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

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1 Received: 3 May 2018 Revised: 2 August 2018 Accepted: 12 September 2018 DOI: /liv CIRRHOSIS AND LIVER FAILURE Long term administration of human albumin improves survival in patients with cirrhosis and refractory ascites Marco Di Pascoli Silvano Fasolato Salvatore Piano Massimo Bolognesi Paolo Angeli Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine DIMED, University of Padova, Padova, Italy Correspondence Marco Di Pascoli, Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine DIMED, University of Padova, Padova, Italy. marco.dipascoli@unipd.it Handling Editor: Dominique Thabut Abstract Background & Aims: In patients with cirrhosis, the clinical benefit of the treatment with human albumin for ascites is debated, and no data are available regarding refractory ascites. In this study, in patients with cirrhosis and refractory ascites, we assessed the effect of long term albumin administration on emergent hospitalization and mortality. Methods: Seventy patients with cirrhosis and refractory ascites, followed at the Unit of Internal Medicine and Hepatology, University and General Hospital of Padova, Italy, were included into the study. Forty five patients were non randomly assigned to receive long term administration of human albumin at the doses of 20 g twice per week (n = 45), in addition to standard medical of care (SOC), and compared to those followed according to SOC. Patients were followed up to the end of the study, liver transplantation or death. Results: The cumulative incidence of 24 month mortality was significantly lower in patients treated with albumin than in the group of patients treated with SOC (41.6% vs 65.5%; P = 0.032). The period free of emergent hospitalization was significantly longer in patients treated with long term administration of albumin (P = 0.008). Analysing separately the causes of inpatient admission, patients treated with albumin showed a reduction in the incidence of overt hepatic encephalopathy, ascites, spontaneous bacterial peritonitis (SBP) and non SBP infections. In addition, a nonsignificant trend towards a reduced probability of hepatorenal syndrome was observed. Conclusion: In patients with cirrhosis and refractory ascites, long term treatment with albumin improves survival and reduces the probability of emergent hospitalizations. KEYWORDS cirrhosis, hospitalization, human albumin, refractory ascites See Editorial on Page 45 Abbreviations: CNNA, culture negative neutrocytic ascites; DH, Day Hospital; HCC, hepatocellular carcinoma; HE, hepatic encephalopathy; HRS, hepatorenal syndrome; LT, liver transplantation; MELD, model for end stage liver disease; MNNB, monomicrobial non neutrocytic bacterascites; NSBB, nonselective beta adrenergic blockers; PMN, polymorphonuclear; SBP, spontaneous bacterial peritonitis; SOC, standard of care; TIPS, transjugular intrahepatic portosystemic shunt John Wiley & Sons A/S. wileyonlinelibrary.com/journal/liv Liver International. 2019;39: Published by John Wiley & Sons Ltd

2 99 1 INTRODUCTION Among the complications of cirrhosis, ascites is the most common. About 60% of patients with compensated cirrhosis develop ascites within 10 years. 1 In cirrhosis, portal hypertension, due to increased intrahepatic resistance and splanchnic blood flow, 2,3 is the main underlying physiopathological condition for the onset of ascites, since it results in an increased pressure in the splanchnic capillaries with an excess of fluid localization in the peritoneal cavity. Moreover, plasma volume expansion secondary to renal water and sodium retention fuels ascites formation. 4 Ascites is the complication which is most frequently responsible for hospital admission in patients with cirrhosis. 5,6 Moreover, the development of ascites is a relevant unfavourable prognostic factor in cirrhosis since, after its occurrence, the mortality rate rises up to 50% within 2 5 years. 7 Refractory ascites is a clinical condition characterized by the inability to resolve ascites through standard medical treatment with low sodium diet and diuretic medications. This may be due to the fact that either diuretic is inadequate to determine a natriuretic effect or their use causes the development of severe side effects, compelling the patient to discontinue them. 8 Refractory ascites occurs in about 10% of ascitic patients per year. 9 In cirrhotic patients with ascites, the onset of its refractoriness worsens the probability of 2 year survival to approximately 30%. 10 Large volume paracentesis combined with intravenous infusion of albumin (6 8 g/l of ascites removed) is the first line treatment for refractory ascites. 