Glibenclamide in aneurysmal subarachnoid hemorrhage: a randomized controlled clinical trial

Bruno Braga Sisnando da CostaDepartment of Neurosurgery, University of São Paulo, São Paulo, Brazil

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Isabela Costola WindlinDepartment of Neurosurgery, University of São Paulo, São Paulo, Brazil

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Edwin KoterbaDepartment of Neurosurgery, University of São Paulo, São Paulo, Brazil

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Vitor Nagai YamakiDepartment of Neurosurgery, University of São Paulo, São Paulo, Brazil

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Nícollas Nunes RabeloDepartment of Neurosurgery, University of São Paulo, São Paulo, Brazil

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Davi Jorge Fontoura SollaDepartment of Neurosurgery, University of São Paulo, São Paulo, Brazil

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Antonio Carlos Samaia da Silva CoelhoDepartment of Neurosurgery, University of São Paulo, São Paulo, Brazil

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João Paulo Mota TellesDepartment of Neurosurgery, University of São Paulo, São Paulo, Brazil

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Manoel Jacobsen TeixeiraDepartment of Neurosurgery, University of São Paulo, São Paulo, Brazil

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Eberval Gadelha FigueiredoDepartment of Neurosurgery, University of São Paulo, São Paulo, Brazil

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OBJECTIVE

Glibenclamide has been shown to improve outcomes in cerebral ischemia, traumatic brain injury, and subarachnoid hemorrhage (SAH). The authors sought to evaluate glibenclamide’s impact on mortality and functional outcomes of patients with aneurysmal SAH (aSAH).

METHODS

Patients with radiologically confirmed aSAH, aged 18 to 70 years, who presented to the hospital within 96 hours of ictus were randomly allocated to receive 5 mg of oral glibenclamide for 21 days or placebo, in a modified intention-to-treat analysis. Outcomes were mortality and functional status at discharge and 6 months, evaluated using the modified Rankin Scale (mRS).

RESULTS

A total of 78 patients were randomized and allocated to glibenclamide (n = 38) or placebo (n = 40). Baseline characteristics were similar between groups. The mean patient age was 53.1 years, and the majority of patients were female (75.6%). The median Hunt and Hess, World Federation of Neurosurgical Societies (WFNS), and modified Fisher scale (mFS) scores were 3 (IQR 2–4), 3 (IQR 3–4), and 3 (IQR 1–4), respectively. Glibenclamide did not improve the functional outcome (mRS) after 6 months (ordinal analysis, unadjusted common OR 0.66 [95% CI 0.29–1.48], adjusted common OR 1.25 [95% CI 0.46–3.37]). Similar results were found for analyses considering the dichotomized 6-month mRS score (favorable score 0–2), as well as for the secondary outcomes of discharge mRS score (either ordinal or dichotomized), mortality, and delayed cerebral ischemia. Hypoglycemia was more frequently observed in the glibenclamide group (5.3%).

CONCLUSIONS

In this study, glibenclamide was not associated with better functional outcomes after aSAH. Mortality and delayed cerebral ischemia rates were also similar compared with placebo.

ABBREVIATIONS

aSAH = aneurysmal SAH; DCI = delayed cerebral ischemia; mFS = modified Fisher scale; mRS = modified Rankin Scale; SAH = subarachnoid hemorrhage; TBI = traumatic brain injury; WFNS = World Federation of Neurosurgical Societies.

OBJECTIVE

Glibenclamide has been shown to improve outcomes in cerebral ischemia, traumatic brain injury, and subarachnoid hemorrhage (SAH). The authors sought to evaluate glibenclamide’s impact on mortality and functional outcomes of patients with aneurysmal SAH (aSAH).

METHODS

Patients with radiologically confirmed aSAH, aged 18 to 70 years, who presented to the hospital within 96 hours of ictus were randomly allocated to receive 5 mg of oral glibenclamide for 21 days or placebo, in a modified intention-to-treat analysis. Outcomes were mortality and functional status at discharge and 6 months, evaluated using the modified Rankin Scale (mRS).

RESULTS

A total of 78 patients were randomized and allocated to glibenclamide (n = 38) or placebo (n = 40). Baseline characteristics were similar between groups. The mean patient age was 53.1 years, and the majority of patients were female (75.6%). The median Hunt and Hess, World Federation of Neurosurgical Societies (WFNS), and modified Fisher scale (mFS) scores were 3 (IQR 2–4), 3 (IQR 3–4), and 3 (IQR 1–4), respectively. Glibenclamide did not improve the functional outcome (mRS) after 6 months (ordinal analysis, unadjusted common OR 0.66 [95% CI 0.29–1.48], adjusted common OR 1.25 [95% CI 0.46–3.37]). Similar results were found for analyses considering the dichotomized 6-month mRS score (favorable score 0–2), as well as for the secondary outcomes of discharge mRS score (either ordinal or dichotomized), mortality, and delayed cerebral ischemia. Hypoglycemia was more frequently observed in the glibenclamide group (5.3%).

