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Summary
Background Evidence is scarce on the efficacy of long-term human albumin (HA) administration in patients with Published Online
decompensated cirrhosis. The human Albumin for the treatmeNt of aScites in patients With hEpatic ciRrhosis May 31, 2018
http://dx.doi.org/10.1016/
(ANSWER) study was designed to clarify this issue. S0140-6736(18)30840-7
See Online/Comment
Methods We did an investigator-initiated multicentre randomised, parallel, open-label, pragmatic trial in 33 academic http://dx.doi.org/10.1016/
and non-academic Italian hospitals. We randomly assigned patients with cirrhosis and uncomplicated ascites who S0140-6736(18)30948-6
were treated with anti-aldosteronic drugs (≥200 mg/day) and furosemide (≥25 mg/day) to receive either standard *Investigators listed at the end
medical treatment (SMT) or SMT plus HA (40 g twice weekly for 2 weeks, and then 40 g weekly) for up to 18 months. of the paper
The primary endpoint was 18-month mortality, evaluated as difference of events and analysis of survival time in Department of Medical and
Surgical Sciences, and Center
patients included in the modified intention-to-treat and per-protocol populations. This study is registered with
for Applied Biomedical
EudraCT, number 2008–000625–19, and ClinicalTrials.gov, number NCT01288794. Research, University of
Bologna, Bologna, Italy
Findings From April 2, 2011, to May 27, 2015, 440 patients were randomly assigned and 431 were included in the (P Caraceni MD,
M Baldassarre PhD, M Tufoni MD,
modified intention-to-treat analysis. 38 of 218 patients died in the SMT plus HA group and 46 of 213 in the SMT
G Zaccherini MD,
group. Overall 18-month survival was significantly higher in the SMT plus HA than in the SMT group (Kaplan-Meier Prof M Bernardi MD);
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]). Department of Clinical
46 (22%) patients in the SMT group and 49 (22%) in the SMT plus HA group had grade 3–4 non-liver related Medicine, Sapienza University
of Rome, Rome, Italy
adverse events.
(O Riggio MD, S Nardelli MD,
C Pasquale MD); Unit of Internal
Interpretation In this trial, long-term HA administration prolongs overall survival and might act as a disease Medicine and Hepatology,
modifying treatment in patients with decompensated cirrhosis. Department of Medicine,
University of Padua, Padua,
Italy (Prof P Angeli PhD,
Funding Italian Medicine Agency. S Piano PhD, M Cavallin MD);
Division of Gastroenterology
Copyright © 2018 Elsevier Ltd. All rights reserved. and Hepatology, Città della
Salute e della Scienza Hospital,
University of Turin, Turin, Italy
Introduction Long-term human albumin (HA) administration to (C Alessandria MD, C Elia MD,
Cirrhosis of the liver is a leading cause of disability and patients with ascites, the most common cause of de A Andrealli MD); Department of
mortality worldwide.1,2 In Europe, 170 000 individuals die compensation,7 has been debated for decades. Because Clinical and Experimental
Medicine, University of
from cirrhosis every year, accounting for 1·8% of all reduced serum albumin concentration is commonly seen Catania, Catania, Italy
deaths, and a similar proportion has been reported from in patients with advanced cirrhosis, a putative rationale (S Neri MD, L Prestianni MD,
the USA.3,4 Complications, such as ascites, gastrointestinal underlying HA use relies on the belief that an improve F Fidone MD); Internal
bleeding, hepatic encephalopathy, and jaundice, herald ment in hypoalbuminaemia would slow down ascites Medicine, Hospital of Faenza,
Azienda Unità Sanitaria Locale
the decompensation of cirrhosis—the final stage of the formation by increasing plasma colloid-osmotic pressure. of Romagna, Faenza, Italy
disease.5 Decompensated cirrhosis carries a poor prognosis However, hypoalbuminaemia per se does not have a pre- (F G Foschi MD, F M Cappa PhD);
because the median survival time is about 2 years, and it eminent pathogenetic role in this process because the Internal Medicine, Hospital of
