Ischemic stroke: thrombolysis window likely extends out to 9 hours

  • Ma H & al.
  • N Engl J Med
  • 9 May 2019

  • International Clinical Digest
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  • Among patients with ischemic stroke and salvageable brain tissue, use of intravenous alteplase (Activase) between 4.5 and 9.0 hours after stroke onset or on awakening with stroke symptoms improves likelihood of achieving no or minor neurologic deficits at 90 days.

Why this matters

  • Window for using intravenous thrombolysis historically limited to 4.5 hours.

Key results

  • Trial stopped early, after 225 of planned 310 patients enrolled, because of loss of equipoise due to positive WAKE-UP trial.
  • Favorable 90-day functional outcome: 35.4% with alteplase vs 29.5% with placebo (adjusted risk ratio, 1.44; P=.04).
  • Symptomatic intracranial hemorrhage: 6.2% with alteplase vs 0.9% with placebo (adjusted risk ratio, 7.22; P=.053).
  • Groups not significantly different on 90-day ordinal distribution of modified Rankin scale scores.

Expert comment

  • In an editorial, Randolph S. Marshall, MD, writes, “The current trial … will need to be validated. It was stopped early owing to the publication of results of another clinical trial, which was not truly equivalent to the EXTEND trial … Further randomized clinical trials that compare intravenous thrombolysis with thrombectomy in the late time window among patients selected on the basis of penumbra-based imaging are warranted. Alternative thrombolytic agents such as tenecteplase are also being tested. Despite the work to be done, the EXTEND trial shattered an important barrier to the treatment of acute stroke.”

Study design

  • Multinational phase 3 randomized controlled trial among patients with ischemic stroke with hypoperfused but salvageable regions of brain on automated perfusion imaging (EXTEND trial).
  • Randomization: intravenous alteplase vs placebo 4.5-9.0 hours after onset of stroke or on awakening with stroke.
  • Main outcome: 90-day modified Rankin scale score of 0 or 1.
  • Funding: Australian National Health and Medical Research Council; others.


  • Premature trial termination, limiting power.
  • Door-to-needle time of ~2 hours longer than guidelines recommend.
  • Some enrolled patients would now be eligible for endovascular thrombectomy.