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EPITHET: Clot-busting drug helps restore perfusion, fails to reduce size of infarct
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Results from a study demonstrated that a drug that targets blood clots succeeded in improving outcomes in certain patients, but missed the primary study endpoint.
Researchers for the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) examined whether late application (more than three hours after an acute ischemic stroke) of recombinant tissue plasminogen activator alteplase could be administered safely and effectively. Patient progress was monitored and assessed by measuring salvageable brain tissue called perfusion–diffusion mismatch with MRI. Stephen M. Davis, MD, professor of neurology at the University of Melbourne, presented the results at the 2008 International Stroke Conference in New Orleans.
“With acute ischemic stroke, we are familiar with the fact that a large proportion of patients have a mismatch between a larger perfusion and a smaller diffusion lesion, typically associated with the occlusion of the corresponding middle cerebral artery,” Davis said. “In the absence of recanalization or reperfusion in these patients, we typically see substantial infarct growth, and this sustained growth at 90 days is associated with poor outcomes.”
Primary endpoint not achieved
The researchers enrolled 101 people in the study from 15 centers in Australia, Belgium, New Zealand and Scotland. Mismatch was present in 80 patients; 37 of these were assigned IV alteplase and 49 were assigned placebo. The primary outcome was the attenuation of infarct growth in patients taking alteplase vs. those taking placebo beyond the three hours the drug is indicated for.
According to the results, the geometric mean infarct growth was 1.24 in the alteplase group vs. 1.78 in the placebo group (RR=0.69; 95% CI, 0.38-1.28) and the median relative infarct growth was 1.18 in the alteplase group vs. 1.79 in the placebo group (RR=0.66; 95% CI, 0.36-0.92). Reperfusion, however, was observed more often among patients taking alteplase than in the placebo group and reperfusion also correlated with less infarct growth, better neurological outcomes and better functional outcomes than in patients with lower or no perfusion.
The researchers also cautioned that the trial was not powered to draw wider conclusions about the performance of alteplase and that more study is needed.
“Our primary outcome of growth was not significant, but we also saw strong trends across a suite of measures in infarct growth attenuation with alteplase in mismatch patients,” Davis concluded. “The EPITHET results present biological support for extension of the time window for alteplase and we believe it is time for a randomized controlled trial based on MR mismatch of alteplase vs. placebo in the three- to six-hour time window, which would require less than 400 patients.” – by Eric Raible
For more information:
- Davis S. Echoplanar Imaging Thrombolytic Evaluation Trial. Presented at: the International Stroke Conference; Feb. 20-22, 2008; New Orleans.