Comparing LAMA with LABA and LTRA as add-on therapies ...

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Advertisement nature npjprimarycarerespiratorymedicine reviewarticles article ComparingLAMAwithLABAandLTRAasadd-ontherapiesinprimarycareasthmamanagement DownloadPDF DownloadPDF Subjects AllergyAsthma AbstractTheGlobalInitiativeforAsthmarecommendsastepwiseapproachtoadjustasthmatreatmenttotheneedsofindividualpatients;inhaledcorticosteroids(ICS)remainthecorepharmacologicaltreatment.However,manypatientsremainpoorlycontrolled,andevidence-basedalgorithmstodecideonthebestorderandrationaleforadd-ontherapiesarelacking.Weexplorethechallengesofasthmamanagementinprimarycareandreviewoutcomesfromrandomisedcontrolledtrialsandmeta-analysescomparingthelong-actingmuscarinicantagonist(LAMA)tiotropiumwithlong-actingβ2-agonists(LABAs)orleukotrienereceptorantagonists(LTRAs)asadd-ontoICSinpatientswithasthma.Inadults,LAMAsandLABAsprovideagreaterimprovementinlungfunctionthanLTRAsasadd-ontoICS.Inchildren,resultswerepositiveandcomparablebetweentherapies,butdataarescarce.Thisinformationcouldaiddecision-makinginprimarycare,supportingtheuseofadd-ontherapytoICStohelpimprovelungfunction,controlasthmasymptomsandpreventexacerbations. IntroductionAsthmaisaseriousglobalhealthissuethataffectsallagegroups,withareported339millionsufferersworldwide,presentinganumberofchallengesforprimarycarephysicians1.Manypatientswithasthmaremainsymptomatic,despitetreatment,formultipledifferentreasons2,3,4,5,6.Ithasbeensuggestedthatpatientsmayoverestimateandthusinaccuratelyreporttheirlevelofdiseasecontrol,becausetheyacceptandtolerateacertainlevelofsymptoms,assumingthemtobeaninevitableconsequenceofasthma7,8.Physiciansmayunderestimatetheprevalenceandseverityofsymptomsandoverestimatethedegreetowhichthepatient’sasthmaiscontrolled,meaningthepatientmaynotreceiveadequatemedicationtoachievecontroloftheirdisease2,7.Reducingasthmasymptomsandfutureriskthroughcorrectadd-ontherapyandmanagementinpatientswhoremainuncontrolleddespitetreatmentisamajorchallengeforthoseworkinginbothsecondaryandprimarycare.TheGlobalInitiativeforAsthma(GINA)strategyrecommendsastepwiseapproachtoasthmamanagementinordertoachievesymptomcontrolandpreventfuturerisks,includingexacerbations,lossoflungfunction,andsideeffectsofmedication(Fig.1)9.Inhaledcorticosteroids(ICS)areconsideredaneffectivelong-termcontrollertreatmentinthemanagementofasthma10.However,ifasthmaremainsuncontrolleddespitemedium-doseICS,increasingthedoseofICSmaynotbeappropriateduetoanincreasedriskoflocalandsystemicsideeffectsandvariationinindividualICSdose-responsivenessbetweenpatients.Inaddition,mostoftheclinicalbenefitofICSuseisseenatlowdoses.Add-ontreatmentsmaythereforeberequired9.Inaddition,evidencesuggeststhattheICSdose–responsecurveisrelativelyflat,with80–90%ofthemaximumachievabletherapeuticeffectinadultasthmaobtainedat200–250 μgoffluticasonepropionateorequivalent(Fig.2);therefore,additionofanadd-ontherapymaybeconsideredtobeamoreeffectiveandsafertreatmentstrategy11,12,13.Fig.1:GINAtreatmentrecommendationsforpatientsaged≤5years,6–11yearsand≥12years9.©2020,GlobalInitiativeforAsthma,reproducedwithpermission.FEV1forcedexpiratoryvolumein1s,GINAGlobalInitiativeforAsthma,ICSinhaledcorticosteroid,Igimmunoglobulin,ILinterleukin,LABAlong-actingβ2-agonist,LTRAleukotrienereceptorantagonist,OCSoralcorticosteroid,SABAshort-actingβ2-agonist.FullsizeimageFig.2:Schematicdose–responsecurvesfordifferentoutcomesforefficacyandadverseeffectswithinhaledcorticosteroids,expressedasfluticasonepropionateinµg/day.ReprintedwithpermissionfromtheAmericanThoracicSociety.Copyright©2020AmericanThoracicSociety.Beasleyetal.12.FEV1forcedexpiratoryvolumein1 