Neuroprotective effect of dapsone in patients with aneurysmal subarachnoid hemorrhage: a prospective, randomized, double-blind, placebo-controlled clinical trial

Abstract

OBJECTIVE In this study, the authors sought to define the differences in the incidence of delayed cerebral ischemia (DCI) between patients treated with dapsone and those treated with placebo. Secondary objectives were to define the clinical outcome at discharge and 3 months and the incidence of brain infarction. METHODS A prospective, randomized, double-blind, placebo-controlled study was performed and included patients with aneurysmal subarachnoid hemorrhage (SAH) within 5 days from ictus who were candidates for aneurysm occlusion, and who had a Fisher grade of 3 or 4. Patients with sulfa or sulfone drug allergies, hemoglobin < 11 g/dl, known G6PD deficiency, and those refusing informed consent were excluded. A minimal relevant effect decrease of 35% in the incidence of DCI was established. Patients were randomly assigned to receive a regimen of dapsone 2.5 ml (100 mg) daily or a placebo (aluminum hydroxide suspension, 2.5 ml daily). Both groups received validated treatment for aneurysmal SAH. The appearance of DCI on CT was assessed in every patient at discharge and 3 months later. We used the chi-square test to compare the DCI incidence between both groups, and the Student t-test or nonparametric tests to compare quantitative variables. RESULTS Overall, 48 patients (70.8% women and 29.2% men) were included. The mean age was 50 years (SD 14.28 years, range 18–72 years). Prerandomization and postrandomization characteristics were balanced, except for the necessity of intra-arterial nimodipine administration in patients treated with placebo (15.4% vs 45.5%, p = 0.029. The incidence of DCI, the primary endpoint, for the whole cohort was 43.8% and was significantly lower in the dapsone group (26.9% vs 63.6%, p = 0.011). In addition, the irreversible DCI incidence was lower in the dapsone group (11.5% vs 54.5%, p = 0.12). A favorable modified Rankin Scale score was more frequent in the dapsone group at discharge and at 3 months (76.9% vs 36.4%, p = 0.005 and 80% vs 38.9%, p = 0.019, respectively). Also, the brain infarction incidence was lower in the dapsone group (19.2% vs 63.6%, p = 0.001). There was no difference between groups regarding adverse events. CONCLUSIONS Dapsone seems to play a role as a prophylactic agent in patients at high risk of developing DCI after aneurysmal SAH. A multicenter investigation is necessary to increase the study population and confirm the consistency of the results observed in this study.

The fragility index in randomised controlled trials of interventions for aneurysmal subarachnoid haemorrhage: A systematic review

“…Study and participant characteristics are provided in Supplemental Table 2. Settings included Europe (seven studies), 11 –17 Asia (eight studies), 18 –25 North America (three studies) 15,26,27 and North Africa (one study). 28 There were 10 single centre studies 13,14,16 –18,24 –28 eight multi-centre studies.…”

“…Settings included Europe (seven studies), 11 –17 Asia (eight studies), 18 –25 North America (three studies) 15,26,27 and North Africa (one study). 28 There were 10 single centre studies 13,14,16 –18,24 –28 eight multi-centre studies. 11,12,15,19 –23 Publication dates ranged from 1989 to 2022.…”

“…11,12,15,19 –23 Publication dates ranged from 1989 to 2022. Thirteen studies looked at pharmacological interventions for aSAH 11,12,14,16,18 –20,22 –24,26 –28 four studies looked at surgical or interventional radiology treatments 15,21,25 one study looked at protocolised patient care. 17 Ten studies used vasospasm (angiographic or symptomatic) as their primary outcome 11,16,18 –21,23,25,26,28 six studies used delayed ischaemic neurological deficit (DIND) or cerebral infarction 12 –14,17,22,27 three studies looked at clinical outcome using the Glasgow outcome scale (GOS) or the modified Rankin scale (mRS).…”

Anti-Inflammatory Drug Therapy in Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis of Prospective Randomized and Placebo-Controlled Trials

“…No studies w identified that indicated a significant positive or negative impact of anti-inflammato therapy on the outcome endpoint of "death". [25][26][27][28][29][30][32][33][34][35][36][37][38]. Squares constitute the odds ratio; the bigger the square, the greater the weight given because of the narrower 95% CI.…”

“…Furthermore, cerebrolysin also resulted in an increased probability to achieve a favorable outcome compared to placebo treatment [38]. One study investigating the effect of da sone reported a beneficial effect regarding functional outcome as endpoint [27]. Furthe more, cerebrolysin also resulted in an increased probability to achieve a favorable ou come compared to placebo treatment [38].…”