Optimizing Risk Stratification in Heart Failure and the Selection of Candidates for Heart Transplantation

(1)

www.revportcardiol.org

Revista

Portuguesa

de

Cardiologia

Portuguese

Journal

of

Cardiology

ORIGINAL

ARTICLE

Optimizing

risk

stratiﬁcation

in

heart

failure

and

the

selection

of

candidates

for

heart

transplantation

Tiago

Pereira-da-Silva

a_,_∗

_,

_Rui

_M.

_Soares

a

_,

_Ana

_Luísa

_Papoila

b_,c

_,

_Iola

_Pinto

d_,e

_,

Joana

Feliciano

a

_,

_Luís

_{Almeida-Morais}

a

_,

_Ana

_Abreu

a

_,

_Rui

_Cruz

_Ferreira

a

a_Department_of_Cardiology,_Hospital_de_Santa_Marta,_Centro_Hospitalar_de_Lisboa_Central,_Lisbon,_Portugal b_Department_of_{Biostatistics}_and_Informatics,_NOVA_Medical_School,_Universidade_NOVA_de_Lisboa,_Lisbon,_Portugal c_Research_Unit,_Centro_Hospitalar_de_Lisboa_Central,_Lisbon,_Portugal

d_Departmental_Area_of_Mathematics,_Instituto_Superior_de_Engenharia_de_Lisboa,_Universidade_NOVA_de_Lisboa,_Lisbon,_Portugal e_Center_for_Mathematics_and_{Applications,}_Faculty_of_Sciences_and_Technology,_Universidade_NOVA_de_Lisboa,_Lisbon,_Portugal

Received22January2017;accepted18June2017 Availableonline5March2018

KEYWORDS Cardiopulmonary exercisetesting; Heartfailure; Heart transplantation; Peakoxygen consumption; Riskstratiﬁcation; Ventilatoryefﬁciency slope Abstract

IntroductionandAims:Selectingpatientsforheart transplantationischallenging. Weaimed

toidentifythemostimportantriskpredictorsinheartfailureandanapproachtooptimizethe

selectionofcandidatesforhearttransplantation.

Methods:Ambulatory patients followed in our center with symptomatic heart failure and

left ventricular ejection fraction ≤40% prospectively underwent a comprehensive baseline

assessment includingclinical,laboratory, electrocardiographic, echocardiographic,and

car-diopulmonary exercise testing parameters. All patients were followed for 60 months. The

combined endpointwas cardiacdeath, urgentheart transplantationorneedfor mechanical

circulatorysupport,upto36months.

Results:In the263enrolledpatients (75%male,age54_±12years),54eventsoccurred.The

independent predictorsofadverseoutcomewereventilatoryefﬁciency(VE/VCO2)slope(HR

1.14,95%CI1.11-1.18),creatininelevel(HR2.23,95%CI1.14-4.36),andleftventricular

ejec-tionfraction(HR0.96,95%CI0.93-0.99).VE/VCO2slopewasthemostaccurateriskpredictor

atanyfollow-uptimeanalyzed(upto60months).Thethresholdof39.0yieldedhighspeciﬁcity

(97%),discriminatedaworseorbetterprognosisthanthatreportedforpost-heart

transplan-tation,andoutperformedpeakoxygenconsumptionthresholdsof10.0or12.0ml/kg/min.For

low-riskpatients(VE/VCO2slope<39.0),sodiumandcreatininelevelsandvariationsinend-tidal

carbondioxidepartialpressureonexerciseidentiﬁedthosewithexcellentprognosis.

Conclusions: VE/VCO2slopewasthemostaccurateparameterforriskstratiﬁcationinpatients

withheartfailureandreducedejectionfraction.ThosewithVE/VCO2slope≥39.0maybeneﬁt

fromhearttransplantation.

reserved.

∗_{Corresponding}_author.

E-mailaddress:[email protected](T.Pereira-da-Silva).

https://doi.org/10.1016/j.repc.2017.06.018

(2)

PALAVRAS-CHAVE Provadeesforço cardiorrespiratória; Insuficiência cardíaca; Transplantação cardíaca; Consumodeoxigénio depico; Estratificaçãode risco; Declivedaeficiência ventilatória

Aprimoramentodaestratificaçãoderisconainsuficiênciacardíacaedaseleção decandidatosatransplantaçãocardíaca

Resumo

Introduçãoeobjetivos: Aseleçãodedoentesparatransplantaçãocardíacaédifícil.Procurámos

identiﬁcarospreditoresderiscomaisrelevantesnainsuﬁciênciacardíacaeumaabordagem

paraaprimoraraselec¸ãodecandidatosatransplantac¸ão.

Métodos: Doentes sintomáticos com insuficiência cardíaca e fração de ejeção ventricular

esquerda≤40%,ambulatórios,seguidosnonossocentro,completaramprospetivamenteuma

avaliac¸ãobasalabrangente,inclusiveparâmetrosclínicos,laboratoriais,eletrocardiográﬁcos,

ecocardiográﬁcoseprovadeesforc¸ocardiorrespiratória;foramseguidospor60meses.Endpoint

combinado:mortedecausacardíaca,transplantac¸ãourgente ounecessidadedeassistência

mecânica,atéaos36meses.

Resultados: Nos263doentesincluídos(75%homens,54±12 anos)ocorreram54 eventos.O

declivedaeﬁciênciaventilatória(decliveVE/VCO2)(HR1,14,IC95%1,11-1,18),acreatinina

(HR2,23,IC95%1,14-4,36)eafrac¸ãodeejec¸ãoventricularesquerda(HR0,96,IC95%

0,93-0,99)forampreditoresindependentesdeeventos.OdecliveVE/VCO2foiomelhorpreditorem

qualquerperíodo analisado(atéaos60meses).Olimiar39,0apresentou elevada

especiﬁci-dade(97%),discriminouumprognósticomelhoroupiordoqueoreportadonopós-transplante

cardíacoesuperouoslimiares10,0ou12,0mL/kg/mindeconsumodeoxigéniodepico.Em

doentesdebaixorisco(decliveVE/VCO2<39,0)osódio,acreatininaeavariac¸ãono

exercí-ciodapressãoparcialdedióxido decarbonoexpirado identiﬁcaramaqueles comexcelente

pronóstico.