imposes a heavy burden on health-care costs, mainly due colloid-osmotic pressure gradient, a factor regulating fluid Bentivoglio, AUSL of Bologna,
Bologna, Italy (F Levantesi MD);
to the need for repeated hospital admissions.5,6 partition between plasma and the interstitial space, is not Liver Unit, Department of
The current approach to patients with decompen reduced in cirrhosis with ascites.8 Moreover, normalisation Hepatology and
sated cirrhosis relies on the individual management of of serum colloid-osmotic pressure achieved by repeated Gastroenterology, Niguarda
each complication. Therefore, there is an unmet need HA administrations did not ensure a persistent control of Hospital, Milan, Italy
(A Airoldi MD, L Cesarini MD);
for an overall therapeutic strategy able to prevent the ascites once abdom inal fluid had been resolved by Gastroenterology Unit,
development of complications, thus reducing hospital diuretics.9 Effective hypovolaemia due to peripheral arterial University Hospital, Ferrara,
readmissions and costs, and improving quality of life vasodilation is a hallmark of decom pensated cirrhosis, Italy (S Boccia MD,
L Simone MD); Department of
and survival. leading to renal sodium and water retention that favours
Gastroenterology, Polytechnic
University of Marche, Ancona, Research in context
Italy (G Svegliati-Baroni MD);
Gastroenterology and Evidence before this study resulting in a 38% reduction in the mortality hazard ratio.
Transplant Hepatology, We searched PubMed for full papers in any language published in The SMT plus HA group also had significantly reduced incidence
Papa Giovanni XXIII Hospital, peer-reviewed journals up to Feb 19, 2018, with the term “liver rates of paracentesis, refractory ascites, spontaneous bacterial
Bergamo, Italy (S Fagiuoli MD);
Department of Experimental
cirrhosis” subsequently filtered by “ascites”, “human albumin”, peritonitis or other bacterial infections, episodes of renal
and Clinical Medicine, and “clinical trial”. Among 122 publications retrieved, two dysfunction, hepatorenal syndrome type 1, and hepatic
University of Florence, reported the results of randomised clinical trials assessing the encephalopathy grade 3–4, whereas the incidence rate of gastro-
Florence, Italy effects of long-term human albumin (HA) in patients with oesophageal variceal bleeding was similar in the two groups.
(R G Romanelli PhD); Division of
Gastroenterology, National
cirrhosis and ascites, whereas the others dealt with single or Finally, SMT plus HA was associated with a better quality of life
Institute of Gastroenterology S short-term HA administration to prevent or treat specific acute and fewer hospital admissions than the SMT group,
De Bellis, Castellana Grotte complications of the disease. In the first study, published in 1999, contributing to a favourable incremental cost-effectiveness
(Bari), Italy (R Cozzolongo MD); HA given at a dose of 25 g every week for 1 year and 25 g every ratio. The expected result of long-term HA administration to
Unit of Gastroenterology and
Hepatology, Biomedical
2 weeks for the next 2 years reduced the probability of developing patients with decompensated cirrhosis is conventionally
Department of Internal and ascites and hospital readmissions, with no effect on survival. An believed to be a better management of ascites than SMT, as
Specialistic Medicine, improved transplant-free survival was instead reported by the convincingly shown by the ANSWER study. However, and more
University of Palermo, second study, published in 2006, by the same research group, in importantly, it shows that long-term HA treatment also reduces
Palermo, Italy
(Prof V Di Marco MD); Azienda
which patient follow-up was extended to a median of 84 months. the incidence of potentially fatal complications of end-stage
Ospedaliera di Rilievo However, the small sample size precluded a firm conclusion, so liver disease, ultimately leading to an improved survival.
Nazionale dei Colli, Cotugno that current guidelines do not support such a treatment. Notably, this therapeutic approach appears to be cost-effective.
