Refractory Refractory AscitesAscites: TIPS is : TIPS is Superior to TapsSuperior to Taps

AshokAshok BabuBabuJanuary 30, 2006January 30, 2006

OutlineOutline

•• Pathogenesis of Pathogenesis of AscitesAscites•• Description of therapiesDescription of therapies•• Focus of this debateFocus of this debate•• Clinical TrialsClinical Trials•• Recent AdvancesRecent Advances•• Cost AnalysisCost Analysis•• ConclusionsConclusions

What is What is AscitesAscites??•• Definition: ABNORMAL accumulation of Definition: ABNORMAL accumulation of

excess fluid in the peritoneal cavityexcess fluid in the peritoneal cavity

Mechanisms of Mechanisms of AscitesAscites

•• Abdominal Organ LeakAbdominal Organ Leak–– Bile, Pancreatic fluid, Urine, etc.Bile, Pancreatic fluid, Urine, etc.

•• Increased Capillary PermeabilityIncreased Capillary Permeability–– Sepsis, Peritonitis, MalignancySepsis, Peritonitis, Malignancy

•• Decreased lymphatic uptakeDecreased lymphatic uptake–– Obstruction due to Obstruction due to carcinomatosiscarcinomatosis

Mechanisms of Mechanisms of AscitesAscites

•• Increased Hydrostatic PressureIncreased Hydrostatic Pressure–– CirrhosisCirrhosis, Hepatic vein thrombosis, IVC , Hepatic vein thrombosis, IVC

Obstruction, congestive heart failureObstruction, congestive heart failure

•• Decreased colloid osmotic pressureDecreased colloid osmotic pressure–– CirrhosisCirrhosis, malnutrition, , malnutrition, NephroticNephrotic syndrome, syndrome,

protein losing protein losing enteropathyenteropathy

Portal Portal HypertensionHypertension

•• Most common cause Most common cause of chronic of chronic ascitesascites is is portal hypertension portal hypertension secondary to cirrhosissecondary to cirrhosis

DiagnosisDiagnosis

•• Serum to Serum to AscitesAscites Albumin GradientAlbumin Gradient–– SAAG=(Serum Albumin) SAAG=(Serum Albumin) –– ((AscitesAscites Albumin)Albumin)–– SAAG > 1.1 SAAG > 1.1 (High Gradient) TRANSUDATE(High Gradient) TRANSUDATE

•• This is due to portal hypertensionThis is due to portal hypertension•• Gradient correlates with portal pressureGradient correlates with portal pressure

–– SAAG < 1.1 SAAG < 1.1 (Low gradient) EXUDATE(Low gradient) EXUDATE•• CarcinomatosisCarcinomatosis, organ leak, peritonitis, SBO, organ leak, peritonitis, SBO

What does newWhat does new--onset onset ascitesascites mean?mean?

•• The appearance of The appearance of ascitesascites is usually a sign is usually a sign of of decompensationdecompensation of of subclinicalsubclinical liver liver diseasedisease

•• Control of Control of ascitesascites provides minimal provides minimal improvement in survival, if anyimprovement in survival, if any

•• Liver transplantation is the only way to Liver transplantation is the only way to improve survival in these patientsimprove survival in these patients

Why Control Why Control AscitesAscites??

•• Discomfort / PainDiscomfort / Pain•• GI symptomsGI symptoms--(early (early satiety)satiety) NutritionNutrition•• Respiratory dysfunctionRespiratory dysfunction•• Spontaneous bacterial peritonitisSpontaneous bacterial peritonitis

–– It is controversial whether controlling It is controversial whether controlling ascitesasciteshas any impact on SBP rates (has any impact on SBP rates (BlendisBlendis, 1999), 1999)

Blendis et al. Am J Gastroenterol. 2000 Dec;95(12):3686-7.

Management of Management of AscitesAscites

•• First Line TherapyFirst Line Therapy–– Sodium Restriction (88 Sodium Restriction (88 mEqmEq/day) (2gm)/day) (2gm)–– K+ Sparing diureticK+ Sparing diuretic——SpironolactoneSpironolactone up to up to

400mg/day400mg/day–– Loop Diuretic (2Loop Diuretic (2ndnd Line and additive)Line and additive)——

FurosemideFurosemide up to 160mg/dayup to 160mg/day

Definition of Refractory Definition of Refractory AscitesAscites

•• <1.5 kg/wk weight loss while on <1.5 kg/wk weight loss while on maximum dose diureticsmaximum dose diuretics

•• <1.5 kg/wk weight loss due to inability to <1.5 kg/wk weight loss due to inability to use maximal dose of diureticsuse maximal dose of diuretics

•• Once Once ascitesascites becomes refractory to becomes refractory to diuretic therapy, 6 month survival is 50diuretic therapy, 6 month survival is 50--60%60%

Arroyo, et al. International Ascites Club. Hepatology. 1996; 23:164-176.