Conclusões:OdecliveVE/VCO2foiomelhorpreditorderiscoemdoentescominsuﬁciência

cardíacaefraçãodeejeçãoreduzida.DoentescomdecliveVE/VCO2≥39,0poderãobeneficiar

detransplantac¸ãocardíaca.

direitosreservados.

Listofabbreviations

PetCO2 variationofend-tidalcarbondioxidepartial pressure

CI conﬁdenceinterval

CPET cardiopulmonaryexercisetesting HF heartfailure

HTX hearttransplantation

IDI integrateddiscriminationimprovement ISHLT International Society for Heart and Lung

Transplantation

LVEF leftventricularejectionfraction NRI netreclassiﬁcationimprovement VO2max peakoxygenconsumption VE/VCO2slope ventilatoryefﬁciencyslope

Introduction

Awide variety of predictors of adverse outcome in heart failure(HF)havebeen describedanditcanbedifﬁcult to choose the most appropriate tools in clinical practice.1,2

Riskstratiﬁcation should be asaccurate aspossible, par-ticularlywhenselectingpatients forheart transplantation (HTX), as procedure-related morbidity and mortality are

non-negligibleanditcannotbeofferedtoallcandidatesdue totheshortageof donors.3_For_ambulatory _patients,_both

theAmericanHeartAssociationandtheInternational Soci-etyforHeartandLungTransplantation(ISHLT)recommend theuseofpeakoxygenconsumption(VO2max)achievedin

cardiopulmonaryexercisetesting(CPET),withoptionaluse ofrisk scoresingrayzones;VO2max<10-12ml/kg/min is

consideredalistingcriterionforHTX.4,5_We_believe_that_risk

stratificationandreferralcriteriaforHTXcanbeimproved using simple parameters. Additional CPET variables have showntobeaccurateforriskstratification,particularlythe ventilatory efficiency (VE/VCO2) slope.6---8 However, most

studiesthathighlightthevalueofergospirometric parame-tershavefocusedmainlyonclinicalandCPETdata,without comprehensive assessment of other parameters, and few had long-term follow-up.6---9 _Identifying_robust _criteria_for

selectingpatientsforHTXshouldbebasedona comprehen-siveprospectiveclinicalandcomplementaryassessment.

Ouraimsweretoidentifythemostaccuratepredictors ofadverseeventsinnon-transplantedpatientswithHFand anapproachtooptimizetheselectionofpatientsforHTX.

Methods

Theinvestigationconformstotheprinciplesoutlinedinthe DeclarationofHelsinki.Theinstitutionalethicscommittee approvedthestudyprotocol.

(3)

Patientselectionandcomplementaryassessment Thissingle-centeranalysisincludedallpatientswithHFwith leftventricularejectionfraction(LVEF)≤40%,inNewYork HeartAssociation classII or III,followed intheheart fail-ure clinic of our institution between 2000 and 2009. All patients referred to the heart failure clinic underwent a comprehensive complementaryassessment. Clinical, labo-ratory,electrocardiographic,echocardiographic, andCPET data were prospectively collected; all these exams were performedwithinaperiodofonemonthineachpatient.

Patients aged <18 years and those with planned per-cutaneous coronary revascularization or cardiac surgery, exercise-limiting comorbidities (cerebrovascular disease, musculoskeletalimpairment,orsevereperipheralvascular disease),previousHTX,orfailuretoachievetheanaerobic thresholdwereexcluded.

Cardiopulmonaryexercisetesting

Maximal symptom-limited treadmill CPET was performed usingthemodiﬁedBruceprotocol(GEMarquetteSeries2000 treadmill).Gasanalysiswasprecededbycalibrationofthe equipment.Minuteventilation,oxygen uptakeand carbon dioxideproductionwereacquiredbreath-by-breath,usinga SensorMedicsVmax229gasanalyzer.Patientswere encour-agedtoexerciseuntiltherespiratoryexchangeratio(ratio between carbon dioxideproduction and oxygen consump-tion)was≥1.10. VO2maxwasdeﬁnedasthehighest30-s

average achieved duringexercise and wasnormalized for body mass, corrected for fat-free mass in obesepatients (bodymassindex>30kg/m2_)._The_ventilatory_threshold_was

determinedbycombiningthestandardmethods(V-slopeand ventilatory equivalents).10 _The _VE/VCO

2 slope was

calcu-latedbyleastsquareslinearregression,usingdataacquired throughouttheexercisesession.10 _Several_composite_CPET

parameterswerealsocalculated. Follow-upandendpoint

Allpatientswerefollowedfor 60monthsfromthedateof completionoftheabove-mentionedcomplementaryexams. Patients were assessed for the occurrence of death, HTX ortheneedformechanicalcirculatorysupport.Datawere obtainedfromoutpatientclinicvisitsandreviewofmedical charts, and were complemented by a standardized tele-phoneinterviewwithallpatientsat12,36and60months offollow-up.

The combined endpoint of cardiac death, urgent HTX (occurringduringanunplannedhospitalizationfor worsen-ingofHF, requiring inotropes)or theneed formechanical circulatorysupportwasanalyzed.

Statisticalanalysis

Categoricaldataarepresentedasfrequencies(percentages) and continuous variables asmean (standard deviation) or median(25th-75thpercentile),asappropriate.Continuous variableswere analyzedusingthe Student’st test, or the Mann-Whitneytestwhennormalitywasnotveriﬁedbythe

Kolmogorov-Smirnovtest; categorical variables were ana-lyzedusingthechi-squaredorFisher’sexacttests.

UnivariateandmultivariateCoxregressionmodelswere appliedtotime untilthe combined endpoint, considering thefollow-uptimes of 12,36and 60months.A complete listof the tested variables and a detailed description of the univariate and multivariate analysis arepresented as supplementarymaterial(SupplementaryTables1and2).

