According to an article published in The Lacnet Neurology, phase III clinical trials of alteplase should now begin. Alteplase is the only licensed therapy for acute ischaemic stroke and is found to have positive effects for some patients, even if administered after the usual 3-hour treatment window.

Acute ischaemic stroke is when the blood supply to part of the brain has diminished, resulting in death of brain tissue and brain dysfunction. Alteplase is a tissue plasminogen activator that dissolves blood clots and is used to treat stroke patients.

Usually, alteplase is given to patients within three hours of the stroke. However, meta-analyses have shown that when alteplase is given intravenously, there is a possibility of improved clinical outcomes that extend beyond three hours. Over time, these benefits quickly decrease. Treatment with alteplase desires to achieve recanalization and to salvage the ischaemic penumbra.

The ischaemic penumbra is an area where viable brain tissue is critically hypoperfused around the irreversibly damaged “infarct core” – where the stroke blockage occurred. Within three hours of stroke onset, at least 80% of patients still have the ischaemic penumbra. Over time, this proportion decreases. It is thought that the clinical gains from alteplase include improved tissue reperfusion and a stopping of infarct growth. However, the degree of irreversible damage and how much of the ischaemic penumbra – if any – is left will impact these results. Magnetic resonance imaging (MRI)can help doctors identify which patients are likely to have ischaemic penumbra – patients who could possibly benefit from alteplase treatment beyond three hours.

The study was conducted by Professor Stephen Davis of the Royal Melbourne Hospital, University of Melbourne, Victoria, Australia, and colleagues. The Echoplanar Imaging Thrombolysis Evaluation (EPITHET) trial consisted of 101 patients, averaging 71.6 years of age, who were randomly assigned to receive alteplase or a placebo 3 to 6 hours after the incidence ischaemic stroke. Fifty-two of the patients received alteplase and 49 received the placebo. Of the total, 99 (86%) had suspected ischaemic penumbra.

In patients who received alteplase, the key measure of infarct/stroke growth was lowered by one third compared to placebo recipient. This difference, however, was not statistically significant. The alteplase group did show significantly better reperfusion, which was associated with better neurological outcome and better functional outcome than patients without reperfusion.

“EPITHET provides further evidence that the time window for thrombolysis treatment might be extended beyond three hours in some patients. These results emphasise the need for phase III trials with primary clinical endpoints in this time window, such as the Third International Stroke Trial (IST-3) and the Third European Cooperative Acute Stroke Study (ECASS-3), before any change in clinical practice is recommended,” conclude the authors.

An accompanying Reflection and Reaction by Dr. Peter Schellinger of the University at Erlangen, Germany, is optimistic about the results of ECASS-3. “The time is right for a joint international effort to plan and undertake” a randomized controlled trial, only with appropriate patients, looking at administration of alteplase beyond three hours or beyond 4.5 hours.

Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial
Stephen M Davis, Geoffrey A Donnan, Mark W Parsons, Christopher Levi, Kenneth S Butcher, Andre Peeters, P Alan Barber, Christopher Bladin, Deidre A De Silva, Graham Byrnes, Jonathan B Chalk, John N Fink, Thomas E Kimber, David Schultz, Peter J Hand, Judith Frayne, Graeme Hankey, Keith Muir, Richard Gerraty, Brian M Tress, Patricia M Desmond
The Lancet Neurology. February 22, 2008.
doi:10.1016/S1474-4422(08)70044-9

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Written by: Peter M Crosta