of the key functions of the liver is to filter out toxic substances,
including ammonia produced by bacteria in the gut. When the
liver is heavily damaged -- due to chronic hepatitis B or C,
long-term heavy alcohol use, or other causes -- toxins can build
up in the body leading to hepatic
encephalopathy (brain impairment), coma, and death.
transplantation is the definitive treatment for liver failure,
but donor organs are in short supply, and in some cases the
existing liver can recover. Researchers have therefore explored
various methods for taking over the damaged liver's crucial
functions, much like renal dialysis does for people with kidney
is an excerpt from press release issued by EASL describing findings
from 2 studies of extracorporeal (out-of-body) liver support
methods. MARS uses human albumin to bind toxins in the blood,
substituting for natural albumin that is no longer produced
in adequate amounts by the damaged liver. Prometheus removes
protein-bound and water-soluble toxins by fractionated plasma
separation and adsorption.
second press release, from the medical technology company Gambro,
further describing findings from the RELIEF study of the MARS
Studies Help Establish Potential of Artificial Liver Support
show limited survival advantage, only in specific patient types
Austria -- Friday, 16th April 2010 -- Results from two studies
presented today at the International Liver Congress 2010 have
shown that treatment with extracorporeal devices may not confer
a survival advantage for severe liver failure patients, despite
positive dialysis effects. However, results among a small sub-group
of patients show promise.
liver support therapy is in its infancy but is valued as a detoxification
treatment option for patients with cirrhosis who have rapid worsening
of their liver function. The objectives of these two studies were
to better understand the potential of two new devices (Molecular
Adsorbent Recirculating System -- MARS -- and Prometheus) in terms
of survival benefits for patients who suffer from cirrhosis.
on the studies, Professor Burroughs from the Royal Free Hospital
NHS Trust, London UK, said: "The accepted prognosis for
these patients is generally poor and current treatment strategies
involve supportive therapy, with the hope that liver function
will recover if sufficient time is allowed. Extracorporeal support
systems such as the two included in these studies are very useful
bridges, but the overall data on survival is disappointing.
The positive data for severely ill patients with hepatorenal
syndrome I or a MELD score over 30, though, does offer some
About the studies
In the first study, 145 patients with cirrhosis and rapid deterioration
of their liver function were recruited across seven European
countries. This study is the first large prospective randomized
controlled trial on the survival of patients with the condition
(HELIOS study). Prometheus is a new extracorporeal liver support
system allowing the removal of protein bound and water soluble
toxins by fractionated plasma separation and absorption (FPSA).
Patients were randomized to standard medical therapy or standard
medical therapy plus FPSA and the primary endpoints of the study
were survival at 28 and 90 days regardless of liver transplantation.
The results show that difference in the overall survival was
not statistically different overall (66% vs. 63% p=0.7 at day
28 and 47% vs. 38% p=0.35 at day 90). Only in pre-defined patient
sub-groups with hepatorenal syndrome type I* and MELD** score
> 30 was a significant survival benefit with treatment with
FPSA observed (p=0.04 and p=0.02 respectively).
(*Hepatorenal syndrome type I is a common type of rapidly progressive
kidney failure that affects individuals with liver cirrhosis,
with a doubling of serum creatinine to a level greater than
2.5 mg/dL or a halving of the creatinine clearance to less than
20 mL/min over a period of less than two weeks.)
(**The Model for End-Stage Liver Disease, or MELD, is a scoring
system for assessing the severity of chronic liver disease.
MELD uses the patient's values for serum bilirubin, serum creatinine,
and the international normalized ratio for prothrombin time
(INR) to predict survival.)
In the second study, 189 patients with acute-on-chronic liver
failure across six European countries were randomized either
to treatment with the Molecular Adsorbent Recirculating System
(MARS) or to standard therapy. Treatment with MARS was scheduled
at low dose (up to ten sessions of 6-8 hours during 21 days)
and the main endpoint was survival at 28 days.
Results showed a significant decrease in serum creatinine (20.0
+/- 33.1% vs. 6.4 +/-33.5% p=0.02) and bilirubin (26.4 +/- 26.1%
vs. 8.9 +/- 22.3% p=0.001) as well as higher improvement in
the hepatic encephalopathy (estimated by the percentage of evaluations
in which HE decreased from II-IV at inclusion to 0-I during
therapy, 56% vs. 39% p=0.06) in the MARS group. The primary
endpoint was not met however, with the proportion of patients
dying within 28 days almost identical in both groups (40.8%
vs 40.0%). Findings show that MARS at low dosage is a safe procedure
which has significant dialysis effect and improves severe hepatic
encephalopathy in patients with cirrhosis and rapid deterioration
of their liver function; however a significant beneficial effect
on survival could not be demonstrated.
