Elsa Solà1, Cristina Solé1, Macarena Simón-Talero2, Marta Martín-Llahí3, José Castellote4, Rita Garcia-Martínez5, Rebeca Moreira6, Maria Torrens5, Francisca Márquez7, Núria Fabrellas1, Gloria de Prada3, Patrícia Huelin3, Eva Lopez Benaiges1, Meritxell Ventura2, Marcela Manríquez8, André Nazar6, Xavier Ariza1, Pilar Suñé9, Isabel Graupera1, Elisa Pose1, Jordi Colmenero1, Marco Pavesi10, Mónica Guevara1, Miquel Navasa1, Xavier Xiol4, Joan Córdoba11, Victor Vargas11, Pere Ginès12. 1. Liver Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain. 2. Liver Unit, Hospital Vall d'Hebron, Barcelona, Spain. 3. Liver Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain. 4. Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain; Liver Unit, Gastroenterology Department, Hospital Universitari de Bellvitge, Institut Català de la Salut, L'Hospitalet de Llobregat, Barcelona, Spain; Grup de Recerca en malalties hepato-bilio-pancreàtiques, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. 5. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. 6. Liver Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. 7. Liver Unit, Gastroenterology Department, Hospital Universitari de Bellvitge, Institut Català de la Salut, L'Hospitalet de Llobregat, Barcelona, Spain. 8. Institut d'Investigació Mèdica de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain; Clinical Research Support Unit, Hospital Universitari de Bellvitge, L'Hospitalet de LLobregat, Barcelona, Spain. 9. Clinical Trials Unit, Pharmacy Department, Hospital Vall d'Hebron, Barcelona, Spain. 10. Data Management Center, EF-CLIF, Barcelona, Spain. 11. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain; Liver Unit, Hospital Vall d'Hebron, Barcelona, Spain. 12. Liver Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain. Electronic address: pgines@clinic.cat.
Abstract
BACKGROUND & AIMS:Patients with decompensated cirrhosis on the waiting list for liver transplantation (LT) commonly develop complications that may preclude them from reaching LT. Circulatory dysfunction leading to effective arterial hypovolemia and activation of vasoconstrictor systems is a key factor in the pathophysiology of complications of cirrhosis. The aim of this study was to investigate whether treatment with midodrine, an alpha-adrenergic vasoconstrictor, together with intravenous albumin improves circulatory dysfunction and prevents complications of cirrhosis in patients awaiting LT. METHODS: A multicenter, randomized, double-blind, placebo-controlled trial (NCT00839358) was conducted, including 196 consecutive patients with cirrhosis and ascites awaiting LT. Patients were randomly assigned to receive midodrine (15-30 mg/day) and albumin (40 g/15 days) or matching placebos for one year, until LT or drop-off from inclusion on the waiting list. The primary endpoint was incidence of any complication (renal failure, hyponatremia, infections, hepatic encephalopathy or gastrointestinal bleeding). Secondary endpoints were mortality, activity of endogenous vasoconstrictor systems and plasma cytokine levels. RESULTS: There were no significant differences between both groups in the probability of developing complications of cirrhosis during follow-up (p = 0.402) or one-year mortality (p = 0.527). Treatment with midodrine and albumin was associated with a slight but significant decrease in plasma renin activity and aldosterone compared to placebo (renin -4.3 vs. 0.1 ng/ml.h, p < 0.001; aldosterone -38 vs. 6 ng/dl, p = 0.02, at week 48 vs. baseline). Plasma norepinephrine only decreased slightly at week 4. Neither arterial pressure nor plasma cytokine levels changed significantly. CONCLUSIONS: In patients with cirrhosis awaiting LT, treatment with midodrine and albumin, at the doses used in this study, slightly suppressed the activity of vasoconstrictor systems, but did not prevent complications of cirrhosis or improve survival. LAY SUMMARY:Patients with cirrhosis who are on the liver transplant waiting list often develop complications which prevent them from receiving a transplant. Circulatory dysfunction is a key factor behind a number of complications. This study was aimed at investigating whether treating patients with midodrine (a vasoconstrictor) andalbumin would improve circulatory dysfunction and prevent complications. This combined treatment, at least at the doses administered in this study, did not prevent the complications of cirrhosis or improve the survival of these patients.
RCT Entities:
BACKGROUND & AIMS:Patients with decompensated cirrhosis on the waiting list for liver transplantation (LT) commonly develop complications that may preclude them from reaching LT. Circulatory dysfunction leading to effective arterial hypovolemia and activation of vasoconstrictor systems is a key factor in the pathophysiology of complications of cirrhosis. The aim of this study was to investigate whether treatment with midodrine, an alpha-adrenergic vasoconstrictor, together with intravenous albumin improves circulatory dysfunction and prevents complications of cirrhosis in patients awaiting LT. METHODS: A multicenter, randomized, double-blind, placebo-controlled trial (NCT00839358) was conducted, including 196 consecutive patients with cirrhosis and ascites awaiting LT. Patients were randomly assigned to receive midodrine (15-30 mg/day) and albumin (40 g/15 days) or matching placebos for one year, until LT or drop-off from inclusion on the waiting list. The primary endpoint was incidence of any complication (renal failure, hyponatremia, infections, hepatic encephalopathy or gastrointestinal bleeding). Secondary endpoints were mortality, activity of endogenous vasoconstrictor systems and plasma cytokine levels. RESULTS: There were no significant differences between both groups in the probability of developing complications of cirrhosis during follow-up (p = 0.402) or one-year mortality (p = 0.527). Treatment with midodrine and albumin was associated with a slight but significant decrease in plasma renin activity and aldosterone compared to placebo (renin -4.3 vs. 0.1 ng/ml.h, p < 0.001; aldosterone -38 vs. 6 ng/dl, p = 0.02, at week 48 vs. baseline). Plasma norepinephrine only decreased slightly at week 4. Neither arterial pressure nor plasma cytokine levels changed significantly. CONCLUSIONS: In patients with cirrhosis awaiting LT, treatment with midodrine and albumin, at the doses used in this study, slightly suppressed the activity of vasoconstrictor systems, but did not prevent complications of cirrhosis or improve survival. LAY SUMMARY:Patients with cirrhosis who are on the liver transplant waiting list often develop complications which prevent them from receiving a transplant. Circulatory dysfunction is a key factor behind a number of complications. This study was aimed at investigating whether treating patients with midodrine (a vasoconstrictor) and albumin would improve circulatory dysfunction and prevent complications. This combined treatment, at least at the doses administered in this study, did not prevent the complications of cirrhosis or improve the survival of these patients.
Authors: Amine Benmassaoud; Suzanne C Freeman; Davide Roccarina; Maria Corina Plaz Torres; Alex J Sutton; Nicola J Cooper; Laura Iogna Prat; Maxine Cowlin; Elisabeth Jane Milne; Neil Hawkins; Brian R Davidson; Chavdar S Pavlov; Douglas Thorburn; Emmanuel Tsochatzis; Kurinchi Selvan Gurusamy Journal: Cochrane Database Syst Rev Date: 2020-01-16
Authors: Manuel Tufoni; Giacomo Zaccherini; Paolo Caraceni; Mauro Bernardi Journal: United European Gastroenterol J Date: 2020-02-26 Impact factor: 4.623