11,12 Transjugular intrahepatic portosystemic shunt (TIPS), by reducing portal pressure, hinders the formation of ascites and is another therapeutic option. On the other hand, large volume paracentesis do not decrease mortality and the use of TIPS is limited due to the considerable number of patients with contraindications and conflicting results on survival ; therefore, these patients should be evaluated as soon as possible for liver transplant (LT) candidacy. The clinical benefit of human albumin long term administration for the treatment of ascites is debated, since the definitive scientific evidence supporting its use is lacking, and especially for refractory ascites, no data are available. Therefore, in this study, we assessed in patients with cirrhosis and refractory ascites the effectiveness of prolonged albumin administration on survival, occurrence of hospitalization due to cirrhosis complications and recurrence of ascites. 2 METHODS 2.1 Study design This is a non randomized prospective study in which patients with cirrhosis and refractory ascites, followed for the execution of repeated large volume paracenteses at the Day Hospital (DH) of the Unit of Internal Medicine and Hepatology (UIMH), University and General Hospital of Padova, Italy, were consecutively enrolled from January 2012 to June When ascites was tense, paracentesis was executed and ascitic fluid was removed as much as possible, to extend the interval to the next paracentesis. Key points Long term treatment with albumin reduces the incidence of 24 month mortality in patients with cirrhosis and refractory ascites. The beneficial effect of albumin on survival is associated with a reduced probability of hospitalization due to overt hepatic encephalopathy, ascites, spontaneous bacterial peritonitis (SBP) and non SBP infections. Inclusion criteria were as follows: (a) cirrhosis as diagnosed by liver biopsy or clinical, biochemical, ultrasound and/or endoscopic findings; (b) age >18 years; and (c) diagnosis of refractory ascites as defined by the criteria of the International Club of Ascites. 16 Patients affected by hepatocellular carcinoma (HCC) beyond Milan criteria (n = 10) or severe extrahepatic diseases (n = 4) were excluded from the study. No patients had undergone TIPS. One patient had undergone liver transplantation 5 years before the occurrence of refractory ascites due to recurrence of cirrhosis and was included in the study. The protocol was approved by the Ethics Committee of the University and General Hospital of Padova. Patients signed informed consent according to local regulation for this kind of studies. All the consecutive patients referred to the DH of our Unit who met the inclusion and exclusion criteria (n = 70) were included into the study. At the time of the inclusion, coinciding with the day when refractory ascites was diagnosed, all patients were offered the treatment with human albumin at the doses of 20 g twice per week, administered by nursing staff at their home or at their referral health centre, in addition to standard of care (SOC) including moderate dietary sodium restriction and the maximal daily tolerated doses of diuretics. Forty five patients accepted the treatment with longterm albumin and were compared with the others (n = 25) who were followed according to SOC. When large volume paracentesis was needed, all patients also received albumin at the dose of 6 8 g/l of ascites removed. 9 In both groups, patients were followed up within the care management programme of our unit and checked up at least monthly as previously described. 17 When ascites was found to be tense at the scheduled visit, paracenteses were executed within a maximum of 2 days. In addition, in case of the occurrence of tense ascites in the timeframe between two visits, patients were instructed to take contact with the DH service to plan the paracentesis. Patient demographics, clinical data, laboratory data and prognostic scores (ie, Child Pugh, MELD and MELD Na scores) were recorded at the time of inclusion. A physical examination and laboratory tests, including polymorphonuclear (PMN) leucocytes count and culture test of the ascitic fluid, were performed at each access to the DH during follow up. Spontaneous bacterial peritonitis (SBP) was diagnosed as

