Infective Endocarditis: Surgical Management and Prognostic Predictors

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www.revportcardiol.org

Revista

Portuguesa

de

Cardiologia

Portuguese

Journal

of

Cardiology

ORIGINAL

ARTICLE

Infective

endocarditis:

Surgical

management

and

prognostic

predictors

Rita

Ilhão

Moreira

a,∗

,

Madalena

Coutinho

Cruz

a

,

Luísa

Moura

Branco

a

,

Ana

Galrinho

a

_,

_Luís

_Coutinho

_Miranda

b

_,

_José

_Fragata

b

_,

_Rui

_Cruz

_Ferreira

a

a_Servic_¸o_de_Cardiologia,_Hospital_de_Santa_Marta,_Centro_Hospitalar_de_Lisboa_Central,_Lisboa,_Portugal

b_Servic_¸o_de_Cirurgia_{Cardiotorácica,}_Hospital_de_Santa_Marta,_Centro_Hospitalar_de_Lisboa_Central,_Lisboa,_Portugal

Received16January2017;accepted5August2017 Availableonline3May2018

KEYWORDS Infective endocarditis; Surgery; Prognosis Abstract

IntroductionandAim:Infectiveendocarditis(IE)isassociatedwithhighmorbidityand mortal-ity.Itisimportanttodeterminewhichfactorsincrease theriskofpooroutcomeinorderto enableearlydetectionandaggressivetreatment,includingsurgery.Theaimofourstudywas toidentifyfactorspredictingcomplicationsandin-hospitalmortalityinpatientswithIEandto analyzeconditionspredisposingtosurgeryanditsoutcome.

Methods:WeperformedaretrospectivestudyincludingpatientswithIEwhounderwent trans-esophagealechocardiographyinatertiaryhospitalcenter(2006-2014).

Results:Atotalof233patientswereanalyzed(69.1%male;meanage63.4±15.2years;mean follow-up28.4±30.7months).Thecomplicationratewas56.6%andin-hospitalmortalitywas 16.3%.Independentpredictorsofmortalitywerechronicobstructivepulmonarydisease (OR 4.89;CI1.36-17.63;p=0.015),clinicalcoursecomplicatedbycerebralembolism(OR9.38;CI 3.26-26.96;p<0.001),andIEduetoStaphylococcusspp.(OR3.78;CI1.32-10.85;p=0.014)and non-HACEKGram-negativebacilli(OR12.85;CI2.61-63.23;p=0.002).Surgerywasperformed in36.9%.Thisgrouphadhigherpercentagesofmales,youngerpatients,aorticvalveIE,large vegetations,perivalvularextension,severevalvularregurgitationandheartfailure.Inpatients withsurgicalindication(n=133),thosewhounderwentsurgeryhadlowerin-hospitalmortality (15.5%vs.32.6%,p=0.028)andbetterlong-termsurvival(log-rankp=0.029).

Conclusion:TheresultsofthisstudymayhelptoidentifyIEpatientswhoareatincreasedrisk ofworseoutcome,offeringtheopportunitytochangethecourseofthediseaseandtoimprove prognosiswithearlierandmoreaggressiveintervention.

∗_{Corresponding}_author.

E-mailaddress:[email protected](R.IlhãoMoreira).

https://doi.org/10.1016/j.repc.2017.08.007

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PALAVRAS-CHAVE

Endocardite infeciosa; Cirurgia; Prognóstico

Endocarditeinfeciosa:tratamentocirúrgicoepreditoresprognósticos Resumo

Introduçãoeobjetivo: A endocardite infeciosa (EI) está a associada a elevada morbi-mortalidade. Torna-seimportantedefinir osfatores queaumentam orisco deum desfecho desfavoráveldemodoatratardeumaformaprecoceeagressiva,incluindotratamento cirúr-gico.Oobjetivodesteestudofoiidentificarfatorespreditivosdecomplicaçõesemortalidade intra-hospitalaremdoentescomEIeanalisarascondiçõespredisponentesparacirurgiaeoseu resultado.

Métodos: EstudoretrospetivoqueincluiudoentescomEI queﬁzeramecocardiograma trans-esofágiconumcentrohospitalarterciário(2006-2014).