The 36-month follow-up period was analyzed to iden-tifyapossibleapproachforselectingpatientsforHTX.7,8,11

Toidentifythemostaccurateindividualpredictorfromthe multivariatemodel,thevariablewiththehighestareaunder thecurve(AUC)onreceiveroperatingcharacteristic(ROC) analysis(VE/VCO2slope, posthoc)wasselected.Toassess

the additive value of other predictors to VE/VCO2 slope,

the AUC of VE/VCO2 slope was compared with the AUC

ofthemodel includingallpredictors ofadverse outcome. TheDeLongtest wasusedtocomparetwocorrelatedROC curves.Inaddition,continuousnetreclassiﬁcation improve-ment(NRI)andintegrateddiscriminationimprovement(IDI) measuresforcensoreddatawerecalculated.12

Thebestcut-offvalue ofVE/VCO2 slopeforidentifying

high-riskpatientswascalculatedusingthemartingale resid-uals.SinceHTXcanonlybeofferedtoasmallsubgroupofHF patients,weidentifiedanothercut-offvaluethatminimized the rate of misclassified high-risk patients, even if sensi-tivitydecreased to reasonable levels.3 _We _thus _identified

aVE/VCO2slope thresholdthatprovidedahighspeciﬁcity

(atleast90%)withatleast50%sensitivity,usingtheinverse probabilityofcensoringweightingapproach.13_Subgroups_of

high-andlow-riskpatientswerecreatedaccordingly. Event-freesurvivalratesofbothsubgroupswereestimatedusing theKaplan-Meiermethodandcomparedusingthelog-rank test.ToassesswhethertheidentiﬁedVE/VCO2slope

thresh-oldissuitableasapotentialindicationforHTX,twoanalyses werecarried out. Firstly, survival rates of high- and low-risksubgroups ofour cohortwere comparedwithsurvival rates after HTX reportedby the ISHLT transplantregistry (quarterlydatareportonsurvivalratesfororthotopicHTX performedinEuropebetweenOctober1,2011and Septem-ber30,2015),usingapreviouslyreportedmethod.9,14_Since

theISHLTreportsoverallsurvival,westudied(forthis anal-ysisonly)timetodeathfromanycause,rightcensoringin theeventofurgentor non-urgentHTX.15 _If_the_95%

conﬁ-denceintervals(CI)of estimatedsurvival 36monthsafter HTXreportedbytheISHLTdidnotoverlapwiththoseof high-andlow-risksubgroupsofourcohort,basedontheVE/VCO2

slopethreshold,thiscanbetakenasevidenceofsigniﬁcant difference.7,15_Secondly,_the_NRI_and_IDI_were_used_to

com-parediscretized VE/VCO2 slope andVO2 max, considering

thecombinedendpointfortheanalysis.

To further stratify prognosis in low-risk patients, high-riskpatients wereexcluded from subsequentanalysisand univariateandmultivariateCoxregressionmodelswere ﬁt-tedtothelow-risksubgroup.Martingaleresidualswereused toidentify cut-off valuesfor the variablesthat remained inthemodel andsubgroupsof high-andlow-risk patients werecreated accordingly.Event-freesurvival rates ofthe subgroupswereestimated usingthe Kaplan-Meiermethod andcomparedusingtheGehan-Breslow-Wilcoxontest.

The level of signiﬁcance considered was ␣=0.05. Data wereanalyzed usingSPSS for Windows,version 20.0 (IBM

(4)

SPSSInc.,Chicago,IL)andthestatisticalprogramR Devel-opmentCoreTeam(2014),R:Alanguageandenvironment forstatisticalcomputing(RFoundationforStatistical Com-puting,Vienna,Austria).

Results

Atotalof 263patientswereincluded.The combined end-pointoccurredin54patients(20.5%)within36monthsand in69(26.2%)within60months.Themainbaselinedataare presented in Table 1, in which patients withand without eventsupto36monthsoffollow-uparecomparedandthe mostimportantriskpredictorsidentiﬁedinunivariateCox regressionarepresented.Completedataonbaseline char-acteristicsand univariateCox regression arepresented in

SupplementaryTables1and2,respectively.

Cumulativeadverseeventsoccurringindifferent follow-up periods are presented in Table 2. The independent predictorsofadverseevents identiﬁedinmultivariateCox regressionwithfollow-uptimesof12,36and60monthsare presentedinTable3.At36monthsof follow-up,VE/VCO2

slope,creatininelevelsandLVEFwereindependent predic-torsofadverseevents.TheVE/VCO2slopehadthehighest

Waldchi-squarevaluein univariateandmultivariate anal-ysisat36monthsandwastheparameterwiththehighest AUCinall multivariatemodels,considering 12,36 and60 monthsoffollow-up.Speciﬁcallyforthe36-monthfollow-up period,the AUCoftheoverall modelincludingall predic-torsofadverseoutcomedidnotdiffersigniﬁcantlyfromthe AUCofthe modelwithVE/VCO2slope alone (DeLongtest

p=0.103).Inaddition,theoverallNRIwas63.4%(95%CI 33.5-93.4%)andtheIDIwas0.019(95%CI[-0.01]-[0.046]),when creatininelevelsandLVEFwereaddedtoVE/VCO2slope;as

the95%CIofIDIincludesthenullvalue,theimprovement inmodelperformanceisnegligible.Sincetheother predic-torsincluded inthemodel(creatininelevelsandLVEF)did notaddsigniﬁcantly toVE/VCO2slope for risk prediction,

onlyVE/VCO2slope wasselectedtoobtain acut-offvalue

forclinicaluse.

Based onthe martingale residuals, the best estimated cut-offvalueforVE/VCO2slopetoidentifypatientsathigher

riskat36monthsoffollow-upwas32.0(speciﬁcity80%, sen-sitivity83%)(SupplementaryFigure1).However,athreshold of39.0providedhigherspeciﬁcity(97%),with52% sensitiv-ity.Theestimated36-monthsurvivalforhigh-risk(VE/VCO2

slope ≥39.0) andlow-risk (VE/VCO2 slope <39.0) patients

wassigniﬁcantlydifferent(Figure1).