Hospital of Naples, Naples,
Italy (V Sangiovanni MD); Added value of this study Implications of all the available evidence
Gastroenterology Unit, The ANSWER study, an investigator-initiated multicentre The ANSWER study results are clinically relevant. Indeed, they
Department of Clinical
Medicine and Surgery,
randomised, parallel, open-label, pragmatic trial, is the first might prompt a change in HA use from targeting specific
Federico II University of Naples, adequately powered study to assess the effects of long-term HA complications to a more comprehensive approach aimed at
Naples, Italy (F Morisco MD); administration in patients with cirrhosis and uncomplicated slowing down the progression of decompensated cirrhosis by
Internal Medicine, Department ascites. Patients received either standard medical treatment acting as a disease-modifying treatment. Long-term HA
of Medical Area, University of
Udine, Udine, Italy
(SMT, n=213) or SMT plus HA (40 g twice weekly for 2 weeks, administration unavoidably requires the use of health-care
(P Toniutto MD); and then 40 g weekly; n=218) for up to 18 months. services and a careful patient compliance. However, the clinical
Gastroenterology, Gemelli The all-cause 18-month mortality, the primary endpoint of the advantages achieved and the favourable results of
Foundation, Catholic study, was evaluated as difference of events and analysis of cost-effectiveness analysis can justify the implementation of this
University, Rome, Italy
(A Tortora MD);
survival time. The incidence rate of mortality was significantly management strategy. Future research should clarify whether
Gastroenterology Unit, lower in the SMT plus HA group than in the SMT group. some patient subgroups would benefit most from long-term HA
Hospital of Cosenza, Cosenza, Consistently, the overall 18-month survival was significantly treatment and whether different doses and timing schedules
Italy (R De Marco MD); Liver higher in the SMT plus HA group than in the SMT group, might be more effective than those used in the present study.
Unit, Tor Vergata University,
Rome, Italy
(Prof M Angelico MD); Division ascites formation.10 Therefore, a beneficial effect of HA after hospital discharge at a dose of 25 g every week for
of Clinical and Molecular
Hepatology, University
might result from blood volume expansion, which would 1 year and 25 g every 2 weeks for the following 2 years,
Hospital of Messina, Messina, taper activated vasoconstrictor and sodium-retaining reduced the probability of developing ascites and hospital
Italy (I Cacciola PhD); Infectious systems and improve renal perfusion. Sustained systemic readmissions, with no effect on survival.13 The second trial
Diseases and Hepatology, inflammation and pro-oxidant state have been shown extended patient follow-up to a median of 84 months,
University Hospital of Parma,
Parma, Italy (G Elia MD);
to contribute to circulatory and extrahepatic organ reporting improved transplant-free survival.14 However,
Department of Clinical and dysfunctions in advanced cirr hosis.11 HA exerts non- the small sample size precluded a firm conclusion, and
Experimental Internal oncotic properties, such as anti oxidant and scavenging current guidelines do not support such a treatment.15,16
Medicine, University of activities, binding and transport of exogenous and With this background and our large randomised clinical
Campania Luigi Vanvitelli,
Naples, Italy (A Federico PhD);
endogenous substances, and regu lation of endothelial trial, we aimed to assess the effect of long-term HA
Gastroenterology and function and inflammatory or immune res ponses.12 administration on overall mortality, management of
Endoscopy Unit, Foundation Such properties would make HA potentially able to ascites, and incidence of complications in patients with
Istituto di Ricovero e Cura a target several pathophysiological mechanisms underlying decompensated cirrhosis. Health-care costs and quality of
Carattere Scientifico Ca’ Granda
Ospedale Maggiore Policlinico,
decompensated cirrhosis, providing another reason life were also assessed to estimate the cost-effectiveness
Milan, Italy (S Massironi PhD); for the use of HA with the broader target of prevent of the intervention.
