The ECASS III trial: Administering recombinant t-PA up to 4.5 hours after onset of acute ischemic stroke improves neurological outcomes [Classics Series]

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1. Alteplase administered between 3 to 4.5 hours after the onset of acute ischemic stroke improves functional outcomes at 90 days, when compared to placebo

Original Date of Publication: September 25, 2008

Study Rundown: Treating acute ischemic stroke patients with intravenous alteplase 3 to 4.5 hours after the onset of symptoms significantly improved neurological outcomes at 3 months compared to placebo. While patients in the alteplase group experienced a significantly higher risk of intracranial hemorrhage, mortality was not significantly different between the two groups.

The ECASS3 trial demonstrated that administering alteplase 3 to 4.5 hours after the onset of acute ischemic stroke significantly improved functional outcomes at 3 months. While the trial was criticized for excluding patients with severe stroke signs and having a change of protocol during the trial, its findings have informed current practice, as current recommendations suggest administering recombinant tissue plasminogen activator (t-PA) up to 4.5 hours after the onset of acute ischemic stroke.

Click to read study in the NEJM (New England Journal of Medicine)

Primer: Last week, we reviewed the NINDS trial, which demonstrated that, compared to placebo, treatment of acute ischemic stroke with t-PA within 3 hours of symptom onset significantly improves functional outcomes three months after the incident.There remained uncertainty regarding the efficacy and safety of administering t-PA more than 3 hours after the onset of acute ischemic stroke. Two previous European trials (i.e., ECASS I and II) had investigated the use of alteplase up to 6 hours after the onset of stroke, but these studies did not demonstrate any benefits. The ECASS III trial was a randomized, controlled trial designed to explore the efficacy and safety of utilizing alteplase, a recombinant t-PA, 3 to 4.5 hours after the onset of stroke.

Relevant Reading:

1. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II). The Lancet 1998;352(9136):1245-1251.
2. Albers GW, Clark WM, Madden KP, et al. ATLANTIS trial: Results for patients treated within 3 hours of stroke onset. Stroke 2002;33:493-496.

In-Depth [randomized, controlled study]: This double-blind, placebo-controlled trial examined the use of alteplase at a dose of 0.9 mg/kg. The study involved 821 patients and had a primary outcome measure of disability at 90 days, as assessed using the modified Rankin Scale. The secondary outcome measure was a global measure at 90 days as determined using the modified Rankin Scale, Barthel Index, NIHSS, and Glasgow Outcome Scale. Safety outcomes included mortality at 90 days, intracranial hemorrhage (any, symptomatic), symptomatic edema, or other events.

With regards to both the primary and secondary endpoints, patients in the alteplase group were significantly more likely to have favourable outcomes, when compared to the placebo group. Patients in the alteplase group, however, experienced significantly higher risk of intracranial hemorrhage, including symptomatic intracranial hemorrhage. There were no significant differences between the two groups in terms of mortality.

By Adrienne Cheung and Andrew Cheung, M.D.

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