Medical Policies - Surgery
Artificial Liver Assist Devices for the Treatment of Liver Failure
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Artificial liver assist devices, including extracorporeal bioartificial liver systems are considered experimental, investigational and/or unproven to treat chronic liver failure or to provide a bridge to liver transplantation.
NOTE 1: Use of an artificial liver assist device includes, but is not limited to, oversight care and monitoring of device functioning, and required patient care services.
NOTE 2: This policy does not address treatment of acute drug overdose and poisoning.
Liver failure results from the loss of liver function and is associated with a high-risk of mortality. For those requiring long-term therapeutic options for patients with liver failure, liver transplantation may be the only solution; however, the number of patients who need a liver transplant exceeds the number of donor organs available.
To temporarily support a failing liver or as a bridge to liver transplantation, an artificial liver assist device may be utilized. There are two types of extracorporeal liver support devices: artificial liver support (ALS) and bioartificial liver support (BLS).
Artificial livers are designed to filter toxins, caused by illness, alcohol, poisons or drugs, from the blood and function similarly to kidney dialysis. (1, 14) These devices often use the same dialysis platform, sorbent-based, with additional modular components and filters. The most advanced liver systems use albumin-based filtration, which removes both protein-bound and water-soluble toxins from the circulating blood. These systems tend to be inadequate for extended, long-term use.
ALS devices are cell-free and improves biochemical parameters of liver failure by the simultaneous removal of protein-bound and water-soluble substances. BLS devices are cell-based, extracorporeal devices that detoxify and synthesize proteins and metabolites in the circulating blood. (2, 14) The BLS device utilizes liver cells or hepatocytes from either hepatoblastoma cell lines or porcine livers, and a combination of physical and chemical procedures. Dependent on the BLS device design, the hepatocytes may or may not have direct contact with the patient’s circulating blood. BLS treatment is considered temporary while the patient is awaiting a compatible donor liver or to help the liver regenerate spontaneously. They can be used up to 30 days.
Clinical trials have reported that the most common adverse event associated with extracorporeal liver support system (ELSS) treatment is transient hypotension. (3, 14) Graft rejection, bleeding, renal failure, thrombocytopenia, sepsis, cardiac arrhythmias, and hypoxia were also associated with the clinical trials and utilization of these devices.
Currently there are no ELSSs that have received U.S. marketing approval from the Food and Drug Administration (FDA). These systems may be available only in the context of clinical trials or compassionate use.
Extracorporeal Liver Assist Device® (ELAD®) by Vital Therapies, Inc. (San Diego, CA) has been granted orphan drug designation for immortalized human liver cells used in the ELAD® system for treating acute liver failure, by the FDA in 2004. (4) This designation is intended to provide financial incentives for developing products to treat rare disease, but it is not equivalent to a marketing approval or clearance.
In 2002, the FDA granted Excorp Medical Inc., (Hong Kong, China) orphan drug designation for its xenogeneic (involving cells or tissues from different species, such as animal to human) hepatocytes used for the hollow fiber bioreactor within the Bioartificial Liver Support System® (BLSS®). (5) As with ELAD®, this designation is not equivalent to a marketing approval or clearance.
One potential competing technology for BLS is the artificial liver. Liver dialysis systems still under clinical evaluation include the Molecular Adsorbents Recirculation System® (MARS®) by Gambro; Lund, Sweden (6) and the Prometheus® system by Fresenius Medical Care; Bad Homburg, German). (7, 14) MARS® has been cleared by the FDA to treat drug overdose and poisoning, but it is not cleared as a BLS. (8, 14)
This policy was developed in January 2016 based on MedLine literature review. The key literature summarized below covers the search through September 7, 2017.
Available Literature Review
The published literature available is comprised of 3 completed clinical trials that provide preliminary results of primary endpoints as shown in Table 1.
Table 1: Completed Clinical Trials with Results Reported by Study Authors (14)
Teperman et al. (2012) (9)
62 patients with acute alcoholic hepatitis or acute decompensation of cirrhosis
ELAD® treatment (n=31) compared with standard medical therapy (controls, n=31)
Overall survival measured at 30 and 90 days. Mean ELAD® was 93 (24-144) hours. In the modified intention to treat analysis, 30- and 90-day overall survival was similar for both groups (ELAD® 13/25 versus standard medical therapy 19/28, p=NS and ELAD® 11/25 versus standard medical therapy 12/28, p=NS, respectively). The 90-day overall survival numerically favored ELAD® in acute alcoholic hepatitis (9/16 versus 6/17, p=NS) while it numerically favored standard medical therapy in non-acute alcoholic hepatitis (2/9 ELAD® versus 6/11 standard medical therapy, p=NS). Utilizing the system, the device may allow for more recovery following acute insult due to substance abuse. Liver transplants were similar in ELAD® (3/29) and standard medical therapy (4/33). For ELAD®, 28 serious adverse effects were reported.
