Long-term administration of human albumin improves survival in patients with cirrhosis and refractory ascites

  • Di Pascoli M, Fasolato S, Piano S, Bolognesi M, Angeli P.
  • Liver Int. 2018. [Epub ahead of print].

Approximately 60% of patients in the compensated stage of liver cirrhosis develop ascites within 10 years (Ginés et al., 1987) leading to worse outcomes, with mortality rates rising to 50% within 2–5 years of ascites development (Fernández‐Esparrach et al., 2001). Mobilising ascites is key to the treatment and management of the condition, however, approximately 10% of ascitic patients each year develop refractory ascites. The refractory nature of these ascites further worsens survival chances with the probability of 2-year survival dropping to 30% (Ginès et al., 2004; Salerno et al., 2010).

First-line treatment of refractory ascites is often large-volume paracentesis combined with an infusion of albumin (6–8 g/L of ascites removed) (Planas et al., 1990; Sola-Vera et al., 2003). However, large-volume paracentesis hasn’t been shown to reduce mortality. Another alternative treatment is transjugular intrahepatic portosystemic shunt (TIPS), but it has several contradictions and conflicting survival data (D’Amico et al., 2005; Salerno et al., 2007; Bureau et al., 2017).

The use of long-term albumin infusion is one potential solution that has been critiqued and discussed for a number of years. Existing literature has shown mixed results for increasing survival, with some studies showing long-term treatment to be effective in preventing ascites (Gentilini et al., 1999) and others showing that the treatment can reduce ascites recurrence, complications and mortality (Romanelli et al., 2006; Caraceni et al., 2018). In contrast, Solà et al. didn’t find a positive effect on complication development or mortality (Solà et al., 2017), although the dose used by Solà et al. was half of that used by Caraceni et al.

However, the potential benefits of long-term albumin treatment for refractory ascites remain unknown. In this non-randomised, prospective study, 70 patients were recruited and given the option to receive human albumin at a dose of 20 g twice per week in addition to standard of care (SOC) or receive SOC alone (all patients received an infusion of albumin during paracentesis). A total of 45 patients opted for the albumin plus SOC treatment while the remaining 25 patients opted for SOC treatment alone.

Patients were followed until end of the study, liver transplant, or death; mean follow up time was 400.8 ± 256.8 days in the albumin group and 318.7 ± 275.8 days for the SOC group. Despite being a non-randomised study, patients’ baseline characteristics didn’t vary significantly between the two treatment arms.

Surviving liver cirrhosis with refractory ascites

During the first 24 months of treatment 15 patients died in each treatment arm. A significant difference was seen when comparing the cumulative incidence of 24-month mortality, with the albumin group having a significantly lower mortality rate compared to the SOC group (41.6% vs. 65.5%; p=0.032) (figure 1). The higher cumulative incidence of mortality seen within the SOC group reflects similar results seen in other studies of patients with cirrhosis and refractory ascites, demonstrating the limited positive effects of SOC on survival (Rössle et al., 2000; Gines et al., 2002). Despite the difference, similar causes of death were observed between the two groups, with terminal hepatic failure, hepatocellular carcinoma (HCC), and spontaneous bacterial peritonitis (SBP) being the most common causes.

Cumulative incidence of mortality over 24 months

Figure 1. Cumulative incidence of mortality over 24 months (Di Pascoli et al., 2018).

Multivariate analysis revealed age (subdistribution hazard ratio [sHR] = 1.05; p=0.004), model for end-stage liver disease (MELD) (sHR = 1.08; p=0.017), and long-term albumin treatment (sHR = 0.49; p=0.047) to be independent predictors of mortality.

Is it possible to prevent emergency hospitalisations?

One of the secondary end-points of this study was the rate of emergency hospitalisations. Given the poor prognosis of liver cirrhosis and the associated complications, hospitalisations are a common occurrence. Long-term treatment with albumin resulted in the albumin group experiencing longer periods free of emergent hospitalisations than those in the SOC group (p=0.008) (figure 2).

Infections and ascites were the most common reasons for hospitalisation in both treatment groups. However, the probability of being hospitalised within 24 months due to hepatic encephalopathy (HE) (26.9% vs. 64.5%; p=0.016), tense ascites (37.1% vs. 71%; p=0.002), SBP (7.9% vs. 50.6%; p=0.004), and non-SBP infections (27.2% vs. 88.6%; p=0.001), were significantly lower in the albumin group compared to the SOC group.

