Inotropic Agents in Heart Failure Due To Systolic Dysfunction PDF

7/11/2015
Inotropicagentsinheartfailureduetosystolicdysfunction
OfficialreprintfromUpToDate
www.uptodate.com2015UpToDate
Author
WilsonSColucci,MD
SectionEditor
StephenSGottlieb,MD
DeputyEditor
SusanBYeon,MD,JD,FACC
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Oct2015.|Thistopiclastupdated:Sep14,2015.
INTRODUCTIONThepositiveinotropicagents,includingdigoxin,inamrinone(formerlyknownas
amrinone),milrinone,andthebetaadrenergicreceptoragonists(table1),havebeneficialhemodynamiceffects
inpatientswithheartfailurewithreducedejectionfraction(HFrEFalsoknownassystolicHF)dueprimarilyto
adirectincreaseincardiacoutputand,toalesserextent,theensuingreductioninneurohumoralactivation,
whichcausesanunloadingoftheheartviaareductionintheplasmalevelsofvasoconstrictorssuchas
angiotensinIIandnorepinephrine.Inamrinoneandmilrinonealsoexertdirectarterialandvenousdilatoractions
thatcontributetotheoverallhemodynamiceffectsofthesedrugs.Inotropictherapyisofpotentialvalueonlyin
patientswithdecreasedcardiaccontractility.ThosewithHFwithpreservedejectionfraction(alsoknownas
diastolicHF)donotneedinotropicsupport.
Theefficacyofacuteintravenousinotropicsupportiswellestablishedinpatientswithseveremyocardial
systolicdysfunction.However,thebenefitofchronicadministrationoforalinotropicagentsinambulatory
patients,withtheexceptionofdigoxin,remainsunproven.Onthecontrary,availabledatasuggestthatthe
chronicuseofmanyofthesedrugsmayincreasemortality.Digoxinistheonlyoralpositiveinotropicagent
availableforlongtermambulatoryuse.
AnoverviewoftherapyofHFrEFispresentedseparately.(See"Overviewofthetherapyofheartfailurewith
reducedejectionfraction".)
DIGOXINDigoxinistheonlysafeandeffectiveoralpositiveinotropicagent.Datasupportingtheefficacyof
digoxintherapyinpatientswithheartfailure(HF)withreducedejectionfractionarepresentedindetail
elsewhere.Animportantfindingisthatthesafetyofdigoxinisrelatedtotheserumdigoxinlevel(figure1)[1,2].
Inadditiontosymptomaticbenefit[3],digoxinappearstobesafeatoptimalserumconcentrationsof0.5to0.8
ng/mLinmenand0.5to0.9ng/mLinwomen,buttoreducesurvivalatconcentrations1.2ng/mLinboth
sexes(figure1)[1,2].Itshouldalsoberecognizedthatdigoxinhasotheractions,mostimportantlytomodify
autonomictone,thatmaybeasimportant,orevenmoreimportant,thanitseffectsonmyocardialcontractility
indeterminingthedrug'sclinicaleffectsduringchronicadministration.(See"Useofdigoxininheartfailuredue
tosystolicdysfunction".)
Useofdigoxinisdiscussedseparately.Ourapproachisconsistentwiththe2013AmericanCollegeof
CardiologyFoundation/AmericanHeartAssociation(ACCF/AHA)guidelinesuggestionthatdigoxinmaybe
consideredforsymptomreliefinpatientswithleftventricularsystolicdysfunctionwithsymptomsofHFto
reducehospitalization[4].
PHOSPHODIESTERASEINHIBITORSPhosphodiesterase(PD)inhibitors,suchasinamrinone(formerly
knownasamrinone),milrinone,andenoximone,decreasetherateofcyclicadenosinemonophosphate(AMP)
degradation.TheensuingincreaseincyclicAMPconcentrationleadstoenhancedcalciuminfluxintothecell,a
riseincellcalciumconcentration,andincreasedcontractility.Thesedrugsalsocausesystemicarterialand
venousdilationviainhibitionofvascularPD[5].
