Supplementary Material for: Sex Disparities in Intracranial Aneurysm Trial Participation: a Systematic Review and Meta-analysis

Objective: Females have a higher incidence of aneurysmal subarachnoid haemorrhage and a higher prevalence and rupture risk of unruptured intracranial aneurysms than men. Underrepresentation of females in clinical trials would, therefore, limit their generalizability. We aimed to evaluate sex disparities in aneurysmal subarachnoid haemorrhage and unruptured intracranial aneurysm trial enrollment and identify factors influencing female representation.

Methods: We searched Ovid Medline, Embase, Cochrane Central, Clinicaltrials.gov, and International Clinical Trials Registry for clinical trials on aneurysmal subarachnoid haemorrhage or unruptured intracranial aneurysms, published before June 2023, with ≥100 adult patients, requiring informed consent for participation. Primary outcome was the proportion of female patients enrolled. Random effects meta-analysis was performed, and multivariate beta-regression was used to assess the impact of trial characteristics and predefined subgroups on female participation.

Results: 134 trials were included, with a total of 38042 patients. Meta-analysis of the proportions of female participants resulted in a pooled proportion of 0.64 (95%-CI 0.63-0.66). Female participation was higher in trials on endovascular treatment (beta-estimate 1.32; 95%-CI 1.01-1.71) and in multicenter studies (beta-estimate 1.16; 95%-CI 1.01-1.33) but lower in Asian (beta-estimate 0.80; 95%-CI 0.67-0.95) and South American trials (beta-estimate 0.67; 95%-CI 0.47-0.97). Recruitment and consent procedures, sex of primary investigator, or burden of trial participation had no significant impact on female representation. Time trend analysis showed no statistically significant change in female participation over time.

Conclusions: Females are not underrepresented in clinical trials for aneurysmal subarachnoid haemorrhage and unruptured intracranial aneurysms. Female participation is higher in trials on endovascular treatment and in multicenter studies and has regional differences, but other factors did not influence female representation. Our findings imply a good generalizability regarding sex distribution of the study results, strengthening the evidence guiding current clinical practice.