Angeli, Paolo

Refractory ascites often requires therapeutic paracentesis, which is associated with potential risks and diminished quality of life. Terlipressin is a vasopressin analog that is indicated for i.v. bolus injection for hepatorenal syndrome, with the potential to reduce large-volume ascites and its complications. Continuous infusion of terlipressin is associated with fewer adverse effects than bolus dosing. The efficacy and safety of continuous infusion of a novel liquid formulation of terlipressin acetate (BIV201) were evaluated in this open-label phase 2 study. Patients with cirrhosis and refractory ascites were randomly assigned (2:1) to receive two 28-day cycles of continuous infusion BIV201 plus standard of care (SOC) separated by a ≤56-day washout (n=10), or SOC alone (n=5). Data analysis was limited by the small sample size and confounded by a potential interaction with gabapentinoids in the BIV201+SOC group. Nonetheless, there were differences in favor of BIV201+SOC versus SOC in the coprimary efficacy endpoints and several quality of life assessments. The beneficial effects of BIV201 on liver complications (mean: 90% CI; BIV201-completers=2.87: 1.51; 5.46 vs. SOC=2.38: 1.20; 4.73) and the change in cumulative ascites (mean: 90% CI; BIV201-completers=−10.76: −26.51; 5.00 vs. SOC=−4.99: −21.95; 11.97) were more pronounced versus SOC in the 5 BIV201+SOC patients who completed both treatment cycles. There were also greater improvements in exploratory quality of life assessments and the percent change in therapeutic paracenteses with BIV201+SOC (−27.94±41.80) versus SOC (−16.67±45.64). Despite the high rate of hyponatremia in the BIV201+SOC group (4/10 patients), the safety profile suggested that continuous BIV201 infusion was well tolerated. These findings support further development of BIV201 in confirmatory trials.

ImportanceThere are no useful treatments to prevent the development of severe complications of liver cirrhosis. Simvastatin and rifaximin have shown beneficial effects in liver cirrhosis.ObjectiveTo assess whether simvastatin combined with rifaximin improves outcomes in patients with decompensated cirrhosis.Design, Setting, and ParticipantsDouble-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.InterventionsPatients 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 MeasuresThe 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).ResultsAmong 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 RelevanceThe addition of simvastatin plus rifaximin to standard therapy does not improve outcomes in patients with decompensated liver cirrhosis.Trial RegistrationClinicalTrials.gov Identifier: NCT03780673

Hepatorenal syndrome (HRS), a serious complication of cirrhosis, is associated with high mortality without treatment. Terlipressin with albumin is effective in the reversal of HRS. Where terlipressin is not available, as in the United States, midodrine and octreotide with albumin are used as an alternative treatment of HRS. The aim was to compare the effectiveness of terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of HRS in a randomized controlled trial. Twenty‐seven patients were randomized to receive terlipressin with albumin (TERLI group) and 22 to receive midodrine and octreotide plus albumin (MID/OCT group). The TERLI group received terlipressin by intravenous infusion, initially 3 mg/24 hours, progressively increased to 12 mg/24 hours if there was no response. The MID/OCT group received midodrine orally at an initial dose of 7.5 mg thrice daily, with the dose increased to a maximum of 12.5 mg thrice daily, together with octreotide subcutaneously: initial dose 100 μg thrice daily and up to 200 μg thrice daily. Both groups received albumin intravenously 1 g/kg of body weight on day 1 and 20‐40 g/day thereafter. There was a significantly higher rate of recovery of renal function in the TERLI group (19/27, 70.4%) compared to the MID/OCT group (6/21, 28.6%), P = 0.01. Improvement in renal function and lower baseline Model for End‐Stage Liver Disease score were associated with better survival. Conclusion : Terlipressin plus albumin is significantly more effective than midodrine and octreotide plus albumin in improving renal function in patients with HRS (H epatology 2015;62:567–574

AbstractAdvanced cirrhosis is often complicated by a multi organ failure syndrome which involves many different organs besides the liver. The high morbidity and mortality secondary to this clinical setting is often related to renal dysfunction, either alone or, more frequently, in combination with other organ dysfunction. A clear defintion of renal dysfunction, an accurate differential diagnostic process of its different phenotypes as well as of full understanding of its pathophysiological mechanisms are crucial to the development of strategies for the management of this complication. This article is based either on the more recent knowledge on renal dysfunction in advanced cirrhosis or current opinions among the members of the International Club of Ascites (ICA) on the management of this complication, obtained through a survey and discussed during the EASL‐ICA Joint Meeting in Berlin in March 2011. It reviews critically our current knowledge and it outlines future perspectives, on the management of renal dysfunction in patients with cirrhosis.