A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome

Abstract

Background & aims: Hepatorenal syndrome (HRS) type 1 is a progressive functional renal failure in subjects with advanced liver disease. The aim of this study was to evaluate the efficacy and safety of terlipressin, a systemic arterial vasoconstrictor, for cirrhosis type 1 HRS.

Methods: A prospective, randomized, double-blind, placebo-controlled clinical trial of terlipressin was performed. Subjects with type 1 HRS were randomized to terlipressin (1 mg intravenously every 6 hours) or placebo plus albumin in both groups. The dose was doubled on day 4 if the serum creatinine (SCr) level did not decrease by 30% of baseline. Treatment was continued to day 14 unless treatment success, death, dialysis, or transplantation occurred. Treatment success was defined by a decrease in SCr level to </=1.5 mg/dL for at least 48 hours by day 14 without dialysis, death, or relapse of HRS type 1.

Results: Fifty-six subjects were randomized to each arm. Treatment success with terlipressin was double that with placebo (25% vs 12.5%, P = .093). SCr level improved from baseline to day 14 on terlipressin (-0.7 mg/dL) as compared with placebo (0 mg/dL), P < .009. Terlipressin was superior to placebo for HRS reversal (34% vs 13%, P = .008), defined by decrease in SCr level </=1.5 mg/dL. Overall and transplantation-free survival was similar between study groups; HRS reversal significantly improved survival at day 180. One nonfatal myocardial infarction occurred with terlipressin, but the total adverse event rate was similar to placebo.

Conclusions: Terlipressin is an effective treatment to improve renal function in HRS type 1.

Trial registration: ClinicalTrials.gov NCT00089570.

Figure 1

Cumulative incidence of HRS reversal by day. Treatment was begun on day 1.

Figure 2

Mean change from baseline in SCr (mg/dL) to end of treatment. Data include all patients in the ITT population at each time point. The mean change from baseline values represents the change from baseline to end of treatment using the last observation carried forward in the ITT population.

Figure 3

Kaplan–Meier plot of overall survival up to day 180. Observations were censored at the last time a patient was known to be alive (represented by open circles).

Figure 4

Overall survival for HRS reversal vs no HRS reversal. Observations were censored at the last time a patient was known to be alive (represented by open circles). All patients are included irrespective of treatment.