News Release

Stroke treatment alteplase gives benefits beyond normal 3-hour treatment window (epithet study)

Peer-Reviewed Publication

The Lancet_DELETED

Alteplase -- the only licensed therapy for acute ischemic stroke -- gives benefits in certain patients even when given after the conventional 3-hour treatment window. Phase III clinical trials of alteplase in these patients should now go ahead. These are the conclusions of authors of an Article published early Online and in the April Edition of The Lancet Neurology, announced this week at The International Stroke Conference in New Orleans, USA.

While alteplase is usually only used on patients who have had a stroke in the previous three hours, meta-analyses of trials of intravenous alteplase suggests that improved clinical outcomes extend beyond three hours. However these benefits rapidly diminish with time. The aims of treatment with alteplase are recanalisation and salvage of the ischaemic penumbra -- a region of critically hypoperfused but viable brain tissue around the irreversibly damaged "infarct core" (where the stroke blockage occurred). The ischaemic penumbra is present in at least 80% of patients within three hours of stroke onset, but this proportion diminishes with time. Potential clinical gains from alteplase relate to how it can improve tissue reperfusion and stop infarct growth -- and these in turn depend on the degree of irreversible damage and the presence and extent of the ischaemic penumbra. By using magnetic resonance imaging techniques, it is possible to identify those patients likely to have an ischaemic penumbra, and it is these patients that could benefit from alteplase treatment beyond three hours.

Professor Stephen Davis, Department of Neurology, Royal Melbourne Hospital, University of Melbourne, Victoria, Australia, and colleagues did a study (the EPITHET trial) of 101 patients (mean age 71.6 years) randomly assigned to receive alteplase or placebo 3-6 hours after onset of ischaemic stroke. Of these, 52 received alteplase and 49 received placebo. 99 (86%) of the patients had suspected ischaemic penumbra.

The researchers found that the main measure of infarct/stroke growth was lowered by one third with alteplase, compared with placebo, although this was not statistically significant. However reperfusion was also better (and this was statistically significant) in the alteplase group -- and this reperfusion was associated with better neurological outcome and better functional outcome than was no reperfusion.

The authors conclude: "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."

In an accompanying Comment, Dr Peter Schellinger, Department of Neurology, University at Erlangen, Germany, also looks forward to the results of ECASS-3. He says that, following this, and the results from EPITHET, he hopes that a randomised controlled trial, exclusively of appropriate patients identified by MRI will be initiated, looking at administration of alteplase beyond three hours or beyond 4.5 hours. He concludes: "The time is right for a joint international effort to plan and undertake such a trial."

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Professor Stephen Davis, Department of Neurology, Royal Melbourne Hospital, University of Melbourne, Victoria, Australia T) +61417245946 E) Stephen.davis@mh.org.au

Dr Peter Schellinger, Department of Neurology, University at Erlangen, Germany E) peter.schellinger@uk-erlangen.de


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