www.revportcardiol.org
Revista Portuguesa de
Cardiologia
Portuguese Journal of Cardiology
ORIGINAL ARTICLE
Short and long-term clinical impact of transcatheter aortic valve implantation in Portugal according to different access routes: Data from the Portuguese National Registry of TAVI
Cláudio Guerreiro
a, Pedro Carrilho Ferreira
b, Rui Campante Teles
c,d,∗, Pedro Braga
a, Pedro Canas da Silva
b, Lino Patrício
e, João Carlos Silva
f, José Baptista
g,
Manuel de Sousa Almeida
c,d, Vasco Gama Ribeiro
h, Bruno Silva
i, João Brito
c,d, Eduardo Infante Oliveira
b, Duarte Cacela
e, Sérgio Madeira
c,d, João Silveira
jaDepartmentofCardiology,CentroHospitalardeVilaNovadeGaia,Portugal
bDepartmentofCardiology,HospitaldeSantaMaria,CentroHospitalarUniversitáriodeLisboaNorte,Portugal
cDepartmentofCardiology,HospitaldeSantaCruz,CentroHospitalardeLisboaOcidental,Carnaxide,Portugal
dCEDOC,NovaMedicalSchool,Lisbon,Portugal
eDepartmentofCardiology,HospitaldeSantaMarta,CentroHospitalardeLisboaCentral,Portugal
fDepartmentofCardiology,CentroHospitalarUniversitáriodeSãoJoão,Portugal
gDepartmentofCardiology,HospitaldosLusíadas,Portugal
hDepartmentofCardiology,HospitaldaCruzVermelhaPortuguesa,Portugal
iDepartmentofCardiology,HospitaldeNélioMendonc¸a,Funchal,Portugal
jDepartmentofCardiology,HospitaldeSantoAntónio,CentroHospitalardoPorto,Portugal
Received14November2019;accepted1February2020 Availableonline28November2020
KEYWORDS
Severeaorticvalvular disease;
TAVI;
Heartfailure
Abstract
Introduction:The Portuguese National Registry of Transcatheter Aortic Valve Implantation recordsprospectivelythecharacteristicsandoutcomesoftranscatheteraorticvalveimplanta- tion(TAVI)proceduresinPortugal.
Objectives: Toassessthe30-dayandone-yearoutcomesofTAVIproceduresinPortugal.
Methods:WecomparedTAVIresultsaccordingtotheprincipalaccessused(transfemoral(TF) vs. non-transfemoral(non-TF)).Cumulative survivalcurvesaccordingto accessroute, other procedural andclinical variableswere obtained.The Valve AcademicResearchConsortium- 2(VARC-2) compositeendpoint ofearly(30-days) safetywas assessed.VARC-2predictorsof 30-daysand1-yearall-causemortalitywereidentified.
∗Correspondingauthor.
E-mailaddress:rcteles@outlook.com(R.C.Teles).
https://doi.org/10.1016/j.repc.2020.02.014
0870-2551/©2020SociedadePortuguesadeCardiologia.PublishedbyElsevierEspa˜na,S.L.U.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Results:BetweenJanuary2007andDecember2018,2346consecutivepatientsunderwentTAVI (2242native,104valve-in-valve;meanage81±7years,53.2%female,EuroSCORE-II-EuroS-II, 4.3%).Devicesuccesswas90.1%andnumericallylowerfornon-TF(87.0%).Thirty-dayall-cause mortalitywas4.8%,withtheTFrouterenderingalowermortalityrate(4.3%vs.10.1%,p=0.001) andhighersafetyendpoint(86.4%vs.72.6%,p<0.001).Theone-yearall-causemortalityratewas 11.4%,andwassignificantlylowerforTFpatients(10.5%vs.19.4%,p<0.002).Aftermultivariate analysis,peripheralarterydisease,previouspercutaneouscoronaryintervention,leftventricu- lardysfunctionandNYHAclassIII-IVwereindependentpredictorsof30-dayall-causemortality.
Atone-yearfollow-up,NYHAclassIII-IV,non-TFrouteandoccurrenceoflife-threateningblee- dingpredicted mortality.Kaplan-Meier survivalanalysisofthefirst yearoffollow-up shows decreasedsurvivalforpatientswithanEuroS-II>5%(p<0.001)andwhounderwentnon-TFTAVI (p<0.001).
Conclusion:Datafromournationalreal-worldregistryshowedthatTAVIwassafeandeffective.
Theuseofanon-transfemoralapproachdemonstratedsafetyintheshortterm.Long-termpro- gnosiswas,however,adverselyassociatedwiththisroute,withcomorbiditiesandthebaseline clinicalstatus.
©2020SociedadePortuguesadeCardiologia.PublishedbyElsevierEspa˜na,S.L.U.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by- nc-nd/4.0/).
PALAVRAS-CHAVE Doenc¸avalvular aórticagrave;
VAP;
Insuficiênciacardíaca
ImpactoclínicoemcurtoelongoprazodaVálvulaAórticaPercutânea(VAP)em Portugaldeacordocomdiferentesacessos---DadosdoRegistoNacionalde CardiologiadeIntervenc¸ãodeVAP
Resumo
Introduc¸ão:ORegistoNacionaldeCardiologiadeIntervenc¸ãodeVálvulasAórticasPercutâneas (RNCI-VaP)documentaprospetivamenteascaracterísticaseresultadosdaVAPemPortugal.
Objetivos: Avaliarosresultadosa30diaseumanodaVAPemPortugal.
Métodos: Comparac¸ãodosresultadosdaVAPdeacordocomoacesso(transfemoral---TFversus nãotransfemoral---nãoTF).Obtiveram-securvasdesobrevivênciacumulativadeacordocom oacesso,variáveisdoprocedimentoeclínicas. Avaliou-seaseguranc¸aprecoce (30dias)do procedimento,deacordocomoscritérios ValveAcademic ResearchConsortium-2(VARC-2).
Identificaram-sepreditoresdemortalidadea30diaseumano.
Resultados: Entrejaneiro2007edezembro2018,realizaram-se2346VAP(2242nativas,104 Valve-in-Valve[VIV];idademédia81±7anos,53,2% mulheres,EuroSCORE-II[EuroS-II]4,3%).
Sucesso do dispositivo foi obtido em 90,1%, inferiorpara o não TF (87,0%). Aos 30 dias, a mortalidade global foi de 4,8%, apresentando oTF menor mortalidade (4,3% versus10,1%, p=0,001)emaiorseguranc¸a(86,4%versus72,6%,p<0,001).Amortalidadeaumanofoi11,4%, significativamentemenorparaoTF(10,5%versus19,4%,p<0,002).Apósanálisemultivariável, identificaram-secomopreditores demortalidadea30diasdoenc¸aarterialperiférica,angio- plastiaprévia, disfunc¸ãoventricular esquerdaeclasseNYHAIII-IV. Aum ano,NYHA III-IV,o acessonãoTFeahemorragiacomriscodevidaforampreditoresdemortalidade.Aanálisede sobrevivênciaaumanoevidencioumenorsobrevivênciaparaEuroS-II>5%(p<0,001)eVAPnão TF(p<0,001).
Conclusões:DadosdoRNCI-VaPmostramqueaVAPfoiseguraeeficaz.OacessonãoTFmostrou seguranc¸aem curtoprazo.Oprognósticoemlongoprazofoiinfluenciadonegativamentepor esteacesso,assimcomocomorbilidadeseoestadoclínicodebasedodoente.
©2020SociedadePortuguesadeCardiologia.PublicadoporElsevierEspa˜na,S.L.U.Este ´eum artigoOpen Accesssobumalicenc¸aCCBY-NC-ND(http://creativecommons.org/licenses/by- nc-nd/4.0/).
Introduction
Severe aortic stenosis (AS) is the most prevalent type of valvularheartdiseaseinthewesternworld,1withparticu- larhighprevalence inolder patients.2 Globaldemography
showsapatternofanagingpopulationandsince1960life expectancyatbirthinPortugalhasincreasedfrom64to82 years.ThiswillincreasetheburdenofASandtheneedto treatit.3,4Surgicalaorticvalve(SAV)replacementisanesta- blished treatment for symptomatic severe AS.5 However,
in the last decade, transcatheter aortic valve implanta- tion(TAVI)hasemergedasaminimallyinvasivetreatment for AS, initially for inoperable andhigh risk patients6 but increasingly, as evidence grows, it is used in lower risk patients.7,8Evidenceisbuildingonthedurabilityoftrans- catheteraorticvalves,withover90%ofpatientsremaining free of structural valve dysfunction between five and 10 years post-implantation.9 This may encourage increased useof thistechnology inyoungerand lowerrisk patients.
Growingexperience,solidevidence,refinedpre-procedural assessment withmulti-slice computed-tomography (MSCT) and new generation transcatheter devices are causing a shifttoward new indications, includinglower-surgicalrisk patients.10,11
Transfemoral (TF) access is the preferred route, since itis lessinvasive,andpatientrecoveryis faster,involving shorterhospitalstays.12Nevertheless,uptoonethirdofeli- giblepatients maynotbeappropriatecandidatesfor aTF approachbecauseofmajorperipheralarterydisease(PAD).
Otherrouteshaveemergedasalternatives,butareassocia- tedwithworseoutcomes,particularlywhenconsideringthe transapical(TA)route.13
Anotherfieldof increasingimportancein TAVIis prost- hetic valve dysfunction (PVD). Currently, patients with previouslyimplanted biologicalSAV canbetreated witha valve-in-valve(ViV)procedureforPVD,whichhasbeenasso- ciatedwithgoodone-yearoutcomes.14
Registries have reported the results of TAVI in several countries, showing consistently high implantation success rates;arecentmeta-analysisreportedanoverallEuropean 30-daymortalityof8%,howeverwithsubstantialdifferences amongregistries.15,16 Mid- andlong-termfollow-up results show survival rates over 80% at one year, with persistent improvementofclinicalstatus.17
ThePortugueseNationalRegistryofTranscatheterAortic Valve Implantation (RNCI-VaP) is a national registry con- ductedwiththemainpurposeofassessingallcomerswith aortic valvediseaseor aortic valveprosthesis dysfunction thatundergoTAVIinPortugal,ensuringcomprehensivecove- rage in Portugal.18 The main goals of the registry are to documentinaprospectiveandconsecutivefashionthecha- racteristics of patients who undergo TAVI, ascertain the results of these treatments in Portugal, develop scienti- fic work basedon data included in the registry, establish treatmentrecommendationsregardingTAVIproceduresand collaborate with other similar international registries. A positionpaperstatementfromthe PortugueseAssociation of Cardiovascular Intervention (APIC) has alreadyunderli- nedtheimportanceofasystematicassessmentandreport of patients whoundergoTAVI in Portugal.19 The members ofthiscommittee areallinterventional cardiologists.Itis divided into an executive board of threemembers which includestheRegistryCoordinatorandthescientificboard.
There is no specific funding for this registry which has been completelydeveloped,maintainedandsponsoredby APIC.
Thisarticleisthefirstreportofreal-worldclinicaldata fromtheRNCI-VaPregistry.Itaimstoidentifypatientand procedurecharacteristicsandevaluate30-dayandone-year outcomesofTAVIinPortugal.
Methods
Patientselection
TheRNCI-VaPisacontinuous,observationalandprospective registry,whichbeganin2007.Atotalof14exclusivelyPortu- gueseprivateandpubliccentersparticipatedintheregistry onavoluntarybasis.Registrydatainclusionandanalysisare theexclusiveresponsibilityofthemembersoftheRNCI-VaP, whichisfreefromindustrybodyinfluence.Theregistrycom- plieswithPortuguesedataprotectionlawsandwasapproved byacentralethicsboard.Allpatientsgavewritteninformed consent.