3 100 TABLE 1 Demographic, clinical and laboratory features of analysed patients according to treatment Feature Albumin (n = 45) Standard of care (n = 25) Age, y 64.2 ± ± Sex, male/female 31/14 15/ Aetiology, viral/ not viral Serum albumin, g/l Serum total bilirubin, µmol/l International normalized ratio Serum creatinine, µmol/l Baseline CTP score Baseline MELD score 15/30 9/ ± ± ± ± ± ± ± ± ± ± ± ± HCC 9 (20.0%) 5 (20.0%) 1 Previous episode of HE Previous episode of SBP Previous episode of HRS Previous episode of variceal bleeding 11 (24.4%) 6 (24.0%) (15.6%) 5 (20.0%) (11.1%) 2 (8.0%) (13.3%) 2 (8.0%) 0.50 NSBB therapy 19 (42.2%) 11 (44%) 0.89 CTP, Child Turcotte Pugh; HCC, hepatocellular carcinoma; HE, hepatic encephalopathy; HRS, hepatorenal syndrome; MELD, model for endstage liver disease; NSBB, nonselective beta adrenergic blockers; SBP, spontaneous bacterial peritonitis. an ascitic fluid PMN count >250/mm 3 with positive culture; culturenegative neutrocytic ascites (CNNA) was diagnosed as an ascitic fluid PMN count >250/mm 3 with negative culture and has a prognosis similar to SBP; monomicrobial non neutrocytic bacterascites (MNNB), which usually represents a transient and spontaneously reversible colonization of ascites or a contamination of the sample during collection, was diagnosed when cultures were positive but ascitic PNM count was normal. 8,18 Patients were followed up till the end of the study, LT or death. No patients underwent TIPS insertion during follow up, as this strategy was only recently implemented in our Hospital. The primary end point of the study was 24 month mortality. Secondary end points were as follows: (a) rate of emergent hospitalization due to any complication of cirrhosis, hepatorenal syndrome (HRS), SBP, infections other than SBP, overt hepatic encephalopathy (HE), gastrointestinal bleeding; (b) the number of paracentesis executed and the volume of ascitic liquid removed monthly; (c) incidence of asymptomatic ascitic fluid infection, as shown by PMN leucocytes count and culture test positivity. P 2.2 Statistical analysis Continuous data are reported as mean and standard deviation (SD), while categorical variables are reported as frequency and proportion. Comparisons between groups were performed through the Student t test for normally distributed continuous data, the Mann Whitney U test for non normally distributed continuous data, and the chi square test or Fisher s exact test for categorical data. Cumulative incidence of death was calculated considering liver transplant a competing event. Cumulative incidence curves were compared using Gray s test. Incidence of complications of cirrhosis was calculated using the Kaplan Meier method and compared with the log rank test. Patients who died or were transplanted during the follow up were censored at the time of death or transplant. Univariate and multivariate Cox regression analyses of predictors of mortality at 24 month were performed using a competing risk approach with the Fine and Gray method and results expressed as P value, subdistribution hazard ratios (shr) and their 95% confidence intervals (95% CI). Variables found to be associated with in hospital mortality with a P value < 0.1 in the univariate analysis were included in a multivariate analysis, with stepwise backward elimination (entry P < 0.05; drop P > 0.1). When scores of liver disease were included in the model, their components were excluded to avoid multicollinearity. Statistical analyses of the data were performed using the SPSS statistical package (version 23.0; SPSS Inc, Chicago, IL, USA) and SAS 9.4 for Windows (SAS Institute Inc, Cary, NC, USA). All tests were two tailed, and P < 0.05 was considered statistically significant. 3 RESULTS 3.1 Patients A total of 70 patients with cirrhosis and refractory were included in the study. The mean follow up of patients was of 408 ± 394 days. Twenty five patients received SOC while 45 patients received also long term administration of human albumin. The mean total weekly dose of albumin administered in patients treated with long term albumin was 60.7 ± 15.2 g (being 20.7 ± 15.2 g the mean weekly dose of albumin administered during paracentesis), vs 22 ± 14.1 g in the SOC group (P < 0.001). No significant difference in clinical and laboratory data was present at baseline between the two groups (Table 1). Thirty patients were on treatment with nonselective beta adrenergic blockers (NSBB) for variceal bleeding prophylaxis (propranolol, mean total daily dose of 40.4 ± 20.3 mg). More in detail, no difference existed between the group of patients treated with SOC and the one of patients who received albumin as regards the proportion on treatment with NSBB (44% vs 42.2%, P = NS) and the mean daily dose of drug used (propranolol 42.2 ± 18.6 mg vs 39.4 ± 21.5 mg, P = NS). The mean follow up was ± days in the group of patients treated with albumin and ± days in the group of patients treated with SOC (P = NS).

