Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial
Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial
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DOI：
10.1016/s0140-6736(19)30195-3
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发表时间：
2019-03-09
期刊：
影响因子：
168.9
通讯作者：
Awad, Issam A.
中科院分区：
文献类型：
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作者：
Hanley, Daniel F.;Thompson, Richard E.;Awad, Issam A.
幕上脑出血引起的急性卒中具有较高的发病率和死亡率。在大型随机试验中，未发现开放性开颅血肿清除术有任何益处。我们评估了是否微创导管排空，然后溶栓（MISTIE），以减少凝块大小为15毫升或更少的目的，将改善功能的结果，在intracerebral hemorrhage.Methods MISTIE III是一个开放标签，盲终点，3期试验在78家医院在美国，加拿大，欧洲，澳大利亚和亚洲。我们招募了年龄≥ 18岁的自发性、非创伤性、幕上脑出血≥ 30 mL的患者。我们使用计算机生成的数字序列，区组大小为4或6，将患者集中随机分配至图像引导的MISTIE治疗组（1.0 mg阿替普酶，每8小时1次，最多9次给药）或标准医疗。主要结局是良好的功能结局，定义为365天时改良兰金量表（mRS）评分为0-3分的患者比例，根据预先规定的基线协变量（稳定性脑内出血大小、年龄、格拉斯哥昏迷量表、稳定性脑室内出血大小和凝块位置）的组间差异进行校正。在改良的意向治疗（mITT）人群中进行主要疗效结局分析，该人群包括所有合格的、随机分配的暴露于治疗的患者。所有随机分配的患者均纳入安全性分析。该研究注册于ClinicalTrials.gov，编号NCT 01827046。结果在2013年12月30日至2017年8月15日期间，506名患者被随机分配：255名（50%）接受MISTIE组，251名（50%）接受标准医疗护理。499例患者（MISTIE组n=250;标准医疗护理组n=249）接受了治疗，并被纳入mITT分析集。mITT主要校正疗效分析估计，MISTIE组45%的患者和标准医疗护理组41%的患者在365天时达到mRS评分0-3（校正风险差异4% [95% CI -4至12]; p=0.33）。使用经基线变量校正的广义有序logistic回归模型对365天mRS进行的敏感性分析显示，MISTIE与标准医疗相比，mRS评分高于5与5或更低、高于4与4或更低、高于3与3或更低以及高于2与2或更低的估计比值比为0.60（p=0.03）、0.84（p=0.42）、0.87（p=0.49）和0.82（p=0.44）。第7天时，MISTIE组255例患者中有2例（1%）死亡，标准医疗护理组251例患者中有10例（4%）死亡（p=0.02），第30天时，MISTIE组24例（9%）患者死亡，标准医疗护理组37例（15%）患者死亡（p=0.07）。MISTIE和标准医疗护理组之间症状性出血和脑细菌感染的患者数量相似（255例患者中6例[2%] vs 251例患者中3例[1%];症状性出血p=0.33; 255例患者中2例[1%] vs 251例患者中0例[0%];脑细菌感染p=0.16）。30天时，MISTIE组255例患者中有76例（30%）和标准医疗护理组251例患者中有84例（33%）发生了1起或多起严重不良事件，两组之间严重不良事件数量的差异具有统计学意义（p=0.012）.解释对于中度至重度脑出血，MISTIE并没有提高脑出血后365天获得良好反应的患者比例。该手术被我们的外科医生样本安全地采用。国家神经疾病和中风研究所和基因技术公司资助。版权所有（C）2019 Elsevier Ltd.保留所有权利。
Background Acute stroke due to supratentorial intracerebral haemorrhage is associated with high morbidity and mortality. Open craniotomy haematoma evacuation has not been found to have any benefit in large randomised trials. We assessed whether minimally invasive catheter evacuation followed by thrombolysis (MISTIE), with the aim of decreasing clot size to 15 mL or less, would improve functional outcome in patients with intracerebral haemorrhage.Methods MISTIE III was an open-label, blinded endpoint, phase 3 trial done at 78 hospitals in the USA, Canada, Europe, Australia, and Asia. We enrolled patients aged 18 years or older with spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more. We used a computer-generated number sequence with a block size of four or six to centrally randomise patients to image-guided MISTIE treatment (1.0 mg alteplase every 8 h for up to nine doses) or standard medical care. Primary outcome was good functional outcome, defined as the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0-3 at 365 days, adjusted for group differences in prespecified baseline covariates (stability intracerebral haemorrhage size, age, Glasgow Coma Scale, stability intraventricular haemorrhage size, and clot location). Analysis of the primary efficacy outcome was done in the modified intention-to-treat (mITT) population, which included all eligible, randomly assigned patients who were exposed to treatment. All randomly assigned patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01827046.Findings Between Dec 30, 2013, and Aug 15, 2017, 506 patients were randomly allocated: 255 (50%) to the MISTIE group and 251 (50%) to standard medical care. 499 patients (n=250 in the MISTIE group; n=249 in the standard medical care group) received treatment and were included in the mITT analysis set. The mITT primary adjusted efficacy analysis estimated that 45% of patients in the MISTIE group and 41% patients in the standard medical care group had achieved an mRS score of 0-3 at 365 days (adjusted risk difference 4% [95% CI -4 to 12]; p=0.33). Sensitivity analyses of 365-day mRS using generalised ordered logistic regression models adjusted for baseline variables showed that the estimated odds ratios comparing MISTIE with standard medical care for mRS scores higher than 5 versus 5 or less, higher than 4 versus 4 or less, higher than 3 versus 3 or less, and higher than 2 versus 2 or less were 0.60 (p=0.03), 0.84 (p=0.42), 0.87 (p=0.49), and 0.82 (p=0.44), respectively. At 7 days, two (1%) of 255 patients in the MISTIE group and ten (4%) of 251 patients in the standard medical care group had died (p=0.02) and at 30 days, 24 (9%) patients in the MISTIE group and 37 (15%) patients in the standard medical care group had died (p=0.07). The number of patients with symptomatic bleeding and brain bacterial infections was similar between the MISTIE and standard medical care groups (six [2%] of 255 patients vs three [1%] of 251 patients; p=0.33 for symptomatic bleeding; two [1%] of 255 patients vs 0 [0%] of 251 patients; p=0.16 for brain bacterial infections). At 30 days, 76 (30%) of 255 patients in the MISTIE group and 84 (33%) of 251 patients in the standard medical care group had one or more serious adverse event, and the difference in number of serious adverse events between the groups was statistically significant (p=0.012).Interpretation For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response 365 days after intracerebral haemorrhage. The procedure was safely adopted by our sample of surgeons.Funding National Institute of Neurological Disorders and Stroke and Genentech. Copyright (C) 2019 Elsevier Ltd. All rights reserved.