Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA.
Department of Neurology, Universitätsklinikum Erlangen, Erlangen, Germany; Department of Neurology, University Duisburg-Essen, Essen, Germany.
Lancet Neurol. 2019 Apr;18(4):338-347. doi: 10.1016/S1474-4422(19)30026-2.
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.
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.
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; p=0·37) and 83 (26%) and 79 (24%), respectively, had serious adverse events (1·12, 0·79-1·60; p=0·53).
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.
Cerevast Therapeutics.
脉冲式超声波能增加颅内血栓接触到阿替普酶（重组组织型纤溶酶原激活物）的机会，从而更有可能实现早期再灌注。我们旨在确定一种新型的、无需操作人员的经颅超声设备能否改善接受阿替普酶治疗后的急性缺血性脑卒中患者的功能结局，该设备能输送低功率高频超声波。
我们在 14 个国家的 76 家医疗中心开展了一项多中心、双盲、3 期、随机对照试验（CLOTBUST-ER）。纳入的患者为发病 3 小时内（北美）或 4.5 小时内（其他所有国家）接受静脉溶栓（阿替普酶推注）治疗的急性缺血性脑卒中患者（美国国立卫生研究院脑卒中量表评分≥10 分）。通过交互式网络应答系统将参与者以 1:1 的比例随机分配至超声治疗组（2 MHz 脉冲式超声波治疗 120 分钟[超声溶栓]）或假超声组（对照组）。使用无需操作人员的设备进行超声治疗，该设备必须在阿替普酶推注后 30 分钟内激活。参与者、研究者和评估结局的人员均对分组情况不知情。主要结局是在症状发作后 3 小时内入组的患者在 90 天时改良 Rankin 量表评分的改善情况，采用有序逻辑回归移位分析，在意向治疗人群中评估其共同优势比（cOR）。本试验在 ClinicalTrials.gov 注册，编号为 NCT01098981。由于无效，试验在第二次中期分析后被资助者提前终止。
2013 年 8 月至 2015 年 4 月，335 名患者被随机分配至干预组，341 名患者被分配至对照组。与对照组相比，干预组 90 天时改良 Rankin 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 名患者中有 51 名（16%）和对照组 329 名患者中有 44 名（13%）死亡（未校正 OR，1.24，95%CI，0.80-1.92；p=0.37），83 名（26%）和 79 名（24%）患者分别发生严重不良事件（1.12，0.79-1.60；p=0.53）。
对接受阿替普酶治疗后的急性缺血性脑卒中患者使用无需操作人员的设备进行超声溶栓是可行的，且极有可能是安全的，但在 90 天时未观察到临床获益。可进一步在依赖于患者转院接受血管内再灌注治疗的脑卒中中心或在无法提供这些治疗作为标准护理的国家进行随机试验，以研究超声溶栓。
Cerevast 治疗公司。
