Crossley Nicolas A, Sena Emily, Goehler Jos, Horn Jannekke, van der Worp Bart, Bath Philip M W, Macleod Malcolm, Dirnagl Ulrich
Center for Stroke Research, Department of Experimental Neurology, Charité Universitätsmedizin Berlin, 10098 Berlin, Germany.
Stroke. 2008 Mar;39(3):929-34. doi: 10.1161/STROKEAHA.107.498725. Epub 2008 Jan 31.
At least part of the failure in the transition from experimental to clinical studies in stroke has been attributed to the imprecision introduced by problems in the design of experimental stroke studies. Using a metaepidemiologic approach, we addressed the effect of randomization, blinding, and use of comorbid animals on the estimate of how effectively therapeutic interventions reduce infarct size.
Electronic and manual searches were performed to identify meta-analyses that described interventions in experimental stroke. For each meta-analysis thus identified, a reanalysis was conducted to estimate the impact of various quality items on the estimate of efficacy, and these estimates were combined in a meta-meta-analysis to obtain a summary measure of the impact of the various design characteristics.
Thirteen meta-analyses that described outcomes in 15,635 animals were included. Studies that included unblinded induction of ischemia reported effect sizes 13.1% (95% CI, 26.4% to 0.2%) greater than studies that included blinding, and studies that included healthy animals instead of animals with comorbidities overstated the effect size by 11.5% (95% CI, 21.2% to 1.8%). No significant effect was found for randomization, blinded outcome assessment, or high aggregate CAMARADES quality score.
We provide empirical evidence of bias in the design of studies, with studies that included unblinded induction of ischemia or healthy animals overestimating the effectiveness of the intervention. This bias could account for the failure in the transition from bench to bedside of stroke therapies.
卒中实验性研究向临床研究转化失败，至少部分原因是实验性卒中研究设计问题导致的不精确性。我们采用元流行病学方法，探讨随机化、盲法以及使用合并症动物对治疗性干预减少梗死体积效果评估的影响。
通过电子检索和手工检索，识别描述实验性卒中干预措施的荟萃分析。对于每一项这样识别出的荟萃分析，进行重新分析以估计各种质量项目对疗效评估的影响，并将这些估计值纳入元荟萃分析，以获得各种设计特征影响的汇总测量值。
纳入了13项描述15635只动物结局的荟萃分析。与采用盲法的研究相比，未采用盲法诱导缺血的研究报告的效应量高13.1%（95%CI，26.4%至0.2%）；与使用合并症动物的研究相比，使用健康动物的研究高估效应量11.5%（95%CI，21.2%至1.8%）。随机化、盲法结局评估或高综合CAMARADES质量评分未发现显著影响。
我们提供了研究设计中存在偏倚的实证证据，未采用盲法诱导缺血或使用健康动物的研究高估了干预措施的有效性。这种偏倚可能是卒中治疗从实验室到临床转化失败的原因。