CONCLUSIONS

In this study, glibenclamide was not associated with better functional outcomes after aSAH. Mortality and delayed cerebral ischemia rates were also similar compared with placebo.

In Brief

Glibenclamide has been shown to improve outcomes in cerebral ischemia, traumatic brain injury, and subarachnoid hemorrhage (SAH). The authors sought to evaluate the effect of glibenclamide on mortality and functional outcomes of patients with aneurysmal SAH (aSAH). Glibenclamide was not associated with better functional outcomes after aSAH. Rates of mortality and delayed cerebral edema were also similar compared with placebo.

Aneurysmal subarachnoid hemorrhage (aSAH) is a common type of stroke, affecting around 600,000 people annually worldwide, and is a significant clinical and socioeconomic burden.1 Up to 50% of patients die after an aSAH episode, which is even more concerning since this type of stroke affects a younger population compared with other stroke subtypes. Furthermore, 30% of patients who remain functionally impaired and 20%–30% of those admitted in good condition have unfavorable outcomes. Hemorrhage extension, vasospasm, and delayed cerebral ischemia (DCI) are responsible for a significant number of these negative results.2,3

Clinical treatment of aSAH and its complications still fails to provide satisfactory results. Nimodipine, a selective calcium channel blocker, remains the only evidence-based treatment option, even though its benefits are limited.4 Prevention of DCI is a crucial aspect of management because it is the leading cause of neurological impairment.5,6

Current clinical and experimental evidence points toward a possible benefit of sulfonylureas in acute ischemic stroke. The pleiotropic neuroprotective effects of glibenclamide have become increasingly understood during the last decade. By blocking Sur1-Trpm4 channels, which are overexpressed during ischemic insults, this drug might protect vascular endothelium by reducing the formation of edema and the occurrence of secondary hemorrhages, inhibit neuronal death (especially in the hippocampus),7 promote neurogenesis, and present antiinflammatory properties.8–10 Some studies have shown promising effects of glibenclamide on ischemic, traumatic, and tumoral brain edema.11–14

No randomized controlled trial has evaluated the use of glibenclamide in aSAH thus far. The typical 3- to 10-day gap from subarachnoid hemorrhage (SAH) to vasospasm and ischemia provides a valuable period for prophylactic intervention. This randomized, placebo-controlled clinical trial sought to investigate the effects of glibenclamide on the clinical course, mortality, and functional outcomes of aSAH patients.

Methods

Ethics

Appropriate ethics and regulatory approval were sought for all patients and procedures in accordance with the International Conference on Harmonization guidelines for good clinical practice (ICH GCP) and with the guidance of the CONSORT checklist (Fig. 1). We obtained informed written consent from all patients or their legal representatives. This study received ethics approval from the Brazilian Health Ministry by “Plataforma Brasil” (http://plataformabrasil.saude.gov.br).

FIG. 1.
FIG. 1.

CONSORT 2010 flow diagram. Figure is available in color online only.

Trial Design

A detailed prespecified protocol for this randomized, placebo-controlled clinical trial was previously published.15 This trial was approved by the institutional ethics committee and registered at ClinicalTrials.gov (registration no. NCT03569540).

Participants

We recruited patients admitted to the neurocritical care unit from July 31, 2017, to May 1, 2020, and obtained written standardized informed consent forms from the patients or their legal representatives. The ascertainment of endpoints was blinded at discharge and at 6 months. The trial took place at the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, at São Paulo, SP, Brazil.

Inclusion and Exclusion Criteria

Inclusion criteria were 1) radiological evidence of SAH by CT or MRI and aneurysmal origin confirmed by DSA, CTA, or MRA; 2) age between 18 and 70 years; and 3) definitive treatment (either clipping or coiling) within 96 hours of ictus. The main reason for the exclusion of randomized patients was due to inadequate administration of the medication through 21 days. The other exclusion criteria included 1) current use of glibenclamide; 2) pregnancy; 3) known liver or kidney disease; 4) functional impairment before bleeding (any grade); 5) Glasgow Coma Scale score 3 or Hunt and Hess grade V at admission; 6) other comorbidity that limits survival (e.g., cancer, AIDS, acute respiratory distress syndrome); 7) alcohol or drug abuse; and 8) current use of anticoagulant drugs (e.g., warfarin).

Randomization and Intervention

Patients were randomly allocated (1:1) to receive 5 mg of glibenclamide or placebo (5 mg of starch). Intravenous glibenclamide is not available in Brazil, and 5 mg is the standard initial dose in our hospital—a small dose to prevent significant hypoglycemia. Bottles containing 21 capsules of either glibenclamide or placebo were coded, and a computer-generated sequence randomly designated patients to either treatment, in blocks of 10 (5 treatment and 5 placebo). All patients began treatment within 96 hours of ictus, as soon as they underwent definitive treatment of their aneurysm (microsurgically or endovascularly) because of the potential harm of early postoperative hypoglycemia. Doses were administered one pill a day orally or through nasogastric tubes. Treatment was continued until the 21st postictus day.

