Intravenous recombinant tissue plasminogen activator (tPA) is recommended for the treatment of acute ischemic stroke within the first 3 hours of stroke onset. However, some randomized controlled trials have suggested that tPA might improve clinical outcome beyond the established 3 hour time limit. The objective of the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) was to evaluate the effect of the administration of tPA 3–6 hours after stroke onset as measured by echoplanar magnetic resonance imaging (MRI), diffusion-weighted MRI (DWI), and perfusion-weighted MRI (PWI). Because the probability of infarction depends on the severity and duration of hypoperfusion in the ischemic penumbra (the salvageable area around the irreversibly damaged infarct core), measurement of the mismatch between the larger PWI and smaller DWI lesion area can be used to estimate the salvageable tissue in the penumbra.

Prof. Stephen M. Davis, Royal Melbourne Hospital, Melbourne, Australia, presented data from the EPITHET study, which examined the effects of tPA on lesion growth and reperfusion as well as clinical outcomes in patients with acute hemispheric ischemic stroke. Mismatch was defined as PWI (T_max delay ∼2 seconds) >20% and over 10 mL greater than the DWI lesion volume. The primary endpoint was infarct growth between baseline DWI and the Day 90 T2 lesion in mismatch patients. Other endpoints included reperfusion, recanalization, symptomatic intracranial hemorrhage, good neurological outcome, and good functional outcome.

Mismatch was present in 86% of patients. Arterial occlusion was present in 62% (54/87) of those with an adequate baseline MRI. The study did not meet its primary endpoint, which was to show that tPA could significantly reduce infarct growth in the area of the brain affected by the stroke as shown by MRI. The geometric mean infarct growth was 1.24 with tPA and 1.78 with placebo (p=0.24). Reperfusion, which was more common with tPA than with placebo, occurred in 39% of mismatch patients, and was associated with less infarct growth (p=0.001) and improved neurological (63% vs 32%; p=0.00l) and functional outcomes (73% vs 28%; p<0.0l).

Reperfusion was associated with improved clinical outcomes. tPA was associated with increased reperfusion and attenuated infarct size in stroke patients with mismatch. Recanalization was not increased by tPA. Although the study was too small to draw definitive conclusions on the effect of tPA, Prof. Davis suggested that the results provide support for further studies on extending the time window for thrombolysis treatment beyond 3 hours in some patients.