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 A 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

Research output: Contribution to journalArticle

68 Citations (Scopus)

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

Fingerprint

Hepatorenal Syndrome
Albumins
Fibrosis
Kidney
Placebos
Creatinine
Ascites
Vasopressin Receptors
Serum
Survival
terlipressin
Transplants
Renal Replacement Therapy
Vasoconstrictor Agents

Keywords

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

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Terlipressin Plus Albumin Is More Effective Than Albumin Alone in Improving Renal Function in Patients with Cirrhosis and Hepatorenal Syndrome Type 1. / Boyer, Thomas D.; Sanyal, Arun J.; Wong, Florence; Frederick, R. Todd; Lake, John R.; O'Leary, Jacqueline G.; Ganger, Daniel; Jamil, Khurram; Pappas, Stephen Chris; Sigal, Samuel H.; Munoz, Santiago J.; Patel, Vishal; Kwo, Paul Y.; Bajaj, Jasmohan S.; Hassanein, Tarek I.; Shetty, Kirti; Satoskar, Rohit; Reddy, K. Rajender; Mayo, Marlyn; Araya, Victor; Hashemi, Nikroo; Feyssa, Eyob; Rossaro, Lorenzo; Kravetz, David; Grewal, Priya; Subramanian, Ram; Korenblat, Kevin; Genyk, Yuri Stepanovich; Regenstein, Fredric; Buell, Joseph F.; Shores, Nathan J.; Emre, Sukru H.; Duchini, Andrea; Zaman, Atif; Olivera-Martinez, Marco A; Porayko, Michael K.; Befeler, Alex S.; Reddy, K. Gautham; Del Pilar Hernandez, Maria; Zucker, Stephen D.; Vargas, Hugo E.; Curry, Michael; Said, Adnan; Kowdley, Kris V.; Box, Terry; Barnes, David Shields; Pépin, Marie Noëlle; Rudraraju, Madhavi; Angulo, Paul; Monsour, Howard P.; Wolf, David; Howell, Charles; Regenstein, Fredric G.; Sanchez, Antonio; Elbeshbeshy, Hany; Fallon, Michael B.; Swales, Colin; Sass, David A.; Sotil, Eva Urtasun; McGuire, Brendan; Gilroy, Richard K.; Guerrero, Juan A.; Wong, Mark N.; Shaikh, Obaid; Gonzalez, Stevan; Kayali, Zeid.

In: Gastroenterology, Vol. 150, No. 7, 01.06.2016, p. 1579-1589.e2.