Internal Medicine, S Sebastiano ing complications, besides improving the management
General Hospital, Frascati
(Rome), Italy (R Guarisco MD);
of ascites. Methods
Internal Medicine, Hospital of The effects of adding long-term HA administration to Study design
Dolo, Azienda Unità Locale diuretic therapy in decompensated cirrhosis have been The human Albumin for the treatmeNt of aScites in
Socio-sanitaria assessed by only one research group in two prospective patients With hEpatic ciRrhosis (ANSWER) study was an
Serenissima,Mestre, Italy
controlled clinical trials. In the first trial, HA administration investigator-initiated multicentre randomised, parallel,
open-label, pragmatic trial done in 33 academic and non- an anti-aldosteronic drug (at a dose ≥200 mg/day) and (A Galioto MD); Internal
academic Italian hospitals. Study protocol, amendments furosemide (≥25 mg/day). Details on patient SMT are Medicine, Hospital of Rimini,
AUSL of Romagna, Rimini, Italy
(appendix), and the informed consent process were first reported in the appendix. (G Ballardini MD); Section of
approved by the ethics committee at the coordinat Patients enrolled in the SMT plus HA group received Gastroenterology, Department
ing centre (University of Bologna, S Orsola-Malpighi an intravenous infusion of 20% HA in 50 mL vials in of Emergency and Organ
Hospital, Bologna, Italy) and then at each participating approximately 30–60 min at a dose of 40 g twice weekly Transplantation, University of
Bari, Bari, Italy (M Rendina MD);
centre. This study fulfils the requirements of the for the initial 2 weeks, and 40 g weekly thereafter. The Graduate School of Health
CONSORT check list.17 We also self-reviewed the trial first dose was administered within 24 h after Economics and Management,
design and conduct using the Cochrane risk of bias tool randomisation. According to protocol, HA was infused Catholic University, Rome, Italy
(appendix).18 by nursing personnel in outpatient settings, such as (M Ruggeri PhD); and Cineca
Interuniversity Consortium,
hospital clinics, local health centres, or home-care Bologna, Italy (A Roncadori BSc)
Participants services according to available facilities, whereas patients Correspondence to:
The target trial population comprised patients with admitted to hospital received HA on the scheduled date Prof Mauro Bernardi,
cirrhosis and persistent uncomplicated ascites despite during their hospital stay. Department of Medical and
ongoing diuretic treatment, who were recruited at partici No concomitant medications were forbidden during the Surgical Sciences, University of
Bologna, S Orsola-Malpighi
pating hospitals during hospital admissions or visits study. Additional information about causes and other University Hospital, 40138
at outpatient clinics. Written informed consent was ob treatments during the study are reported in the appendix. Bologna, Italy
tained from all patients and informants. The inclusion After enrolment, patients were assessed monthly for up mauro.bernardi@unibo.it
criteria were, diagnosis of liver cirrhosis with uncompli to 18 months or study interruption or death. At each visit, See Online for appendix
cated ascites; ongoing diuretic treatment with an anti- clinical, laboratory, and instrumental data (if needed) were
aldosteronic drug (at a dose ≥200 mg/day and furosemide collected by the attending physicians, including interviews
≥25 mg/day), stable for at least 4 days before enrolment; on dietary sodium and alcohol intake, which could be
and oesophagogastroduodenoscopy done in the past extended to relatives. Data were recorded on an electronic
12 months, abdominal ultrasonography done in the past case report form accessible via the internet. The study was
30 days, and laboratory tests required by the protocol in interrupted when patients underwent liver transplantation
the past 7 days. Participants younger than 18 years or TIPS insertion, needed three or more therapeutic
were excluded. paracenteses per month (the reason for this criterion is
The main exclusion criteria aimed to avoid the en detailed in the appendix), or refused to continue their
rolment of patients with refractory ascites, recent participation in the study, or because of medical judgment.
com plications of cirrhosis, transjugular intrahepatic
portosystemic shunt (TIPS), active hepatocellular carci
noma, liver transplantation, ongoing alcohol abuse, 440 patients randomised
extrahepatic organ failure, and albumin use for the
treatment of ascites in the month preceding enrolment.
For a more detailed list of the exclusion criteria and
220 assigned to receive SMT 220 assigned to receive SMT plus HA
the diagnostic criteria defining cirrhosis, ascites, and
complications see the appendix.
