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Meta-Analysis
. 2010 Dec;30(12):1905-13.
doi: 10.1038/jcbfm.2010.116. Epub 2010 Jul 21.

Factors affecting the apparent efficacy and safety of tissue plasminogen activator in thrombotic occlusion models of stroke: systematic review and meta-analysis

Emily S Sena  1 , Catherine L Briscoe, David W Howells, Geoffrey A Donnan, Peter A G Sandercock, Malcolm R Macleod
Affiliations
Meta-Analysis

Factors affecting the apparent efficacy and safety of tissue plasminogen activator in thrombotic occlusion models of stroke: systematic review and meta-analysis

Emily S Sena et al. J Cereb Blood Flow Metab. 2010 Dec.

Abstract

Thrombolysis with recombinant tissue plasminogen activator (rtPA) improves outcome in animal models of stroke and in clinical trial, but is associated with increased intracranial hemorrhage. Here, we explore the impact of biologic and experimental design factors on efficacy and bleeding. We conducted a systematic review of studies describing the effect of tPA in thrombotic occlusion models of ischemic stroke followed by random effects meta-analysis, meta-regression, and trim and fill. We identified 202, 66, 128, and 54 comparisons reporting infarct volume, neurobehavioral score, hemorrhage, and mortality, respectively. The rtPA reduced infarct volume by 25.2% (95% confidence interval=21.8 to 28.6, 3388 animals), improved neurobehavioral score by 18.0% (12.6% to 23.3%, n=1243), increased the risk of hemorrhage (odds ratio=1.71, 1.42 to 2.07, n=2833) and had no significant effect on mortality (odds ratio=0.82, 0.62 to 1.08, n=1274). There was an absolute reduction in efficacy of 1.1% (0.7% to 1.4%) for every 10 minutes delay to treatment. Cumulative meta-analysis showed that the estimate of efficacy fell as more data became available. Publication bias inflated efficacy by 5.1% (infarct volume) and 8.1% (neurobehavioral score). This data set was large enough to be adequately powered to estimate with precision the impact of biologic and experimental factors on the efficacy and safety of rtPA.

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Figures

Figure 1
Figure 1
Effect of reported study quality on, the estimate of efficacy on (A) infarct volume and (B) neurobehavioral score. The shaded gray bar represents the 95% confidence limits of the global estimate. The vertical error bars represent the 95% confidence intervals for the individual estimates. The width of each bar reflects the log of the number of animals contributing to that comparison. Stratification by study quality accounts for a significant proportion of the heterogeneity observed between studies.
Figure 2
Figure 2
Individual comparison ranked according to their effect on (A) infarct volume, (B) neurobehavioral score, (C) odds of hemorrhage, and (D) odds of mortality. The shaded gray bar represents the 95% confidence limits of the global estimate. The vertical error bars represent the 95% confidence intervals for the individual estimates.
Figure 3
Figure 3
Cumulative meta-analysis; studies included by publication date and the effect of this on the estimate of efficacy.
Figure 4
Figure 4
Effect of time of outcome assessment on (A) infarct volume, (B) neurobehavioral score, and (C) odds of mortality. The shaded gray bar represents the 95% confidence limits of the global estimate. The vertical error bars represent the 95% confidence intervals for the individual estimates. The size of each point reflects the log of the number of animals contributing to that comparison. Each stratification accounts for a significant proportion of the heterogeneity observed between studies.
Figure 5
Figure 5
Effect on hypertension on (A) infarct volume, (B) neurobehavioral score. The effect time of administration on (C) infarct volume and (D) neurobehavioral score. The effect of the gender of the animal on (E) infarct volume and (F) neurobehavioral score and the effect of anesthetic used on (G) infarct volume and (H) neurobehavioral score. The shaded gray bar represents the 95% confidence limits of the global estimate. The vertical error bars represent the 95% confidence intervals for the individual estimates. The size of each point reflects the log of the number of animals contributing to that comparison. Each stratification accounts for a significant proportion of the heterogeneity observed between studies.
Figure 6
Figure 6
Effect on tissue plasminogen activator (tPA) dose on (A) infarct volume and (B) odds of mortality. The shaded gray bar represents the 95% confidence limits of the global estimate. The vertical error bars represent the 95% confidence intervals for the individual estimates. The size of each point reflects the log of the number of animals contributing to that comparison. Each stratification accounts for a significant proportion of the heterogeneity observed between studies.
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References

    1. The NINDS rt-PA Stroke Study Group Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581–1587. - PubMed
    1. Crossley NA, Sena E, Goehler J, Horn J, Van Der WB, Bath PMW, MacLeod M, Dirnagl U. Empirical evidence of bias in the design of experimental stroke studies: a metaepidemiologic approach. Stroke. 2008;39:929–934. - PubMed
    1. Dirnagl U. Bench to bedside: the quest for quality in experimental stroke research. J Cereb Blood Flow Metab. 2006;26:1465–1478. - PubMed
    1. Duval S, Tweedie R. A nonparametric ‘trim and fill' method of accounting for publication bias in meta-analysis. J Am Stat Assoc. 2000;95:89–98.
    1. Fisher M, Albers GW, Donnan GA, Furlan AJ, Grotta JC, Kidwell CS, Sacco RL, Wechsler LR. Enhancing the development and approval of acute stroke therapies: Stroke Therapy Academic Industry roundtable. Stroke. 2005;36:1808–1813. - PubMed

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