title: Efficacy of Alteplase in a Mouse Model of Acute Ischemic Stroke: A Retrospective Pooled Analysis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Inserm UMR-S U919, University Caen Normandie, GIP Cyceron, Caen, France.|Experimental Stroke Research Platform, CURB, University Caen Normandie, Caen, France.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Orset
authors.affiliation: Experimental Stroke Research Platform, CURB, University Caen Normandie, Caen, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Haelewyn
authors.affiliation: University of Manchester, Faculty of Medical and Health Sciences, Manchester, United Kingdom.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Allan
authors.affiliation: Neurologische Universitätsklinik, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.|Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Saema
authors.initials: S
authors.lastname: Ansar
authors.affiliation: Dept of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.|Department of Neurology, Neurovascular Area, Clinical Neurosciences Research Laboratory, Hospital Clínico Universitario, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.
authors.forename: Francesco
authors.initials: F
authors.lastname: Campos
authors.affiliation: Inserm UMR-S U919, University Caen Normandie, GIP Cyceron, Caen, France.|Dept of Stroke Medicine and Department of Neuroradiology; Université Lyon 1; CREATIS, CNRS UMR 5220-INSERM U1044 ; Hospices Civils de Lyon ; Lyon, France.
authors.forename: Tae Hee
authors.initials: TH
authors.lastname: Cho
authors.affiliation: Dept of Stroke Medicine and Department of Neuroradiology; Université Lyon 1; CREATIS, CNRS UMR 5220-INSERM U1044 ; Hospices Civils de Lyon ; Lyon, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Durand
authors.affiliation: EA4475 Pharmacologie de la Circulation Cérébrale, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
authors.forename: Mohamad
authors.initials: M
authors.lastname: El Amki
authors.affiliation: Department of Neurology, Universitätsmedizin Mannheim, University of Heidelberg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Fatar
authors.affiliation: Unidad de Investigación Neurovascular, Departamento Farmacología, Facultad de Medicina, Universidad Complutense and Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.
authors.forename: Isaac
authors.initials: I
authors.lastname: Garcia-Yébenes
authors.affiliation: Inserm UMR-S U919, University Caen Normandie, GIP Cyceron, Caen, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Gauberti
authors.affiliation: Department of Neurology, Universitätsmedizin Mannheim, University of Heidelberg, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Grudzenski
authors.affiliation: Unidad de Investigación Neurovascular, Departamento Farmacología, Facultad de Medicina, Universidad Complutense and Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Lizasoain
authors.affiliation: Departments of Radiology, and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, USA.
authors.forename: Eng
authors.initials: E
authors.lastname: Lo
authors.affiliation: Inserm UMR-S U919, University Caen Normandie, GIP Cyceron, Caen, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Macrez
authors.affiliation: EA4475 Pharmacologie de la Circulation Cérébrale, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Margaill
authors.affiliation: University of Manchester, Faculty of Medical and Health Sciences, Manchester, United Kingdom.
authors.forename: Samaneh
authors.initials: S
authors.lastname: Maysami
authors.affiliation: Neurologische Universitätsklinik, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
authors.forename: Stephen
authors.initials: S
authors.lastname: Meairs
authors.affiliation: Dept of Stroke Medicine and Department of Neuroradiology; Université Lyon 1; CREATIS, CNRS UMR 5220-INSERM U1044 ; Hospices Civils de Lyon ; Lyon, France.
authors.forename: Norbert
authors.initials: N
authors.lastname: Nighoghossian
authors.affiliation: Inserm UMR-S U919, University Caen Normandie, GIP Cyceron, Caen, France.|Inserm UMR-S U919, University Caen Normandie, GIP Cyceron, Caen, France.
authors.forename: Josune
authors.initials: J
authors.lastname: Orbe
authors.affiliation: Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA-University of Navarra, Pamplona, Spain.
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Paramo
authors.affiliation: Departments of Biostatistics and Clinical Research, Centre Hospitalier Universitaire (CHU), Caen ; EA4655 Risques Microbiens, Université de Caen Normandie, Caen, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Parienti
authors.affiliation: University of Manchester, Faculty of Medical and Health Sciences, Manchester, United Kingdom.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Rothwell
authors.affiliation: Inserm UMR-S U919, University Caen Normandie, GIP Cyceron, Caen, France.
authors.forename: Marina
authors.initials: M
authors.lastname: Rubio
authors.affiliation: Dept of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.|School of Pharmacy and Dept. of Pharmacology/Therapeutics, University College Cork, Ireland.
authors.forename: Christian
authors.initials: C
authors.lastname: Waeber
authors.affiliation: Inserm UMR-S U919, University Caen Normandie, GIP Cyceron, Caen, France.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Young
authors.affiliation: Inserm UMR-S U919, University Caen Normandie, GIP Cyceron, Caen, France.|Department of Neurology, CHU Côte de Nacre, Caen.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Touzé
authors.affiliation: Inserm UMR-S U919, University Caen Normandie, GIP Cyceron, Caen, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Vivien
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator
keywords: magnetic resonance imaging; middle cerebral artery; stroke; thrombolytic therapy; tissue-type plasminogen activator