by Martha Kerr
Tissue plasminogen activator (t-PA) may be effective for longer than the currently approved three hours after the onset of acute ischemic stroke, in some cases.
Results of the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) were announced at the American Stroke Association (ASA)'s International Stroke Conference 2008 by principal investigator Dr. Stephen M. Davis of Royal Melbourne Hospital and the University of Melbourne, Australia. Results are being simultaneously released in an early online edition of the April issue of
The Lancet Neurology.The findings show a decrease in cerebral infarct growth and improved clinical outcomes in patients with ischemic stroke with a perfusion-weighted (PWI) and diffusion-weighted (DWI) magnetic resonance imaging (MRI) mismatch who receive t-PA up to six hours after symptom onset.
The only t-PA agent currently approved by the Food and Drug Administration is alteplase (Activase, Genentech Inc., South San Francisco, CA), and it is approved for use within three hours of onset of an ischemic stroke.
EPITHET involved 101 patients presenting three to six hours after the onset of ischemic stroke. Patients were randomized to alteplase or placebo. Mean age was 71.6 years. Median baseline National Institutes of Health Stroke Scale (NIHSS) score was 13.
There was a PWI-DWI mismatch in 86 per cent of patients, who were the focus of EPITHET.
Neurological outcome was evaluated three to five days after stroke and CT scans were performed at 90 days.
The geometric exponential infarct growth was decreased 30 per cent with alteplase, with a 61 per cent decrease in median relative infarct growth with active treatment. "There was quite a strong trend toward improvement" with alteplase in most of the endpoints, Dr. Davis told meeting attendees, although he acknowledged that the numbers did not reach statistical significance.
Reperfusion was more common with alteplase than placebo, at 56 and 26 per cent, respectively, and "reperfusion correlates strongly with outcome," Dr. Davis commented.
Dr. Davis told Reuters Health that the importance of the study is that it may be possible "to select responders [to t-PA] more than three hours out - those with a [DWI-PWI] mismatch...We don't recommend using MRI in the first three hours."
Co-investigator Dr. Geoffrey A. Donnan of Austin Hospital, Australia, added that "the key is to enrich the treatment population with patients with a mismatch...If the next phase of trials is strongly positive, with a good clinical outcome, these patients [presenting up to six hours after stroke onset] would be routinely treated....We're going out in increments of three hours. We have to be very, very sure we are not causing damage."
The incident of adverse bleeding events was 7.7 per cent in EPITHET, which Dr. Donnan noted is 'spot on' with the observed adverse event rate of six to eight per cent with t-PA.
In an editorial in The Lancet Neurology, Dr. Peter D. Schellinger of the University at Erlangen, Germany, says that the results of EPITHET, as well as the Third European Cooperative Acute Stroke Study (ECASS-3), of which he is an investigator, and other, similar studies, indicate that "the time is right for a joint international effort to plan and undertake" a trial to determine whether the treatment window for t-PA in ischemic stroke can be safely widened in selected patients.
Source: Reuters