Resultados: Foram avaliados 233 pacientes (69,1% homens; idade média 63,4±15,2 anos; follow-up médio 28,4±30,7 meses). A taxa de complicações foi 56,6% e mortalidade intra-hospitalar 16,3%. Preditores independentes de mortalidade foram doença pulmonar obstrutivacrónica(OR4,89;CI1,36-17,63;p=0,015),emboliacerebral(OR9,38;CI3,26-26,96; p<0,001) e EI por Staphylococcus spp. (OR 3,78; CI 1,32-10,85; p=0,014) e bacilos Gram-negativosnãoHACEK(OR12,85;CI2,61-63,23;p=0,002).Fez-secirurgiaem36,9%.Essegrupo apresentavamaiorpercentagemdehomens,jovens,EIdaválvulaaórtica,vegetaçõesgrandes, extensão perivalvular,regurgitação valvular grave einsuficiência cardíaca.No subgrupo de doentescomindicaçãocirúrgica(133),aquelessubmetidosacirurgiativeramumamortalidade intra-hospitalarmenor(15,5%versus32,6%,p=0,028)emelhorsobrevidaemlongoprazo (log-rankp=0,029).

Conclusão:OsresultadosdesteestudopodemajudaraidentificardoentescomEIque apresen-tammaiorriscodeumdesfechodesfavorável,permitemalterarocursodadoençaemelhorar oprognósticoatravésdeumaintervençãomaisprecoceeagressiva.

Introduction

The challenges associated withinfective endocarditis (IE) aregreaterthanever.The patientsaffectedareolderand sickerthaninthepast,andoftenhavemanycomorbidities.1

The role of surgeryin active IEhas expanded progres-sively,andnowadaysalmosthalfofpatientswithIEundergo surgery.2 _There_are_three_main_indications: _valve

dysfunc-tionleadingtoheartfailure,uncontrolledinfection,andfor preventionofembolism.

Despiteimprovementsinmanagement,IEisstill associ-atedwithhighmortalityandseverecomplications.Prognosis is inﬂuenced by many factors and early identiﬁcation of high-riskpatientsmaychangethecourseofthediseaseand improveoutcome.

The aimofthisstudywastoidentifyfactorspredicting in-hospitalmortalityandcomplicationsandtoanalyze con-ditionspredisposingtosurgicaltherapyanditsoutcomein asingletertiaryhospitalwithfacilitiesforsurgicaltherapy.

Methods

Studypopulation

All patients who underwent transesophageal echocardio-graphy in a tertiary hospital center with cardiac surgery facilities due to suspicion of IE and diagnosed with IE

between 2006 and 2014 were recorded in a uniform database.

The study included casesfrom ourhospital,as well as fromcommunityandreferralhospitals.

Criteriaanddeﬁnitions

Patientswere included iftheymetcriteriafor deﬁnite or possible IE(if considered and treated as endocarditis) by the modiﬁed Dukecriteria.3 _Patients_with_cardiac

device-relatedIEwereexcluded.

In-hospital mortality was deﬁned as all in-hospital deaths, includingpatients transferredtoother acutecare facilities.

The complications analyzed were heart failure, perivalvular extension, and cerebral and peripheral embolism. Perivalvular extension was deﬁned by the presenceofabscesses,pseudoaneurysmsorﬁstulae.

Regarding timing, prosthetic valve endocarditis was deﬁnedasearlyifitoccurredwithin12monthsofprevious surgery. Surgicaltherapywasdeﬁnedasearlyifthe inter-ventionwasperformedwithinsevendaysofdiagnosis,and lateifperformedthereafter.

Indicationsforsurgerywereinaccordancewiththe cur-rentEuropeanSocietyofCardiologyguidelines.4_Follow-up

datawereobtainedbyreviewofmedicalrecords,outpatient clinicalvisits,andtelephonecontact.

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Ethicalandhospitalpermissionswereobtainedfromthe appropriatelocalauthorities.

Statisticalanalysis

Descriptiveresultsareexpressedasmeans±standard devi-ationormedians(interquartilerange).Categoricalvariables areexpressedasabsolutenumbersandproportions. Inferen-tialstatisticsusingparametricornonparametrictestswere used asappropriate for the type of data. The chi-square test or Fisher’sexact test were used toanalyze all cate-goricalvariables.The Student’sttestwasusedtoanalyze continuousvariableswithanormaldistribution.

