Terlipressin Plus Albumin Is More Effective Than Albumin Alone in Improving Renal Function in Patients with Cirrhosis and Hepatorenal Syndrome Type 1

Thomas D. Boyer, Arun J. Sanyal, Florence Wong, R. Todd Frederick, John R. Lake, Jacqueline G. O'Leary, Daniel Ganger, Khurram Jamil, Stephen Chris Pappas, Samuel H. Sigal, Santiago J. Munoz, Vishal Patel, Paul Y. Kwo, Jasmohan S. Bajaj, Tarek I. Hassanein, Kirti Shetty, Rohit Satoskar, K. Rajender Reddy, Marlyn Mayo, Victor ArayaNikroo Hashemi, Eyob Feyssa, Lorenzo Rossaro, David Kravetz, Priya Grewal, Ram Subramanian, Kevin Korenblat, Yuri Stepanovich Genyk, Fredric Regenstein, Joseph F. Buell, Nathan J. Shores, Sukru H. Emre, Andrea Duchini, Atif Zaman, Marco Antonio Olivera-Martinez, Michael K. Porayko, Alex S. Befeler, K. Gautham Reddy, Maria Del Pilar Hernandez, Stephen D. Zucker, Hugo E. Vargas, Michael Curry, Adnan Said, Kris V. Kowdley, Terry Box, David Shields Barnes, Marie Noëlle Pépin, Madhavi Rudraraju, Paul Angulo, Howard P. Monsour, David Wolf, Charles Howell, Fredric G. Regenstein, Antonio Sanchez, Hany Elbeshbeshy, Michael B. Fallon, Colin Swales, David A. Sass, Eva Urtasun Sotil, Brendan McGuire, Richard K. Gilroy, Juan A. Guerrero, Mark N. Wong, Obaid Shaikh, Stevan Gonzalez, Zeid Kayali

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1579-1589.e2
JournalGastroenterology
Volume150
Issue number7
DOIs
StatePublished - Jun 1 2016

Keywords

  • Acute Kidney Injury
  • Clinical Trial
  • Large-Volume Paracentesis
  • REVERSE Study

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Boyer, T. D., Sanyal, A. J., Wong, F., Frederick, R. T., Lake, J. R., O'Leary, J. G., Ganger, D., Jamil, K., Pappas, S. C., Sigal, S. H., Munoz, S. J., Patel, V., Kwo, P. Y., Bajaj, J. S., Hassanein, T. I., Shetty, K., Satoskar, R., Reddy, K. R., Mayo, M., ... Kayali, Z. (2016). Terlipressin Plus Albumin Is More Effective Than Albumin Alone in Improving Renal Function in Patients with Cirrhosis and Hepatorenal Syndrome Type 1. Gastroenterology, 150(7), 1579-1589.e2. https://doi.org/10.1053/j.gastro.2016.02.026