输送，该器械必须在阿替普酶推注后30分钟内激活。参与者、研究者和评估结果的人都不知道小组分配。主要结局是症状发作3小时内入组的患者在90天时改良兰金量表评分的改善，在意向治疗人群中使用有序logistic回归偏移分析评估为共同比值比（cOR）。本试验在ClinicalTrials.gov注册，编号NCT 01098981。研究结果在2013年8月至2015年4月期间，335名患者被随机分配到干预组，341名患者被随机分配到对照组。与对照组相比，干预组90天时改良兰金量表评分改善的校正cOR为1.05（95% CI 0.77-1.45; p=0.74）。干预组317例患者中有51例（16%）死亡，对照组329例患者中有44例（13%）死亡（未校正OR 1.24，95%CI 0.80 -1. 00）。九十二; 13=0.37）和83例（26%）和79例（24%）分别发生严重不良事件（1.12，0.79-1.60; p=0.53）。解释急性缺血性卒中后使用阿替普酶治疗的患者，通过独立于操作者的设备进行超声溶栓是可行的，很可能是安全的，但在90天时没有观察到临床获益。超声溶栓可以在依赖患者转移进行血管内再灌注治疗的卒中中心进行的随机试验中或在这些治疗尚不能作为标准治疗提供的国家进行进一步研究。版权所有（C）2019 Elsevier Ltd.保留所有权利。
Background Pulsed-wave ultrasound increases the exposure of an intracranial thrombus to alteplase (recombinant tissue plasminogen activator), potentially facilitating early reperfusion. We aimed to ascertain if a novel operator-independent transcranial ultrasound device delivering low-power high-frequency ultrasound could improve functional outcome in patients treated with alteplase after acute ischaemic stroke.Methods We did a multicentre, double-blind, phase 3, randomised controlled trial (CLOTBUST-ER) at 76 medical centres in 14 countries. We included patients with acute ischaemic stroke (National Institutes of Health Stroke Scale score >= 10) who received intravenous thrombolysis (alteplase bolus) within 3 h of symptom onset in North America and within 4.5 h of symptom onset in all other countries. Participants were randomly allocated (1:1) via an interactive web response system to either active ultrasound (2 MHz pulsed-wave ultrasound for 120 min [sonothrombolysis]; intervention group) or sham ultrasound (control group). Ultrasound was delivered using an operator-independent device, which had to be activated within 30 min of the alteplase bolus. Participants, investigators, and those assessing outcomes were unaware of group assignments. The primary outcome was improvement in the modified Rankin Scale score at 90 days in patients enrolled within 3 h of symptom onset, assessed in the intention-to-treat population as a common odds ratio (cOR) using ordinal logistic regression shift analysis. This trial is registered with ClinicalTrials.gov , number NCT01098981. The trial was stopped early by the funder after the second interim analysis because of futility.Findings Between August, 2013, and April, 2015, 335 patients were randomly allocated to the intervention group and 341 patients to the control group. Compared with the control group, the adjusted cOR for an improvement in modified Rankin Scale score at 90 days in the intervention group was 1.05 (95% CI 0.77-1.45; p=0.74). 51 (16%) of 317 patients in the intervention group and 44 (13%) of 329 patients in the control group died (unadjusted OR 1.24, 95% CI 0 .80-1. 92; 13=0.37) and 83 (26%) and 79 (24%), respectively, had serious adverse events (1.12, 0.79-1.60; p=0.53).Interpretation Sonothrombolysis delivered by an operator-independent device to patients treated with alteplase after acute ischaemic stroke was feasible and most likely safe, but no clinical benefit was seen at 90 days. Sonothrombolysis could be further investigated either in randomised trials undertaken in stroke centres that are dependent on patient transfer for endovascular reperfusion therapies or in countries where these treatments cannot yet be offered as the standard of care. Copyright (C) 2019 Elsevier Ltd. All rights reserved.