LessonsLearnedfromHeartFailureTrialswithRespecttoRenalOutcomes
JavedButler,MDMPHMBAProfessorofMedicine
ProfessorofPhysiologyandBiophysicsDirector,DivisionofCardiovascularMedicine
Co-Director,HeartInstituteStonyBrookUniversity,NewYork
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PersistentCongestionandOutcomesinAcuteHeartFailure
• Persistentclinicalandsub-clinicalcongestionatdischargeafteranAHFhospitalizationisassociatedwithworseoutcomes.
LucasC,etal.AmHeartJ.2000;140:840-847.
FonarowGC,etal.Circulation.1994;90(pt.2):1-488.
LogeartD,etal.JAmCollCardiol.2004;43:635-641
SignsandsymptomsPulmonaryCapillaryWedgePressure NatriureticPeptideLevels
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• 6797HFsubjects(NYHAIII-IV)fromSOLVDTrials• MultivariateanalysisofsurvivalinsubjectswithbaselineserumCr<1.5vs.Cr1.5-2.0(Cr>2.0excluded)
• Outcome RR 95%CIp-value
• AllCauseMortality 1.41 1.25-1.59p<0.001PumpFailureDeath 1.5 1.25-1.8p<0.001SuddenDeath 1.28 0.99-1.63p=0.051
Driesetal.,1998
PredictiveValueOfRenalDysfunctionInHeartFailure
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EffectofWorseningRenalFunctioninHospitalizedHeartFailurePatients
• Averagelengthofstaywas7±4daysforcasesand5±3daysforcontrols(p=0.001)
• Proportionofpatientswhostayedinthehospitalfor>10dayswas14%forcasesand3%forcontrols(p<0.05)
• Hospitalmortalityratewas5.2%forcasesand1.6%forcontrols(p<0.05)
• ButlerJetalAmHeartJ2004;147:331-338
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Question• 68yearoldpatient
• HTN,DM,CKD,andHF• BaselineEF20%-comesinwithAHF• BP110/70,HR82,Cr2.0• OnLisinopril20qd,spironolactone25qd,carvedilol12.5bid,furosemide40bid,ASA
• Day1–startedonlasix80IVbid• MRA• ACEI• LowerACEidose• Day2–BP106/72,Cr2.4,UOnetnegative800cc
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Verycomplextopic
• Willnotdiscussepidemiology,outcomes,or(speculated)pathophysiologyofbothdiseasesco-existing
• Renalfunctionastargetoftherapy• RenalfunctionchangesinheartfailuretrialsKDIGO
Thestoryofworseningrenalfunction(i.e.changeinserumcreatinine>0.3mg/dl)
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Buttheques3onis–whodecidedthatachangeinserumcrea3nine>0.3mg/dl–akaWRFisaproblemandatargetoftherapy?
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Over700paperspublishedrelated
toWRF
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Lesson
• Observationalstudies• Greatforhypothesisgeneration• Greatforsafetyassessment• Notgreatforcausalityascertainment
• Understandpathophysiology• Targetoftherapyshouldactuallybepresent,or• Atriskpopulation
• WRFWHF
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Ifyouhavetimeonlytoread2pages!
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Advantages
• Morerapidremovaloffluidexcessandimprovementinsymptoms
• Higherclearanceofsodiumload• Isotonicfluidremoval• Decreasedriskofelectrolyteabnormali3es(ie,hypokalemia)
• Decreasedriskofworseningrenalfunc3on• Lackofac3va3onoftheRASSandtheSNS• Removalofproinflammatorycytokines• ShortenedLOS• Decreasedrateofreadmissionsforheartfailure
• Significantcostperprocedure• Nursingtrainingandstaffingrequired• Excessivevolumeremovalresul3nginhypotension,WRF,andARF
• Allergicreac3ontoextracorporealcircuit• Catheter-relatedcomplica3ons(infec3onandthrombosis)
• Hemorrhage-complica3ngsystemican3coagula3on
• Hemorrhagefromvenousreturndisconnec3on
• Airembolism• Hemolysisandhyperkalemia
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FreedomFromReadmissionforHF
100-
80-
60-
40-
20-
-102030405060708090
Days
Percen
tageofP
a3en
ts
FreeFromReh
ospitaliza3
on
No.Pa3entsatRiskUltrafiltra3onArm88858077757270666445StandardCareArm86837774666359585241
P=.037
Ultrafiltra3onArm(16Events)
StandardCareArm(28Events)
0
CostanzoMRetal.JAmCollCardiol.2007;49:675-683.
