Gestione dell’ascite refrattaria: albumina e

dintorni Dr.CiroCelsa

ScuoladiSpecializzazioneinMalattie

dell’ApparatoDigerenteDipartimentodiPromozionedellaSalute,Materno-Infantile,MedicinaInternaeSpecialisticad’Eccellenza(PROMISE)

UniversitàdiPalermo

Agenda

• Refractoryascites:•  Pathophysiology•  Clinics

• Albumin:•  Propertiesandimpactonpathophysiologicalmechanisms•  Researchofliterature

•  TIPS/OLT

•  Futureremarks:ALFApump

Agenda

• Refractoryascites:•  Pathophysiology

Prognostic stages of cirrhosis

Compensatedcirrhosis Decompensatedcirrhosis Furtherdecompensation

Clinicallysignificantportalhypertension(CSPH)

Novarices Withvarices•  Varicealhemorrhage•  Ascites•  Hepaticencefalopathy

Onedecompensatingevent Seconddecompensatingevent

•  Recurrentvaricealhemorrhageorhepaticencefalopathy

•  Refractoryascites•  Hyponatremia•  Hepatorenalsyndrome•  Jaundice

Death

AdaptedfromD’AmicoGetal.JournalofHepatology,2006

Peripheral arterial vasodilation hypothesis

PortalHypertension

↑↑Splanchnicandsystemicvasodilation

↓↓Effectivearterialbloodvolume

↑↑Activationofneurohumoralsystems

Sodiumandwaterretention

ASCITESAdaptedfromSchrieretal.Hepatology,1988

↑ReleaseofNOandothervasodilators

New Pathophysiological Hypothesis

Bernardietal.JournalofHepatology,2015

Agenda

• Refractoryascites:•  Pathophysiology•  Clinics

Refractory ascites

EASLCPGforthemanagementofpatientswithdecompensatedcirrhosis.JournalofHepatology,2018

Survival of patients with refractory ascites

93.3%

6.7%

82%Renalfailure78%Encephalopaty75%Hyponatremia39%Hyperkalemia7%Hypokalemia

Planasetal.ClinicalGastroenterologyandHepatology,2006

5-yearprobabilityofsurvival:15.3%

Survival of patients with refractory ascites

93.3%

6.7%

82%Renalfailure78%Encephalopaty75%Hyponatremia39%Hyperkalemia7%Hypokalemia

Planasetal.ClinicalGastroenterologyandHepatology,2006

5-yearprobabilityofsurvival:15.3%

Apartfromlivertransplantation,thereisnotanytherapeuticinterventionthatchangessurvivalin

decompensatedcirrhosis

Agenda

• Refractoryascites:•  Pathophysiology•  Clinics

• Albumin:•  Propertiesandimpactonpathophysiologicalmechanisms

Albumin non oncotic functions

Bindingandtransport

Immunomodulation

Anti-oxidantfunctions

HemostaticeffectEndothelialstabilization

Albumin binds Clostridium Difficile toxins

•  HypoalbuminemiaisassociatedwithahigherriskofsevereClostridiumDifficileinfection

•  HumanalbuminspecificallybindsToxinAandBofClostridiumDifficile,impairinginternalizationintohostcellsatphysiologicalconcentrations

DiMasiA.,etal.JournalofInfectiousDiseases,2018

Albumin immunomodulatory effects

FernandezJ,etal.Gastroenterology,2019

Highalbumindosesincreaseserumalbuminlevels Highalbumindosesreduceinflammation

Albumin qualitative abnormalities in cirrhosis Healthycontrols(n=40) AD(n=285) ACLF(n=237) Pvalue

HMA(%) 71(68-74) 53(42-62) 45(33-56) <0.001

HNA1+HNA2(%) 28(25-30) 46.4(37.5-56.9) 51.8(42.2-65.6) <0.001

HNA2(%) 1.3(0.3-1.9) 4.5(2.5-8.8) 9.8(5.6-14.8) <0.001

ClariaJ,etal.Hepatology,2016

DomenicaliM,etal.Hepatology,2014

Potential of albumin as a disease modifying agent

Portalhypertension

Splanchnicvasodilation Bacterialtranslocation

Effectivearterialhypovolemia

Activationofvasoconstrictorsystems

Hyponatremia Renalhypoperfusion Cerebralhypoperfusion MultiorganfailuresAscites

Potential of albumin as a disease modifying agent

Portalhypertensionincirrhosis

Splanchnicvasodilation Bacterialtranslocation

Effectivearterialhypovolemia

Activationofvasoconstrictorsystems

Hyponatremia Renalhypoperfusion Cerebralhypoperfusion MultiorganfailuresAscites

Endothelialstabilization Immunomodulation

•  Oncoticpressure•  Endothelialstabilization

•  Capillarypermeability

•  Oncoticpressure•  Capillarypermeability

•  Oncoticpressure•  Immunomodulation

•  Endothelialstabilization•  Antioxidant

Agenda

• Refractoryascites:•  Pathophysiology•  Clinics

• Albumin:•  Propertiesandimpactonpathophysiologicalmechanisms•  Researchofliterature