7 ineligible 2 ineligible (wrong inclusion)
Randomisation and masking 3 withdrew consent
4 wrong inclusion
At the statistical data centre, eligible patients were
randomly assigned (1:1) to receive either standard medi
cal treatment (SMT) or SMT plus HA with a computer- 213 included in the modified 218 included in the modified
intention-to-treat analysis intention-to-treat analysis
generated and blinded assignment sequence with
randomly permuted blocks of four, stratified accord
ing to the need for therapeutic paracentesis in the 41 ended the study prematurely 42 ended the study prematurely
month preceding enrolment (yes or no) and natraemia 16 patient’s decision 22 patient’s decision
8 protocol violation 3 medical judgment
(<135 mmol/L and ≥135 mmol/L). A placebo controlled 17 lost to follow-up 4 protocol violation
trial was not ethically justified because of the absence of 13 lost to follow-up
safe alternatives to HA. Neither patients, nor investi
gators, nor statisticians were masked to treatment 172 completed the study according 176 completed the study according
assignment. The entire statistical analysis was done once to prespecified cause of study to prespecified cause of study
the database had been definitively frozen. termination and included in termination and included in
per-protocol population per-protocol population
Procedures
Figure 1: Trial profile
SMT was aligned with the indications from the available For the SMT group, wrong inclusions were one advanced hepatocellular carcinoma, one neoplastic ascites,
clinical practice guidelines.15,16,19 According to the inclusion and two refractory ascites. For the SMT plus HA group, wrong inclusions were one advanced hepatocellular
criteria, patients entering the study had to be treated with carcinoma and one refractory ascites. HA=human albumin. SMT=standard medical treatment.
adjusted life-years (QALY) from the EQ-5D utility index Insulin-treated diabetes 50 (38%) 35 (30%)
and the incremental cost-effectiveness ratio (ICER). Genito-urinary disease 17 (13%) 9 (8%)
According to the National Institute for Health and Care Quality of life
Excellence (NICE),25 an ICER of €35 000 per QALY was EQ-5D utility index 0·79 (0·19) 0·78 (0·19)
taken as the threshold to consider a treatment cost- EQ-VAS score 57·2 (18·6) 57·2 (19·1)
effective. We also did a non-parametric bootstrap analysis Data are n (%), median (IQR) or mean (SD). SMT=standard medical treatment. HA=human albumin.
to test the robustness of the preliminary cost-effectiveness NASH=non-alcoholic steatohepatitis. HCC=hepatocellular carcinoma. MELD=model for end stage liver disease.
MELD-Na=MELD score incorporating serum sodium concentration. SBP=spontaneous bacterial peritonitis. LT=liver
assessment (appendix).26 transplantation. EQ-5D=EuroQol Group 5-Dimension Self-Report Questionnaire. EQ-VAS=EuroQol visual analogue
Data were managed with PL/SQL Developer, version scale. *Episodes requiring admission to hospital in the past 3 months. †Serum creatinine >1·5 mg/dL in the past
9.0.6.1665 (Allround automation, Enschede, Netherlands) 3 months. ‡SBP, non-SBP bacterial infections, gastrointestinal bleeding, hepatic encephalopathy.
and analyses were done by the non-profit Interuniversity Table 1: Baseline characteristics
Consortium for data collection, data processing, and
statistical analysis (CINECA, Bologna, Italy) using
R open-source statistical software, version 3.3.1. Behring, Biotest Italia, Grifols Italia, Kedrion Biopharma)
The trial was monitored by an external contract according to Italian legislation governing non-profit
research organisation (Yghea, Bologna, Italy) and over trials.
seen by a data safety and monitoring board of phys The study was registered in the European Clinical Trial
icians not involved in the study (appendix). Per-protocol Database (EudraCT2008-000625-19) and ClinicalTrials.
HA was supplied by a company pool (Baxalta, CSL gov (NCT01288794).