4 Mortality During the first 24 months of follow up, 15 patients in the albumin group and 15 patients in the SOC group died. The causes of death in the group of patients treated with long term albumin were terminal hepatic failure (n = 5), HCC (n = 3), SBP (n = 1), non SBP infection (n = 1), HRS (n = 1), multiorgan failure (n = 1), brain haemorrhage (n = 1), other than HCC malignancy (n = 1), sudden death (n = 1), while in the group of patients treated with SOC were SBP (n = 4), terminal hepatic failure (n = 3), HCC (n = 3), HRS (n = 2), multiorgan failure (n = 2), non SBP infection (n = 1). During the same period of time, five patients in the albumin group and two patients in the SOC group underwent LT. The cumulative incidence of 24 month mortality was significantly lower in patients treated with long term administration of albumin than in those treated with SOC (41.6% vs 65.5%; P = 0.032; Figure 1). On univariate analysis, besides long term treatment with albumin, age, serum albumin and INR, and Child Turcotte Pugh at baseline were found to be associated with the risk of mortality, while only a trend was found for bilirubin and MELD score. Interestingly, the use of NSBB was not associated with an increased risk of mortality. On multivariate analysis, age (shr = 1.05; P = 0.004), MELD (shr = 1.08; P = 0.017) and long term treatment with albumin (shr = 0.49; P = 0.047) were found to be independent predictors of mortality (Table 2). 3.3 Hospitalizations The period free of emergent hospitalization was significantly longer in patients treated with albumin than those treated with SOC TABLE 2 Predictors of mortality Parameter shr 95% CI P Univariate analysis Treatment with albumin Age, y Sex (male) Aetiology (viral) Presence of HCC Therapy with NSBB Baseline serum creatinine, µmol/l Baseline serum total bilirubin, umol/l Baseline international normalized ratio Baseline albumin, g/l Baseline MELD Baseline CTP Presence of varices Multivariate analysis Treatment with albumin Age, y Baseline MELD CI, confidence interval; CTP, Child Turcotte Pugh; HCC, hepatocellular carcinoma; MELD, model for end stage liver disease; NSBB: nonselective beta adrenergic blockers; shr, subdistribution hazard ratio. FIGURE 1 In patients with cirrhosis and refractory ascites, the cumulative incidence of 24 mo mortality was significantly reduced by long term administration of albumin compared to treatment according to standard of care FIGURE 2 In patients with cirrhosis and refractory ascites, longterm administration of albumin significantly improved the 24 mo probability of being free from emergent hospitalizations

5 102 TABLE 3 Probability of emergent hospitalization due to complications of cirrhosis during the 24 mo follow up Complication Albumin (%) (Figure 2). The main causes of emergent hospitalization in both groups were infections and ascites (Table 3). Compared to patients in the SOC group, in patients treated with long term administration of albumin, the 24 month probability of inpatient admission due to HE (64.5% vs 26.9%; P = 0.016), tense ascites (71.0% vs 37.1%; P = 0.002), SBP (50.6% vs 7.9%; P = 0.004) and non SBP infections (88.6% vs 27.2%; P = 0.001) was significantly reduced. In addition, there was a non significant trend towards a reduced probability of HRS (57.7% vs 22.5%; P = NS), and no difference was found between the two groups regarding the occurrence of variceal bleeding (4.5% vs 2.4%; P = NS; Figure 3; Table 3). 3.4 Resort to paracentesis Standard of care (%) HRS 22.5% 57.7% HE 26.9% 64.5% Ascites 37.1% 71.0% SBP 7.9% 50.6% Non SBP infection 27.2% 88.6% Variceal bleeding 2.4% 4.5% HE, hepatic encephalopathy; HRS, hepatorenal syndrome; SBP, spontaneous bacterial peritonitis. During the follow up period, a total of 1970 paracenteses were performed. Three major complications due to the procedure were observed (0.15%): two cases of hemoperitoneum and one of persistent dripping of ascitic liquid after needle removal. Patients with hemoperitoneum were transferred to the ward, and in one case, transfusion of red blood cell concentrate was needed for anaemia. No fatal events caused by the procedure occurred. Only a non significant trend towards a reduction of number and volume of paracentesis was observed in patients treated with albumin: the number of monthly paracentesis was 1.8 ± 1.2 vs 2.2 ± 1.3 in those in the SOC group, the monthly litres of ascites removed were 12.7 ± 11.1 vs 15.1 ± 10.3 in those in the SOC group. 