Statistical signiﬁcance was established at a two-tailed levelof<5%.Factorsassociatedwithmortalityonunivariate analysiswereenteredintoamultivariatestepwiselogistic regression model. The cumulative mortalityrate was cal-culated usingtheKaplan-Meiermethod.Allanalyses were performed withSPSSfor Windows,version22.0(IBMSPSS, Inc.,Chicago,IL,USA).

Results

Intotal,233patientswerediagnosedwithIEduringthestudy period,ofwhom108(46.4%)caseswereconsideredas deﬁ-niteand125(53.6%)aspossibleIEaccordingtothemodiﬁed Dukecriteria. The meanagewas63.4±15.2years(range: 13-89)and161weremale.

Baseline characteristics, comorbidities, echocardio-graphic ﬁndingsandisolatedmicroorganismsareshown in

Table 1. A substantial proportion of the population were affectedbycomorbidities,themostfrequentbeingchronic heartfailureanddiabetes(32.2%and26.1%,respectively), whilethemostcommonpredisposingconditionwasthe pres-enceofaprostheticvalve,with22.7%beingconsideredearly prostheticvalveIE.

The aortic valve wasmost often affected, in 55.7% of cases,followed bythemitralvalve, with7.7%of patients having both aortic and mitral valve involvement. Though right-sidedIEwasmorefrequentinintravenousdrugusers (p=0.017),left-sidedIEwasstillmoreprevalentinthisgroup (77.8%vs.22.2%).Allpatientsunderwenttransthoracicand transesophageal echocardiographyandmorethan 90%had evidenceofvegetations,whichwerelargerthan10mmin 48.5%.Abscesswasthemostcommonparavalvular compli-cation,followedbypseudoaneurysmandﬁstula.Regarding isolatedmicroorganisms,Staphylococcusspp.wasthemost frequentetiologicalagent(27.9%),followedby Streptococ-cusspp.Bloodculture-negativeIEwaspresentinmorethan athirdofthepatients.

Mortalityandcomplications

Thirty-eightpatientsdiedduring hospitalstay (16.3%)and 30-day mortalitywas22.7%. Theresults of univariateand multivariate analysis for in-hospital and 30-day mortal-ity are presented in Table 2 and Supplementary Table 1 (Appendix).Inmultivariateanalysis,independentpredictors ofin-hospitalmortalitywerechronicobstructivepulmonary disease (COPD), clinical course complicated by cerebral

Table1 Baseline clinical characteristicsof the patients (n=233).

Meanage,years 63.4±15.2

Malegender 161(69.1%)

Comorbidities,n(%)

Diabetes 61(26.1%)

Chronicrenalfailure 37(15.8%)

COPD 22(9.4%)

Chronichepaticfailure 15(6.4%)

Chronicheartfailure 75(32.2%)

Anemia 50(21.4%)

Coloncancer 17(7.3%)

HIVpositive 6(2.6%)

Congenitalcardiomyopathy 15(6.4%)

Previousnativevalvulopathy 39(16.7%)

PreviousIE 25(10.7%) IVdruguser 18(7.7%) ProstheticvalveIE 92(39.4%) Affectedvalve,n(%) Aortic 130(55.7%) Mitral 89(38.2%) Tricuspid 18(7.7%) Pulmonary 2(0.8%) Echocardiographicﬁndings,n(%) Vegetation>10mm 113(48.5%) Abscess 30(12.9%) Pseudoaneurysm 16(6.9%) Fistula 4(1.7%)

Severevalvularregurgitation 50(21.5%)

Isolatedmicroorganisms,n(%)

Staphylococcusspp. 65(27.9%)

Streptococcusspp. 38(16.3%)

Non-HACEKGramnegative 14(6.0%)

Negative 85(36.4%)

COPD: chronic obstructive pulmonary disease; HIV: human immunodeﬁciency virus; IE: infective endocarditis; IV: intra-venous.

embolismandIEduetoStaphylococcusspp.andnon-HACEK Gram-negativebacilli,thelatterbeingthestrongest predic-tor.