Athresholdof39.0forVE/VCO2slopewasassessedasa

potentiallistingcriterionforHTX.Firstly,the95%CIsof esti-matedsurvival (considering all-causedeath) for high-and low-risksubgroupsdidnotoverlap withthoseof post-HTX reportedbytheISHLT.15_Secondly,_the_VE/VCO

2slopehada

higherAUCthanVO2 max, consideringboth ascontinuous

variables(AUCofVO2 max0.79,95%CI0.72-0.87;DeLong

testforcomparisonp=0.009).Moreover,therewasa signiﬁ-cantimprovementinthepercentageofcorrectclassiﬁcation using the VE/VCO2 slope threshold of 39.0, in

compari-sontodiscretizedVO2 max(Table 4):considering theVO2

maxthresholdof 10.0 ml/kg/min,the overallNRI and IDI were82.2%(95%CI52.3-112.1%) and0.278(95%CI 0.182-0.373),respectively;consideringtheVO2maxthresholdof

12.0ml/kg/min,theoverallNRIandIDIwere93.3%(95%CI 63.4-123.2%)and0.226(95%CI0.141-0.311),respectively. Since the data consistently favored the use of VE/VCO2

slopeasanindicationforHTX,high-riskpatients(VE/VCO2

slope ≥39.0) were excluded from subsequent analysis. In theother 229 patients,27(11.8%) eventsoccurred during 36monthsoffollow-up.Sodiumandcreatininelevels,LVEF, andvariationachievedinCPET(anaerobicthresholdminus baseline)oftheend-tidalcarbondioxidepartialpressure( PetCO2)wereindependentpredictors ofadverseeventsat

36monthsoffollow-up(Table3).The AUCwassimilarfor these predictors. ForLVEF, the ﬂatness of the martingale residualssmootherdidnotenableasuitablecut-offpointto beidentiﬁedthatdiscriminatedhigh-andlow-riskpatients (SupplementaryFigure2);sodium≤136.0mEq/l,creatinine ≥1.0mg/dlandPetCO2≤0.45kPa(3.4mmHg)were

asso-ciatedwithhigher risk ofadverse events (speciﬁcity 63%, 61% and 63%,sensitivity 77%, 74%and 74%, respectively). Eightsubgroupswerecreatedaccordingtothethree men-tioned cut-off values (Supplementary Figure 3).Prognosis wassimilar for patients withup toone variable(sodium, creatinine or PetCO2) with abnormal values (classiﬁed

accordingtothethresholdsidentified);prognosiswas simi-larforpatientswithtwovariableswithabnormalvalues,and event-freesurvivalwasworstwhenthethreevariableswere classifiedasabnormal. Threegroups werecreated accord-ingly(Figure2);prognosiswassignificantlydifferentforthe threecategories.

Discussion

Themostaccuratepredictorofadverseoutcomeinpatients withHFwithreducedLVEFwasVE/VCO2slopeandthebest

thresholdforidentifyingpatientswhomaybeneﬁtfromHTX was 39.0. Sodiumlevels, creatinine levels and PetCO2

wereabletoidentifylow-riskpatients withexcellent out-come.

Riskstratiﬁcation in HF andselecting patients for HTX arechallenging.Mancinietal.18_showed_in_an_ancillary_study

thatVO2maxisavaluableparameterforselectingpatients

forHTX,andsubsequentlyreﬁnedtheircut-offvalues.11,19

Currently,theAmericanHeartAssociationrecommends list-ing ambulatory patients for HTX when VO2 max is <10

ml/kg/min with achievement of anaerobic metabolism, and to defer when VO2 max is >14 ml/kg/min.4 Mancini

etal.19 _proposed_a_similar_decision_algorithm,_also

recom-mendingassessmentusingtheHeartFailureSurvivalScore (HFSS). The ISHLT recommends listing when VO2 max is

<12 ml/kg/minonbeta-blockers, deferringwhenit is >14 ml/kg/min, andusingtheHFSSin thegrayzone.5 _Only _in

thepresenceof asubmaximalCPETshouldVE/VCO2slope

beconsideredasalistingcriterion,accordingtotheISHLT guidelines.5_Risk_{stratiﬁcation}_and_patient_selection_for_HTX

couldprobablybeimproved.7_However,_the_use_of

random-izedcontrolledtrialstoaddresstheissueoflistingcriteria is hindered by ethical and social considerations. In this context, data from robust registries on non-transplanted HF patients receiving contemporary pharmacological and devicetherapyareofgreatvalue.

Weevaluatedanextensiverangeofclinical,laboratory, electrocardiographic,echocardiographic,andCPET

(5)

param-Table1 BaselinedataandunivariateCoxregressionanalysisforpredictingadverseeventsupto36monthsoffollow-up.

Variable Allpatients Eventsa _No_eventsa _p _Chi-square_Hazard_ratio,

95%CI

p

Clinicalandelectrocardiographicdata

Age(years)b ₅₄₍₁₂₎ ₅₄₍₁₂₎ ₅₃₍₁₂₎ _0.718 _0.1 _1.00,_0.98-1.02 _0.781 Malec ₁₉₇₍₇₅₎ ₄₄₍₈₁₎ ₁₅₃₍₇₃₎ _0.141 _2.3 _0.61,_0.33-1.15 _0.125 Diabetesc ₅₄₍₂₁₎ ₈₍₁₅₎ ₄₆₍₂₂₎ _0.248 _0.1 _1.12,_0.60-2.08 _0.728 Ischemicetiologyc ₉₇₍₃₇₎ ₂₈₍₅₂₎ ₆₉₍₃₃₎ _0.009 _4.3 _2.06,_1.13-3.75 _0.018 NYHAII(vs.III)c ₂₀₀₍₇₆₎ ₂₈₍₅₂₎ ₁₇₂₍₈₂₎ _<0.001 _37.3 _0.22,_0.12-0.42 _<0.001 Sinusrhythmc ₂₁₄₍₈₁₎ ₃₆₍₆₇₎ ₁₇₈₍₈₅₎ _0.003 _11.7 _2.52,_1.28-4.96 _0.008 Loopdiureticc ₂₃₄₍₈₉₎ ₅₄₍₁₀₀₎ ₁₈₀₍₈₆₎ _0.002 _4.2 _24.9,_1.1-546.0 _0.041 ACEi/ARBc ₂₅₅₍₉₇₎ ₅₄₍₁₀₀₎ ₂₀₁₍₉₆₎ _0.309 _1.2 _0.05,_0.01-12.7 _0.285 Betablockerc ₂₃₃₍₈₉₎ ₄₈₍₈₉₎ ₁₈₅₍₈₉₎ _0.999 _1.5 _1.41,_0.81-2.43 _0.224

