Hyperkalemia and management of renin-angiotensin-aldosterone system inhibitors in chronic heart failure with reduced ejection fraction : a systematic review

www.revportcardiol.org

Revista

Portuguesa

de

Cardiologia

Portuguese

Journal

of

Cardiology

REVIEW

ARTICLE

Hyperkalemia

and

management

of

renin-angiotensin-aldosterone

system

inhibitors

in

chronic

heart

failure

with

reduced

ejection

fraction:

A

systematic

review

Cândida

Fonseca

_,

_Dulce

_Brito

_,

_Patrícia

_Branco

_,

_João

_Miguel

_Frazão

_,

José

Silva-Cardoso

_,

_Paulo

_Bettencourt

a_{HeartFailureClinic,SãoFranciscoXavierHospital,CentroHospitalardeLisboaOcidental(CHLO),Lisboa,Portugal} b_{NOVAMedicalSchool/FaculdadedeCiênciasMédicas,UniversidadeNovadeLisboa,Lisboa,Portugal}

c_{CardiologyDepartment,CentroHospitalarUniversitárioLisboaNorte(CHLN),Lisboa,Portugal} d_{CCUL,FacultyofMedicine,UniversidadedeLisboa,Lisboa,Portugal}

e_{NephrologyDepartment,SantaCruzHospital,CentroHospitalardeLisboaOcidental(CHLO),Carnaxide,Portugal}

f_{InstituteforResearchandInnovationinHealthSciences(i3S)andInstituteforBiomedicalEngineering(INEB),Universidade}

doPorto,Porto,Portugal

g_{NephrologyDepartment,CentroHospitalarUniversitáriodeSãoJoão(CHUSJ)andFacultyofMedicine,UniversidadedoPorto,}

Porto,Portugal

h_{CenterforHealthTechnologyandServicesResearch(CINTESIS),Porto,Portugal}

i_{CardiologyDepartment,CentroHospitalarUniversitáriodeSãoJoão(CHUSJ),Porto,Portugal} j_{InternalMedicineDepartment,CUFPortoHospital,Porto,Portugal}

k_{FacultyofMedicine,UniversityofPorto,Porto,Portugal}

KEYWORDS Clinical decision-making; Clinicaloutcomes; Drugtherapy; Heartfailure; Hyperkalemia; Renin-angiotensin-aldosteronesystem inhibitors Abstract

IntroductionandObjectives:Renin-angiotensin-aldosteronesysteminhibitors(RAASi)arethe cornerstoneoftreatmentofheartfailurewithreducedejectionfraction(HFrEF).RAASi opti-mization inreal-life careischallenged byhyperkalemia, apotentially fataladverse event, whichcannecessitatedowntitrationordiscontinuationofRAASiandnegativelyimpactsurvival inHFrEF.Theliteratureonthisproblemissparse.Weperformedasystematicreviewof stud-iesonHFrEFtoinvestigatetheprevalence,incidence,andriskfactorsofhyperkalemia,RAASi prescriptionrates,frequencyofRAASidowntitrationordiscontinuationduetohyperkalemia, andthepotentialnegativeeffectofthelatteronprognosis.

Methods:WeconductedaMEDLINE(PubMed)searchincludingobservationalandinterventional studiespublishedbetweenJanuary1987andMay2018.

∗_{Correspondingauthor.}

E-mailaddress:[email protected](C.Fonseca). https://doi.org/10.1016/j.repc.2020.03.015

0870-2551/©2020SociedadePortuguesadeCardiologia.PublishedbyElsevierEspa˜na,S.L.U.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Results:Atotalof30observationaland18interventionalstudieswereincludedinthereview. The incidence ofhyperkalemia reportedwas between 0% and63% in observationalstudies andwasbetween0%and30%inclinicaltrials.Riskfactorsfor hyperkalemiaincludedRAASi prescription,olderage,diabetes,andchronickidneydisease.Inreal-lifestudies,RAASiwere downtitratedordiscontinuedin3-22%ofHFrEFpatients;hyperkalemiawasthereportedcause in5% ofcases.Noreportswere foundontheimpactonprognosisofRAASidowntitrationor discontinuationduetohyperkalemia.

Conclusions:Hyperkalemia andRAASidowntitrationor discontinuationarefrequent, partic-ularly in real-life HFrEF studies. Further research is needed to clarify the role of RAASi downtitrationordiscontinuationduetohyperkalemiaandtoassessitslong-termprognostic impactinHFrEFpatients.

©2020SociedadePortuguesadeCardiologia.PublishedbyElsevierEspa˜na,S.L.U.Thisisan openaccessarticleundertheCCBY-NC-NDlicense( http://creativecommons.org/licenses/by-nc-nd/4.0/). PALAVRAS-CHAVE Tomadadedecisão clínica; Resultadosclínicos; Terapêutica medicamentosa; Insuficiência cardíaca; Hipercaliemia; Inibidoresdosistema renina-angiotensina-aldosterona

Hipercaliemiaeotimizac¸ãodosinibidoresdosistema

renina-angiotensina-aldosteronanainsuficiênciacardíacacrónicacomdisfunc¸ão sistólica:umarevisãosistemática

Resumo

Introduc¸ãoeobjetivos: Osinibidoresdosistemarenina-angiotensina-aldosterona(iSRAA) con-stituem pedrasbasilarespara o tratamentodainsuficiência cardíacacom frac¸ãode ejec¸ão reduzida(IC-FER).Aotimizac¸ãodosiSRAAédificultadapelaocorrênciadehipercalemia,que obrigaàreduc¸ão/interrupc¸ãodoiSRAA,podendoimpactarnegativamentenasobrevivênciados doentescomIC-FER.Estaquestãoéraramenteabordadanaliteratura.

Métodos: RealizámosumarevisãosistemáticadosestudossobredoentescomIC-FERpara inves-tigaraprevalência,incidênciaefatoresderiscoparahipercaliemia,frequênciadeutilizac¸ão deiSRAA,frequênciadereduc¸ão/interrupc¸ãodosiSRAAporhipercaliemiaeopossívelimpacto negativodareduc¸ão/interrupc¸ãodos iSRAAno prognóstico.A pesquisafoifeita naMedline (PubMed)incluindoestudosobservacionaiseinterventivospublicadosentrejaneirode1987e maiode2018.

Resultados: Foramincluídos30estudosobservacionaise18interventivos.Afrequênciarelatada dehipercalemiavariouentre0%e63%emestudosobservacionaiseentre0%e30%emensaios clínicos.FatoresderiscoparahipercalemiaincluíramusodeiSRAA,idadeavanc¸ada,diabetes edoenc¸arenalcrónica.Emestudosdevidareal,osiSRAAforaminterrompidosem3%a22%dos doentescomIC-FER,sendoahipercalemiaacausaem5%destescasos.Nãoforamencontrados relatosdoimpactoprognósticodareduc¸ão/interrupc¸ãodosiSRAAdevidaàhipercalemia.

Conclusões:Ahipercaliemiaereduc¸ão/interrupc¸ãodosiSRAAsãofrequentes,principalmente emestudosdevidarealdeIC-FER.Novosestudosserãonecessáriosparaesclareceropapelda reduc¸ão/interrupc¸ãodosiSRAAdevidaahipercalemiaeparaavaliaroseuimpactoprognóstico alongoprazoemdoentescomIC-FER.

©2020SociedadePortuguesadeCardiologia.PublicadoporElsevierEspa˜na,S.L.U.Este ´eum artigoOpen Accesssobumalicenc¸aCCBY-NC-ND( http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Heart failure (HF) is a prevalent, fatal and costly syndrome.1---4 _{HF phenotypes are categorized by clinical}

practice guidelines according to left ventricular ejection fraction(LVEF):HFwithreducedejectionfraction(HFrEF) is defined as LVEF <40%, and HF withpreserved ejection fraction (HFpEF) as LVEF ≥50%.1 _{Depending on the}

def-inition and cohorts considered, the prevalence of HFpEF can varyfrom 22% to73%.1 _{To date, however, there is a}

paucityofevidenceontreatmentsthateffectivelyreduce

morbidityormortalityinpatientswithHFpEF.1,5_Incontrast,

the treatment ofHFrEF has evolvedrapidlyover thepast thirtyyears,withmajorclinicalbenefits.1,5

Renin-angiotensin-aldosteronesystem inhibitors(RAASi) --- angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), and mineralocor-ticoid receptor antagonists (MRA) --- are recommended for the treatment of HFrEF by all clinical practice guide-lines with a class I recommendation, level of evidence

