2. Academic Validation
  3. 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

  • Stroke. 2016 May;47(5):1312-1318. doi: 10.1161/STROKEAHA.116.012238.
Cyrille Orset 1 2,  Benoit Haelewyn 2,  Stuart M Allan 3,  Saema Ansar 4 5,  Francesco Campos 6 7,  Tae Hee Cho 1 8,  Anne Durand 8,  Mohamad El Amki 9,  Marc Fatar 10,  Isaac Garcia-Yébenes 11,  Maxime Gauberti 1,  Saskia Grudzenski 10,  Ignacio Lizasoain 11,  Eng Lo 12,  Richard Macrez 1,  Isabelle Margaill 9,  Samaneh Maysami 3,  Stephen Meairs 4,  Norbert Nighoghossian 8,  Josune Orbe 1 1,  Jose Antonio Paramo 13,  Jean-Jacques Parienti 14,  Nancy J Rothwell 3,  Marina Rubio 1,  Christian Waeber 6 15,  Alan R Young 1,  Emmanuel Touzé # 1 16,  Denis Vivien # 1
Affiliations

Affiliations

  • 1 Inserm UMR-S U919, University Caen Normandie, GIP Cyceron, Caen, France.
  • 2 Experimental Stroke Research Platform, CURB, University Caen Normandie, Caen, France.
  • 3 University of Manchester, Faculty of Medical and Health Sciences, Manchester, United Kingdom.
  • 4 Neurologische Universitätsklinik, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
  • 5 Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, Lund, Sweden.
  • 6 Dept of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
  • 7 Department of Neurology, Neurovascular Area, Clinical Neurosciences Research Laboratory, Hospital Clínico Universitario, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.
  • 8 Dept of Stroke Medicine and Department of Neuroradiology; Université Lyon 1; CREATIS, CNRS UMR 5220-INSERM U1044 ; Hospices Civils de Lyon ; Lyon, France.
  • 9 EA4475 Pharmacologie de la Circulation Cérébrale, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
  • 10 Department of Neurology, Universitätsmedizin Mannheim, University of Heidelberg, Germany.
  • 11 Unidad de Investigación Neurovascular, Departamento Farmacología, Facultad de Medicina, Universidad Complutense and Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.
  • 12 Departments of Radiology, and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, USA.
  • 13 Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA-University of Navarra, Pamplona, Spain.
  • 14 Departments of Biostatistics and Clinical Research, Centre Hospitalier Universitaire (CHU), Caen ; EA4655 Risques Microbiens, Université de Caen Normandie, Caen, France.
  • 15 School of Pharmacy and Dept. of Pharmacology/Therapeutics, University College Cork, Ireland.
  • 16 Department of Neurology, CHU Côte de Nacre, Caen.
  • # Contributed equally.
PMID: 27032444 DOI: 10.1161/STROKEAHA.116.012238
Abstract

Background and purpose: 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 data set from preclinical studies, to examine the effects of early versus late administration of intravenous recombinant tissue-type plasminogen activator.

Methods: We collected data from 26 individual studies from 9 international centers (13 researchers; 716 Animals) that compared recombinant tissue-type plasminogen activator with 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 (<3 hours) versus late (≥3 hours) drug administration. Final infarct volumes, assessed by histology or magnetic resonance imaging, 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.

Results: When compared with saline controls, early recombinant tissue-type plasminogen activator administration was associated with a significant benefit (absolute difference, -6.63 mm(3); 95% confidence interval, -9.08 to -4.17; I(2)=76%), whereas late recombinant tissue-type plasminogen activator treatment showed a deleterious effect (+5.06 mm(3); 95% confidence interval, +2.78 to +7.34; I(2)=42%; Pint<0.00001). Results remained unchanged after subgroup analyses.

Conclusions: Our results provide the basis needed for the design of future preclinical studies on recanalization therapies using this model of thromboembolic stroke in mice. The power analysis reveals that a multicenter trial would require 123 Animals per group instead of 40 for a single-center trial.

Keywords

magnetic resonance imaging; middle cerebral artery; stroke; thrombolytic therapy; tissue-type plasminogen activator.

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