Overall,the complicationratewas56.6%andthemost frequent complications were (in descending order): heart failure (37.3%); perivalvular extension (25.8%); cerebral embolism(23.2%);andperipheralembolism(13.0%).In mul-tivariateanalysis,thevariablessigniﬁcantlyassociatedwith eachcomplicationwere:forheartfailure,previoushistory ofCOPD(oddsratio[OR]3.86;conﬁdenceinterval[CI] 1.16-12.81;p=0.028)andpresenceofvalvularregurgitation(OR 2.74;CI1.26-5.96;p=0.011);forperivalvularextension,IE affectingtheaorticvalve(OR6.63;CI2.34-18.76;p<0.001) and prosthetic valve endocarditis (OR 2.83; IC 1.21-6.61; p=0.016); for cerebral embolism, IE affecting the mitral valve (OR 2.38; IC 1.12-5.04; p=0.024); and for periph-eralembolism,Staphylococcusspp.(OR3.22;CI1.21-8.59; p=0.019) and age under 65 years (OR 3.34; CI 1.25-8.94; p=0.017).

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Table2 Univariateandmultivariateanalysisofin-hospitalmortality.

Variable In-hospitalmortality

Univariateanalysis Multivariateanalysis

OR(CI) p OR(CI) p

Age 1.003(0.980-1.025) 0.826

Malegender 1.199(0.574-2.504) 0.630

Comorbidities

Diabetes 0.804(0.342-1.890 0.617

Chronicrenalfailure 2.077(0.875-4.929) 0.097

COPD 3.852(1.460-0.160) 0.006 4.876(1.354-17.561) 0.002

Chronichepaticfailure 0.859(0.184-4.016) 0.846

Chronicheartfailure 1.996(0.955-4.172) 0.066

Coloncancer 2.522(0.819-7.762) 0.107 HIVpositive 1.309(0.142-2.072) 0.812 Previousvalvulopathy 2.836(1.202-6.693) 0.017 2.401(0.773-7.459) 0.132 IVdruguser 0.940(0.198-4.456) 0.938 ProstheticIE 1.746(0.868-3.516) 0.118 Vegetation>10mm 1.523(0.660-3.516) 0.324 Isolatedmicroorganisms Staphylococcusspp. 3.046(1.436-6.460) 0.004 3.760(1.310-10.797) 0.014 Streptococcusspp. 0.121(0.016-0.918) 0.041 Enterococcusspp. 1.325(0.412-4.262) 0.637

Non-HACEKGramnegative 3.990(1.185-3.431) 0.025 12.759(2.592-62.806) 0.002

Fungi 4.941(0.302-0.948) 0.263 Negative 0.315(0.124-0.802) 0.150 Complications Heartfailure 1.714(0.771-3.811) 0.186 Perivalvularextension 2.078(0.925-4.664) 0.076 Cerebralembolism 4.898(2.125-1.292) <0.001 9.321(3.241-26.808) <0.001 Peripheralembolism 1.986(0.713-5.529) 0.189 Therapy Surgery(vs.nosurgery) 0.938(0.450-1.958) 0.865

Earlysurgery(vs.late) 2.343(0.694-7.906) 0.170

CI:conﬁdenceinterval;COPD:chronicobstructivepulmonarydisease;HIV:humanimmunodeﬁciencyvirus;IE:infectiveendocarditis; OR:oddsratio;IV:intravenous.

Surgicalmanagementofinfectiveendocarditis

Valvesurgerywasperformed in 86patients (36.9%),early in 44.2% of cases (Figure 1). The main indications for surgerywereheartfailure(50.0%)anduncontrolled infec-tion(46.8%),followedbypreventionofembolism(15.6%).

Comparing patients who underwent surgical treatment with those whoreceived only medical therapy (Table 3), theformerweremorelikelytobemale,youngerand intra-venousdrugusers.AorticvalveIEwasmorefrequentinthe surgicalgroup,buttherewerenodifferencesregarding pros-theticvalveendocarditis. Surgical therapy wasassociated with the presence of perivalvular abscesses, vegetations >10mmandseverevalvularregurgitation.Heartfailureand perivalvularextension weremore common in thesurgical group,withoutdifferenceinemboliccomplications.

When theoverallcohortwasanalyzed,surgerywasnot associated with decreased in-hospital mortality (15.5% in thesurgicalgroupvs.16.3%inthemedicalgroup,p=0.865).

Total 233 (100%) Surgical indication 133 (57%) Medical therapy 147 (63%) Surgical therapy 86 (37%)

(64% of patients with surgical indication)

Early surgery 38 (44%)

Late surgery 48 (56%)

Figure 1 Flowchart of the destination therapy of the patients.

