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

Daniel F Hanley, Richard E Thompson, Michael Rosenblum, et al

Lancet Published:February 07, 2019 DOI:https://doi.org/10.1016/S0140-6736(19)30195-3

Summary

Background 背景

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.

幕上脑出血引起的急性卒中伴随高罹患率及病死率。大规模随机临床试验并为发现开颅血肿清除术的益处。我们采用微创导管血肿清除后溶栓(MISTIE)使血块大小降低到15 mL以内，评估这种方法能否改善脑出血患者的功能预后。

Methods 方法

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.

MISTIE III是一项开放标签、终点设盲、3期临床试验，在美国、加拿大、欧洲、澳大利亚和亚洲的78个中心进行。我们入选了自发性、非创伤性幕上脑出血（30 mL或以上）的18岁以上患者。我们采用计算机生成的数字序列进行中心随机，区组大小为4或6，将患者随机分为影像指导MISTIE治疗（rTPA 1·0 mg q8h，最多9个剂量）或标准治疗。主要预后指标为功能预后良好，定义为365天时改良Rankin分级(mRS)达到0–3分的患者比例，并对预先确定的基线协变量（脑出血大小稳定性，年龄，格拉斯哥昏迷评分，脑室内出血大小稳定性，及血块部位）进行组间校正。针对校正后意向治疗(mITT)人群进行主要疗效指标的分析，包括所有符合入选标准且随机分组并接受治疗的患者。所有随机分组患者均纳入安全性分析。研究在 ClinicalTrials.gov注册，注册号NCT01827046。

Findings 结果

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).

2013年12月30日至2017年8月15日间，共有506名患者接受随机分组：255名 (50%)分至MISTIE组，251名 (50%)分至标准治疗组。499名患者（MISTIE组250名；标准治疗组249名）接受治疗，纳入mITT分析。mITT主要校正后疗效分析显示，MISTIE组45%的患者以及标准治疗组41%的患者在365天时达到mRS评分0–3分（校正后风险差异4% [95% CI −4 to 12]; p=0·33）。采用广义有序logistic回归模型对极限变量进行校正，对365天的mRS评分进行敏感性分析。结果显示，与标准治疗相比，MISTIE组mRS评分> 5分与5分或以下，> 4分与4分或以下，> 3分与3分或以下，以及> 2分与2分或以下相比的比数比分别为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名患者中2人 (1%)以及标准治疗组251名患者中10人(4%)死亡(p=0·02)，30天时，MISTIE组24人 (9%)以及标准治疗组中37人(15%)死亡(p=0·07)。MISTIE组与标准治疗组症状性出血及脑细菌感染的患者数相似（症状性出血2/255 [2%] vs 3/251 [1%]；p=0·33；脑细菌感染2/255 [1%] vs 0/251 [0%] of 251；p=0·16）。30天时，MISTIE组255名患者中76人 (30%)及标准治疗组251名患者中84人(33%) 发生严重不良事件，严重不良事件数组间存在统计学显著差异(p=0·012)。

Interpretation 结论

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.

对于中至大量脑出血而言，MISTIE不能改善脑出血后365天达到良好反应的患者比例。我们的外科医生能够安全进行此项操作。

Funding 资助

National Institute of Neurological Disorders and Stroke and Genentech.