Efficacy of Alteplase in a Mouse Model of Acute Ischemic Stroke: A Retrospective Pooled Analysis.
Efficacy of Alteplase in a Mouse Model of Acute Ischemic Stroke: A Retrospective Pooled Analysis.
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DOI：
10.1161/strokeaha.116.012238
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发表时间：
2016-05
期刊：
影响因子：
8.3
通讯作者：
Vivien D
中科院分区：
文献类型：
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作者：
Orset C;Haelewyn B;Allan SM;Ansar S;Campos F;Cho TH;Durand A;El Amki M;Fatar M;Garcia-Yébenes I;Gauberti M;Grudzenski S;Lizasoain I;Lo E;Macrez R;Margaill I;Maysami S;Meairs S;Nighoghossian N;Orbe J;Paramo JA;Parienti JJ;Rothwell NJ;Rubio M;Waeber C;Young AR;Touzé E;Vivien D
关于用于治疗中风的实验药物未能转化为临床情况的争论，在文献中引起了相当大的关注。在此背景下，我们对临床前研究中的大量数据集进行了回顾合并分析，以检验早期静脉注射重组组织型纤溶酶原激活剂(rt-PA)与晚期静脉注射重组组织型纤溶酶原激活剂(rt-PA)的效果。我们收集了来自9个国际中心(13名研究人员，716只动物)的26项单独研究的数据，这些研究比较了rt-PA和对照组，在一个独特的小鼠模型中，凝血酶原位注射到大脑中动脉导致血栓栓塞性中风。研究分为早期(<；3h)和晚期(≥3h)给药。在每项研究中比较组织学或MRI评估的最终脑梗塞体积，并将绝对差异合并到随机效应荟萃分析中。检测给药时间对给药效果的影响。与生理盐水对照组相比，早期应用rt-PA有显著的益处(绝对差值=−6.63mm3；95%可信区间，−9.08to−4.17；I2=76%)，而晚期rt-PA治疗显示出有害影响(+5.06mm3；95%可信区间，+2.78%至+7.34；I2=42%，Pint<；0.00001)。分组分析后，结果保持不变。我们的研究结果为利用这种小鼠血栓栓塞性卒中模型进行再通治疗的未来临床前研究的设计提供了必要的基础。功率分析显示，多中心试验需要每组123只动物，而不是单中心试验的40只。
The debate over the fact that experimental drugs proposed for the treatment of stroke fail in the translation to the clinical situation, has attracted considerable attention in the literature. In this context, we present a retrospective pooled analysis of a large dataset from pre-clinical studies, in order to examine the effects of early versus late administration of intravenous recombinant tissue type plasminogen activator (rt-PA). We collected data from 26 individual studies from 9 international centers (13 researchers, 716 animals) that compared rt-PA to controls, in a unique mouse model of thromboembolic stroke induced by an in situ injection of thrombin into the middle cerebral artery. Studies were classified into early (<3h) versus late (≥3h) drug administration. Final infarct volumes, assessed by histology or MRI, were compared in each study and the absolute differences were pooled in a random-effect meta-analysis. The influence of time of administration was tested. When compared to saline controls, early rt-PA administration was associated with a significant benefit (absolute difference = −6.63 mm3; 95%CI, −9.08 to −4.17; I2=76%) whereas late rt-PA treatment showed a deleterious effect (+5.06 mm3; 95%CI, +2.78 to +7.34; I2=42%, Pint<0.00001). Results remained unchanged following subgroup analyses. Our results provide the basis needed for the design of future pre-clinical studies on recanalization therapies using this model of thromboembolic stroke in mice. The power analysis reveals that a multi-center trial would require 123 animals per group instead of 40 for a single center trial.