Initiation of tissue plasminogen activator within 3 to 6 hours of onset of symptoms of an ischemic stroke can restore cerebral blood flow and improve clinical outcome in some patients, according to a late-breaking trial presented at the American Stroke Association's International Stroke Conference 2008.

However, the study did not succeed in meeting its primary endpoint, significant decrease in infarction size as shown by magnetic resonance imaging (MRI).

Tissue plasminogen activator is the only drug approved by the U.S. Food and Drug Administration for urgent treatment of ischemic strokes, and it is approved for use only within 3 hours of stroke symptoms. The current study sought to assess the benefits and risks of extending that time period.

The Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) is the first randomized, double-blinded, placebo-controlled trial examining whether the thromblytic agent could be administered safely and effectively more than three hours after an acute ischemic stroke in patients with potentially salvageable brain tissue as detected by magnetic resonance imaging (MRI).

The study will be simultaneously published in Lancet Neurology.

Previous studies have shown that a subset of stroke patients, those with salvageable brain tissue called "perfusion-diffusion mismatch" on MRI, may experience enhanced blood flow and better clinical outcomes if treated with the agent.

Researchers at 15 centers in Australia, Belgium, New Zealand and Scotland screened 1,224 patients whose stroke symptoms had begun 3 to 6 hours earlier. Of 101 randomized patients, mismatch was present in 86 percent. Of those, 37 patients received active treatment and 43 received placebo solution. Average age was 71 years and average time-to-treatment was about 5 hours from stroke onset.

"While the effect of late application of tPA on infarct growth - which was the primary outcome - was not significant, there was a strong trend toward infarct reduction," said lead author Stephen M. Davis, MD, professor of neurology at the University of Melbourne, Melbourne, Australia.

In addition, active treatment was associated with significant restoration of blood flow at 3 to 5 days and improved functional outcomes at 90 days. However, while Davis noted the study was too small to draw definitive conclusions on drug effect, he suggested that the results provide support for further studies on extending the time window for use.