Functional and Patient-Reported Outcomes in the Atorvastatin versus Placebo Trial of Hemorrhagic Cerebral Cavernous Malformations: An Exploratory Study

Abstract – Introduction: Limited longitudinal data exist regarding functional and patient-reported outcome (PRO) in symptomatic hemorrhage (SH) from cerebral cavernous malformation enrolled in clinical trials. Methods: We assessed functional outcome using the modified Rankin Scale (mRS) and NIH Stroke Scale (NIHSS), and PRO using European Quality of Life 5-Dimension and Visual Analog Scale (EQ-5D-3L and VAS) and PRO-measurement information system (PROMIS-29) at baseline, 1 year, and 2 years in patients randomized to atorvastatin and placebo in the prospective, double-blinded Atorvastatin Treatment of Cavernous Angioma Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) trial. Sensitivity analyses compared score change in cases with and without prospective SH and in those with or without a ≥6% increase in lesional iron content on quantitative susceptibility mapping (QSM), consistent with occult bleeding. Results: Of 64 patients with paired QSM and outcome data, baseline characteristics were similar; baseline mRS distributions differed between groups but were similar at years 1 and 2. No significant differences in functional and PRO appeared between the atorvastatin and placebo groups. While there was a decline in PROMIS-29 sleep disturbance (57.1% SH vs. 7.7% no SH; p < 0.01), fatigue (57.1% SH vs. 21.2% no SH; p = 0.06), and social role (44.4% SH vs. 16% no SH; p = 0.07) domains with prospective SH over 2 years, the small numbers of patients limit the generalizability. These functional and PRO declines were generally specific but poorly sensitive for identifying SH or occult bleeding. Discussion: Despite more frequently reported side effects with atorvastatin in the trial, there were no significant differences in functional or PRO in the atorvastatin and placebo groups. Functional and PRO decline were highly specific but poorly sensitive for identifying prospective SH or occult bleeding.