Treatments for Refractory Portal Treatments for Refractory Portal Hypertensive Hypertensive AscitesAscites

•• Surgical Surgical PortosystemicPortosystemic ShuntShunt•• PeritoneovenousPeritoneovenous ShuntShunt•• TransjugularTransjugular IntrahepaticIntrahepatic PortosystemicPortosystemic

Shunt (TIPS)Shunt (TIPS)•• Repeated Large Volume Repeated Large Volume ParacentesisParacentesis with with

Albumin resuscitationAlbumin resuscitation•• Liver TransplantationLiver Transplantation

Surgical Surgical PortosystemicPortosystemicShuntsShunts

•• Used in 1960Used in 1960’’s for treatment of s for treatment of refractory refractory ascitesascites–– Abandoned due to high rates of Abandoned due to high rates of

surgical morbidity / mortalitysurgical morbidity / mortality–– Complete shunts had high rate of Complete shunts had high rate of

hepatic failure/encephalopathyhepatic failure/encephalopathy

•• Has a defined role in Has a defined role in varicealvaricealhemorrhage with TIPS failurehemorrhage with TIPS failure

PeritoneovenousPeritoneovenous Shunt (Denver or Shunt (Denver or LeVeenLeVeen))

•• Catheter connecting peritoneal cavity to Catheter connecting peritoneal cavity to central vein with one way valvecentral vein with one way valve

•• 1010--20% 20% perioperativeperioperative mortalitymortality•• 50% or more occluded at 1 year50% or more occluded at 1 year•• DIC secondary to LPS or DIC secondary to LPS or procoagulantsprocoagulants in in

ascitesascites•• No longer used except in special No longer used except in special

circumstancecircumstance

TransjugularTransjugular IntrahepaticIntrahepaticPortosystemicPortosystemic Shunt (TIPS)Shunt (TIPS)

•• Very effective therapy for Very effective therapy for refractory refractory ascitesascites

•• EndovascularlyEndovascularly placed in placed in about 100 minutes about 100 minutes averageaverage

•• Same day operationSame day operation

TIPSTIPS--Technical ConsiderationsTechnical Considerations•• Goal portal to venous gradient < 12mmHgGoal portal to venous gradient < 12mmHg•• StentStent diameter can be adjusted between 8 diameter can be adjusted between 8

to 10mmto 10mm•• Morbidity: Morbidity:

–– Hepatic encephalopathyHepatic encephalopathy–– Liver failureLiver failure–– Cardiac FailureCardiac Failure–– Exacerbation of renal failureExacerbation of renal failure

TIPSTIPS--Technical ConsiderationsTechnical Considerations•• The bane of this procedure WAS The bane of this procedure WAS stentstent

stenosisstenosis or occlusionor occlusion•• NeointimalNeointimal hyperplasia affected all hyperplasia affected all

uncovered uncovered stentsstents——likely because liver likely because liver parenchyma/bile could infiltrate the parenchyma/bile could infiltrate the stentstent

•• 50% of patients require re50% of patients require re--intervention by intervention by one yearone year

Serial Serial ParacentesisParacentesis•• Effective in relieving Effective in relieving ascitesascites but HIGH but HIGH

recurrence raterecurrence rate•• Required 1Required 1--2x per month2x per month

–– 8.4L accumulates every 2 weeks in a patient 8.4L accumulates every 2 weeks in a patient who adheres to restricted Na diet and has who adheres to restricted Na diet and has minimal renal Na clearanceminimal renal Na clearance

•• High incidence of High incidence of paracentesisparacentesis induced induced circulatory dysfunctioncirculatory dysfunction

ParacentesisParacentesis Induced Circulatory Induced Circulatory DysfunctionDysfunction•• Defined as an asymptomatic rise in plasma Defined as an asymptomatic rise in plasma reninrenin

activity, increase in activity, increase in creatininecreatinine, and , and hyponatremiahyponatremia following LVPfollowing LVP

