Thrombolysis for acute ischaemic stroke.
Thrombolysis for acute ischaemic stroke.
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DOI：
10.1002/14651858.cd000213.pub3
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发表时间：
2014-07-29
影响因子：
8.4
通讯作者：
del Zoppo, Gregory J.
中科院分区：
文献类型：
--
作者：
Wardlaw, Joanna M.;Murray, Veronica;Berge, Eivind;del Zoppo, Gregory J.
关键词：
大多数中风是由于血凝块堵塞了大脑中的动脉。及时使用溶栓药物治疗可以在脑损伤发生之前恢复血液流动，并改善一些人中风后的恢复。然而，溶栓药物也会导致严重的脑出血，这可能是致命的。重组组织型纤溶酶原激活剂（rt-PA）获批在欧洲和美国分别用于中风后4.5小时和3小时内的特定患者。一些国家的年龄上限为80岁，而另一些国家的年龄上限主要为非严重中风。自2009年上次审查更新以来，可获得的数据增加了40%。确定溶栓治疗是否以及在何种情况下可能是一种有效和安全的治疗急性缺血性卒中的方法。我们检索了Cochrane卒中组试验注册（最近检索于2013年11月）、MEDLINE（1966年至2013年11月）和EMBASE（1980年至2013年11月）。我们还手工检索会议记录和期刊，检索参考文献列表，联系制药公司和试验人员。任何溶栓剂与确定缺血性卒中患者对照的随机试验。两位综述作者应用纳入标准，提取数据并评估试验质量。我们与所有主要试验的研究人员验证了提取的数据，如果有的话，获得了额外的未发表的数据。我们纳入了27项试验，涉及10,187名受试者，检测尿激酶、链激酶、rt-PA、重组前尿激酶或去氨替酶。四项试验采用动脉给药，其余试验采用静脉给药。大多数数据来自中风后6小时开始治疗的试验。约44%的试验（约70%的参与者）测试静脉注射rt-PA。在早期的研究中，很少有参与者（0.5%）的年龄超过80岁；在这次更新中，由于IST-3的纳入，16%的参与者年龄超过80岁（该试验中53%的参与者年龄超过80岁）。最近发表的试验使用了计算机随机化，因此与先前版本的综述相比，基线不平衡的可能性更小。超过50%的试验符合高度隐蔽性标准；对主要结果的随访几乎没有损失。溶栓治疗主要在缺血性卒中后6小时内进行，可显著降低卒中后3至6个月死亡或依赖患者的比例（修正Rankin 3至6）（优势比（or） 0.85, 95%可信区间（CI） 0.78至0.93）。溶栓治疗增加了症状性颅内出血（OR 3.75, 95% CI 3.11至4.51）、早期死亡（OR 1.69, 95% CI 1.44至1.98；13项试验，7458名受试者）和中风后3至6个月死亡的风险（OR 1.18, 95% CI 1.06至1.30）。溶栓后早期死亡主要是由于颅内出血。卒中3小时内治疗在减少死亡或依赖性方面更有效（or 0.66, 95% CI 0.56 ~ 0.79），而不增加死亡（or 0.99, 95% CI 0.82 ~ 1.21； 11项试验，2187名受试者）。试验之间存在异质性。同期抗血栓药物增加了死亡风险。测试rt-PA的试验显示，治疗长达6小时的死亡或依赖性显著降低（or 0.84, 95% CI 0.77至0.93,P = 0.0006； 8项试验，6729名受试者），具有显著的异质性；3小时内治疗更有益（OR 0.65, 95% CI 0.54 ~ 0.80, P < 0.0001； 6项试验，1779名受试者），无异质性。80岁以上的参与者与80岁以下的参与者受益相同，特别是如果在中风后3小时内接受治疗。在中风后6小时内进行溶栓治疗可减少死亡或依赖患者的比例。那些在前三小时内接受治疗的人比后来接受治疗的人获得更多的益处。尽管症状性颅内出血、7 - 10天死亡和最终随访时死亡人数增加（rt-PA试验除外，它对最终随访时死亡没有影响），但总体获益是明显的。需要进一步的试验来确定最新的时间窗口，轻度中风患者是否受益于溶栓，寻找减少症状性颅内出血和死亡的方法，并确定在常规实践中进行溶栓的最佳环境。
Most strokes are due to blockage of an artery in the brain by a blood clot. Prompt treatment with thrombolytic drugs can restore blood flow before major brain damage has occurred and improve recovery after stroke in some people. Thrombolytic drugs, however, can also cause serious bleeding in the brain, which can be fatal. One drug, recombinant tissue plasminogen activator (rt-PA), is licensed for use in selected patients within 4.5 hours of stroke in Europe and within three hours in the USA. There is an upper age limit of 80 years in some countries, and a limitation to mainly non-severe stroke in others. Forty per cent more data are available since this review was last updated in 2009. To determine whether, and in what circumstances, thrombolytic therapy might be an effective and safe treatment for acute ischaemic stroke. We searched the Cochrane Stroke Group Trials Register (last searched November 2013), MEDLINE (1966 to November 2013) and EMBASE (1980 to November 2013).We also handsearched conference proceedings and journals, searched reference lists and contacted pharmaceutical companies and trialists. Randomised trials of any thrombolytic agent compared with control in people with definite ischaemic stroke. Two review authors applied the inclusion criteria, extracted data and assessed trial quality. We verified