Three recent relevant studies

• MACHTtrial(Solàetal.JournalofHepatology,2018)

• ANSWERtrial(Caracenietal.TheLancet,2018)

•  Long-termadministrationofalbumininrefractoryascites(DiPascolietal.,LiverInternational,2019)

MACHT Trial • Multicenterdoubleblindrandomizedplacebo-controlledtrial

• Patients:•  Cirrhoticwithascitesincludedonwaitinglistforlivertransplantation

•  Intervention•  Albumin(40gevery15days)•  Midodrine(15-30mg/dayadjustedtomeanarterialpressure)•  …plusstandardofcare

VersusStandardofcareplusplacebo

EndpointIncidenceofcomplicationsofcirrhosis

(renalfailure,hyponatremia,bacterialinfections,encephalopathy,GIbleeding)

MACHT Trial: flow chart 606patientsscreened

410excludedMostfrequentreasons:highdistanceofhometo

hospital,deniedconsent,previousTIPSorlivertransplant

196patientsrandomized(ITT)

99Midodrine+Albumin 97Placebo

87Midodrine+Albumin 86Placebo

12excluded 11excluded

MACHT Trial: flow chart 606patientsscreened

410excludedMostfrequentreasons:highdistanceofhometo

hospital,deniedconsent,previousTIPSorlivertransplant

196patientsrandomized(ITT)

99Midodrine+Albumin 97Placebo

87Midodrine+Albumin 86Placebo

12excluded 11excluded

ENDPOINT 32/87(37%) 37/86(43%)P=0.4

MACHT trial: Main Results Probabilityofdevelopinganycomplications Probabilityofmortality

• Mediandurationoftreatment:80days• Mediantimetodevelopthefirstcomplication:

•  M+A:16days(IQR0-38days)•  Placebo:26days(IQR13-39days)

MACHT trial: Main Results

•  RenalfailureandhyponatremiaepisodeswerelesssevereinM+Agroup

•  Nosignificantdifferencesintheincidenceofanycomplication

•  Nodifferencesindiureticrequirements

•  Nodifferencesinadverseevents

Strenghts

• Multicenter

• Double-blindedplacebocontrolled

MACHT trial: Methodological Issues

Weaknesses

• Shortintervalbetweenrandomizationandtreatmentinterruption(63daysinM+Avs105daysinplacebo)

• Albumindose

ANSWER Trial • Multicenteropen-labelrandomizedpragmaticclinicaltrial

• Patients:•  Cirrhoticwithpersistentuncomplicatedascitesintreatmentwithantialdosteronicdrug(>200mg/day)+Furosemide(>25mg/day)

•  Intervention•  Albumin(40gtwiceaweekforthefirsttwomonthsandthereafter40gweekly)•  …plusstandardofcare

VersusStandardMedicalTreatment

EndpointAllcause18-monthmortality

ANSWER Trial: Flow Chart Stratificationaccordingto:

•  Needfortherapeuticparacentesisinthemonthprecedingenrollment

•  Natremia(<or≥135mEq/L)

Endofthestudy:•  Death•  TIPS•  OLT•  3paracentesis/month•  Endfollow-up:18mo.

ANSWER Trial: Main Results

Thechronicuseofalbuminsustainedlyincreasedserumalbuminlevels

Thechronicuseofalbuminsignificantlyreducedtheneedoffirstparacentesisandtheincidenceofrefractoryascites

34%

62%

ANSWER Trial: Main Results

Thechronicuseofalbuminsignificantlydecreasedtheincidenceofthemajorityofcomplicationsofcirrhosis

ANSWER Trial: Main Results

Thechronicuseofalbuminsignificantlyincreasedsurvival

77%

66%

Strenghts

• Multicenter,investigator-initiated

• Pragmatictrial•  Designedtoassesstherealworld-effectivenessofintervention

• Assessmentofcost-effectiveness(ICER)

ANSWER trial: Methodological Issues

Weaknesses

•  Openlabeldesign

•  Applicabilityindifferentlocalsettings

•  Heterogeneityofpatients•  50%onlyascites•  50%ascitesandotherdecompensatingevents

Albumin in refractory ascites • Nonrandomizedprospectivestudy

• Patients:•  CirrhoticwithrefractoryascitestreatedwithrepeatedLVP

•  Intervention•  Albumin(20gtwiceaweek)•  …plusstandardofcare

Standardofcare

Endpoint24-monthmortality

DiPascolietal.,LiverInternational,2019

Study Flow Chart 84consecutivepatientswithrefractoryascites

(2012-2016)

14excludedHCCMilanOut:n=10

Severecomorbidities:n=4

70patientsreceivedtheoffertobetreatedwith:a)  Albumin20gtwiceperweek(athomeorinDH)b)  SMT:Dietarysodiumrestriction+maximaldosesofdiuretics

45acceptedAlbumin 25didnotaccepted

DiPascolietal.,LiverInternational,2019

SOCEndofthestudy:•  Death•  OLT•  Endofthefollowup:24mo.

