Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial

Neurosurgery. 2019 Dec 1;85(6):843-853. doi: 10.1093/neuros/nyy539.


Background: More than a million Americans harbor a cerebral cavernous angioma (CA), and those who suffer a prior symptomatic hemorrhage have an exceptionally high rebleeding risk. Preclinical studies show that atorvastatin blunts CA lesion development and hemorrhage through inhibiting RhoA kinase (ROCK), suggesting it may confer a therapeutic benefit.

Objective: To evaluate whether atorvastatin produces a difference compared to placebo in lesional iron deposition as assessed by quantitative susceptibility mapping (QSM) on magnetic resonance imaging in CAs that have demonstrated a symptomatic hemorrhage in the prior year. Secondary aims shall assess effects on vascular permeability, ROCK activity in peripheral leukocytes, signal effects on clinical outcomes, adverse events, and prespecified subgroups.

Methods: The phase I/IIa placebo-controlled, double-blinded, single-site clinical trial aims to enroll 80 subjects randomized 1-1 to atorvastatin (starting dose 80 mg PO daily) or placebo. Dosing shall continue for 24-mo or until reaching a safety endpoint.

Expected outcomes: The trial is 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). A decrease in QSM change would be a signal of potential benefit, and an increase would signal a safety concern with the drug.

Discussion: With firm mechanistic rationale, rigorous preclinical discoveries, and biomarker validations, the trial shall explore a proof of concept effect of a widely used repurposed drug in stabilizing CAs after a symptomatic hemorrhage. This will be the first clinical trial of a drug aimed at altering rebleeding in CA.

Keywords: Atorvastatin; Cavernous angioma; Cavernous angioma with symptomatic hemorrhage (CASH); Cerebral cavernous malformation (CCM); Clinical trial; Symptomatic hemorrhage.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Randomized Controlled Trial

MeSH terms

  • Atorvastatin / pharmacology
  • Atorvastatin / therapeutic use*
  • Cerebral Hemorrhage / diagnostic imaging
  • Cerebral Hemorrhage / drug therapy*
  • Double-Blind Method
  • Female
  • Follow-Up Studies
  • Hemangioma, Cavernous / diagnostic imaging
  • Hemangioma, Cavernous / drug therapy*
  • Hemangioma, Cavernous, Central Nervous System / diagnostic imaging
  • Hemangioma, Cavernous, Central Nervous System / drug therapy*
  • Humans
  • Magnetic Resonance Imaging / methods
  • Male
  • Proof of Concept Study*
  • Prospective Studies
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Treatment Outcome
  • rhoA GTP-Binding Protein / antagonists & inhibitors
  • rhoA GTP-Binding Protein / metabolism


  • Protein Kinase Inhibitors
  • RHOA protein, human
  • Atorvastatin
  • rhoA GTP-Binding Protein