3.5 Asymptomatic ascitic liquid infection For each therapeutic paracentesis, PMN leucocytes count and culture test of the ascitic fluid were performed. SBP occurred in two cases (0.1%). CNNA was diagnosed in seven cases (0.4%), and MNNB in 22 cases (1.1%). No differences in the probability of asymptomatic SBP, CNNA and MNNB were observed between patients treated with long term administration of albumin and patients in the SOC group (respectively, 0.1% vs 0%, 0.3% vs 0.5%, 1.0% vs 1.5%; P = NS). The bacterial species identified are listed in Table 4. P 4 DISCUSSION In cirrhosis, refractory ascites is defined as ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of inadequate response to sodium restriction and diuretic therapy or the development of diuretic induced complications, such as hyponatremia and HE, that impede the use of an effective dosage. 9 For refractory ascites, the treatment of choice is large volume paracentesis in outpatient clinic, but TIPS and LT should be also considered. In this study, we examined in patients with refractory ascites the effect of prolonged albumin administration on survival, hospitalization due to cirrhosis complications and recurrence of ascites. Till now, no data have been published regarding long term treatment with albumin for refractory ascites. In one study, long term treatment with albumin has been shown to be effective in preventing recurrence of ascites in patients with cirrhosis, 19 while in another cohort of patients admitted for first onset of ascites, the chronic administration of albumin reduced not only ascites recurrence but also mortality. 20 These results were recently confirmed in a large multicentre randomized clinical trial, showing that in patients with cirrhosis and non refractory ascites, long term administration of human albumin at the same doses used in our present study ameliorates the control on ascites formation, reduces complications and improves survival. 21 On the other hand, in patients with cirrhosis in the waiting list for liver transplantation, Solà et al 22 did not confirm a positive effect of albumin in association with midodrine on complications development and mortality, but it is noteworthy that the dose of albumin administered was half compared to the one used in our study. In Italy, human albumin can be prescribed for the treatment of ascites within the national health system, but out of hospital prescriptions are reimbursable only for patients with ascites that is not responsive to standard diuretic therapy. On the other hand, this therapeutic strategy at the moment is not recommended by international guidelines. In our study, patients treated with SOC had a cumulative incidence of 24 month mortality of 65%, which is very similar to the results of previous randomized studies carried out in patients with cirrhosis and refractory ascites. 23,24 Longterm treatment with albumin at the doses of 20 g twice per week significantly improved survival and therefore may be considered as a novel strategy, especially for patients in waiting list for LT, who could benefit most from a lengthening of life expectancy. In the group of patients treated with SOC, ascitic decompensation and HE were the main causes of hospitalization, similarly to the general population of patients with cirrhosis. 6 Even if albumin administration did not reduce significantly the frequency and volume of paracentesis performed at DH, it prevented admissions as inpatient. In particular, long term treatment with albumin significantly reduced emergent hospitalizations due to HE, SBP and other infections, and ascitic decompensation. It is not clear to us why albumin prevented emergent hospitalizations due to tense ascites but did not affect the amount of ascites monthly removed. We speculate that long term administration of albumin may limit episodes