Research output: Contribution to journalArticle

Boyer, TD, Sanyal, AJ, Wong, F, Frederick, RT, Lake, JR, O'Leary, JG, Ganger, D, Jamil, K, Pappas, SC, Sigal, SH, Munoz, SJ, Patel, V, Kwo, PY, Bajaj, JS, Hassanein, TI, Shetty, K, Satoskar, R, Reddy, KR, Mayo, M, Araya, V, Hashemi, N, Feyssa, E, Rossaro, L, Kravetz, D, Grewal, P, Subramanian, R, Korenblat, K, Genyk, YS, Regenstein, F, Buell, JF, Shores, NJ, Emre, SH, Duchini, A, Zaman, A, Olivera-Martinez, MA, Porayko, MK, Befeler, AS, Reddy, KG, Del Pilar Hernandez, M, Zucker, SD, Vargas, HE, Curry, M, Said, A, Kowdley, KV, Box, T, Barnes, DS, Pépin, MN, Rudraraju, M, Angulo, P, Monsour, HP, Wolf, D, Howell, C, Regenstein, FG, Sanchez, A, Elbeshbeshy, H, Fallon, MB, Swales, C, Sass, DA, Sotil, EU, McGuire, B, Gilroy, RK, Guerrero, JA, Wong, MN, Shaikh, O, Gonzalez, S & 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, vol. 150, no. 7, pp. 1579-1589.e2. https://doi.org/10.1053/j.gastro.2016.02.026
Boyer, Thomas D. ; Sanyal, Arun J. ; Wong, Florence ; Frederick, R. Todd ; Lake, John R. ; O'Leary, Jacqueline G. ; Ganger, Daniel ; Jamil, Khurram ; Pappas, Stephen Chris ; Sigal, Samuel H. ; Munoz, Santiago J. ; Patel, Vishal ; Kwo, Paul Y. ; Bajaj, Jasmohan S. ; Hassanein, Tarek I. ; Shetty, Kirti ; Satoskar, Rohit ; Reddy, K. Rajender ; Mayo, Marlyn ; Araya, Victor ; Hashemi, Nikroo ; Feyssa, Eyob ; Rossaro, Lorenzo ; Kravetz, David ; Grewal, Priya ; Subramanian, Ram ; Korenblat, Kevin ; Genyk, Yuri Stepanovich ; Regenstein, Fredric ; Buell, Joseph F. ; Shores, Nathan J. ; Emre, Sukru H. ; Duchini, Andrea ; Zaman, Atif ; Olivera-Martinez, Marco A ; Porayko, Michael K. ; Befeler, Alex S. ; Reddy, K. Gautham ; Del Pilar Hernandez, Maria ; Zucker, Stephen D. ; Vargas, Hugo E. ; Curry, Michael ; Said, Adnan ; Kowdley, Kris V. ; Box, Terry ; Barnes, David Shields ; Pépin, Marie Noëlle ; Rudraraju, Madhavi ; Angulo, Paul ; Monsour, Howard P. ; Wolf, David ; Howell, Charles ; Regenstein, Fredric G. ; Sanchez, Antonio ; Elbeshbeshy, Hany ; Fallon, Michael B. ; Swales, Colin ; Sass, David A. ; Sotil, Eva Urtasun ; McGuire, Brendan ; Gilroy, Richard K. ; Guerrero, Juan A. ; Wong, Mark N. ; Shaikh, Obaid ; Gonzalez, Stevan ; Kayali, Zeid. / Terlipressin Plus Albumin Is More Effective Than Albumin Alone in Improving Renal Function in Patients with Cirrhosis and Hepatorenal Syndrome Type 1. In: Gastroenterology. 2016 ; Vol. 150, No. 7. pp. 1579-1589.e2.
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title = "Terlipressin Plus Albumin Is More Effective Than Albumin Alone in Improving Renal Function in Patients with Cirrhosis and Hepatorenal Syndrome Type 1",
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.",
keywords = "Acute Kidney Injury, Clinical Trial, Large-Volume Paracentesis, REVERSE Study",
author = "Boyer, {Thomas D.} and Sanyal, {Arun J.} and Florence Wong and Frederick, {R. Todd} and Lake, {John R.} and O'Leary, {Jacqueline G.} and Daniel Ganger and Khurram Jamil and Pappas, {Stephen Chris} and Sigal, {Samuel H.} and Munoz, {Santiago J.} and Vishal Patel and Kwo, {Paul Y.} and Bajaj, {Jasmohan S.} and Hassanein, {Tarek I.} and Kirti Shetty and Rohit Satoskar and Reddy, {K. Rajender} and Marlyn Mayo and Victor Araya and Nikroo Hashemi and Eyob Feyssa and Lorenzo Rossaro and David Kravetz and Priya Grewal and Ram Subramanian and Kevin Korenblat and Genyk, {Yuri Stepanovich} and Fredric Regenstein and Buell, {Joseph F.} and Shores, {Nathan J.} and Emre, {Sukru H.} and Andrea Duchini and Atif Zaman and Olivera-Martinez, {Marco A} and Porayko, {Michael K.} and Befeler, {Alex S.} and Reddy, {K. Gautham} and {Del Pilar Hernandez}, Maria and Zucker, {Stephen D.} and Vargas, {Hugo E.} and Michael Curry and Adnan Said and Kowdley, {Kris V.} and Terry Box and Barnes, {David Shields} and P{\'e}pin, {Marie No{\"e}lle} and Madhavi Rudraraju and Paul Angulo and Monsour, {Howard P.} and David Wolf and Charles Howell and Regenstein, {Fredric G.} and Antonio Sanchez and Hany Elbeshbeshy and Fallon, {Michael B.} and Colin Swales and Sass, {David A.} and Sotil, {Eva Urtasun} and Brendan McGuire and Gilroy, {Richard K.} and Guerrero, {Juan A.} and Wong, {Mark N.} and Obaid Shaikh and Stevan Gonzalez and Zeid Kayali",
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language = "English (US)",
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pages = "1579--1589.e2",
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TY - JOUR