•• Incidence about 20Incidence about 20--40%40%•• Has been associated with decreased survivalHas been associated with decreased survival•• Incidence can be decreased with colloid Incidence can be decreased with colloid

replacementreplacement•• Has NEVER been shown that colloid replacement Has NEVER been shown that colloid replacement

actually improves survival in this groupactually improves survival in this group•• Current Standard is to administer 8g albumin per Current Standard is to administer 8g albumin per

liter of fluid removedliter of fluid removed

Focus of This DebateFocus of This Debate•• There are really only 2 viable therapies for There are really only 2 viable therapies for

diuretic refractory diuretic refractory ascitesascites::–– TIPSTIPS–– Serial Large Volume Serial Large Volume ParacentesisParacentesis with with

albumin infusionalbumin infusion

TIPS vs. LVPTIPS vs. LVP——11stst TrialTrial——19921992--9494

•• 25 patients25 patients——13 TIPS, 12 LVP (no colloid)13 TIPS, 12 LVP (no colloid)•• InclusionInclusion——Refractory Refractory AscitesAscites•• ExclusionExclusion—— hepatic encephalopathy, SBP, hepatic encephalopathy, SBP,

Cr> 1.5, or sepsisCr> 1.5, or sepsis

TIPS vs. LVPTIPS vs. LVP——11stst TrialTrial——19921992--9494•• TIPS technical resultsTIPS technical results

–– Only 77% successful placementOnly 77% successful placement–– Mean gradient reduction 20 to 14 mmHgMean gradient reduction 20 to 14 mmHg–– 30% occlusion rate at 6 months30% occlusion rate at 6 months

•• AscitesAscites ControlControl–– 40% resolution with TIPS40% resolution with TIPS–– NO resolution with NO resolution with paracentesisparacentesis

TIPS vs. LVPTIPS vs. LVP——11stst TrialTrial——19921992--9494•• Hepatic EncephalopathyHepatic Encephalopathy

–– None in None in paracentesisparacentesis groupgroup–– One mild / 2 severe HE in TIPS groupOne mild / 2 severe HE in TIPS group

•• MortalityMortality–– TIPSTIPS——29% 29% surivalsurival at one yearat one year–– ParacentesisParacentesis——60% survival at one year60% survival at one year–– Mortality differential was largely due to ChildMortality differential was largely due to Child’’s s

C patients (4 per group)C patients (4 per group)

11stst AuthorAuthor YEARYEAR n n (TIPS/LVP)(TIPS/LVP)

Albumin Albumin with LVPwith LVP

FollowupFollowup(months)(months)

RossleRossle 20002000 29/3129/31 8 g/L8 g/L 4545

GinesGines 20022002 35/3535/35 8 g/L8 g/L 1010

SanyalSanyal 20032003 52/5752/57 66--8 g/L8 g/L 4040

SalernoSalerno 20042004 33/3333/33 8 g/L8 g/L 1717

Four Recent Four Recent PRCTPRCT’’ss

Four Recent Four Recent PRCTPRCT’’ss

•• Blinding: NONEBlinding: NONE•• Inclusion Criteria:Inclusion Criteria:

–– All were cirrhoticAll were cirrhotic–– Refractory or Recurrent Refractory or Recurrent AscitesAscites

11stst AuthorAuthor BiliBili(mg/(mg/dLdL))

HEHE CreatCreat(mg/(mg/dLdL))

PVT PVT excludedexcluded

RossleRossle > 5> 5 > > GrGr II > 3> 3 YESYES

GinesGines > 10> 10 > > GrGr II > 3> 3 YESYES

SanyalSanyal > 5> 5 > > GrGr II > 1.5> 1.5 YESYES

SalernoSalerno > 6> 6 > > GrGr IIII > 3> 3 YESYES

Four Recent Four Recent PRCTPRCT’’ssExclusion CriteriaExclusion Criteria

Four Recent Four Recent PRCTPRCT’’ssOutcomesOutcomes——Technical ResultTechnical Result

