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

  • Caraceni P, Riggio O, Angeli P, Alessandria C, Neri S, Foschi FG, et al.
  • Lancet. 2018;391:2417–29.

Cirrhosis of the liver is a leading cause of mortality, with 170,000 patients in Europe dying from the condition each year, equating to 1.8% of all deaths (Blachier et al., 2013). The condition is also the leading cause of disability worldwide and often has a poor prognosis (GBD 2015 Disease and Injury Incidence and Prevalence Collaborators, 2016); median survival of patients with a diagnosis of decompensated cirrhosis is just 2 years (D’Amico et al., 2006; Stepanova et al., 2017). The associated complications of decompensated cirrhosis – including ascites, gastrointestinal bleeding, hepatic encephalopathy, and jaundice (D’Amico et al., 2006) – often result in reduced quality of life (QoL). With the combined high prevalence, complications, and mortality rates, there is a financial strain on health-care systems (D’Amico et al., 2006; Stepanova et al., 2017). In an effort to ease this burden, Caraceni et al. investigated if long-term human albumin (HA) infusions could be part of the solution to this ongoing problem.

The current approach for treating decompensated cirrhosis relies on individual management of each complication. To reduce the burden on health-care systems and improve overall patient QoL and survival, an overall therapeutic strategy is required. One potential solution debated for decades, is long-term HA infusions, with some believing that HA may be able to target several of the pathophysiological mechanisms underlying decompensated cirrhosis (Ginés et al., 1987).

However, data surrounding the efficacy of this treatment is very limited. One study reported HA administration reduced the probability of developing ascites and reduced hospital readmissions, but no effect on survival was observed (Gentilini et al., 1999). A second study by the same investigators found HA improved transplant-free survival, but the small sample size meant that no firm conclusions could be drawn. As such, guidelines do not support the use of HA in this setting (Romanelli et al., 2006).

Questioning current guidelines: the ANSWER trial

Hoping to expand on the existing data with a larger sample of patients, the human Albumin for the treatmeNt of aScites in patients With hEpatic ciRrhosis (ANSWER) study was designed to investigate the long-term effectiveness of HA in patients with decompensated cirrhosis.

The ANSWER trial was an investigator-initiated, multicentre, randomised, parallel, open-label, pragmatic study carried out across 33 academic and non-academic hospitals in Italy between 2011–2015. Patients with cirrhosis and uncomplicated ascites despite ongoing diuretic treatment (an anti-aldosteronic drug ≥200 mg/day and furosemide ≥25 mg/day) were randomised to either receive standard medical treatment (SMT; n=213) or SMT plus HA (n=218).

The SMT plus HA group received intravenous infusions of 20% HA at a dose of 40 g twice weekly for the first 2 weeks, followed by 40 g weekly for up to 18 months.

Monthly assessments were performed up to 18 months or until study interruption or death. Study interruption occurred when liver transplantation was performed, transjugular intrahepatic portosystemic shunt (TIPS) was inserted, ≥3 therapeutic paracenteses per month were required, the patient refused to continue their participation within the study, or medical judgement deemed it necessary to interrupt the study. Study interruption was observed in both treatment arms of the study with 172 patients in the SMT group completing the trial and 176 patients in the SMT plus HA group.

Long-term HA infusions seen to increase survival

To measure the efficacy of long-term HA treatment, 18-month mortality was used as the primary endpoint. When comparing survival between the two treatment groups, a higher number of deaths were reported in the SMT group than the SMT plus HA group (46 vs. 38). This difference was significant when comparing all-cause mortality; the SMT plus HA group had 0.27 deaths per person-18 months (95% CI 0.19–0.37), whereas the SMT group had a reported 0.44 deaths per person-18 months (95% CI 0.32–0.80), resulting in an incidence rate ratio of 0.61 (95% CI 0.39–0.96; p=0.027).

Overall survival reflected similar results (K-M 77% SMT plus HA vs. 66% SMT; p=0.0285) leading to a 38% reduction in mortality HR (0.62 [95% CI 0.40–0.95]) (figure 1).

Kaplan-Meier estimates for probability of overall survival

Figure 1. Kaplan-Meier estimates for probability of overall survival (Caraceni et al., 2018).

A multivariate Cox regression analysis also estimated that 7 patients were to be treated to avoid one death at 18 months (95% CI 5–19). 

Cirrhosis management and complications

As well as the primary endpoint of 18-month mortality, a number of secondary endpoints were included, covering the management of cirrhosis, the number of refractory ascites, and the complications of cirrhosis.

Interestingly, not only was HA seen to be beneficial for survival, but also for the management of ascites. The probability of remaining free of paracentesis throughout the study was almost twice as high in the SMT plus HA group than the SMT group (K-M 62% vs. 34%; p<0.0001). This translated into an incidence rate of 3.5 cases per person-year for SMT and 1.55 cases per person-year for SMT plus HA – a 54% reduction.

