EBQ:ECASS III

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?

Conclusion

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

• ECASS III extended the treatment window for IV alteplase in acute ischemic stroke from 3 hours to 4.5 hours
• The study demonstrated a modest but statistically significant benefit of alteplase given between 3-4.5 hours after stroke onset
• This trial was pivotal in changing international stroke guidelines to extend the thrombolysis window
• The benefit was smaller than in the 0-3 hour window, reinforcing the importance of early treatment
• Symptomatic intracranial hemorrhage was more common with alteplase but did not increase overall mortality

Study Design

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

Population

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

Interventions

• IV alteplase (0.9 mg/kg, maximum 90 mg; 10% as bolus, remainder infused over 60 minutes) given 3-4.5 hours after symptom onset
• Placebo group received matching IV placebo infusion
• All patients received standard stroke care including admission to a stroke unit

Outcomes

Primary Outcome

• Modified Rankin Scale 0-1 at 90 days: alteplase 52.4% vs placebo 45.2% (OR 1.34, 95% CI 1.02-1.76, p=0.04)

Secondary Outcomes

• Global outcome (combined mRS, Barthel, NIHSS, GOS): OR 1.28 (95% CI 1.00-1.65, p=0.05)
• Symptomatic intracranial hemorrhage: alteplase 2.4% vs placebo 0.2% (p=0.008)
• Mortality at 90 days: alteplase 7.7% vs placebo 8.4% (p=0.68, not significant)
• Any intracranial hemorrhage: alteplase 27.0% vs placebo 17.6% (p=0.001)

Criticisms

• Industry-sponsored (Boehringer Ingelheim) trial with potential for bias
• Excluded patients >80 years old, those with severe stroke (NIHSS >25), prior stroke with diabetes, and those on oral anticoagulants, limiting generalizability
• The benefit was modest (NNT ~14) and narrower than in the 0-3 hour window
• Higher rate of symptomatic ICH with alteplase, though mortality was not increased
• Results may not apply to populations excluded from the trial, particularly elderly patients and those with prior stroke

Funding

• Boehringer Ingelheim