A.1,5,6 _{Recently, theuse ofangiotensin receptor-neprilysin}

addition, the guidelines recommend that most patients withHFrEFreceivetripletherapy,includinganACEiorARB orARNi,abeta-blocker,andanMRA.1,5,6_{Allofthesedrugs}

willbemosteffectiveiftitratedtotherecommendedhigh target doses tested in clinical trials or tolerated by the patient.1,5,6 _{However, in spite of the consensual benefits}

of high dosages of RAASi, recent clinical practice-based studies report that upto two-thirds of HFrEF patients do not receive RAASi at the guideline-recommended target doses.7---12 _{Moreover, clear reasons for not achieving the}

targetdosesorfordiscontinuingRAASiarenotconsistently reported.7---9,11,12 _{Nevertheless, when reported,one of the}

mainreasons forRAASidowntitrationor discontinuationis hyperkalemia.8,9,11

PatientswithHFrEF treatedwithRAASiarereportedto beathigherriskofdevelopinghyperkalemia,asarepatients withadvancedstagesofchronickidneydisease(CKD), dia-betes,andresistanthypertension.5,11,13,14_{Notably,theseare}

prevalent comorbidities in patients with HF.15 _{It is}

esti-matedthatupto40%ofpatientswithchronicHFdevelop hyperkalemia in clinical practice.11 _{Hyperkalemiais}

com-monly associated with excessive intake of potassium salt substitutesandwithvariousmedicationswhichareusedto treatHFrEF,includingRAASi,beta-blockers,and potassium-sparingdiuretics.1,9,11,14,16_{Ashyperkalemiacanbeaserious}

and life-threatening condition in patients withHF and/or

CKD,11,17---21_{anditslong-termtreatmentiscurrentlylimited}

by issues of efficacy, patient adherence, tolerability, and safety,22 _{clinical practiceguidelinesand expert consensus}

documents recommend close monitoring of hyperkalemia and RAASi downtitration or discontinuation according to different cut-offs of potassium levels.1,5,6,9,11,23 _However,

hyperkalemia management and RAASi optimization in the dailycareofHFrEFpatientsarechallenging.Severalstudies in real-lifesettings show thatserum potassium levelsare not properlymonitored in patientsreceiving RAASi.11,24---27

Moreover, RAASi downtitration or discontinuation due to hyperkalemiamayworsenpatients’healthoutcomes, espe-ciallyintheHFrEFpatientsubgroupwhowouldbenefitmost fromthistherapy.1,5,6,11,14,21,28---32 _{Ithasbeen reportedthat}

RAASi downtitration or discontinuation is associated with increasedmortalityinpatientswithHF,CKD,ordiabetes.9---11

Concernsabouthyperkalemiaappeartobeanother sig-nificantfactorintheclinicaldecision-makingprocessinthe care of HFrEF and RAASi optimization. Nevertheless, few publishedstudieshavefocusedonthefrequency,cut-offsor riskfactorsofhyperkalemiaanditsassociationwithadverse outcomes among patients with HFrEF in current clinical practice.Hence,ascopingsystematicreviewofthe litera-tureisneededtoexaminetheextentandnatureofreporting of hyperkalemia in the context of RAASi use in HFrEF, to identify gaps in the most recent literature, and tomake recommendationsforfutureresearch.Theauthors accord-inglyperformed a systematic review of observational and interventionalstudiesonadultpatientswithHFrEF receiv-ingRAASi.Specifically,reportingofthefollowingissueswas addressed:(i)prevalenceorincidenceofhyperkalemia,(ii) estimatesofriskfactorsforhyperkalemia,(iii)RAASi pres-criptionratesandhyperkalemia-relatedreasonsforfailure toachievetargetRAASidosesorfordiscontinuation,and(iv) theeffectofhyperkalemia-attributedRAASidowntitration ordiscontinuationonmortalityorhospitalization.

Methods

Criteriaforidentificationofstudies

Participants

Studieswereidentifiedwiththefollowinginclusioncriteria forparticipants:(i)≥18yearsold;(ii)prescribedor receiv-ingRAASi therapy withinany periodbefore or during the study,regardless of treatment status (ongoing, discontin-ued,ornottreated);and(iii)diagnosisofchronicHF,stable orclinically andhemodynamicallystabilized after decom-pensation, with confirmed or probable reduced ejection fraction,i.e.HFrEF(alsoknownasleftventricular dysfunc-tion,systolicdysfunction,orsystolicHF).ConfirmedHFrEF wasdefinedasLVEF<50%,descriptionofmoderatetosevere systolicdysfunction,or asotherwisedefined bythe study investigators.ProbableHFrEFwasdefinedasareportofan HFdiagnosis with prescription or use of RAASi withinany periodbeforeorduringthestudy,andanyofthefollowing conditions:(i)prescriptionor useofbeta-blockertherapy; or(ii)prescriptionoruseofotherpharmacologicaltherapies commonlyusedforthetreatmentofHFrEF,asrecommended bycurrentclinicalpracticeguidelinesforHF.1,5,6_Datawere

collectedonlywhenavailableforpatientswithHFrEFasa totalsampleorasasubgroupofthetotalsample.

Typesofstudies

Interventionalstudies,observationalstudiesandsystematic reviewswithorwithoutmeta-analysisinanyclinicalsetting (e.g., inpatients at discharge, outpatients, primary care, hospital)wereincluded.

Interventionandcomparison

Reportswereincludedwhichhaddataontheprescriptionor useofalldrugclassescollectivelyknownasRAASi,i.e.ACEi, ARB,ARNi,orMRA,describinganydosageorregimensversus anycomparatoror control (suchasother RAASi, standard oroptimalpharmacologicaltherapyfor HF,placebo,or no treatment).

Outcomemeasures

Reportson HFrEF wereincluded that provideddata onat leastoneofthe followingoutcomes,regardlessof follow-up duration: (i) prevalence or incidence of hyperkalemia (numberor percentageof patients);or (ii)significant risk estimatesofhyperkalemia(p<0.05)byunivariateor multi-variateanalysis(oddsratio[OR],hazardratio[HR],orrisk ratio[RR]with95%confidenceinterval[CI]);or(iii)useor prescriptionofRAASiatbaseline/randomization/studystart and/oratstudyend/hospitaldischarge(numberor percent-ageofpatients),orpatientsatRAASitargetdose(number or percentage of patients), hyperkalemia-related reasons for failuretoachieve RAASi target dose or RAASi downti-trationordiscontinuation(reason,numberorpercentageof patients);or (iv) outcome estimates due tohyperkalemia or RAASi downtitration or discontinuation (percentage of patients,p-value,OR,HRor RRwith95%CI)forall-cause mortality,HF-and/orcardiovascular(CV)-relatedmortality, all-cause hospitalization, HF- and/or CV-related hospital-ization, or related composite endpoints. Data on hyper-kalemia were collected asdefined by the authors of the

C.

Fonseca

et

Table1 Summaryofmaincharacteristicsoftheincludedobservationalstudies.

Study(year) Studydesign Samplesize,n Interventionor exposure (control)

Population Analyzedsubgroups(n) Age,yearsa _{Female,% Comorbidities}

Abbasetal.35_{(2015) Pr,pop-and}

registry-based

1491894 MRA Sp+ACEi/ARB (matched controls)

HF+ACEi/ARB Cases(1062)Matchedcontrols (10620)

76.8 61 RD:32.4-14.7%DM: 64.7-44.7% Antonetal.13_{(2003) Rt,registry-based 110 MRA}

Sp+ACEi/ARB HF+ACEi/ARB+Sp+HK Total 71 38 DM:47% BIOSTAT-CHF Beusekampetal.12 (2018) Pr,multicenter, international 1666 ACEi/ARBand/or BB

HFrEF(LVEF<40%) Total 69 23 HT:59%CKD:45%DM:32% Cavallarietal.38_{(2010) Pr,cohort,}

multicenter

62 MRASp HFrEF(LVEF<45%)+ ACEi/ARB

Total 52 40 HT:77-60%DM:34-33% COMPARE-HF

Hernandezetal.49

(2012)

Rt,registry-based 5887 MRAatdischarge HFrEF(LVEF≤35%) MRAatdischarge(1070) 76.8 35 HT:71.0%RD:9.3%DM: 39.8%

NoMRAatdischarge(4817) 77.8 36 HT:72.4%RD:12.3%DM: 38.1%

Deticeketal.42_{(2016) Pr,survey 198 ACEi,ARB,MRA HF(LVSD) LVSD,LVEF<55%(59) 74 42 HT:78%CKD:32.0%DM:}

29.0% EFFECT

Koetal.51_{(2006) Rt,}

population-and

registry-based

9165 MRASp HF(34.7%LVEF<40%) Sp,EFFECT(1502) 73.4 45% CKD:53.1%b_;DM:39%

HFrEF(LVEF<40%) Spatdischarge,ideal(415) - - -ESC-HFLong-Term Registry Maggionietal.8_{(2013) Pr,} registry-based, multicenter, pan-European

12440 HFtherapy HFrEF(LVEF≤45%) HFrEF,LVEF≤45%(4792) - - -Frohlichetal.44_{(2016) Rt,}

registry-based, multicenter

722 ACEi/ARB HFrEF(LVEF<45%) Total 69 32 HT:59%DM:30% Gladowskietal.46_{(2003) Rt,registry-based 2697 ACEi HFrEF(LVEF<40%) LVEF<40%(1028) - - RD:19%DM:40%}

Golandetal.47_{(2011) Rt,registry-based 100 MRASp+}

ACEi/ARB+BB

HF+Sp - 69.9 21 HT:66% GWTG-HF

Gilstrapetal.45_{(2017) Rt,registry-based 16052 ACEi/ARB HFrEF(LVEF≤40%) Total 78.34 58 HT:76.51%RD:14.63%CKD:}