SelectionofsymptomaticpatientswithsevereASorPVD forTAVIfollowedamultidisciplinaryapproachinwhichall individual cases were discussed within a heart team and the procedures performed in hospitals with on-site car- diac surgery.20 Patients were included if considered high riskfor traditionalaorticvalvereplacement (AVR)surgery ordeemedinoperable.Patientswereexcludediftheirlife expectancywithTAVIwas≤1year orthepatient’s quality of life wasunlikely to improve withTAVI. MSCT wasrou- tinely performed to select the access route, and aspects suchassize,tortuosityandcalcificationwereassessed.Ifa femoralapproach wasnot possible, an alternative access was planned (transcarotid, transaortic, transubclavian or transapical). MSCT data also enabled characterization of the aortic annulus and valve, sinus of Valsalva, coronary ostiaandascendingaorta.Thedecisionregardingtheaccess route,theprosthesistypeandsizeweremadeaccordingto each center’s routine,taking into consideration the clini- calandmorphologicalassessment.AtallTAVIcenters,the procedurewasperformedwiththesupportofatleastone anesthesiologist.
Dataacquisitionandqualitycontrol
Datawereentered intoadedicated databaseand sent to theNational CardiologyDataCollectionCenterofthePor- tugueseSociety ofCardiology.Eventsandvaluescollected aresitereported,andtherearenocorelaboratories.Data wereexamined and validated, and the participating cen- terscontactedintheeventofanyqueriesordiscrepancies.
Supervision of the RNCI-VaP is the responsibility of the principal investigators (A.L., A.F., B.S., E.I.O., E.J., F.S., J.S.,J.S.M., L.R., R.C.,S.B.)andtheregistrycoordinator (R.C.T.).
Studyvariablesandoutcomes
Studyvariableswerebasedontherecommendationsofthe updatedVARC-2 consensusdocument.21 Theyincluded the following in-hospital and 30-daysoutcomes: i) immediate procedural mortality (up to 72 hours post-procedure); ii) proceduralmortality(all-causemortalitywithin30daysor during index procedure hospitalization if the postopera- tivelengthofstay waslongerthan30days);iii) early(30 days)safety(definedasfreedomfromall-causemortality,all
Figure1 Evolutioninthenumberoftranscatheteraorticvalveimplantation(TAVI)proceduresinPortugalsincethebeginningof thePortugueseRegistryofTAVIin2007untiltheendof2018(datapresentedinnumberofproceduresperyear;n=2380globalTAVI procedures;n=2346TAVIproceduresintheregistry).
stroke,life-threateningbleeding,acutekidneyinjurystage 2or3,coronaryarteryobstruction requiringintervention, majorvascularcomplicationandvalve-relateddysfunction requiring a repeat procedure); iv) myocardial infarction;
v)stroke andtransient ischemicattack (TIA);vi) bleeding complications(definedbytheBleedingAcademicResearch Consortiumcriteria);vii)acutekidneyinjury(acutekidney injurynetwork classification);viii) vascularcomplications;
ix)otherTAVI-relatedcomplications.All-causemortalitywas assessedat30daysandatone-yearfollow-up.Prospective follow-up of adverse events wasreported by the investi- gators. At 30-days and one-year, 48 (2%) and 530 (22%) patients,respectively,werelosttofollow-up.
Devicedescription
The national registry is open to any type of commercial device. To date, 12 different valves and their iterations havebeenusedincluding:MedtronicCoreValveTM,Edwards SapienTM,AbbottPorticoTM,BostonScientificAcurateneoTM andLotusEdgeTM,DirectFlowMedicalTM,NVTAllegraTAVI SystemTFTM,andMedtronicEngagerTM.Thetechnicalspeci- ficationsofthesedeviceshavebeendescribedelsewhere.22
Statisticalanalysis
Distribution of continuousvariables wasdetermined using theShapiro-Wilktestandtheyareexpressedasmean±SDor asmedian±IQR,whereappropriate.Categoricalvariables arereported as frequencies and percentages. Continuous
variableswerecomparedusingtheunpairedStudent’sttest or theWilcoxonrank-sum test,asappropriate.Chi-square test or Fisherexact test wasusedtocompare categorical variables.
Multivariateanalysisforthepredictionofall-causemor- talityduring30-daysandone-yearfollow-upwasperformed usingCoxregression,byincludingallstatisticallysignificant variablesintheunivariateanalysisandthoseconsideredcli- nicallyrelevant.Theresultsareexpressedashazardratios (HR)and95%confidenceintervals(CI95%).Survivalcurves were obtained with the Kaplan-Meier method. A log-rank test wasusedto comparesurvival between groups during follow-up.
Apvalue<0.05 wasconsidered statisticallysignificant.
Allanalyseswereperformed usingSPSSstatisticssoftware (version23.0,SPSS,Inc.,Chicago,IL).
