Efficacy of Medical Treatment Options for Reducing the Risk Of Bleeding in Patients with Cerebral Cavernous Malformations: A Systematic Review And Network Meta-Analysis

Introduction: Cerebral cavernous malformations (CCMs) are low-flow vascular lesions of the central nervous system, characterized by abnormal clusters of capillaries lined with endothelial cells. The most critical clinical manifestation of CCMs is intracerebral hemorrhage (ICH), and its risk can increase with factors such as prior bleeding, lesion location, and associated developmental venous anomalies. Although surgery is the primary treatment option for CCMs, surgical intervention in deep-seated lesions may carry significant risks. Consequently, various medications have been proposed as potential pharmacological stabilizing agents; however, the relationship between bleeding risk and medication use remains unclear, and no consensus or standardized guidelines currently exist. This study aims to evaluate the potential roles of three commonly used medication groups in modifying hemorrhage risk in CCMs: statins, antithrombotics, and beta-blockers. Methods: This study followed PRISMA guidelines and was registered in PROSPERO (CRD420251069357). PubMed, Embase, Cochrane, and Scopus were searched from inception to July 9, 2025. Eligible studies included patients with sporadic or familial CCMs reporting ICH outcomes in those receiving statins, antithrombotics, or beta-blockers either as monotherapy or in combination, compared with no medical treatment. Studies involving surgical intervention were excluded. The primary outcome was prospective (re)bleeding during follow-up, and the secondary outcome was the association of prior medication use with hemorrhagic presentation at diagnosis. Odds ratios (ORs) were calculated for each medication group, and a multivariate meta-analysis with surface under the cumulative ranking curve (SUCRA) scores was performed to compare efficacy. Results: Seven studies including 3,092 patients were included in the analysis. The multivariate meta-analysis showed that statin therapy significantly reduced the odds of (re)bleeding during follow-up compared with both beta-blockers [ln(OR)= –1.15, 95% CI: –2.24, –0.05] and no treatment [ln(OR)= –1.14, 95% CI: –1.96, –0.32]. Combination therapy with statins, antithrombotics, and beta-blockers also lowered the odds of (re)bleeding relative to no treatment [ln(OR)= –1.43, 95% CI: –2.82, –0.05], ranking highest in SUCRA analysis, followed by statin monotherapy. Furthermore, statin plus antithrombotic therapy significantly reduced the odds of (re)bleeding compared with beta-blockers [ln(OR)= –1.39, 95% CI: –2.46, –0.32]. Beta-blocker monotherapy showed a tendency toward increased risk compared with antithrombotic monotherapy [ln(OR)= 0.88, 95% CI: 0.12, 1.63], while patients receiving no treatment had higher odds of presenting with (re)bleeding relative to both statin plus antithrombotic therapy [ln(OR)= 1.13, 95% CI: 0.27, 2.00] and antithrombotic monotherapy [ln(OR)= 0.62, 95% CI: 0.09, 1.14]. In the SUCRA ranking, statin plus antithrombotic therapy was associated with the lowest risk of (re)bleeding at the time of diagnosis. Conclusion: Our findings suggest a potential stabilizing role for statin-based therapies in CCMs, warranting confirmation in future prospective randomized controlled trials, particularly for patients with lesions in eloquent regions or without a clear surgical indication, where medical therapy may serve as a valuable alternative. Publication History Article published online: 27 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany