Impact on Long-Term Cardiovascular Outcomes of Different Cardiac Resynchronization Therapy Response Criteria

www.revportcardiol.org

Revista

Portuguesa

de

Cardiologia

Portuguese

Journal

of

Cardiology

ORIGINAL

ARTICLE

Impact

on

long-term

cardiovascular

outcomes

of

different

cardiac

resynchronization

therapy

response

criteria

Inês

Rodrigues

_,

_Ana

_Abreu

_,

_Mário

_Oliveira

_,

_Pedro

_S.

_Cunha

_,

Helena

Santa

Clara

_,

_Paulo

_Osório

_,

_Ana

_Lousinha

_,

_Bruno

_Valente

_,

Guilherme

Portugal

_,

_Pedro

_Rio

_,

_Luís

_A.

_Morais

_,

_Vanessa

_Santos

_,

Miguel

M.

Carmo

_,

_Rui

_C.

_Ferreira

a_{CardiologyDepartment,HospitaldeSantaMarta,CentroHospitalardeLisboaCentral,Lisbon,Portugal} b_{ExerciseandHealthLaboratory,CIPER,FacultyofHumanKinetics,UniversityofLisbon,Lisbon,Portugal}

Received29October2017;accepted18February2018 Availableonline10December2018

KEYWORDS Cardiac resynchronization therapy; Heartfailure; Predictorsofevents; Responsecriteria Abstract

Introduction:Thereisalackofconsensusonthedefinitionofresponsetocardiac resynchro-nizationtherapy(CRT),anditisnotclearwhichresponsecriteriahavemostinfluenceoncardiac event-freesurvival.

Objectives: Toassessthepredictivevalueofvariousresponsecriteriainpatientsundergoing CRTandtheagreementbetweenthem.

Methods:We performed asecondary analysisofthe BETTER-HFtrial.Patient responsewas classified at six months after CRT according toeleven criteria used inprevioustrials. The predictivevalueofresponsecriteriaforsurvivalfreefrommortality,cardiactransplantation andheartfailurehospitalizationwasassessedbyCoxregressionanalysis.Agreementbetween thedifferentresponsecriteriawasassessedusingCohen’skappa(␬).

Results:A total of115patients were followed for ameanof25 months. Duringfollow-up, 15deathsoccurred(13%)and29patientshadatleastoneadversecardiacevent(25%).Only fiveoftheelevenresponsecriteriawerepredictorsofevent-freesurvival.Themostpowerful isolated clinical andechocardiographic predictors were areduction of_≥1 NYHA functional class(HR0.39forresponders;95%CI0.18-0.83,p=0.014)andanincreaseofatleast15%inleft ventricular ejection fraction(HR 0.43, 95%CI 0.20-0.90,p=0.024), respectively.Agreement betweenthedifferentresponsecriteriawaspoor.

∗_{Correspondingauthor.}

E-mailaddress:inesgoncalvesrodrigues@gmail.com(I.Rodrigues).

https://doi.org/10.1016/j.repc.2018.02.010

0870-2551/©2018SociedadePortuguesadeCardiologia.PublishedbyElsevierEspa˜na,S.L.U.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Conclusions:Mostcurrentlyusedresponsecriteriadonotpredictclinicaloutcomesandhave pooragreement.Itisessentialtoestablishaconsensusonthedefinition ofCRTresponsein ordertostandardizestudies.

©2018SociedadePortuguesadeCardiologia.PublishedbyElsevierEspa˜na,S.L.U.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(

http://creativecommons.org/licenses/by-nc-nd/4.0/). PALAVRAS-CHAVE Terapiade ressincronizac¸ão cardíaca; Insuficiência cardíaca; Preditores deeventos; Critériosderesposta

Impactodosdiferentescritériosderespostaàterapiaderessincronizac¸ão noseventoscardiovascularesalongoprazo

Resumo

Introduc¸ão:Nãoexisteconsensonadefinic¸ãoderespondedoràressincronizac¸ãocardíaca(TRC), edesconhece-sequalocritérioderespostaquepoderátermaiorinfluêncianasobrevidalivre deeventoscardíacos.

Objectivos:Avaliarovalorpreditivodevárioscritériosderespostaemdoentessubmetidosà TRC,eanalisaraconcordânciaentreeles.

Métodos: SubanálisedoensaioBETTER-HF.Osdoentesforamclassificadosaosseismesesapós TRCemrespondedores,deacordocomonzecritériosutilizadosnaliteratura.Ovalorpreditivo dosdiferentescritériosderespostaparaumasobrevidalivredemorte,transplantecardíacoe hospitalizac¸ãoporinsuficiênciacardíacafoiavaliadousandoaregressãodeCox.Aconcordância entreosdiferentescritériosfoiavaliadausandoocoeficientekdeCohen.

Resultados: 115doentesforamseguidosduranteum períodomédiode25meses. Duranteo follow-upocorreram15mortes(13%)e29doentestiveram,pelomenos,umeventocardíaco adverso(25%).Apenascincodosonzecritériosderespostaforampreditoresdesobrevidalivre deeventos.Ospreditoresclínicoseecocardiográficosisoladosmaispoderososforamareduc¸ão de,pelomenos, uma classefuncionalde NYHA (HR 0,39;IC 95% 0,18-0,83,p=0,014)e um aumentode,pelomenos,15%nafrac¸ãodeejec¸ãoventricularesquerda(FEVE)(HR0,43;IC95% 0,20-0,90,p=0,024),respetivamente.Aconcordânciaentreosdiferentescritériosderesposta foifraca.

Conclusão:Amaioriadoscritériosderespostautilizadosnãoprevêoutcomesclínicos etêm fracaconcordância.Éessencialcriarumconsensonadefinic¸ãoderespostaàTRCdeformaa uniformizarosestudos.

©2018SociedadePortuguesadeCardiologia.PublicadoporElsevierEspa˜na,S.L.U.Este ´eum artigoOpen Accesssobumalicenc¸aCCBY-NC-ND(

http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Cardiac resynchronization therapy (CRT) is an approved treatmentinselectedheartfailure(HF)patients,with bene-ficialeffectsonsymptoms,cardiacremodelingandfunction, andsurvival.1---5_{However,thereisnoconsensusregardingthe}

bestdefinitionofresponsetoCRT.Numerouscriteria, includ-ing clinical and combinedendpoints, reverse remodeling, andimprovementinleftventricularejectionfraction(LVEF), arecurrently usedin the literature todefine response to CRT,andthisisfurthercomplicatedbythepooragreement betweendifferentresponsecriteria.6

Thereareseveralissuesinvolvedintheproblemof defin-ingresponsetoCRT.HFisacomplexandprogressivedisease, anddespiteimprovementsin device-basedtreatment,the prognosis is still very poor in patients with advanced HF. Somehavequestionedwhetherabsenceofchange(i.e.no deteriorationinfunction)afterCRTshouldalsobe consid-eredaresponsetotreatment.7_{Furthermore,patientsand}

physiciansmayhavedifferentperceptionsofthebenefitsof

CRT.8_{AlltheseissuesmakethedefinitionofresponsetoCRT}

particularlychallenging.

Theaimof thisstudywastoassesstheimpacton out-comesof differentresponse criteriacurrentlyusedin the literature in patients undergoing CRT,and the agreement betweenthem.

Methods

Weperformedasecondary analysisoftheBETTER-HFtrial (ClinicalTrials.govidentifierNCT02413151),9_{aprospective,}

interventional,single-centerrandomizedclinicaltrialofthe effect of cardiac rehabilitation on clinical and echocar-diographic response in patients with HF with reduced ejectionfraction(HFrEF)treatedbyCRT.Onehundredand twenty-one adult HFrEF patients referred for CRT were prospectively enrolled between April 2011 and February

2015.PatientsunderwentbaselineassessmentbeforeCRT, including clinical parameters, laboratory tests, transtho-racic echocardiogram and cardiopulmonary exercise test (CPET),andwerereassessedatsixmonthsafterCRT.

All patients provided written informed consent before anyprocedure.Thestudywasapprovedbytheinstitutional reviewboardandethicscommittee.

Studypopulation

TheBETTER-HFtrial9_{includedconsecutivepatientsreferred}

forCRTwithorwithoutindicationfordefibrillator implan-tation.

The inclusioncriteriawerestableHFpatientsreceiving optimalHFpharmacologictherapyforatleastthreemonths, age≥18years,LVEF<35%,QRSduration≥120ms,referral forCRTatSantaMartaHospitalaccordingtoEuropean Soci-ety of Cardiology (ESC) recommendations,10---12 _{and stable}

conditionfor>1month(nohospitalizationforcongestiveHF, nochangeinmedication,andnochangeinNewYorkHeart Association[NYHA]functionalclass).

Exclusion criteria were residence far from the hospi-tal making frequent hospital visits difficult or impossible; incapacitating orthopedic, neurologic or other conditions precluding exercise testing; refusal to participate in the study;inabilitytosigninformedconsent;previoustreatment withanintravenousinotropicagentwithinthe30daysprior toimplantation;ordeathorCRTdeviceremovalduringthe firstsixmonths.

Datacollection

Baseline and follow-up data up to November 2015 were obtained from hospital files, systematic follow-up phone calls,andthenationalhealthdatabase,whichholds infor-mationfromnationalhealthcareproviders.

Assessment

Patient assessment included NYHA functional class at baseline and six months after CRT implantation, the HeartQoLquality-of-lifescore,13 _{transthoracic}

echocardio-graphy(LVEF,leftventricular end-systolicvolume[LVESV], leftventricularend-diastolicvolume[LVEDV]andstroke vol-ume), CPET (peak oxygen consumption [peak VO2]), and

blood samples (serum creatinine and B-type natriuretic peptide [BNP])for a more objectivequantification of the physiologicandclinicalbenefitsofCRT.

Baselinedemographicdata(ageandgender),HFetiology, riskfactors(hypertension,hyperlipidemia,diabetes, smok-ing and obesity), medication and electrocardiogram were alsorecorded.

Theprimaryendpointwasacompositeofall-causedeath, hearttransplantationandhospitalizationforHF(unplanned hospitalizationformorethan24hourscausedbyHF decom-pensation)duringfollow-up.

Table1 Analyzedresponsecriteria. Clinical

1.↓≥1NYHAclass14---17 2.↑QoL≥0.512 3.↑peakVO2>10%18

4.↓≥1NYHAclassor↑peakVO2>10%andalive,no hospitalizationforHF17 Echocardiographic 5.↑LVEF≥5%(absolute)13,19 6._{↑LVEF≥15%}20,21 7.LVESV<15%ofbaseline22 8.↓LVESV>15%14,23---28 9.↓LVEDV>15%14 10.↑Strokevolume≥15%21,29,30 Combined

11._↑LVEF≥5%(absolute)and_↓≥1NYHAclassor_↑QoL ≥0.531

↑:higher:_↓:lower;LVEDV:leftventricularend-diastolicvolume; LVEF:leftventricularejectionfraction;LVESV:leftventricular end-systolicvolume; NYHA:NewYorkHeartAssociation func-tionalclass;peakVO2:oxygenconsumptionatpeakexercise;

QoL:HeartQoLquality-of-lifescore.

Cardiacresynchronizationtherapyresponse criteria

Taking into account the seventeen different primary responsecriteriaidentifiedbyFornwaltetal.6_inareviewof

the26publicationswithmostcitationsaddressingresponse to CRT, and adapting them to our routine assessment of CRTpatients,weincluded intheanalysiselevendifferent responsecriteria: fourclinical,sixechocardiographic,and onecombinedcriterion,aslistedinTable1.

Statisticalanalysis

Data analysis wasperformed using IBM SPSS® version 20. Continuousdatawereexpressedasmean±standard devia-tionandcomparedusingthenon-parametricWilcoxonrank test. Categorical data were displayed as frequencies and percentages, and compared using the chi-square test or Fisher’sexacttestasappropriate.

Responsecriteriathatwerepotentialpredictorsof sur-vivalfreefrommajoradverse cardiacevents(MACE)were assessedbyunivariateCoxregressionanalysis.Theresults are expressed as hazard ratios (HR) with 95% confidence intervals (CI). The best predictive criteria (clinical and echocardiographic)weresubsequentlycombined(apatient whohad fulfilled both response criteriawas classified as a responder) to determine whether the predictive value improvedwitheachisolatedcriterion.Thetwo-sidedlevel ofsignificancewassetatp<0.05.

Agreementbetweenthedifferentresponsecriteriawas assessedusingCohen’skappa(␬),rangingfrom-1(perfect disagreement)to+1(perfectagreement),with0indicating thatagreementisexactlythatexpectedbychance.32_␬

val-ues≥0.75 wereconsideredasstrong agreement,0.4-0.75 asmoderateagreement,and≤0.4aspooragreement.33

Results

Baselinecharacteristicsandmajoradversecardiac eventsatfollow-up

Ofthe121consecutivepatientsincludedintheBETTER-HF trial,9_{sixwereexcludedfromthisanalysis(intwo,the}

sys-temwasremoved inthefirstsixmonthsdue toinfection, twodiedbeforethesix-month reassessment,and twodid notundergothesix-monthexams).

Atotalof115patientswithadvancedHFwereincluded (73.9%inNYHAclassIII-IV),meanage68years,68%male. IschemicHFwaspresent in 37%of thepatients andatrial fibrillationin24%.MeanbaselineQRSdurationwas146ms and mean LVEF was 27%. A CRT defibrillator (CRT-D) was implantedin95patients(82.6%)andaCRTpacemaker (CRT-P)intheremaining.

Duringameanfollow-upof25±13months,atleastone MACEoccurredin29patients(25%).Fifteenpatients(13%)

died (two fromsudden cardiacdeath[SCD],10 from con-gestive HF, and three from systemic infection), 25 were hospitalizedforHF(21.7%),andone(0.8%)underwentheart transplantation. The incidence of SCD(two patients with CRT-D) was1% per year. There were nosignificant differ-encesbetweenpatientswithandwithoutMACEinmostof thebaselinecharacteristicsanalyzed,exceptforserum cre-atinineandBNPlevels,bothofwhichwerehigherinpatients with MACE (serum creatinine 1.28±0.52 mg/dl vs. 1.04± 0.39 mg/dl, p=0.007; BNP 734±683 pg/ml vs. 392±390 pg/ml,p=0.005).

The characteristics of the overall population at base-lineandaccordingtooccurrenceofMACEarepresentedin Table2.

Predictivevalueofresponsecriteria

Patients without MACE during the follow-up period were more frequently responders by all the response criteria,

Table2 Characteristicsoftheoverallpopulationatbaselineandaccordingtotheoccurrenceofmajoradversecardiacevents. Total(n=115) WithMACE(n=29) WithoutMACE(n=86) p

Male,n(%) 78(67.8) 23(79.3) 55(64.0) 0.126

Age,years 68.4±10.1 68.4±9.1 68.4±10.4 0.602

IschemicHF,n(%) 42(36.5) 12(41.4) 30(34.9) 0.530

Cardiovascularriskfactors

Hypertension,n(%) 102(88.7) 23(79.3) 79(91.9) 0.065 Hyperlipidemia,n(%) 80(69.6) 20(69.0) 60(69.8) 0.935 Diabetes,n(%) 47(40.9) 10(34.5) 37(43.0) 0.418 Smoking,n(%) 24(20.9) 9(31.0) 15(17.4) 0.119 Obesity(BMI≥30),n(%) 30(26.1) 8(27.6) 22(25.6) 0.832 Cardiovascularmedication BB,n(%) 100(87.0) 27(93.1) 73(84.9) 0.349 ACEI/ARB,n(%) 103(89.6) 26(89.7) 77(89.5) 1.000 Diuretics,n(%) 106(92.2) 28(96.6) 78(90.7) 0.445 NYHA≥III,n(%) 85(73.9) 21(72.4) 64(74.4) 0.812 QoL 0.95±0.69 1.03±0.80 0.93±0.66 0.831 Baselineelectrocardiogram QRS,ms 146_±22 143_±23 147_±21 0.487 LBBB,n(%)(n=85) 78(91.8) 21(91.3) 57(91.9) 1.000 AF,n(%) 28(24.3) 9(31.0) 19(22.1) 0.622 Baselineechocardiogram LVEF,% 27±7 25±7 27±7 0.243 LVESV,ml 154±58 165±60 150±57 0.116 LVEDV,ml 208±71 222±69 202±72 0.109 BaselineCPET PeakVO2,ml/kg/min 14.5±5.3 15.0±5.7 13.4±4.1 0.299

Baselinebloodtests

BNP(pg/ml) 493_±515 734_±683 392_±390 0.005

Creatinine(mg/dl) 1.10±0.44 1.28±0.52 1.04±0.39 0.007

Follow-up,months 25±13 22±12 26±13 0.189

ACEI:angiotensin-convertingenzymeinhibitor;AF:atrialfibrillation;ARB:angiotensinreceptorblocker;BB:beta-blocker;BMI:body massindex;BNP:B-typenatriureticpeptide;CPET:cardiopulmonaryexercisetesting;HF:heartfailure;LBBB:leftbundlebranchblock; LVEDV:leftventricularend-diastolicvolume;LVEF:leftventricularejectionfraction;LVESV:leftventricularend-systolicvolume;MACE: majoradversecardiacevents;NYHA:NewYorkHeartAssociationfunctionalclass;PeakVO2:oxygenconsumptionatpeakexercise;QoL: HeartQoLquality-of-lifescore.

Table3 Responseratesinpatientswithandwithoutmajoradversecardiacevents.

Responsecriteria Responserates

WithMACE(n=29) WithoutMACE(n=86) p Clinical,n(%)

1._↓NYHA≥1 17(58.6) 71(82.6) 0.017

2.↑QoL≥0.5 18(62.1) 66(76.7) 0.230

3._↑peakVO2>10% 15(51.7) 45(52.3) 0.839

4.↓NYHA≥1or↑peakVO2>10%andalive,nohospitalizationforHF 18(62.1) 78(90.7) 0.000

Echocardiographic,n(%) 5.↑LVEF≥5%(absolute) 15(51.7) 66(76.7) 0.010 6.↑LVEF≥15% 15(51.7) 67(77.9) 0.006 7.LVESV<15%ofbaseline 24(82.8) 77(89.5) 0.253 8._↓LVESV>15% 10(34.5) 51(59.3) 0.037 9.↓LVEDV>15% 6(20.7) 35(40.7) 0.067 10._↑Strokevolume_≥15% 13(44.8) 45(52.3) 0.458 Combined,n(%)

11.↑LVEF≥5%(absolute)and↓NYHA≥1or↑QoL≥0.5 12(41.4) 59(68.6) 0.015

↑:higher;↓:lower;LVEDV:leftventricularend-diastolicvolume;LVEF:leftventricularejectionfraction;LVESV:leftventricular end-systolicvolume;NYHA:NewYorkHeartAssociationfunctionalclass;peakVO2:oxygenconsumptionatpeakexercise;QoL:HeartQoL quality-of-lifescore.

achievingsignificantlyhigherresponserates ontheNYHA, LVEFandLVESVcriteria(Table3).

Ofalltheresponsecriteriaanalyzed,onlyfivewere pre-dictorsofMACE.Thestrongestpredictorwasthecombined clinical criterionincludingreductionofat leastone NYHA class or >10% improvement in peak VO2 and being alive,

withnohospitalizationforHFin thefirstsixmonthsafter CRTimplantation(HR0.21;95%CI0.10-0.46,p<0.001).The moststronglypredictiveisolatedclinicalresponsecriterion wasreductionofatleastoneNYHAclass,whichwas associ-atedwith61%lowerriskforfutureMACE(HR0.39;95%CI 0.18-0.83, p=0.014).The bestechocardiographic response

criterion wasa relative increase in LVEF of at least 15%, whichwasassociatedwith57% lowerriskfor futureMACE (HR0.43,95%CI0.20-0.90,p=0.024)(Table4andFigure1). The combination of the best clinical and echocardio-graphiccriteria(reductionofatleastoneNYHAclassor>10% improvementinpeakVO2andbeingalive,withno

hospital-izationforHFinthefirstsixmonthsafterCRTimplantation, andincreaseinLVEFofatleast15%)wasmorestrongly pre-dictivethanthe echocardiographiccriterion butnotmore sothantheclinicalcriterionalone(HR0.256,95%CI 0.118-0.554,p=0.001).Thecombination of reductionofat least oneNYHA class and increase in LVEF of at least 15% was

Table4 Predictorsofmajoradversecardiacevents.

Responsecriteria Univariateanalysis

HR(95%CI) p

Clinical

1.↓NYHA≥1 0.39(0.18-0.83) 0.014

2._↑QoL≥0.5 0.57(0.22-1.44) 0.233

3.↑peakVO2>10% 0.70(0.35-2.03) 0.695

4.↓NYHA≥1or↑peakVO2>10%andalive,nohospitalizationforHF 0.21(0.10-0.46) <0.001

Echocardiographic 5._↑LVEF≥5%(absolute) 0.45(0.21-0.94) 0.033 6.↑LVEF≥15% 0.43(0.20-0.90) 0.024 7.LVESV<15%ofbaseline 0.44(0.17-1.18) 0.103 8.↓LVESV>15% 0.59(0.27-1.30) 0.190 9.↓LVEDV>15% 0.54(0.22-1.33) 0.179 10.↑Strokevolume≥15% 0.91(0.42-1.97) 0.816 Combined

11.↑LVEF≥5%(absolute)and↓NYHA≥1or↑QoL≥0.5 0.47(0.22-0.99) 0.049

LVEF:leftventricularejectionfraction;LVEDV:leftventricularend-diastolicvolume;LVESV:leftventricularend-systolicvolume;NYHA: NewYorkHeartAssociationfunctionalclass;peakVO2:oxygenconsumptionatpeakexercise;QoL:HeartQoLquality-of-lifescore.

Figure1 Survivalcurvesofcumulativeoccurrenceofmajoradversecardiaceventsinrespondersornon-responderstocardiac resynchronization therapy according to the most strongly predictive response criteria. (A) Criterion of ↓NYHA ≥1; (B) crite-rionof↓NYHA≥1 or↑peakVO2>10%andalive,nohospitalizationfor heart failure;(C)criterion of↑LVEF ≥5%(absolute); (D) criterionof_{↑LVEF≥15%;}(E)criterionof_↑LVEF≥5%(absolute)and_↓NYHA≥1or_{↑HeartQoL≥0.5.↑:}higher:_↓:lower;CI: confi-denceinterval;CRT:cardiacresynchronizationtherapy;HF:heartfailure;HR:hazardratio;LVEF:leftventricularejectionfraction; NYHA:NewYorkHeartAssociationfunctionalclass;QoL:HeartQoLquality-of-lifescore.

morepredictiveofnoMACEthaneitherofthetwocriteria alone(HR0.292,95%CI0.132-0.646,p=0.002).

Agreementbetweenresponsecriteria

Agreement between the different response criteria as a group(␬=0.24±0.25),andalsobetweenechocardiographic response criteria and clinical criteria (␬=0.19±0.21 and 0.25±0.36,respectively)waspoor.Ofthetotalof55pairs analyzed, the majority (78.2%) had poor agreement, and only three (5.5%) had ␬ values in the range of strong agreement. Excluding response criteria whose definition includedmultiplevariables,andassessingtheisolated

clin-ical criteria, there was a moderate agreement between improvement in NYHA functional class and qualityof life (␬=0.56),butpooragreementbetweentheseandincrease in peakVO2 (␬=-0.16and␬=-0.10,respectively). Between

thesixechocardiographiccriteria,onlythreepairsachieved moderateagreement,higherLVEF/lowerLVESV(␬=0.60)and lowerLVEDV/higherLVESV(␬=0.51)(Figure2).

Discussion

While thebeneficial effects ofCRT onsymptoms, cardiac remodelingandfunction,andsurvivalhavebeenwell estab-lishedinmultipletrials,thereisstillnoconsensusregarding

Figure 2 Agreement between response criteria was strong inonly 7.6%ofresponse criteria pairs. Cohen’s ␬ valuesare color-codedaccordingtothefollowingranges:darkgray=strong agreement(␬≥0.75),lightgray=moderateagreement(␬ 0.4-0.75), none=poor agreement (_{␬ ≤0.4). ↑:} higher: _↓: lower; Comb:combined;HF:heartfailure;LVEDV:leftventricular end-diastolicvolume;LVEF:leftventricularejectionfraction;LVESV: left ventricular end-systolic volume; NYHA: New York Heart Associationfunctionalclass;peakVO2:oxygenconsumptionat peakexercise;QoL:HeartQoLquality-of-lifescore.

thebestdefinitionof responsetoCRT.The primaryresult ofthepresentanalysisisthatinoursampleofHFpatients treatedbyCRT,onlyaminority(fiveoutof11)ofcommonly usedcriteriaofresponsetoCRTintheliteraturepredicted MACE-freesurvival25monthsafterCRTimplantation.A pre-viousstudybyBoidoletal.,34_{including97patientsfollowed}

foroneyear,showedsimilarfindings,withonlyeightof15 analyzed criteria differentiating patients withMACE from thosewhoremainedevent-free.Theseresultshighlightthe lackofuniformityandpredictiveabilityofthemultiple cri-teriausedintheliterature.

ThemostpowerfulisolatedpredictorsofMACEidentified wereNYHAfunctionalclassandLVEF.Patientswhofulfilled theseseparatelyhadalowerriskofmajoreventsat follow-up of 61% and57%, respectively. Similarly, Boidol et al.34

concludedthatimprovementinNYHAfunctionalclasswas the most strongly predictive clinical criterion (adjusted relativerisk[RR]4.4;p=0.002),whilethemoststrongly pre-dictiveechocardiographicresponsecriterionwasadecrease inLVESVindex(adjustedRR3.49;p=0.002).

Arecent studybyRickardetal.35 _assessed

echocardio-graphic predictors of long-term survival following CRT in 436patientsfollowedfor5.4±2.3years.Variouschangesin LVESV,LVEDVandLVEFweretested.Theauthorsconcluded that LVEF improvement and LVESV reduction were similar intermsofprognosisandwerebothsuperiortodefinitions using LVEDV, as was shown in our study, in which LVEDV reductionwasalsonotapredictorofevent-freesurvival.

On the other hand, we found that combining clinical and echocardiographic parametersadds predictive power. Although the combination of criteria may hamper their

application in daily clinical practice,this could be away toimproveidentificationofpatientswhowillhaveabetter prognosis.

OurpopulationincludedpatientswithCRTdeviceswith orwithoutdefibrillator.Wedonotconsiderthisa confound-ingfactor,astheincidenceofSCDwaslow (1%peryear), andonlyoccurredintwoischemicpatientswithCRT-D.

Another finding of our study was the poor agree-ment between the response criteria analyzed as a group (␬=0.25),andbetweenclinicalandechocardiographic crite-ria.ThiswasalsofoundbyFornwaltetal.,6_whoconcluded

thatagreementbetween differentmethods todefine CRT responsewaspoor75%ofthetimeandpointedoutthatthis severelylimitstheabilitytogeneralizeandcompareresults betweenstudies.Thisdiscrepancybetweendifferent crite-riacouldinpartbeexplainedbythedifferentaspectsofHF statusthattheyassess.36

Toourknowledge,thecurrentstudyisthelargest com-paringtheimpactonlong-termcardiaceventsofcommonly usedechocardiographic andclinical CRTresponsecriteria. Wedemonstratethatthecriteriahavepooragreementwith eachotheranddonothavethesameimpactonprognosis. Itisessentialtoestablishaconsensusonthedefinitionof CRTresponseinordertostandardizestudies.More impor-tantly,ifthereisbetterunderstandingofwhichpatientswill achievethebestresponsetoCRT,thismayleadtochanges inselectionfortreatment.

Limitations

The current study has the limitations inherent to any single-centerstudy,whichmayincludeselectionbias.Also, patients whodied within six months of CRT implantation wereexcludedfromouranalysis,andsonoconclusionscan be drawn for this specific population. Response was only assessedatsixmonthsafterCRT implantation,and there-forewecannotknowifthesameresultswouldbefoundif responsehadbeenassessedbeforeorafterthistime.

Moreover,echocardiographic responsestoCRT is inher-entlylimitedbyinter-andintraobservervariability,which isalimitationinanystudyinvolvingtheseparameters.

Arelativelimitationisthefollow-upduration.Although thiswasoneofthelongeststudiescomparingdifferent clin-icalandechocardiographicresponsecriteria,thepredictive valueofdifferentcriteriaisstillunknownintermsoftheir impactonlonger-termcardiacevents.

Conclusion

InadvancedHFpatientstreatedbyCRT,notallofthe com-monlyusedresponsecriteriapredictedoutcomes,andthere waspooragreementbetweenthem.ImprovementinNYHA functionalclassandinLVEFweretheisolatedcriteriawith themostpowerfulpredictivevalueforMACE-freesurvival. The association of these two criteriaimproved their pre-dictivevalue. Thesefindingsmaymeanthatthesecriteria aretobepreferredtootherswhendefiningCRTresponsein futurestudies.Itisessentialtoestablishaconsensusonthe definitionofCRTresponseinordertostandardizestudies.

Conflicts

of

interest

Theauthorshavenoconflictsofinteresttodeclare. Allauthorstakeresponsibilityforallaspectsofthe relia-bilityandfreedomfrombiasofthedatapresentedandtheir discussedinterpretation.

Acknowledgments

Theauthorswishtothankallthe staffof theSantaMarta Electrophysiology andPacingDepartment and Echocardio-graphicLaboratoryfortheirassistancewiththisproject.

References

1.Cazeau S,LeclercqC,Lavergne T,et al.Effects ofmultisite biventricularpacinginpatientswithheartfailureand intraven-tricularconductiondelay.NEnglJMed.2001;344:873---80. 2.AbrahamWT,FisherWG,SmithAL,etal.Cardiac

resynchroniza-tioninchronicheartfailure.NEnglJMed.2002;346:1845---53. 3.Bristow MR, Saxon LA, Boehmer E, et al.

Cardiac-resynchronization therapy with or without an implantable defibrillationinadvancedchronicheartfailure.NEnglJMed. 2004;350:2140---50.

4.ClelandJG,DaubertJC,ErdmannE,etal.Theeffectofcardiac resynchronizationonmorbidityandmortalityinheartfailure. NEnglJMed.2005;352:1539---49.

5.MossAJ,HallWJ,CannomDS,etal.Cardiac-resynchronization therapyforthepreventionofheart-failureevents.NEnglJMed. 2009;361:1329---36.

6.FornwaltBK,SpragueWW,BeDellP,etal.Agreementispoor amongcurrentcriteriausedtodefineresponsetocardiac resyn-chronizationtherapy.Circulation.2010;121:1985---91. 7.BaxJJ,GorcsanJ.EchocardiographyandnoninvasiveImaging

incardiacresynchronizationtherapy:resultsofthePROSPECT (PredictorsofResponsetoCardiacResynchronizationTherapy) StudyinPerspective.JAmCollCardiol.2009;53:1933---43. 8.AuricchioA,PrinzenFW.Non-responderstocardiac

resynchro-nizationtherapy---themagnitudeoftheproblemandtheissues. CircJ.2011;75:521---7.

9.ClinicalTrials.gov[Internet].Bethesda(MD):NationalLibraryof Medicine (US). 2000Feb 29 ---Identifier NCT02413151, Exer-ciseTraining Following CardiacResynchronizationTherapy in Patients With ChronicHeart Failure; 2015 April 9. Available from:https://clinicaltrials.gov/ct2/show/NCT02413151. 10.DicksteinK,VardasP,AuricchioA,etal.2010FocusedUpdate

ofESCGuidelinesondevicetherapyinheartfailure:anupdate ofthe2008ESCGuidelinesforthediagnosisandtreatmentof acute and chronic heart failure and the 2007 ESC guide-lines for cardiac and resynchronization therapy. Developed with the special contribution of the Heart Failure Associa-tionandtheEuropeanHeartRhythmAssociation.EurHeartJ. 2010;31:2677---87.

11.McMurrayJJ,AdamopoulosS,AnkerSD,etal.ESCGuidelines forthediagnosisandtreatmentofacuteandchronicheart fail-ure2012.TheTaskForcefor theDiagnosisandTreatmentof AcuteandChronicHeartFailure2012oftheEuropeanSociety ofCardiology.DevelopedincollaborationwiththeHeartFailure Association(HFA)oftheESC.EurHeartJ.2012;33:1787---847. 12.Brignole M, Auricchio A, Baron-Esquivias G, et al. 2013 ESC

Guidelines on cardiac pacing and cardiac resynchronization therapy.TheTaskForceoncardiacpacingandresynchronization therapyoftheEuropeanSocietyofCardiology(ESC).Developed incollaborationwiththeEuropeanHeartRhythmAssociation (EHRA).EurHeartJ.2013;34:2281---329.

13.OldridgeN,HoferS,McGeeH,etal.TheHeartQoL:PartII. Vali-dationofanewcorehealth-relatedqualityoflifequestionnaire forpatientswithischemic heartdisease.EurJPrevCardiol. 2014;21:98---106.

14.Bleeker GB, Bax JJ, Fung JWH, et al. Clinical versus echocardiographic parameters to assess response to car-diac resynchronization therapy. Am J Cardiol. 2006;97: 260---3.

15.Molhoek SG, Bax JJ, Bleever GB, et al. Comparison of responsetocardiacresynchronizationtherapyinpatientswith sinus rhythm versuschronic atrialfibrillation. Am JCardiol. 2004;94:1506---9.

16.MolhoekSG,BaxJJ,BoersmaE,etal.QRSdurationand short-eningtopredictclinicalresponsetocardiacresynchronization therapyin patientswithend-stageheartfailure. PacingClin Electrophysiol.2004;27:308---13.

17.MolhoekSG,Bax JJ,VanErvenL, et al.Comparison of ben-efitsfromcardiac resynchronizationtherapyinpatientswith ischemic cardiomyopathyversusidiopathic dilated cardiomy-opathy.AmJCardiol.2004;93:860---3.

