Under Review Journal Club Article
Hacke W, et al. "Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke". The New England Journal of Medicine. 2008. 359(13):1317-1329.
PubMed Full text PDF

Clinical Question

Is ateplase safe and effective for ischemic stroke patients when administered 3 to 4.5 hours after the onset of symptoms?


Patients with ischemic stroke who received IV ateplase 3 to 4.5 hours after symptom onset had significant improvement in clinical outcomes. However, ateplase was associated with more frequent symptomatic intracranial hemorrhage.

Major Points

Study Design

  • Double blinded, multicenter, randomized controlled trial
    • multiple centers across Europe


N= 821 (enrolled between July 29, 2003 and November 13, 2007 from 130 sites in 19 European countries)

Treatment group N= 418
Placebo group N= 403

Patient Demographics

  • No significant difference between ateplase and placebo group except for stroke severity and history of stroke.
    • Ateplase group had an NIHSS score average of 10.7 while the placebo group had a score of 11.6
    • 14.1% of the placebo group had a history of stroke while only 7.7% of the ateplase group had a history of stroke.

Inclusion Criteria

  • Age: 18-80
  • Acute ischemic stroke
  • Symptom onset 3-4.5 hours prior to study intervention
  • Continuous symptoms for at least 30 minutes without improvement prior to intervention

Exclusion Criteria

  • Time of symptom onset unknown
  • Intracranial hemorrhage
  • Improvement in symptoms/minimal symptoms prior to administration of study drug
  • Severe stroke (NIHSS >25 or by imaging)
  • Previous stroke, head trauma, surgery, or severe trauma within 3 months
  • History of stroke + diabetes
  • Seizure at symptoms onset
  • Administration of Heparin within 48 hours of symptom onset and elevated PTT
  • Platelets <100,000
  • SBP>185 or DBP>110
  • Glucose <50 or >400
  • Symptoms suggesting SAH
  • On anticoagulation
  • Disorders with increased risk of bleeding



Primary Outcome

Secondary Outcomes

Subgroup analysis

Criticisms & Further Discussion