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

Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism
Emily S SenaMalcolm Macleod

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). Th...Continue Reading

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Citations

Jul 23, 2013·PLoS Biology·Konstantinos K TsilidisJohn P A Ioannidis
Jul 23, 2013·PLoS Medicine·C R Hooijmans, M Ritskes-Hoitinga
Jun 7, 2014·PloS One·Jennifer A HirstCarl Heneghan
Nov 20, 2013·Nature Reviews. Neurology·David W HowellsMalcolm R Macleod
Feb 20, 2014·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Emily S SenaDavid W Howells
Dec 5, 2013·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Seema YousufDonald G Stein
Jun 21, 2012·International Journal of Stroke : Official Journal of the International Stroke Society·Sandeep AnkolekarPhilip M W Bath
Jun 21, 2012·International Journal of Stroke : Official Journal of the International Stroke Society·David W HowellsMalcolm R Macleod
Jan 8, 2014·International Journal of Stroke : Official Journal of the International Stroke Society·Ana AntonicDavid W Howells
Jun 18, 2015·International Journal of Rheumatic Diseases·Gillian Laura Currie, Malcolm Robert Macleod
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Dec 30, 2014·ILAR Journal·Annette M O'Connor, Jan M Sargeant
Jan 14, 2017·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Sarah Sj RewellDavid W Howells
Jun 6, 2014·Nature·Malcolm R Macleod
Nov 22, 2017·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Samuel KnaussAlexander Kunz
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Jul 26, 2014·Stroke; a Journal of Cerebral Circulation·Ulrich Dirnagl
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Jun 30, 2016·Stroke; a Journal of Cerebral Circulation·Ulrich Dirnagl
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Jan 5, 2019·Circulation. Cardiovascular Quality and Outcomes·Donglan ZhangDavid C Hess
Jan 10, 2016·Neuroradiology·Robert FahedTim E Darsaut

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