Elsevier

The Lancet

Volume 391, Issue 10138, 16–22 June 2018, Pages 2417-2429
The Lancet

Articles
Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial

https://doi.org/10.1016/S0140-6736(18)30840-7Get rights and content

Summary

Background

Evidence is scarce on the efficacy of long-term human albumin (HA) administration in patients with decompensated cirrhosis. The human Albumin for the treatmeNt of aScites in patients With hEpatic ciRrhosis (ANSWER) study was designed to clarify this issue.

Methods

We did an investigator-initiated multicentre randomised, parallel, open-label, pragmatic trial in 33 academic and non-academic Italian hospitals. We randomly assigned patients with cirrhosis and uncomplicated ascites who were treated with anti-aldosteronic drugs (≥200 mg/day) and furosemide (≥25 mg/day) to receive either standard medical treatment (SMT) or SMT plus HA (40 g twice weekly for 2 weeks, and then 40 g weekly) for up to 18 months. The primary endpoint was 18-month mortality, evaluated as difference of events and analysis of survival time in patients included in the modified intention-to-treat and per-protocol populations. This study is registered with EudraCT, number 2008–000625–19, and ClinicalTrials.gov, number NCT01288794.

Findings

From April 2, 2011, to May 27, 2015, 440 patients were randomly assigned and 431 were included in the modified intention-to-treat analysis. 38 of 218 patients died in the SMT plus HA group and 46 of 213 in the SMT group. Overall 18-month survival was significantly higher in the SMT plus HA than in the SMT group (Kaplan-Meier estimates 77% vs 66%; p=0·028), resulting in a 38% reduction in the mortality hazard ratio (0·62 [95% CI 0·40–0·95]). 46 (22%) patients in the SMT group and 49 (22%) in the SMT plus HA group had grade 3–4 non-liver related adverse events.

Interpretation

In this trial, long-term HA administration prolongs overall survival and might act as a disease modifying treatment in patients with decompensated cirrhosis.

Funding

Italian Medicine Agency.

Introduction

Cirrhosis of the liver is a leading cause of disability and mortality worldwide.1, 2 In Europe, 170 000 individuals die from cirrhosis every year, accounting for 1·8% of all deaths, and a similar proportion has been reported from the USA.3, 4 Complications, such as ascites, gastrointestinal bleeding, hepatic encephalopathy, and jaundice, herald the decompensation of cirrhosis—the final stage of the disease.5 Decompensated cirrhosis carries a poor prognosis because the median survival time is about 2 years, and it imposes a heavy burden on health-care costs, mainly due to the need for repeated hospital admissions.5, 6

The current approach to patients with decompensated cirrhosis relies on the individual management of each complication. Therefore, there is an unmet need for an overall therapeutic strategy able to prevent the development of complications, thus reducing hospital readmissions and costs, and improving quality of life and survival.

Long-term human albumin (HA) administration to patients with ascites, the most common cause of decompensation,7 has been debated for decades. Because reduced serum albumin concentration is commonly seen in patients with advanced cirrhosis, a putative rationale underlying HA use relies on the belief that an improvement in hypoalbuminaemia would slow down ascites formation by increasing plasma colloid-osmotic pressure. However, hypoalbuminaemia per se does not have a pre-eminent pathogenetic role in this process because the colloid-osmotic pressure gradient, a factor regulating fluid partition between plasma and the interstitial space, is not reduced in cirrhosis with ascites.8 Moreover, normalisation of serum colloid-osmotic pressure achieved by repeated HA administrations did not ensure a persistent control of ascites once abdominal fluid had been resolved by diuretics.9 Effective hypovolaemia due to peripheral arterial vasodilation is a hallmark of decompensated cirrhosis, leading to renal sodium and water retention that favours ascites formation.10 Therefore, a beneficial effect of HA might result from blood volume expansion, which would taper activated vasoconstrictor and sodium-retaining systems and improve renal perfusion. Sustained systemic inflammation and pro-oxidant state have been shown to contribute to circulatory and extrahepatic organ dysfunctions in advanced cirrhosis.11 HA exerts non-oncotic properties, such as antioxidant and scavenging activities, binding and transport of exogenous and endogenous substances, and regulation of endothelial function and inflammatory or immune responses.12 Such properties would make HA potentially able to target several pathophysiological mechanisms underlying decompensated cirrhosis, providing another reason for the use of HA with the broader target of preventing complications, besides improving the management of ascites.