However,consideringonlythesubgroupofpatientswith sur-gical indicationaccordingtotheguidelines(133patients),

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Table3 Clinicalcharacteristicsofpatientstreatedwithsurgeryvs.nosurgery.

Variable Surgery(n=86) Nosurgery(n=147) p

Meanage,years _59.4±15.3 _65.4±15.1 0.001

Malegender 78.2% 64.4% 0.027

Comorbidities

Diabetes 25.6% 26.9% 0.833

Chronicrenalfailure 11.6% 19.4% 0.128

COPD 12.8% 7.5% 0.189

Chronichepaticfailure 1.2% 9.7% 0.011

Chronicheartfailure 38.4% 28.4% 0.121

Anemia 18.6% 23.1% 0.424

Coloncancer 3.4% 9.6% 0.082

HIVpositive 2.3% 3.0% 0.769

Congenitalcardiomyopathy 8.0% 5.5% 0.440

Previousnativevalvulopathy 21.7% 13.4% 0.112

PreviousIE 10.4% 11.3% 0.842 IVdruguser 14.1% 3.6% 0.010 ProstheticvalveIE 42.5% 37.6% 0.453 Affectedvalve Aortic 64.4% 51.0% 0.046 Mitral 31.0% 42.3% 0.086 Tricuspid 9.2% 6.7% 0.488 Pulmonary 1.1% 0.7% 0.699 Echocardiographicﬁndings Vegetation>10mm 62.3% 40.7% 0.004 Abscess 19.5% 9.4% 0.026

Severevalvularregurgitation 44.4% 7.9% <0.001

Isolatedmicroorganisms

Staphylococcusspp. 32.5% 24.6% 0.217

Streptococcusspp. 15.0% 17.5% 0.643

Non-HACEKGramnegative 7.5% 4.8% 0.413

Negative 32.9% 39.2% 0.364 Complications Heartfailure 60.8% 22.1% <0.001 Perivalvularextension 39.2% 18.0% 0.001 Cerebralembolism 20.8% 23.7% 0.651 Peripheralembolism 11.3% 15.0% 0.586

COPD:chronicobstructivepulmonarydisease;HIV:humanimmunodeﬁciencyvirus;IE:infectiveendocarditis;IV:intravenous.

surgicaltreatmentwasassociatedwithasigniﬁcant reduc-tioninin-hospitalmortality(15.5%vs.32.6%,p=0.028).

The mean follow-up was 28.4±30.7 months and was achievedin95.3%ofthepopulation.Seventypatientsdied during the follow-up period, with one-year mortality of 33.0%andﬁve-yearmortalityof42.9%.

Therewerenodifferencesbetweenthegroupsregarding all-causemortalityintheoverallcohort(log-rankp=0.241) (Figure 2A). In patients with surgical indication, surgical treatmentcontinuedtohaveabeneﬁcialeffect,withbetter long-termsurvival(log-rankp=0.029)(Figure2B).

Regardingtimingoftheprocedure,earlysurgerywasnot associated with increased mortality compared with later surgery(OR2.34,CI0.69-7.91,p=0.176).

Discussion

The ﬁndings of the present study can be summarized as follows: (i) in-hospital mortality from IE was >15% and morethan half ofthe patientshad acomplicated clinical course;(ii)COPD,cerebralembolismandIEdueto Staphy-lococcus spp. and non-HACEK Gram-negative bacilli were independentpredictorsofworsein-hospitaloutcomes;and (iii)surgerywasassociatedwithlowerin-hospitaland long-termmortalityinpatientswithsurgicalindication.

The characteristics of our population were similar to those described in other studies, including those in Por-tuguese cohorts.5 _In _our _study _the _patients’ _mean _age

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A

Overall population 1.0 p=0.241 p=0.029 Surgery No surgery Surgery No surgery 0.8 Cum ulativ e sur viv al Cum ulativ e sur viv al 0.6 0.4 0.2 0.0 1.0 0.8 0.6 0.4 0.2 0.0 0.0 Number at risk Surgery 86 147 119 64 44 99 24 79 59 15 7 39 86 47 30 64 44 15 9 24 15 5 2 7 No surgery Number at risk Surgery No surgery 20.0

Follow-up (months) Follow-up (months)

