Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA.
Lancet Neurol. 2013 Nov;12(11):1049-58. doi: 10.1016/S1474-4422(13)70223-0. Epub 2013 Sep 27.
In animal models of ischaemic stroke, 25% albumin reduced brain infarction and improved neurobehavioural outcome. In a pilot clinical trial, albumin doses as high as 2 g/kg were safely tolerated. We aimed to assess whether albumin given within 5 h of the onset of acute ischaemic stroke increased the proportion of patients with a favourable outcome.
We did a randomised, double-blind, parallel-group, phase 3, placebo-controlled trial between Feb 27, 2009, and Sept 10, 2012, at 69 sites in the USA, 13 sites in Canada, two sites in Finland, and five sites in Israel. Patients aged 18-83 years with ischaemic (ie, non-haemorrhagic) stroke with a baseline National Institutes of Health stroke scale (NIHSS) score of 6 or more who could be treated within 5 h of onset were randomly assigned (1:1), via a central web-based randomisation process with a biased coin minimisation approach, to receive 25% albumin (2 g [8 mL] per kg; maximum dose 750 mL) or the equivalent volume of isotonic saline. All study personnel and participants were masked to the identity of the study drug. The primary endpoint was favourable outcome, defined as either a modified Rankin scale score of 0 or 1, or an NIHSS score of 0 or 1, or both, at 90 days. Analysis was by intention to treat. Thrombolytic therapies were permitted. This trial is registered with ClinicalTrials.gov, number NCT00235495.
422 participants were randomly assigned to receive albumin and 419 to receive saline. On Sept 12, 2012, the trial was stopped early for futility (n=841). The primary outcome did not differ between patients in the albumin group and those in the saline group (186 [44%] vs 185 [44%]; risk ratio 0·96, 95% CI 0·84-1·10, adjusted for baseline NIHSS score and thrombolysis stratum). Mild-to-moderate pulmonary oedema was more common in patients given albumin than in those given saline (54 [13%] of 412 vs 5 [1%] of 412 patients); symptomatic intracranial haemorrhage within 24 h was also more common in patients in the albumin group than in the placebo group (17 [4%] of 415 vs 7 [2%] of 414 patients). Although the rate of favourable outcome in patients given albumin remained consistent at 44-45% over the course of the trial, the cumulative rate of favourable outcome in patients given saline rose steadily from 31% to 44%.
Our findings show no clinical benefit of 25% albumin in patients with ischaemic stroke; however, they should not discourage further efforts to identify effective strategies to protect the ischaemic brain, especially because of preclinical literature showing convincing proof-of-principle for the possibility of this outcome.
National Institute of Neurological Disorders and Stroke, US National Institutes of Health; and Baxter Healthcare Corporation.
在缺血性中风的动物模型中，25%白蛋白可减少脑梗死并改善神经行为学预后。在一项初步临床试验中，高达 2g/kg 的白蛋白剂量可安全耐受。我们旨在评估在急性缺血性中风发作后 5 小时内给予白蛋白是否会增加预后良好的患者比例。
我们在美国 69 个地点、加拿大 13 个地点、芬兰 2 个地点和以色列 5 个地点进行了一项随机、双盲、平行组、3 期、安慰剂对照试验，时间为 2009 年 2 月 27 日至 2012 年 9 月 10 日。纳入年龄在 18-83 岁之间、基线 NIHSS 评分（NIHSS）为 6 分或以上且可在发病后 5 小时内接受治疗的缺血性（即非出血性）中风患者，通过中央网络随机化过程，以偏倚硬币最小化方法按 1:1 的比例随机分配至接受 25%白蛋白（2g[8mL] /kg；最大剂量 750mL）或等渗盐水。所有研究人员和参与者均对研究药物的身份进行了盲法。主要终点是良好的预后，定义为 90 天时改良 Rankin 量表评分 0 或 1，或 NIHSS 评分 0 或 1，或两者均为 0 或 1。分析采用意向治疗。允许使用溶栓治疗。该试验在 ClinicalTrials.gov 注册，编号为 NCT00235495。
422 名患者被随机分配接受白蛋白治疗，419 名患者接受生理盐水治疗。2012 年 9 月 12 日，由于无效（n=841），试验提前停止。白蛋白组和生理盐水组患者的主要结局无差异（186[44%]vs 185[44%]；风险比 0.96，95%CI 0.84-1.10，根据基线 NIHSS 评分和溶栓分层进行调整）。与接受生理盐水的患者相比，接受白蛋白的患者中更常见轻度至中度肺水肿（412 名患者中有 54 名[13%]vs 412 名患者中有 5 名[1%]）；白蛋白组在 24 小时内发生症状性颅内出血的患者也多于安慰剂组（415 名患者中有 17 名[4%]vs 414 名患者中有 7 名[2%]）。尽管在试验过程中接受白蛋白的患者的良好预后率保持在 44-45%，但接受生理盐水的患者的良好预后累积率从 31%稳步上升至 44%。
我们的研究结果表明，25%白蛋白对缺血性中风患者无临床益处；然而，这不应阻止我们进一步努力寻找有效的策略来保护缺血性大脑，特别是因为临床前文献提供了令人信服的证据，证明了这种结果的可能性。
这项研究的资金来源包括美国国立神经病学和中风研究所、美国国立卫生研究院和百特医疗保健公司。
