Stroke Re

Sixty percent of patients who received intravenous (IV) desmoteplase (125 μg/kg) showed clinical improvement, as did 29% who took 90 μg/kg of desmoteplase, and 25% of those taking placebo. Reperfusion within eight hours of treatment was achieved in 53% of patients in the higher-tier dose group, in 18% of patients in the lower-tier group, and in 38% of those who were randomized to placebo. These results, from the Dose Escalation study of Desmoteplase in Acute ischemic Stroke (DEDAS), closely replicate the 125-μg/kg findings from the Desmoteplase In Acute ischemic Stroke (DIAS) trial that were published in the January Stroke and presented at last year’s International Stroke Conference.

Thus far, IV tissue plasminogen activator (t-PA) is the only FDA-approved therapy for acute ischemic stroke, but it must be given within three hours of stroke onset. However, according to Dr. Furlan, “Even eight years after FDA approval, only about 5% of acute stroke patients get t-PA, so 95% of acute stroke patients still do not get therapy. The main reason for the low IV t-PA usage rate is the three-hour treatment window.”

BENEFITS OF DESMOTEPLASE

Desmoteplase has a favorable preclinical profile in that it is less toxic to brain cells and does not activate beta-amyloid, which has been linked to the brain hemorrhage risk following thrombolytic therapy. Also, because it has a half-life of more than four hours, it can be given as a bolus injection, which may also help reduce the reocclusion rate.

The DIAS and DEDAS trials were the first stroke studies that used MRI to select patients that still had salvageable brain tissue. “This is why we’re doing three to nine hours,” Dr. Furlan said. “We think we may be able to identify patients who still have brain tissue at risk that can be saved, even out to nine hours, with new imaging technology.”

DEDAS included 38 patients, ages 18 to 85 (average, 72), with an NIH Stroke Scale score between 4 and 20, and at least 20% perfusion/diffusion mismatch on MRI. The primary safety end point was symptomatic intracranial hemorrhage. Main efficacy end points were reperfusion rates and clinical outcome. Patients were randomized to two tiers—90 μg/kg and 125 μg/kg IV desmoteplase—versus placebo.

Overall, between the two studies, the brain hemorrhage rate was about 2%, which is less than the 6% rate with three-hour IV t-PA, according to Dr. Furlan. “In terms of our efficacy outcomes, both by reperfusion of the brain as measured by MRI as well as clinical outcome, we saw a very positive trend in favor of desmoteplase at the 125-μg/kg dose,” he said. “The reperfusion data were statistically significant, better than placebo.”

The clinical outcome was not as favorable in the 90-μg/kg tier in the DEDAS trial—unlike in the DIAS study—and the reason may be partly explained by the 40% MR protocol violator rate in that group. “This was a misreading of the scan, which is not unexpected in a clinical trial and, indirectly, provides some validation of selecting patients with MRI for this kind of therapy,” commented Dr. Furlan.

Dr. Furlan suggested that the lower hemorrhage rate observed with desmoteplase compared with t-PA may be due to several factors. “In animal models, the hemorrhage rates with desmoteplase are lower than with other agents like t-PA,” he said. “There’s some reason to believe that the drug itself may have some favorable hemorrhage properties. The second key thing is how we selected our patients. The farther out you go from three hours, the risk/benefit ratio becomes greater, so fewer patients are going to benefit and more will have hemorrhages unless we can safely select patients with salvageable brain using perfusion imaging.”

The average time from stroke onset to treatment in the DEDAS and DIAS trials was seven hours, “so this is far beyond the current treatment window,” Dr. Furlan noted. “We estimate that if we had the nine-hour window, we could triple or quadruple the number of patients we could treat [who have had] acute ischemic stroke. Then when we looked at the three- to six-hour patients versus the six- to nine-hour patients—again, the numbers are small—we didn’t see any evidence of difference in terms of either reperfusion efficacy, safety, or clinical outcomes. Even in the six- to nine-hour group, we saw good safety, clear evidence of reperfusion efficacy, and a strong clinical efficacy signal at the 125-μg/kg dose.”

There was an imbalance in baseline stroke severity among the treatment groups. Baseline NIH Stroke Scale scores were worse in the placebo arm (12) versus 14 and 15 in the two treatment arms. “Of course, that could affect some of the clinical outcomes,” Dr. Furlan acknowledged.

Regarding all serious adverse events, no statistically significant difference was found and no excess mortality was observed in the treatment arms compared with controls. The two treatment arms did have a higher rate of asymptomatic brain hemorrhages—40% versus 12% in the control group, a finding that was not surprising, said Dr. Furlan. “Most of these were apparent within 24 hours, which was based on an MRI scan, which of course is going to be more sensitive to showing silent hemorrhages, compared with CT. But these numbers, even 40%, are quite comparable to other thrombolytic trials and likely reflect improved reperfusion rates with active treatment. If we look at major systemic bleeding, nonbrain bleeding, again, no statistically significant difference between the two treatment arms or controls [was observed]. So from a safety standpoint, the results were quite encouraging.”

Final infarct volume at 30 days was another measure of efficacy that Dr. Furlan’s group looked at. “We saw lesion growth in the control arm and in the 90-μg/kg arm but no lesion growth in the 125-μg/kg arm,” reported Dr. Furlan.

EXTENDING THE TREATMENT WINDOW

“We concluded that in the DEDAS trial, there was no evidence of increased mortality or symptomatic brain hemorrhage out to nine hours, from stroke onset, with either 90 or 125 μg/kg of desmoteplase,” Dr. Furlan commented. “There was strong indication of improved reperfusion and clinical efficacy with the 125-μg/kg dose tier. So we now have two independent studies showing very similar results.

“There is a huge public education/public awareness problem with acute stroke, even with a nine-hour drug. In fact, now that the public kind of knows about three-hour [treatment window for] t-PA, we’re concerned that they may think, ‘Well, if it is beyond three hours, there’s no reason to go to the hospital.’ So I think it’s important for patients to know that there may be things we can do beyond three hours, and they need to get to the hospital as quickly as possible.”

The next step will be DIAS2, a clinical efficacy trial that has been approved by the FDA and will include 186 patients. For the first time, DIAS2 will compare CT perfusion to MRI perfusion for patient selection. DIAS2 will also have a reocclusion substudy, an issue that neither DIAS nor DEDAS specifically addressed and is “a problem that stroke neurology is only starting to become aware of,” said Dr. Furlan. “We’re going to use transcranial Doppler ultrasound to look at reocclusion within the first 48 hours.”

NR

—Colby Stong

// posted by Biopeo @ 6:31 AM