10.09%c_DM:26.7%

Juurlinketal.19_{(2004) Rt,ecologic}

study, population-and registry-based

16961 MRASp,ACEi, ARB

and RAASi in heart failure with reduced ejection fraction 521 Table1 (Continued)

Study(year) Studydesign Samplesize,n Interventionor exposure (control)

Population Analyzedsubgroups(n) Age,yearsa _{Female,% Comorbidities}

BeganSp,afterRALES(12422) 78.6 50 DM:40%

Kaneetal.50_{(2017) Rt,registry-based 174 ACEi/ARB HFrEF(LVEF≤40%) Reduced/discontinued(30) 62 27 HT:97%CKD:50%DM:53%}

Continued/increased(144) 66 35 HT:98%CKD:34%DM:57% Lachaineetal.54_{(2011) Rt,}

population-and registry-based 82018 MRASp,ACEi, ARB,BB HF Total,chronicHF(82018) 77.2 52 -ChronicHFusingSp(12344) 78.5 48 -ChronicHFnotusingSp(69674) - - -Leeetal.55_{(2013) Rt,registry-based 2358 MRASp(Sp}

non-use)

HFrEF(LVEF<40%) Total 69.2 34 HT:62.7%RD:3.0%d_DM:

30.6%

IncidentSpuse(521) 63.5 30 HT:55.7%RD:1.3%d_DM:

29.2%

Spnon-use(1837) 70.9 35 HT:64.7%RD:3.5%d_DM:

31.0% Limaetal.56_{(2008) Pr,cohort 186 MRASp(Sp}

non-use)

HFrEF(LVEF≤45%) Total 55.5 35 HT:58.2%RD:14.8%e_DM:

20.3%

Spuse(56) 53 24 HT:54.6%RD:15.2%e_DM:

15.2%

Spnon-use(130) 58 45 HT:61.8%RD:14.5%e_DM:

25.4% Lopesetal.57_{(2008) Rt,cohort,}

registry-based

134 MRASp+ ACEi/ARB+HF therapy(Sp non-use)

HFrEF(LVEF<35%) Total 66 41 DM:27.2% Spuse(76) 65.7 19 DM:23.7% Spnon-use(58) 66.7 22 DM:32.8% Spwithdrawal(19) 67.3 3 DM:15.8% Spmaintenance(57) 65.9 16 DM:26.3% Micheletal.58_{(2015) Nested}

case-control, pop-andregistry based

19194 Riskfactorsfor HK

HF CasesofHK(2176) 74 42 HT:58.2%CKD:6.2%DM: 30.7%

NorwegianHeartFailure Registry

DeBloisetal.40_{(2015) Registry-based,}

multicenter

5761 ACEi,ARB HFrEF(LVEF≤40%) Allpatients(5761) 70.2 29 HT:31% UsingACEi/ARB(5160) 69.6 28 HT:31% NotusingACEi/ARB(583) 74.7 35 HT:36% Polsonetal.63_{(2017) Rt,registry-based 15999 RAASi HF HFreceivingRAASi(3426) 69.5 44}

-C.

Fonseca

et

Table1 (Continued)

Study(year) Studydesign Samplesize,n Interventionor exposure (control)

Population Analyzedsubgroups(n) Age,yearsa _{Female,% Comorbidities}

QUALIFY

Komajdaetal.7_{(2016) Pr,longitudinal}

survey, international

7092 ACEi,ARB,MRA HFrEF(LVEF≤40%) - 63.1 26 HT:64.6%CKD:17.8%DM: 34.3%

Komajdaetal.52_{(2017) Pr,longitudinal}

survey, international

6669 ACEi,ARB,MRA HFrEF(LVEF≤40%) Total -

-Goodadherence(1543) 62.7 25 HT:71%CKD:19.8%DM: 38.9% Moderateadherence(3631) 63 25 HT:64.2%CKD:18.4%DM: 33.5% Pooradherence(1495) 63.5 29 HT:58.2%CKD:14.1%DM: 30.3% SahebSharif-Askari etal.67₍₂₀₁₄₎

Pr 398 ACEi,ARB,MRA HFrEF(LVEF≤40%) - 62 29 -Saitoetal.

Saitoetal.69_{(2005) Rt,registry-based 259 MRASp+FS+}

ACEi/ARB(FS+ ACEi/ARB) HF+Sp 25mg/dSp+40mg/dFS+ ACEi/ARB(86) 67.2 37 -50mg/dSp+40mg/dFS+ ACEi/ARB(49) 67 18 -Saitoetal.68_{(2006) Rt,registry-based 59 MRASp+CVD+}

FS+ACEi/ARB

HF+Sp Total25mg/dSp+20mg/d CVD+40mg/dFS+5mg/dEna (31)/Can(28)

65.5 -Shahetal.27_{(2005) Rt,registry-based 840 MRASp HF+Sp Withfollow-up(556) 69 1}

-and RAASi in heart failure with reduced ejection fraction 523 Table1 (Continued)

Study(year) Studydesign Samplesize,n Interventionor exposure (control)

Population Analyzedsubgroups(n) Age,yearsa _{Female,% Comorbidities}

NoHK(473) 69 1 -Steinmanetal.73_{(2013) Interview-and}

registry-based

295 ACEi,ARB HFrEF - 74 2 DM:41% Svenssonetal.74_{(2004) Pr,registry-based 125 MRASp HFrEF(LVEF≤45%) Total 72.9 27}

-TakingSp(60) - - -InitiatedSp(65) - - -Tamarisiaetal.75_{(2004) Casecontrol}

study

926 MRASp+ ACEi/ARB+HF therapy

HFrEF(LVEF<35%) Total 59 - -Sp-tolerant(134) 57 37 DM:34% SpdiscontinuationduetosK>5 mmol/l(33) 66 27 DM:55% SpdiscontinuationduetosCr >2.5mg/dlandincrease≥0.5 mg/dl(34) 62 42 DM:42% TSOC-HFrEFregistry

Changetal.39_{(2017) Pr,survey,}

multicenter 1509 Non-prescription and under-prescriptionof HFtherapy SystolicHF Total 63.9 28

-Withametal.78_{(2004) Rt,registry-based 226 MRASp HF(evidenceofLVSD) Total 73.3 31 HT:42.5%DM:22.1%} a _{Valuesaremeanormedian.}

b _StageIII. c _StageIV/V.

d _{eGFR<30ml/min/1.73m}2_. e _{eGFR<50ml/min.}

ACEi:angiotensin-convertingenzymeinhibitor;ARB:angiotensinreceptorblocker;BB:beta-blocker;BIOSTAT-CHF:BIOlogyStudytoTAiloredTreatmentinChronicHeartFailure;Can: candesartan;CKD:chronickidneydisease;COMPARE:ComparativeEffectivenessofTherapiesforHeartFailure;CVD:carvedilol;d:day;DM:diabetesmellitus;EFFECT:EnhancedFeedback forEffectiveCardiacTreatment;eGFR:estimatedglomerularfiltrationrate;Ena:enalapril;ESC:EuropeanSocietyofCardiology;FS:furosemide;GWTG:GetWithTheGuidelines-Heart FailureRegistry;HF:heartfailure;HFrEF:heartfailurewithreducedejectionfraction;HK:hyperkalemia;HT:hypertension;LVEF:leftventricularejectionfraction;LVSD:leftventricular systolicdysfunction;MRA:mineralocorticoidreceptorantagonist;Pop:population;Pr:prospective;QUALIFY:QUAlityofadherencetoguidelinerecommendationsforLIfe-savingtreatment inheartfailure:aninternationalsurveY:anobservationalstudy;RAASi:renin-angiotensin-aldosteronesysteminhibitors;RD:renaldysfunction;Rt:retrospective;sCr:serumcreatinine; sK:serumpotassium;Sp:spironolactone;TSOC:TaiwanSocietyofCardiology.

C.

Fonseca

et

Table2 Summaryofmaincharacteristicsoftheincludedinterventionalstudies.

