title: Trends in acute ischemic stroke trials through the 20th century.
abstract: OBJECTIVE
  The advent of controlled clinical trials revolutionized clinical medicine over the course of the 20th century. The objective of this study was to quantitatively characterize developments in clinical trial methodology over time in the field of acute ischemic stroke.
  
  
  METHODS
  All controlled trials targeting acute ischemic stroke with a final report in English were identified through MEDLINE and international trial registries. Data regarding trial design, implementation, and results were extracted. A formal 100-point scale was used to rate trial quality.
  
  
  RESULTS
  A total of 178 controlled acute stroke trials were identified, encompassing 73 949 patients. Eighty-eight trials involved neuroprotective agents, 59 rheological/antithrombotic agents, 26 agents with both neuroprotective and rheological/antithrombotic effects, and 5 a nonpharmacological intervention. Only 3 trials met conventional criteria for a positive outcome. Between the 1950s and 1990s, the number of trials per decade increased from 3 to 99, and mean trial sample size increased from 38 (median, 26) to 661 (median, 113). During 1980-1999, median time window allowed for enrollment decreased per half decade from 48 to 12 hours. Reported pharmaceutical sponsorship increased substantially over time, from 38% before 1970 to 68% in the 1990s. Trial quality improved substantially from a median score of 12 in the 1950s to 72 in the 1990s.
  
  
  CONCLUSIONS
  Accelerating trends in acute stroke controlled trials include growth in number, sample size, and quality, and reduction in entry time window. These changes reflect an increased understanding of the pathophysiology of acute stroke, the imperative for treatment initiation within a critical time window, and more sophisticated trial design.
authors.affiliation: University of California at Los Angeles (UCLA) Stroke Center, Department of Neurology, UCLA Medical Center, Los Angeles, CA 90095, USA. ckidwell@ucla.edu
authors.forename: C S
authors.initials: CS
authors.lastname: Kidwell
authors.forename: D S
authors.initials: DS
authors.lastname: Liebeskind
authors.forename: S
authors.initials: S
authors.lastname: Starkman
authors.forename: J L
authors.initials: JL
authors.lastname: Saver
mesh_terms: D000208:Acute Disease; D000925:Anticoagulants / Q000627:therapeutic use; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control; D002545:Brain Ischemia / Q000150:complications / Q000628:therapy*; D018849:Controlled Clinical Trials as Topic / Q000592:standards / Q000706:statistics & numerical data / Q000639:trends*; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006801:Humans; D015337:Multicenter Studies as Topic / Q000639:trends; D018696:Neuroprotective Agents / Q000627:therapeutic use; D011785:Quality Assurance, Health Care / Q000706:statistics & numerical data; D012106:Research / Q000639:trends; D012107:Research Design / Q000592:standards / Q000706:statistics & numerical data / Q000639:trends*; D018401:Sample Size; D020521:Stroke / Q000150:complications / Q000628:therapy*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000925:Anticoagulants; D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; D010959:Tissue Plasminogen Activator