Research in context

Evidence before this study

We searched PubMed for full papers in any language published in peer-reviewed journals up to Feb 19, 2018, with the term “liver cirrhosis” subsequently filtered by “ascites”, “human albumin”, and “clinical trial”. Among 122 publications retrieved, two reported the results of randomised clinical trials assessing the effects of long-term human albumin (HA) in patients with cirrhosis and ascites, whereas the others dealt with single or short-term HA administration to prevent or treat specific acute complications of the disease. In the first study, published in 1999, HA given at a dose of 25 g every week for 1 year and 25 g every 2 weeks for the next 2 years reduced the probability of developing ascites and hospital readmissions, with no effect on survival. An improved transplant-free survival was instead reported by the second study, published in 2006, by the same research group, in which patient follow-up was extended to a median of 84 months. However, the small sample size precluded a firm conclusion, so that current guidelines do not support such a treatment.

Added value of this study

The ANSWER study, an investigator-initiated multicentre randomised, parallel, open-label, pragmatic trial, is the first adequately powered study to assess the effects of long-term HA administration in patients with cirrhosis and uncomplicated ascites. Patients received either standard medical treatment (SMT, n=213) or SMT plus HA (40 g twice weekly for 2 weeks, and then 40 g weekly; n=218) for up to 18 months. The all-cause 18-month mortality, the primary endpoint of the study, was evaluated as difference of events and analysis of survival time. The incidence rate of mortality was significantly lower in the SMT plus HA group than in the SMT group. Consistently, the overall 18-month survival was significantly higher in the SMT plus HA group than in the SMT group, resulting in a 38% reduction in the mortality hazard ratio. The SMT plus HA group also had significantly reduced incidence rates of paracentesis, refractory ascites, spontaneous bacterial peritonitis or other bacterial infections, episodes of renal dysfunction, hepatorenal syndrome type 1, and hepatic encephalopathy grade 3–4, whereas the incidence rate of gastro-oesophageal variceal bleeding was similar in the two groups. Finally, SMT plus HA was associated with a better quality of life and fewer hospital admissions than the SMT group, contributing to a favourable incremental cost-effectiveness ratio. The expected result of long-term HA administration to patients with decompensated cirrhosis is conventionally believed to be a better management of ascites than SMT, as convincingly shown by the ANSWER study. However, and more importantly, it shows that long-term HA treatment also reduces the incidence of potentially fatal complications of end-stage liver disease, ultimately leading to an improved survival. Notably, this therapeutic approach appears to be cost-effective.

Implications of all the available evidence

The ANSWER study results are clinically relevant. Indeed, they might prompt a change in HA use from targeting specific complications to a more comprehensive approach aimed at slowing down the progression of decompensated cirrhosis by acting as a disease-modifying treatment. Long-term HA administration unavoidably requires the use of health-care services and a careful patient compliance. However, the clinical advantages achieved and the favourable results of cost-effectiveness analysis can justify the implementation of this management strategy. Future research should clarify whether some patient subgroups would benefit most from long-term HA treatment and whether different doses and timing schedules might be more effective than those used in the present study.

The effects of adding long-term HA administration to diuretic therapy in decompensated cirrhosis have been assessed by only one research group in two prospective controlled clinical trials. In the first trial, HA administration after hospital discharge at a dose of 25 g every week for 1 year and 25 g every 2 weeks for the following 2 years, reduced the probability of developing ascites and hospital readmissions, with no effect on survival.13 The second trial extended patient follow-up to a median of 84 months, reporting improved transplant-free survival.14 However, the small sample size precluded a firm conclusion, and current guidelines do not support such a treatment.15, 16

With this background and our large randomised clinical trial, we aimed to assess the effect of long-term HA administration on overall mortality, management of ascites, and incidence of complications in patients with decompensated cirrhosis. Health-care costs and quality of life were also assessed to estimate the cost-effectiveness of the intervention.

Section snippets

Study design

The human Albumin for the treatmeNt of aScites in patients With hEpatic ciRrhosis (ANSWER) study was an investigator-initiated multicentre randomised, parallel, open-label, pragmatic trial done in 33 academic and non-academic Italian hospitals. Study protocol, amendments (appendix), and the informed consent process were first approved by the ethics committee at the coordinating centre (University of Bologna, S Orsola-Malpighi Hospital, Bologna, Italy) and then at each participating centre. This

Results

From April 2, 2011, to May 27, 2015, 440 patients were randomly assigned to receive either SMT (n=220) or SMT plus HA (n=220). Six patients, who were withdrawn from the study within 30 days from enrollment, were excluded because of wrong inclusion, and three patients, who did not receive any treatment, were excluded because of consent withdrawal. Therefore, the modified intention-to-treat analysis included 213 patients in the SMT group and 218 in the SMT plus HA group (figure 1). Data on

Discussion

The present randomised, multicentre, pragmatic trial is the first prospective study providing robust evidence for a survival advantage conferred by the addition of long-term HA administration to the standard-of-care in a large cohort of patients with cirrhosis and uncomplicated ascites. This statement is supported by the findings that HA administration significantly reduced overall mortality rate, thus improving 18-month survival. The benefit of HA administration was supported when TIPS

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