Mixed findings for intravenous glyburide in cerebral oedema prevention
medwireNews: A US research team reports mixed results for a placebo-controlled phase II trial of intravenous glyburide in patients presenting with a large hemispheric infarction and at risk for cerebral oedema.
In the double-blind Glyburide Advantage in Malignant Edema and Stroke (GAMES-RP) trial, the sulfonylurea receptor 1 (SUR1) inhibitor and placebo were comparable in terms of the composite primary endpoint of the proportion of participants who achieved a modified Rankin Scale score of 0–4 at 90 days without undergoing decompressive craniectomy (41 vs 39%).
But administration of intravenous glyburide did lead to a significant improvement in several tertiary endpoints. Specifically, at 72–96 hours post-treatment the midline shift at the septum pellucidum level was significantly reduced in the intravenous glyburide versus placebo arm, at a median of 4.6 and 8.5 mm, respectively.
And the average serum levels of matrix metalloproteinase-9 (MMP-9) – a potential marker of cerebral swelling – were also significantly lower at 24–72 hours among intravenous glyburide-treated participants than those given placebo, at 211 versus 346 ng/mL.
Furthermore, intravenous glyburide treatment was associated with reduced all-cause mortality at 30 days (15 vs 36%) and 90 days (17 vs 36%) compared with placebo, although the difference was only significant at the 30-day timepoint.
Researcher Kevin Sheth (Yale University School of Medicine, New Haven, Connecticut) and colleagues say that these tertiary outcome results suggest that “exposure to intravenous glyburide might have reduced oedema”, in line with the effects seen in preclinical experiments.
They believe that the primary endpoint may have been confounded by variations in practice, with 90% of depressive craniectomies performed in eight of the 18 participating sites. And as the decision to undertake a depressive craniectomy was left to the individual centres, it is possible that the provided clinical guidelines were “applied inconsistently”, the team writes in The Lancet Neurology.
Sheth et al randomly assigned 77 patients with large anterior circulation ischaemic stroke, defined by a baseline lesion volume of 82–300 cm3 on diffusion-weighted magnetic resonance imaging, to receive either intravenous glyburide or placebo within 10 hours of diagnosis.
Forty-one patients received intravenous glyburide, initially as a 0.13 mg bolus injection for 2 minutes, followed by a 0.16 mg/h infusion for 6 hours and then 0.11 mg/h for the remaining 66 hours.
The researchers explain that the trial was terminated early because of funding limitations and they were unable to recruit the planned number of participants. But they think that the results indicate a role for SUR1 in the pathogenesis of ischaemic cerebral oedema, “and support further study of intravenous glyburide for this indication”.
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