Oral nimodipine 60 mg every 4 hours was initiated on admission and maintained for 21 days, in accordance with the institution’s standard procedures. Definitive treatment of the aneurysm occurred as soon as possible, following the standards adopted at our institution.

Patient Monitoring

Patient monitoring included blood glucose every 6 hours and daily urea, creatinine, and liver enzymes. Hypoglycemia (< 70 mg/dL) was immediately corrected with intravenous glucose, according to our institutional protocol. Patients with recurrent hypoglycemia for 24–48 hours during medication use had treatment suspended and, if glycemia was normalized after suspension, they were withdrawn from the study intervention. The experimental treatment drugs were administered between lunch and dinner, around 4 pm, to avoid fasting and hypoglycemia.

Data Collection and Outcomes

Demographic data and past medical history were collected from each patient. Hemorrhage severity was estimated clinically according to the Hunt and Hess and World Federation of Neurosurgical Societies (WFNS) grading scales and radiologically according to the modified Fisher scale (mFS). At the end of the treatment (21st day), the patients’ functional status was evaluated according to the modified Rankin Scale (mRS).

After 6 months, an experienced clinician, blinded to treatment allocation, evaluated the patients’ functional status using the mRS. The primary outcome was the distribution of the 6-month mRS score. The study’s main hypothesis was that patients treated with glibenclamide would have better functional outcomes and lower mortality after 6 months.

Secondary outcomes included the 6-month mRS dichotomous analysis (favorable outcome defined as an mRS score 0–2), the discharge mRS (dichotomous and ordinal analyses), the occurrence of DCI, and death. Quality of life and cognitive assessment as measured by neuropsychological tests were also secondary outcomes but are not reported in this paper. These secondary outcomes were preselected to provide supportive evidence related to the primary outcome.

An interim analysis was performed when the first 20 patients completed the 6-month follow-up. The independent data and safety monitoring board decided that the trial should proceed.

Statistical Methods

We estimated a sample size of 80 patients, which would yield 80% power at the 5% significance level (two-sided) to detect a treatment effect equivalent to a 7% absolute increase in the proportion of patients with a more favorable functional outcome. This calculation was based on an ordinal analysis of the mRS score, assuming the treatment effect follows a proportional odds model (which was confirmed by the parallel lines test).

Data were analyzed according to the modified intention-to-treat principle. Primary outcome results are presented as unadjusted and adjusted odds ratios and the corresponding 95% confidence interval, with an OR < 1 indicating a positive therapeutic effect of glibenclamide.

Data are presented as mean ± SD or median (IQR), according to normality tests (Shapiro-Wilk’s). All statistical analyses were performed using IBM SPSS Statistics for Windows (version 24.0, IBM Corp.). The analysis was blinded for group allocations.

Results

Of 90 recruited patients, only 78 completed the 21-day treatment period and 2 were excluded due to early persistent hypoglycemia (< 70 mg/dL during the first 48 hours, returning to normoglycemia after medication withdrawal). Therefore, the following results refer to 78 patients, of whom 38 received glibenclamide and 40 received placebo. Twenty-three patients (29.5%) died and the rate of hypoglycemia was 5.3% (present only in the glibenclamide group) (Fig. 2).

FIG. 2.
FIG. 2.

Distribution of functional outcomes, according to the mRS, at discharge (upper) and at 6 months of follow-up (lower). X = controls; Y = treated patients. Figure is available in color online only.

Table 1 details the characteristics of both groups, which were similar. The mean patient age was 53.1 ± 11.4 years, and the majority of patients were female (75.6%) and White (55.1%). The median Hunt and Hess, mFS, and WFNS scores were 3 (IQR 2–4), 3 (IQR 3–4), and 3 (IQR 1–4), respectively; 38.2% of the sample presented with Hunt and Hess grade IV, 32% presented with mFS grade 4, and 19% presented with WFNS grade V. The study medication was initiated at a median of 3 days after aSAH ictus in both groups.

TABLE 1.

