Recurrent Symptomatic Hemorrhage in Cerebral Cavernous Malformations After Discontinuation of Atorvastatin or Placebo

BACKGROUND: A recent randomized prospective controlled trial demonstrated that atorvastatin for up to 2 years was safe but did not significantly alter rebleeding in cerebral cavernous malformations. However, any consequences of discontinuing atorvastatin remain unknown. We hypothesized that symptomatic hemorrhage (SH) recurs more frequently in cerebral cavernous malformations after discontinuation of atorvastatin than placebo. METHODS: We conducted a 12-month posttreatment follow-up of patients enrolled in the Atorvastatin Therapy in Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) trial (41 randomized to atorvastatin, 39 to placebo) to identify potential recurrent SH after trial drug discontinuation. Every SH was adjudicated by review of imaging and corresponding symptoms. Patients were excluded from follow-up for <90% compliance with study drug, for its discontinuation <3 months after trial enrollment, for statin reinitiation <3 months after discontinuation, or for lack of follow-up. Cases were censored during follow-up upon cerebral cavernous malformation resection/radiation or later statin reinitiation. RESULTS: Follow-up included 33 patients who had been randomized to placebo and 32 who had taken atorvastatin. Four SH events occurred at 3, 49, 84, and 225 days after atorvastatin discontinuation, and 1 SH at 395 days after discontinuing placebo. There was significantly lower symptomatic hemorrhage-free survival in the atorvastatin-discontinuation group (log-rank χ2=4.136, P=0.042). The hazard ratio was 0.162 (95% CI, 0.027-0.977) for placebo versus atorvastatin discontinuation. CONCLUSIONS: Discontinuation of atorvastatin was associated with a higher risk of recurrent SH compared with placebo discontinuation. Additional studies are warranted to confirm this hypothesis-generating observation, examine potential mechanisms, and how best to mitigate this risk. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02603328.