5·0
consent withdrawal. Therefore, the modified intention-to-
* * * * * * * * * *
4·5 * * * * * * * * treat analysis included 213 patients in the SMT group and
218 in the SMT plus HA group (figure 1). Data on screened
Serum albumin concentration (g/dL)
4·0
3·5
patients were incomplete in many participating centres, so
comprehensive information about screening cannot be
3·0
provided. However, screening was properly recorded at
2·5
four highly recruiting centres where data were gathered
2·0
(appendix). Baseline demographic, clinical, and laboratory
1·5
features were well balanced between the two groups
1·0
SMT plus HA (table 1). 41 patients in the SMT group and 42 in the SMT
0·5 SMT *p<0·0001 plus HA group ended their follow-up prematurely. Thus,
0
0 3 6 9 12 15 18 172 patients in SMT group and 176 patients in SMT plus
Time (months) HA group completed the study according to the
Number of patients
SMT 213 115 84 76 53 52 51 prespecified causes of study termination (per-protocol
SMT plus HA 218 153 123 109 103 88 86 population). Although liver transplantation and TIPS
Figure 2: Serum albumin concentration throughout the study period
placement were similar between the two groups, patients
Serum albumin concentration in patients receiving SMT or SMT plus HA. receiving SMT had a more frequent need for three or more
Dots are mean values and bars are SD. HA=human albumin. SMT=standard paracenteses per month and had more deaths than those
medical treatment. receiving SMT plus HA (figure 1) There were 46 deaths,
18 liver transplantations, 8 TIPS placements, and
100 42 needing three or more paracenteses per month in the
SMT group and 38 deaths, 19 liver transplantations, 6 TIPS
80 placements, and 18 needing three or more paracenteses
per month in the SMT plus HA group. As a result, the
Overall survival (%)
0·6 0·4
0·4 0·2
Hyponatraemia with serum sodium concentration <130 mmol/L 0·51 (0·40–0·67) <0·001
Hyperkalaemia with serum potassium concentration ≥5·5 mmol/L 0·58 (0·41–0·82) 0·002
Gastro-oesophageal variceal bleeding*† 0·93 (0·41–2·17) 0·848
unrelated to cirrhosis exceeded the 5% frequency Table 2: Incidence rate of hospital admissions
threshold within SMT and SMT plus HA groups
(table 3). The non-liver-related serious adverse events
requiring admission to hospital are listed in the fact that only seven patients had to be treated to save a
appendix. life heightens the clinical relevance of these results.
An improved survival of patients with cirrhosis and
Discussion first-onset ascites receiving long-term HA was reported
The present randomised, multicentre, pragmatic trial is after a median follow-up of 84 months by a single-centre
the first prospective study providing robust evidence for randomised trial14 more than a decade ago. However, its
a survival advantage conferred by the addition of long- small patient sample size precluded the adoption of this
term HA administration to the standard-of-care in a treatment by current clinical practice guidelines.15,16 We
large cohort of patients with cirrhosis and uncomplicated believe that the much larger, adequately powered patient
ascites. This statement is supported by the findings sample size, and the more stringent methods adopted
that HA administration significantly reduced overall in the present trial overcome the main limitations of
mortality rate, thus improving 18-month survival. The that study.
benefit of HA administration was supported when TIPS Our study also provided other major findings. HA
placement and liver transplantation were considered administration eased the management of ascites by
competing risk events. Moreover, long-term HA treat significantly reducing the need for therapeutic para
ment was the sole independent protective factor against centesis. The decision to perform paracentesis might
mortality at competing risks multivariable analysis and be largely influenced by the subjective judgment of
this advantage was specific to liver-related deaths. The attending physicians. Therefore, the fact that the amount
Table 3: Summary of grade 3–4 non-liver-related adverse events according to the Common Terminology Criteria for Adverse Events version 4.0
classification
of ascitic fluid withdrawn per paracentesis was the same reported many years ago in anecdotal series.9,29,30 Thus,
in the two groups of our study is notable, suggest another important finding is that gastro-oesophageal
ing a fairly standard behaviour among investigators. variceal bleeding and related deaths were not increased
The favourable effect of HA administration on ascites by the HA dose given in the present study. We observed a
management is also testified by the significant reductions non-significantly higher incidence of other portal-
in the incidence of refractory ascites and diuretic-related hypertensive bleeds—ie, from portal gastropathy and
side-effects, such as renal dysfunction, hyponatraemia, haemorrhoids—with a higher hospital admission rate,
and hyperkalaemia, in the SMT plus HA group. without any increase in the related mortality. Whether or
Even more importantly, the incidence of ominous not this result is favoured by the mild anti-platelet
complications of cirrhosis, such as SBP and non-SBP- aggregation effect of HA31 remains to be determined.
