Treatment of decompensated cirrhosis with simvastatin 40 mg/day plus rifaximin was associated with a significant increase in adverse events compared with simvastatin 20 mg/day plus rifaximin, according to research published in The Lancet Gastroenterology and Hepatology.
Statins have beneficial effects on intrahepatic circulation and decrease portal hypertension and rifaximin modulates the gut microbiome and might prevent bacterial translocation in patients with cirrhosis. As a part of the LIVERHOPE project, researchers evaluated the safety of 2 different simvastatin doses in combination with rifaximin vs placebo in patients with decompensated cirrhosis. The LIVERHOPE-SAFETY study was a multicenter, randomized, double-blind, placebo-controlled, phase 2 trial that included patients from 6 countries across Europe.
Fifty patients were recruited between July 2017 and January 2018, and were randomly assigned 1:1:1 to receive either simvastatin 40 mg/day plus rifaximin 1200 mg/day, simvastatin 20 mg/day plus rifaximin 1200 mg/day, or an identical placebo dose of both medications (n=18, 16, and 16, respectively) over the course of 12 weeks. The primary study end point was the development of liver or muscle toxicity.
The final intention-to-treat analysis included 44 patients (n=16, 14, and 14, in each group, respectively) with a median follow-up period of 84 days (interquartile range 36-84). Most patients were compliant with their treatment regimen (mean compliance 91% for simvastatin and 90% for rifaximin). After further exclusions for lack of compliance, the final per-protocol population included 37 patients with similar baseline demographic, clinical, and analytic data across all 3 groups.
Treatment was prematurely halted in the simvastatin 40 mg/day group per the recommendation of the data safety monitoring board and based on safety issues. All but 1 patient in this group had stopped treatment due to grade 3 severe adverse events or had already completed the treatment period. Additionally, patients in this group showed significant increases in both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) compared with the placebo group (mean between-group differences AST 130 IU/L; 95% CI, 54-205; P =.0009 and ALT 61 IU/L; 95% CI, 22-100; P =.0025). Conversely, no significant differences in either measure were noted between the simvastatin 20 mg/day group and the placebo group (mean between-group differences AST -14 IU/L; 95% CI, -91 to 64; P =.728 and ALT -8 IU/L; 95% -49 to 33; P =.698). Mean AST and ALT were significantly higher in the simvastatin 40 mg/day group compared with the simvastatin 20 mg/day group as well (AST 143 IU/L; 95% CI, 66-220; P =.0003 and ALT 69 IU/L; 95% CI, 29-109; P =.0009).
No significant changes were noted in alkaline phosphate among any groups.
Creatine kinase also significantly increased in the simvastatin 40 mg/day group compared with placebo patients (mean 1009 IU/L; 95% CI, 208-1809; P =.014). Conversely, no significant changes were noted between the simvastatin 20 mg/day and placebo groups (4.2 IU/L; 95% CI, -804 to 813; P =.992).
The number of patients that developed de novo muscle symptoms, including cramps, aches, and weakness, without meeting muscle toxicity criteria was not significantly different among groups: 5 patients in the simvastatin 40 mg/day group, 6 in the simvastatin 20 mg/day group, and 3 in the placebo group (P =.424).
Study limitations included the small sample size and the possibility that a “slight imbalance” in some baseline characteristics may have affected the study results.
“In studies investigating the efficacy of simvastatin in patients with decompensated cirrhosis, 20 mg/day should be preferred to a 40 mg/day dose,” the researchers concluded.
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Pose E, Napoleone L, Amin A, et al. Safety of two different doses of simvastatin plus rifaximin in decompensated cirrhosis (LIVERHOPE-SAFETY): a randomised, double-blind, placebo-controlled, phase 2 trial [published online October 10, 2019]. Lancet Gastroenterol Hepatol. doi: 10.1016/S2468-1253(19)30320-6