11stst

AuthorAuthorSuccess Success

RateRatePostPost--TIPS TIPS GradientGradient

1 yr TIPS 1 yr TIPS dysfunctiondysfunction

Assisted Assisted PatencyPatency

RossleRossle 100%100% 1010 45%45%

38%38%

73%73%

41%41%

GinesGines 97%97% 8.78.7

93%93%

91%91%

90%90%SanyalSanyal 94%94% 8.38.3

SalernoSalerno 89%89% 8.78.7 82%82%

Four Recent Four Recent PRCTPRCT’’ssOutcomesOutcomes

Taps per Patient

0.7 0.91.7 1.4

99.7

6.15.1

0

2

4

6

8

10

12

Rossle Gines Sanyal Salerno

Study Author

Aver

age

# ta

ps p

er

patie

nt

TIPSParacentesis

Four Recent Four Recent PRCTPRCT’’ssOutcomesOutcomes

Encephalopathy

21

77

42

61

10

66

23

57

0

20

40

60

80

100

Rossle Gines Sanyal Salerno

Author

Perc

enta

ge o

f Pat

ient

s

TIPSParacentesis

p < 0.05

Four Recent Four Recent PRCTPRCT’’ssOutcomesOutcomes

Mortality over Study Period

5257

40 39

74

51

37

61

01020304050607080

Rossle Gines Sanyal Salerno

Per

cent

age

of P

atie

nts

TIPSParacentesisp = 0.11

p = 0.84

p = 0.02p = 0.51

New DevicesNew DevicesePTFEePTFE Covered Covered StentsStents

New DevicesNew DevicesePTFEePTFE Covered Covered StentsStents

•• PRCTPRCT——Pts with Pts with varicealvariceal bleeding or bleeding or refractory refractory ascitesascites

•• 39 39 ePTFEePTFE, 41 Standard Uncovered , 41 Standard Uncovered StentStent•• Mean postMean post--TIPS gradient was 6.9 mmHgTIPS gradient was 6.9 mmHg•• 1 year mean follow1 year mean follow--upup——routine U/S and routine U/S and

angioangio performedperformed•• Dysfunction defined as 50% Dysfunction defined as 50% stenosisstenosis or or

gradient > 12 mmHggradient > 12 mmHg

New DevicesNew DevicesePTFEePTFE Covered Covered StentsStents

StentStent TypeType TIPS TIPS dysfunctiondysfunction

P=0.005P=0.005

Hepatic Hepatic EncephEnceph..P=0.06P=0.06

MortalityMortalityP=0.17P=0.17

CoveredCovered 12.8%12.8% 22%22% 30%30%

UncoveredUncovered 44%44% 41%41% 46%46%

Cost AnalysisCost Analysis•• Large Volume Large Volume ParacentesisParacentesis Plus AlbuminPlus Albumin

–– AlbuminAlbumin----$10/gm$10/gm——Average 64 grams per tapAverage 64 grams per tap----$640$640–– Physician FeePhysician Fee----$250$250–– Hospital FeeHospital Fee----$550$550–– TOTAL BILLTOTAL BILL----$1440$1440–– Average 1 tap per month requirementAverage 1 tap per month requirement

•• TIPSTIPS–– Primary InsertionPrimary Insertion----$10,500$10,500–– TIPS Revision/AngioplastyTIPS Revision/Angioplasty----$3,000$3,000–– Revision Rate of 1.2 patients per monthRevision Rate of 1.2 patients per month——Based on 15% per Based on 15% per

year dysfunction rate of year dysfunction rate of ePTFEePTFE shuntsshunts

Cost AnalysisCost Analysis

•• 2 years comparison2 years comparison–– 100 patients per group100 patients per group–– Assume 30% survival at 2 yearsAssume 30% survival at 2 years–– Linear Death Rate (3 per month in each Linear Death Rate (3 per month in each

group)group)

Cost AnalysisCost AnalysisCumulative Costs

0

500

1000

1500

2000

2500

Year 1 Year 2

Dol

lars

(Tho

usan

ds)

TIPSLVP/Albumin

Cost AnalysisCost Analysis

•• Total cost per patient at 2 years:Total cost per patient at 2 years:–– TIPS: $11360 per patientTIPS: $11360 per patient–– LVP/Albumin: $22637 patientLVP/Albumin: $22637 patient

ConclusionsConclusions

•• TIPS is definitively a superior therapy for TIPS is definitively a superior therapy for diuretic refractory diuretic refractory ascitesascites

•• If patient selection is done properly If patient selection is done properly ((BilirubinBilirubin <3<3--5, Cr<3.0, <5, Cr<3.0, <GrGr I HE) it I HE) it carries minimal morbidity and mortalitycarries minimal morbidity and mortality

•• Using the new generation of covered Using the new generation of covered stentsstents, TIPS has a CLEAR cost advantage , TIPS has a CLEAR cost advantage over serial over serial paracentesisparacentesis