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(Stroke. 2008;39:929.)
© 2008 American Heart Association, Inc.

Original Contributions

Empirical Evidence of Bias in the Design of Experimental Stroke Studies

A Metaepidemiologic Approach

Nicolas A. Crossley, MSc; Emily Sena, BSc; Jos Goehler; Jannekke Horn, MD; Bart van der Worp, MD; Philip M.W. Bath, MD; Malcolm Macleod, PhD Ulrich Dirnagl, MD

From the Center for Stroke Research (N.A.C., J.G., U.D.), Department of Experimental Neurology, Charité Universitätsmedizin, Berlin, Germany; the Department of Clinical Neurosciences (E.S., M.M.), University of Edinburgh, Edinburgh, Scotland; the Division of Stroke Medicine (P.M.W.B.), University of Nottingham, Nottingham, England; the Department of Intensive Care (J.H.), Academical Medical Center, Amsterdam, The Netherlands; and the Department of Neurology (B.v.d.W.), Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.

Correspondence to Ulrich Dirnagl, MD, Center for Stroke Research, Dept. of Experimental Neurology, Charité Universitätsmedizin Berlin, 10098 Berlin, Germany. E-mail ulrich.dirnagl{at}charite.de

Background and Purpose— 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.

Methods— 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.

Results— 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.

Conclusions— 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.

Key Words: animal experimentation • cerebrovascular accident • meta-analysis