Rebellion21: Alteplase for Stroke of Unknown Time of Onset

In this 9 minute video from day 2 of Rebellion in EM 2021, I go over the evidence for advanced imaging use in acute ischemic stroke of unknown time of onset to help guide treatment with intravenous alteplase.

What They Did:

  • Systematic review and meta-analysis of individual patient data of trials
  • RCTs of IV tPA vs standard care or placebo in adults with stroke of unknown time of onset + perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-MRI)

Primary Outcome: Favorable functional outcome (Score of 0 to 1 on the mRS) at 90d


  • 4 trials met eligibility criteria (843 patients could have meta-analysis performed)
    • WAKE-UP 503 patients using 0.9mg/kg alteplase
      • Terminated early due to cessation of funding
    • EXTEND 225 patients using 0.9mg/kg alteplase
      • Terminated early due to results of WAKE-UP
    • THAWS 131 patients using 0.6mg/kg alteplase
      • Terminated early due to results of WAKE-UP
    • ECASS-4 119 patients using 0.9mg/kg alteplase
      • Terminated early due to lack of recruitment
    • All 4 trials stopped early
  • Favorable Functional Outcome (mRS 0 to 1) at 90d (Primary Outcome):
    • Alteplase: 47%
    • Control: 39%
    • aOR 1.49; 95% CI 1.10 to 2.03; p = 0.011
    • NNT = 12
  • Death at 90d:
    • Alteplase: 6%
    • Control: 3%
    • aOR 2.06; 95% CI 1.03 to 4.09; p = 0.40
  • Symptomatic ICH:
    • Alteplase: 3%
    • Control: <1%
    • aOR 5.58; 1.22 to 25.50; p = 0.024


  • All 4 trials stopped early and only had modest sample sizes which limits the strength/precision of the findings and can overestimate benefit of the individual trials
  • Only one study used 0.6mg/kg of intravenous alteplase and therefore no definitive conclusions can be made about lower dosing vs higher dosing from this meta-analysis
  • The requirement of advanced imaging beyond non-contrast CT and vessel imaging might still be a potential limitation for implementation in some regions


  • The availability of perfusion imaging can affect all stroke care, where time is no longer brain. There will be plenty of patients who present <3 hours with no penumbra and no mismatch. This group may not require thrombolysis and perfusion imaging can help confirm that and spare them the potential harms
  • One thing to consider in this study is that despite having a lower number of deaths in the control group (mRS 6) compared to alteplase there were far more patients who were bedridden (mRS 5). This is a tough one to wrestle with from a patient care standpoint.  Do we save a life at the expense of being bedridden or do we spare the patient being bedridden at the expense of death?

Bottom Line: This meta-analysis provides level 1a evidence for the use of advanced brain imaging beyond non-contrast CT to help guide treatment with intravenous alteplase in patients with acute ischemic stroke with an unknown time of onset.  However, despite a consistently better functional outcome at 90d with alteplase compared to placebo or standard of care there was still an increased risk of symptomatic intracranial hemorrhage and a higher mortality which has also been consistent across all randomized clinical trials. 


  1. Thomalla G et al. Intravenous Alteplase for Stroke with Unknown Time of Onset Guided by Advanced Imaging: Systematic Review and Meta-Analysis of Individual Patient Data. Lancet 2020. PMID: 33176180

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)

Cite this article as: Salim Rezaie, "Rebellion21: Alteplase for Stroke of Unknown Time of Onset", REBEL EM blog, September 25, 2021. Available at:

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