related bacterial infections, HRS type 1, and severe The nature of this study cannot unveil the mech
hepatic encephalopathy, was also strikingly reduced. anisms underlying HA benefit. However, HA could have
These results were reinforced by the competing risks mitigated effective hypovolaemia, which is a major
analyses showing that HA administration was associated pathogenic factor for ascites formation inducing renal
with a delay in the occurrence of the first episodes of sodium retention and endangering renal perfusion.10
these complications apart from non-SBP bacterial This mitigation would explain a better control of ascites
infections. These effects probably represented the basis and related complications, such as renal impairment,
for the improved survival of patients receiving long-term electrolyte disturbances, HRS type 1, and SBP. Moreover,
HA. The diagnosis of hepatic encephalopathy and non- HA non-oncotic properties could have antagonised
SBP bacterial infections must be recognised as difficult mechanisms, leading to the systemic inflammation and
and potentially influenced by subjective interpretation. immune dysfunction characterising decompensated
To temper these potential sources of bias, we only cirrhosis.11,12 This result would account for the significant
recorded the episodes of hepatic encephalopathy grade 3 reduced incidence of complications not closely linked to
and 4, with which clinical evidence is more straight haemodynamic alterations, such as hepatic encephalo
forward, and used prespecified diagnostic criteria for pathy and non-SBP bacterial infections. Whether a serum
non-SBP bacterial infections that follow those used in albumin concentration threshold needs to be reached to
many studies specifically dealing with this issue.27,28 achieve therapeutic effects from HA supplementation
Bleeding from oesophageal varices, likely to be caused warrants further studies. A significant and sustained
by blood volume expansion after the prolonged admin increase in serum albumin concentration was seen in the
istration of huge amounts of HA (up to 100 g/day), was SMT plus HA group with respect to SMT. This difference
was reached within 1–2 months, when the benefits of HA receive placebo infusion, the choice of the fluid to be
started to be manifest. used in patients with decompensated cirrhosis can be
HA administration also influenced patients’ quality of problematic. Indeed, any potential alternative presents
life. Under baseline conditions, the EQ-5D values were shortcomings: sodium-containing solutions would en
similar in the two groups, and close to a report in Italian hance sodium overload, glucose solution is unsuitable in
patients with cirrhosis.32 During the follow-up, a lower diabetics and might favour hyponatraemia, and synthetic
decay of both utility index and VAS score was seen in the colloids are potentially associated with side-effects such as
SMT plus HA than the SMT group. The resulting anaphylaxis, coagulo pathy, or renal failure.34–36 Lastly,
differences reached significance from the 3rd to the outcome assessors and analysts were also not blinded.
12th month, a relevant result in such severely ill patients. However, the outcome analysts belong to an independent
Long-term HA administration is deemed to be an non-profit consortium (CINECA, Bologna, Italy) and did
expensive treatment, and an attempt to determine the cost- the entire statistical assessment once the database had
effectiveness of this intervention is warranted. Hospital been definitively frozen. This precaution would at least
admissions represent a major health-care cost in patients temper the risk of bias related to this type of unmasking.
with decompensated cirrhosis.6 Thus, an important result A second limitation stems from the ethical need to
of our study is that HA treatment was associated with a interrupt the study when patients needed three or more
significant reduction in the number of hospital admissions paracenteses per month (appendix). This shortened the
and total days spent in the hospital. These findings, follow-up duration especially in the SMT group. However,
combined with fewer paracenteses, lower expenditure to censoring patients in a very advanced disease stage, when
treat complications, and reduced HA use for evidence- event incidence is likely to be higher, might have lessened
based indications, are likely to balance the costs of long- rather than magnified the differences between the
term HA administration. In Italy, cost drivers are based on two groups. Finally, weekly intravenous infusions require
National Health Service reimbursement rates and are frequent use of health-care services. However, the entire
much lower than in other high-income countries. Despite procedure can be done in less than 1 h in an outpatient
this, the ICER:QALY ratio calculated in this study was setting or even at home, if domiciliary care is available.
below the threshold adopted by NICE to consider a Even though the weekly schedule entails careful patient
treatment cost-effective.25 Furthermore, the bootstrap compliance, this study shows that most patients were
analysis further supported this finding, providing even strongly committed to follow a demanding treatment
more favourable results. if they perceived a health benefit from therapy. We
Long-term HA administration was generally very well believe that the clinical advantages, including the lives
tolerated as only three mild allergic reactions and two saved and fewer admissions to hospital, justify the HA
severe side-effects—represented by sepsis—occurred, care management.
