Simvastatin plus Rifaximin to prevent ACLF in patients with decompensated cirrhosis. A randomised, double-blind, placebo-controlled, phase-3 trial: the liverhope efficacy trial

Abstract

Background and aims: Preliminary data suggest that simvastatinmay have beneficial effects indecompensatedcirrhosis.Rifaximinis effective in preventing recurrent hepatic encephalopathy but it is not known whether it can prevent other complications of cirrhosis. The current study was aimed at assessing whether simvastatin associated with rifaximin improves the natural history of decompensated cirrhosis. Method: Double‐blind, placebo‐controlled, phase 3 trial in patients with decompensated cirrhosis from14 European university hospitals. Patients with Child Pugh Turcotte (CPT) Bor Cwere randomlyassigned to receive either simvastatin 20mg/day plus rifaximin 1,200mg/day or placebo of both for 12 months, stratified according to Child Pugh class. Primaryend pointwas time to first episode of Acute‐On‐Chronic Liver Failure (ACLF), analyzed using Cox regression analysis with competing risk for death or transplant and stratified by CPT class. Secondary end points included transplant‐free survival, composite of ACLF, death and transplant, and composite of cirrhosis decompensating events (newonset/ worsening ascites, hepatic encephalopathy, variceal bleeding, acute kidney injury and infections). Results: 254 patients were randomized. After exclusion of 17 patients, 237 (194 CPT B and 43 CPT C) composed the intention to treat population: 117 and 120 in the treatment and placebo groups, respectively. Most patients were male (72%) with mean age of 57y; alcohol was the most frequent cause of cirrhosis (80%). There were no differences in the primary end point of incidence of ACLF: 20 vs 13 subjects presented 23 and 13 episodes of ACLF respectively in the treatment and placebo groups [HR 1.73 (0.73‐4.10), p = 0.21]. Twelve vs 11 patients died and 3 vs 8 patientswere transplanted in treatment and placebo groups, respectively [HR for transplant‐free survival 0.678 (0.34‐1.33)]. No differenceswere found either in the composite of ACLF + death + transplant [HR 0.831 (0.45‐1.53), p = 0.55] nor in the compositeof any decompensatingevent [HR0.788 (0.52‐1.18),p=0.25]. Incidence of adverse events was similar in both groups (413 vs 396, p = 0.59), albeit three patients in the treatment group (2.6%) developed rhabdomyolysis, likely attributable to treatment with simvastatin. Conclusion: In decompensated cirrhosis, treatment with simvastatin plus rifaximin for 12 months was not associated with reduction of ACLF, complications or death. These results do not support the use of this combination therapy in decompensated cirrhosis. [Figure presented]