Study(year) Studydesign Studysize,n Intervention (control)

Population Analyzedsubgroups(n) Age,yearsa _{Female,% Comorbidities}

ARTS

Pittetal.62_{(2013) RCT,multicenter 458 MRAFin,2.5-10}

mg/d

(placebo/open-labelSp,25-50 mg/d)

HFrEF(LVEF≤40%) A,Finvs.placebo(65) 66.3 20.0 HT:43.1%;DM:13.8%

B,Finvs.placebo/Sp(392) 72.1 20.4 HT:66.6%;DM:34.2% ARTS-HF

Filippatosetal.43_{(2016) RCT,multicenter 1055 MRAFin,2.5-10}

mg/d(MRAEpl 25-50mg/d)

HFrEF(LVEF≤40%) Total 71.2 22.7 HT:73.5%;CKD:35.1%b_;DM:

26.5%c_,37.7%d Epl(221);Fin2.5-5mg/d(172); Fin5-10mg/d(163);Fin7.5-15 mg/d(167);Fin10-20mg/d (169);Fin15-20mg/d(163) - - -ARTS-HFJapan

Satoetal.70_{(2016) RCT,multicenter 72 MRAFin,2.5-10}

mg/d(MRAEpl 25-50mg/d)

HFrEF(LVEF≤40%) Total 73.1 26.4 HT:70.8%;CKD:41.7%b_;DM:

16.7%c_,41.7%d Epl(13);Fin2.5-5mg/d(13); Fin5-10mg/d(13);Fin7.5-15 mg/d(11);Fin10-20mg/d(11); Fin15-20mg/d(11) - - -ATLAS

Rydenetal.66_{(2000) RCT,post-hoc}

analysis

3164 ACEiLsn,2.5-5 mg/d(ACEiLsn, 32.5-35mg/d)

HFrEF(LVEF≤30%) High-dose(1568) Low-dose(1596)

- - -Diabetic(611) 65 22.0 -ATMOSPHERE

McMurrayetal.81_{(2016) RCT,multicenter 7016 ACEiEna,5-10mg}

bid(aliskiren, 300mg/dor Ena+aliskiren)

HFrEF(LVEF≤35%) Ena+aliskiren(2340) 63.2 21.1 HT:61.8%;DM:28.4% Aliskiren(2340) 63.3 22.7 HT:62.4%;DM:26.8% Ena(2336) 63.3 21.4 HT:61.0%;DM:27.9% CHARM

CHARM-LowLVEF

Youngetal.79_{(2004) PooledRCT,}

prespecified analysis

4576 ARBCan,4-32 mg/d(placebo)

HFrEF(LVEF≤40%) Total(4576) 65 -

-Can(2289) 65.1 25.9 HT:48.4%;DM:28.6% Placebo(2287) 65.3 26.1 HT:49.6%;DM:28.5%

and RAASi in heart failure with reduced ejection fraction 525 Table2 (Continued)

Study(year) Studydesign Studysize,n Intervention (control)

Population Analyzedsubgroups(n) Age,yearsa _{Female,% Comorbidities}

DESTINY-HF

Anandetal.36_{(2010) RCT,multicenter 115 ARBVal,}

80-320mgqd (ARBVal, 40-160mgbid)

HFrEF(LVEF<40%) Total 65 21.0 -Val40mgbid-max320mg

(160mgbid)(60) 67.3 16.7 HT:60%;CKD:13%;DM:45% Val80mgqd-max320mgqd (55) 63.4 25.5 HT:82%;CKD:13%;DM:40% EMPHASIS-HF

Zannadetal.30_{(2011) RCT,multicenter 2737 MRAEpl,25-50}

mg/d(placebo)

HFrEF(LVEF≤30%) Total - -

-Epl(1364) 68.7 22.7 HT:66.7%;CKD:32.2%;DM: 33.7%

Placebo(1373) 68.6 21.9 HT:66.2%;CKD:34.5%;DM: 29.1%

Rossignoletal.21_{(2014) RCT,post-hoc}

analysis

2736 MRAEpl,25-50 mg/d(placebo)

HFrEF(LVEF≤30%) Total;Epl(1364);placebo (1373)

- - -Hamroffetal.48_{(1997) RCT,open-label}

phase

43 ARBLsr,25-50 mg/d+ACEi

HF+ACEi Total 61.4 49 DM:39% HEAAL

Konstametal.53_{(2009) RCT,multicenter 3846 ARBLsr,150}

mg/d(ARBLsr,50 mg/d)

HFrEF(LVEF≤40%) Lsr150mg(1921) 66 30 HT:60%;DM:31% Lsr50mg(1913) 66 29 HT:60%;DM:32% Kiernanetal.20_{(2012) RCT,post-hoc}

analysis 3846 ARBLsr,150 mg/d(ARBLsr,50 mg/d) HFrEF(LVEF≤40%) Lsr150mg(828) - - -Lsr50mg(889) - - -HK(326) 67 32.5 DM:43.9% NoHK(3508) 66 29.6 DM:30.1% Rossignoletal.65_{(2014) RCT,post-hoc}

analysis 3846 ARBLsr,150 mg/d(ARBLsr,50 mg/d) HFrEF(LVEF≤40%) Lsr150mg(828);Lsr50mg (889) - - -Mitrovicetal.59_{(2009) Open-label}

controlledtrial, multicenter

414 ARBCan,8-32 mg/d+standard treatment

HFrEF(LVEF≤40%) Total 68.2 18.8 DM:40.8% +Sp(158);8mg+BB(378);8mg

-BB(36);16mg-BB(32);32mg +BB(270);32mg-BB(25) PARADIGM-HF

McMurrayetal.28_{(2014) RCT,multicenter 8399 ARNiLCZ696,}

100-200mgbid (ACEiEna,10mg bid)

HFrEF(LVEF≤40%) Ena(4212) 63.8 22.6 HT:70.5%;DM:34.6% LCZ696(4187) 63.8 21.0 HT:70.9%;DM:34.7%

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Table2 (Continued)

Study(year) Studydesign Studysize,n Intervention (control)

Population Analyzedsubgroups(n) Age,yearsa _{Female,% Comorbidities}

RALES

RALESInvestigators64

(1996)

RCT,multicenter 214 MRASp,12.5-75 mg/d(placebo)

HFrEF(LVEF≤35%) Placebo(40) 61 18 -12.5mg(41);25mg(44);50mg

(46);75mg(41)

- - -Pittetal.29_{(1999) RCT,multicenter 1663 MRASp,25-50}

mg/d(placebo)

HFrEF(LVEF<35%) Placebo(841) 65 27 -Sp(822) 65 27 -Vardenyetal.77_{(2012) RCT,post-hoc}

analysis

1658 MRASp,25-50 mg/d(placebo)

HFrEF(LVEF<35%) eGFR<60ml/min/1.73m2_{(792) 70 30.6 HT:27.5%;DM:26.2%}

eGFR≥60ml/min/1.73m2

(866)

61.2 23.3 HT:20%;DM:18.5% Vardenyetal.76_{(2013) RCT,post-hoc}

analysis

1663 MRASp,25-50 mg/d(placebo)

HFrEF(LVEF<35%) AfricanAmericans(120) 53.8 34 HT:14%;DM:11% Non-AfricanAmericans(1543) 66.1 26 HT:24%;DM:23% Vardenyetal.14_{(2014) RCT,post-hoc}

analysis

1663 MRASp,25-50 mg/d(placebo)

HFrEF(LVEF<35%) Sp(822) - - -Placebo(841) - - -Placebo,noHKduringtrial

(794)

65 26.7 HT:23.7%;DM:22.7% Placebo,HKduringtrial(47) 68.6 31.9 HT:21.3%;DM:31.9% Sp,noHKduringtrial(666) 64.5 26.1 HT:23.1%;DM:18.2% Sp,HKduringtrial(156) 68.8 28.8 HT:25%;DM:34.0% Solomonetal.72_{(2016) SRand}

meta-analysis

Neprilysin+RASi (RASialone)

HFrEF IMPRESStrial,omapatrilat 40mgqd/Lsn20mgqd(573)

- - -OVERTUREtrial,Ena10mg

bid/omapatrilat40mgqd (5770) - - -PARADIGM-HF,Ena10mg bid/Sac-Val200mgbid(8399) - - -SOLVD

Kostisetal.31_{(1996) RCT,multicenter 6769 ACEiEna,}

2.5-10mgbid (placebo)

HFrEF(LVEF≤35%) Total;Ena(3382);placebo (3387)

- - -deDenusetal.41_{(2006) RCT,post-hoc}

analysis

6722 ACEiEna (placebo)

HFrEF(LVEF<35%) Ena(3364) 59.8 14.2 DM:19.1% Placebo(3358) 59.9 14.7 DM:19.5% Bowlingetal.37_{(2013) RCT,post-hoc}

analysis

2502 ACEiEna,2.5-20 mg/d(placebo)

HFrEF(LVEF≤35%) Total - - CKD:41%e

CKD,placebo(538) 64.5 25 HT:45%;CKD:100%;DM: 29%

CKD,Ena(498) 64.1 24 HT:50%;CKD:100%;DM: 30%

and RAASi in heart failure with reduced ejection fraction 527 Table2 (Continued)

Study(year) Studydesign Studysize,n Intervention (control)

Population Analyzedsubgroups(n) Age,yearsa _{Female,% Comorbidities}

NoCKD,placebo(714) 57.7 16 HT:39%;CKD:0%;DM:25% NoCKD,Ena(752) 57.6 16 HT:38%;CKD:0%;DM:21% TIME-CHF

Muzzarellietal.60_{(2012) RCT,sub-analysis 566 ACEi+ARB,Sp,}

intensified NT-BNP-guided therapy(standard symptom-guided therapy) HFrEF(18%HFpEF) NoHK(490) 76.4 42 HT:75%;RD:52%;DM:32% HK>5.5mmol/l(76) 78 30 HT:72%;RD:75%;DM:46% Brunner-LaRocca etal.16₍₂₀₁₅₎ RCT,post-hoc analysis 462 ACEi+ARB,Sp, intensified NT-BNP-guided therapy(standard symptom-guided therapy)

HFrEF(LVEF≤45%) WRFIII(97) 75 28 HT:75%;RD:68%;DM:38%

NoWRFIII(365) 76 36 HT:70%;RD:50%;DM:32% TITRATION

Sennietal.71_{(2016) RCT,multicenter 429 ARNiSac/Val,}

50-200mgbid over3wk (50-200mgbid over6wks)

HFrEF(LVEF≤35%) Total 64 21.3 CKD:33.7%;DM:12.2%

Condensedregimen(247) 64.2 22.7 CKD:33.6%;DM:12.6% Conservativeregimen(251) 63.8 19.9 CKD:33.9%;DM:12.0% High-dose(247) 63.1 20.6 CKD:29.6%

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Table2 (Continued)

Study(year) Studydesign Studysize,n Intervention (control)

Population Analyzedsubgroups(n) Age,yearsa _{Female,% Comorbidities}

ACEi/ARB-naïve(33) - - -Train-the-Trainer Peters-Klimmetal.61 (2008) Cluster-randomized study, cross-sectional analysis

167 Trainthetrainer group(standard training) HFrEF(LVEF≤40%) - 68.2 31.1 HT:76.1%;RD:22.2%;DM: 35.9% Peters-Klimmetal.25 (2012) Cluster-randomized study, cross-sectional analysis

168 Trainthetrainer group(standard training)

HFrEF(LVEF≤40%) Trainthetrainer(91) 68.4 30.8 HT:74.7%;RD:20.9%;DM: 35.2%

Standard(77) 69 31.2 HT:77.9%;RD:23.4%;DM: 37.7%

Zannadetal.80_{(1992) RCT,multicenter 278 ACEiLsn,5-20}

mg/d(ACEiEna, 5-20mg/d)

HFrEF(LVEF<45%) Lsn(138) 63 14 -Ena(140) 61 19

-a _{Valuesaremeanormedian.} b _{Withouttype2DM.} c _WithoutCKD. d _WithCKD.

e _{eGFR<60ml/min/1.73m}2_.

ACEi:angiotensin-convertingenzymeinhibitor;ARB:angiotensinreceptorblocker;ARNi:angiotensinreceptor-neprilysininhibitor;ARTS:minerAlocorticoidReceptorAntagonistTolerability Study;ATLAS:AssessmentofTreatmentwithLisinoprilAndSurvival;ATMOSPHERE:AliskirenTrialtoMinimizeOutcomesinPatientswithHeartFailure;BB:beta-blocker;bid:twicea day;BNP:brainnatriureticpeptide;Can:candesartan;CHARM:CandesartaninHeartFailure-AssessmentofReductioninMortalityandMorbidity;CKD:chronickidneydisease;COMPARE: ComparativeEffectivenessofTherapiesforHeartFailure;d:day;DESTINY-HF:DiovanEvaluationofSafetyTwIcevsoNcedailYstudyinHeartFailure;DM:diabetesmellitus;EFFECT: EnhancedFeedbackforEffectiveCardiacTreatment;eGFR:estimatedglomerularfiltrationrate;EMPHASIS-HF:EplerenoneinMildPatientsHospitalizationandSurvivalStudyinHeart Failure;Ena:Enalapril;Epl:eplerenone; Fin:finerenone;HEAAL:Heart failureEndpoint evaluationofAngiotensin IIAntagonistLosartan; HF: heartfailure;HK:hyperkalemia;HT: hypertension;LVEF:leftventricularejectionfraction;Lsn:lisinopril;Lsr:losartan;MRA:mineralocorticoidreceptorantagonist;NT-BNP:N-terminalbrainnatriureticpeptide; PARADIGM-HF:Prospectivecomparisonofangiotensinreceptorneprilysininhibitor(ARNI)withangiotensin-convertingenzymeinhibitor(ACEI)toDetermineImpactonGlobalMortalityandmorbidity inHeartFailure;HFpEF:heartfailurewithpreservedejectionfraction;qd:oncedaily;RALES:RandomizedAldactoneEvaluationStudy;RASi:renin-angiotensinsysteminhibitors;RCT: randomizedclinicaltrial;RD:renaldysfunction;Sac:sacubitril;SOLVD:StudiesofLeftVentricularDysfunction;SR:systematicreview;Sp:spironolactone;TIME-CHF:TrialofIntensified versusStandardMedicalTherapyinElderlyPatientswithCongestiveHeartFailure;wk:week;Val:valsartan;WRF:worseningrenalfunction.

studies,comprisingabnormallyhighserumorplasma potas-siumconcentrations(5.0mmol/lorabove),diagnosiscode of hyperkalemia, clinically important hyperkalemia, or hyperkalemiaasaninvestigator-reportedadverseevent.

Exclusioncriteria

Reports were excluded according toany of the following criteria: (i) patients on acute, emergency and intra-venoustherapyforacuteHF;(ii)patientsreceivingdialysis (hemodialysis or peritoneal dialysis)or renal transplanta-tion patients; (iii) publication types such as unpublished or unavailable as full-text original article, abstract, case report, comment, clinical conference, or review; (iv) not written in English; (v) hyperkalemia not a component of thereasonsforRAASidowntitrationordiscontinuation;and (vi) no data onany of the above-mentioned outcomesof interest.

Searchmethods

This systematicreview followedthePRISMAguidelinesfor conductandreporting.33_{Studieswereidentifiedby}

search-ing the MEDLINE (PubMed) database for original full-text journal articles published between January 1, 1987 and thepresent. The lastsearch wasrunonMay 14, 2018for ‘hyperkalemia’or ‘potassium’ or‘guideline adherence’or ‘practiceguidelinesastopic’,crossed with‘heart failure’ and ‘raasi’ or’mineralocorticoid receptor antagonists’ or ‘angiotensin-converting enzyme inhibitors’or ‘angiotensin receptor antagonists’, for full-text articles published in English.ThefullsearchstrategyisshowninSupplementary MaterialS1.

Selectionofstudies

One reviewer screened titles and abstracts of all records identifiedintheelectronicsearchandclassifiedthemas eli-gibleornoteligible.Thefulltextofthereportsidentifiedas eligiblewasthenretrieved,screened,andidentifiedas eli-gible,potentiallyeligibleorunclear,ornoteligible,andthe reasons for exclusion of reports were recorded.A second reviewerscreened the potentially eligibleor unclear full-textreportsandidentifiedthemaseligibleornoteligible andrecordedthereasonsfor exclusion.Anydisagreement was solved by consensus or by consulting a third review author. Two reviewers identified and excluded duplicated andcollatedreportsofthesamestudy.

Datacollectionandmanagement

An electronicspreadsheet wasusedtorecord study char-acteristics and outcome data from the included studies. One reviewer extracted data from the included studies. Disagreements wereresolved by consensus.One reviewer double-checkedthat datawereenteredcorrectlyby com-paring the data presented in the systematic review with the electronicspreadsheet. Datathat werenot published in a numerical format (e.g., presented graphically in the publishedpaper)werenotcollected.

Dataitems

Datawereextractedfromeachincludedstudyon(i)study characteristics, including study type, inclusion criteria or study population, duration of follow-up and treatment, numberofparticipantsrandomized/included/analyzed,and description of analyzed subgroups; (ii) description of the intervention/exposure(s) and of comparator(s), including agent and dosage; and (iii) participant characteristics at baseline, including age and/or age subgroups, gen-der, serum creatinine levels, potassium levels, and HF disease characteristics, including HF diagnosis, New York HeartAssociation(NYHA) class,LVEF,mainetiology of HF, brain natriuretic peptide (BNP) level, HF-related conco-mitantmedication (includingbeta-blockers), andselected comorbidities,includingCKD,diabetes, hypertension,and myocardialischemia.

Dataanalysis

The main aim was to review the quantity and nature of the evidence for the management of RAASi and hyper-kalemia,anditsconsequencesandoutcomes.Becauseofthe expectedheterogeneity betweenstudypopulations, inter-ventions,andoutcomemeasures, ameta-analysiswasnot performed.As thiswasintended asa scopingreview,34 _no

synthesisoftheevidenceorevaluationofthequalityofthe studieswascarriedout.

Results

A flow diagram of the literature search and the

selec-tion process of the reports is shown in Figure 1.

The MEDLINE (PubMed) search resulted in 457 reports. In total, this systematic review included 62 full-text reports7,8,12---14,16,19---21,25,27---31,35---81 _{from 48 studies on HFrEF}

populations.

The characteristics of the studies and study

populations are shown in Tables 1 and 2

and Supplementary Table ST1. A total of 32

reports7,8,12,13,19,27,35,38---40,42,44---47,49---52,54---58,63,67---69,73---75,78

of 30 observational studies involving samples

rang-ing from 5968 _{to 1 491 894}35 _{participants were}

included in this systematic review (Table 1).

Most of these studies were registry-based or

surveys.7,8,12,13,19,27,35,39,40,42,44---47,49---51,54,55,57,58,63,67,69,73,74,78

In addition, this review included 29 reports

(18 studies) of randomized clinical trials

(RCTs),28---31,36,43,48,53,59,62,64,70,71,80,81 _{sub-analyses of}

RCTs,14,16,20,21,37,41,60,65,66,76,77,79 _{or cluster-randomized}

studies25,61 _{with samplesranging from43}48 _to839928

par-ticipants,andonesystematic reviewandmeta-analysisof RCTs72_(Table2).