Aldosteronereceptorblockerc ₁₇₆₍₆₇₎ ₄₃₍₈₀₎ ₁₃₃₍₆₄₎ _0.035 _5.6 _2.00,_1.12-3.54 _0.018

BaselineCRTc ₇₂₍₂₇₎ ₁₄₍₂₆₎ ₅₈₍₂₈₎ _0.342 _1.3 _1.72,_0.64-3.36 _0.462 BaselineICDc ₈₅₍₃₂₎ ₁₈₍₃₃₎ ₆₇₍₃₂₎ _0.117 _1.4 _1.41,_0.79-2.64 _0.236 Laboratorydata Creatinine(mg/dl)b _1.1_(0.3) _1.2_(0.3) _1.1_(0.3) _<0.001 _15.1 _3.93,_1.66-9.26 _0.001 Sodium(mEq/l)b ₁₃₇₍₃₎ ₁₃₄₍₄₎ ₁₃₇₍₃₎ _<0.001 _62.0 _0.73,_0.66-0.81 _<0.001 NT-proBNP(pg/ml)b ₂₃₀₄₍₂₈₂₁₎ ₄₂₆₉₍₄₇₂₄₎ ₁₈₉₈₍₂₀₂₉₎ _<0.001 _38.3 _1.01,_1.00-1.01 _<0.001 ElevatedtroponinTc ₃₇₍₁₄₎ ₁₃₍₂₄₎ ₂₄₍₁₁₎ _0.004 _14.3 _3.54,_1.54-8.12 _0.003 Echocardiographicdata LVEDD(mm/m2₎b ₃₉₍₆₎ ₄₂₍₇₎ ₃₉₍₅₎ _0.006 _8.8 _0.16,_0.04-0.64 _0.010 LVEF(%)b ₂₈₍₇₎ ₂₃₍₆₎ ₂₈₍₈₎ _<0.001 _26.7 _0.92,_0.90-0.95 _<0.001 MRc ₄₂₍₁₆₎ ₉₍₁₇₎ ₃₃₍₁₆₎ _0.988 _1.5 _0.92,_0.30-1.55 _0.872 RVSDc ₄₂₍₁₆₎ ₁₉₍₃₅₎ ₂₃₍₁₁₎ _<0.001 _37.9 _7.09,_3.28-15.33 _<0.001

Cardiopulmonaryexercisetestingdata

HRrecovery(1stminute)(min)d ₁₈_(13-29) ₁₃_(8-18) ₁₉_(15-30) _<0.001 _33.5 _0.90,_0.85-0.93 _<0.001

doubleproduct(mmHg/min)b ₁₁₉₁₁₍₅₃₇₄₎ ₈₅₆₄_(4443)12619₍₅₅₄₇₎ _<0.001 _26.2 _1.00,_1.00-1.00 _<0.001

PeakRERb _1.10_(0.10) _1.13_(0.10) _1.09_(0.09) _0.008 _5.6 _45.75,_2.59-808.94 _0.011

VO2max(ml/kg/min)e,b 20.0(5.3) 15.6(4.7) 21.1(5.7) <0.001 56.8 0.78,0.71-0.85 <0.001

VO2max(%predicted)e,b 67(15) 51(14) 71(16) <0.001 69.1 0.91,0.81-0.94 <0.001

Circulatorypower(mmHg/ml/kg/min)b ₃₁₁₅₍₁₁₂₃₎ ₂₁₈₅₍₈₉₅₎ ₃₂₈₉₍₁₁₃₂₎ _<0.001 _48.3 _0.99,_0.99-0.99 _<0.001

Peakoxygenpulse(%predicted)b ₉₁₍₃₀₎ ₇₄₍₂₃₎ ₉₅₍₃₀₎ _<0.001 _28.7 _0.97,_0.96-0.98 _<0.001

OUESb _1.8_(0.6) _1.4_(0.4) _1.9_(0.6) _<0.001 _49.9 _0.11,_0.05-0.27 _<0.001

AT-VO2(ml/kg/min)b 16.1(4.0) 12.6(3.6) 17.0(4.1) <0.001 61.1 0.74,0.66-0.81 <0.001

VE/VCO2slopef,b 31(7) 40(9) 29(5) <0.001139 1.27,1.19-1.35 <0.001

PeakVE/VCO2f,b 35(8) 42(10) 33(7) <0.001 76.4 1.14,1.09-1.19 <0.001

ATVE/VCO2f,b 33(7) 40(9) 31(6) <0.001 78.3 1.17,1.08-1.23 <0.001

VE/VCO2slope/VO2max(ml/kg/min)-1 b 1.7(0.9) 2.9(1.4) 1.5(0.6) <0.001130 5.00,3.12-8.31 <0.001

BaselinePetCO2(kPa)b 4.4(0.6) 4.2(0.7) 4.4(0.6) 0.017 8.21 0.52,0.30-0.89 0.018

ATPetCO2(kPa)g,b 4.9(0.8) 4.3(0.8) 5.0(0.7) <0.001 49.4 0.27,0.17-0.44 <0.001

PetCO2(kPa)g,b 0.5(0.4) 0.1(0.4) 0.6(0.4) <0.001 84.3 0.03,0.01-0.17 <0.001 Score

HFSSb _8.7_(1.0) _7.9_(0.9) _8.8_(0.9) _<0.001 _51.2 _0.33,_0.22-0.49 _<0.001

a _Cardiac_death,_urgent_heart_{transplantation}_or_mechanical_circulatory_support_up_to₃₆_months_of_follow-up_(n=54). b _Values_expressed_as_mean_(standard_deviation).

c _Values_expressed_as_n_(%).

d _Values_expressed_as_median_(25th-75th_percentile). e,f,g_Of_these,_only_VO

2max,VE/VCO2slope(entireexercise)andPetCO2wereenteredinthemultivariatemodel,toavoid

multi-collinearity.

