Steffen Mitzner

54 th ASAIO Conference San Francis co

21, 2008June

Univers ity of Ros tockGermany

Albumin Dialys is: MARS

Indications and Clinical Res ults

International MARS Registry

INDICATION n INCLUSION STATUS REMARK

Chirr w HRS 13 AoCLF, HRS Type I

need for RRT

Completed Liver Transpl 2000

AoCLF 24 AoCLF,

Bili > 20mg/dL

Completed Hepatology 2002

ALF 13 HyperALF; HE III/IV Completed Liver Transpl 2003

AoCLF in alcoholic liver disease

16 AoCLF, Bili>15mg/dL,

HE ≥ II°, HRS

Completed Liver Transpl

2004

Hypoxic liver failure post LOF

40 Hypoxic LF,

Bili > 8mg/dL

Completed ASAIO J 2004

Chirr w HE 70 AoCHF, HE III/IV FDA controlled

Completed Hepatology 2007

ALF (FULMAR-trial) 120 ALF (French criteria)

EnrolementCompleted

AoCLF with hyperbili + HE/HRS

(MARS-RELIEF)

230 AoCLF, Bili > 5mg/dL + HE ≥ II° or HRS

Ongoing

- MARS Randomized clinical trials

MARS- Reduction of Albumin bound Toxins

Liver Transplantation, Vol 6, 2000: 603-613

Serum Bilirubin

Start EndHours

umol/l

0 1 2 3 4 5 6 70

100

200

300

400

Serum Bile Acids

Start

0 1 2 3 4 5 6 70

50

100

150

200

umol/l

Hours

P<0,0001 P<0,0001

normal

Serum Bile Acids Serum Bilirubinumol/l

Start Start EndEnd

- Albumin Dialys is MARS Clinical e ffec tsSummary

• ( Cardiovas cular s ys tem SVRI ↑, MAP ↑)

University of Rostock, 2008

• ( QOL pruritus ↓, fatigue ↓)

• ( Liver function PDR ICG ↑, )others

• ( Kidney function Urine output ↑, . Creat ↓)

• (Cerebral function HE↓, ICP↓)

• Organ perfus ion ↑ ( , )brain kidney

• Portal pres s ure ↓

• Liver failure with Hyperdynamic Hypotens ion

Indications for Liver s upport therapy

MARS in Hyperacute ALF

SVRI MAP

Schmidt et al., Liver Transplantation 2003;9:290-297

Hypothermia MARS

-200

0

200

400

600

0 1 2 3 4 5 6 7

Time in hours

SVR

I cha

nge

in d

yn s

/cm

E5/m

E2

p = 0.004

p < 0.0001

-5

0

5

10

15

0 1 2 3 4 5 6 7

Time in hours

MA

P ch

ange

in m

mH

g

p < 0.0001

N.S.

Cardiac index Heart rate

-1

-0,8

-0,6

-0,4

-0,2

0

0,2

0 1 2 3 4 5 6 7

Time in hours

CI c

han

ge

in L

/min

/mE

2

p = 0.0007

p = 0.03

-25

-20

-15

-10

-5

0

5

10

0 1 2 3 4 5 6 7

Time in hours

Hea

rt r

ate

chan

ge

in b

eats

/min

p < 0.0001

N.S.

Schmidt et al., Liver Transplantation 2003;9:290-297

Hypothermia MARS

MARS in Hyperacute ALF

Main Visit Number

MA

P c

han

ge

fro

m b

as

elin

e/ m

mH

g

De

cre

ase

Incre

ase

-40

-30

-20

-10

0

10

20

30

Standard Medical TherapyMARS plus Standard Medical Therapy

85,5+14

77,6+11

Baseline

p=0,04 *p=0,06

(Baseline)

1 2 3 4 5

n.s. p=0,011 * p=0,013 *

p=0,021 *

Time MARS was adminis tred

Heemann U. et al Hepatology 2002; 36: 949-58

MARS in Acute Decompensation of Chronic Liver FailureProspective randomized two- center trial

BEFORE AFTER45

50

55

60

65

70

75

80

85

67.3

76.3

BEFORE AFTER45

50

55

60

65

70

75

80

85

69.3 68.8

BEFORE AFTER45

50

55

60

65

70

75

80

85

71.5

66.2

Liver support: Effect on mean arterial pressure

SMT MARS

PROMETHEUS

P = 0.050 P = 0.014

P = 0.844

. 2006;10: 108Laleman W et al Crit Care R

Liver support: Effect on systemic vascular resistance index

SMT MARS

PROMETHEUS

P = 0.389 P = 0.036

P = 0.120

VOOR NA600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

SV

RI (d

yn

es.s

ec.c

m-5

.m2

)