EASL is the leading European scientific society involved in
promoting research and education in hepatology. EASL attracts
the foremost hepatology experts as members and has an impressive
track record in promoting research in liver disease, supporting
wider education and promoting changes in European Liver policy.
of the European Association for the Study of Liver (EASL) adds
to the growing body of evidence supporting the clinical benefits
of Gambro's Molecular Adsorbents Recirculating System (MARS)
RELIEF trial -- the largest trial to date involving the use
of extracorporeal liver support -- compared MARS therapy to
standard medical therapy in patients with acute-on-chronic liver
failure (AOCLF.) Treatment of AOCLF is one of the relatively
new MARS applications and the purpose of the RELIEF trial was
to assess its efficacy and safety for this indication.
The RELIEF trial demonstrated a significant decrease in serum
bilirubin and creatinine levels and an improvement in hepatic
encephalopathy for patients treated with MARS therapy in comparison
to patients receiving standard medical therapy. Although the
study did not demonstrate a statistically significant difference
in survival between MARS therapy and standard medical therapy,
as indicated in the trial abstract and in the press release
issued by EASL, the RELIEF findings show that MARS therapy,
at low dosage, is a safe procedure, which has significant dialysis
effect and improves severe hepatic encephalopathy in patients
with cirrhosis and rapid deterioration of their liver function.
The MARS therapy is today the most widely used extracorporeal
liver support therapy. This therapy has been in clinical use
since 1993 and commercially available since 1999. Its clinical
indications are many, including AOCLF, acute liver failure,
graft dysfunction after liver transplantation, liver failure
after hepatic resection, intractable pruritus in cholestatic
liver diseases, and drug overdose and poisoning. The MARS system
is used in 45 countries around the world and its safety and
efficacy have been demonstrated by clinical experience with
more than 9,000 patients (about 36,000 treatments) who have
benefited from its use.
"This latest clinical trial adds additional evidence to
support that MARS is an important therapeutic tool in controlling
the most serious complications of liver disease," says
Dr. Josep Torner, Medical Director of Gambro's Liver Business.
"An ongoing collaboration with the hepatology community
is critical to better define the indications for MARS and improve
our understanding of the mechanisms of liver failure."
(In the U.S., the MARS system is cleared for use in the treatment
of drug overdose and poisonings only. It is not indicated in
the U.S. for the treatment of chronic liver conditions or as
a bridge to liver transplant.)
MARS: Liver Unit, Hospital General Universitario Gregorio
Maranon, CIBEREHD, Madrid, Spain; Department and Lab of Hepatology,
University Hospitals, Leuven, Belgium; Dept. Hepatolog, Rigshospitalet,
Copenhagen, Denmark; Institute of Hepatology, University College
London, London, UK; Servicio de Gastroenterologia, Hospital
Ramon y Cajal; University of Alcala, CIBEREHD, Madrid, Spain;
First Department of Medicine, Martin-Luther-University, Halle,
Prometheus: Department of Gastroenterology, Hepatology and Endocrinology,
Medical School Hannover, Hannover, Germany; Department of Nephrology
& Department of Gastroenterology and Hepatology, University
Hospital Essen, Essen, Germany; Department of Internal Medicine
III & Department of Internal Medicine I, Goethe University,
Frankfurt/Main, Germany; Ghent University Hospital, Gent, Belgium;
Liver Unit, Hospital Clinic, Barcelona, Spain; Department of
Nephrology & Hypertension, Medical School Hannover, Hannover,
Germany; Medical Department, University of Mainz, Mainz, Germany;
Semeiotica Medica, University of Bologna, Bologna, Italy; Institute
of Liver Studies, King's College Hospital, London, UK; Paracelsus
Medical University Salzburg, Salzburg, Austria; University Hospital
Merkur, Zagreb, Croatia; Fresenius Medical Care, Bad Homburg,
New studies help establish potential of artificial liver support
devices. Press release. April 21, 2010. April 16, 2010.
Gambro. A study presented at the 45th Annual Meeting of the European
Association for the Study of Liver (EASL) adds to the growing body
of evidence supporting the clinical benefits of Gambro's Molecular
Adsorbents Recirculating System (MARS) therapy. Press release. April
R Banares, F Nevens, FS Larsen, and others (Relief Study Group).
Extracorporeal liver support with the molecular adsorbent recirculating
system (MARS) in patients with acute-on-chronic liver failure (AoCLF).
The Relief Trial. 45th Annual Meeting of the European Association
for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18,
K Rifai, A Kribben, G Gerken, and others. Extracorporeal liver support
by fractionated plasma separation and absorption (Prometheus) in
patients with acute-on-chronic liver failure (HELIOS study): a prospective
randomized controlled multicenter study. 45th Annual Meeting of
the European Association for the Study of the Liver (EASL 2010).
Vienna, Austria. April 14-18, 2010. (Abstract).