Archived Policies - Surgery


Artificial Liver Assist Devices for the Treatment of Liver Failure

Number:SUR709.034

Effective Date:01-01-2016

End Date:10-31-2016

Coverage:

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.

Description:

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.

Background

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 liver support devices: artificial livers and bioartificial livers (BALs).

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.

BALs are cell-based, extracorporeal devices that detoxify and synthesize proteins and metabolites in the circulating blood. (2, 14) The BALs utilizes liver cells or hepatocytes from either hepatoblastoma cell lines or porcine livers, and a combination of physical and chemical procedures. Dependent on the BAL design, the hepatocytes may or may not have direct contact with the patient’s circulating blood. BAL 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 BAL 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.

Regulatory Status

Currently there are no BAL systems 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 immortalize 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 BAL 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 BAL. (8, 14)

Rationale:

This policy was developed in January 2016 based on MedLine literature review. The key literature summarized below covers the search through December 2, 2015.

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)

Study Patient Population Intervention Primary Outcome

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%).

Table Key:

ELAD: extracorporeal liver assist device;

n: number;

NS: nonsignificant

In 2001, Sechser et al. reviewed the current literature at the time on artificial liver support 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 (BAL) 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 BALs filled with hepatocytes, but some investigators expressed concern about the origin of hepatocytes used in the BAL 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 BAL systems. (13, 14) Certain human cell lines used in BAL 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 BAL treatment, as the cells were reportedly contained within the bioreactor cartridge and did not enter the patient’s bloodstream. (14)

Ongoing and Completed Clinical Trials

A search of ClinicalTrials.gov in December 2015 yielded the following completed clinical trials:

NCT No.

Trial Name

Planned Enrollment

Completion Date

Completed

NCT00771446

Safety & Efficacy of the Extracorporeal Liver Assist Device (ELAD) System in Patients With Hepatic Insufficiency

18

Oct 2008

NCT01471028

Assess Safety and Efficacy of ELAD (Extracorporeal Liver Assist System) in Subjects With Alcohol-Induced Liver Failure

203

Aug 2015

NCT00973817

Efficacy and Safety of the Extracorporeal Liver Assist Device (ELAD) in Acute on Chronic Hepatitis (SILVER)

62

May 2011

NCT00030225

Phase 2 Evaluation of the ELAD System in the Management of Acute Liver Failure

19

Feb 2003

Ongoing

There were no ongoing clinical trials that would likely influence this policy.

Table Key:

NCT: National Clinical Trial.

Practice Guidelines and Position Statements

No guidelines or statements were identified.

Summary

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 evidence available has been 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 onto a liver allografting. Without concrete published scientific evidence, the use of these devices is considered experimental, investigational and/or unproven.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

0405T

HCPCS Codes

None

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

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

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. PMID

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).

Policy History:

Date Reason
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.

Archived Document(s):

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