IntravenoustherapyAdministrationofanintravenousPDinhibitor,suchasinamrinoneormilrinone,can
provideacutehemodynamicandsymptomaticbenefitinpatientswithadvancedheartfailurewithreduced
ejectionfraction(HFrEFNewYorkHeartAssociation[NYHA]functionalclassIIIorIV)(table2).Initial
uncontrolledobservationssuggestedthatprolongedoutpatienttherapywithintravenousmilrinone,either
continuousorweekly,couldimprovefunctionalstatusandreducehospitalization[68].
However,thepossiblebenefitoftheroutineuseofsuchtherapywasnotconfirmedintheOPTIMECHF,a
controlledtrialin949patientsadmittedtothehospitalwithanacuteexacerbationofchronicHFandamean
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leftventricularejectionfraction(LVEF)of23percentpatientsrequiringinotropicsupportwereexcluded[9].
Thepatientswererandomlyassignedtointravenousmilrinoneorplacebofor48to72hoursandthenfollowed
for60days.Milrinonetherapywasassociatedwithsignificantincreasesinhypotensionrequiringintervention
andatrialarrhythmiasandwithnonsignificantincreasesinmortalityinhospital(3.8versus2.3percent)andat
60days(10.3versus8.9percent).
Inaposthocanalysis,patientswithischemiccardiomyopathydidsignificantlyworsewithmilrinoneintermsof
theprimaryendpointofdaysofhospitalizationandthecombinedendpointofhospitalizationplusdeath[10].In
contrast,milrinonehadaneutraltomodestlybeneficialeffectinpatientswithanonischemiccardiomyopathy.
AnadversemortalityeffectofmilrinonewasalsosuggestedinaretrospectiveanalysisfromtheAcute
DecompensatedHeartFailure(ADHERE)nationalregistry[11].Afterattemptedadjustmentfordifferencesin
risk,milrinoneanddobutaminewereassociatedwithincreasedmortalitycomparedtopatientswhowere
treatedwithnitroglycerinornesiritide.However,sincesickerpatientsweretreatedwiththeinotropes,one
cannotknowiftheadjustmentsweresufficient.Useoftheseagentsisdiscussedbelow.(See'Useof
dobutamineormilrinone'below.)
OraltherapyChronicuseofanoralPDinhibitor,suchasmilrinoneorenoximone,hasbeenassociatedwith
increasedmortalitycomparedtoplacebo[12,13].AmetaanalysisfromtheCochraneDatabaseincluded21
randomizedtrialswithatotalof8408patientstreatedwithaPDinhibitororplacebowithgreaterthanthree
monthsfollowup[14].ThelargestincludedtrialsweretheVESTtrial,whichstudiedvesnarinone[15],andthe
PROMISEtrialwhichstudiedmilrinone[12].Comparedtoplacebo,useofaPDinhibitorwasassociatedwitha
significant17percentincreaseinmortality(relativerisk1.17,95%CI1.061.30).PDinhibitorsincreased
cardiacdeath,suddendeath,arrhythmias,andvertigo.Theseadverseeffectswereseenwithorwithout
concurrentvasodilatortherapy.
InthePROMISEtrialinwhich1088patientswithNYHAclassIIIorIVHFrEFwererandomlyassignedtooral
milrinone(40mg/day)orplacebo[12].Atsixmonths,milrinonetherapywasassociatedwithasignificant28
percentincreaseinallcausemortality(30versus24percentwithplacebo)anda34percentincreasein
cardiovascularmortality.Patientstreatedwithmilrinonehadagreaterincidenceofhospitalizations,more
adversecardiovascularsideeffects(syncopeandhypotension),andhigherdrugdiscontinuationrate.Although
therewasnosubgroupinwhichmilrinonewasassociatedwithasurvivalbenefit,thelargemajorityofexcess
mortalitywasobservedinpatientswithclassIVsymptoms.
WhytheoraluseofPDinhibitorsworsenslongtermoutcomeisnotclear,butlikelyisdueatleastinpartto
increasedventricularandatrialarrhythmias.ItispossiblethatthechronicuseofPDinhibitorsinlowerdoses
maybesafer[16],butthelongtermefficacyandsafetyofthisapproachremainstobedemonstratedin
controlledtrials.