40.0 60.0 80.0 100.0 120.0 0.0 20.0 40.0 60.0 80.0 100.0 120.0

Patients with surgical indication

B

Figure2 Kaplan-Meierestimateofall-causemortality.(A)Intheoverallcohort, theprobabilityofall-causemortalitydidnot differsigniﬁcantlybetween patientswho underwentsurgeryandthosetreatedwithmedicaltherapyonly; (B)inpatients with surgicalindication,surgicaltreatmentledtobetterlong-termsurvival.

descriptions,6 _but _in_agreement _with_more_recent _series.1

Overall,themostcommonlyobservedcomorbiditiesinour cohortwerechronicheartfailureanddiabetes (32.2%and 26.1%,respectively).Inalargemultinationalobservational study,diabeteswasthemainunderlyingcondition(16.2%).1

The higher prevalence of comorbidities observed in our study,includingchronicheart failure,couldbeduetothe factthat somepatients hadbeen referred tooursurgical hospital,andsothepercentageof sickerpatients maybe overestimated.

In agreementwithrecentstudies,1,7,8_there_was_a

pre-dominanceofStaphylococcusspp.overStreptococcusspp., which used to be the most prevalent pathogen.6 _The

higherincidenceofculture-negativeendocarditiscouldbe explainedbyfrequentpreviousantibioticadministrationdue tothe suspicionof other localized infections, although IE duetofastidiousandintracellularmicroorganismsmayalso havecontributedtothisﬁnding.9

The reported in-hospital mortality of patients with IE variesfrom12%to30%.1,10---12_In_our_study,_in-hospital

mor-talityof16.3%wasobserved,suggestingthatourpopulation issimilartootherregistries.

PrognosisinIEisinﬂuencedbyfourmainfactors:patient characteristics, the presence or absence of cardiac and non-cardiaccomplications,theinfectingorganism andthe echocardiographic ﬁndings.4 _Multivariate _analysis _in _our

study identiﬁed COPD, Staphylococcus spp., non-HACEK Gram-negative bacilli and cerebral embolism as indepen-dent predictors of in-hospital mortality. Of these four factors,non-HACEK Gram-negativebacilli hadthe highest oddsratio.Otherstudieshaveconﬁrmedtheassociationof thesefactorswithworseprognosis.1,13,14 _A_possible

expla-nationforthedismalprognosisassociatedwithnon-HACEK Gram-negativebacilliendocarditiscouldthatthese microor-ganismsarehealthcare-related agents.15 _Increasing_age,16

diabetes,17_prosthetic_valve_involvement,18_heart_failure_and

paravalvularcomplications13 _have_been _identiﬁed_in _other

studiesasriskfactorsforhighermortality.

In our study, clinical course was complicated in more thanhalfofthepatients.Heartfailureisthemostfrequent complicationof IE19,20 _and_is_associated_with_severe_acute

valvular regurgitation,19 _which _was _also _observed _in _our

study.Uncontrolled infection,the nextmostlikelyreason forsurgicalintervention,20---22_is_frequently_due_to

perivalvu-lar extension,which is more commonin aortic valveand prostheticvalveendocarditis,22_as_also_demonstrated_in_our

study.

Embolic events are a life-threatening complication. Predictorsofcerebralembolismhavebeenidentiﬁedin pre-vious studiesandincludesizeandmobilityof vegetations, causalmicroorganismandtheaffectedvalve.23---25_Our_study

identiﬁed mitral valve IE as an independent predictor of embolism. Large vegetationsonthe mitralvalve are usu-allyassociatedwithahigherincidenceofembolism,25 _and

thisisprobablythereasonforourﬁnding.Regarding periph-eralembolism,olderpatientsinthepresentstudyhadlower ratesofperipheralembolism,asreportedpreviously,16

pos-sibly simplydue tobeingunderdiagnosedbecauseof mild clinicalsignsandsymptoms.