18.Lecoq G, Leclercq C, Leray E, et al. Clinical and electro-cardiographic predictors of a positive response to cardiac resynchronizationtherapyinadvancedheartfailure.EurHeart J.2005;26:1094---100.

19.BaxJJ,MarwickTH,MolhoekSG,etal.Leftventricular dyssyn-chronypredictsbenefitofcardiacresynchronizationtherapyin patientswithend-stageheartfailurebeforepacemaker implan-tation.AmJCardiol.2003;92:1238---40.

20.GorcsanJ, Tanabe M, BleekerGB, et al. Combined longitu-dinal and radial dyssynchrony predicts ventricular response afterresynchronizationtherapy. J AmCollCardiol. 2007;50: 1476---83.

21.Suffoletto MS, Dohi K, Cannesson M, et al. Novel speckle-trackingradial strain from routine black-and-white echocar-diographic images to quantify dyssynchrony and predict response to cardiac resynchronization therapy. Circulation. 2006;113:960---8.

22.StellbrinkC,BreithardtOA,FrankeA,etal.Impactofcardiac resynchronization therapy using hemodynamically optimized pacingonleftventricularremodelinginpatientswith conges-tiveheartfailureandventricularconductiondisturbances.JAm CollCardiol.2001;38:1957---65.

23.NotarbartoloD,MerllinoJD,SmithAL,etal.Usefulnessofthe peakvelocitydifferencebytissueDopplerimagingtechniqueas aneffectivepredictorofresponsetocardiacresynchronization therapy.AmJCardiol.2004;94:817---20.

24.Chung ES, Leon AR, Tavazzi L, et al. Results of the Pre-dictors of Response to CRT (PROSPECT) trial. Circulation. 2008;117:2608---16.

25.Yu CM, Chan YS, ZhangQ, et al. Benefits of cardiac resyn-chronizationtherapyforheartfailurepatientswithnarrowQRS complexesandcoexistingsystolicasynchronyby echocardiog-raphy.JAmCollCardiol.2006;48:2251---7.

26.Yu CM, Fung JWH, Chan YS, et al. Comparison of efficacy ofreverseremodelingandclinicalimprovementforrelatively narrowandwide QRScomplexesaftercardiac resynchroniza-tion therapy for heart failure. J Cardiovasc Electrophysiol. 2004;15:1058---65.

27.Yu CM, Zhang Q, Chan YS, et al. TissueDoppler velocity is superiortodisplacementandstrainmappinginpredictingleft ventricularreverseremodellingresponseaftercardiac resyn-chronizationtherapy.Heart.2006;92:1452---6.

28.Yu CM, Zhang Q, Fung JWH, et al. A novel tool to assess systolicasynchrony and identifyresponders ofcardiac resyn-chronizationtherapybytissuesynchronizationimaging.JAm CollCardiol.2005;45:677---84.

29.DohiK,SuffolettoMS,SchwartzmanD,etal.Utilityof echocar-diographic radial strain imaging to quantify left ventricular

dyssynchronyandpredictacuteresponsetocardiac resynchro-nizationtherapy.AmJCardiol.2005;96:112---6.

30.GorcsanJ,KanzakiH, BazazR,et al.Usefulnessof echocar-diographic tissue synchronization imaging to predict acute responsetocardiacresynchronizationtherapy.AmJCardiol. 2004;93:1178---81.

31.WhiteJA,YeeR,YuanXP,etal.Delayedenhancementmagnetic resonanceimagingpredictsresponsetocardiac resynchroniza-tion therapy in patients with intraventricular dyssynchrony. JAmCollCariol.2006;48:1953---60.

32.HulleySB,CummingsSR,BrownerWS,etal.Designingclinical research:anepidemiologicapproach.2nded.Philadelphia,PA: LippincottWilliams&Wilkins;2001.

33.FleissJL.Statisticalmethodsforratesandproportions.2nded. NewYork:JohnWiley&Sons;1981.

34.BoidolJ,SredniawaB,KowalskiO,etal.Manyresponsecriteria arepoorpredictors ofoutcomes aftercardiac resynchroniza-tiontherapy:validationusingdatafromtherandomizedtrial. Europace.2013;15:835---44.

35.RickardJ,BaranowskiB, WilsonTangWH,et al. Echocardio-graphicpredictorsoflong-termsurvivalinpatientsundergoing cardiacresynchronizationtherapy:whatistheoptimalmetric? JCardiovascElectrophysiol.2017;28:410---5.

36.European Heart Rhythm Association (EHRA); European Soci-etyofCardiology(ESC); HeartRhythmSociety;HeartFailure Society ofAmerica (HFSA); American Societyof Echocardio-graphy (ASE); American Heart Association (AHA); European Association of Echocardiography(EAE) ofESC; Heart Failure Association of ESC (HFA)Daubert JC, Saxon L, Adamson PB, et al. 2012 EHRA/HRS expert consensus statement on car-diac resynchronization therapy inheart failure:implant and follow-uprecommendationsandmanagement.HeartRhythm. 2012;9:1525---76.