Desmoteplase clot buster disappoints in trial

July 24, 2007

The most highly anticipated stroke imaging trial of the year has left radiologists scratching their heads about the disappointing results. No more than 47% of acute stroke patients administered the clot-dissolving protein desmoteplase three to nine hours after the onset of symptoms showed improvement. The positive outcome rate was about the same among patients given a placebo.

The most highly anticipated stroke imaging trial of the year has left radiologists scratching their heads about the disappointing results. No more than 47% of acute stroke patients administered the clot-dissolving protein desmoteplase three to nine hours after the onset of symptoms showed improvement. The positive outcome rate was about the same among patients given a placebo.

Researchers used functional MRI or perfusion CT in the Desmoteplase In Acute Ischemic Stroke study (DIAS II) to identify candidates for treatment. Promising candidates exhibited a positive diffusion-perfusion mismatch, meaning the MR perfusion volume of their brains delineating treatable stroke damage was at least 20% larger than the volume's diffusion core correlating with dead or irretrievably damaged tissue. CT perfusion used different parameters to generate the same results.

In total, 186 patients received either placebo or one of two doses of desmoteplase within three to nine hours of symptom onset.

Compared with placebo, the clot-dissolving protein desmoteplase did not change clinical outcomes for acute ischemic stroke patients in the phase III clinical trial. Results were presented at the European Stroke Conference on May 31 in Glasgow by Dr. Werner Hacke, director of neurology at the University of Heidelberg in Germany.

The existing emergency treatment for acute ischemic stroke, tPA, must be administered within three hours of onset, but early desmoteplase studies suggested that this treatment window could be expanded, particularly in patients with perfusion-diffusion mismatch. In the current study, however, clinical outcome did not differ among the three groups.

"This study should not be misinterpreted as proving that desmoteplase after three hours does not work or that patient selection after three hours with mismatch imaging is not reliable," said Dr. Anthony Furlan, coprincipal investigator and section head of stroke and neurologic intensive care at The Cleveland Clinic. "Rather, this study further emphasizes the complexity of treating acute stroke after three hours and the need for larger, more sophisticated clinical trials, the design of which will be informed by the results of trials like this one and other acute imaging based studies."

Patients in the blind randomized multicenter study were selected using either MRI or CT and received placebo treatment or either 90 mcg/kg or 125 mcg/kg of desmoteplase as an intravenous bolus. Ninety days after treatment, patients were evaluated using the National Institutes of Health Stroke Scale, the Modified Rankin Scale, and the Barthel Index. Only those patients able to function independently with few or no deficits were considered positive responders.

Clinical outcomes did not differ statistically among the three groups: 47.4% of patients treated with 90 mcg/kg responded positively compared with 36.4% in the 125 mcg/kg group. In the placebo group, 46% of the patients showed improvement. These data are not consistent with earlier trials, which demonstrated the drug's potential. The high rate of responders in the placebo group is unusual in stroke studies.

Intravenous desmoteplase treatment appears safe, but clinical benefits remain uncertain, according to Furlan.

"We were disappointed in the results but not entirely surprised, since we were trying to answer many new questions with a small sample size," he said. "The hope was that by using new imaging technology to select patients for treatment, we could optimize patient selection. However, DIAS II indicates that the problem of reperfusion therapy after three hours is more complex than we anticipated."

Researchers are analyzing the results to determine whether MR and CT are equivalent for the purposes of selecting appropriate patients. Investigators plan to explore how the site of occlusion and the location of the stroke, such as right or left brain and deep versus cortical damage, may affect desmoteplase treatment outcomes. Furlan suggests that a study with at least 600 participants would yield more information.

Stroke is a leading cause of death worldwide, affecting approximately 700,000 people annually in the U.S. alone, and it is expected to cost the U.S. healthcare system more than $60 billion in 2007. The FDA has granted desmoteplase fast track status. The highly fibrin-specific clot-dissolving protein is genetically engineered, based on an enzyme found in the saliva of the vampire bat, Desmodus rotundus.

For more information from the Diagnostic Imaging archives:

Study favors MRI over CT for acute stroke diagnosis

Report from Stanford MDCT: Prototype 256-slice CT proves its might in stroke imaging

Stroke imaging data lag behind technology

Men benefit more than women from tPA stroke treatment

Stroke care demands radical approach