Surgeryisperformedin23-53%ofpatientswithIEinmost series,2,10,26 _including _Portuguese _cohorts,5 _and _our _study

wasconsistent withthisprevalence(36.9%). Factors asso-ciatedwiththeneedforsurgeryweredemographics(male andyoungerpatientsmoreoftenunderwentsurgery)andthe affectedvalve(theaorticvalvewasmorecommonlytreated inthesurgicalgroup,probablyduetoahigherincidenceof perivalvularextensionoftheinfection,aswealso demon-strated). Although intravenous drug users usually have a predominance of right-sided IE caused by Staphylococcus

spp., onlyrarelyneeding surgerybecausetheyareusually responsivetomedicaltherapyalone,27_in_our_study

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ofsurgicaltherapy.Thisprobablyresultsfromthefactthat weareasurgicalcenterandmostcasesthatareindicated forsurgeryarereferredtous.Also,therehasrecentlybeen anincreaseinleft-sidedIEinintravenousdrugusers.28

Someechocardiographicﬁndingsandcomplicationssuch as acute severe valvular regurgitation and perivalvular extension were also associated with surgical treatment. However,embolismwasnotmoreprevalentinthesurgical group. Embolism is usuallymore frequent inthe ﬁrsttwo weeksoftherapyandlesssothereafter.29_Although_surgery_is

notcontraindicatedinIEcomplicatedbyembolism, includ-ing ischemic stroke unless the neurological prognosis is judged too poor,29---31 _the _optimal _timing _remains

contro-versial becauseof therisk ofrecurrent embolismandthe hemorrhagicriskassociatedwithsurgery.29

Some studies appear to question the importance of surgery in IE patients, asthey found no survival beneﬁt. However,intheInternationalCollaborationon Endocarditis-ProspectiveCohortStudyof1552patientswithnativevalve IE,32 _surgery _during _the _index _{hospitalization} _was

associ-ated with a signiﬁcant reduction in in-hospital mortality (12.1%vs.20.7%,p<0.001).Afterpropensity matchingand adjustmentforsurvivalbias,thesurvivalbeneﬁtofsurgery remained (absolute risk reduction of 5.9%), especially in patientswithcomplications.32_Furthermore,_a_{meta-analysis}

byHeadetal.33_demonstrated_a_highly_signiﬁcant_beneﬁt_of

surgery(p=0.0008).Inourcohortwefoundnosignificant dif-ferenceinmortalitybetweenpatientswhohadvalvesurgery and those who did not in the overall population, but in patientswithsurgicalindicationaccordingtotheguidelines, mortality wassignificantly lower in those whounderwent surgery(15.5%vs.32.6%,p=0.028).Thisshowsthatsurgery by itself is not associated withhigher mortality, and the fact thatoverall mortalitywasbetterappears toindicate aprognosticbenefitofsurgerywhenperformedinselected patients.

Regardingsurgicaltiming,we alsofound noincrease in mortalityinpatientswhounderwentearlyvs.latesurgery.In aprospectiverandomizedstudybyKangetal.onpatients withleft-sided IE, severe valvedisease andlarge vegeta-tions, there was no difference in survival at six months betweenthosewhounderwentearlysurgery(within48hours afterrandomization)orafter,butthoseoperatedearlyhad signiﬁcantlylowerratesofthecompositeendpointofdeath fromanycause,embolicevents,orrecurrenceofIEatsix months(hazardratio0.08,CI0.01-0.65;p=0.02).34

Study

limitations

Ourstudyhassomelimitations.First,itwasaretrospective observational study, and therefore information was lim-itedtomedicalrecordsandimportantdatamayhavebeen incomplete.Thisstudyreportedﬁndingsofasingletertiary referral center, whichlimitsgeneralization ofthe results. Finally,sincesomecasescamefromotherhospitalcenters, thepercentageofcomplicatedcasesmaybeoverestimated, andsomepatients(4.7%)werelosttofollow-upbecauseof transfertotheirhospitalsoforigin.

However,thisstudyinvolves ananalysisofasigniﬁcant numberofpatientsandenablessomeinterestingconclusions tobedrawn.

Conclusion

TheresultsofthepresentstudyhelptoidentifyIEpatients whoareatincreasedriskofworseoutcome.Weidentiﬁed COPD,clinicalcoursecomplicatedbycerebralembolismand IEduetoStaphylococcusspp.andnon-HACEKGram-negative bacilli as independentpredictors of in-hospital mortality. More than half of the patients presented complicated IE, andpredictivefactorsforeachcomplicationwereanalyzed. Surgerywasperformed inmorethan onethirdofpatients and in patients with surgical indication it was associated withimprovedlong-termsurvival.

RapididentiﬁcationofpatientswithIEathigherriskof mortalitymayoffertheopportunitytochangethecourseof thediseaseandimproveprognosis.

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.2017.08.007.

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