Effect of IV glyburide on adjudicated edema endpoints in the GAMES-RP Trial

Abstract

Objective: In this secondary analysis of the Glyburide Advantage in Malignant Edema and Stroke (GAMES-RP) Trial, we report the effect of IV glyburide on adjudicated, edema-related endpoints.

Methods: Blinded adjudicators assigned designations for hemorrhagic transformation, neurologic deterioration, malignant edema, and edema-related death to patients from the GAMES-RP phase II randomized controlled trial of IV glyburide for large hemispheric infarct. Rates of these endpoints were compared between treatment arms in the per-protocol sample. In those participants with malignant edema, the effects of treatment on additional markers of edema and clinical deterioration were examined.

Results: In the per-protocol sample, 41 patients received glyburide and 36 received placebo. There was no difference in the frequency of hemorrhagic transformation (n = 24 [58.5%] in IV glyburide vs n = 23 [63.9%] in placebo, p = 0.91) or the incidence of malignant edema (n = 19 [46%] in IV glyburide vs n = 17 [47%] in placebo, p = 0.94). However, treatment with IV glyburide was associated with a reduced proportion of deaths attributed to cerebral edema (n = 1 [2.4%] with IV glyburide vs n = 8 [22.2%] with placebo, p = 0.01). In the subset of patients with malignant edema, those treated with IV glyburide had less midline shift (p < 0.01) and reduced MMP-9 (matrix metalloproteinase 9) levels (p < 0.01). The glyburide treatment group had lower rate of NIH Stroke Scale (NIHSS) increase of ≥4 during the infusion period (n = 7 [37%] in IV glyburide vs n = 12 [71%] in placebo, p = 0.043), and of change in level of alertness (NIHSS subscore 1a; n = 11 [58%] vs n = 15 [94%], p = 0.016).

Conclusion: IV glyburide was associated with improvements in midline shift, level of alertness, and NIHSS, and there were fewer deaths attributed to edema. Additional studies of IV glyburide in large hemispheric infarction are warranted to corroborate these findings.

Clinicaltrialsgov identifier: NCT01794182.

Level of evidence: This study provides Class II evidence that for patients with large hemispheric infarction, IV glyburide improves some edema-related endpoints.

© 2018 American Academy of Neurology.

Figures

Figure 1. Kaplan-Meier survival curve for edema-related mortality

Mortality was lower in patients treated with IV glyburide (n = 1, 2%) as compared to placebo-treated patients (n = 8, 22%; log-rank test, p = 0.009).

Figure 2. Changes in intermediate endpoints in patients with malignant edema

In the subgroup of patients who experienced malignant edema (n = 36), IV glyburide was associated with (A) less MLS (**p = 0.001) and (B) lower MMP-9 (**p = 0.001). For each panel, the median value is shown, the box plots define the interquartile range, and the whiskers the minimum and maximum values. (C) The time course of total NIHSS score over time was not different in the treatment arms in the overall cohort (p = 0.11). (D) In patients with malignant edema who were treated with IV glyburide, there was a reduction in NIHSS score relative to the placebo arm (p = 0.001) during the drug infusion. MLS = midline shift; MMP-9 = matrix metalloproteinase 9; NIHSS = NIH Stroke Scale.