Patient characteristics and treatment strategy according to allocated groups

VariableTotal (n = 78)Groupp Value
Control (n = 40)Glibenclamide (n = 38)
Age, yrs53.1 ± 11.452.7 ± 11.353.6 ± 11.60.732
Female59 (75.6)27 (67.4)32 (84.2)0.086
Race0.709
 White43 (55.1)22 (55.0)21 (55.3)
 Brown21 (26.9)13 (32.5)9 (23.7)
 Black14 (17.9)6 (15.0)8 (21.1)
Prognostic scales
 Hunt & Hess grade3 (2–4)3 (2–4)3 (2–4)0.469
 mFS grade3 (3–4)3 (3–4)3 (3–4)0.570
 WFNS grade3 (1–4)2.5 (1–4)3 (1–4)0.805
Ictus-to-medication, days3 (2–4)3 (2–4)3 (3–4)0.535
Ictus-to-definitive treatment, days3 (2–4)3 (2–4)2.5 (1–4)0.030
Definitive treatment0.051
 Surgical clipping50 (64.1)30 (75.0)20 (52.6)
 Endovascular coiling28 (35.9)10 (25.0)18 (47.4)
Hydrocephalus requiring shunt20 (25.6)10 (25.0)10 (26.3)0.894

Data are presented as mean ± SD, median (IQR), or number of patients (%).

The glibenclamide group was treated statistically significantly earlier than the placebo group (2.5 [1–4] vs 3 [2–4] days, p = 0.030) and more frequently by endovascular methods (47.4% vs 25.0%, p = 0.051). One patient was treated with both microsurgical clipping and endovascular embolization. Approximately one-quarter of the patients in both groups needed ventricular shunting to treat hydrocephalus at some point during the 21-day study period (Table 1).

The primary outcome, mRS score at 6 months, was similar between the groups. Glibenclamide did not improve the functional outcome after 6 months (ordinal analysis, unadjusted common OR 0.66 [95% CI 0.29–1.48]). Similar results were found for analyses considering the dichotomized 6-month mRS score (favorable score 0–2), as well as for the secondary outcome of mRS score (either ordinal or dichotomized) at discharge, as shown in Table 2. Ordinal regression was modeled for the identification of variables associated with worse 6-month functional outcomes. Older age, higher WFNS grade, microsurgical clipping (vs coiling), and DCI were associated with worse mRS scores but not treatment allocation (adjusted common OR 1.25 [95% CI 0.46–3.37]) (Table 3). Death up to the time of discharge occurred in 18.4% of the glibenclamide group, compared with 27.5% of the control group (p = 0.341). At 6 months, there was also no statistically significant difference in mortality between the glibenclamide (28.9%) and control (30%) groups (p = 0.655).

TABLE 2.

Primary and secondary outcomes

OutcomeGeneral (n = 78)Groupp Value
Control (n = 40)Glibenclamide (n = 38)
Discharge mRS score4 (2–5)4.5 (2–6)3 (1–5)0.126
 Favorable (0–2)28 (35.9)13 (32.5)15 (39.5)0.379
 03 (3.8)03 (7.9)0.123
 117 (21.8)10 (25.0)7 (18.4)
 28 (10.3)3 (7.5)5 (13.2)
 39 (11.5)3 (7.5)6 (15.8)
 411 (14.1)5 (12.5)6 (15.8)
 513 (16.7)9 (22.5)4 (10.5)
 617 (21.8)10 (25)7 (18.4)
6-mo mRS score2 (0–6)3 (0–6)1.5 (0–6)0.318
 Favorable (0–2)43 (55.1)20 (50.0)23 (60.5)0.235
 024 (30.8)10 (25.0)14 (36.8)0.321
 112 (15.4)7 (17.5)5 (13.2)
 27 (9.0)3 (7.5)4 (10.5)
 34 (5.1)2 (5.0)2 (5.3)
 44 (5.1)4 (10.0)0
 54 (5.1)2 (5.0)2 (5.3)
 623 (29.5)12 (30.0)11 (28.9)
DCI16 (20.8)12 (30.0)4 (10.5)0.038

Data are presented as median (IQR) or number of patients (%).

TABLE 3.

Ordinal regression for the identification of variables associated with worse 6-month functional outcomes (mRS)

VariableCoefficientSEWaldOR95% CIp Value
Age0.090.0311.491.091.04–1.150.001
mFS score0.510.322.621.670.9–3.120.105
WFNS grade0.810.1917.682.251.54–3.29<0.001
Glibenclamide (vs placebo)0.220.510.201.250.46–3.370.658
No hydrocephalus0.220.620.131.250.37–4.240.723
Microsurgery1.890.619.706.652.02–21.90.002
No DCI−2.770.7214.890.060.02–0.26<0.001

SE = standard error.

In the unadjusted analysis, DCI was more common in the control group (30.0% vs 10.5%, p = 0.038). However, a multivariable logistic regression analysis adjusted for potential confounders, including treatment modality and ictus-to-definitive treatment delay, revealed that the latter was the independent predictor of DCI (Table 4). Glibenclamide did not modify the DCI probability in this adjusted analysis. The glibenclamide group had been treated earlier and more frequently by the endovascular approach.

TABLE 4.