s,PEFpeakexpiratoryflow.FullsizeimageLong-actingβ2-agonist(LABA;e.g.salmeterol,formoterol,vilanterol,indicaterol14,15,16),leukotrienereceptorantagonist(LTRA;e.g.montelukastandzafirlukast[discontinued]15,17)andlong-actingmuscarinicantagonist(LAMA;tiotropium18[theonlyLAMAcurrentlyindicatedforuseinpatientswithasthma])add-oncontrollertherapieshavebeenshowntoimprovelungfunctionandasthmacontrolandreduceexacerbationsinasthmapatients,havesafetyprofilessimilartoplacebo,andarecurrentlyindicatedforuseinpatientswithasthma.Moreinformationontheseclassesofagents,includingindicationsandtheirmodesofaction,isdetailedinTable1.Table1Drugnames,indicationsandmodeofactionofLABAs,LTRAsandLAMAs.FullsizetableWithmultipleadd-ontherapiesavailableforthemanagementofasthma,therehavebeenseveralsystematicreviewspublishedthatevaluatetheefficacyandsafetyofadd-ontherapiescomparedwitheitherplacebooranotheradd-ontherapy14,15,16,17,19,20.However,nonecompareLABA,LTRAandLAMAasadd-ontreatmentstoICSinasingleconsolidatedreview,andtherearenohead-to-headtrialsevaluatingallthreetreatmentswithinthesametrial.Herewesystematicallyanalyseandreviewtheliteraturetoexplorethechallengesofasthmamanagement,theimpactofpoorasthmacontrolonpatients’livesandcompareoutcomesfrompublishedstudies.Weexaminetheeffectofthreeadd-ontreatmentsonlungfunction,asthmacontrol,exacerbationsandsafety,withtheaimofassistingprimarycarephysiciansinselectingthemostappropriateadd-ontreatmenttoICS.ResultsSearchresultsTheliteraturesearchidentified14relevantpublicationsthatmettheinclusioncriteriaforthisreview:2Cochranereviewsand12additionalrandomisedcontrolledtrials(RCTs)thatwerenotincludedwithintheCochranereviews. ThesearchstringsforLABAstudiesgenerated164publications,ofwhich1meta-analysisand4additionalRCTsmetthecriteriaforinclusioninthisreview16,21,22,23. ThesearchstringsforLTRAstudiesgenerated54publications,ofwhich3RCTsmetthecriteriaforinclusioninthisreview24,25,26. ThesearchstringsforLAMAstudiesgenerated106publications,ofwhich8RCTsmetthecriteriaforinclusioninthisreview21,22,27,28,29,30,31. AsthmacontrolinadultpatientsLABA(salmeterol)significantlyimprovedasthmacontrolwhenaddedtoICScomparedwithplacebo(measuredbyAsthmaControlQuestionnaire[ACQ])21.TheLTRA(montelukast)didnothaveaneffectonasthmacontrolwhencomparedwithplacebo(measuredbyACQ)(Table2)32.DataforLAMA(tiotropium)aremorevaried(Table2)21,27,28,29,30,31.Paggiaroetal.reportedthattherewasnodifferenceofeffectbetweentiotropium(5 µgand2.5 µg)andplaceboonACQscore.FourpaperscomparedtheeffectofLABAsdirectlywithtiotropium.TherewasnosignificantdifferencebetweenLABAsandtiotropiumonasthmacontrolasmeasuredbyACQ(Table2)21,33,34.OnestudyincludeddifferenceinMini-AsthmaQualityofLifeQuestionnaire(Mini-AQLQ)responsescoresasasecondaryefficacyendpoint.Atstudyendpointat16weeks,salmeterol(50 µg)significantlyimprovedoverallMini-AQLQscorecomparedwithplacebo,buttherewasnosignificantdifferenceinresponsescoresbetweenthetiotropium(5 µg)andplacebogroups.Whendirectlycompared,therewasnodifferenceintreatmentresponsebetweensalmeterol(50 µg)andtiotropium(5 µg)atstudyendpoint22.Nostudiescomparedasthmacontrol,measuredbyACQ,inLABAvsLTRAortiotropiumvsLTRA.Table2ACQ-7responderrates,exacerbationsandAEs.FullsizetableLungfunctioninadultpatientsLABAssignificantlyimprovedforcedexpiratoryvolumein1 s(FEV1),morningandeveningpeakexpiratoryflow(PEF)(salmeterol/formoterol)andforcedvitalcapacity(FVC)(salmeterol)comparedwithplaceboorICSalone(Figs.3–5)16,21,22,23.TheliteraturereportingtheeffectofLTRAsasadd-ontoICSonlungfunctionisvaried(Figs.3–5),suggestingnobeneficialeffectofmontelukastonFEV1orFVCcomparedwithICSalone24.ResultsfortheeffectofmontelukastonPEFareconflicting.Onlyonestudyofzafirlukast(nowdiscontinued)wasidentified,withtheauthorsreportingsignificantimprovementsinFEV1andbothmorningandeveningPEFcomparedwithplacebo26.Fig.3:MeandifferenceinFEV1.ALAACRCAmericanLungAssociationAsthmaClinicalResearchCenters,AUCareaundercurve,BIDtwicedaily,CIconfidenceinterval,FEV1forcedexpiratoryvolumein1 