1008 977.5

VOOR NA600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

SV

RI

(dyne.s

ec.c

m-5

.m2)

1088

1219

VOOR NA600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

SV

RI

(dyne

.sec.c

m-5

.m2)

934.2841.5

. 2006;10: 108Laleman W et al Crit Care R

Liver support: Changes in endogenous vasoactive substances: Effect on nitric oxide

*

*P < 0.001 vs SMT and PROM

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

0 100 200 300 400

P=0.016

Delta SVRI (dyne.s.cm-5.m-2)

Del

ta N

Ox

(nM

)NOx (µM)

-80

-60

-40

-20

0

20

40

De

lta

ch

an

ge 6

SMT

-50.6

MARS

10.9

PROM

. 2006;10: 108Laleman W et al Crit Care R

*

0 5 10 15 20 250

5

10

15

20

25

mm

Hg

Time (hr)

MARS SMT

MARS: Impact on Portal PressureMARS: Impact on Portal Pressure

MARS

. ., . 2005Jalan R et al J Hepato l

• Liver failure with increas ed ( )Intracranial Pres s ure ICP

Indications for Liver s upport therapy

(% c

han

ge f

rom

baseli

ne)

0 1 2 3 4 5 6 750

100

150

200

250

300

0 1 2 3 4 5 6 750

100

0 1 2 3 4 5 6 750

100

150

200

250

300

SHAM

ALF

MARS

ICP

P < 0.05

0 1 2 3 4 5 6 750

100

0 1 2 3 4 5 6 750

100

150

200

250

300

0 1 2 3 4 5 6 750

100

0 1 2 3 4 5 6 750

100

150

200

250

300

SHAM

ALF

MARS

Time (hours)

ICP

P < 0.05

(% c

han

ge f

rom

baseli

ne)

0 1 2 3 4 5 6 750

100

150

200

250

300

0 1 2 3 4 5 6 750

100

0 1 2 3 4 5 6 750

100

150

200

250

300

SHAM

ALF

MARS

ICP

P < 0.05

0 1 2 3 4 5 6 750

100

0 1 2 3 4 5 6 750

100

150

200

250

300

0 1 2 3 4 5 6 750

100

0 1 2 3 4 5 6 750

100

150

200

250

300

SHAM

ALF

MARS

Time (hours)

ICP

P < 0.05

0 1 2 3 4 5 6 750

100

0 1 2 3 4 5 6 750

100

150

200

250

300

0 1 2 3 4 5 6 750

100

0 1 2 3 4 5 6 750

100

150

200

250

300

SHAM

ALF

MARS

ICP

P < 0.05

0 1 2 3 4 5 6 750

100

0 1 2 3 4 5 6 750

100

150

200

250

300

0 1 2 3 4 5 6 750

100

0 1 2 3 4 5 6 750

100

150

200

250

300

SHAM

ALF

MARS

Time (hours)

ICP

P < 0.05

(% c

han

ge f

rom

baseli

ne)

0 1 2 3 4 5 6 750

100

150

200

250

300

0 1 2 3 4 5 6 750

100

0 1 2 3 4 5 6 750

100

150

200

250

300

SHAM

ALF

MARS

ICP

P < 0.05

0 1 2 3 4 5 6 750

100

0 1 2 3 4 5 6 750

100

150

200

250

300

0 1 2 3 4 5 6 750

100

0 1 2 3 4 5 6 750

100

150

200

250

300

SHAM

ALF

MARS

Time (hours)

ICP

P < 0.05

(% c

han

ge f

rom

baseli

ne)

0 1 2 3 4 5 6 750

100

150

200

250

300

0 1 2 3 4 5 6 750

100

0 1 2 3 4 5 6 750

100

150

200

250

300

SHAM

ALF

MARS

ICP

P < 0.05

0 1 2 3 4 5 6 750

100

0 1 2 3 4 5 6 750

100

150

200

250

300

0 1 2 3 4 5 6 750

100

0 1 2 3 4 5 6 750

100

150

200

250

300

SHAM

ALF

MARS

Time (hours)

ICP

P < 0.05

0 1 2 3 4 5 6 750

100

0 1 2 3 4 5 6 750

100

150

200

250

300

0 1 2 3 4 5 6 750

100

0 1 2 3 4 5 6 750

100

150

200

250

300

SHAM

ALF

MARS

ICP

P < 0.05

0 1 2 3 4 5 6 750

100

0 1 2 3 4 5 6 750

100

150

200

250

300

0 1 2 3 4 5 6 750

100

0 1 2 3 4 5 6 750

100

150

200

250

300

SHAM

ALF

MARS

Time (hours)