leading to treatment interruption in three cases. HA Another limitation regards the cost-effectiveness
batches analysis in the cases of sepsis did not reveal analysis as non-health care or indirect costs were not
contamination, suggesting that these side-effects were accounted for in our study. However, our cost analysis
due to venepuncture. Moreover, a concomitant previously followed a third-party payer perspective that pro
unrecognised pneumonia in one patient casts doubts on vides reimbursement of the Diagnosis Related Group and
the role of HA administration in that case. ambulatory tariffs, which include the cost of personnel
The main limitation of this study is that it is an open- but not indirect costs.
label trial. Weekly HA administration led patients to be In conclusion, long-term weekly HA administration in
seen, usually by nurses, more frequently than those patients with decompensated cirrhosis acts as a cost-
enrolled in the SMT group. Thus, impending compli effective disease-modifying treatment since it not only
cations could have been treated more promptly. However, provides a better control of ascites but also reduces the
closer patient surveillance might have disclosed a higher incidence of complications and related hospital
number of events, thereby increasing the incidence of admissions, and improves survival and quality of life. The
complications in the SMT plus HA group. In any case, identification of patient subgroups who would benefit
such a difference reflects what would happen in real-world most from long-term HA administration merits additional
clinical practice, a feature of pragmatic trials.33 Although investigation. These results might prompt a change in HA
pragmatic trials might have a reduced internal validity use in decompensated cirrhosis from targeting specific
because of the absence of blinding, they are likely to have complications to a more comprehensive approach aimed
a better external validity provided they are founded on at slowing down the progression of the disease.
large sample-size, prolonged follow-up, and hard primary Contributors
endpoints. All these features were observed in the present The original concept of the ANSWER trial was developed by MBe and
study, involving centres with diverse clinical settings. PC. The study was designed and planned by PC, OR, PA, and MBe. The
chief investigators were MBe and PC. Acquisition of the data was done
Notably, no significant centre effect was seen on primary by PC, OR, PA, CA, SNe, FGF, FL, AAi, SB, GS-B, SF, RGR, RC, VDM,
outcome. Furthermore, besides the ethical concern related VS, FM, PT, AT, RDM, MA, IC, GE, AF, SM, RG, AG, GB, MRe, SNa,
to the weekly patient attendance to hospital services to SP, CE, LP, FMC, LC, LS, CP, MC, AAn, FF, MT, and GZ. Statistical
analysis was done by AR and MBa. Cost-effectiveness analysis was done Anne Prudence Collins for editing the English manuscript, the study
by MRu. Data analysis and interpretation was done by PC, MBe, MT, patients and their relatives for their participation, and the physicians and
GZ, and MBa. The manuscript was drafted by PC and MBe. All authors nursing staff of the participating centres for their cooperation.
critically reviewed the manuscript and approved the final draft for
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Declaration of interests
practice guidelines on the management of ascites, spontaneous
GZ is part of the speakers’ bureau for Octapharma. MBe is part of the
bacterial peritonitis, and hepatorenal syndrome in cirrhosis.
speakers’ bureau for Grifols SA, Octapharma AG, Baxalta, CLS Behring J Hepatol 2010; 53: 397–417.
GmbH, and PPTA, and is a consultant for Baxalta and Grifols SA.
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MRe is part of the speakers’ bureau for Grifols, Biotest, and Kedrion Association for the Study of Liver Diseases Practice Guideline
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are part of speakers’ bureau for Baxalta. PA is part of the speakers’ Hepatology 2013; 57: 1651–53.
bureau for Baxalta and Kedrion Biopharma. PC is part of the speakers’ 17 Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010
bureau for Grifols SA, Octapharma AG, Baxalta, and Kedrion explanation and elaboration: updated guidelines for reporting
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board for Grifols SA, and has a research grant from Octapharma AG. 18 Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane
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SF is part of the speakers’ bureau for Grifols and Kedrion Biopharma. BMJ 2011; 343: d5928.
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cirrhosis: report on the consensus conference of the International
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