Logistic regression for the identification of variables associated with DCI

VariableCoefficientSEWaldOR95% CIp Value
Glibenclamide (vs placebo)−0.880.691.630.410.11–1.600.202
Age−0.040.031.910.960.91–1.020.167
Embolization−0.850.771.230.430.09–1.930.268
Days from ictus to aneurysm treatment0.460.205.491.591.08–2.340.019
mFS0.580.411.981.790.80–4.010.160

Discussion

This is the first randomized controlled trial designed to evaluate the effects of glibenclamide in patients with aSAH. The study failed to demonstrate any differences regarding mortality and functional outcomes between controls and patients treated with glibenclamide. DCI was not prevented by the administration of glibenclamide.

Aneurysmal SAH is a severe condition capable of causing death in the acute setting and also later due to vasospasm and mechanisms that lead to delayed ischemic neurological deficits.1 Nimodipine remains the only preventive treatment backed by solid evidence,4 even though numerous other alternatives are being studied.16

Glibenclamide

Glibenclamide is a second-generation sulfonylurea that has been used for diabetes for more than 50 years. It acts by inhibiting sulfonylurea receptor 1 and has received attention recently as a neuroprotective agent.17 This drug has been studied in the context of neurology for its role in edema reduction.

As reported by Chen et al.,18 sulfonylureas are capable of binding Sur1-Trpm4 receptors, inhibiting their uncontrolled opening, which leads to edema. Their benefits, therefore, are mostly observed when initiated early after neurological insult. The findings of Gerzanich et al.19 and Sheth et al.12 support the role of glibenclamide in reducing edema after stroke or traumatic brain injury (TBI). Our study is the first to evaluate the use of glibenclamide in patients with aSAH.

An experimental model of SAH was employed to evaluate the effects of glibenclamide in rats.9 That study observed an increase in blood-brain barrier permeability 24 hours after SAH, with a destabilization of tight junctions and zona occludens (ZO-1). However, the use of glibenclamide significantly reduced ZO-1 abnormalities, resulting in less edema. The same study also observed a significant reduction in inflammatory biomarkers with the use of this sulfonylurea.

Functional Outcomes

Patients treated with glibenclamide had functional outcomes that were similar to those of control patients. Our sample included patients from various racial groups, which is different from most studies with this drug, which included mostly White patients.2,20–22

Eisenberg et al.23 and Khalili et al.13 administrated glibenclamide to patients with TBI and did not demonstrate significant benefits in terms of functional outcomes. A study by Sheth et al.12 of large hemispheric infarcts also failed to demonstrate functional benefit in patients who underwent decompressive craniectomy.

Mortality

Patient mortality in this study was comparable with that of previous literature on aSAH.24 In our analysis, glibenclamide did not influence mortality compared with placebo. A study by Thompson et al.25 analyzed glibenclamide for the treatment of brain tumors and also reached similar results in terms of mortality compared to placebo.

Delayed Cerebral Ischemia

Although the unadjusted analysis suggested a possible glibenclamide benefit regarding DCI, the multivariable adjusted analysis did not confirm this association. Reasons for this may include a higher propensity for endovascular treatment in the glibenclamide group, which was associated with less DCI and better functional outcomes compared with microsurgery. For many reasons (e.g., presence of hematomas), patients with higher WFNS and Hunt and Hess grades are usually treated microsurgically. Therefore, one cannot infer from this study that endovascular treatments are associated with less vasospasm. Furthermore, the glibenclamide group underwent definitive treatment earlier than controls, and the time delay between the ictus and treatment was associated with less DCI.

Treatment Duration and Adverse Effects

We chose to treat patients for 21 days, which is a longer period than that in most studies evaluating vasospasm.2,20–22 This decision was based on important studies by Kirkpatrick et al.26 and Allen et al.27 in which the patients were treated for 21 days.

In studies that used intravenous glibenclamide,12,23,28 the average time sought for the start of medication was 10 hours, which is directly correlated to the disease in question, since all stroke treatments are initiated as soon as possible. In aSAH, although the bleeding also starts pathologically at the same time, even when treatment is initiated as soon as possible, clinical vasospasm is usually detectable only after a few days.

Hypoglycemia is a notorious adverse effect after the administration of sulfonylureas. We opted to introduce glibenclamide only after definitive treatment to avoid hypoglycemia before or during procedures. The dosage that we used of 5 mg daily is similar to that reported by Zafardoost et al.29 but lower than that of Khalili et al.,13 which was 10 mg daily.

We observed a rate of hypoglycemia of 5.3%, similar to the rates of Khalili et al.13 (6.5%) and Eisenberg et al.23 (7%). Despite the intravenous use of glibenclamide by Eisenberg et al.,23 it is possible that hypoglycemia could be attributed to the oral formulation in comparison with the intravenous formulation; Zweckberger et al.,30 Jiang et al.,31 and Sheth et al.12 tested intravenous glibenclamide on patients with or in models of stroke or TBI and did not report hypoglycemia. In contrast, Zafardoost et al.29 did not report cases of hypoglycemia using the same dosage as that of the intravenous dosage but administered orally.