A wide range of RAASi classes and

combina-tions were analyzed in the included studies: six

reports on ACEi (four studies),31,37,41,46,66,80 _six

reports (four studies) on losartan,20,36,38,53,59,65 _three

reports on ARNi,28,71,72 _{20 reports (17 studies) on}

MRA,21,27,29,30,38,43,49,51,55---57,62,64,70,74,75,78 _{one report on}

unspecified RAASi,63 _{and seven reports (six studies) on}

ACEi, ARB, and MRA.7,8,19,42,52,54,67 _{The combinations of}

ACEiand/orARB,ACEi/ARBandMRA,andenalapriland/or aliskirenwerethe subjectofseven reports,12,40,44,45,50,58,73

Figure1 Flowdiagramoftheselectionofreports(basedonMoheretal.33_).

11 reports (nine studies),13,16,25,35,39,47,60,61,68,69 _{and one}

report,81 _{respectively.}

Forty-fivereportshaddataonhyperkalemiaprevalence or incidence in HFrEF patients receiving RAASi. Hyper-kalemia was reported as a secondary endpoint, adverse event,orclinicaloutcome.Amongobservationalstudiesin real-life settings,12,13,19,27,35,38,44,45,47,49,51,54---57,63,68,69,74,75,78

the proportion of patients with hyperkalemia

varied between 0%51,69 _{and 63%}27

(Supplemen-tary Table ST2), while reports of interventional

studies14,20,21,25,28---31,36,37,41,43,53,59,60,62,64,65,70---72,76,77,81

describedhyperkalemiaincidencesbetween0%36,43,70,71_and

30%77 _{(Supplementary Table ST3). Interestingly,}

observa-tionalstudiesthatreporteda0%prevalenceofhyperkalemia analyzedahighlyselectedpopulationand/orahigher cut-off for hyperkalemia. This is the case of the EFFECT study by Ko et al.,51 _{which reported a 0% prevalence of}

hyperkalemiainasubgroupanalysisofidealHFrEFpatients withsimilarcharacteristics tothoseintheRALES trial13,64

(i.e.,atlowerriskofdevelopinghyperkalemiabyexcluding patients with baseline creatinine >2.5mg/dl, or baseline serumpotassium>5mmol/l).Ontheotherhand,thesame study reportedan 18% prevalence of hyperkalemia in the totalheterogeneoussampleofpatientswithHF(HFrEFand HFpEF).51_{Anotherobservationalstudy,bySaitoetal.,}52_also

reported0% prevalencein a subgroup of HFpatients who werereceivingonlyoneACEiorARB,andwereselectedby exclusioncriteriasuchasDM,CKD,serumcreatinineoutside

thenormalrange,orreceivinganyother drugsthatmight affect serumpotassium levels. As in clinical trials, these selectedpopulationsarenotrepresentativeofthemajority of HFrEF patients in daily clinical practice. By contrast, hyperkalemialevelswerehigherinstudiesonsubgroupsof HFrEFpatientsreceivingcombinedRAASitherapy(38%),13,74

higherdosesofspironolactone(24%),64 _{baselinecreatinine}

≥2.5mg/dl(63%),27_{orestimatedglomerularfiltrationrate}

(eGFR)<30ml/min/1.73m2_(22%)41 _{or<60ml/min/1.73m}2 (26%).77

Figure 2 provides an overview of the prevalence or incidenceofhyperkalemiaacrossstudiesthatdefined hyper-kalemia as serum potassium values >5.5 mmol/l or >6.0 mmol/l. The reported proportions of HFrEF patients with hyperkalemiavariesdependingonthestudytypeandRAASi therapy.Overall,observationalstudieswithcombinedRAASi therapyaddedtoHFtherapypresentedhigherhyperkalemia levelsthanthoseofinterventionalstudies(Figure2).

Table 3 displays an overview of the 15 reports (12 studies) that estimated risk factors for hyperkalemia. Closer inspection of this table shows that the risk of hyperkalemiainHFrEFpatientswassignificantlyassociated with RAASi use, aswell as with age, diabetes, CKD, and elevated baselinepotassiumlevels.Ingeneral,higher risk estimates were observed in observational studies than in clinical trials.Four-fold to13-foldincreasesin therisk of hyperkalemiawereassociatedwithspironolactoneorother MRAuseaddedtobackgroundACEiand/orARBtherapy,35,49

and RAASi in heart failure with reduced ejection fraction 531

Table3 Riskfactorssignificantlyassociatedwithhyperkalemiabyunivariateormultivariateanalysisinobservationalandinterventionalstudiesonpatientswithheartfailure withreducedejectionfractionreceivingrenin-angiotensin-aldosteronesysteminhibitors.

Study(year) Interventionvs.control(n) Follow-updurationa

Riskfactor Estimate[95%CI] Observationalstudies

Abbasetal.35_{(2015) Sp+ACEi/ARB(1062)vs.matchedcontrolswithnoHK(10620)}

398(397)days Age OR8.73[5.05-15.08]b_,<70yearsc OR12.32[9.35-6.23]b_,≥70yearsc RAASi OR13.59[11.63-15.88]b_,Sp OR11.05[8.67-14.08]b_,Spc OR13.00[9.82-17.21]b_,SpSTc OR9.12[6.78-12.26]b_,SpLTc

Antonetal.13_{(2003) Sp+ACEi/ARB(110)}

12months

Diabetes OR2.23[1.02-4.89]d

Otherfactors OR5.18[2.14-12.6]d_,Hct<0.36

OR4.28[1.69-10.7]e_,Hct<0.36

COMPARE-HF

Hernandezetal.49_{(2012) MRAatdischarge(1070)vs.noMRA(4817)}

3years

RAASi HR5.96[1.31-27.15]f

HR2.51[1.45-4.34]g

HR1.48[1.20-1.84]h

Leeetal.55_{(2013) Sp(521)vs.Spnon-use(1837)}

2.5(1.3-3.5)years

CKD HR3.86[1.63-9.13]i_{,eGFR<30ml/min/1.73m}2

Sp HR3.46[1.97-6.06]i_{,Sp,incidentuse}

Limaetal.56_{(2008) Sp(56)vs.Spnon-use(130)}

23.65days

CKD RR9.6[8.03-11.20]e_,finalurea

Micheletal.58_{(2015) CasesofHK(2176)vs.controls(4000)}

3.9(3.21)years

Diabetes OR1.52[1.31-1.75]j_,typeII

OR1.43[1.10-1.87]j_{,typeII+eGFR≥60ml/min}

OR6.34[5.19-7.74]j_{,typeII+eGFR<60ml/min}

OR4.34[3.51-5.37]j_{,typeII+eGFR30-59ml/min}

OR23.22[16.25---33.18]j_{,typeII+eGFR<30ml/min}

CKD OR3.81[3.29---4.42]j_{,eGFR<60ml/min}

OR16.32[12.96---20.56]j_{,eGFR<30ml/min}

OR4.57[3.82---5.46]j_{,eGFR30-44ml/min}

OR1.82[1.53---2.16]j_{,eGFR45-59ml/min}

RAASi OR3.23[2.77-3.77]j_{,Sp,currentuse}

OR10.68[6.61---17.26]j_{,Sp,use<30days}

OR4.99[3.42---7.27]j_{,Sp,use1-3months}

OR3.40[2.62---4.43]j_{,Sp,use>3-12months}

OR2.17[1.76---2.66]j_{,Sp,use>12months}

OR1.70[1.41-2.04]j_{,ACEi,currentuse}

OR5.47[3.66---8.19]j_{,ACEi,use<30days}

OR3.00[2.14---4.21]j_{,ACEi,use1-3months}

OR1.71[1.33---2.19]j_{,ACEi,use>3-12months}

OR1.39[1.13---1.72]j_{,ACEi,use>12months}

OR4.46[3.47---5.74]j_{,K+-diuretics+ACEi} OR4.97[3.87---6.39]j_,Sp+ACEi OR3.29[2.41---4.50]j_,Sp+ARB OR2.03[1.18---3.50]j_,ACEi+ARB OR6.81[2.50---18.52]j_,ACEi+ARB+Sp OR7.49[3.25-17.80]j_{,diuretic+trimethoprim} OR7.03[3.69-13.41]]j_{,ACEi+trimethoprim}

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Table3 (Continued)

Study(year) Interventionvs.control(n) Follow-updurationa

Riskfactor Estimate[95%CI]