Results
Studypopulation
Patient populationand procedural characteristics.From January2007toDecember2018,atotalof2346consecutive patients were included in the Portuguese National Regis- tryofTAVI,withnoexclusioncriteria.Inthelast10years, therehas been an exponentialincrease in the number of proceduresperformed, withaslightdecelerationin 2018, asillustratedinFigure1.Thebaselinecharacteristicsofthe populationareshowninTable1.Themeanageofourglobal cohortwas81±7yearswiththeyoungestandoldestpatients
Table1 Baselinecharacteristicsofthestudypopulationandaccordingtothetranscatheteraorticvalveimplantationaccess route.a
Variable All(n=2346) TF(n=2131) Non-TF(n=214) pvalue(TFvs.non-TF)
Age,years 81.1±7.1(20-96) 81.3±7.1 79.2±7.0 <0.001
Female 53.2(1246/2341) 54.5(1159/2127) 40.6(87/214) 0.001
Riskfactors
Diabetes 33.1(683/2062) 32.7(608/1858) 36.8(75/204) 0.241
Previoushistory
Stroke 12.0(246/2055) 11.6(216/1855) 15.0(30/200) 0.169
PAD 16.1(323/2012) 13.5(245/1813) 39.2(78/199) <0.001
CAD 43.8(900/2054) 42.3(783/1852) 57.9(117/202) <0.001
PCI 23.1(472/2047) 22.7(419/1845) 26.2(53/202) 0.254
CABG 17.7(367/2070) 16.5(307/1866) 29.4(60/204) <0.001
CKD 37.5(767/2043) 36.9(679/1842) 43.8(88/201) 0.056
COPD 22.0(454/2065) 21.7(404/1862) 24.6(50/203) 0.328
PreviousECG
Atrialfibrillation 25.4(512/2013) 25.3(460/1817) 26.5(52/196) 0.928
Pacemaker/CRT 7.1(142/2013) 7.0(128/1817) 7.1(14/196)
Clinicalstatus
ClassI-II 31.9(631/1981) 32.7(581/1778) 24.6(50/203) 0.043
ClassIII-IV 68.1(1350/1981) 67.3(1197/1778) 75.4(153/203)
EuroS-II 4.3(2.5-7.1) 4.3(2.5-7.0) 4.8(2.9-7.9) 0.058
STSmortality 4.7(3.0-7.1) 4.7(3.0-7.1) 4.4(2.9-6.9) 0.475
Baselineechocardiography
LVEF<50% 27.8(538/1934) 27.3(474/1736) 32.3(64/198) 0.154
Meanbaselinegradient,mmHg 49.4±16.1 49.6±16.3 48.6±14.8 0.461 Aorticvalvearea,cm2 0.64±.0.20 0.64±0.21 0.66±0.21 0.101 TAVIindication
AS 93.2(2190/2347) 93.5(1993/2131) 91.6(196/214) 0.133
Aorticdisease 2.3(53/2347) 2.1(44/2131) 4.2(9/214)
Prosthesisdysfunction 4.4(104/2347) 4.4(94/2131) 4.2(9/214) Surgicalrisk
Highrisk 49.7(1167/2346) 50.3(1072/2131) 44.4(95/214) <0.001 Surgicalcontraindicationb 22.0(517/2346) 20.6(439/2131) 36.4(78/214)
Othernon-specified 28.3(664/2346) 29.1(620/2131) 19.1(41/214)
Bridgeballoonaorticvalvuloplasty 2.9(57/1946) 2.7(48/1749) 4.6(9/196) 0.174
CABG:coronaryarterybypassgraft;CAD:coronaryarterydisease;CKD:chronickidneydisease;COPD:chronicobstructivelungdisease;
CRT:cardiac resynchronizationtherapy;EuroS-II: EuroScore II;LVEF: left ventricularejection fraction; non-TF: non-transfemoral;
PAD:peripheralarterydisease; PCI:percutaneouscoronaryintervention;TAVI:transcatheteraortic valveimplantation;STS:Society ofThoracicSurgery;TF:transfemoral;TA:transapical.
a CKD,definedasglomerularfiltrationrate<60mL/min/m2.
b Surgicalcontraindication,includingporcelainaorta,prohibitiverespiratoryfunctiontests,livercirrhosis,previouscoronaryartery bypasssurgerywithpatentthoracicartery,asperheartteamdiscussion.
Note:Dataarepresentedasmean±standarddeviationorn(%).
aged20and96,respectively.ThemedianEuroS-IIwas4.3%
(IQR2.5-7.1)andtheSTSscoremortalityriskwas4.7%(IQR 3.0-7.1).ThemajorityofpatientswereinNYHAfunctional class III or IV (68.1%). The predominant route wastrans- femoral(90.9%).Self-expandablevalves(SEV),particularly Medtronic CoreValve,wereusedmore frequently (69.1%), while theremaining30.9%wereballoon-expandable(BEV) EdwardsValves.Proceduralcharacteristicsarepresentedin Table2.
Transapical accesswasthemost usednon-transfemoral (non-TF) route (64%, 137/214). Patients who were
underwent to non-TF prosthesis implantation (9.1%) weresignificantlyyounger(non-TF79±7vs.TF81±7years, p<0.001),hadalowerprevalenceoffemales(non-TF40.6%
vs. TF 54.5%, p=0.001) and showed a higher prevalence ofPAD andcoronary arterydisease (CAD),includingmore patients that had previously undergone surgical coronary revascularization.Asexpected,thisgrouptendedtohavea highersurgicalriskprofile,withanEuroS-IIof4.8%(IQR2.9- 7.9)(vs.TF4.3[IQR3.2-8.6],p=0.058),whichwasclearly significant whenconsidering only transapical access route patients (TA 5.2% [3.2-8.6], p=0.012). Half of the global
Table2 Proceduralcharacteristicsofthestudypopulationandaccordingtotheaccessroute.
Variable All(n=2346) TF(n=2131) Non-TF(n=214) pvalue(TFvs.non-TF)
TAVIroute - - na
Transfemoral 90.9(2131/2345) Transapical 5.8(137/2345) Transaortic 2.0(48/2345) Transubclavian 0.9(20/2345) Transcaval 0.4(9/2345)
Valvetype <0.001
CoreValve 52.0(1217/2341) 54.3(1153/2125) 29.0(62/214) Edwardsvalve 30.9(723/2341) 27.7(588/2125) 63.1(135/214)
Other 17.1(401/2341) 18.1(384/2125) 7.9(17/214)
SEV 69.1(1618/2341) 72.3(1537/2125) 36.9(79/214) <0.001
BEV 30.9(723/2341) 27.7(588/2125) 63.1(135/214)
Post-dilatation 20.5(408/1986) 21.4(383/1789) 12.8(25/195) 0.001
Secondprosthesis 2.2(44/1986) 2.5(44/1789) 0 0.001
Repeatprocedure 1.3(26/2056) 1.2(23/1849) 1.5(3/205) 0.739
BEV:balloon-expandablevalve;SEV:self-expandablevalve;TAVI:transcatheteraorticvalveimplantation;TF:transfemoral.
Note:Dataarepresentedasmean±standarddeviationorn(%).
cohortwasconsideredbytheheartteamaspresentinghigh surgicalrisk(49.7%).Inthenon-TFgroup,whencompared with the TF group, a significantly higher proportion pre- senteda surgical contraindicationsupporting the decision (non-TF 36.4% vs. TF 20.6%, p<0.001). In this particular group,asexpected,BEVsweremorefrequentlyimplanted (BEV63.1%vs.SEV36.9%),andlesspost-dilatationwasused (non-TF12.8% vs.TF21.4%,p=0.001).There wasalsoless ofaneedforasecondprosthesisduringanindexprocedure (non-TF0vs.TF2.5%,p=0.001).