IthasbeenproposedthattheuseofaPDinhibitormaypermitthesuccessfulinitiationandupwardtitrationof
betablockade.Suchanapproachmightbeeffectiveinmedicallyrefractorypatients.(See"Useofbeta
blockersandivabradineinheartfailurewithreducedejectionfraction".)IthasalsobeenproposedthataPD
inhibitorandbetablockermightbeusedtogetherlongterm.Inarandomizedshorttermstudy,the
hemodynamicresponsestoenoximoneweremaintainedorenhancedbymetoprololorcarvedilol[17],andina
seriesof30patientswithrefractoryNYHAclassIVHFwhoweretreatedwiththecombinationofenoximone
andmetoprolol,thisregimenwaswelltoleratedby80percentofpatients[18].Whiletheshortorlongtermuse
ofaPDinhibitorwithbetablockademaybeusefulinselectedcircumstances(eg,tostabilizehemodynamics
inapatientwithdecompensationinthesettingofnewbetablockade),thesafetyandefficacyoftheroutine
useofthiscombinationhasnotbeenestablished.
BETAADRENERGICRECEPTORAGONISTSChronicstimulationofthebetaadrenergicreceptorhas
beenconsideredatherapeuticoptioninpatientswithadvancedheartfailure(HF)withreducedejectionfraction.
Bothdobutamineandselectivebetablockerswithintrinsicsympathomimeticactivity(ISA)havebeen
evaluated.
Dobutamine
EfficacySymptomaticimprovementhasbeendemonstratedinpatientswithadvancedHFafter
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treatmentwithacontinuousinfusionofdobutamine(atarateof5to7.5g/kgpermin)forthreetofivedays
[1921].Ithasbeensuggestedthatthebenefitcanlastfor30daysormoreinselectedcases,aphenomenon
thathasbeencalleda"dobutamineholiday"[21].Possiblemechanismsincludeasustainedimprovementin
myocardialcontractilityandleftventricularperformance,atraininglikeeffectonskeletalmuscles,andan
improvementinvascularendothelialfunction[22].(See"Skeletalmuscledysfunctionandexerciseintolerance
inheartfailure".)
Thereare,however,noplacebocontrolleddatadocumentingimprovedsurvivalfromeitherintermittentor
continuousdobutamine[2326].Asmallstudyrandomlyassigned38patientstoambulatory,intermittent,low
dosedobutamine(2.5g/kgperminadministeredfor48hoursperweekforsixmonths),ortooptimalstandard
therapy[24].Dobutaminedidnotaffectmortalityorimprovefunctionalstatusitdid,however,reduce
hospitalizationforallcausesandforworseningofHF.Anothercontrolledtrial,theresultsofwhichhavenever
beenpublished,evaluatedintermittentambulatorydobutamineinfusionin60patientsthetrialwasstopped
prematurelybecauseofexcessmortalityinthedobutaminegroup[26].
Asaresultofthepotentiallyincreasedmortalityrisk,theadministrationofintravenousdobutaminehasbeen
limitedtotheinpatientmanagementofpatientswithseveredecompensatedHF.Inthissetting,dobutamine
appearstobeaseffectiveasmilrinone[27].
However,asnotedabove,milrinonemayincreasemortalitycomparedtoplaceboinpatientswhodonotrequire
inotropicsupportatpresentation[9].Inaddition,anonrandomizedretrospectivestudyfromADHERE
suggestedthat,afterattemptedadjustmentfordifferencesinrisk,milrinoneanddobutaminewereassociated
withincreasedmortalitycomparedtopatientstreatedwithnitroglycerinornesiritide[11].Sincesickerpatients
weretreatedwiththeinotropes,onecannotknowiftheadjustmentsweresufficient.
EffectofbetablockersOralbetablockers,suchasmetoprololandcarvedilol,arepartofthestandard
managementofHFduetosystolicdysfunction.Inarandomized,shorttermstudy,pretreatmentwithcarvedilol
markedlyreducedtheinotropicresponsetodobutamine,whereasmetoprololhadonlyaslightinhibitoryeffect
[17].Thereasonforthisdifferenceisnotfullyunderstood.
HypersensitivitymyocarditisAneosinophilichypersensitivitymyocarditishasbeenreportedin2.4to
23percentofpatientstreatedwithadobutamineinfusion,particularlyifprolonged[28,29].(See"Etiologyand
pathogenesisofmyocarditis",sectionon'Hypersensitivitymyocarditis'.)