Otherfactors OR3.01[2.61-3.48]j_{,diuretics,currentuse}

OR9.16[5.99-14.02]j_{,diuretics,use<30days}

OR4.74[3.36-6.67]j_{,diuretics,use1-3months}

OR2.98[2.35---3.77]j_{,diuretics,use>3-12months}

OR2.16[1.79-2.61]j_{,diuretics,use>12months}

OR2.63[1.96-3.54]j_{,amiloride,currentuse}

OR0.81[0.67-0.99]j_{,loopdiuretics,currentuse}

OR0.60[0.46-0.77]j_{,thiazidesandrelateddiuretics,current}

use

OR0.81[0.69-0.96]j_{,calciumchannelblockers,currentuse}

Svenssonetal.74_{(2004) Sp25mgqd(125)vs.placebo}

11months

Otherfactors RR0.37[0.15-0.85]e_{,decreasedLVEFper10%increase}

RR3.36[1.17-9.69]e_,NYHA

Interventionalstudies EMPHASIS-HF

Rossignoletal.21_{(2014) Epl(1364)vs.placebo(1373)}

21months,median

CKD HR2.23[1.56-3.19]d_{,WRF,eGFRdecrease>20%}

HR1.77[1.36-2.30]d_{,bsleGFR≤median,eGFRdecrease>20%}

RAASi HR1.67[1.29-2.17]d_{,Epl,eGFRdecrease>20%}

Otherfactors HR1.69[1.25-2.29]d_{,hypertension,eGFRdecrease>20%}

HR0.71[0.50-1.00]d_{,whiteethnicity,eGFRdecrease>20%}

HEAAL

Kiernanetal.20_{(2012) Lsr150mg(828)vs.Lsr50mg(889) Age HR1.18[1.06-1.32]}l_{,olderage,per10yearsolder}

Diabetes HR1.77[1.42-2.22]l

RAASi HR1.51[1.21-1.89]l_{,150mgLsr(vs.50mg)}

HR1.76[1.40-2.22]l_,ARBuse

HR2.29[1.35-3.90]l_{,ACEiintoleranceduetoAE}

K+ HR2.57[2.15-3.07]l_{,bslK+,per1mmol/l}

Otherfactors HR1.41[1.03-1.93]l_{,bsldiureticuse}

HR1.20[1.11-1.30]l_{,Hb,per1g/dllower}

Rossignoletal.65_{(2014) Lsr150mg(828)vs.Lsr50mg(889)}

4.7(3.7-5.5)years

Diabetes HR1.361[1.152-1.608]d

CKD HR1.789[1.489-2.150]d_{,incident20%reductionineGFR}

HR0.984[0.980-0.989]d_,bsleGFR RAASi HR1.261[1.065-1.493]d_,MRA K+ HR2.517[2.217-2.858]d_,bslK+ Otherfactors HR0.942[0.892-0.996]d_,bslHb HR0.801[0.674-0.952]d_,white NYHAIII/IV,HR1.289[1.088-1.529]d RALES

RALESInvestigators64_{(1996) Sp12.5(41),25(44),50(46),or75(41)mgvs.placebo(40)}

12wk

CKD BslsCr RAASi DoseofSp

TypeofACEi(captoprilvs.other) RR2.93,highACEidosage

and RAASi in heart failure with reduced ejection fraction 533 Table3 (Continued)

Study(year) Interventionvs.control(n) Follow-updurationa

Riskfactor Estimate[95%CI] K+ BslK+

Vardenyetal.77_{(2012) Sp25-50mgqdvs.placebo RAASi OR3.7[2.5-5.7]}m_,Spusen

OR1.53[1.16-2.02]m_,Spusen_{,lowereGFRvs.highereGFR}

OR2.9[1.8-4.6]m_,Spuseo

OR3.1[2.2-4.4]m_,Spusep

OR3.8[1.2-6.4)m_,Spuseq

OR3.6[1.5-8.6]m_{,SpusewithWRF,withvs.withoutWRF}

Vardenyetal.14_{(2014) Sp25-50mgqd(822)vs.placebo(841)}

24months

Age HR1.02[1.0-1.03]r_,age/1year

Diabetes HR1.47[1.09-2.0]r

RAASi HR3.20[2.26-4.47]r_,Sp

HR1.04[1.03-1.05]r_{,doseofSp/12.5mg/day}

HR5.96[1.47-24.2]r_{,bslACEi/ARBuse}

K+ HR1.94[1.47-2.57]r_{,bslK+/1mmol/l}

Otherfactors HR1.51[1.11-2.05]r_,NYHA

HR0.53[0.31-0.90]r_,bslBBuse

HR1.09[1.0-1.2]r_{,bslSBP/10mmHg}

SOLVD

deDenusetal.41_{(2006) ACEiEna(3364)vs.placebo(3358)}

2.7(1.2)years

CKD HR1.29[1.01-1.65]r_,sCrmodel

OR1.55[1.23-1.95]r

HR1.85[1.32-2.59]r_{,renalfunction,sCrmodel}

HR1.30[1.11-1.52]r_{,renalfunction,CGmodel}

OR1.75[1.33-2.31]r_{,Crclearance30-59ml/min}

OR4.2[1.97-8.85]r_{,Crclearance<30ml/min}

RAASi HR1.94[1.56-2.40]r_{,Ena,sCrmodel}

HR1.92[1.54-2.39]r_,Ena,CGmodel

K+ HR1.26[1.20-1.33]r_{,bslK+/0.2-mmol/lincrease,sCrmodel}

HR1.26[1.19-1.32]r_{,bslK+/0.2-mmol/lincrease,CGmodel}

OR2.17[1.77-2.66]r_{,bslK+≥4.5mmol/l}

Otherfactors HR1.48[1.00-2.18]r_{,atrialfibrillation,sCrmodel}

HR1.53[1.04-2.26]r_{,atrialfibrillation,CGmodel}

HR1.60[1.08-2.36]r_{,bslNYHAIII/IV(vs.I),sCrmodel}

HR1.52[1.02-2.26]r_{,bslNYHAIII/IV(vs.I),CGmodel}

OR1.49[1.10-2.01]r_{,bslNYHAIII/IV}

HR2.00[1.29-3.10]r_{,bslloopdiureticuse,preventionphase,}

sCrmodel

HR1.97[1.26-3.07]r_{,bslloopdiureticuse,preventionphase,}

CGmodel TIME-CHF

Muzzarellietal.60_{(2012) ACEi+ARB,Sp,NT-BNP-guidedmedicalvs.standard}

symptom-guidedtherapy(566) 18months

C.

Fonseca

et

Table3 (Continued)

Study(year) Interventionvs.control(n) Follow-updurationa

Riskfactor Estimate[95%CI]

RAASi OR1.20[1.00-1.42]r_{,doseofSpper12.5mg}

OR2.52[1.45-4.35]r_{,dosechange25mg}

OR3.24[1.52-6.91]r_{,dosechange>25mg}

OR1.36[1.14-1.63]r_{,maximumdoseSpper12.5mg}

OR1.28[1.07-1.52]r_{,maximumdosechangesper12.5mg}

OR1.59[1.19-2.14]r_{,meandoseper12.5mg}

K+ OR2.92[1.75-4.89]r_,K+permmol/l

Otherfactors OR2.56[1.22-5.38]r_,gout

OR3.08[1.37-6.95]r_,NYHAIV a _{Valuesaremean,mean(SD),ormedian(IQR),unlessotherwisestated.}

b _{Hospitalizationwithadischargediagnosisofhyperkalemia.} c _{AdjustedforNYHAclass.}

d _{K+level>5.5mmol/l.} e _{K+level>6.0mmol/l.}

f _{Hyperkalemiareadmission,primarydiagnosiswithin30days.} g_{Hyperkalemiareadmission,anydiagnosiswithin30days.} h _{Hyperkalemiareadmission,anydiagnosiswithin1year.}

i_{K+level>5.9mmol/l.}

j _{Hyperkalemiaasserumpotassiumlevels≥10%upperboundofthenormalrangeofthepractice’sreferrallaboratory(most≥5.5mmol/l).} l_{Hyperkalemiaasaninvestigator-reportedAE.}

m _{Hyperkalemiaaspotassiumlevel>5.5mmol/loraninvestigator-reportedAE.} n _{BaselineeGFR<60ml/min/1.73m}2_{:Sp(390),placebo(402).}

o _{BaselineeGFR≥60ml/min/1.73m2:Sp(430),placebo(436).} p _{NoWRF:Sp(683),placebo(781).}

q _{WRF:Sp(139),placebo(60).} r _{Potassiumlevel>5.4mmol/l.} k_{Clinicallyimportanthyperkalemia.}

ACEi:angiotensin-convertingenzymeinhibitor;AE:adverseevent;ARB:angiotensinreceptorblocker;BB:betablocker;bsl:baseline;CI:confidenceinterval;CKD:chronickidneydisease; CG:Cockcroft-Gault;COMPARE-HF:ComparativeEffectivenessofTherapiesforHeartFailure;Cr:creatinine;eGFR:estimatedglomerularfiltrationrate;EMPHASIS-HF:EplerenoneinMild PatientsHospitalizationandSurvivalStudyinHeartFailure;Ena:enalapril;Epl:eplerenone;Hb:hemoglobin;Hct:hematocrit;HEAAL:HeartfailureEndpointevaluationofAngiotensinII AntagonistLosartan;HFrEF:heartfailurewithreducedejectionfraction;HK:hyperkalemia;HR:hazardratio;K+:potassiumlevel;Lsr:losartan;LT:longterm;MRA:mineralocorticoid receptorantagonist;NYHA:NewYorkHeartAssociationclass;OR:oddsratio;qd:oncedaily;RAASi:renin-angiotensin-aldosteronesysteminhibitors;RALES:RandomizedAldactone EvaluationStudy;RR:riskratio;SBP:systolicbloodpressure;sCr:serumcreatinine;SOLVD:StudiesofLeftVentricularDysfunction;Sp:spironolactone;ST:shortterm;TIME-CHF:Trialof IntensifiedversusStandardMedicalTherapyinElderlyPatientswithCongestiveHeartFailure;WRF:worseningrenalfunction.