doubleproduct:productofpeakminusbaselineheartrateandsystolicbloodpressure;PetCO2:anaerobicthresholdminusbaseline

end-tidalcarbondioxidepartialpressure;ACEi:angiotensin-convertingenzymeinhibitor;ARB:angiotensinreceptorblocker;AT: anaer-obicthreshold;Chi-square:Waldchi-squarevalue;CI:confidenceinterval;Circulatorypower:productofpeakoxygenconsumptionand systolicbloodpressure;CRT:cardiacresynchronizationtherapy,withorwithoutdefibrillator;HFSS:HeartFailureSurvivalScore;HR:heart rate;HRrecovery(1stminute):peakheartrateminusheartrateatfirstminuteofrecovery;ICD:implantablecardioverter-defibrillator; LVEDD:leftventricularend-diastolicdiameter;LVEF:leftventricularejectionfraction;MR:moderateorseveremitralregurgitation; NT-proBNP:N-terminalpro-B-typenatriureticpeptide;NYHA:NewYorkHeartAssociation;OUES:oxygenuptakeefficiencyslope16_;_peak

oxygenpulse:peakoxygenconsumption/heartrateratio;PetCO2:end-tidalcarbondioxidepartialpressure;RER:respiratoryexchange

ratio(ratiobetweencarbondioxideproductionandoxygenconsumption);RVSD:rightventricularsystolicdysfunction;VO2max:peak

oxygenconsumption;VO2max(%predicted):basedonWassermanandHansen’sformula;VCO2:carbondioxideproduction;VE:minute

(6)

Table2 Adverseeventsat12,36and60monthsoffollow-up.

12months 36months 60months

n (%) n (%) n (%)

Combinedendpointa ₂₇ _10.3 ₅₄ _20.5 ₆₉ _26.2

Death 22 8.4 47 17.9 66 25.1

Cardiacdeath 18 6.8 36 13.7 49 18.6

Suddendeath 9 3.4 13 4.9 18 6.8

Worseningofheartfailure 9 3.4 23 8.7 31 11.8

Hearttransplantation 12 4.6 19 7.2 22 8.4

Urgenthearttransplantation 8 3.0 15 5.7 17 6.5

Mechanicalcirculatorysupportb ₁ _0.4 ₃ _1.1 ₃ _1.1

a_Cardiac_death,_urgent_heart_{transplantation}_or_mechanical_circulatory_support.

b _All_patients_were_in_Interagency_Registry_for_Mechanically_Assisted_Circulatory_Support_(INTERMACS)_proﬁles₁_or_2.17

Table3 MultivariateCoxregression.

Chi-square Hazardratio,95%CI p AUC,95%CI

12-monthfollow-upa VE/VCO2slope 47.8 1.14,1.10-1.18 <0.001 0.91,0.87-0.95 LVEF 4.1 0.94,0.89-0.99 0.044 0.76,0.68-0.84 OverallAUC - - - 0.91,0.88-0.95 36-monthfollow-upb VE/VCO2slope 89.0 1.14,1.11-1.18 <0.001 0.87,0.81-0.93 Creatininelevels 5.4 2.23,1.14-4.36 0.020 0.69,0.65-0.74 LVEF 4.7 0.96,0.93-0.99 0.030 0.72,0.65-0.78 OverallAUC - - - 0.89,0.84-0.94 60-monthfollow-upc VE/VCO2slope 35.0 1.11,1.08-1.16 <0.001 0.87,0.81-0.92 Creatininelevels 7.8 2.25,1.27-3.96 0.005 0.68,0.61-0.75 PetCO2 5.1 0.39,0.17-0.89 0.024 0.84,0.79-0.90 LVEF 3.9 0.97,0.94-0.99 0.047 0.72,0.66-0.79 OverallAUC - - - 0.89,0.84-0.94

36-monthfollow-up(low-risk)d,e

Sodiumlevels 18.8 0.79,0.71-0.88 <0.001 0.73,0.61-0.85 Creatininelevels 5.7 2.75,1.20-6.29 0.017 0.71,0.62-0.81 LVEF 5.6 0.94,0.89-0.99 0.018 0.72,0.64-0.80 PetCO2 4.3 0.30,0.10-0.94 0.039 0.73,0.63-0.84 a_C-index_0.90,_95%_CI_0.86-0.94. b _C-index_0.88,_95%_CI_0.83-0.92. c _C-index_0.86,_95%_CI_0.82-0.90. d _C-index_0.83,_95%_CI_0.76-0.91. e _Excluding_patients_with_VE/VCO

2slope≥39.0.

AUCforindividualvariablesandfortheoverallmodelarepresented,foreachfollow-uptime.

PetCO2: anaerobicthreshold minusbaseline end-tidalcarbon dioxide partialpressure;AUC: areaunderthereceiving operating

characteristiccurve;Chi-square:Waldchi-squarevalue;CI:conﬁdenceinterval;LVEF:leftventricularejectionfraction;VCO2:carbon

dioxideproduction;VE:minuteventilation.

Table4 Proportionofpatientscorrectlyandincorrectlyclassiﬁedat36monthsoffollow-up.

High-risk,n(%) Low-risk,n(%)

Correct Incorrect Correct Incorrect

VO2max≤10.0ml/kg/min 7(87.5) 1(12.5) 208(81.6) 47(18.4)

VO2max≤12.0ml/kg/min 10(71.4) 4(28.6) 205(82.3) 44(17.7)

VE/VCO2slope≥39.0 27(79.4) 7(20.6) 202(88.2) 27(11.8)

(7)

Figure1 Event-freesurvivalupto36monthsoffollow-upaccordingtoVE/VCO2slopethresholdof39.0,and95%CIofestimated

survivalforeachsubgroup. CI:95%conﬁdenceinterval;ISHLT:InternationalSocietyforHeart andLungTransplantation; VCO2:

carbondioxideproduction;VE:minuteventilation.

