Abstract / Summary
Background: Cerebral cavernous malformations (CCM) are vascular lesions prone to hemorrhage, but the influence of modifiable cardiovascular risk factors and commonly prescribed therapies on bleeding risk remains unclear.
Methods: We performed a systematic review and meta-analysis according to PRISMA 2020. PubMed/MEDLINE, Embase, and Scopus were searched from inception through August 31, 2025. Eligible observational studies and randomized trials reported adults with CCM stratified by modifiable cardiovascular risk factors or systemic therapies. Hemorrhagic presentation at diagnosis and prospective symptomatic hemorrhage or rebleeding during follow-up were extracted and interpreted as distinct clinical endpoints. Comparable adjusted and crude estimates were pooled separately using random-effects models; randomized trials with non-comparable populations or endpoints were summarized narratively. Risk of bias and certainty of evidence were assessed using design-appropriate Cochrane tools and GRADE, respectively.
Results: Of 1275 records identified, 30 full texts were reviewed, and 22 studies met inclusion criteria, comprising 7331 patients with CCM. Most pooled analyses evaluated hemorrhagic presentation at diagnosis. Smoking was associated with increased odds of hemorrhagic presentation (aOR 1.41, 95% CI 1.03-1.93), and obesity showed an uncertain signal toward higher odds (aOR 1.77, 95% CI 1.00-3.13). Antithrombotic therapy was associated with lower odds of hemorrhagic presentation (aOR 0.46, 95% CI 0.29-0.73), while statins showed a nonsignificant association (aOR 0.79, 95% CI 0.52-1.20). Randomized propranolol and atorvastatin trials were considered separately because their prospective endpoints and trial populations were not directly comparable with the observational presentation-based analyses.
Conclusions: Evidence regarding systemic cardiovascular factors and therapies in CCM remains sparse and predominantly of low or very low certainty. The observed associations are preliminary, may reflect residual confounding and treatment-selection bias, and should not be interpreted as causal or as direct estimates of future hemorrhage risk. Prospective multicenter studies with standardized clinical and imaging definitions are needed before these findings can inform treatment decisions.