Abstract Body: Background. Cerebral cavernous malformations (CCM) carry a high risk of rebleeding after symptomatic hemorrhage (SH), with serious clinical sequelae. Atorvastatin was shown to prevent CCM growth and bleeding in animal models. This single site Phase I/IIa proof of concept trial evaluated whether atorvastatin at oral dose of 80 mg daily for 2 years, produces a difference compared to placebo in lesional iron deposition on quantitative susceptibility mapping (QSM) on magnetic resonance imaging (MRI) in CCMs that had suffered a SH in the preceding year, and other exploratory secondary outcomes. A decrease in QSM change would signal potential benefit, and an increase would signal safety concern with the drug.
Methods. The trial was powered to detect an absolute difference of 20% in the mean percent change in lesional QSM per year (2-tailed, power 0.9, alpha 0.05), accounting for patient attrition, with sample size recalculation at trial midpoint. Eighty subjects were randomized 1-1 to atorvastatin or placebo, and 64 contributed at least one annual paired QSM assessment, exceeding the sample size needed, all with > 90% active drug compliance.
Findings. The mean annual lesional QSM percent change in sex adjusted mixed model averaged over 2 years was 10.9 (95% CI -3.2 to +25) in atorvastatin and 12.1 (95% CI -2.5 to +27) in placebo subjects, a 10% non-significant reduction. This effect was greater in males (33% reduction) and in CCMs at brainstem location (76% reduction), both non-significant. There were no significant differences in SH rates, subclinical bleeds, vascular permeability of lesion or brain on dynamic contrast enhanced quantititve perfusion, or leukocyte Rho kinase activity. Cholesterol levels were lower and adverse events were more common with atorvastatin.
Interpretation. Atorvastatin treatment was safe in CCMs with recent SH, with a non-significantly decreased hemorrhage risk during 2 years of follow-up.
Funding. U.S. National Institutes of Health R01NS107887. Clinicaltrials.gov NCT02603328.