In-hospitaland30-daysresults
In-hospitalresultsareshowninTable3.Themediandura- tionofhospitalizationdecreasedovertheyears(2007-2014 median9[IQR7-14]vs.2015-2018median7days[IQR5-11], p<0.001);Figure2),without significant differencesaccor- dingtotheselectedroute.
Based on the VARC-2 criteria, the immediate implant successwasgloballyhigh(90.1%),withnumericallybetter results for TF compared to a non-TF approach, although the difference was not significant (TF 90.4% vs. non-TF 87.0%,p=0.174).Therewasalowrateofprocedure-related complicationsinbothaccessrouteapproaches.TFpatients hadalowerprevalenceofcardiactamponade(TF0.5%vs.
non-TF2.2%,p<0.001),perioperativemyocardialinfarction (TF4.4%vs.non-TF40.9%,p<0.001)andAcuteKidneyInjury Networkstage2or3(TF3.9%vs.non-TF6.9%vs.p<0.001).
Anon-TFapproach,particularlytransapicalandtransaortic, wasassociatedwithahigheroccurrenceoflife-threatening andmajorbleeding,andalsomajorvascularcomplications (non-TF7.3%vs.TF6.3%,p=0.001).Strokeoccurredin4.6%
ofourcohort, mainlynon-disabling (55%,48/88), andthe prevalenceofTIAwasverylow(1.8%).
Globally,moderate orsevere aortic valveregurgitation occurredin 7.4% of patients, without significant differen- ces between both approaches. Overall, 19.0% of patients
Figure 2 Median duration ofhospitalization for the global cohortaccordingtotheyearstrata 2007-2014and2015-2018 (p<0.001forcomparison).
required a definitive pacemaker during follow-up, with a numericallylowerrateinthe non-TFgroup(non-TF15.0%
vs.TF19.5%,p=0.153).
Overall, 30-day mortalitywas 4.8%, andthe combined safety endpoint occurred in 85.0% of patients. Both end- points were significantly better for the TF group, with a lower 30-day mortality rate (TF 4.3% vs. non-TF 10.1%, p=0.001)and higher30-day safety endpoint (TF86.4% vs.
non-TF72.6%,p<0.001).Itisinterestingtonotethetimeline stratificationcurveeffectinFigure3,showingtheevolution of30-day mortalityincidence,withasignificantreduction since2011,from14.1%tolessthan4%inmorerecentyears.
Follow-upandmortality
The median clinical follow-up duration was 259 (IQR 96- 616) days,with an accumulated mortality rate of 14.0%.
Table3 In-hospitalandfollow-upresultsofthestudypopulationandaccordingtotheaccessroute.
Variable All(n=2346) TF(n=2131) Non-TF(n=214) pvalue(TFvs.non-TF)
In-hospitaldays 8(6-12) 8(6-12) 8(6-11) 0.425
Immediateimplantsuccess 90.1(1545/1714) 90.4(1395/1543) 87.0(147/169) 0.174 30-daysafety 85.0(1468/1727) 86.4(1339/1550) 72.6(127/175) <0.001
30-daymortality 4.8(110/2297) 4.3(89/2087) 10.1(21/208) 0.001
Procedure-relatedcomplications
Coronaryobstruction 1.8(14/772) 1.9(14/738) 0 1.0
ECCsupport 1.3(12/954) 1.2(11/909) 0.5(1/177) 0.442
Tamponade 1.0(8/775) 0.5(4/740) 2.2(4/177) <0.001
ViV 1.1(8/725) 1.2(8/690) 0 1.0
Conversiontosurgery 0.4(4/954) 0.3(3/909) 0.5(1/177) 0.176
In-hospitalcomplications
Stroke 4.6(88/1893) 4.7(81/1714) 4.0(7/177) 0.916
Disabling 2.1(40/1893) 2.1(36/1714) 2.3(4/177) 0.777
Nondisabling 2.5(48/1893) 2.6(45/1714) 1.7(3/177)
TIA 1.8(35/1937) 1.8(32/1757) 1.7(3/178) 0.916
AKIN
AKINstage2 2.1(40/1892) 2.0(35/1717) 2.9(5/173) <0.001
AKINstage3 2.1(39/1892) 1.9(32/1717) 4.0(7/173)
Pacemakerrequirement 19.0(374/1964) 19.5(343/1762) 15.0(30/200) 0.153 Vascularcomplication
Major 6.8(120/1766) 6.3(110/1741) 7.3(13/177) 0.001
Minor 16.5(291/1766) 18.1(315/1741) 6.2(11/177)
Bleeding
Life-threatening 4.6(94/2054) 4.1(77/1861) 8.9(17/191) <0.001
Major 8.7(179/2054) 7.4(138/1861) 21.5(41/191)
Minor 13.6(279/2054) 14.0(261/1861) 9.4(18/191)
AMI
Perioperative 7.5(145/1945) 4.4(78/1779) 40.9(67/164) <0.001
NYHAonfollow-up
ClassI-II 94.3(1201/1274) 94.3(1074/1139) 93.9(125/133) 0.133
ClassIII-IV 5.7(73/1274) 5.7(65/1139) 6.1(8/133)
Moderate-severeAR 7.4(82/1114) 8.6(77/897) 6.9(9/131) 0.347
Prosthesisdysfunction 10.1(112/1114) 9.8(88/897) 7.2(10/137) 0.508 1-yearrehospitalization 9.6(98/1017) 9.0(81/898) 14.3(17/119) 0.071 1-yearmortality 11.4(194/1706) 10.5(162/1541) 19.4(32/165) 0.002 Overallmortality 14.0(321/2300) 12.5(261/2090) 28.8(60/208) <0.001
AKIN:acutekidneyinjury;AMI:acutemyocardialinfarction;AR:aorticregurgitation;ECC:extracorporealcirculation;NYHA:NewYork HeartAssociation;TIA:transientischemicattack;ViV:valve-in-valve.
