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

This study summary is an excerpt from the book 2 Minute Medicine’s The Classics in Medicine: Summaries of the Landmark Trials

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

Original Date of Publication: September 2008

Study Rundown: Previously, the National Institute of Neurological Disorders and Stroke (NINDS) trial demonstrated that, compared to placebo, treatment of acute ischemic stroke with tissue plasminogen activator (t-PA) within 3 hours of symptom onset significantly improved functional outcomes 3 months after the incident. However, 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.

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 groups. Some clinicians criticized the trial for excluding patients with severe stroke signs and for a change of protocol during the trial. Regardless, its findings have informed practice as current recommendations suggest administering recombinant t-PA up to 4.5 hours after the onset of acute ischemic stroke.

Click to read the study in NEJM

In-Depth [randomized controlled trial]: This double-blind, placebo-controlled trial examined the use of alteplase at a dose of 0.9 mg/kg. Patients were eligible for the trial if they had a stroke with a clearly defined time of onset, a measurable deficit, and a computed tomographic scan of the brain that demonstrated no evidence of intracranial hemorrhage at baseline. Exclusion criteria included stroke or serious head trauma in the preceding 3 months, major surgery in the past 14 days, history of intracranial hemorrhage, rapidly improving or minor symptoms, and seizure at the onset of stroke. 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. Patients in the alteplase group were significantly more likely to have favorable outcomes of both the primary and secondary outcomes when compared to the placebo group. Patients in the alteplase group, however, experienced a significantly higher risk of intracranial hemorrhage, including symptomatic intracranial hemorrhage, in the first 36 hours after treatment (p < 0.001). There were no significant differences between the groups in terms of mortality.

Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, et al. Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. The New England Journal of Medicine. 2008 Sep 25;359(13):1317–29.

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