The phenomenon of hypoglycemia is seldom or almost never observed in most studies, especially in studies such as those on TBI;13,29 those populations are usually younger and previously healthy, in contrast with stroke studies.12,23 The application of oral glibenclamide has been criticized in the review by Jha et al.,32 in which the authors mention the risk of the medication’s supratherapeutic peaks and the risk of serial dosages, particularly in the context of low gastric pH (which influences the plasma level of the drug). However, intravenous glibenclamide is not available in Brazil, and 5 mg is the standard initial dose with low rate of collateral effects.

Study Limitations

This study presents limitations, including possible unknown confounders, losses to follow-up leading to a small sample, and different results due to the treatment approaches (microsurgical or endovascular). Time until medication initiation could also have interfered with treatment efficacy because once Sur1-Trmp4 channels are open, the drug no longer has effects. Further studies are necessary to investigate the role of glibenclamide on selected patients with aSAH, especially to prevent the formation of edema. Nonetheless, this is the first trial that evaluates the impact of glibenclamide on the mortality and clinical outcomes in patients with aSAH.

Conclusions

In this study, glibenclamide was not associated with better functional outcomes after aSAH. Mortality and DCI rates were also similar compared with placebo. Hypoglycemia was more frequently observed in the glibenclamide group.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: all authors. Acquisition of data: all authors. Analysis and interpretation of data: all authors. Drafting the article: all authors. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Rabelo. Statistical analysis: all authors. Administrative/technical/material support: all authors. Study supervision: all authors.

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    Sheth KN, Elm JJ, Molyneaux BJ, Hinson H, Beslow LA, Sze GK, et al. Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2016;15(11):11601169.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Khalili H, Derakhshan N, Niakan A, Ghaffarpasand F, Salehi M, Eshraghian H, et al. Effects of oral glibenclamide on brain contusion volume and functional outcome of patients with moderate and severe traumatic brain injuries: a randomized double-blind placebo-controlled clinical trial. World Neurosurg. 2017;101:130136.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Boggs DH, Simard JM, Steven A, Mehta MP. Potential of glyburide to reduce intracerebral edema in brain metastases. Expert Rev Neurother. 2014;14(4):379388.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    da Costa BBS, Windlin IC, Koterba E, Yamaki VN, Rabelo NN, Solla DJF, et al. Glibenclamide in aneurysmatic subarachnoid hemorrhage (GASH): study protocol for a randomized controlled trial. Trials. 2019;20(1):413.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16

    Shen J, Shen J, Zhu K, Zhou H, Tian H, Yu G. Efficacy of statins in cerebral vasospasm, mortality, and delayed cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis of randomized controlled trials. World Neurosurg. 2019;131:e65e73.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Kurland DB, Tosun C, Pampori A, Karimy JK, Caffes NM, Gerzanich V, Simard JM. Glibenclamide for the treatment of acute CNS injury. Pharmaceuticals (Basel). 2013;6(10):12871303.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18

    Chen M, Dong Y, Simard JM. Functional coupling between sulfonylurea receptor type 1 and a nonselective cation channel in reactive astrocytes from adult rat brain. J Neurosci. 2003;23(24):85688577.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    Gerzanich V, Stokum JA, Ivanova S, Woo SK, Tsymbalyuk O, Sharma A, et al. Sulfonylurea receptor 1, transient receptor potential cation channel subfamily M member 4, and KIR6.2:role in hemorrhagic progression of contusion. J Neurotrauma. 2019;36(7):10601079.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Tseng MY, Czosnyka M, Richards H, Pickard JD, Kirkpatrick PJ. Effects of acute treatment with pravastatin on cerebral vasospasm, autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid hemorrhage: a phase II randomized placebo-controlled trial. Stroke. 2005;36(8):16271632.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    van den Bergh WM, Algra A, van Kooten F, Dirven CM, van Gijn J, Vermeulen M, Rinkel GJ. Magnesium sulfate in aneurysmal subarachnoid hemorrhage: a randomized controlled trial. Stroke. 2005;36(5):10111015.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Vergouwen MD, Meijers JC, Geskus RB, Coert BA, Horn J, Stroes ES, et al. Biologic effects of simvastatin in patients with aneurysmal subarachnoid hemorrhage: a double-blind, placebo-controlled randomized trial. J Cereb Blood Flow Metab. 2009;29(8):14441453.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Eisenberg HM, Shenton ME, Pasternak O, Simard JM, Okonkwo DO, Aldrich C, et al. Magnetic resonance imaging pilot study of intravenous glyburide in traumatic brain injury. J Neurotrauma. 2020;37(1):185193.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, et al. Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol. 2011;10(7):618625.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Thompson EM, Pishko GL, Muldoon LL, Neuwelt EA. Inhibition of SUR1 decreases the vascular permeability of cerebral metastases. Neoplasia. 2013;15(5):535543.

