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

Gyanendra Kumar, Drew Uhrig, Susan Fowler, Matthew C. Delaney, Andrei Alexandrov

Research output: Contribution to journalReview article

2 Citations (Scopus)

Abstract

Background and 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)659-667
Number of pages9
JournalCNS Drugs
Volume29
Issue number8
DOIs
StatePublished - Aug 7 2015

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Tissue Plasminogen Activator
Meta-Analysis
Randomized Controlled Trials
Stroke
Mortality
Placebos
National Institute of Neurological Disorders and Stroke
Publication Bias
PubMed
Nervous System
Physicians
Survival

All Science Journal Classification (ASJC) codes

  • Clinical Neurology
  • Psychiatry and Mental health
  • Pharmacology (medical)

Cite this

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. / Kumar, Gyanendra; Uhrig, Drew; Fowler, Susan; Delaney, Matthew C.; Alexandrov, Andrei.

In: CNS Drugs, Vol. 29, No. 8, 07.08.2015, p. 659-667.

Research output: Contribution to journalReview article

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abstract = "Background and 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. Conclusion: 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.",
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