BetablockerswithISAIthasbeensuggestedthatbetablockersthatalsohavesignificantintrinsic
sympathomimeticactivity(ISA)mayofferasaferwayofprovidingchronicinotropicsupporttothefailingheart.
However,aprospective,multicenterstudyof512patientsdemonstratedasignificantexcessmortalityin
patientstreatedwithonesuchagent,xamoterol,ascomparedwithplacebo(9.1versus3.7percentwithin100
days)[30].
USEOFDOBUTAMINEORMILRINONEGivenconcernsaboutincreasedmortalitywithshortterm
intravenoustherapywithmilrinoneordobutamineinpatientswithacutedecompensatedheartfailure(HF)
[9,11,31],wesuggestthatthesedrugsnotbeusedintheroutinemanagementofsuchpatients.However,
administrationofaninotropeshouldbeconsideredinpatientswithseverehemodynamiccompromisewithlow
cardiacoutputthatisnotadequatelymanagedbydiureticsandvasodilators,orcardiogenicshock[31].(See
"Treatmentofacutedecompensatedheartfailure:Componentsoftherapy",sectionon'Inotropicagents'.)
Withrespecttolongtermintravenoustherapywithapositiveinotropicagent,the2013AmericanCollegeof
CardiologyFoundation/AmericanHeartAssociation(ACCF/AHA)guidelineconcludedthatlongterminfusionof
aninotropicagentmaybeusefuluntildefinitivetherapy(eg,coronaryrevascularization,mechanicalcirculatory
support,orhearttransplantation)orresolutionoftheacuteprecipitatingproblem[4].Itwasfelttobereasonable
asbridgetherapyinpatientswithstageDHFrefractorytostandardmedicalanddevicetherapywhoare
eligibleforandawaitingmechanicalcirculatorysupportorcardiactransplantation.Itwasalsofeltreasonableto
consideritsuseaspalliativetherapyforsymptomcontrolinselectedpatientswithstageDHFdespiteoptimal
medicalanddevicetherapy.
CALCIUMSENSITIZINGAGENTSTheagentsdescribedaboveactthroughacommonpathwayinvolving
betareceptors,cyclicadenosinemonophosphate(AMP),proteinkinaseA,increasedcalciuminflux,and
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cyclinginthecardiomyocyte.However,theseeffectsoncalciumfluxmayincreasearrhythmicrisksandresult
inworseoutcomes.
Analternativeapproachistoenhancemyocardialresponsetoagivenconcentrationofcalcium[3234].Several
compoundshavebeenidentifiedthatincreasethesensitivityofthemyocardialcontractileapparatusto
calcium,causinganincreaseintensiondevelopmentandmyocardialcontractility.(See"Excitationcontraction
couplinginmyocardium".)
Oneconcernregardingsuchcompoundsisthepossibleimpairmentofmyocardialrelaxation[35].However,at
leastoneofthesecompounds,levosimendan,appearstohaveafavorableeffectonrelaxationpropertiesin
failinghearts[34].
Mostcalciumsensitizingagentshaveadditionalpharmacologicproperties,suchasphosphodiesterase
inhibition,whichmayincreaseinotropyandvasodilationandcontributesignificantlytotheirclinicalprofile.
PimobendanPimobendanisaninotropicagentwithphosphodiesteraseinhibitingandcalciumsensitizing
effects.Acuteintravenousadministrationofpimobendantopatientswithheartfailurewithreducedejection
fraction(HFrEF)resultsinincreasesinstrokevolumeandcardiacindexandreductionsinleftventricularend
diastolicpressure,systemicvascularresistance,andmeanarterialpressurewithassociatedsmallelevationin
heartrate[36].Intworandomized,placebocontrolledtrials(PMRGandPICO)ofpatientswithHFrEF,12to
24weekadministrationoforalpimobendanresultedinimprovementsinexerciseduration[37,38],althoughin
thelargerstudytherewasanonsignificanttrendtowardgreatermortality(hazardratio1.8,95%CI0.9to3.5)
[38].
