NIHR DC Discover

Elderly woman in hospital bed attached to drip.

NIHR Signal Albumin administrations can prolong survival for some people with liver disease

Published on 23 October 2018

doi: 10.3310/signal-000664

Weekly intravenous albumin can prolong the life for people with liver cirrhosis and uncomplicated ascites. Over about 18 months, 17% of patients given albumin died compared with 22% given standard care alone over 11 months.

People with very severe (end-stage) cirrhosis develop various complications including a build-up of fluid in the abdomen (ascites).

This is the first large trial to study the effects of long-term albumin infusions. In addition to improved survival, albumin also reduced hospital admissions and other complications, such as liver transplantation and was estimated to be an effective use of resources in Italy.

This trial may prompt a change in clinical practice. Further research may help identify which patient groups could benefit most from treatment and what the transferability of this evidence is to the UK.

Share your views on the research.

Why was this study needed?

It is estimated that over 4,000 people die from cirrhosis in the UK each year. Average survival for people with decompensated (advanced) cirrhosis is two years. The condition places a high demand on the health service with frequent admissions to hospital for management of ascites and other complications such as internal bleeding and brain complications such as encephalopathy.

The build-up of fluid in the abdomen, ascites, is commonly managed using diuretics or by draining the fluid from the abdomen (paracentesis). Albumin may be able to address the underlying problem, keeping fluid in the circulation which would, in turn, support heart and kidney function.

Previous studies suggest a potential benefit from regular albumin infusions but were too small to draw firm conclusions on survival. This large multicentre randomised controlled trial, with 18-month follow-up, was pragmatic and intended to provide clear evidence about the effect of a regular albumin infusion protocol in clinical practice.   

What did this study do?

The ANSWER trial recruited 440 adults from 33 hospitals across Italy. Eligible participants had cirrhosis with uncomplicated ascites and were stable on diuretic treatment. Various exclusions were applied, including liver cancer, recent complications, organ failure and prior albumin treatment.

Participants were assigned to standard care only or with the addition of weekly intravenous albumin infusions (40g twice weekly for two weeks, then 40g weekly thereafter). Follow-up was 18 months.

The study was a pragmatic open-label trial, meaning both patients and researchers knew which group they were allocated to. This increases the risk of measurement bias for subjective measures, and participants receiving infusions were seen more frequently than the standard care group, meaning that they might either have had complications treated more promptly or could have received more attentive treatment.

These caveats are not unusual in pragmatic trials that seek to answer important questions in practice, and the biases are unlikely to have changed the direction of effect for objective outcomes such as mortality. A large number of patient exclusions were applied for this trial, limiting its generalisability.

What did it find?

  • Fewer people who received albumin infusions died during follow-up: 17% (38 of 218) compared with 22% of those who had usual care (46 of 213). Albumin reduced the risk of 18-month mortality by 38% (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.40 to 0.95).
  • Albumin infusions reduced the need for paracentesis. Only 12% of patients needed three or more drainage procedures each month compared with 29% receiving usual care alone (HR 0.33, 95% CI 0.19 to 0.58). Albumin also more than halved the rate of refractory ascites (HR 0.43, 95% CI 0.29 to 0.62). 
  • Albumin was associated with 45% reduction in total hospital days, from 19.39 days (95% CI 18.71 to 20.09) in the usual care group compared with 10.70 days (95% CI 10.27 to 11.15) in the albumin group. Albumin also reduced rates of other complications including bacterial infection, encephalopathy and kidney failure.
  • People in the usual care group showed greater decline in quality of life than people receiving albumin, as measured by standard questionnaires at 3, 6 and to 12 months. There was no difference between groups at 18 months.
  • From the Italian health service perspective, albumin treatment was estimated to cost an additional €2,488 each year with a 0.117 gain in quality-adjusted years of life (QALY). This was likely to be cost-effective at €21,265 per QALY, using the UK NICE benchmark of €35,000.

What does current guidance say on this issue?

NICE 2016 guidelines on management of cirrhosis recommend preventive oral antibiotics for people with ascites.

At the current time, NICE does not give any recommendation for or against the use of albumin infusions.

What are the implications?

The study suggests people with cirrhosis and uncomplicated ascites might live longer if they received regular intravenous albumin.

There are some caveats worth considering when interpreting this study and it remains uncertain whether some groups of patients might respond differently to albumin. 

Medium to long-term albumin treatment would be expensive. The reduced rate of complications and hospital admissions may off-set these costs, but a UK assessment of the cost-effectiveness shown here may be needed before this treatment could be recommended for usual care in the UK.

Citation and Funding

Caraceni P, Riggio O, Angeli P, et al; ANSWER Study Investigators. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial. Lancet. 2018;391(10138):2417-29.

This study was funded by the Italian Medicine Agency.

Bibliography

British Liver Trust. Cirrhosis of the liver. Bournemouth: British Liver Trust; 2018.

Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut. 2006;55 Suppl 6:vi1-12.

NICE. Cirrhosis in over 16s: assessment and management. NG50. London: National Institute for Health and Care Excellence; 2016.

Why was this study needed?

It is estimated that over 4,000 people die from cirrhosis in the UK each year. Average survival for people with decompensated (advanced) cirrhosis is two years. The condition places a high demand on the health service with frequent admissions to hospital for management of ascites and other complications such as internal bleeding and brain complications such as encephalopathy.

The build-up of fluid in the abdomen, ascites, is commonly managed using diuretics or by draining the fluid from the abdomen (paracentesis). Albumin may be able to address the underlying problem, keeping fluid in the circulation which would, in turn, support heart and kidney function.