Figure2 Prevalenceorincidenceofhyperkalemiainobservationalstudies(A)andinterventionalstudies(B)inpatientswithheart failurewithreducedejectionfractionreceivingrenin-angiotensin-aldosteronesysteminhibitors(RAASi),whichdefinedhyperkalemia asserumpotassiumlevels>5.5mmol/l(graybars)or>6.0mmol/l(blackbars).TheRAASianalyzedareindicatedbelowthestudy names.ACEi:angiotensin-convertingenzymeinhibitors;Alis:aliskiren;ARB:angiotensinreceptorblockers;ARTS:minerAlocorticoid ReceptorAntagonistTolerabilityStudy;ATMOSPHERE:AliskirenTrialtoMinimizeOutcomesinPatientswithHeartFailure;BB: beta-blockers;BIOSTAT-CHF:BiologyStudytoTailoredTreatmentinChronicHeartFailure;DESTINY-HF:DiovanEvaluationofSafetyTwIce vsoNcedailYstudyinHeartFailure;EMPHASIS-HF:EplerenoneinMildPatientsHospitalizationandSurvivalStudyinHeartFailure; Ena:enalapril;Epl:eplerenone;Fin:finerenone;HEAAL:HeartfailureEndpointevaluationofAngiotensinIIAntagonistLosartan; HF:heartfailure;K:potassium;PARADIGM-HF:Prospectivecomparisonofangiotensinreceptorneprilysininhibitorwith angiotensin-convertingenzymeinhibitortoDetermineImpactonGlobalMortalityandmorbidityinHeartFailure;RALES:RandomizedAldactone Evaluation Study;Sac:sacubitril; Sp:spironolactone; TIME-CHF:TrialofIntensified versus StandardMedical Therapy inElderly PatientswithCongestiveHeartFailure;Val:valsartan.

hematocrit <0.36,13 _{CKD alone}41,56 _{or concurrent with}

diabetes,58 _{and concomitant use of potassium-sparing}

diureticsplustrimethoprimorACEi58_(Table3).

The study selection process identified 83 reports con-tainingdataonprescription/use/discontinuationofRAASiin HFrEFpatients,ofwhich58werefromobservational stud-ies examining real-world clinical practice(Supplementary TableST4).Ofthe83reports,49(59%)didnotdescribeany reasonsforRAASidowntitrationordiscontinuation,while10 (12%)reportsdescribedthesereasonsbutdidnotspecifically includehyperkalemiaasareason.Finally,24(29%)reports includedhyperkalemiaasareasonforRAASidowntitration ordiscontinuation.

Twenty-four reports contained data on proportions of HFrEF patients in whom RAASi therapy was reduced or discontinued due to hyperkalemia. Of these, 11 reports were from observational studies7,8,46,47,50,57,67,69,73,75,78 _and

13 werefromclinical trials.20,28,30,31,43,48,61,62,70,71,79---81 _Data

onthe studies that reportedhyperkalemia asa reasonto reduceordiscontinueRAASitherapyinpatientswithHFrEF are summarized in Supplementary Table ST5. The ESC-HF

Long-TermRegistrywasthe firstpan-Europeanlarge-scale studytocollectandreportreasonsfornon-useorunderuse ofrecommendedRAASitargetdosesinthedailycareofHF, distinguishingHFrEFpatients.8_{Inreal-lifesettings,}

prescrip-tionoruselevelsofRAASiwerereportedtobefrom78%67_to

93%78_{forACEi/ARB,66%}7_to91%57_forACEi,12%57_to28%46_for

ARB,and16%46_to69%7_{forMRAinpatientswithHFrEF.}

More-over,anotherlarge-scalereal-lifestudy(QUALIFY)reported proportionsofthesepatientsatRAASitargetdosesof28%for ACEi,40%forARB,and99%forMRA.7_{AsshowninFigure3,}

regarding discontinuationor intoleranceof RAASi in real-lifesettings,theproportionofHFrEF patientsvariedfrom 3%8_to22%67 _{forACEi/ARB,hyperkalemiabeingreportedas}

areasonin 4%8,67 _to21%73 _{ofcases.Notably,MRAuse was}

reportedasdiscontinuedornottoleratedin3%8_to46%67_of

patients,withhyperkalemia beingreportedasareasonin 8%67_to36%8_{ofcases(Figure3).}

Data were collected from 17 reports (14

studies)12,16,19---21,30,37,39,40,42,45,49,50,52,53,65,66 _{on the effect}

ofhyperkalemia or ofRAASi downtitrationor discontinua-tionontheprognosisofpatientswithHFrEF(Supplementary

Figure3 Percentageofpatientswithheartfailurewithreducedejectionfractioninobservationalstudies(A)andinterventional studies(B)thathavearecordofdowntitrationordiscontinuationofrenin-angiotensin-aldosteronesysteminhibitor(RAASi)therapy duetohyperkalemia.Nottolerated(blackbars)correspondstodiscontinuationofRAASi;contraindicated(graybars)tonon-use, non-prescription, ordiscontinuation; anddowntitrated(whitebars) to dosereduction, non-uptitration,or notatRAASi target doses.TheRAASianalyzedareindicatedbelowthestudynames.ACEi:angiotensin-convertingenzymeinhibitors;Alis:aliskiren; ARB:angiotensinreceptorblockers;ARTS:minerAlocorticoidReceptorAntagonistTolerabilityStudy;ATMOSPHERE:AliskirenTrialto MinimizeOutcomesinPatientswithHeartFailure;Can:candesartan;CHARM:CandesartaninHeartFailure-AssessmentofReduction inMortalityandMorbidity; EMPHASIS-HF:Eplerenone inMild PatientsHospitalization andSurvival Study inHeartFailure; Ena: enalapril;Epl:eplerenone;ESC:EuropeanSocietyofCardiology;Fin:finerenone;HF:heartfailure;Lsr:losartan;LT:longterm; LVEF:left ventricular ejectionfraction;MRA:mineralocorticoidreceptorantagonists; PARADIGM-HF:Prospective comparisonof angiotensinreceptorneprilysininhibitorwithangiotensin-convertingenzymeinhibitortoDetermineImpactonGlobalMortalityand morbidityinHeartFailure;QUALIFY:QUAlityofadherencetoguidelinerecommendationsforLIfe-savingtreatmentinheartfailure: aninternationalsurveY:anobservationalstudy;Sac:sacubitril;SOLVD:StudiesofLeftVentricularDysfunction;Sp:spironolactone; TITRATION:SafetyandTolerabilityofInitiatingLCZ696inHeartFailurePatients;val:valsartan.

TableST6). Noreports werefound onthe effectofRAASi downtitrationor discontinuationspecificallydue to hyper-kalemia. Nevertheless, several real-life reports, e.g. GWTG-HF,45 _{Kane et al.}50_,QUALIFY52 _{and the TSOC-HFrEF}

registry,39 _{showedthatHFrEFpatientswhoreceivedlower}

RAASidosagesordiscontinuedRAASitherapy hadahigher risk of mortality and/or hospitalization than those who receivedhigherdosagesor continuedthetherapy.In addi-tion,a large-scale real-lifestudy by Juurlink etal.19 _and

clinicaltrialssuchasHEAAL20_{andEMPHASIS-HF}21_indicated

thathyperkalemiawasassociatedwithincreasedmortality and/or hospitalizations in patients with HFrEF receiving RAASi.

Discussion

This systematic review set out to examine the reporting ofhyperkalemiainpatientswithHFrEFreceivingRAASi.As

hyperkalemiaisassociatedwithworseoutcomes,ithasbeen describedasareasonforRAASidowntitrationor discontinu-ation,preventingoptimizedRAASitherapyinHFrEFpatients whomostbenefitfromthistherapy.Thefirstobjectiveinthis systematic reviewwastoexaminethereportingof preva-lenceandincidenceofhyperkalemiainpatientswithHFrEF receivingRAASi.Themostobviousfindingstoemergefrom theanalysisisthathyperkalemiaisfrequentin30%to63%of thesepatients,dependingonthestudysetting(clinicaltrial versusreal-life),backgroundHFtherapy(combinationRAASi therapy),age,and/orpresenceofcomorbiditiessuchasCKD or diabetes.Theseresultsmatchthoseobservedin recent reviews,whichsuggestthattheincidenceofhyperkalemiain clinicaltrialsisprobablyunderestimated.11,82_Thatis,

clin-icaltrialsusuallyselectsamplesofHFrEFpatientsatlower risk of developing hyperkalemia, for instance by exclud-ing patients with baseline creatinine >2.5mg/dl or eGFR <30ml/min/1.73m2_{. This might hinderthe extrapolation}