ThelongtermefficacyandsafetyofpimobendanfortreatmentofHFrEFhasnotbeenestablished.Inthe
EPOCHstudy,306patientswithNewYorkHeartAssociation(NYHA)functionalclassIIorIIIHFandleft
ventricularejectionfraction(LVEF)45percentdespiteconventionaltherapywererandomlyassignedto52
weeksoftreatmentwithpimobendanorplacebo[39].Theprimarycombinedendpointofsuddencardiacdeath,
hospitalizationforHF,ordeathfromHFwaslessfrequentinthepimobendangroup(10.1versus15.3percent)
butthisdifferencewasnotstatisticallysignificant.Thecombinedadversecardiaceventrateinthepimobendan
groupwassignificantlylowerthanintheplacebogroup(15.9versus26.3percent)butthisendpointincluded
additionorincreaseindosesofbackgroundmedicationsanddecreaseinspecificactivityscale.
PimobendaniscurrentlyapprovedforuseonlyinJapan[32].
LevosimendanLevosimendanisapositiveinotropicdrugwithvasodilatoreffects.Severalstudieshave
evaluateditsefficacyandsafetyinpatientswithHF[33,4043].Despiteimprovementinindicesofcardiac
performanceandHF,thereisnoclearevidenceofshortorlongtermclinicalbenefit.
Theshorttermhemodynamiceffectsofintravenousadministrationoflevosimendanincludeadosedependent
reductionincardiacfillingpressuresandanincreaseincardiacindex[40,41,44].TheLIDO(n=203)and
SURVIVE(n=1327)trialsrandomlyassignedpatientswithsevereHFtoeitherlevosimendanordobutamine
andevaluatedoutcomesat24hours[42,45].Theformerstudyfoundgreaterhemodynamicimprovementwith
levosimendan,whilethelatterfoundnodifferenceinthepercentageofpatientswhoreportedmorethanamild
improvementindyspnea(82versus83percent,respectively).
Longertermstudiesofpatientswithacutedecompensatedheartfailure(ADHF)andsystolicdysfunctiondonot
clearlysupportasurvivalbenefit:
IntheLIDOtrialcitedabove,levosimendanwasassociatedwithasignificantmortalitybenefitatboth
oneandsixmonths(8versus17percentand26versus38percent,respectively).
AsimilareffectwasnotedwithintwodaysofanacutemyocardialinfarctionintheRUSSLANtrialof504
patients[43].Comparedtoplacebo,asixhourinfusionoflevosimendandidnotaffecttheprimaryend
pointofhypotensionorclinicallysignificantmyocardialischemia,butsignificantlyimprovedthesecondary
endpointofdeathorworseningheartfailureatonedayandtwoweeks(12versus20percent),witha
strongtrendtowardimprovementatsixmonths(23versus31percent).
IntheSURVIVEtrial,a24hourinfusionoflevosimendan,comparedtodobutamine,didnotreduceall
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causemortality,cardiovascularmortality,ordaysoutofthehospitalat180days[45].
IntheREVIVEIandREVIVEIIsequentialtrials,700patientswithADHFwhoremaineddyspneicafter
intravenousdiureticswererandomlyassignedtointravenouslevosimendanorplacebofor24hours[46].
AlthoughpatientsinthelevosimendangroupreportedgreaterimprovementinsymptomsandlowerBtype
natriureticpeptidelevelsforuptofivedays,levosimendanwasassociatedwithmorefrequent
hypotensionandcardiacarrhythmiasandanumericallyhigherriskofdeathinthetwotrials(40versus40
p=0.29)at90days.
Giventheaboveresults,weconcludethattheefficacyandsafetyoflevosimendanhavenotbeenestablished.
LevosimendaniscurrentlyapprovedforintravenoususeinsomecountriesinEuropeandSouthAmerica,but
remainsinvestigationalintheUnitedStates[32,33].The2012EuropeanSocietyofCardiology(ESC)HF
guidelinesnotethattheefficacyandsafetyoflevosimendanarestilluncertain,thoughtheysuggestapotential
pharmacologicrationaleforintravenouslevosimendan(oraphosphodiesteraseinhibitor)toreversetheeffectof
betablockadeifbetablockadeisthoughttobecontributingtohypoperfusion[47].