Previous studies suggest a potential benefit from regular albumin infusions but were too small to draw firm conclusions on survival. This large multicentre randomised controlled trial, with 18-month follow-up, was pragmatic and intended to provide clear evidence about the effect of a regular albumin infusion protocol in clinical practice.   

What did this study do?

The ANSWER trial recruited 440 adults from 33 hospitals across Italy. Eligible participants had cirrhosis with uncomplicated ascites and were stable on diuretic treatment. Various exclusions were applied, including liver cancer, recent complications, organ failure and prior albumin treatment.

Participants were assigned to standard care only or with the addition of weekly intravenous albumin infusions (40g twice weekly for two weeks, then 40g weekly thereafter). Follow-up was 18 months.

The study was a pragmatic open-label trial, meaning both patients and researchers knew which group they were allocated to. This increases the risk of measurement bias for subjective measures, and participants receiving infusions were seen more frequently than the standard care group, meaning that they might either have had complications treated more promptly or could have received more attentive treatment.

These caveats are not unusual in pragmatic trials that seek to answer important questions in practice, and the biases are unlikely to have changed the direction of effect for objective outcomes such as mortality. A large number of patient exclusions were applied for this trial, limiting its generalisability.

What did it find?

  • Fewer people who received albumin infusions died during follow-up: 17% (38 of 218) compared with 22% of those who had usual care (46 of 213). Albumin reduced the risk of 18-month mortality by 38% (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.40 to 0.95).
  • Albumin infusions reduced the need for paracentesis. Only 12% of patients needed three or more drainage procedures each month compared with 29% receiving usual care alone (HR 0.33, 95% CI 0.19 to 0.58). Albumin also more than halved the rate of refractory ascites (HR 0.43, 95% CI 0.29 to 0.62). 
  • Albumin was associated with 45% reduction in total hospital days, from 19.39 days (95% CI 18.71 to 20.09) in the usual care group compared with 10.70 days (95% CI 10.27 to 11.15) in the albumin group. Albumin also reduced rates of other complications including bacterial infection, encephalopathy and kidney failure.
  • People in the usual care group showed greater decline in quality of life than people receiving albumin, as measured by standard questionnaires at 3, 6 and to 12 months. There was no difference between groups at 18 months.
  • From the Italian health service perspective, albumin treatment was estimated to cost an additional €2,488 each year with a 0.117 gain in quality-adjusted years of life (QALY). This was likely to be cost-effective at €21,265 per QALY, using the UK NICE benchmark of €35,000.

What does current guidance say on this issue?

NICE 2016 guidelines on management of cirrhosis recommend preventive oral antibiotics for people with ascites.

At the current time, NICE does not give any recommendation for or against the use of albumin infusions.

What are the implications?

The study suggests people with cirrhosis and uncomplicated ascites might live longer if they received regular intravenous albumin.

There are some caveats worth considering when interpreting this study and it remains uncertain whether some groups of patients might respond differently to albumin. 

Medium to long-term albumin treatment would be expensive. The reduced rate of complications and hospital admissions may off-set these costs, but a UK assessment of the cost-effectiveness shown here may be needed before this treatment could be recommended for usual care in the UK.

Citation and Funding

Caraceni P, Riggio O, Angeli P, et al; ANSWER Study Investigators. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial. Lancet. 2018;391(10138):2417-29.

This study was funded by the Italian Medicine Agency.

Bibliography

British Liver Trust. Cirrhosis of the liver. Bournemouth: British Liver Trust; 2018.

Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut. 2006;55 Suppl 6:vi1-12.

NICE. Cirrhosis in over 16s: assessment and management. NG50. London: National Institute for Health and Care Excellence; 2016.

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

Published on 5 June 2018

Caraceni, P.,Riggio, O.,Angeli, P.,Alessandria, C.,Neri, S.,Foschi, F. G.,Levantesi, F.,Airoldi, A.,Boccia, S.,Svegliati-Baroni, G.,Fagiuoli, S.,Romanelli, R. G.,Cozzolongo, R.,Di Marco, V.,Sangiovanni, V.,Morisco, F.,Toniutto, P.,Tortora, A.,De Marco, R.,Angelico, M.,Cacciola, I.,Elia, G.,Federico, A.,Massironi, S.,Guarisco, R.,Galioto, A.,Ballardini, G.,Rendina, M.,Nardelli, S.,Piano, S.,Elia, C.,Prestianni, L.,Cappa, F. M.,Cesarini, L.,Simone, L.,Pasquale, C.,Cavallin, M.,Andrealli, A.,Fidone, F.,Ruggeri, M.,Roncadori, A.,Baldassarre, M.,Tufoni, M.,Zaccherini, G.,Bernardi, M.

Lancet , 2018

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.

Decompensated cirrhosis is an advanced stage of liver disease in which the following symptoms may develop:

  • Jaundice
  • Bruising or bleeding
  • Fluid build up in the abdomen (ascites)
  • Problems with memory and concentration (hepatic encephalopathy)

Expert commentary

Ascites, a common feature of decompensated cirrhosis, is associated with high levels of morbidity and mortality. Standard treatment with aldosterone antagonists often relieves symptoms but has no impact on survival.

The ANSWER study resolves a persisting controversy on the use of intravenous albumin. In a well-designed, well-executed study the team has shown a survival benefit accompanied by important secondary endpoints such as lower requirement for drainage of intra-abdominal fluid, reduced incidence of cirrhosis complications and reduced hospital admissions.

This study will inevitably change clinical practice in this group of patients.

Mark Thursz, Professor of Hepatology, Imperial College London