Ultrafiltra3onversusIVDiure3csforPa3entsHospitalizedforADHF:UNLOADTrial
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ResourcesU3liza3onforHFin90Days
Resource UF SC PValue
Rehospitaliza3ons/Pa3ent 0.22 0.46 .037
Numberofrehospitaliza3ondaysperpa3ent 1.4 3.8 .022
Daysrehospitalized 123 330 .022
Unscheduledoffice+EDvisits(%) 21 44 .009
CostanzoMRetal.JAmCollCardiol.2007;49:675-683.
Ultrafiltra3onversusIVDiure3csforPa3entsHospitalizedforADHF:UNLOADTrial
Heartfailurefocusedoutcomes–needallcauserelatedhospitaliza3ons
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EligibilityCriteria
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Limitations
• PatientPopulation• CRSvs.diureticresistant• Robustdiuresis–notinCRS?
• SmallN• Treatmentdifferences
• 92(56-138)hr.forsteppedcare• 40(28-67)hr.forUF• UF–9%crossoverand30%IVdiuretics
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Lessons
• Whilewearetryingtounderstandscienceandpathophysiology–needtogivealotofattentiontohowwillweanswerallthequestionswhen
• A.Interestinphysiologyisdown• B.Conductofclinicaltrialsisveryexpensive• C.Regulatoryrequirementsandacademicsupport(includingnon-monetory)makesitevenmoredifficult
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Lessons• “Overt”diuresis
• Metneed• Currentdiureticsworks• Aggressivesteppedcareapproachesneedtobeimplemented
• Curbtheenthusiasmforpragmatictrialstoappropriatecircumstances
• Understand • Sub-clinicalcongestion• Redistribution
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• 12/2014to4/2016• 360patientsenrolledfrom22sites.
• 182patientsrandomizedtohigh-dosespironolactone
• 178tousualcare• 132placebo• 46continuedlowdose
spironolactone
StudyFlowandEnrollment–ATHENAHF
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Results-PrimaryEndpointUsualCare Spironolactone P
LogNTproBNP
Baseline 8.23(7.58,8.94) 8.43(7.90,9.17)
96h(ordischarge) 7.64(6.93,8.45) 7.89(7.19,8.68)
Change -0.49(-0.98,-0.14) -0.55(-0.92,-0.18) 0.57
DyspneascaleCongestionscoreUrineoutputWeightLoopdiureticuseIn-hospitalWHF
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HighDoseSpironolactoneinAcuteHeartFailureATHENA-HF
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Lesson
• Whilewedon’tknowhowbesttosub-segmentpatients(clinical,imaging,biomarker,others)–progresswillrequireunderstandingpathophysiologicsubgroups.KDIGO
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However
• DatalimitedtoGFR>30• HyperkalemiaandCKDintersection
• AwholeworldofheartfailurepatientswithGFR<30mlandthosewithhyperkalemianeedstobeexplored
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Anotherissue
• Renalfunctionisimportanttounderstanddiseaseandtreatment• Becarefulinmakingrenalfunctionasendpoint
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Sotoendonaverydepressingnote
• Didknowwhatcardio-renalsyndromeis?• HFrEF
• AlmostnodatainthosewithGFR<30• Hyperkalemia
• HFpEFandAHF• Nopositivetrialsofar-solimitedrenallessonsfromHFclinicaltrials
• Renalfunctionmaybeaprimarylearning,notnecessarilysecondary!
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Onthebrightside
• KDIGOwillcontinuetohaveopportunitiestoinvitemetocoolplacestotalkaboutthisissuesfortheforeseeablefuture• THANKYOU KDIGO
