International Stroke Conference 2008: EPITHET: Patients who suffer a stroke and have a perfusion-diffusion mismatch may benefit from tPA beyond the 3-hour window

According to the results of the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET), extending the treatment window for intravenous (IV) tissue plasminogen activator (alteplase) (tPA) beyond the established 3 hours after ischemic stroke onset significantly increases reperfusion in patients who have a perfusion-diffusion mismatch identified by magnetic resonance imaging (MRI). The results of this phase 2 trial were presented at the International Stroke Conference 2008 in New Orleans, Louisiana, February 20 to 22, 2008. Infarct growth was also reduced by approximately one-third in patients who received tPA compared with those who received placebo, although this reduction was not significant.

The study included 101 patients eligible for tPA under the standard criteria. Patients were randomized to receive tPA (n=52) or placebo (n=49) 3 to 6 hours after onset of ischemic stroke. A total of 86% of patients had a perfusion-diffusion mismatch, a signature of salvageable tissue in the ischemic penumbra, according to Stephen M. Davis, MD, Department of Neurology, Royal Melbourne Hospital, University of Melbourne, Australia.

The primary end point was infarct growth. Geometric mean infarct growth was 1.24 in patients randomized to tPA versus 1.78 in those randomized to placebo, corresponding to a nonsignificant 31% reduction with tPA (P=.239). The median relative infarct growth was 1.18 in the tPA group and 1.79 in the placebo group, a 34% reduction with tPA that narrowly failed to achieve significance (P=.054).

EPITHET also measured reperfusion as a secondary end point. More than half (56%) of patients assigned to tPA had reperfusion ≥90% compared with 26% of those randomized to placebo (P=.01). The median reperfusion percentage was 91% in the tPA group and 65% in the placebo group (P=.045). Dr Davis said that patients who experienced reperfusion also experienced less growth and better clinical outcomes.

Among patients with a perfusion-diffusion mismatch, functional outcome was excellent (defined as an mRS score of 0 or 1) in 15% more patients randomized to tPA compared with placebo, although this improvement was not significant.

"There is a biological rationale for using tPA beyond 3 hours, and this particularly applies to patients with mismatch," Dr Davis said. He stated that a phase 3 clinical trial of tPA during the 3- to 6-hour window in "mismatch patients" is warranted, and that such a trial would require approximately 400 patients to demonstrate a clinical benefit with tPA in this population.

The EPITHET results have been published in Lancet Neurology (2008;7:299–309.)