Division of Clinical Neurosciences, University of Edinburgh, Western General Hospital, Edinburgh, UK.
Lancet. 2012 Jun 23;379(9834):2364-72. doi: 10.1016/S0140-6736(12)60738-7. Epub 2012 May 23.
Recombinant tissue plasminogen activator (rt-PA, alteplase) improved functional outcome in patients treated soon after acute ischaemic stroke in randomised trials, but licensing is restrictive and use varies widely. The IST-3 trial adds substantial new data. We therefore assessed all the evidence from randomised trials for rt-PA in acute ischaemic stroke in an updated systematic review and meta-analysis.
We searched for randomised trials of intravenous rt-PA versus control given within 6 h of onset of acute ischaemic stroke up to March 30, 2012. We estimated summary odds ratios (ORs) and 95% CI in the primary analysis for prespecified outcomes within 7 days and at the final follow-up of all patients treated up to 6 h after stroke.
In up to 12 trials (7012 patients), rt-PA given within 6 h of stroke significantly increased the odds of being alive and independent (modified Rankin Scale, mRS 0-2) at final follow-up (1611/3483 [46·3%] vs 1434/3404 [42·1%], OR 1·17, 95% CI 1·06-1·29; p=0·001), absolute increase of 42 (19-66) per 1000 people treated, and favourable outcome (mRS 0-1) absolute increase of 55 (95% CI 33-77) per 1000. The benefit of rt-PA was greatest in patients treated within 3 h (mRS 0-2, 365/896 [40·7%] vs 280/883 [31·7%], 1·53, 1·26-1·86, p<0·0001), absolute benefit of 90 (46-135) per 1000 people treated, and mRS 0-1 (283/896 [31·6%] vs 202/883 [22·9%], 1·61, 1·30-1·90; p<0·0001), absolute benefit 87 (46-128) per 1000 treated. Numbers of deaths within 7 days were increased (250/2807 [8·9%] vs 174/2728 [6·4%], 1·44, 1·18-1·76; p=0·0003), but by final follow-up the excess was no longer significant (679/3548 [19·1%] vs 640/3464 [18·5%], 1·06, 0·94-1·20; p=0·33). Symptomatic intracranial haemorrhage (272/3548 [7·7%] vs 63/3463 [1·8%], 3·72, 2·98-4·64; p<0·0001) accounted for most of the early excess deaths. Patients older than 80 years achieved similar benefit to those aged 80 years or younger, particularly when treated early.
The evidence indicates that intravenous rt-PA increased the proportion of patients who were alive with favourable outcome and alive and independent at final follow-up. The data strengthen previous evidence to treat patients as early as possible after acute ischaemic stroke, although some patients might benefit up to 6 h after stroke.
UK Medical Research Council, Stroke Association, University of Edinburgh, National Health Service Health Technology Assessment Programme, Swedish Heart-Lung Fund, AFA Insurances Stockholm (Arbetsmarknadens Partners Forsakringsbolag), Karolinska Institute, Marianne and Marcus Wallenberg Foundation, Research Council of Norway, Oslo University Hospital.
重组组织型纤溶酶原激活物（rt-PA，阿替普酶）可改善急性缺血性脑卒中患者接受治疗后短期内的功能结局，但是其使用受到限制，并且使用范围广泛。IST-3 试验增加了大量新的数据。因此，我们在更新的系统评价和荟萃分析中评估了急性缺血性脑卒中患者接受 rt-PA 治疗的所有随机试验证据。
我们搜索了截至 2012 年 3 月 30 日的发病后 6 小时内静脉内给予 rt-PA 与对照组治疗的急性缺血性脑卒中的随机试验。我们在主要分析中针对所有在 6 小时内接受治疗的患者进行了预先设定的结局在 7 天内和最终随访时的汇总比值比（OR）和 95%置信区间（CI）。
在多达 12 项试验（7012 例患者）中，发病后 6 小时内给予 rt-PA 显著增加了最终随访时存活且独立（改良 Rankin 量表，mRS 0-2）的患者比例（1611/3483 [46.3%] vs 1434/3404 [42.1%]，OR 1.17，95%CI 1.06-1.29；p=0.001），每 1000 人治疗中增加 42 个（19-66），良好结局（mRS 0-1）每 1000 人治疗中增加 55 个（95%CI 33-77）。rt-PA 的益处最大的是在发病后 3 小时内接受治疗的患者（mRS 0-2，365/896 [40.7%] vs 280/883 [31.7%]，1.53，1.26-1.86，p<0.0001），每 1000 人治疗中增加 90 个（46-135），mRS 0-1 每 1000 人治疗中增加 87 个（46-128）。发病后 7 天内死亡人数增加（250/2807 [8.9%] vs 174/2728 [6.4%]，1.44，1.18-1.76；p=0.0003），但是在最终随访时，这种差异不再显著（679/3548 [19.1%] vs 640/3464 [18.5%]，1.06，0.94-1.20；p=0.33）。症状性颅内出血（272/3548 [7.7%] vs 63/3463 [1.8%]，3.72，2.98-4.64；p<0.0001）是早期死亡人数增加的主要原因。年龄超过 80 岁的患者与 80 岁或以下的患者获得了相似的益处，特别是在早期治疗时。
这些数据表明，静脉内 rt-PA 增加了存活且结局良好和最终随访时存活且独立的患者比例。这些数据加强了尽早治疗急性缺血性脑卒中患者的先前证据，尽管一些患者可能在发病后 6 小时内受益。
英国医学研究理事会、中风协会、爱丁堡大学、英国国家卫生服务局卫生技术评估计划、瑞典心肺基金会、AFA 保险公司（Arbetsmarknadens Partners Forsakringsbolag）、卡罗林斯卡学院、玛丽安和马库斯·沃伦伯格基金会、挪威研究委员会、奥斯陆大学医院。
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