Early treatment with terlipressin in patients with hepatorenal syndrome yields improved clinical outcomes in North American studies

Abstract

Hepatorenal syndrome type 1 (HRS-1) is a serious complication of advanced cirrhosis and a potentially reversible form of acute kidney injury that is associated with rapidly deteriorating kidney function. Liver transplantation remains the only curative treatment for decompensated cirrhosis. However, terlipressin, a vasopressin analog, successfully reverses HRS-1, and may improve patient survival while awaiting liver transplantation. Patients with higher baseline serum creatinine have a reduced response to treatment with terlipressin. These post hoc analyses examined pooled data from 352 patients with HRS-1 treated with terlipressin in 3 North American-centric, Phase III, placebo-controlled clinical studies (i.e. OT-0401, REVERSE, and CONFIRM)-across 3 serum creatinine subgroups (i.e. <3, ≥3-<5, and ≥5 mg/dL)-to further delineate their correlation with HRS reversal, renal replacement therapy-free survival, and overall survival. Serum creatinine was significantly associated with HRS reversal in univariate and multivariate logistic regression analyses (P<0.001). The incidence of HRS reversal inversely correlated with serum creatinine subgroup (<3 mg/dL, 49.2%; ≥3-<5 mg/dL, 28.0%; ≥5 mg/dL, 9.1%). At Day 30 follow-up, renal replacement therapy-free survival was significantly higher for patients with HRS-1 in the lower serum creatinine subgroups than in the higher subgroup (<5 vs. >5 mg/dL; p=0.01). Terlipressin-treated patients with HRS-1, with a lower baseline serum creatinine level, had a higher overall survival (p<0.001) and higher transplant-free survival at Day 90 (p=0.04). Patients with HRS-1 and lower serum creatinine levels who were treated with terlipressin had higher HRS reversal and survival outcomes, highlighting the significant need to identify and treat patients with HRS-1 early when they often have lower serum creatinine levels, and likely a greater response to terlipressin.

Trial registration: ClinicalTrials.gov NCT02770716 NCT00089570 NCT01143246.

FIGURE 1

Percent of patients in the terlipressin treatment group who had HRS reversal^a by baseline serum creatinine subgroup (terlipressin group, pooled ITT population^b). ^aThe incidence of HRS reversal across the 3 Phase III studies was defined as at least 1 serum creatinine value of ≤1.5 mg/dL while on treatment (on treatment was defined as up to 24 h after the final dose of study drug) by Day 14 or discharge. ^†Pooled data were collated from the following Phase III studies: OT-0401, REVERSE, and CONFIRM. Abbreviations: HRS indicates hepatorenal syndrome; ITT, intent-to-treat.

FIGURE 2

Percent of patients at each follow-up visit (Day 30, 60, 90) who were alive without RRT by baseline serum creatinine subgroup (terlipressin group, pooled ITT population^a). ^aPooled data were collated from the following Phase III studies: OT-0401, REVERSE, and CONFIRM. ^bThe p value is based on comparison of baseline serum creatinine categories at Day 30; p=0.01. Abbreviations: ITT indicates intent-to-treat; RRT, renal replacement therapy.

FIGURE 3

Overall survival up to 90 days by baseline serum creatinine subgroup (terlipressin group, pooled ITT population^a). ^aPooled data were collated from the following Phase III studies: OT-0401, REVERSE, and CONFIRM. The p value was calculated using a log-rank test comparing the 3 baseline categories of serum creatinine. Abbreviations: ITT indicates intent-to-treat.

FIGURE 4

Transplant-free survival^a up to 90 days using cumulative incidence function with competing risks of transplant and death by baseline serum creatinine subgroup (terlipressin group, pooled ITT population^b). ^aA Fine and Gray proportional hazards model was used to produce cumulative incidence function estimates of transplant-free survival, with transplant as a competing risk for death. ^bPooled data were collated from the following Phase III studies: OT-0401, REVERSE, and CONFIRM. ITT indicates intent-to-treat.