Note:Dataarepresentedasmean±standarddeviationorn(%).
Duringthefirstyearof follow-up,all-causemortalityrate was11.4%,andwassignificantlylowerfor TFpatients(TF 10.5%vs.non-TF19.4%,p=0.002).Clinically,themajorityof patientsimproved theirfunctionalcapacity, witha reduc- tioninthepercentageofpatientsinNYHAclassIIIandIVof 59.4%and8.8%at baselineto4.5%and1.3%at follow-up, respectively(p<0.05)(Figure4).
Thirty-dayandone-yearpredictorsofmortality Following adjustments for gender, age, previous medi- cal history, surgical risk scores and type of valve, the
independentpredictorsof 30-dayall-causemortalitywere PAD(HR2.24,CI95%1.41-3.53,p<0.001),previousPCI(HR 1.68,CI95%1.07-2.63,p=0.024),LVdysfunction(LVEF<50%:
HR1.67,CI95%1.07-2.63,p=0.021)andaworsefunctional statusat baseline(NYHAclassIII-IV:HR1.98,95%CI1.13- 3.47,p=0.017)(Table4).Atone-yearfollow-up,asshownin Table5,predictors ofmortalitywereNYHAclassIII-IV(HR 2.11,95%CI 1.06-4.16),non-transfemoralroute (HR1.76, 95%CI1.01-3.09,p=0.046),occurrence oflife-threatening bleeding(HR2.44, 95% CI1.09-5.47,p=0.030).There was alsoa trendwithregard tochronic obstructivepulmonary disease (HR 1.68, 95% CI 0.97-2.93, p=0.063).Valve type didnotinfluencemortality.
Figure3 Evolutionin30-daymortalityfrom2011totheendof2018(datapresentedinmortalityrateperyear).
Figure4 ComparisonbetweenNewYorkHeartAssociationfunctionalclassatbaselineandfollow-up(p<0.05forcomparison).
Kaplan-Meiersurvivalanalysisofthefirstyearoffollow- upalsoshowsdecreasedsurvivalofpatientswhounderwent non-transfemoralTAVI(log-rankp<0.001)andthosewithhig- hersurgicalrisk(EuroS-II>5%)(log-rankp<0.001).Therewas alsoatrendofdecreasedsurvivalinolderpatients(log-rank p=0.053)(Figure5,A-E).
Discussion
SinceitsintroductioninPortugalin2007,thenumberofTAVI procedureshasgrownexponentially,18similartothepattern seen following theadoptionof thistechnologyin Western countries.23
Table4 Predictorsof30-daymortality.
Variable Univariate,HR(CI95%) pvalue Multivariateanalysis,HR(CI95%) pvalue
PAD 2.447(1.584-3.780) <0.001 2.235(1.414-3.534) <0.001
Nontransfemoralroute 2.178(1.338-3.546) 0.002
PCI 1.957(1.291-2.965) 0.002 1.677(1.070-2.629) 0.024
LVEF<50% 1.881(1.238-2.858) 0.003 1.667(1.079-2.578) 0.021
NYHAIII-IVpreprocedure 1.851(1.132-3.026) 0.014 1.982(1.131-3.474) 0.017
CAD 1.500(1.000-2.249) 0.050
Atrialfibrillation 1.237(0.794-1.927) 0.346
Age 1.023(0.994-1.054) 0.118
ViV 0.372(0.092-1.506) 0.166
Otheradjustedvariables:Aorticvalvearea,meangradient,coronaryarterybypassgraft,chronicobstructivelungdisease,chronickidney disease,EuroS-II,SocietyofThoracicSurgerymortalityriskscore,typeofvalve(self-expandablevalveandballoon-expandablevalve), sizeofprosthesis,permanentpacemakerneed,moderateorsevereparavalvularaorticleak.
Abbreviations:CAD:coronaryarterydisease;CI:confidenceinterval;HR:hazardratio;LVEF:leftventricularejectionfraction;NYHA:
NewYorkHeartAssociation;PAD:peripheralarterydisease;PCI:percutaneouscoronaryintervention;ViV:valve-in-valve.
Table5 Predictorsof1-yearmortality.
Variable Univariate,HR(CI95%) pvalue Multivariateanalysis,HR(CI95%) pvalue
Age 1.021(1.000-1.043) 0.05
Non-TFroute 1.675(1.143-2.453) 0.008 1.769(1.011-3.096) 0.046
NYHAIII-IVpreprocedure 2.051(1.397-3.011) <0.001 2.110(1.068-4.169) 0.032 Atrialfibrillation 1.839(1.344-2.516) <0.001
ViV 0.734(0.345-1.563) 0.423
LVEF<50% 1.208(0.972-1.673) 0.255
CAD 1.005(0.748-1.350) 0.976
COPD 1.665(1.213-2.286) 0.002 1.688(0.971-2.933) 0.063
PAD 1.387(0.961-2.001) 0.081
EuroS-II 1.016(0.992-1.039) 0.187
STSriskscoremortality 1.041(1.020-1.060) <0.001 Permanentpacemaker 1.147(0.800-1.644) 0.454
Life-threateningbleeding 2.848(1.514-5.355) 0.001 2.443(1.091-5.472) 0.030 AKIN>=stage2 3.149(1.746-5.681) <0.001
Vascularmajorcomplication 2.083(1.242-3.495) 0.005 Moderate-severeAR 2.376(1.312-4.301) 0.004
Otheradjustedvariables:Aorticvalvearea,meangradient,coronaryarterybypassgraft,chronicobstructivelungdisease,chronickidney disease,EuroS-II,SocietyofThoracicSurgerymortalityriskscore,typeofvalve(self-expandablevalveandballoon-expandablevalve), sizeofprosthesis,permanentpacemakerneed,moderateorsevereparavalvularaorticleak.
