The idea of supplying albumin to patients with advanced cirrhosis has been debated for the last half-century. However, solid scientific evidence supporting this notion is lacking. Data from a randomized controlled trial named ANSWER now fills this gap, and the results were presented at the International Liver Congress this year.1
Investigators found that long-term weekly infusion with human albumin to cirrhotic patients, in addition to standard medical care, reduced the risk of death by 38%.1 The treatment also improved the management of ascites, and reduced the incidence of severe complications of the disease and the need for hospitalization.1
“Long-term albumin administration to patients with decompensated cirrhosis could be seen as a disease-modifying treatment,” said Mauro Bernardi, MD, Professor at the Department of Clinical Medicine, University of Bologna, who was the lead investigator of the study.2
Decompensated cirrhosis is the end stage of any condition in which the liver progressively becomes scarred, and is marked by the development of variceal hemorrhage, ascites, encephalopathy and jaundice.3 With current standard of care, i.e. diuretics and paracentesis, and hopefully liver transplantation, the one-year-mortality rate is 20% in patients with ascites.4 Given the poor prognosis in these patients, therapies to improve survival in decompensated cirrhosis are an important unmet need in hepatology.
Albumin is a relatively small protein synthesized by liver cells that plays a critical role in regulating fluid distribution in the body. As a result of reduced liver function, hypoalbuminemia is typically found in patients with advanced cirrhosis. 5 Since 1960s, the therapeutic uses of albumin in cirrhosis are largely limited to the acute management of hypovolemia-associated complications, 5 while its prolonged use in the treatment of ascites is still debated, due to the lack of definitive evidence of a clinical benefit.5 Results from the ANSWER study now fills this gap.
In the ANSWER study, 440 patients with advanced cirrhosis and uncomplicated ascites were randomized 1:1 to receive either standard diuretic treatment (≥200 mg/day anti-mineralocorticoids and ≥25 mg/day furosemide) or standard treatment in combination with human albumin (40 g intravenously twice weekly in the first two weeks and then once weekly). 1 Patients were followed for 18 months or until frequent refractory ascites occurred, a transjugular intrahepatic portosystemic shunt was required, or the patient underwent liver transplantation or died. The primary endpoint was overall survival (OS) .1
Patients receiving human albumin was found to have a significantly higher survival rate, with a 18-month OS of 78% in the albumin arm, compared with 66% of those treated with standard-of-care therapy alone (p=0.028), resulting in a 38% relative risk reduction.1
In addition, significant improvements were observed in several secondary endpoints (Table 1), including a 54% reduction in the incidence rate ratio (IRR) of paracentesis in the albumin arm (p< 0.0001).1
Albumin infusion was generally well-tolerated. As reported by Professor Bernardi, a total of four patients developed adverse reactions to albumin, two of whom experienced a mild allergic reaction, while two developed severe, life-threatening sepsis, including pneumonia and disseminated intravascular coagulation, but in all four cases the patients eventually recovered.6
The results of the ANSWER study were warmly received at the congress.
“The reduction in mortality observed in the albumin-treated arm of this randomized controlled study is a novel and important piece of information”, said Annalisa Berzigotti, Associate Professor of Hepatology at the Faculty of Medicine of the University of Berne, and EASL Governing Board Member.
“Based on this data, weekly administration of albumin should be considered in patients with cirrhosis and ascites to prevent life-threatening complications,” she stated in an EASL statement.7
However, the positive reactions were mixed with concerns regarding the high cost of long-term albumin treatment, particularly it requires weekly infusion.
Frank Tacke, MD, PhD, Professor of Medicine at the Department of Gastroenterology, Metabolic Diseases and Intensive Care Medicine from University Hospital Aachen, and vice secretary of the EASL, commented “The results are exciting; the fact that albumin improves survival is crystal clear…However, it’s an expensive treatment, so cost-effectiveness analyses will be important.”6
To address the question of cost, Professor Bernardi stated that his team is currently performing a cost-effectiveness analysis, but he also noted the reduced cost of hospitalization and paracentesis in albumin treatment have to be taken into consideration when making the analysis.8
Taken together, long-term albumin infusion may provide a much-needed therapeutic option to patients with decompensated cirrhosis if the cost is justified.
1. Caraceni. P, Riggio. O, Angeli. P, Bernardi M. Long-term albumin administration improves survival in patients with decompensated cirrhosis: final results of the “ANSWER” study. International Liver Congress 2017; 2017; Amsterdam. p. # LBO-08.
2. Long-Term Albumin Tx Ups Survival in Liver Failure. Medpage. (Accessed May 4, 2017, at https://www.medpagetoday.com/meetingcoverage/easl/64773.)
3. Garcia-Tsao G, Friedman S, Iredale J, Pinzani M. Now there are many (stages) where before there was one: In search of a pathophysiological classification of cirrhosis. Hepatology (Baltimore, Md) 2010;51:1445-9.
4. Zipprich A, Garcia-Tsao G, Rogowski S, Fleig WE, Seufferlein T, Dollinger MM. Prognostic indicators of survival in patients with compensated and decompensated cirrhosis. Liver international : official journal of the International Association for the Study of the Liver 2012;32:1407-14.
5. Bernardi M, Ricci CS, Zaccherini G. Role of human albumin in the management of complications of liver cirrhosis. Journal of clinical and experimental hepatology 2014;4:302-11.
6. Dziadziuszko, R Phase 1 study of ceritinib 450 mg or 600 mg taken with a low-fat meal versus 750 mg in fasted state in ALK+ metastatic NSCLC World Lung Cancer Conference December 7, 2016.
7. FDA approves new combination treatment for acute myeloid leukemia FDA, 2017 (Accessed 5th May, 2017, at https://wwwfdagov/newsevents/newsroom/pressannouncements/ucm555778htm)
8. L.Q. Chow FB, E.M. Bertino, D.-W. Kim, M.J. van den Bent, H. Wakelee, P.Y. Wen, P. Cazorla Arratia, J. Shen, F. Branle. Ceritinib in Patients with Anaplastic Lymphoma Kinase-Rearranged Non-Small Cell Lung Cancer Metastatic to the Brain and/or Leptomeninges: The Phase II Ascend-7 Study. Annals of Oncology 2015;26 (Supplement 1):29–i44.