the extracted data with investigators of all major trials, obtaining additional unpublished data if available. We included 27 trials, involving 10,187 participants, testing urokinase, streptokinase, rt-PA, recombinant pro-urokinase or desmoteplase. Four trials used intra-arterial administration, while the rest used the intravenous route. Most data come from trials that started treatment up to six hours after stroke. About 44% of the trials (about 70% of the participants) were testing intravenous rt-PA. In earlier studies very few of the participants (0.5%) were aged over 80 years; in this update, 16% of participants are over 80 years of age due to the inclusion of IST-3 (53% of participants in this trial were aged over 80 years). Trials published more recently utilised computerised randomisation, so there are less likely to be baseline imbalances than in previous versions of the review. More than 50% of trials fulfilled criteria for high-grade concealment; there were few losses to follow-up for the main outcomes. Thrombolytic therapy, mostly administered up to six hours after ischaemic stroke, significantly reduced the proportion of participants who were dead or dependent (modified Rankin 3 to 6) at three to six months after stroke (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.78 to 0.93). Thrombolytic therapy increased the risk of symptomatic intracranial haemorrhage (OR 3.75, 95% CI 3.11 to 4.51), early death (OR 1.69, 95% CI 1.44 to 1.98; 13 trials, 7458 participants) and death by three to six months after stroke (OR 1.18, 95% CI 1.06 to 1.30). Early death after thrombolysis was mostly attributable to intracranial haemorrhage. Treatment within three hours of stroke was more effective in reducing death or dependency (OR 0.66, 95% CI 0.56 to 0.79) without any increase in death (OR 0.99, 95% CI 0.82 to 1.21; 11 trials, 2187 participants). There was heterogeneity between the trials. Contemporaneous antithrombotic drugs increased the risk of death. Trials testing rt-PA showed a significant reduction in death or dependency with treatment up to six hours (OR 0.84, 95% CI 0.77 to 0.93, P = 0.0006; 8 trials, 6729 participants) with significant heterogeneity; treatment within three hours was more beneficial (OR 0.65, 95% CI 0.54 to 0.80, P < 0.0001; 6 trials, 1779 participants) without heterogeneity. Participants aged over 80 years benefited equally to those aged under 80 years, particularly if treated within three hours of stroke. Thrombolytic therapy given up to six hours after stroke reduces the proportion of dead or dependent people. Those treated within the first three hours derive substantially more benefit than with later treatment. This overall benefit was apparent despite an increase in symptomatic intracranial haemorrhage, deaths at seven to 10 days, and deaths at final follow-up (except for trials testing rt-PA, which had no effect on death at final follow-up). Further trials are needed to identify the latest time window, whether people with mild stroke benefit from thrombolysis, to find ways of reducing symptomatic intracranial haemorrhage and deaths, and to identify the environment in which thrombolysis may best be given in routine practice.