MedWire News: The results of the DIAS-2 study have shown a surprising lack of benefit for desmoteplase over placebo in patients treated up to 9 hours after stroke.
The DIAS (Desmoteplase In Acute ischemic Stroke)-2 findings contradict those of the phase II DIAS-1 and DEDAS (Dose Escalation study of Desmoteplase in Acute ischemic Stroke) studies. Both these previous trials demonstrated clinical efficacy of desmoteplase over placebo for up to 9 hours after stroke in patients with at-risk tissue on brain imaging.
But the 186 patients who were treated at 3–9 hours after stroke in DIAS-2 had milder strokes overall than those in DIAS-1 and DEDAS. Median core lesion volume was just 10.6 ml and the median perfusion-/diffusion-weighted imaging mismatch volume was 52.5 ml. The median National Institutes of Health Stroke Scale (NIHSS) score was 9 in the DIAS-2 study, compared with 12 in the phase II studies.
“The milder the initial stroke is, the better the spontaneous outcome,” Werner Hacke (University of Heidelberg, Germany) and colleagues note in The Lancet Neurology.
“A difference of 2 to 3 points compared with the previous studies might explain most of the positive placebo response.”
A clinical response at day 90 was defined as the composite of at least an 8-point improvement in NIHSS score, or a final score of 1 or less, plus a modified Rankin Scale score of 0–2 and a Barthel Index score of 75–100.
This outcome was achieved by 46% of the placebo group, 47% of the desmoteplase 90 µg/kg group, and 36% of the desmoteplase 125 µg/kg group. Symptomatic intracranial hemorrhage occurred in 0.0%, 3.5%, and 4.5%, respectively.
Mortality was more frequent with high-dose desmoteplase than with the low dose or placebo, at 21% versus 11% and 6%, respectively. But most deaths in the high-dose group were not treatment-related and occurred in patients who were older and had more severe strokes than average.
Editorialist Michael Hill (University of Calgary, Canada) proposed an additional explanation for the negative DIAS-2 results, suggesting the inclusion of patients without vascular occlusions might have obscured any treatment benefit in DIAS-2.
Recanalization was not assessed, despite being the purpose of thrombolytic therapy and a prerequisite for recovery in most patients, he noted.
Just 30% of patients had visible occlusions – about half the rate reported in DIAS-1 and DEDAS. The response rates in these patients were 27%, 36%, and 18% with high- and low-dose desmoteplase and placebo, respectively. The corresponding rates for nonoccluded patients were 40%, 50%, and 57%.
“Although desmoteplase might yet prove to be the thrombolytic of choice, the DIAS-2 trial design forged too far ahead of the imaging science,” concluded Hill.
“The lessons learned must be applied to the DIAS-3 study.”
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