INOTROPESINPATIENTSAWAITINGHEARTTRANSPLANTPatientswithsevereheartfailure(HF)
withreducedejectionfractionwhoareawaitinghearttransplantationconstituteauniquepopulationwithrespect
totheroleoftherapyforhemodynamicsupport.Inthissetting,thegoalofHFmanagementistomaintainthe
patient'sclinicalstabilitylongenoughtoenablethepatienttoundergotransplantationwhenadonorheart
becomesavailable.Avarietyofapproacheshavebeenusedto"bridge"apatienttohearttransplantation,
includingtheuseofmechanicalventricularassistdevices.(See"Managementofrefractoryheartfailure"and
"Indicationsandcontraindicationsforcardiactransplantation",sectionon'Majorsocietyguidelines'and
"Intermediateandlongtermmechanicalcirculatorysupport".)
Intravenousinotropicagentsareanotheroptionforthetemporaryhemodynamicsupportofahearttransplant
candidate.Theclinicalimprovementsseenwithinotropes(reducedhospitalization,lessfrequentworseningof
HF)arebeneficialbecausethepatientismaintainedinanoptimalclinicalconditionpriortosurgery.Such
patientscanbedischargedfromthehospitalifclinicallystableandmanagedonanoutpatientbasiswiththe
assistanceofavisitingnurseandahomeinfusiontherapyprogram.Theincreasedriskofsuddendeath
associatedwiththeseagentscanbemitigatedwiththeuseofanimplantablecardioverterdefibrillator(ICD)
and,ifappropriate,pharmacotherapy(usuallyamiodarone)forthesuppressionofventriculararrhythmias.(See
"Secondarypreventionofsuddencardiacdeathinheartfailureandcardiomyopathy",sectionon'Useofan
ICD'.)
Thebenefitofoutpatientintravenousinotropictherapyasabridgetohearttransplantationwasillustratedina
reportof21patientswithsevereHFwhoweretreatedwithdobutamine(12patients),milrinone(eightpatients),
ordopamine(onepatient)forameandurationof146days[48].AllbutoneofthepatientsreceivedanICDprior
tohospitaldischarge.Intravenousinotropictherapyresultedinsignificantimprovementsinfunctionalcapacity,
renalfunction,andhemodynamicsaswellasadecreaseinthenumberofhospitalizations.Fifteenpatients
underwenthearttransplantation,threedied,andthreewerestillawaitingtransplantationattheendoffollowup.
Therewerefiveepisodesofcatheterinfectionorthrombosisduringhomeinfusiontherapy,oneresultinginfatal
septicshock.(See"Diagnosisofintravascularcatheterrelatedinfections".)
SUMMARY
Theonlysafeandeffectiveoralpositiveinotropicagentisdigoxinbutithasarelativelynarrow
therapeuticwindow.(See'Digoxin'above.)
Seriousquestionshavebeenraisedaboutthelongtermsafetyofotheroralpositiveinotropicagents,
includingphosphodiesteraseinhibitorssuchasmilrinone,enoximone,andvesnarinone,aswellasother
agentssuchxamoterolandibopamine.Whenaddedtoconventionaltherapywithdigitalis,diuretics,and
angiotensinconvertingenzyme(ACE)inhibitors,eachoftheseagentshasbeenassociatedwithan
increaseinmortality.Theadverseoutcomeswiththeseagentsmayresultinpartfromproarrhythmic
effectsleadingtosuddendeath.(See'Oraltherapy'aboveand'BetablockerswithISA'above.)
Givenconcernsaboutincreasedmortalitywithshorttermintravenoustherapywithmilrinoneor
dobutamineinpatientswithacutedecompensatedheartfailure(HF),wesuggestthatthesedrugsnotbe
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usedintheroutinemanagementofsuchpatients.However,administrationoftheseinotropesshouldbe
consideredinpatientswithseverehemodynamiccompromisethatisnotadequatelymanagedby
diureticsandvasodilators,orcardiogenicshock.(See'Intravenoustherapy'aboveand'Dobutamine'
above.)
Withrespecttolongtermintravenoustherapywithapositiveinotropicagent,longterminfusionofan
inotropicagentmaybeharmfulandisnotgenerallyrecommendedinpatientswithcurrentorprior
symptomsofheartfailure(HF),exceptaspalliationinpatientswithendstageHFrefractorytostandard
medicaltherapy.(See'Useofdobutamineormilrinone'above.)
