Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials.
Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials.
复制标题
DOI：
10.1016/s0140-6736(14)60584-5
复制
发表时间：
2014-11-29
期刊：
影响因子：
168.9
通讯作者：
Hacke, Werner
中科院分区：
文献类型：
--
作者：
Emberson, Jonathan;Lees, Kennedy R.;Lyden, Patrick;Blackwell, Lisa;Albers, Gregory;Bluhmki, Erich;Brott, Thomas;Cohen, Geoff;Davis, Stephen;Donnan, Geoffrey;Grotta, James;Howard, George;Kaste, Markku;Koga, Masatoshi;von Kummer, Ruediger;Lansberg, Maarten;Lindley, Richard I.;Murray, Gordon;Olivot, Jean Marc;Parsons, Mark;Tilley, Barbara;Toni, Danilo;Toyoda, Kazunori;Wahlgren, Nils;Wardlaw, Joanna;Whiteley, William;del Zoppo, Gregory J.;Baigent, Colin;Sandercock, Peter;Hacke, Werner
阿替普酶可有效治疗急性缺血性卒中，但在卒中发作后较长时间、老年患者以及卒中程度最轻或最严重的患者中使用阿替普酶仍存在争议。我们评估了这些因素在影响接受阿替普酶治疗的患者的良好卒中结局中的作用。我们对来自9项比较阿替普酶与安慰剂或开放对照的随机试验中6756例患者的个体患者数据进行了预先指定的荟萃分析。我们纳入了所有已完成的静脉注射阿替普酶治疗急性缺血性卒中的随机化III期试验，这些试验的数据可用。回顾性检查证实，没有遗漏合格的试验。我们将良好的中风结局定义为3-6个月时没有明显残疾，定义为修改后的兰金评分为0或1。其他结局包括症状性颅内出血（定义为7天内的2型脑实质出血，并分别定义为36小时内的SITS-MOST 2型脑实质出血）、7天内的致死性颅内出血和90天死亡率。阿替普酶增加了良好卒中结局的几率，早期治疗与更大比例的获益相关。787例接受阿替普酶治疗的患者中有259例（32.9%）在3.0 h内治疗，762例接受对照治疗的患者中有176例（23.1%）结局良好（OR 1.75，95% CI 1.35 ~ 2.27）;延迟大于3.0小时，最多4.5小时，1375例患者中有485例（35.3%）结局良好，1437例患者中有432例（30.1%）结局良好1229例患者中有401例（32.6%）延迟超过4.5 h后获得良好结局，而1166例患者中有357例（30.6%）延迟超过4.5 h后获得良好结局（OR 1.15，95%CI 0.95 - 1.40）。无论年龄或卒中严重程度如何，比例治疗获益相似。阿替普酶显著增加症状性颅内出血的几率（2型脑实质出血定义：3391例中231例[6.8%] vs 3365例中44例[1.3%]，OR 5.55，95%CI 4.01 - 7.70，p<0.0001; SITS-MOST定义124 [3.7%] vs 19 [0.6%]，OR 6.67，95% CI 4.11 - 10.84，p<0.0001）和7天内致死性颅内出血（91 [2.7%] vs 13 [0.4%]; OR 7.14，95% CI 3.98 - 12.79，p<0.0001）。无论治疗延迟、年龄或卒中严重程度如何，阿替普酶引起的致死性颅内出血的相对增加相似，但在卒中更严重的患者中，阿替普酶引起的绝对超额风险更大。其他早期死亡原因没有过量，对后期死亡原因也没有显著影响。因此，阿替普酶组90天时的死亡率为608例（17.9%），对照组为556例（16.5%）（风险比1.11，95% CI 0.99 - 1.25，p= 0.07）。因此，综合考虑，尽管颅内出血导致的早期死亡风险平均绝对增加约2%，但在3-6个月时，该风险被无残疾生存率的平均绝对增加所抵消，在3.0 h内治疗的患者中，无残疾生存率增加约10%，在3.0 h后治疗的患者中，无残疾生存率增加约5%，直至4.5 h。无论年龄或卒中严重程度如何，尽管在治疗后最初几天内致死性颅内出血的风险增加，但在卒中发作后4.5小时内给予阿替普酶可显著改善卒中结局良好的总体几率，早期治疗与更大比例的获益相关。英国医学研究理事会、英国心脏基金会、格拉斯哥大学、爱丁堡大学。
Alteplase is effective for treatment of acute ischaemic stroke but debate continues about its use after longer times since stroke onset, in older patients, and among patients who have had the least or most severe strokes. We assessed the role of these factors in affecting good stroke outcome in patients given alteplase. We did a pre-specified meta-analysis of individual patient data from 6756 patients in nine randomised trials comparing alteplase with placebo or open control. We included all completed randomised phase 3 trials of intravenous alteplase for treatment of acute ischaemic stroke for which data were available. Retrospective checks confirmed that no eligible trials had been omitted. We defined a good stroke outcome as no significant disability at 3–6 months, defined by a modified Rankin Score of 0 or 1. Additional outcomes included symptomatic intracranial haemorrhage (defined by type 2 parenchymal haemorrhage within 7 days and, separately, by the SITS-MOST definition of parenchymal type 2 haemorrhage within 36 h), fatal intracranial haemorrhage within 7 days, and 90-day mortality. Alteplase increased the odds of a good stroke outcome, with earlier treatment associated with bigger proportional benefit. Treatment within 3·0 h resulted in a good outcome for 259 (32·9%) of 787 patients who received alteplase versus 176 (23·1%) of 762 who received control (OR 1·75, 95% CI 1·35–2·27); delay of greater than 3·0 h, up to 4·5 h, resulted in good outcome for 485 (35·3%) of 1375 versus 432 (30·1%) of 1437 (OR 1·26, 95% CI 1·05–1·51); and delay of more than 4·5 h resulted in good outcome for 401 (32·6%) of 1229 versus 357 (30·6%) of 1166 (OR 1·15, 95% CI 0·95–1·40). Proportional treatment benefits were similar irrespective of age or stroke severity. Alteplase significantly increased the odds of symptomatic intracranial haemorrhage (type 2 parenchymal haemorrhage definition 231 [6·8%] of 3391 vs 44 [1·3%] of 3365, OR 5·55, 95% CI 4·01–7·70, p<0·0001; SITS-MOST definition 124 [3·7%] vs 19 [0·6%], OR 6·67, 95% CI 4·11–10·84, p<0·0001) and of fatal intracranial haemorrhage within 7 days (91 [2·7%] vs 13 [0·4%]; OR 7·14, 95% CI 3·98–12·79, p<0·0001). The relative increase in fatal intracranial haemorrhage from alteplase was similar irrespective of treatment delay, age, or stroke severity, but the absolute excess risk attributable to alteplase was bigger among patients who had more severe strokes. There was no excess in other early causes of death and no significant effect on later causes of death. Consequently, mortality at 90 days was 608 (17·9%) in the alteplase group versus 556 (16·5%) in the control group (hazard ratio 1·11, 95% CI 0·99–1·25, p=0·07). Taken together, therefore, despite an average absolute increased risk of early death from intracranial haemorrhage of about 2%, by 3–6 months this risk was offset by an average absolute increase in disability-free survival of about 10% for patients treated within 3·0 h and about 5% for patients treated after 3·0 h, up to 4·5 h. Irrespective of age or stroke severity, and despite an increased risk of fatal intracranial haemorrhage during the first few days after treatment, alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4·5 h of stroke onset, with earlier treatment associated with bigger proportional benefits. UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.