T1 - Terlipressin Plus Albumin Is More Effective Than Albumin Alone in Improving Renal Function in Patients with Cirrhosis and Hepatorenal Syndrome Type 1

AU - Boyer, Thomas D.

AU - Sanyal, Arun J.

AU - Wong, Florence

AU - Frederick, R. Todd

AU - Lake, John R.

AU - O'Leary, Jacqueline G.

AU - Ganger, Daniel

AU - Jamil, Khurram

AU - Pappas, Stephen Chris

AU - Sigal, Samuel H.

AU - Munoz, Santiago J.

AU - Patel, Vishal

AU - Kwo, Paul Y.

AU - Bajaj, Jasmohan S.

AU - Hassanein, Tarek I.

AU - Shetty, Kirti

AU - Satoskar, Rohit

AU - Reddy, K. Rajender

AU - Mayo, Marlyn

AU - Araya, Victor

AU - Hashemi, Nikroo

AU - Feyssa, Eyob

AU - Rossaro, Lorenzo

AU - Kravetz, David

AU - Grewal, Priya

AU - Subramanian, Ram

AU - Korenblat, Kevin

AU - Genyk, Yuri Stepanovich

AU - Regenstein, Fredric

AU - Buell, Joseph F.

AU - Shores, Nathan J.

AU - Emre, Sukru H.

AU - Duchini, Andrea

AU - Zaman, Atif

AU - Olivera-Martinez, Marco A

AU - Porayko, Michael K.

AU - Befeler, Alex S.

AU - Reddy, K. Gautham

AU - Del Pilar Hernandez, Maria

AU - Zucker, Stephen D.

AU - Vargas, Hugo E.

AU - Curry, Michael

AU - Said, Adnan

AU - Kowdley, Kris V.

AU - Box, Terry

AU - Barnes, David Shields

AU - Pépin, Marie Noëlle

AU - Rudraraju, Madhavi

AU - Angulo, Paul

AU - Monsour, Howard P.

AU - Wolf, David

AU - Howell, Charles

AU - Regenstein, Fredric G.

AU - Sanchez, Antonio

AU - Elbeshbeshy, Hany

AU - Fallon, Michael B.

AU - Swales, Colin

AU - Sass, David A.

AU - Sotil, Eva Urtasun

AU - McGuire, Brendan

AU - Gilroy, Richard K.

AU - Guerrero, Juan A.

AU - Wong, Mark N.

AU - Shaikh, Obaid

AU - Gonzalez, Stevan

AU - Kayali, Zeid

PY - 2016/6/1

Y1 - 2016/6/1

N2 - 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.

AB - 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.

KW - Acute Kidney Injury

KW - Clinical Trial

KW - Large-Volume Paracentesis

KW - REVERSE Study

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U2 - 10.1053/j.gastro.2016.02.026

DO - 10.1053/j.gastro.2016.02.026

M3 - Article

C2 - 26896734

AN - SCOPUS:84971377051

VL - 150

SP - 1579-1589.e2

JO - Gastroenterology

JF - Gastroenterology

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