Terlipressin for Hepatorenal Syndrome in Patients With Early‐Stage Acute‐on‐Chronic Liver Failure

BACKGROUND & AIMS: Hepatorenal syndrome-acute kidney injury (HRS-AKI) is a life-threatening complication of decompensated cirrhosis. The US Food and Drug Administration approved terlipressin use for HRS-AKI based on the CONFIRM study, which demonstrated a significant improvement in HRS reversal with terlipressin versus placebo. The label notes elevated risk of respiratory failure in patients with volume overload or acute-on-chronic liver failure (ACLF) grade 3 and limited benefit when serum creatinine (SCr) exceeds 5 mg/dL. METHODS: We performed a post hoc analysis of CONFIRM excluding patients with ACLF grade 3 or SCr ≥ 5 mg/dL. This allowed us to assess the efficacy and safety of terlipressin in a population where the benefit-to-risk profile is more favourable. Efficacy outcomes included HRS reversal, renal replacement therapy (RRT), liver transplantation (LT), RRT-free survival, LT-free survival and overall survival. Changes in SCr, Model for End Stage Liver Disease (MELD) and sodium were also assessed. RESULTS: HRS reversal occurred in 43% (60/141) of patients with terlipressin versus 17% (13/75) with placebo (p < 0.001). Terlipressin was associated with significantly larger reductions (vs. placebo) in SCr (p < 0.001) and increases in serum sodium (p < 0.001). Importantly, LT rates were similar even though MELD scores decreased. 90-day survival was similar between treatment arms. Notably, selecting patients with a favourable benefit-to-risk profile led to a similar incidence of respiratory failure between treatment arms (11% with terlipressin vs. 7% with placebo; p = 0.360). CONCLUSIONS: In patients with HRS-AKI without baseline ACLF grade 3 or SCr ≥ 5 mg/dL, terlipressin improved clinical outcomes and was not associated with an increased risk of respiratory failure. TRIAL REGISTRATION: CONFIRM, ClinicalTrials.gov identifier: NCT02770716.