Searching for therapies for advanced cirrhosis

Abstract

818–828 (2021) high mortality associated with cirrhosis has changed little over the years Two new multicentre, randomized clinical trials report mixed results for the management of decompensated cirrhosis, showing no benefit of daily albumin infusions in this setting (ATTIRE trial) but that terlipressin was efficacious for the treatment of type 1 hepatorenal syndrome (HRS; CONFIRM study). Both trials reported potentially concerning serious adverse events, particularly related to pulmonary complications. In the openlabel, parallelgroup ATTIRE trial, 777 hospitalized patients with decompensated cirrhosis (the majority owing to alcohol) and serum albumin levels <30 g/l were randomly assigned to receive either targeted 20% human albumin solution daily for up to 14 days or until discharge to increase serum albumin levels to >30 g/l (n = 380), or standard care in the UK (albumin infusions for draining ascites or renal failure; n = 397). The composite primary end point was new infection, kidney dysfunction or death between days 3 and 15 after treatment initiation. Crucially, there was no statistically significant difference between the percentage of patients with a primary end point event in the targeted albumin group and the standard care group (29.7% versus 30.2%). Furthermore, more severe or lifethreatening serious adverse events (including pulmonary oedema) occurred in the albumin group than the standard care group. “Prior to ATTIRE, it was widely believed that albumin was the most appropriate fluid for resuscitation in hospitalized cirrhosis patients,” explain authors Louise China and Alastair O’Brien. “These data strongly support both the need to abandon the use of this costly therapy, and a reappraisal of our understanding of this complex condition,” they add, noting that the high mortality associated with cirrhosis has changed little over the years and calling for renewed focus on preventing the major causes of liver disease, excessive alcohol consumption and obesity. In the phase 3 CONFIRM trial, 300 patients with cirrhosis and type 1 HRS were randomly assigned in a 2:1 ratio to receive terlipressin (a vasoconstrictor; n = 199) or placebo (n = 101) for up to 14 days, with concomitant use of albumin strongly recommended in both groups. The primary end point was verified reversal of HRS. “Terlipressin, despite being a very old drug, is not approved in North America for any indication whatsoever,” points out author Florence Wong. “This was the largest randomized controlled trial on the use of terlipressin for the treatment of type 1 HRS.” Importantly, terlipressin was more efficacious than placebo in improving renal function; verified HRS reversal was reported in 32% of the terlipressin group versus 17% in the placebo group (P = 0.006). However, more adverse events (abdominal pain, nausea, diarrhoea or respiratory failure) were reported with terlipressin than placebo. There was no difference in either overall or transplantfree survival, but a higher percentage of patients receiving terlipressin (22 patients, 11%) died within 90 days due to respiratory disorders than those receiving placebo (two patients, 2%). “We clearly need to identify a group of patients with cirrhosis and renal dysfunction who would benefit the most from terlipressin,” notes Wong. “One of the options is to treat patients at a lower level of serum creatinine, say stage 2 acute kidney injury rather than waiting for a fixed threshold of serum creatinine [level] of 2.5 mg/dL to be reached before starting treatment.” Katrina Ray t H e r a P Y