Efficacy of Medical Treatment Options for Reducing the Risk of Bleeding in Patients With Sporadic and Familial Cerebral Cavernous Malformations: A Systematic Review and Network Meta-Analysis

Cerebral cavernous malformations (CCMs) carry a significant hemorrhage risk.While surgery remains the primary treatment, deep-seated or eloquent lesions pose high operative risks, prompting interest in potential pharmacological approaches aimed at lesion stabilization.However, standardized medical management guidelines remain absent.This study evaluates the associations of statins, antithrombotics (ATs), and beta-blockers (BBs) with CCM hemorrhage risk.Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (International Prospective Register of Systematic Reviews (PROSPERO): CRD420251069357), a systematic review of PubMed, Embase, Cochrane, and Scopus (inception to February 3, 2026) was conducted.Eligible studies compared bleeding outcomes in CCM patients receiving statins, ATs, or BBs versus no medical treatment.A multivariate meta-analysis utilized odds ratios (ORs) and surface under the cumulative ranking curve (SUCRA) scores to evaluate follow-up (re)bleeding (primary outcome) and hemorrhagic presentation at diagnosis (secondary outcome).Seven studies (n = 3,092) were included.Statin therapy was associated with lower odds of follow-up (re)bleeding versus BBs (OR = 0.32, 95% confidence interval (CI): 0.11-0.95) and no treatment (OR = 0.32, 95% CI: 0.14-0.73).Triple combination therapy (statin + AT + BB) was also associated with lower odds of (re)bleeding compared with no treatment (OR = 0.24, 95% CI: 0.06-0.95) and ranked highest according to SUCRA.Statin + AT was associated with lower (re)bleeding odds versus BBs (OR = 0.25, 95% CI: 0.09-0.73).Conversely, BB monotherapy was associated with higher odds of (re)bleeding compared with AT monotherapy (OR = 2.41, 95% CI: 1.13-5.10).Untreated patients had higher odds of hemorrhagic presentation compared with statin + AT (OR = 3.10, 95% CI: 1.31-7.39)and AT monotherapy (OR = 1.86, 95% CI: 1.09-3.13).In the SUCRA ranking, statin + AT had the lowest ranked risk of hemorrhagic presentation at diagnosis.In the absence of established pharmacological strategies, statin-and AT-based regimens were associated with lower CCM hemorrhage odds.However, the available evidence is predominantly observational and limited, with substantial potential for confounding by indication.Together with the null findings of the randomized AT CASH EPOC trial, these findings should be considered hypothesis-generating and are insufficient to guide clinical practice pending prospective randomized validation.