European Cooperative Acute Stroke Study-4: Extending the time for thrombolysis in emergency neurological deficits ECASS-4: ExTEND

Int J Stroke. 2016 Feb;11(2):260-7. doi: 10.1177/1747493015620805.


Rationale and hypothesis: Thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) is an effective and approved therapy for acute ischemic stroke within 4.5 h of onset except for USA, Canada, Croatia, and Moldovia with a current 3 h label. We hypothesized that ischemic stroke patients selected with significant penumbral mismatch on magnetic resonance imaging (MRI) at 4.5-9 h after onset of stroke will have improved clinical outcomes when given intravenous rt-PA (alteplase) compared to placebo.

Study design: ECASS-4: ExTEND is an investigator driven, phase 3, randomized, multi-center, double-blind, placebo-controlled study. Ischemic stroke patients presenting within 4.5 and 9 h of stroke onset, who fulfil clinical requirements (National Institutes of Health Stroke Score (NIHSS) 4-26 and pre-stroke modified Rankin Scale (mRS) 0-1) will undergo MRI. Patients who meet imaging criteria (infarct core volume <100 ml, perfusion lesion: infarct core mismatch ratio >1.2 and perfusion lesion minimum volume of 20 ml) additionally will be randomized to either rt-PA or placebo.

Study outcome: The primary outcome measure will be the categorical shift in the mRS at day 90. Clinical secondary outcomes will be disability at day 90 dichotomized as favorable outcome mRS 0-1 at day 90. Tertiary endpoints include reduction in the NIHSS by 11 or more points or reaching 0-1 at day 90, reperfusion and recanalization at 24 h post stroke as well as depression, life quality, and cognitive impairment at day 90. Safety endpoints will include symptomatic intracranial hemorrhage (ICH) and death.

Keywords: acute stroke therapy; clinical trial; ischemic stroke; magnetic resonance imaging; recombinant tissue plasminogen activator; thrombolytic therapy.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Clinical Protocols / standards*
  • Double-Blind Method
  • Humans
  • Magnetic Resonance Imaging
  • Neuroimaging
  • Stroke / drug therapy*
  • Thrombolytic Therapy / methods*
  • Time Factors
  • Tissue Plasminogen Activator / administration & dosage
  • Tissue Plasminogen Activator / therapeutic use*
  • Treatment Outcome


  • Tissue Plasminogen Activator