德国汉堡大学埃彭多夫附属医院Götz Thomalla团队研究了静脉注射阿替普酶治疗晚期影像学指导的发病时间不明的脑卒中的疗效。2020年11月8日，该研究发表在《柳叶刀》杂志上。
患有中风且发病时间未知的患者此前被排除在溶栓治疗之外。为了确定当使用影像学生物标志物鉴定出可挽救的组织时，静脉使用阿替普酶治疗此类患者是否安全有效，研究组针对2020年9月21日之前发布的试验，对单个患者的数据进行了系统回顾和荟萃分析。
研究组检索灌注-扩散MRI、灌注CT或具有弥散加权成像流体衰减返转恢复（DWI-FLAIR）不匹配，发病时间未知的中风成人患者，接受静脉注射阿替普酶与标准治疗或安慰剂的随机试验。主要结局为90天时的功能预后良好（改良Rankin量表[mRS]为0-1），表明无残障。次要结局为90天时mRS向更好的功能结局和独立结局（mRS 0–2）转变。
在249个确定的摘要中，有四项试验符合研究组的纳入标准：WAKE-UP、EXTEND、THAWS和ECASS-4。这四项试验提供了843位患者的个人数据，其中429位（51％）接受阿替普酶治疗，414位（49％）接受安慰剂或标准治疗。阿替普酶组420例患者中有199例（47％）预后较好，对照组409例患者中有160例（39％），组间差异显著，且各研究间异质性较低。
阿替普酶组的患者向更好的功能结局和独立结局转变的可能性显著高于对照组。阿替普酶组中有90名（21％）患者严重残疾或死亡（mRS评分4-6），而对照组中有102名（25％），差异不显著。阿替普酶组死亡27例（6％），对照组死亡14例（3％），差异显著。阿替普酶组有症状性颅内出血的发生率显著高于对照组，分别为3％与不到1%。
研究结果表明，对于患有DWI-FLAIR或灌注不匹配的中风发作时间不明的患者，静脉使用阿替普酶90天后的功能预后显著优于安慰剂或标准治疗。
附：英文原文
Title: Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data
Author: Gtz Thomalla, Florent Boutitie, Henry Ma, Masatoshi Koga, Peter Ringleb, Lee H Schwamm, Ona Wu, Martin Bendszus, Christopher F Bladin, Bruce C V Campbell, Bastian Cheng, Leonid Churilov, Martin Ebinger, Matthias Endres, Jochen B Fiebach, Mayumi Fukuda-Doi, Manabu Inoue, Timothy J Kleinig, Lawrence L Latour, Robin Lemmens, Christopher R Levi, Didier Leys, Kaori Miwa, Carlos A Molina, Keith W Muir, Norbert Nighoghossian, Mark W Parsons, Salvador Pedraza, Peter D Schellinger, Stefan Schwab, Claus Z Simonsen, Shlee S Song, Vincent Thijs, Danilo Toni, Chung Y Hsu, Nils Wahlgren, Haruko Yamamoto, Nawaf Yassi, Sohei Yoshimura, Steven Warach, Werner Hacke, Kazunori Toyoda, Geoffrey A Donnan, Stephen M Davis, Christian Gerloff, Boris Raul Acosta, Karen Aegidius, Christian Albiker, Anna Alegiani, Miriam Almendrote, Angelika Alonso, Katharina Althaus, Pierre Amarenco, Hemasse Amiri, Bettina Anders, Adriana Aniculaesei, Jason Appleton, Juan Arenillas, Christina Back, Christian Bhr, Jürgen Bardutzky, Flore Baronnet-Chauvet, Rouven Bathe-Peters, Anna Bayer-Karpinska, Juan L. Becerra, Christoph Beck, Olga Belchí Guillamon, Amandine Benoit, Nadia Berhoune, Daniela Bindila, Julia Birchenall, Karine Blanc-Lasserre, Miguel Blanco Gonzales, Tobias Bobinger, Ulf Bodechtel, Eric Bodiguel, Urszula Bojaryn, Louise Bonnet, Benjamin Bouamra, Paul Bourgeois, Florent Boutitie, Lorenz Breuer, Ludovic Breynaert, David Broughton, Raf Brouns, Sébastian Brugirard, Bart Bruneel, Florian Buggle, Serkan Cakmak, Ana Calleja, David Calvet, David Carrera, Hsin-Chieh Chen
Issue&Volume: 2020-11-08
Abstract: Background
Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers.
Methods
We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903.
Findings
Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I 2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22–25·50]; p=0·024).
Interpretation
In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death.
DOI: 10.1016/S0140-6736(20)32163-2
Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32163-2/fulltext
LANCET：《柳叶刀》，创刊于1823年。隶属于爱思唯尔出版社，最新IF：202.731
官方网址：http://www.thelancet.com/
投稿链接：http://ees.elsevier.com/thelancet
本期文章：《柳叶刀》：Online/在线发表
