Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies

Abstract

Background: The goal of hepatorenal syndrome type 1 (HRS-1) treatment is to improve renal function. Terlipressin, a synthetic vasopressin analogue, is a systemic vasoconstrictor used for the treatment of HRS-1, where it is available.

Aim: To compare the efficacy of terlipressin plus albumin vs. placebo plus albumin in patients with HRS-1.

Methods: Pooled patient-level data from two large phase 3, randomised, placebo-controlled studies were analysed for HRS reversal [serum creatinine (SCr) value ≤133 μmol/L], 90-day survival, need for renal replacement therapy and predictors of HRS reversal. Patients received intravenous terlipressin 1-2 mg every 6 hours plus albumin or placebo plus albumin up to 14 days.

Results: The pooled analysis comprised 308 patients (terlipressin: n = 153; placebo: n = 155). HRS reversal was significantly more frequent with terlipressin vs. placebo (27% vs. 14%; P = 0.004). Terlipressin was associated with a more significant improvement in renal function from baseline until end of treatment, with a mean between-group difference in SCr concentration of -53.0 μmol/L (P < 0.0001). Lower SCr, lower mean arterial pressure and lower total bilirubin and absence of known precipitating factors for HRS were independent predictors of HRS reversal and longer survival in terlipressin-treated patients.

Conclusions: Terlipressin plus albumin resulted in a significantly higher rate of HRS reversal vs. albumin alone in patients with HRS-1. Terlipressin treatment is associated with improved renal function. (ClinicalTrials.gov identifier: OT-0401, NCT00089570; REVERSE, NCT01143246).

Figure 1

Patient disposition in the (a) OT‐0401 and (b) REVERSE studies. The REVERSE study patient disposition is reprinted from Gastroenterology, 150, Boyer TD, Sanyal AJ, Wong F, et al., Terlipressin plus albumin is more effective than albumin alone in improving renal function in patients with cirrhosis and hepatorenal syndrome type 1, 1579–1589, copyright 2016, with permission from Elsevier.

Figure 2

Incidence of hepatorenal syndrome reversal in the pooled analysis and in the individual OT‐0401 and REVERSE studies. * P = 0.008 vs. placebo. ^† P = 0.004 vs. placebo.

Figure 3

Mean change in serum creatinine from baseline to the end of treatment in the pooled analysis of the OT‐0401 and REVERSE studies. LS, least‐squares mean; SE, standard error.

Figure 4

(a) Transplant‐free survival up to 90 days in the overall pooled population from the OT‐0401 and REVERSE studies (intent‐to‐treat population); (b) overall survival up to 90 days in the overall pooled population from the OT‐0401 and REVERSE studies (intent‐to‐treat population); (c) transplant‐free survival up to 90 days in the pooled population from the OT‐0401 and REVERSE studies stratified by HRS reversal status and treatment arm; and (d) overall survival up to 90 days in pooled population from the OT‐0401 and REVERSE studies stratified by HRS reversal status and treatment arm.

Figure 5

(a) Cumulative incidence of RRT in the pooled terlipressin and placebo populations from the OT‐0401 and REVERSE studies. (b) Proportion of patients alive at day 90 with HRS reversal without RRT. RRT, renal replacement therapy.