Simvastatin and Rifaximin in Decompensated Cirrhosis: A Randomized Clinical Trial

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.

Trial registration: ClinicalTrials.gov Identifier: NCT03780673.

Figure 1.. Flow of the Study Population

HCC indicates hepatocellular carcinoma. ^aOne unit is equivalent to 10 g of alcohol. ^bCreatine kinase levels of more than 50% of the upper limit of normal at inclusion, history of rhabdomyolysis, history of intestinal obstruction, or contraindication or known sensitivity to statins or rifaximin. ^cPatients were stratified according to Child-Pugh class B or C. ^dPatients met the inclusion criteria and none of the exclusion criteria at the screening visit, but at the randomization visit did not meet inclusion criteria or did meet some of the exclusion criteria. ^eThree were episodes of recurrent hepatic encephalopathy. ^fEight were episodes of recurrent hepatic encephalopathy.

Figure 2.. Cumulative Incidence of ACLF According to Study Group

Cumulative incidence of acute-on-chronic liver failure (ACLF) is shown for (A) the intention-to-treat population (primary analysis), (B) the modified intention-to-treat population, (C) the per-protocol population, and (D) the post hoc analysis including the population that was randomized but did not receive the study medication. The diagnosis of ACLF was based on the criteria of the European Association for the Study of the Liver–Chronic Liver Failure consortium. ACLF is a severe decompensation of cirrhosis accompanied by failure of 1 or more organs or systems (including liver, kidney, brain, respiratory system, circulatory system, and coagulation) and is associated with poor short-term and mid-term prognosis. The Fine and Gray Cox model approach using the randomization Child-Pugh strata under a competing risk strategy (death and transplant) was used to estimate cumulative incidence of ACLF. Median observation time was 365 days (IQR, 360-365 days).