Background & Aims Hepatorenal syndrome type 1 (HRS-1) in patients with cirrhosis and ascites is a functional, potentially reversible, form of acute kidney injury characterized by rapid (<2 wk) and progressive deterioration of renal function. Terlipressin is a synthetic vasopressin analogue that acts, via vascular vasopressin V1 receptors, as a systemic vasoconstrictor. We performed a phase 3 study to evaluate the efficacy and safety of intravenous terlipressin plus albumin vs placebo plus albumin in patients with HRS-1. Methods Adult patients with cirrhosis, ascites, and HRS-1 (based on the 2007 International Club of Ascites criteria of rapidly deteriorating renal function) were assigned randomly to groups given intravenous terlipressin (1 mg, n = 97) or placebo (n = 99) every 6 hours with concomitant albumin. Treatment continued through day 14 unless the following occurred: confirmed HRS reversal (CHRSR, defined as 2 serum creatinine [SCr] values ≤1.5 mg/dL, at least 40 hours apart, on treatment without renal replacement therapy or liver transplantation) or SCr at or above baseline on day 4. The primary end point was the percentage of patients with confirmed CHRSR. Secondary end points included the incidence of HRS reversal (defined as at least 1 SCr value ≤1.5 mg/dL while on treatment), transplant-free survival, and overall survival. The study was performed at 50 investigational sites in the United States and 2 in Canada, from October 2010 through February 2013. Results Baseline demographic/clinical characteristics were similar between groups. CHRSR was observed in 19 of 97 patients (19.6%) receiving terlipressin vs 13 of 99 patients (13.1%) receiving placebo (P =.22). HRS reversal was achieved in 23 of 97 (23.7%) patients receiving terlipressin vs 15 of 99 (15.2%) receiving placebo (P =.13). SCr decreased by 1.1 mg/dL in patients receiving terlipressin and by only 0.6 mg/dL in patients receiving placebo (P <.001). Decreases in SCr and survival were correlated (r2 =.882; P <.001). Transplant-free and overall survival were similar between groups. A significantly greater proportion of patients with CHRSR who received terlipressin survived until day 90 than patients who did not have CHRSR after receiving terlipressin (P <.001); this difference was not observed in patients who did vs did not have CHRSR after receiving placebo (P =.28). There were similar numbers of adverse events in each group, but patients in the terlipressin group had more ischemic events. Conclusions Terlipressin plus albumin was associated with greater improvement in renal function vs albumin alone in patients with cirrhosis and HRS-1. Patients had similar rates of HRS reversal with terlipressin as they did with albumin. ClinicalTrials.gov no: NCT01143246.
Bibliographical noteFunding Information:
Conflicts of interest These authors disclose the following: Thomas D. Boyer is a consultant for Ikaria Therapeutics, LLC, a Mallinckrodt Company; Arun J. Sanyal has stock options in Genfit, has served as a consultant for AbbVie, Inc, AstraZeneca, Exalenz Bioscience, Ltd, FibroGen, Inc, Genfit, Immuron, Ltd, Ikaria Therapeutics LLC, a Mallinckrodt Company, Nimbus Therapeutics, Nitto Denko Corporation, Salix Pharmaceuticals, Takeda Pharmaceuticals, and Tobira Therapeutics, has been an unpaid consultant for Echosens and Intercept Pharmaceuticals, and his institution has received grant support from Exalenz Bioscience, Ltd, Gilead Sciences, Inc, Ikaria Therapeutics LLC, a Mallinckrodt Company, Novartis Pharmaceuticals Corporation, Salix Pharmaceuticals, and Tobira Therapeutics; Florence Wong is a consultant for Ikaria Therapeutics LLC, a Mallinckrodt Company, has served on the advisory board for Grifols, Inc, and has received grant support from Gilead Sciences, Inc; R. Todd Frederick has served as a consultant for AbbVie, Inc, Bristol-Myers Squibb, Gilead Sciences, Inc, Salix Pharmaceuticals, and Vital Therapies, Inc; John R. Lake has served as a consultant for AbbVie, Inc, Bristol-Myers Squibb, Novartis Pharmaceuticals Corporation, and Vital Therapies, Inc, has received research grant support from Cumberland Pharmaceuticals, Eisai, Inc, Gilead Sciences, Inc, Ocera Therapeutics, and Salix Pharmaceuticals, and has received speaking fees from Gilead Sciences, Inc, and Novartis Pharmaceuticals Corporation; Jacqueline G. O’Leary has served on an advisory board for Grifols, Inc, has served as a consultant for Novartis Pharmaceuticals Corporation and Astellas, and has served as a consultant and received speaking fees from Gilead Sciences, Inc, and AbbVie Inc; Khurram Jamil is an employee of Ikaria Therapeutics LLC, a Mallinckrodt Company; and Stephen Chris Pappas is a consultant for Orphan Therapeutics and Ikaria Therapeutics LLC, a Mallinckrodt Company. The remaining author disclose no conflicts.
Funding This study was sponsored by Ikaria Therapeutics, LLC, a Mallinckrodt Company. The sponsor participated in the design and conduct of the study, interpretation of study data, and writing of this report.
© 2016 AGA Institute.
- Acute Kidney Injury
- Clinical Trial
- Large-Volume Paracentesis
- REVERSE Study