Language

English

Publication Date

3-11-2025

Journal

JAMA

DOI

10.1001/jama.2024.27441

PMID

39908052

PMCID

PMC11800124

PubMedCentral® Posted Date

2-5-2023

PubMedCentral® Full Text Version

Post-print

Abstract

Importance: There are no useful treatments to prevent the development of severe complications of liver cirrhosis. Simvastatin and rifaximin have shown beneficial effects in liver cirrhosis.

Objective: To assess whether simvastatin combined with rifaximin improves outcomes in patients with decompensated cirrhosis.

Design, setting, and participants: Double-blind, placebo-controlled, phase 3 trial conducted among patients with decompensated cirrhosis in 14 European hospitals between January 2019 and December 2022. The last date of follow-up was December 2022.

Interventions: Patients were randomly assigned to receive simvastatin, 20 mg/d, plus rifaximin, 1200 mg/d (n = 117), or identical-appearing placebo (n = 120) for 12 months in addition to standard therapy, stratified according to Child-Pugh class B or C.

Main outcomes and measures: The primary end point was incidence of severe complications of liver cirrhosis associated with organ failure meeting criteria for acute-on-chronic liver failure. Secondary outcomes included transplant or death and a composite end point of complications of cirrhosis (ascites, hepatic encephalopathy, variceal bleeding, acute kidney injury, and infection).

Results: Among the 237 participants randomized (Child-Pugh class B: n = 194; Child-Pugh class C: n = 43), 72% were male and the mean age was 57 years. There were no differences between the 2 groups in terms of development of acute-on-chronic liver failure (21 [17.9%] vs 17 [14.2%] patients in the treatment and placebo groups, respectively; hazard ratio, 1.23; 95% CI, 0.65-2.34; P = .52); transplant or death (22 [18.8%] vs 29 [24.2%] patients in the treatment and placebo groups, respectively; hazard ratio, 0.75; 95% CI, 0.43-1.32; P = .32); or development of complications of cirrhosis (50 [42.7%] vs 55 [45.8%] patients in the treatment and placebo groups, respectively; hazard ratio, 0.93; 95% CI, 0.63-1.36; P = .70). Incidence of adverse events was similar in both groups (426 vs 419; P = .59), but 3 patients in the treatment group (2.6%) developed rhabdomyolysis.

Conclusions and relevance: The addition of simvastatin plus rifaximin to standard therapy does not improve outcomes in patients with decompensated liver cirrhosis.

Keywords

Aged, Female, Humans, Male, Middle Aged, Acute-On-Chronic Liver Failure, Ascites, Double-Blind Method, Drug Therapy, Combination, Gastrointestinal Hemorrhage, Hepatic Encephalopathy, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Liver Cirrhosis, Liver Transplantation, Rifaximin, Simvastatin, Acute Kidney Injury, Follow-Up Studies, Intention to Treat Analysis, Treatment Outcome, Gastrointestinal Agents, Bacterial Infections, Severity of Illness Index

Comments

Trial registration: ClinicalTrials.gov Identifier: NCT03780673.

Published Open-Access

yes

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