title: Intravenous Recombinant Tissue Plasminogen Activator Does Not Impact Mortality in Acute Ischemic Stroke at Any Time Point up to 6 Months: A Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials.
abstract: OBJECTIVE
  Concerns about the harms of intravenous alteplase (recombinant tissue plasminogen activator) continue to deter physicians from treating patients with acute ischemic stroke with the only drug proven to positively impact outcomes and reduce disability. Recent literature indicates an increase in mortality with alteplase within 7 days, an effect that does not persist from 3 months onwards. The objective of this meta-analysis was to pool mortality estimates from randomized controlled clinical trials (RCTs) at 7 days, 30 days, 90 days, and 6 months after stroke onset.
  
  
  METHODS
  PubMed, Embase, Scopus, CENTRAL, and clinicaltrials.gov were searched through to April 2014, using "hedges" for tissue plasminogen activator, acute ischemic stroke, and placebo. Two independent authors abstracted data and assessed study quality. Data were pooled using Dersimonian and Laird's random effects model.
  
  
  RESULTS
  Eleven RCTs (n = 6905) were included in the final analysis. Two authors independently performed study selection and data abstraction. There was no publication bias and total variance attributable to heterogeneity was not significant (I(2) < 50%) at any time point. There was no difference in mortality between alteplase and placebo groups at any time point. Trials that randomized patients beyond 3 h (excluded patients within the 3-h window) did not drive the mortality difference seen at any time point. Exclusion sensitivity analysis revealed that exclusion of the NINDS trial rendered the 7-day difference significant towards increased mortality with alteplase. Quality adjustment did not alter the results.
  
  
  CONCLUSIONS
  Intravenous alteplase did not impact mortality in patients with acute ischemic stroke at any of the measured time points up to 6 months (i.e., there was no increase in the risk of death with alteplase). Therefore, intravenous alteplase should be given to all eligible patients with acute ischemic stroke to improve long-term neurologic outcomes. The effects of alteplase on early survival are more complex than previously understood.
authors.affiliation: Department of Neurology, Comprehensive Stroke Center, University of Alabama at Birmingham, 1813 6th Ave South, RWUH M226, Birmingham, AL, 35249, USA. kumarg@uab.edu.
authors.forename: Gyanendra
authors.initials: G
authors.lastname: Kumar
authors.affiliation: Department of Neurology, Comprehensive Stroke Center, University of Alabama at Birmingham, 1813 6th Ave South, RWUH M226, Birmingham, AL, 35249, USA.
authors.forename: Drew
authors.initials: D
authors.lastname: Uhrig
authors.affiliation: Becker Medical Library, Washington University in St. Louis, St. Louis, MO, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Fowler
authors.affiliation: Department of Emergency Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: DeLaney
authors.affiliation: Department of Neurology, University of Tennessee-Memphis, Memphis, TN, USA.
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Alexandrov
mesh_terms: D061605:Administration, Intravenous; D002545:Brain Ischemia / Q000188:drug therapy* / Q000401:mortality; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D020521:Stroke / Q000188:drug therapy* / Q000401:mortality; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator