Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial.
Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial.
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DOI：
10.1016/s0140-6736(16)32410-2
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发表时间：
2017-02-11
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影响因子：
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通讯作者：
CLEAR III Investigators
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作者：
Hanley DF;Lane K;McBee N;Ziai W;Tuhrim S;Lees KR;Dawson J;Gandhi D;Ullman N;Mould WA;Mayo SW;Mendelow AD;Gregson B;Butcher K;Vespa P;Wright DW;Kase CS;Carhuapoma JR;Keyl PM;Diener-West M;Muschelli J;Betz JF;Thompson CB;Sugar EA;Yenokyan G;Janis S;John S;Harnof S;Lopez GA;Aldrich EF;Harrigan MR;Ansari S;Jallo J;Caron JL;LeDoux D;Adeoye O;Zuccarello M;Adams HP Jr;Rosenblum M;Thompson RE;Awad IA;CLEAR III Investigators
脑室内出血是脑出血的一种亚型，死亡率为50%，幸存者严重残疾。我们的目的是测试尝试用阿替普酶清除脑室内出血与盐水冲洗相比是否改善了功能结局。在这项随机、双盲、安慰剂对照、多地区试验中，（CLEAR III），在重症监护室中常规放置脑室外引流的受试者，稳定的非创伤性脑出血量小于30 mL，脑室内出血阻塞第3或第4脑室，无基础病理学，适应性随机分配（1：1），通过基于网络的系统接受多达12次给药，间隔8小时，通过脑室外引流接受1 mg阿替普酶或0.9%生理盐水。治疗医生、临床研究人员和参与者对治疗分配设盲。在整个给药期间，每24小时进行一次CT扫描。主要疗效结局为良好的功能结局，定义为盲态评价者在180天时中心裁定的改良兰金量表评分（mRS）≤ 3。本研究注册于ClinicalTrials.gov，NCT 00784134。2009年9月18日至2015年1月13日，500例患者被随机分配：249例分配至阿替普酶组，251例分配至生理盐水组。180-阿替普酶组249例受试者中的246例和安慰剂组251例受试者中的245例的随访数据可用于分析。各组的主要疗效结局相似（阿替普酶组结局良好48% vs生理盐水组45%;风险比[RR] 1·06 [95% CI 0·88-1·28; p=0-554]）。校正脑室内出血大小和丘脑内出血后，发现差异为3.5%（RR 1.08 [95% CI 0.90 - 1.29]，p=0-420）。在180天时，治疗组的病死率较低（46例[18%] vs生理盐水组73例[29%]，风险比0.60 [95% CI 0.41 - 0.86]，p=0-006），但mRS 5的比例较高（42例[17%] vs 21例[9%]; RR 1.99 [95% CI 1.22 - 3.26]，p=0-007）。阿替普酶治疗组中，尿路炎（17例[7%]阿替普酶vs 31例[12%]生理盐水; RR 0.55 [95% CI 0.31 - 0.97]，p=0-048）和严重不良事件（114例[46%]阿替普酶vs 151例[60%]生理盐水; RR 0.76 [95% CI 0.64 - 0.90]，p=0-002）的发生率较低。症状性出血（阿替普酶组6例[2%] vs生理盐水组5例[2%]; RR 1.21 [95% CI 0.37 - 3.91]，p=0-771）相似。在脑室内出血和常规脑室外引流的患者中，与生理盐水冲洗相比，在mRS 3临界值时，阿替普酶冲洗未显著改善功能结局。基于方案使用阿替普酶伴脑室外引流似乎是安全的。需要进一步研究以确定通过阿替普酶完全清除脑室内出血的频率增加是否会改善功能状态。
Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88–1·28; p=0–554]). A difference of 3·5% (RR 1·08 [95% CI 0·90–1·29], p=0–420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41–0·86], p=0–006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22–3·26], p=0–007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31–0·97], p=0–048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64–0·90], p=0–002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37–3·91], p=0–771) was similar. In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status.