Duan et al. (2010) (10)
49 patients with acute chronic liver failure
ELAD® treatment (n=32) compared with standard of care (controls; n=17)
Transplant free survival was measured for the 49 patients enrolled at 84 days, ELAD® 21/32 (65.6%) versus controls 7/17 (41.1%). Of the 84-day survivors, 2/21(9.5%) ELAD® and 2/7 (28.6%) controls died; 1/21 (4.8%) ELAD® and 0/7 controls were transplanted; 4/21 (19.0%) ELAD® and 2/7 (28.6%) controls were lost to follow-up. Survival analysis reveals a statistically significant improvement in treatment free survival for the ELAD® treated subjects when compared to the controls. Median survival of the controls was 37 days, whereas median survival of ELAD® treated patients was at least 3 years.
Hillebrand et al. (2010) (11)
18 patients with acute chronic liver failure (acute decompensation of cirrhosis)
Standard medical treatment plus ELAD® treatment (n=14) compared to standard medical treatment alone (n=14)
Transplant free and overall survival was measured at 30 and 90 days. More patients achieved 30-day transplant free survival in the standard medical treatment plus ELAD® group/test group (23%) versus standard medical treatment/control group alone (0%). There was no difference in 30-day overall survival (standard medical treatment + ELAD® 46% versus controls 50%). The 90-day overall survival was improved for the test group (39%) versus the control group (25%) as was the 90-day transplant free survival (test group 15% versus control group 0%). The rate of liver transplantation was higher for the control group 75%) versus the test group (23%).
ELAD®: extracorporeal liver assist device;
In 2001, Sechser et al. reviewed the current literature at the time on artificial liver support (ALS) devices for fulminant liver failure to bridge patients until a suitable liver allograft was obtained or the patient’s own liver regenerated sufficiently to resume normal function. (12) The momentum was to move from plasma exchange treatment and mechanical liver support devices that filtered toxins to more promising hybrid devices incorporating mechanical and biologic support systems, such as liver assist and extracorporeal devices. The authors’ conclusion was hybrid systems appear to be the best option to date, but what type of tissue to use (human or porcine), how much of the liver tissue to use, and final, optimal device or system design to be used for patients with fulminant liver failure.
In 2012, Gu et al. reviewed the status of the bioartificial liver support (BLS) device use in conjunction with adverse events, particularly immunological reactions, potential of viruses, and liver tumors. (3, 14) No obvious immunologic reactions were observed during the treatment with BLS systems filled with hepatocytes, but some investigators expressed concern about the origin of hepatocytes used in the BLS systems. The potential for viruses and other pathogens to pass from freshly harvested porcine cells from live animals to patients who receive the treatment remains a concern with the use of porcine-cell-based bioreactors in BLS systems. (13, 14) Certain human cell lines used in BLS research were derived from hepatoblastoma, a rare liver tumor usually seen in infants and small children. (14) However, no clinical trial results suggested that these cells caused cancer in patients receiving BLS treatment, as the cells were reportedly contained within the bioreactor cartridge and did not enter the patient’s bloodstream. (14)
A 2017 publication from the United Kingdom by Jain and Dhawan, appraised current practices using extracorporeal liver support systems (ELSS), which encompass both artificial and BAL devices, to treat pediatric liver failure. (15) According to the review results, these devices/systems are not widely accepted as routine therapy in adult liver failure and have not seen a benefit for utility in pediatric patients. This could be a result of the scarcity of the devices for children. The authors concluded that the results of recent multicenter trials using ALSs have shown some potential.
The following is a German 2017 review study by Gerth et al., comparing ALS and BLS methods to treat acute liver failure. (16) Their review revealed there are no prospective randomized studies on the treatment of liver failure by intoxication; however there have been several case series reporting positive treatment effects using the MARS® therapies, particularly in mushroom poisoning or acetaminophen intoxication. The authors stated, “In acute liver failure (ALF) studies, the usage of BLS showed no survival advantage. Using ALS systems, a positive effect on mortality could be demonstrated in patient subgroups after several consecutive MARS® therapies. The first randomized controlled trial demonstrating a survival benefit used large-volume plasmapheresis. Apparently, immunomodulatory and hemodynamic effects of the treatment play a crucial role in this context. In patients with acute-on-chronic liver failure (ACLF) accompanied by hyperbilirubinemia without any further organ failure (singular hepatic dysfunction), prognostic favorable effects by using a BLS system have been shown. However, once other extrahepatic organ systems are affected, indicating a progressive transition to multi-organ failure, a survival advantage could be achieved with the MARS® and Prometheus system. Decisive for a successful therapy is the exact indication of the respective liver dialysis procedure for this very heterogeneous disease. Future studies are needed to define more accurate patient selection criteria for each liver support [therapy device/system].”
Ongoing and Completed Clinical Trials
A search of ClinicalTrials.gov in September 2017 yielded the following completed clinical trials:
There were no completed clinical trials that would likely influence this policy.
Safety and Efficacy of hiHep Bioartificial Liver Support System to Treat Acute Liver Failure
Jun 2020 (has not recruited)
NCT: National Clinical Trial.