  • 26

    Kirkpatrick PJ, Turner CL, Smith C, Hutchinson PJ, Murray GD. Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial. Lancet Neurol. 2014;13(7):666675.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Allen GS, Ahn HS, Preziosi TJ, Battye R, Boone SC, Boone SC, et al. Cerebral arterial spasm—a controlled trial of nimodipine in patients with subarachnoid hemorrhage. N Engl J Med. 1983;308(11):619624.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Pergakis M, Badjatia N, Chaturvedi S, Cronin CA, Kimberly WT, Sheth KN, Simard JM. BIIB093 (IV glibenclamide): an investigational compound for the prevention and treatment of severe cerebral edema. Expert Opin Investig Drugs. 2019;28(12):10311040.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Zafardoost P, Ghasemi AA, Salehpour F, Piroti C, Ziaeii E. Evaluation of the effect of glibenclamide in patients with diffuse axonal injury due to moderate to severe head trauma. Trauma Mon. 2016;21(5):e25113.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Zweckberger K, Hackenberg K, Jung CS, Hertle DN, Kiening KL, Unterberg AW, Sakowitz OW. Glibenclamide reduces secondary brain damage after experimental traumatic brain injury. Neuroscience. 2014;272:199206.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Jiang B, Li L, Chen Q, Tao Y, Yang L, Zhang B, et al. Role of glibenclamide in brain injury after intracerebral hemorrhage. Transl Stroke Res. 2017;8(2):183193.

  • 32

    Jha RM, Bell J, Citerio G, Hemphill JC, Kimberly WT, Narayan RK, et al. Role of sulfonylurea receptor 1 and glibenclamide in traumatic brain injury: a review of the evidence. Int J Mol Sci. 2020;21(2):409.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Collapse
  • Expand

Illustration from Morshed et al. (pp 1–8). Copyright Ken Probst. Published with permission.

  • View in gallery
    FIG. 1.

    CONSORT 2010 flow diagram. Figure is available in color online only.

  • View in gallery
    FIG. 2.

    Distribution of functional outcomes, according to the mRS, at discharge (upper) and at 6 months of follow-up (lower). X = controls; Y = treated patients. Figure is available in color online only.

  • 1

    Macdonald RL. Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol. 2014;10(1):4458.

  • 2

    Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, et al. Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke. 2012;43(6):14631469.

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  • 3

    Wijdicks EF, Kerkhoff H, van Gijn J. Long-term follow-up of 71 patients with thunderclap headache mimicking subarachnoid haemorrhage. Lancet. 1988;2(8602):6870.

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    Vivancos J, Gilo F, Frutos R, Maestre J, García-Pastor A, Quintana F, et al. Clinical management guidelines for subarachnoid haemorrhage. Diagnosis and treatment. Neurologia. 2014;29(6):353370.

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    Ducruet AF, Gigante PR, Hickman ZL, Zacharia BE, Arias EJ, Grobelny BT, et al. Genetic determinants of cerebral vasospasm, delayed cerebral ischemia, and outcome after aneurysmal subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2010;30(4):676688.

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  • 6

    Dorhout Mees SM, Rinkel GJ, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, van Gijn J. Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2007;(3):CD000277.

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  • 7

    Patel AD, Gerzanich V, Geng Z, Simard JM. Glibenclamide reduces hippocampal injury and preserves rapid spatial learning in a model of traumatic brain injury. J Neuropathol Exp Neurol. 2010;69(12):11771190.

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  • 8

    Sheth KN, Kimberly WT, Elm JJ, Kent TA, Yoo AJ, Thomalla G, et al. Exploratory analysis of glyburide as a novel therapy for preventing brain swelling. Neurocrit Care. 2014;21(1):4351.

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  • 9

    Simard JM, Geng Z, Woo SK, Ivanova S, Tosun C, Melnichenko L, Gerzanich V. Glibenclamide reduces inflammation, vasogenic edema, and caspase-3 activation after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2009;29(2):317330.

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  • 10

    Tosun C, Kurland DB, Mehta R, Castellani RJ, deJong JL, Kwon MS, et al. Inhibition of the Sur1-Trpm4 channel reduces neuroinflammation and cognitive impairment in subarachnoid hemorrhage. Stroke. 2013;44(12):35223528.

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  • 11

    Kimberly WT, Battey TW, Pham L, Wu O, Yoo AJ, Furie KL, et al. Glyburide is associated with attenuated vasogenic edema in stroke patients. Neurocrit Care. 2014;20(2):193201.