Continuousintravenousinotropictherapyandmechanicalventricularassistdevicesupportareoptionsfor
thehemodynamicsupportofpatientsawaitinghearttransplantation.Withappropriateprotectionagainst
therisksofsuddendeathandcatheterinfection,selectedpatientsmayreceiveinotropictherapyonan
outpatientbasis.(See'Inotropesinpatientsawaitinghearttransplant'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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28. TakkenbergJJ,CzerLS,FishbeinMC,etal.Eosinophilicmyocarditisinpatientsawaitingheart
transplantation.CritCareMed200432:714.
29. JohnsonMR.Eosinophilicmyocarditisintheexplantedheartsofcardiactransplantrecipients:Interesting
pathologicfindingorpathophysiologicentityofclinicalsignificance?CritCareMed200432:888.
30. Xamoterolinsevereheartfailure.TheXamoterolinSevereHeartFailureStudyGroup.Lancet1990
336:1.
31. DecGW.Acutedecompensatedheartfailure:theshrinkingroleofinotropictherapy.JAmCollCardiol
200546:65.
32. KassDA,SolaroRJ.Mechanismsanduseofcalciumsensitizingagentsinthefailingheart.Circulation
2006113:305.
33. DeLucaL,ColucciWS,NieminenMS,etal.Evidencebaseduseoflevosimendanindifferentclinical
settings.EurHeartJ200627:1908.
34. GivertzMM,AndreouC,ConradCH,ColucciWS.Directmyocardialeffectsoflevosimendaninhumans
withleftventriculardysfunction:alterationofforcefrequencyandrelaxationfrequencyrelationships.
Circulation2007115:1218.
35. HajjarRJ,GwathmeyJK.Calciumsensitizinginotropicagentsinthetreatmentofheartfailure:acritical
view.CardiovascDrugsTher19915:961.
36. HassenfussG,HolubarschC,HeissJW,etal.InfluenceofthecalciumsensitizerUDCG115on
hemodynamicsandmyocardialenergeticsinpatientswithidiopathicdilatedcardiomyopathy.Comparison
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37. KuboSH,GollubS,BourgeR,etal.Beneficialeffectsofpimobendanonexercisetoleranceandquality
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38. LubsenJ,JustH,HjalmarssonAC,etal.Effectofpimobendanonexercisecapacityinpatientswith
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76:223.
39. EffectsofPimobendanonChronicHeartFailureStudy(EPOCHStudy).Effectsofpimobendanon
adversecardiaceventsandphysicalactivitiesinpatientswithmildtomoderatechronicheartfailure:the
effectsofpimobendanonchronicheartfailurestudy(EPOCHstudy).CircJ200266:149.
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Topic3488Version10.0
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GRAPHICS
Chronicinotropicagentsinheartfailure
Digitalis
Digoxinandothers
Phosphodiesteraseinhibitors
Milrinone
Enoximone*
Calciumsensitizingagents
Pimobendan*
Levosimendan*
Phosphodiesteraseinhibitorswithsodiumandpotassiumchannelmodulatingeffects
Vesnarinone
Betareceptoragonists
Dopamine
Dobutamine
Xamoterol
Growthhormone(somatropin)
*NotapprovedbyUSFDA.AvailableinmanycountriesoutsideofUS.
NotapprovedbyUSFDAandlimitedornoavailabilityoutsideUS.
NotapprovedformanagementofheartfailurebyFDA.
Graphic63265Version3.0
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SerumdigoxininHFiscorrelatedwithsurvival
Among3782patientswithheartfailure(HF)receivingdigoxinorplacebointhe
DIGtrial,therewasasignificantassociationbetweenserumdigoxin
concentration(SDC)andallcausemortality.Comparedtoplacebo,survival
wassignificantlybetterforpatientswithSDC0.5to0.8ng/mL,and
significantlyworseforpatientswithSDC1.2ng/mL.
DatafromRathoreSS,CurtisJP,WangY,etal.JAMA2003289:871.
http://www.uptodate.com/contents/inotropicagentsinheartfailureduetosystolicdysfunction?topicKey=CARD%2F3488&elapsedTimeMs=8&source
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7/11/2015
Comparisonofthreemethodsofassessingcardiovascular
disability
Class
NewYorkHeart
Association
functional
classification [1]
Canadian
Cardiovascular
Society
functional
classification [2]
Specificactivity
scale [3]
Patientswithcardiac
Ordinaryphysical
Patientscanperform
diseasebutwithout
resultinglimitationsof
activity,suchas
walkingandclimbing
tocompletionany
activityrequiring7
physicalactivity.