The need for 3 or more paracentesis per month was also lower in the SMT plus HA group than the SMT group (K-M 12% vs. 29%; p<0.0001), with a risk reduction of 67% (HR 0.33 [95% CI 0.19–0.58]; p<0.0001). Furthermore, a significant difference in the number of refractory ascites was also observed a cumulative incidence of 0.25 in the SMT plus HA groups and 0.48 in the SMT group (p<0.0001).

The need to perform paracentesis may be subjective to the attending physician’s judgement, however, the mean volume tapped from each paracentesis was similar between the two treatment groups suggesting a fairly standard behaviour among physicians treating the two groups.

Treatment with HA also appeared to have a protective benefit from many of the common complications of cirrhosis; incidence rates were significantly reduced by 30–67.5% for spontaneous bacterial peritonitis (SBP), non-SBP bacterial infections, renal dysfunction, hepatorenal syndrome (HRS) type 1, hepatic encephalopathy grade 3 or 4, hyponatraemia and hyperkalaemia.

Long-term HA: a suitable future treatment?

The benefits of long-term HA appeared to go further than mortality and ascites management. Caraceni et al. also reported higher QoL scores, fewer hospital admissions and fewer days spent in hospital in the SMT plus HA group compared to the SMT group. When considering the wider benefits of HA as a treatment for cirrhosis, the number of hospital admissions is key to reducing the burden on health-care systems. Despite HA being considered an expensive treatment and the resource use required for weekly intravenous administrations, the analysis of this study found SMT plus HA to be below the threshold adopted by the National Institute of Health and Care Excellence (NICE) to consider the treatment cost-effective (McCabe et al., 2008).

Safety is also a key consideration; therefore, it is important to note that no significant difference was observed between the two treatment groups for grade 3–4 non-liver related adverse events. However, two cases of mild allergic reaction, one episode of dizziness and two cases of severe sepsis (one of which was possibly unrelated to HA infusion) were reported in the SMT plus HA group. Previous studies have indicated bleeding from oesophageal varices is linked to HA treatment due to blood volume expansion (Kunkel et al., 1948; Faloon et al., 1949; Wilkinson & Sherlock, 1962), therefore an important outcome of the ANSWER trial was that gastro-oesophageal variceal bleeding and related deaths were not increased.

Although this study is limited by the open-label approach, the results may reflect real-life clinical practice as treating physicians would be aware of the individual’s treatment regimen. In addition, patients in the SMT plus HA group were in contact with medical staff more frequently than those in the SMT group due to the nature of weekly infusions. This increased exposure may influence survival as adverse events would theoretically be treated more promptly. On the other hand, reported adverse events could be expected to be higher than the SMT group for this same reason. Although the difference in contact with medical staff may be considered a limitation of the study, weekly infusions of HA in real-life clinical practice would involve an increased frequency of routine appointments.

The results from this study offer evidence that long-term weekly HA administration can act as an effective disease-modifying treatment in patients with decompensated cirrhosis, providing ascites control, fewer associated complications and hospital admissions, and importantly increased survival. Further research is required to investigate if these benefits are seen in particular types of patients and if a serum albumin concentration threshold exists. Whether or not the current evidence is enough to influence clinical practice and change current guidelines remains to be seen.

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References

Blachier M, Leleu H, Peck-Radosavljevic M, Valla DC, Roudot-Thoraval F. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol. 2013;58:593–608.

Caraceni P, Riggio O, Angeli P, Alessandria C, Neri S, Foschi FG, et al. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial. Lancet. 2018;391:2417–29.

D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44:217–31.

Faloon WW, Eckhardt RD, Murphy TL, Cooper AM, Davidson CS. An evaluation of human serum albumin in the treatment of cirrhosis of the liver. J Clin Invest. 1949;28:583–94.

GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1545–602.

Gentilini P, Casini-Raggi V, Di Fiore G, Romanelli RG, Buzzelli G, Pinzani M, et al. Albumin improves the response to diuretics in patients with cirrhosis and ascites: results of a randomized, controlled trial. J Hepatol. 1999;30:639–45.

Ginés P, Quintero E, Arroyo V, Terés J, Bruguera M, Rimola A, et al. Compensated cirrhosis: natural history and prognostic factors. Hepatology. 1987;7:122–8.

Kunkel HG, Labby DH, Ahrens EH Jr, Shank RE, Hoagland CL. The use of concentrated human serum albumin in the treatment of cirrhosis of the liver. J Clin Invest. 1948;27:305–19.

McCabe C, Claxton K, Culyer AJ. The NICE cost-effectiveness threshold: what it is and what that means. Pharmacoeconomics. 2008;26:733–44.

Romanelli RG, La Villa G, Barletta G, Vizzutti F, Lanini F, Arena U, et al. Long-term albumin infusion improves survival in patients with cirrhosis and ascites: an unblinded randomized trial. World J Gastroenterol. 2006;12:1403–7.

Stepanova M, De Avila L, Afendy M, Younossi I, Pham H, Cable R, et al. Direct and indirect economic burden of chronic liver disease in the United States. Clin Gastroenterol Hepatol. 2017;15:759–66.

Wilkinson P, Sherlock S. The effect of repeated albumin infusions in patients with cirrhosis. Lancet. 1962;2:1125–9.

 

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