Albumin in refractory ascites: Main Results

24-monthmortality:41.6%vs65.5%

Albumin in refractory ascites: Main Results

Strenghts

• Real-worldstudy

Methodological Issues

Weaknesses

•  Nonrandomized,single-center

•  Selectionbias

•  NoTIPS

Comparison among the three studies Study Patients Studydesign Primary

endpointMELD Albumindose Follow-up

Solàetal. PatientswithdecompensatedcirrhosisinwaitlistforLT

Doubleblindedplacebo-controlledtrial(mITTanalysisn=177)

Incidenceofcirrhosiscomplications

17inalbumin+midodrinegroup16inSMTgroup

40geverytwoweeks(plusmidodrine15-30mg/day)

63daysinalbumin+midodrinegroup.105daysinSMTgroup.

Caracenietal.

Ascitesrequiringatleast200mg/dayofantialdosteronicand25mg/dayoffurosemide

Multicenteropen-label«real-world»clinicaltrial.(mITTanalysisn=431)

Mortality 12inalbumingroup13inSMTgroup

40gtwiceaweekforthefirsttwomonths,then40gweekly

17.6monthsinalbumingroup.11.5monthsinSMTgroup

DiPascolietal.

Refractoryascites Singlecenter,nonrandomized(n=70)

Mortality 14.9inalbumingroup.15.2inSMTgroup

20gtwiceaweek

400.8daysinalbumingroup.318.7daysinSMTgroup

AdaptedfromBañaresR,BernardiM,LiverInternational,2019

Open issues

• Definitionofmosteffectivedose,scheduleandduration

•  Identificationofpatientssubgroupsthatcouldobtainthemostbenefit

•  Identificationofacut-offvalueofserumalbuminconcentrationtoreachtoobtainaclinicalbenefit

Serum albumin as a guide to long-term treatment

• Apost-hocanalysisofASNWERtrialevaluatedwhetherbaseline(BL)andon-treatment(OT)serumalbumin(SA)concentrationpredictclinicaloutcomes

• AccordingtodifferentBLSA(0.1g/dLincrease),18-mosurivalwas35-98%incontrolsand70-98%inthetreatedarm

•  1-monthOT-SAof3.7and4.2g/dLwereassociatedwith77%and90%18-monthsurvival,respectively.

1-monthOT-SAofabout4g/dLisassociatedwithveryhigh18-month

survival

Caracenietal.ILC2019.PS-083

Agenda

• Refractoryascites:•  Pathophysiology•  Clinics

• Albumin:•  Propertiesandimpactonpathophysiologicalmechanisms•  Researchofliterature

•  TIPS

TIPS versus LVP •  7controlledclinicaltrials(1996-2017)

•  6meta-analyses(2004-2014)

TIPS versus LVP Urinesodiumexcretion

AlbillosA,etal.JournalofHepatology,2005

Recurrenceofascites

SalernoF,etal.Hepatology,2004

TIPS versus LVP: Survival

SalernoF,etal.Gastroenterology,2007

≈10%

PTFE-TIPS in recurrent ascites

TIPSinsertionisrecommendedinpatientswithrecurrentascites(I;1)asitimprovessurvival(I;1)andinpatientswithrefractoryascitesasitimprovethecontrolofascites(I;1).

EASLCPGforthemanagementofpatientswithdecompensatedcirrhosis,2018

Hepaticencephalopathy

BureauC,etal.Gastroenterology,2017

Transplant-freesurvival

Agenda

• Refractoryascites:•  Pathophysiology•  Clinics

• Albumin:•  Propertiesandimpactonpathophysiologicalmechanisms•  Researchofliterature

•  TIPS/OLT

•  Futureremarks:ALFApump

Automated Low-Flow Ascites (ALFA) Pump

BureauC,etal.JournalofHepatology,2017

ALFA pump: Efficacy

BureauC,etal.JournalofHepatology,2017

Alfa-pumpreducesthenumberofparacentesis Alfa-pumpimprovesqualityoflife

Alfa-pumpdidnotimprovesurvival

ALFA pump: Safety…

BureauC,etal.JournalofHepatology,2017

… and costs

Conclusions • Refractoryascitesisassociatedwithsystemicinflammationandoxidativestress,relatedtobacterialtranslocation.

• Albuminwithitspleiotropiceffectsmaybeapathophysiologicaltherapyforadvancedcirrhosisandlong-termtreatmentimprovessurvivalinpatientswithresponsiveascites.

•  TIPSshouldbeconsideredinrecurrentandrefractoryascitesbecauseitmayimprovesurvival.

•  Theefficacyandsafetyofothertreatmentsneedfurtherinvestigations.