Abbreviations:AKIN:AcuteKidneyInjuryNetwork;AR:aorticregurgitation;CAD:coronaryarterydisease;COPD:chronicobstructive pulmonarydisease;EuroS-II:EuroScoreII;HR:hazardratio;LVEF:leftventricularejectionfraction;Non-TF:non-transfemoral;NYHA:
NewYorkHeartAssociation;PAD:peripheralarterydisease;PCI:percutaneouscoronaryintervention;STS:SocietyofThoracicSurgeons.
Improved survival rates after TAVI, with a significant decrease in periprocedural mortality, reflect innovative devicetechnology,butalsotheincreaseduseoftransfemo- ralTAVI,learningcurvesandoptimizedpatientselection.24 Theincreasingavailabilityofsmallerdelivery systemsand operatorexperiencehavebroughtaboutanincreaseinthe numberofpatientstreatedwithaTFapproach,andappro- ximately90%ofourpatientswereeffectivelytreatedusing TFaccess,apercentageslightlyabovethe80%reportedin FRANCE TAVI, witha corresponding decline in transapical access.25 The predominant useof SEVin ourregistry may have,ontheonehand,been influencedbythesteadyrise inTFTAVI,andontheotheraccordingtotheiravailability inPortugal.As expected,balloon-expandablevalves(BEV) werethemainvalvesystemusedinTATAVI.Nevertheless,it
isnoteworthytomentionthatcurrentlythereisnotenough evidence toclaim the superiority of one device over the other.26 Valveselectionshouldbetailoredaccordingtothe patient’s clinical and anatomicalcharacteristics, which is standardofpracticeat thedifferentPortugueseTAVIcen- ters.
Evidence showing that ViV procedures for prosthesis dysfunction have favorable outcomes14 also contribu- ted to the increasing number of these procedures in Portugal.
Approximately50%ofpatientswereconsideredhighrisk forsurgeryfollowingaheartteamassessment.Thiswasnot exclusivelydefinedaccording toconventionalsurgical risk scores,infact,inourcohortthemeanEuroS-IIwasinthe intermediatestrata. Otherfactors,suchasadvancedage,
Figure5 Cumulativesurvivalcurvesaccordingtoaccessroute(A),EuroS-IIstrata(B),timeframesinyearsofnationalexperience (C),typeofvalve(D),agestrata(E).*p<0.05.
associatedcomorbiditiesandfrailtyweredeterminingfac- tors, although the latter has not yet been fullyreflected intheregistry.Evidenceshowsthatdecisionmakinginval- vularheartdiseaseinvolves acomplexalgorithmtodefine therisk-benefitratio.Currentlythereisnosinglevalidated
specific TAVIriskscore,suggesting thatthebestapproach shouldbebasedonthecombinationoftheexistingsurgical scorestogetherwithfrailtyparametersandthepresenceof specificorganfailure.ThemaingoalshouldbetoavoidTAVI futility.21,22
Ouranalysisrevealed an incidenceof strokeafter TAVI of4.6%,ofwhichalmosthalfweredisabling.Althoughthis resultisbelowtheincidenceofstrokereportedinthePART- NERcohorts Aand B (5.5and 6.7% respectively),27,28 and similartotheincidenceofperi-operative strokefollowing surgical AVR in elderly patients, which ranges from 3 to 7%,29thisisstillamatterofconcernandanareaofimpro- vement that needs to be addressed. Embolic protection devices (EPD)are notused by default at Portuguese TAVI centers, however, sofar, although published results show thatEPDmayhelpreducethevolumeandsizeofperiproce- duralsilentischemicbrainlesionsidentifiedonMRI,itdid notreducetheincidenceofnewlesionsandclinicallysig- nificantneurologicalevents.30,31The clinicalimpactofEPD needsfurtherinvestigationinrandomizedtrialspriortoits widespreaduse.
Thepacemakerimplantationrateinourregistrywas19%
intheoverallcohort,withasignificantdifferencebetween TF19,5%andTA10.7%approach.Thisattributedtothedif- ferencesbetweenthepredominantprosthesistypeusedin each of theaccessroutes cohorts,SEVand BEV,respecti- vely.Arecentmeta-analysisofdifferentregistriesshowed pacemakers were a requirement in 8% of SapienTFs and 22%forCoreValve,15inline withourdata,buthigherthan thosereportedin thePARTNERtrials,probablybecauseof thehigheranatomiccomplexityofreal-worldpatients.
Ourregistryreportedanoverall7.4%incidenceofmode- rate paravalvular leak (>=2), which is similar to other Europeanregistriesandexplainedbytheoperatorlearning curves,standardization oftechniques and newgeneration deviceswithextendedsealingskirts.32
Concerning hardoutcomes,in thePARTNERstudy,mor- tality was3.4and 5%in cohorts A andB,respectively.6,33 Different registries present wide variability in mortality ranging from 5.4 to 12.4%, however, they compare diffe- rent patients risk profiles, types of prosthesis and access routes.29,34---36Inourglobalcohort,30-daymortalityhasbeen decreasing sincethe beginningof the TAVIprogram, from 14.1%in2011toapproximately4%inthelast3years,which isinlineorslightlybelowotherreportedregistries.14,25Itis probablyattributabletothefactthatalthough ourcohort hadanadvancedmeanageof81years,themeanriskprofile wasintermediate.Thereis,infact,agrowingbodyofevi- dence that supports the extension of TAVI toincreasingly lower risk patients, consistently demonstrating its nonin- feriority in comparisonwith conventional surgery.8,11 It is also important to highlight that the low mortality of our cohortevidencesthatmostofthefatalitieswereunrelated toperiproceduralcomplications,whichhadlowprevalence.
Amajorconclusionfromthesedataisthatourfocusshould beonbetterpredictionofrisksandbenefitsoftheprocedure andappropriatepatientselection.
Regardingthenon-TFapproach,andparticularlytheTA, when comparing with TF route, the former was associa- ted with a lower 30-day safety composite outcome and higher mortalityin our registry, similarto whathas been reportedin other studies.33,37---39 The explanationis multi- factorial,butclearlyTApatientshadincreasedprevalence ofsignificantco-morbiditiesandahigherriskprofile.Asig- nificant contributionmight be derivedfromthe increased rate ofprocedural complications, suchaslife-threatening
andmajorbleeding,perioperativemyocardialinfarctionand cardiactamponade.
