title: Terlipressin Plus Albumin Is More Effective Than Albumin Alone in Improving Renal Function in Patients With Cirrhosis and Hepatorenal Syndrome Type 1.
abstract: OBJECTIVE
  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 (r(2) = .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.
authors.affiliation: Department of Medicine, University of Arizona, Tucson, Arizona. Electronic address: tboyer@deptofmed.arizona.edu.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Boyer
authors.affiliation: Department of Medicine, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Arun J
authors.initials: AJ
authors.lastname: Sanyal
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Florence
authors.initials: F
authors.lastname: Wong
authors.affiliation: Department of Medicine, California Pacific Medical Center, San Francisco, California.
authors.forename: R Todd
authors.initials: RT
authors.lastname: Frederick
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: John R
authors.initials: JR
authors.lastname: Lake
authors.affiliation: Department of Medicine, Baylor University Medical Center, Dallas, Texas.
authors.forename: Jacqueline G
authors.initials: JG
authors.lastname: O'Leary
authors.affiliation: Department of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ganger
authors.affiliation: Ikaria Therapeutics, LLC, a Mallinckrodt Company, Hampton, New Jersey.
authors.forename: Khurram
authors.initials: K
authors.lastname: Jamil
authors.affiliation: Orphan Therapeutics, Lebanon, New Jersey.
authors.forename: Stephen Chris
authors.initials: SC
authors.lastname: Pappas
mesh_terms: D000328:Adult; D000418:Albumins / Q000008:administration & dosage*; D002170:Canada; D004359:Drug Therapy, Combination; D005260:Female; D006530:Hepatorenal Syndrome / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D007677:Kidney Function Tests; D008103:Liver Cirrhosis / Q000150:complications*; D008236:Lypressin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008297:Male; D008875:Middle Aged; D000077585:Terlipressin; D016896:Treatment Outcome; D014662:Vasoconstrictor Agents / Q000008:administration & dosage*
chemical_list: D000418:Albumins; D014662:Vasoconstrictor Agents; D008236:Lypressin; D000077585:Terlipressin
keywords: Acute Kidney Injury; Clinical Trial; Large-Volume Paracentesis; REVERSE Study