The probability of being free from emergency hospitalisations over 24-months after undergoing long-term albumin infusion or SOC

Figure 2. The probability of being free from emergency hospitalisations over 24-months after undergoing long-term albumin infusion or SOC (Di Pascoli et al., 2018).

Large-volume paracentesis: frequency, volume, and complications

Interestingly, the number of paracentesis and volume of fluid removed wasn’t significantly different between the two treatment groups, although a trend towards fewer paracenteses (1.8 ± 1.2 vs. 2.2 ± 1.3) and reduced volume (12.7 ± 11.1 vs. 15.1 ± 10.3) were seen in the albumin group compared to the SOC group. One hypothesis for the volume removed remaining high in the albumin group, despite reducing emergent hospitalisations, is that the long-term use of albumin limits episodes of rapid ascites development.

A complication which can be of concern is ascites liquid infection. Polymorphonuclear (PMN) leucocytes and culture test of the ascitic fluid were performed on each paracentesis, finding very low incidences of SBP (0.1%), culture-negative neutrocytic ascites (CNNA) (0.4%), and monomicrobial non‐neutrocytic bacterascites (MNNB) (1.1%).

Despite this study being limited due to the single-centre and non-randomised nature, it has demonstrated the potential benefits of long-term albumin on survival and emergent hospitalisations compared to SOC in patients with liver cirrhosis and refractory ascites. Increasing survival is key for patients waiting for liver transplant, as the waiting lists are often long and unpredictable. Could treatment with long-term albumin, therefore be a viable treatment option for patients awaiting liver transplant? To fully answer this question, and the ongoing debate of long-term albumin use, additional larger, multicentre, randomised trials are needed to further assess its efficacy in this patient population.

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References

Bureau C, Thabut D, Oberti F, Dharancy S, Carbonell N, Bouvier A, et al. Transjugular intrahepatic portosystemic shunts with covered stents increase transplant-free survival of patients with cirrhosis and recurrent ascites. Gastroenterology. 2017;152:157–63.

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, Luca A, Morabito A, Miragalia R, D’Amico M. Uncovered transjugular intrahepatic portosystemic shunt for refractory ascites: a meta‐analysis. Gastroenterology. 2005;129:1282–93.

Di Pascoli M, Fasolato S, Piano S, Bolognesi M, Angeli P. Long-term administration of human albumin improves survival in patients with cirrhosis and refractory ascites. Liver Int. 2018. [Epub ahead of print].

Fernández‐Esparrach G, Sánchez‐Fueyo A, Ginès P, Uriz J, Quintó L, Ventura PJ, et al. A prognostic model for predicting survival in cirrhosis with ascites. J Hepatol. 2001;34:46–52.

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.

Ginès P, Cárdenas A, Arroyo V, Rodés J. Management of cirrhosis and ascites. N Engl J Med. 2004;350:1646–54.

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.

Planas R, Ginès P, Arroyo V, Llach J, Panés J, Vargas V, et al. Dextran-70 versus albumin as plasma expanders in cirrhotic patients with tense ascites treated with total paracentesis. Results of a randomized study. Gastroenterology. 1990;99:1736–44.

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.

Rössle M, Ochs A, Gülberg V, Siegerstetter V, Holl Jm Deibert P, et al. A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with ascites. N Engl J Med. 2000;342:1701–7.

Salerno F, Cammà C, Enea M, Rössle M, Wong F. Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta‐analysis of individual patient data. Gastroenterology. 2007;133:825–34.

Salerno F, Guevara M, Bernardi M, Moreau R, Wong F, Angeli P, et al. Refractory ascites: pathogenesis, definition and therapy of a severe complication in patients with cirrhosis. Liver Int. 2010;30:937–47.

Solà E, Solé C, Simón‐Talero M, Martín-Llahí M, Castellote J, Garcia-Martínez R, et al. Midodrine and albumin for prevention of complications of cirrhosis in patients in the waiting list for liver transplantation. A randomized, multicenter, double-blind, placebo-controlled trial. J Hepatol. 2017;66:11.

 

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