Based on VARC 2 criteria, the predictors for 30-day all-cause mortality were PAD, significant CAD with pre- viousPCI,depressedleftventricularejectionfraction(LVEF) and an advanced heart failure (HF) clinical status. Bue- llesfeld et al. showed the patient’s baseline functional statetobeanindependentpredictorofhospitalmortality40 andtheItalianregistryindicatedthatan ejectionfraction under 40%, diabetes, prior valvuloplasty and procedure- related complications were associated with worse short termprognosis.29 The Ibero-American registryalsounder- linedtheimportanceofpost-TAVIcomplicationsandlogistic EuroS-IIaspredictors ofmortality at 30days.16 Also,in a recent meta-analysisstage>=2 AKI wasa strong predictor for30-day mortality,although interestinglymany patients sawanimprovementinrenalfunctionafterTAVIratherthan kidneyinjuryduetorenaldecongestionandincreasedper- fusion. Preprocedural pro-brain natriuretic peptide levels werealsoa strong predictorof 30-day andmidterm mor- tality.This is believed toberelated toadvancedHF with systolicanddiastolicdysfunction.Likewise,baselineclinical status,representedbypriorhospitalizationsandpreproce- dural LVEF<=30%, had a significant impact on short term mortality.41
As independent predictors of one-year all-cause mor- tality we identified patient characteristics before the procedure, such as pre-procedural NYHA class III/IV and chronicobstructivepulmonarydisease,andproceduralfac- tors such as the non-NF access route, which may be a surrogate for significant PAD. These results are corrobo- rated by other registries and trials, showing also that some comorbidities are related to worse long-term pro- gnosis, such as advanced age,17 frailty,35 male gender, end-stagerenal disease,34 porcelain aorta,35 low gradient aortic stenosis,42 reduced LVEF,17 NYHA class,36 mitral insufficiency grade>=2+,42 residual postintervention aor- tic regurgitation,6 intraprocedural conversion to surgery, peri-intervention stroke,39 or postintervention pulmonary embolism.42
In our registry there was a sub-optimal percentage of patientslosttofollow-upatone-year(22%),althoughaccep- tablewhencomparedtootherobservationalstudies.43,44,45 This can be explained by the nature of this prospective nationwide real-world registry that involves participating centerswithvariousdifferencesrelatingtothevolumeof procedures,follow-upapproachanddataregistration.Also, comparedtootherEuropeancountries,thesmallnumberof 0.346to0.7TAVIcenterspermillioninhabitantsintheregis- tryhistory,canlimitpatientaccessibilitytothosehospital centersbecauseofdistance,whichisaknownpredictorof losstofollow-up.47 Itisworthmentioningthatanautoma- ticregistration of a patient’s vitalstatus in the RNCI-VaP couldbeaneffectivewayofstrengtheningthequalityand completenessofdatainthefuture.
Despite the acknowledged potential bias, the findings fromthis landmark study should help us to select appro- priate candidates for TAVI accurately,with the main goal ofreferringpatientsinwhomtreatmentbenefitoutweighs therisk,thusimprovingclinicalbenefitandavoidingfutility.
Nevertheless,abalanceneedstobeachievedbecauseeven
inhighriskpatientswithseveralcomorbidities,health-rela- tedimprovementsinqualityoflifeandreducedcongestive HFhospitalizationsshouldbetakeninaccount.
Study limitations
The data from the RNCI-VaPregistry is self-reported and consequently subject toinclusion bias. Nevertheless, this registryisrepresentativeofthecurrentstandardsofprac- ticeinPortugal,becauseitobtaineddataon96.5%ofthe totalnumberofimplantedvalves.
For some relevant variables we could not obtain data from all patients, which is a limitation inherent to the characteristics of a national registrythat depends onthe voluntary participation of the investigators, potentially causingselectionbias.Eventswerereportedbytheinvesti- gatorsandwerenotindependentlyreviewed,sowecannot ruleoutthepossibilityofunderoroverreportingofevents.
Also,theRNCI-VaPdoesnotcurrentlyhaveeitherinternalor externalauditing.Assuch,definitiveconclusionsregarding causeandeffectcannotbedrawnfromthisstudy.
Althoughweacknowledgetheselimitations,theinvesti- gatorsoftheRNCI-VaPconsiderthisregistrytobeessential toensure the safe and successful clinical applicability of theconstantlyevolvingtranscatheter aorticvalvetechno- logyinPortugal.Thispaperincludesthefirstpublisheddata onpatientstreatedwithTAVIinPortugal.Itisnoteworthy thatthesuccessandcomplicationratesweresimilartothose reportedbyotherEuropeancountries’registries.32
Conclusions
TheRNCI-VaPshowsthatTAVIhasbeen implementedwith great success in Portugal. In this real-world all-comers all-centersregistry ofpatients who underwentTAVI (both conventionaland ViV),the procedure wassafe andeffec- tive. Characteristics related to the access route, patient comorbiditiesandbaseline clinicalstatus adverselyaffec- tedlong-term prognosis and shouldtherefore be takenin considerationwhenselectingpatientsfortheprocedure.
Thesystematicassessmentandreportingofpatientswho underwentTAVIinPortugalisofparamountimportance,eli- citingapragmaticassessmentofTAVIresultsinthedifferent centersandstimulatingscientificmulticentricproduction.
Author contributions
CG,PCFandRCT:studyconcept,designanddraftingofthe manuscript;CG,PCF, SM,RCT: analysisandinterpretation ofdata;PB,PCS,LP,JCS,JB,MA,VGR,BS,JB,EIO,DC,JS:
criticalrevisionofthemanuscriptforimportantintellectual content.
Disclosure statement
Theauthorsreportnofinancialrelationshipsorconflictsof interestregardingthecontentherein.
Conflicts of interest
Theauthorshavenoconflictsofinteresttodeclare.
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