Evidence before this study
Cerebral cavernous malformations (CCM) affect more than a million Americans, predisposing to risk of brain bleeding. Once a lesion bleeds, it has a high risk or rebleeding with grave consequences, often requiring invasive and risky brain surgery. There is no drug currently with proven benefit in preventing CCM hemorrhage. Mechanistic and animal studies (many in the Awad lab at UCM) have suggested Rho kinase (ROCK) inhibition could be a therapeutic target for cerebral cavernous malformations (CCMs), and atorvastatin at doses achieving pleotropic ROCK inhibition has been shown to decrease lesion growth and bleeding in mouse models of CCM. Human studies to date had indicated uncertainty about whether this therapy impacts CCM bleeding rate. And there had been concern about potentially increased brain bleeding with statins in general.
Added value of this study
This is the first prospective randomized double blinded clinical trial in people with CCM and previous symptomatic hemorrhage. Our study incorporated a novel imaging biomarker validated by UCM researchers, which measures a change in lesional iron deposition by quantitative susceptibility mapping (QSM) on MRI when a CCM bleeds. A decrease in QSM change by a drug would signal potential benefit, and an increase would signal a safety concern.
Implications of all the available evidence
Our trial demonstrated no effect of atorvastatin compared with placebo on rebleeding in patients with CCM who had suffered a symptomatic hemorrhage in the previous year. No safety concerns were noted. The results do not justify the use of atorvastatin with the aim of preventing CCM rebleeding. Drugs with stronger and more specific ROCK inhibition properties than atorvastatin might be needed to achieve a meaningful benefit.
What this means is that If a CCM patient is currently taking statin or needs it for cardiac or cholesterol indications, he/she should not worry about any harm from in the presence of a CCM lesion that has recently bled. At the same time, we cannot recommend statin use specifically for the purpose of preventing bleeding in CCM
The first-in-disease trial articulated a roadmap for testing future drugs in this disease where there is currently no known proven therapy.