    • Crossref
    • PubMed
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  • 12

    Sheth KN, Elm JJ, Molyneaux BJ, Hinson H, Beslow LA, Sze GK, et al. Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2016;15(11):11601169.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Khalili H, Derakhshan N, Niakan A, Ghaffarpasand F, Salehi M, Eshraghian H, et al. Effects of oral glibenclamide on brain contusion volume and functional outcome of patients with moderate and severe traumatic brain injuries: a randomized double-blind placebo-controlled clinical trial. World Neurosurg. 2017;101:130136.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Boggs DH, Simard JM, Steven A, Mehta MP. Potential of glyburide to reduce intracerebral edema in brain metastases. Expert Rev Neurother. 2014;14(4):379388.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    da Costa BBS, Windlin IC, Koterba E, Yamaki VN, Rabelo NN, Solla DJF, et al. Glibenclamide in aneurysmatic subarachnoid hemorrhage (GASH): study protocol for a randomized controlled trial. Trials. 2019;20(1):413.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16

    Shen J, Shen J, Zhu K, Zhou H, Tian H, Yu G. Efficacy of statins in cerebral vasospasm, mortality, and delayed cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis of randomized controlled trials. World Neurosurg. 2019;131:e65e73.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Kurland DB, Tosun C, Pampori A, Karimy JK, Caffes NM, Gerzanich V, Simard JM. Glibenclamide for the treatment of acute CNS injury. Pharmaceuticals (Basel). 2013;6(10):12871303.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18

    Chen M, Dong Y, Simard JM. Functional coupling between sulfonylurea receptor type 1 and a nonselective cation channel in reactive astrocytes from adult rat brain. J Neurosci. 2003;23(24):85688577.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    Gerzanich V, Stokum JA, Ivanova S, Woo SK, Tsymbalyuk O, Sharma A, et al. Sulfonylurea receptor 1, transient receptor potential cation channel subfamily M member 4, and KIR6.2:role in hemorrhagic progression of contusion. J Neurotrauma. 2019;36(7):10601079.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Tseng MY, Czosnyka M, Richards H, Pickard JD, Kirkpatrick PJ. Effects of acute treatment with pravastatin on cerebral vasospasm, autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid hemorrhage: a phase II randomized placebo-controlled trial. Stroke. 2005;36(8):16271632.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    van den Bergh WM, Algra A, van Kooten F, Dirven CM, van Gijn J, Vermeulen M, Rinkel GJ. Magnesium sulfate in aneurysmal subarachnoid hemorrhage: a randomized controlled trial. Stroke. 2005;36(5):10111015.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Vergouwen MD, Meijers JC, Geskus RB, Coert BA, Horn J, Stroes ES, et al. Biologic effects of simvastatin in patients with aneurysmal subarachnoid hemorrhage: a double-blind, placebo-controlled randomized trial. J Cereb Blood Flow Metab. 2009;29(8):14441453.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Eisenberg HM, Shenton ME, Pasternak O, Simard JM, Okonkwo DO, Aldrich C, et al. Magnetic resonance imaging pilot study of intravenous glyburide in traumatic brain injury. J Neurotrauma. 2020;37(1):185193.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, et al. Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol. 2011;10(7):618625.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Thompson EM, Pishko GL, Muldoon LL, Neuwelt EA. Inhibition of SUR1 decreases the vascular permeability of cerebral metastases. Neoplasia. 2013;15(5):535543.

  • 26

    Kirkpatrick PJ, Turner CL, Smith C, Hutchinson PJ, Murray GD. Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial. Lancet Neurol. 2014;13(7):666675.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Allen GS, Ahn HS, Preziosi TJ, Battye R, Boone SC, Boone SC, et al. Cerebral arterial spasm—a controlled trial of nimodipine in patients with subarachnoid hemorrhage. N Engl J Med. 1983;308(11):619624.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Pergakis M, Badjatia N, Chaturvedi S, Cronin CA, Kimberly WT, Sheth KN, Simard JM. BIIB093 (IV glibenclamide): an investigational compound for the prevention and treatment of severe cerebral edema. Expert Opin Investig Drugs. 2019;28(12):10311040.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Zafardoost P, Ghasemi AA, Salehpour F, Piroti C, Ziaeii E. Evaluation of the effect of glibenclamide in patients with diffuse axonal injury due to moderate to severe head trauma. Trauma Mon. 2016;21(5):e25113.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Zweckberger K, Hackenberg K, Jung CS, Hertle DN, Kiening KL, Unterberg AW, Sakowitz OW. Glibenclamide reduces secondary brain damage after experimental traumatic brain injury. Neuroscience. 2014;272:199206.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Jiang B, Li L, Chen Q, Tao Y, Yang L, Zhang B, et al. Role of glibenclamide in brain injury after intracerebral hemorrhage. Transl Stroke Res. 2017;8(2):183193.

  • 32

    Jha RM, Bell J, Citerio G, Hemphill JC, Kimberly WT, Narayan RK, et al. Role of sulfonylurea receptor 1 and glibenclamide in traumatic brain injury: a review of the evidence. Int J Mol Sci. 2020;21(2):409.

    • Crossref
    • Search Google Scholar
    • Export Citation

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