HPE Human albumin handbook | Page 19

that the beneficial effects of albumin were only seen in patients receiving an intermediate dose of diuretics ( K-canrenoate 200mg / day plus furosemide 25mg / day ), and the cost / benefit ratio was only favourable to albumin in the first in-hospital part of the study . A subsequent trial performed by the same research group in 100 consecutive cirrhotic patients admitted for first-onset ascites and followed for a median time of 84 months , reported that longterm albumin administration ( 25g / week for the first year , then 25g every two weeks ) was able to reduce ascites recurrence and increase patient survival with respect to standard medical treatment . 27 Unfortunately , the relatively low number of patients in this study prevented to reach firm conclusions and , at present , long-term albumin treatment in this patient setting is not recommended by current guidelines . 11
Over the last year , three studies assessing the effect of long-term albumin administration to patients with decompensated cirrhosis were published . The ANSWER study , a non-profit , multicentre , randomised , open-label , pragmatic clinical trial enrolled patients with cirrhosis and persisting non-complicated ascites . 28 Patients were randomised to either standard medical treatment ( SMT ; 213 patients ), which included albumin administration for well-established indications , or SMT plus 40g albumin ( HA ) twice a week for the initial two weeks and then 40g / week ( 218 patients ). The primary endpoint , 18-month overall mortality , was reached , as a significantly lower mortality was seen in the albumin arm . As far as the secondary endpoints were concerned , the cumulative incidence rate of paracentesis was reduced by 54 % and the incidence of refractory ascites by 46 % in the SMT + HA arm .
The cumulative incidence of complications of cirrhosis , including SBP , non-SBP bacterial infections , episodes of renal dysfunction , hyponatremia , hyperkalaemia , HRS and severe HE , was also significantly lowered by albumin administration . The ANSWER study also assessed quality of life , which ameliorated in the SMT + HA arm , and the number and duration of hospitalisations , which were significantly reduced .
Long-term albumin treatment appears a promising treatment in decompensated cirrhosis , able to not only ease the control of ascites , but also to influence the course of the disease
Therefore , long-term albumin administration resulted to be cost-effective .
The main results of the ANSWER trial have been confirmed by a prospective , non-randomised clinical trial , which enrolled patients with cirrhosis and refractory ascites . 29 The 45 patients who received albumin ( 20g twice a week ) up to 24 months had a significantly lower mortality than the 25 patients receiving the standard of care . Moreover , the cumulative incidence of re-hospitalizations due to complications of cirrhosis , such as hepatic encephalopathy , accumulation of ascites and bacterial infections , was significantly lower in patients treated with albumin . However , the midodrine albumin in cirrhotic patients awaiting liver transplantation ( MACHT ) study , challenged these results . 30 This placebo controlled clinical trial randomised 87 patients to receive either 40g albumin every 15 days plus the α 1
-receptor agonist midodrine ( from 15 to 30mg / day according to their pressor response ) and 86 to receive SMT and placebos for a planned follow up of 12 months . Despite a mild improvement in effective volaemia , no differences were seen in either the probability of developing complications , which was the primary end-point of the study or survival .
The discrepancies between these studies can be explained by differences in protocol , patient characteristics , sample size , and , mainly , albumin dose and duration of its administration . In fact , treatment largely exceeded one year in the ANSWER study , while was about two months in the MACHT trial due to high rate of liver transplantation . Furthermore , the amount of albumin administered in the MACHT trial was about half with respect to the ANSWER study . This accounts for the lack of effect on serum albumin concentration in the former , while a significant and sustained increase by 0.6 – 0.8g / l occurred in the latter .
Although several issues pertaining to patient features and dose and schedule of albumin administration require further investigation , longterm albumin treatment appears a most promising treatment for patients with decompensated cirrhosis , able to not only ease the control of ascites , but also to influence the course of the disease .