6 103 FIGURE 3 In patients with cirrhosis and refractory ascites, long term administration of albumin significantly improved the 24 mo probability of being free from emergent hospitalizations due to ascites, hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP) and non SBP infections, while it determined a non significant trend towards a reduced probability of hepatorenal syndrome (HRS), and no differences were found regarding the occurrence of variceal bleeding compared to treatment according to standard of care of rapid development of ascites, which may have encouraged patients to refer to emergency room instead of the DH service. We hypothesize that the positive effect of albumin on survival and the onset of cirrhosis complications may be secondary to its beneficial effects on haemodynamics, nutrition status and scavenging of endogenous and exogenous toxic substances. The use of NSBB in patients in the decompensated stage of cirrhosis has been widely debated in the recent years. Different studies led to opposite conclusions about their safety, 25 and in Baveno VI consensus, NSBB dose reduction or discontinuation was suggested in patients with refractory ascites, if they display hypotension, renal failure or hyponatremia. This study supports the results of the retrospective study by Robins et al, 26 showing that low doses of NSBB do not affect survival, while deleterious effects may occur when higher doses are administered. 27 A total of 1970 paracenteses were performed in this study and, as major complications, two cases of hemoperitoneum and one of persistent dripping of ascitic fluid after needle removal occurred.

7 104 TABLE 4 Bacteria responsible for spontaneous bacterial peritonitis and monomicrobial non neutrocytic bacterascites, identified in the series of 1970 paracenteses SBP MNNB 1 Escherichia coli 6 Staphylococcus epidermidis 1 Streptococcus salivarius 3 Escherichia coli 2 Stenotrophomonas maltophilia 2 Streptococcus salivarius 1 Enterococcus caseliflavus 1 Enterococcus faecium 1 Kocuria varians 1 Leuconostoc mesenteroides 1 Pantoea agglomerans 1 Rothia mucilaginosa 1 Serratia marcescens 1 Staphylococcus haemoliticus 1 Staphylococcus warneri MNNB, monomicrobial non neutrocytic bacterascites; SBP, spontaneous bacterial peritonitis. These data confirm that the occurrence of hemoperitoneum due to paracentesis performance is a very rare event (0.1%), being the risk even lower than that reported in set of data from other studies (0.5% 1%), 28,29 and that paracentesis is generally a very safe procedure. In the setting of routine outpatient therapeutic paracentesis, also ascitic fluid infection is a rare eventuality. Indeed, SPB, CNNA and MNNB were diagnosed in 0.1%, 0.4% and 1.1% of the procedures respectively. The prevalence of MNNB was probably even lower, considering that species like Staphylococcus epidermidis are likely contaminants. These results confirmed the ones from previous studies that evaluated the prevalence of SBP (0% 0.1%) and MNNB (0% 3%) in smaller settings of paracenteses. 30 Gram negative bacilli, especially Escherichia coli, and Streptococcus are the major causes of SBP and the most common isolates from ascitic fluid cultures, 31 and our study, that analysed bacteria isolation in large volume paracentesis, is in line with these data. Because of the very low rate of positive tests and the absence of randomized trials showing a benefit from testing all the patients for ascitic PMN count and culture, the opportunity of this approach is still debated. It has to be underlined that during follow up, no patients underwent insertion of TIPS, which is a recognized good option for the treatment of refractory ascites, since this strategy was only recently implemented in our Hospital. The main limitations of this study are that it was conducted in a single centre and patients were not randomized to treatment, while the division of patients into the two groups was based on their acceptance to be treated long term with albumin, which may introduce a selection bias. Large multicentre randomized clinical trials are needed to validate the strategy of long term albumin administration in patients with cirrhosis and refractory ascites. In conclusion, in patients with cirrhosis and refractory ascites, long term treatment with albumin significantly improved survival and reduced inpatient hospitalization. Large volume paracentesis is a safe procedure, and the prevalence of asymptomatic ascitic fluid infection is low. 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