Figure2 Event-freesurvivalupto36monthsoffollow-up(excludingpatientswithVE/VCO2slope≥39.0)and95%CIofestimated

survivalforeachsubgroup,accordingtothecombinationofsodium(136.0mEq/l),creatinine(1.0mg/dl)andvariationof

end-tidalcarbondioxide partialpressure(0.45kPa)cut-offvalues.Group1:uptooneabnormalparameter; group2:twoabnormal

parameters;group3: threeabnormal parameters.CI:95%conﬁdenceinterval; ISHLT:InternationalSocietyfor Heartand Lung

Transplantation;VCO2:carbondioxideproduction;VE:minuteventilation.

etersaspotentialpredictorsofadverseoutcome.Thesingle best parameter of all those studied was VE/VCO2 slope, yieldingthehighestWaldchi-squarevalueandthehighest AUCat12, 36and60monthsof follow-up,andwitheven morediscriminativepowerthantheHFSS,whichcombines differentvariables.Ofnote,VO2maxdidnotremaininany multivariatemodelin ourcohort.The 60-monthfollow-up periodwasnotused toidentifyan approachfor selecting patientsfor HTX,sinceprognosticreassessmentshouldbe undertakenearlier.7,8 _{Nevertheless,} _the _long-term

follow-upcarriedout conﬁrmedthe consistentlyhigheraccuracy ofVE/VCO2slopeoveralongperiod,incomparisontoother

parameters.This ﬁnding hasnot been properlyaddressed in previous studies.6---8 _Arena _et _al.6 _showed _that _the _risk

ofadverseeventsincreasescontinuouslyoverdifferent cat-egories of VE/VCO2 slope. However,thresholds areuseful

forclinicalpractice,andVE/VCO2slopevaluesof34.0and

35.0havebeenproposedasoptimalcriteriaforclassifying patientswithHFashigh-andlow-risk.5,14_In_line_with_these

thresholds,theriskofadverseeventsbegantoriseforvalues

above32.0inourcohort,asshownbyanalysisofthe mar-tingaleresiduals.Althoughthespecificityforthisthreshold wasnotlow(80%),a non-negligibleproportionofpatients wouldbeclassifiedashigh-riskeventhoughtheywouldnot experiencean adverse outcome. If this was considered a listingcriterion for HTX,issuesrelatedtothe shortageof donors and tothe morbidity and mortality following HTX mightarise, bylistingpatients whowere at aless severe stageofHF.Therefore,thethresholdof39.0,whichprovides very high specificity with reasonable sensitivity, may be moreappropriateforselectingpatientsforHTXthanlower cut-offvalues.5,14 _Freedom_from_the_combined_endpoint_at

36months of follow-up wasverylow (19.3%) for patients withVE/VCO2slope≥39.0.Eventhoughthisthresholdwas

notprimarilyidentiﬁedtopredicttotalmortality,the95%CI ofestimatedoverallsurvivalofhigh-andlow-risksubgroups did not overlap with those of post-HTX reported by the ISHLT.15_This_ﬁnding_suggests_that,_for_our_cohort,_survival_of

hypotheticallytransplantedpatients wouldbebetterthan survival of non-transplanted high-risk patients and worse

(8)

thansurvivalofnon-transplantedlow-riskpatients.In addi-tion, the threshold of 39.0 for VE/VCO2 slope was more

accurate than the cut-off values of 10 or 12 ml/kg/min forVO2max,whicharerecommendedaslistingcriteria.4,5

VE/VCO2slopehaspreviouslybeenreportedasprovidinga

discriminativepoweratleastasgoodasVO2maxfor

predict-ingadverseevents.6,9_{Nevertheless,}_the_majority_of_studies

thathighlightedthevalueofVE/VCO2 slopedidnotassess

thisparameterinthelightofacomprehensiveassessment of clinical, laboratory, electrocardiographic, echocardiog-raphic and CPET parameters, and few had a long-term follow-up.6---8_Compared_to_previous_studies,_we_carried_out_a

morecomprehensive(andprospective)baselineassessment, withalong-termfollow-up,andemployingarobust statis-ticalanalysiswithconsistentresults.Basedonourresults, patientswithVE/VCO2slope≥39.0maybeneﬁtfromHTX.

Forlow-risk non-transplantedpatientswithsodium lev-els>136.0mEq/l,creatininelevels<1.0mg/dlandPetCO2

>0.45kPa(3.4mmHg),orpatientswithuptooneofthese variablesclassiﬁedasabnormal,theprognosiswasexcellent andtotalmortalitywaslowerthanthatreportedfor post-HTX.15_Sodium_and_creatinine_levels_are_known_independent

predictorsofadverse eventsinHFandareincludedinrisk scoressuchastheHFSSandtheMeta-AnalysisGlobalGroup inChronicHeartFailurescore.1,2_PetCO

2atrestandatthe

anaerobicthresholdwereshowntostratifyriskbeyondthe VE/VCO2 slope, and combiningthem into a single

param-eter( PetCO2)may bemore practicaland accurate.20,21

We suggest that particular attention should be paid to sodiumlevels,creatininelevelsandPetCO2,inadditionto

VE/VCO2slope,particularlyforidentifyinglow-riskpatients

inclinicalpractice.

Somelimitations ofthestudyshouldbeacknowledged. Firstly,theanalyzedcohortwasnotlarge.However,itwas possibletoidentifythemostimportantindependent predic-torsofadverseoutcomeinHFandastrategyforoptimizing theselectionofpatientsforHTX,andtheresultswere con-sistentusingdifferentstatisticalanalyses.Thesamplesize issimilartothoseofotherstudiesthathighlightedthevalue ofCPETparameters,includingfortheselectionofpatients forHTX.6,14,18,20,21 _Secondly,_this_was_a_{single-center}_study.

Nevertheless,thismeant thattheCPETprotocolwas con-sistentin allcases,andmay havereducedthe numberof physiciansresponsiblefor the interpretationof theexam, reducinginterobservervariability.Thirdly,listingforHTXis acomplexandmultidisciplinarydecisionandshouldnotrely solelyon‘magicnumbers’ofspeciﬁcparametersfrom com-plementaryexams;however,thresholdsareusefulinclinical practice,aspointedoutabove.Inaddition,theaimwasnot toreplacebuttopotentiallyoptimizecurrentlistingcriteria forHTX.Thedecision thresholdwe proposeisinline with current practicein differentcenters,where clinical deci-sions aresupported by VE/VCO2 slope data inaddition to

VO2max,eventhoughcurrentguidelinesdonotaddressthis

approach.4,5,7_A_further_validation_study_would_certainly_be

useful.