Practice Guidelines and Position Statements
No guidelines or statements were identified.
Summary of Evidence
To date, there have not been well-designed studies in peer-reviewed journals that support the efficacy of these devices or the effect on health outcomes. The available evidence available includes review editorials, presentations, and product information. The completed clinical trials are few, with some having been terminated early or withdrawn due to flaws within the study design or product design. Devices and treatment protocols under investigation vary. Orphan drug designation allows for further clinical investigation. When FDA clearance has been granted, the utilization of the device is not for bridging the patient on to a liver allografting. Without concrete published scientific evidence, the use of these devices is considered experimental, investigational and/or unproven.
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1. Podoll AS, DeGolovine A, Finkel KW. Liver support systems – a review. ASAIO J. 2012 Sep-Oct; 58(5):443-9. PMID 22820917
2. Pless G. Artificial and bioartificial liver support. Organogenesis. 2007 Jan-Mar; 3(1):20-4. PMID 20645071
3. Gu J, Shi X, Ren H, et al. Systematic review: extracorporeal bio-artificial liver-support system for liver failure. Hepatol Int. 2012 Oct; 6(4):670-83. PMID 26201519
4. ELAD® – Product Information. San Diego, California: Vital Therapies, Inc. Available at <http://www.vitaltherapies.com> (accessed – 2015 December 2).
5. Bioartificial Liver System. Minneapolis, Minnesota: Excorp Medical. Available at <http://www.excorp.com> (accessed – 2015 December 2).
6. MARS® – Product Information. Lund, Sweden: Gambro. Available at <http://www.gambro.com> (accessed – 2015 December 2).
7. Rademacher S, Oppert M, Japrres A. Artificial extracorporeal liver support therapy in patients with severe liver failure. Expert Rev Gastroenterol Hepatol. 2011 Oct; 5(5):591-9. PMID 21910577
8. FDA – Classification of Sorbent Hemoperfusion Systems. Food and Drug Administration – Gastroenterology and Urology Devices Panel (2013 June 27). Available at <http://www.fda.gov> (accessed – 2015 December 2).
9. Teperman L. A phase 2b study of safety & efficacy of a human cell-based biological liver support system (ELAD) in subjects with acute-on-chronic hepatitis (AOCH) due either to acute alcoholic hepatitis or acute decompensation of cirrhosis. Presented at the International Liver Transplantation Society Annual Meeting; 2012 May 12-19; San Francisco, CA.
10. Duan Z, Xin S, Zhang J, et al. 3-year follow up of acute-on-chronic liver failure (ACLF) subjects in a randomized, controlled, multicenter trial of the ELAD® Bioartificial Liver Support System in 49 Chinese subjects reveals significant transplant-free survival (TFS) benefit. Study Poster and Presented by Vital Therapies in Chicago, IL; 2010 Oct 13.
11. Hillebrand DJ, Frederick RT, Williams WW, et al. Safety and efficacy of the extracorporeal liver assist device (ELAD) in patients with acute on chronic liver failure. J Hepatol. 2010 Apr; 52:S323-4.
12. Sechser A, Osorio J, Freise C, et al. Artificial liver support devices for fulminant liver failure. Clin Liver Dis. 2001 May; 5(2):415-30. PMID 11385970
13. Frühauf JH, Mertsching H, Giri S, et al. Porcine endogenous retrovirus released by a bioartificial liver infects primary human cells. Liver Int. 2009 Nov; 29(10):1553-61. PMID 19686312
14. ECRI Institute. Bioartificial Liver System as Bridge to Liver Transplantation. Plymouth Meeting (PA): ECRI Institute; 2013 September. 7 p. (Health Technology Forecast).
15. Jain V, Dhawan A. Extracorporeal liver support systems in paediatric liver failure. J Pediatr Gastroenterol Nutr. 2017 Jun; 64(6):855-63. PMID 28248208
16. Gerth HU, Pohlen M, PavenstÃädt H, et al. Extracorporeal liver support of liver failure (published in German). Z Gastroenterol. 2017 Apr; 55(4):383-93. PMID 28293919
|10/15/2018||Reviewed. No changes.|
|11/15/2017||Document updated with literature review. Coverage unchanged.|
|11/1/2016||Reviewed. No changes.|
|1/1/2016||New medical document. Artificial liver assist devices, including extracorporeal bioartificial liver systems are considered experimental, investigational and/or unproven to treat chronic liver failure or to provide a bridge to liver transplantation. NOTE 1: Use of an artificial liver assist device includes, but is not limited to, oversight care and monitoring of device functioning, and required patient care services. NOTE 2: This policy does not address treatment of acute drug overdose and poisoning.|
|Title:||Effective Date:||End Date:|
|Artificial Liver Assist Devices for the Treatment of Liver Failure||11-15-2017||10-14-2018|
|Artificial Liver Assist Devices for the Treatment of Liver Failure||11-01-2016||11-14-2017|
|Artificial Liver Assist Devices for the Treatment of Liver Failure||01-01-2016||10-31-2016|