ICP

P < 0.05

MARS: Impact on Intracranial PressureMARS: Impact on Intracranial Pressure

Sen S. et al., Crit. Care Med. 2006

Pig model of ALF

• Liver failure with Renal Ins uffic iency Hepatorenal Syndrome

Indications for Liver s upport therapy

: MARS in HRS Type I MAP and Urine volume

0

20

40

60

80

100

120

MAP Urine volume

MA

P (

mm

Hg

)

0

200

400

600

800

1000

1200

uri

ne

vo

lum

e (

ml/d

ay)

MARS pre treatment MARS post treatment HDF pre treatment HDF post treatment

p < 0,05

Mitzner et al. Liver Transplantation 2000; 6: 277-86

SMT group(n=11)

MARS group

(n=12)

P-value

In-hospital deaths 6 1 < 0.05

Worsening of hepatic encephalopathy (° IV) 3 0 < 0.05

Severe hypotension 2 3 NS

Worsening of renal function (HRS) 7 1 < 0.05

Developing electrolyte disorders 10 4 < 0.05

New formation of ascites 1 0 NS

Coagulopathy 3 4 NS

Variceal bleed 1 0 NS

Heemann et al.: Hepatology 2002;36:949-958

: MARS in AoCHF Impact on renal function

• Liver failure with Hepatic Encephalopathy

Indications for Liver s upport therapy

MARS in End Stage Liver Disease and Advanced HE:Prospective, controlled, randomized multi- center trial

Baseline data / Results

- 70 pat. in 8 centers (6 USA and 2 European)

- Age 52.7 ± 10.9, 44% female

MELD 31 ± 10, CTP 12.7 ± 1.3, HE grade III 56%, HE grade IV 44%

- HE-assessment every 12 hours for 5 days (10 per pat.)

-”Responder”: 2-grade-improvement

- primary endpoint: Improvement proportion %

Hassanein T et al. Hepatology 2007; 46: 1853-62

- ITT analysis: SMT (n=31) vs. MARS (n=39) 38 vs. 62% (p=0.04)- PP analysis: SMT (n=29) vs. MARS (n=33) 38 vs. 70% (p=0.007)- MARS group had signif. improvement in serum ammonia, total bilirubin,

bile acids, creatinine, and aromatic acids

Primary Endpoint (ITT)

0.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50

4.00

0 12 24 36 48 60 72 84 96 108 120

hours

cum

me

an

nu

m i

mp

rov

em

en

ts

MARS

SMT

p = 0.044

n = 70

Hassanein T et al. Hepatology 2007; 46: 1853-62

• Supportive Therapy prior to Liver Trans plantation

Indications for Liver s upport therapy

MARS before Liver Trans plantation

Koivusalo AM et al. Transpl Proceed 2005;37:3315-17

56 (29 , 22 , 5 )patients with ALF toxic unknown other . All pats fullfilled TX criteria or had inges ted a le thal dos e of a known

( . . , )toxic agent e g paracetamol Amanita phallo ides 3 ., 22 /Mean number of Rx per pat target duration h s es s ion

6 : 88%, 1 84%month s urvival year s urvival 30 (1 : 79%) Recovery of native function in pats y s urvival

17 (1 : 94%)Succes s ful LTx in pats y s urvival

• Improvement of Survival

Indications for Liver s upport therapy

Kjaergard LL et al. JAMA 2003; 289:217-222

- : Cochrane Hepato Biliary Group Sys tematic Review

… s upport s ys tems appeared to reduce 33% mortality by in

( 0,67; 95%ACLF RR 0,51-0,90)CI

0

0,2

0,4

0,6

0,8

1

0 5 10 15 20 25 30

treatment days

cu

mu

lati

ve s

urv

ival

MARS(n=8) HDF(n=5)

p = 0,0123

MARS in Hepatorenal Syndrome

Survivalrates

Mitzner S et al. Liver Transplantation 2000; 6: 277-86

Survival rates

0 5 10 15 20 25 30 350,0

0,2

0,4

0,6

0,8

1,0 MARS (n=12)

Control (n=12)

Survival

Days

<0,05p

Hepatology 2002; 36: 949- 58

MARS in Acute Decompensation of chronic liver failure

Prospective randomized two- center trial

Conclusions

•MARS is in clinical use since 1998. It is the best studied liver support system at present time.

•Indications treated include ACLF, ALF, PNF, postop. LF, HRS, pruritus and others in adults and pediatric cases.

•The system successfully removes albumin-bound as well as water-soluble substances.

•Clinical effects include improvement of hemodynamic, cerebral, kidney, and liver function.

•Increased survival in the MARS-group could be demonstrated in several RCTs.

•Patient selection should be strict. Early onset of treatment ensures best clinical results at reasonable costs.

WELCOME

to the ISAD 2008

September 12-14, 2008Rostock, Germany

www.albumin-dialysis.org