References 1 Garcia-Martinez R et al . Albumin : Pathophysiologic basis of its role in the treatment of cirrhosis and its complications . Hepatology 2013 ; 58:1836 – 46 . 2 Jalan R et al . Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality . Hepatology 2009 ; 50:555 – 64 . 3 Oettl K et al . Oxidative albumin damage in chronic liver failure : relation to albumin binding capacity , liver dysfunction and survival . J Hepatol 2013 ; 59 : 978 – 83 . 4 Domenicali M et al . Posttranscriptional changes of serum albumin : clinical and prognostic significance in hospitalized patients with cirrhosis . Hepatology 2014 ; 60:1851 – 60 . 5 O ’ Brien AJ et al . Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2 . Nat Med 2014 ; 20:518 – 23 . 6 Bernardi M et al . Mechanisms of decompensation and organ failure in cirrhosis : From peripheral arterial vasodilation to systemic inflammation
hypothesis . J Hepatol 2015 ; 63:1272 – 84 . 7 Wong F et al . International Ascites Club . Sepsis in cirrhosis : report on the 7th meeting of the International Ascites Club . Gut 2005 ; 54:718 – 25 . 8 Angeli P et al . Diagnosis and management of acute kidney injury in patients with cirrhosis : revised consensus recommendations of the International Club of Ascites . J Hepatol 2015 ; 62:968 – 74 . 9 Sort P et al . Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis . N Engl J Med 1999 ; 341:403 – 9 . 10 Salerno F , Navickis RJ , Wilkes MM . Albumin infusion improves outcomes of patients with spontaneous bacterial peritonitis : a meta-analysis of randomized trials . Clin Gastroenterol Hepatol 2013 ; 11:123 – 30 . 11 EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis . J Hepatol 2018 ; 69 : 406 – 60 . 12 Arroyo V , Terra C , Ginès P . Advances in the pathogenesis and treatment of type-1 and type-
2 hepatorenal syndrome . J Hepatol 2007 ; 46:935 – 46 . 13 Belcher JM et al . Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury . Hepatology 2014 ; 60:622 – 32 . 14 Ariza X et al . Analysis of a urinary biomarker panel for clinical outcomes assessment in cirrhosis . PLoS One 2015 ; 10 : e0128145 . 15 Ortega R et al . Terlipressin therapy with and without albumin for patients with hepatorenal syndrome : results of a prospective , nonrandomized study . Hepatology 2002 ; 36:941 – 8 . 16 Fernández J et al . A randomized unblinded pilot study comparing albumin versus hydroxyethyl starch in spontaneous bacterial peritonitis . Hepatology 2005 ; 42:627 – 34 . 17 Bortoluzzi A et al . Positive cardiac inotropic effect of albumin infusion in rodents with cirrhosis and ascites : molecular mechanisms . Hepatology 2013 ; 57:266 – 76 . 18 Runyon BA . Management of adult patients with ascites due to cirrhosis : an update . Hepatology 2009 ; 49:2087 – 107 . 19 Bernardi M et al . Albumin
infusion in patients undergoing large-volume paracentesis : a meta-analysis of randomized trials . Hepatology 2012 ; 55 : 1172 – 81 . 20 Guevara M et al . Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis . A randomized , controlled study . J Hepatol 2012 ; 57:759 – 65 . 21 Thevenot T et al . Effect of albumin in cirrhotic patients with infection other than spontaneous bacterial peritonitis . A randomized trial . J Hepatol 2015 ; 62:822 – 30 . 22 Bernardi M , Zaccherini G . Approach and management of dysnatremias in cirrhosis . Hepatol Int 2018 ; 12:487 – 99 . 23 Azhari H , Swain MG . Role of peripheral inflammation in hepatic encephalopathy . J Clin Exp Hepatol 2018 ; 8:281 – 5 . 24 Jalan R , Kapoor D . Reversal of diuretic-induced hepatic encephalopathy with infusion of albumin but not colloid . Clin Sci ( Lond ) 2004 ; 106:467 – 74 . 25 Sharma BC et al . Randomized controlled trial comparing lactulose plus albumin versus lactulose alone for treatment of hepatic encephalopathy .
J Gastroenterol Hepatol 2017 ; 32:1234 – 9 . 26 Gentilini P 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 . 27 Romanelli RG et al . Longterm albumin infusion improves survival in patients with cirrhosis and ascites : an unblinded randomized trial . World J Gastroenterol 2006 ; 12:1403 – 7 . 28 Caraceni P et al . Longterm albumin administration in decompensated cirrhosis ( ANSWER ): an open-label randomised trial . Lancet 2018 ; 391:2417 – 29 . 29 Di Pascoli M et al . Long-term administration of human albumin improves survival in patients with cirrhosis and refractory ascites . Liver Int 2019 ; 39:98 – 105 . 30 Solà E et al . Midodrine and albumin for prevention of complications in patients with cirrhosis awaiting liver transplantation . A randomized placebo-controlled trial . J Hepatol 2018 ; 69:1250 – 9 .
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