Elsevier

Journal of Hepatology

Volume 69, Issue 6, December 2018, Pages 1250-1259
Journal of Hepatology

Research Article
Midodrine and albumin for prevention of complications in patients with cirrhosis awaiting liver transplantation. A randomized placebo-controlled trial

https://doi.org/10.1016/j.jhep.2018.08.006Get rights and content

Highlights

  • Circulatory dysfunction is a key pathogenic factor in complications of cirrhosis.

  • Improvement in circulatory function may prevent complications of cirrhosis.

  • We assessed the effects of the oral vasoconstrictor midodrine associated with albumin.

  • Midodrine plus albumin decreased renin and aldosterone levels.

  • However, midodrine plus albumin did not prevent complications or improve survival.

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.

Introduction

The natural history of decompensated cirrhosis is characterized by the development of recurrent complications of the disease, leading to frequent hospital admissions, impaired quality of life and increased mortality.[1], [2], [3], [4], [5] Liver transplantation (LT) is the definitive treatment for patients with end-stage liver disease. Patients with decompensated cirrhosis achieve good outcomes after LT with three-year survival above 80%.[5], [6], [7], [8] However, one of the major concerns is the development of complications while on the waiting list, which may be a cause of death or may delay or preclude patients with decompensated cirrhosis from receiving LT.[9], [10], [11], [12]

Some strategies have proved to be useful in preventing specific complications of cirrhosis, such as beta-blockers for prevention of gastrointestinal (GI) bleeding, antibiotic prophylaxis for spontaneous bacterial peritonitis (SBP) or addition of rifaximin to lactulose treatment for recurrent hepatic encephalopathy (HE).[6], [13], [14], [15] Nevertheless, these approaches cannot completely prevent the development of these complications, and there are no strategies available to prevent other frequent complications, such as bacterial infections other than SBP, ascites, acute kidney injury or hyponatremia. Therefore, there is an unmet need for effective strategies to prevent the development of complications in patients with decompensated cirrhosis, particularly those on the waiting list for LT, in order to improve outcomes and increase the probability of patients receiving LT.

The common hallmark in the pathophysiology of complications of advanced cirrhosis is circulatory dysfunction, characterized by effective arterial hypovolemia. The reduction in effective arterial blood volume leads to the activation of endogenous vasoconstrictor systems (renin-angiotensin-aldosterone system, sympathetic nervous system, vasopressin) that are responsible for some of the major complications of cirrhosis.[16], [17], [18] Based on this pathophysiological basis, targeting circulatory dysfunction appears to be a promising therapeutic approach to decrease the development of complications.

Vasoconstrictors and albumin have been shown to be useful to improve circulatory function in patients with advanced cirrhosis and, the combination of both drugs is currently the standard of care for the management of hepatorenal syndrome (HRS).[6], [18], [19], [20], [21], [22] There is large amount of evidence showing that albumin is effective in preventing circulatory dysfunction following large-volume paracentesis, HRS in the setting of SBP and for the management of type 1 HRS.[6], [18], [20], [21], [22], [23], [24] There is data showing that the administration of albumin together with diuretics for one year in patients after their first episode of ascites was associated with significantly improved survival;25 but information on the potential benefits of long-term albumin administration is scarce. Besides its oncotic properties, albumin has properties that could also be useful for the prevention of complications of cirrhosis, including antioxidant and immunomodulatory effects, as well as a possible positive impact on endothelial function.26 Midodrine is an alpha-1 agonist that has been shown to improve circulatory and kidney function in patients with cirrhosis and ascites.[27], [28], [29] Compared to other vasoconstrictors, midodrine has the advantage that is active orally and, therefore, could be easily used in a long-term strategy. Three randomized pilot studies, in small patient samples, have been reported assessing the effects of midodrine in patients with cirrhosis and refractory ascites.[30], [31], [32] These studies showed that the administration of midodrine was associated with an improvement of systemic hemodynamics and better control of ascites; however, they failed to demonstrate improvement of other complications of cirrhosis. Despite the scarcity of randomized clinical trials, midodrine is currently used in daily clinical practice in patients with cirrhosis in many countries. In fact, a survey that we performed in 2017 among members of the International Club of Ascites (ICA), showed that out of the 83 members that answered the survey, 49% frequently used midodrine for the management of patients with decompensated cirrhosis; and this percentage increased to 86% if only physicians from North America were considered (E. Solà, unpublished). The situations in which midodrine is mainly used are HRS, refractory ascites and arterial hypotension.

On this background, we designed a randomized controlled trial to assess the efficacy of long-term administration of oral midodine and intravenous (i.v.) albumin for prevention of complications in patients with decompensated cirrhosis on the waiting list for LT.

Section snippets

Trial design

The MACHT (midodrine and albumin for cirrhotic patients in the waiting list for liver transplantation) study was a multicenter, randomized (1:1), double-blind, placebo-controlled trial that included 196 consecutive patients with cirrhosis and ascites awaiting LT from the three liver transplant centers in Catalonia (Spain) from August 2008 to March 2015 (Hospital Clínic Barcelona, Hospital Vall d’Hebron and Hospital de Bellvitge). Patients were randomly assigned to receive midodrine and i.v.

Characteristics of study population

Six hundred and six patients were assessed for eligibility. A total of 410 patients were excluded because they fulfilled exclusion criteria or denied consent (Fig. 1). The remaining 196 patients were randomly assigned to receive either treatment with midodrine and albumin (99 patients) or placebo of both drugs (97 patients). Twelve patients from the midodrine plus albumin (M + A) group and 11 patients from the placebo group were excluded because they did not receive any dose of study

Discussion

In this multicenter, randomized, placebo-controlled trial in patients with decompensated cirrhosis in the waiting list for LT, treatment with midodrine and albumin was not effective compared to placebo in the prevention of complications of cirrhosis. In fact, there were neither differences in the incidence of complications during follow-up, nor in the time to development of the first complication. However, treatment with midodrine and albumin attenuated the severity of complications related to

Financial support

The work mentioned has been sponsored by the Instituto de Salud Carlos III through the Plan Estatal de Investigación Cientifica y Técnica y de Innovación specifically from the Mineco Grant number: EC07/90077 co funded by the European Regional Development Fund (ERDF). Agencia de Gestió d’Ajuts Universitaris I de Recerca (AGAUR) 2017/SGR 1281. CERCA programme/Generalitat de Catalunya. PG is a recipient of an ICREA Academia Award. XX was recipient of a grant from the Instituto de Salud Carlos III

Conflict of interest

PG declares that he has received research funding from Ferring Pharmaceuticals, Grifols S.A. He has participated on Advisory Boards for Novartis and Promethera, Sequana and Intercept.

Please refer to the accompanying ICMJE disclosure forms for further details.

Authors’ contributions

The authors listed above have all contributed to this manuscript and approve the final version of the submission. ES, CS contributed to the acquisition of data, the analysis and interpretation of the data, drafting of the manuscript, critical revision of the manuscript; MS, MM, RG, RM, MT, PM, NF, GP, PH, EL, MV, MM, AN, XA, IG, EP, JC, MN participated in the generation and collection of data, assembly of data, interpretation of data, and/or critical revision of the manuscript for important

Acknowledgement

This paper is dedicated to the memory of Joan Corboba (1964–2014), colleague and friend.

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