Conclusions

Amongalargevarietyofpredictorsofadverseoutcomein ambulatory patientswithHF withreducedLVEF, themost

accuratewasVE/VCO2slope. PatientswithVE/VCO2slope

of39.0orhighermaybeneﬁtfromHTX.BeyondtheVE/VCO2

slope,sodiumlevels,creatinine levelsandPetCO2were

abletoidentifypatientswithexcellentoutcome.

Funding

None.

Conﬂicts

of

interest

Theauthorshavenoconﬂictsofinteresttodeclare.

Appendix

A. Supplementary

material

Supplementary material associated with this article can be found in the online version at doi:10.1016/ j.repc.2017.06.018.

References

1.PocockSJ,AritiCA,McMurrayJJ,etal.,Meta-AnalysisGlobal GroupinChronicHeartFailure.Predictingsurvivalinheart fail-ure:ariskscorebasedon39372patientsfrom30studies.Eur HeartJ.2013;34:1404---13.

2.Zugck C, Krüger C, Kell R, et al. Risk stratiﬁcation in middle-agedpatientswithcongestiveheartfailure: prospec-tivecomparisonoftheHeartFailureSurvivalScore(HFSS)anda simpliﬁedtwo-variablemodel.EurJHeartFail.2001;3:577---85.

3.TaylorDO,EdwardsLB,AuroraP,etal.Registryofthe Interna-tionalSocietyforHeartandLungTransplantation:twenty-ﬁfth ofﬁcialadulthearttransplantreport---2008.JHeartLung Trans-plant.2008;27:943---56.

4.FrancisGS,GreenbergBH,HsuDT,etal.,ACCF/AHA/ACPTask Force. ACCF/AHA/ACP/HFSA/ISHLT2010 clinicalcompetence statementonmanagementofpatientswithadvancedheart fail-ureandcardiactransplant:areportoftheACCF/AHA/ACPTask ForceonClinicalCompetenceandTraining.JAmCollCardiol. 2010;56:424---53.

5.MehraMR,KobashigawaJ,StarlingR,etal.Listingcriteriafor hearttransplantation:InternationalSocietyforHeartandLung Transplantationguidelines for thecare ofcardiac transplant candidates---2006.JHeartLungTransplant.2006;25:1024---42.

6.ArenaR,MyersJ,AbellaJ,etal.Developmentofaventilatory classiﬁcationsysteminpatientswithheartfailure.Circulation. 2007;115:2410---7.

7.FerreiraAM,TabetJY,FrankensteinL, etal.Ventilatory efﬁ-ciencyandtheselectionofpatientsforhearttransplantation. CircHeartFail.2010;3:378---86.

8.MyersJ,OliveiraR,DeweyF,etal.Validationofa cardiopul-monaryexercise testscore in heartfailure. CircHeart Fail. 2013;6:211---8.

9.MezzaniA, Corrà U, BosiminiE, et al. Contribution ofpeak respiratoryexchangeratiotopeakVO2prognosticreliabilityin

patientswithchronicheartfailureandseverelyreduced exer-cisecapacity.AmHeartJ.2003;145:1102---7.

10.Guazzi M, Adams V, Conraads V, et al., European Associa-tionforCardiovascularPrevention&Rehabilitation;American Heart Association. EACPR/AHA Scientiﬁc Statement. Clini-cal recommendations for cardiopulmonary exercise testing dataassessment in speciﬁc patient populations. Circulation. 2012;126:2261---74.

(9)

11.O’NeillJO,YoungJB,PothierCE,etal.Peakoxygen consump-tion as a predictor of death in patients with heart failure receivingbeta-blockers.Circulation.2005;111:2313---8.

12.PencinaMJ,D’AgostinoRBSr,D’AgostinoRBJr,etal. Evalu-atingtheaddedpredictiveabilityofanewmarker:fromarea undertheROCcurvetoreclassiﬁcationandbeyond.StatMed. 2008;27:157---72.

13.HarrellFE.CasestudyinCoxregression.In:HarrellFE, edi-tor.Regressionmodelingstrategies:withapplicationstolinear models,logisticregression,andsurvivalanalysis.1sted.New York,NY:Springer;2001.p.509---22.

14.Chua TP, Ponikowski P, Harrington D, et al. Clinical corre-latesand prognosticsigniﬁcance of theventilatory response to exercise in chronic heart failure. J Am Coll Cardiol. 1997;29:1585---90.

15.ISHLT. Transplant Registry Quarterly Reports for Heart in Europe. Available at: http://www.ishlt.org/registries/ quarterlyDataReport.asp[accessed15.01.17].

16.BabaR,NagashimaM,GotoM,etal.Oxygenuptakeefﬁciency slope: a new index of cardiorespiratory functional reserve

derivedfromtherelationbetweenoxygenuptakeandminute ventilation during incremental exercise. J Am Coll Cardiol. 1996;28:1567---72.

17.StevensonLW,PaganiFD,YoungJB,etal.INTERMACSproﬁles ofadvancedheartfailure:thecurrentpicture.JHeartLung Transplant.2009;28:535---41.

18.ManciniDM,EisenH,KussmaulW,etal.Valueofpeakexercise oxygen consumptionfor optimaltimingofcardiac transplan-tationinambulatorypatientswithheartfailure.Circulation. 1991;83:778---86.

19.ManciniD,LietzK.Selectionofcardiactransplantation candi-datesin2010.Circulation.2010;122:173---83.

20.ArenaR,PeberdyMA,MyersJ,etal.Prognosticvalueofresting end-tidalcarbon dioxideinpatientswithheartfailure.IntJ Cardiol.2006;109:351---8.

21.ArenaR,GuazziM,MyersJ.Prognosticvalueofend-tidalcarbon dioxideduringexercisetestinginheartfailure.IntJCardiol. 2007;117:103---8.