Ordinaryphysical
activitydoesnot
stairs,doesnotcause
angina.Anginawith
strenuousorrapid
metabolic
equivalents,eg,can
carry24lbupeight
causeunduefatigue,
palpitation,dyspnea,
oranginalpain.
prolongedexertionat
workorrecreation.
stepsdooutdoor
work(shovelsnow,
spadesoil)do
recreationalactivities
(skiing,basketball,
squash,handball,
jog/walk5mph).
II
Patientswithcardiac
Slightlimitationof
Patientscanperform
diseaseresultingin
slightlimitationof
physicalactivity.They
arecomfortableat
rest.Ordinaryphysical
ordinaryactivity.
Walkingorclimbing
stairsrapidly,walking
uphill,walkingorstair
climbingaftermeals,
tocompletionany
activityrequiring5
metabolic
equivalents,eg,have
sexualintercourse
activityresultsin
fatigue,palpitation,
dyspnea,oranginal
pain.
incold,inwind,or
whenunderemotional
stress,oronlyduring
thefewhoursafter
awakening.Walking
morethantwoblocks
withoutstopping,
garden,rake,weed,
rollerskate,dance
foxtrot,walkat4
mphonlevelground,
butcannotanddo
ontheleveland
climbingmorethan
oneflightofordinary
stairsatanormal
paceandinnormal
notperformto
completionactivities
requiring7
metabolic
equivalents.
conditions.
III
Patientswithcardiac
Markedlimitationof
Patientscanperform
diseaseresultingin
markedlimitationof
physicalactivity.They
arecomfortableat
rest.Lessthan
ordinaryphysical
activity.Walkingone
totwoblocksonthe
levelandclimbingone
flightinnormal
tocompletionany
activityrequiring2
metabolic
equivalents,eg,
showerwithout
ordinaryphysical
activitycauses
fatigue,palpitation,
dyspnea,oranginal
pain.
conditions.
stopping,stripand
makebed,clean
windows,walk2.5
mph,bowl,playgolf,
dresswithout
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stopping,butcannot
anddonotperform
tocompletionany
activitiesrequiring
>5metabolic
equivalents.
IV
Patientswithcardiac
diseaseresultingin
inabilitytocarryon
anyphysicalactivity
Inabilitytocarryon
anyphysicalactivity
withoutdiscomfort
anginalsyndrome
Patientscannotordo
notperformto
completionactivities
requiring>2
withoutdiscomfort.
Symptomsofcardiac
insufficiencyorofthe
anginalsyndrome
maybepresenteven
maybepresentat
rest.
metabolic
equivalents.Cannot
carryoutactivities
listedabove(Specific
activityscaleIII).
atrest.Ifanyphysical
activityisundertaken,
discomfortis
increased.
References:
1. TheCriteriaCommitteeoftheNewYorkHeartAssociation.NomenclatureandCriteriafor
DiagnosisofDiseasesoftheHeartandGreatVessels,9thed,Little,Brown&Co,Boston,
1994.p.253.
2. LucienC.Gradingofanginapectoris.Circulation197654:5223.
3. GoldmanL,HashimotoB,etal.Comparativereproducibilityandvalidityofsystemsfor
assessingcardiovascularfunctionalclass:Advantagesofanewspecificactivityscale.
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Disclosures
Disclosures:WilsonSColucci,MDGrant/ResearchSupport:NovartisRiboCor[Heartfailure].Consultant/AdvisoryBoards:
NovartisMerckMastPharmaceuticalsCardioxylPharmaceuticals[Heartfailure].Speaker'sBureau:Novartis[Heartfailure].
StephenSGottlieb,MDGrant/Research/ClinicalTrialSupport:Pfizer[amyloidosis(tafamidis)]Novartis[heartfailure(seralaxin)]
Resmed[sleepapnea(CPAP)]Respircardia[sleepapnea(remede)]Amgen[heartfailure(omecamtivmecarbil)].
Consultant/AdvisoryBoards:Novartis[heartfailure(seralaxin)]BMS[heartfailure]Relypsa[hyperkameia(patiromer)].SusanB
Yeon,MD,JD,FACCNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvetting
throughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriately
referencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy
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