Hanley Daniel F, Lane Karen, McBee Nichol, Ziai Wendy, Tuhrim Stanley, Lees Kennedy R, Dawson Jesse, Gandhi Dheeraj, Ullman Natalie, Mould W Andrew, Mayo Steven W, Mendelow A David, Gregson Barbara, Butcher Kenneth, Vespa Paul, Wright David W, Kase Carlos S, Carhuapoma J Ricardo, Keyl Penelope M, Diener-West Marie, Muschelli John, Betz Joshua F, Thompson Carol B, Sugar Elizabeth A, Yenokyan Gayane, Janis Scott, John Sayona, Harnof Sagi, Lopez George A, Aldrich E Francois, Harrigan Mark R, Ansari Safdar, Jallo Jack, Caron Jean-Louis, LeDoux David, Adeoye Opeolu, Zuccarello Mario, Adams Harold P, Rosenblum Michael, Thompson Richard E, Awad Issam A
Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA.
Johns Hopkins University, School of Medicine, Brain Injury Outcomes Division, Baltimore, MD, USA.
Lancet. 2017 Feb 11;389(10069):603-611. doi: 10.1016/S0140-6736(16)32410-2. Epub 2017 Jan 10.
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.
National Institute of Neurological Disorders and Stroke.
脑室内出血是脑出血的一种亚型，死亡率达50%，幸存者会有严重残疾。我们旨在测试与生理盐水冲洗相比，使用阿替普酶清除脑室内出血是否能改善功能结局。
在这项随机、双盲、安慰剂对照、多中心试验（CLEAR III）中，入住重症监护病房、常规放置脑室外引流管、稳定的非创伤性脑出血体积小于30 mL、脑室内出血阻塞第三或第四脑室且无潜在病理状况的参与者，通过基于网络的系统进行适应性随机分组（1:1），接受通过脑室外引流管给予的最多12剂、间隔8小时的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均对治疗分配不知情。在给药期间每24小时进行一次CT扫描。主要疗效结局为良好的功能结局，由盲法评估人员进行中心判定，定义为180天时改良Rankin量表评分（mRS）为3或更低。本研究已在ClinicalTrials.gov注册，注册号为NCT00784134。
2009年9月18日至2015年1月13日期间，500例患者被随机分组：249例进入阿替普酶组，251例进入生理盐水组。阿替普酶组249例参与者中的246例和安慰剂组251例参与者中的245例有180天的随访数据可供分析。每组的主要疗效结局相似（阿替普酶组良好结局为48%，生理盐水组为45%；风险比[RR]为1.06[95%CI 0.88 - 1.28；p = 0.554]）。在对脑室内出血大小和丘脑脑出血进行调整后，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%]对比生理盐水组73例[29%]，风险比0.60[95%CI 0.41 - 0.86]，p = 0.006），但mRS为5的比例更高（42例[17%]对比21例[9%]；RR 1.99[95%CI 1.22 - 3.26]，p = 0.007）。阿替普酶组的脑室炎（17例[7%]对比生理盐水组31例[12%]；RR 0.55[95%CI 0.31 - 0.97]）和严重不良事件（114例[46%]对比151例[60%]；RR 0.76[95%CI 0.64 - 0.90]）发生率较低。症状性出血（阿替普酶组6例[2%]对比生理盐水组5例[2%]；RR 1.21[95%CI 0.37 - 3.91]，p = 0.771）相似。
对于脑室内出血且常规放置脑室外引流管的患者，与生理盐水冲洗相比，阿替普酶冲洗在mRS为3的界值时并未显著改善功能结局。基于方案使用阿替普酶进行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更频繁地完全清除脑室内出血是否能改善功能状态。
美国国立神经疾病和中风研究所。