s,LABAlong-actingβ2-agonist,LAMAlong-actingmuscarinicagonist,LTRAleukotrienereceptorantagonist,NRnotreported,NSnon-significant,QDoncedaily.FullsizeimageFig.4:MeandifferenceinPEF.BIDtwicedaily,CIconfidenceinterval,LABAlong-actingβ2-agonist,LAMAlong-actingmuscarinicagonist,LTRAleukotrienereceptorantagonist,NRnotreported,NSnon-significant,PEFpeakexpiratoryflow,QDoncedaily.FullsizeimageFig.5:MeandifferenceinFVC.ALAACRCAmericanLungAssociationAsthmaClinicalResearchCenters,AUCareaundercurve,BIDtwicedaily,CIconfidenceinterval,FVCforcedvitalcapacity,LABAlong-actingβ2-agonist,LAMAlong-actingmuscarinicagonist,LTRAleukotrienereceptorantagonist,NRnotreported,NSnon-significant,QDoncedaily.FullsizeimageOfthesevenavailablestudiesofLAMAs(tiotropium),allbuttwotrialarmsfromtwostudiesreportedsignificantimprovementsinFEV1(peak,troughandareaunderthecurve[AUC])andFVCcomparedwithplacebo(Figs.3,5)21,22,27,28,29,30,31.Inallthepublishedstudiesinadults21,22,27,28,29,30,31,tiotropiumsignificantlyimprovedmorningandeveningPEFcomparedwithplaceboorICSalone,exceptforonetiotropium2.5 µgtrialarm,whichreportednosignificantdifferencebetweentiotropiumandplaceboontroughPEFresponse(Fig.4)29.AsystematicreviewcomparingtheuseofLABAswithLTRAsasadd-ontoICSreportedthatLABAs(salmeterolorformoterol)haveasignificantlygreatereffectonFEV1andPEFcomparedwithLTRAs(montelukastorzafirlukast)(Figs.3,4)15.TherearenodataavailablecomparingtheeffectofLABAsandLTRAsonFVC.FourpaperscomparedtheeffectoftiotropiumwiththeLABAssalmeterolandformoterolonlungfunctionparameters(Figs.3,4)33.ExacerbationsinadultpatientsLABAsprovidednumericalimprovementinthenumberofpatientsreportingatleastoneexacerbationcomparedwithplacebo(Table2)21,22,23.DataforLTRAs(montelukastandzafirlukast[nowdiscontinued])arevaried(Table2).LAMA(tiotropium)bothsignificantlyandnon-significantlyreducedthenumberofpatientsexperiencingatleastoneexacerbation(Table2)27.Ameta-analysiscomparingLABAwithLTRAreporteda2%reductioninriskofexacerbationsinpatientsusingLABA+ICSvsLTRA+ICScombinationtherapy(Table2)15.BothtiotropiumandLABAshadacomparableeffectontheriskofexacerbations21,22,33,34.SafetyinadultpatientsOverall,comparableproportionsofpatientsreportadverseevents(AEs)withLABA,LTRAandtiotropiumtreatmentasadd-ontoICSwithbothplaceboandwithoneanother(Table2)15,21,22,23,25,26,27,28,29,30,31,34.EfficacyandsafetyofLABAs,LTRAsandLAMAsinpaediatricpatientsArecentsystematicreviewbyVogelbergetal.comparedtheefficacyandsafetyofLABAs,LTRAsandLAMAs(tiotropium)inpaediatricpatientsaged4–17yearswithasthma35.LABAtreatmentasadd-ontoICSimprovedlungfunctionwhencomparedwithplacebo,asmeasuredbyFEV1andFEV1%predicted.Therewasnodifferenceinriskofexacerbationsrequiringoralcorticosteroid(OCS)betweenLABAsplusICScomparedwithICSalone,althoughitshouldbenotedthatnotalltrialswerepoweredtoassessexacerbations.TheproportionofpatientsexperiencingAEsorseriousAEs(SAEs)withtheadditionofLABAtoICSwasbroadlysimilar35.AnadditionalRCTof512patientsaged5–12yearswithpersistentasthmareportedimprovementsinlungfunctionandasthmacontrol,andnodifferencesinriskofexacerbationsandAEs,inpatientsreceivingLABAs(formoterol)comparedwiththosereceivingplaceboasadd-ontoICS36.However,inasystematicreviewcomparingLABAplusICSvshigher-doseICSinchildrenwithasthma,combinationtherapyledtoatrendtowardsanincreasedriskoforalsteroid-treatedexacerbationsandhospitaladmissions16.ForLTRA(montelukast),astudybySimonsetal.describedagreaterimprovementfrombaselineFEV1inpatientsreceivingmontelukastcomparedwithplacebo37.Inaddition,asystematicreviewfoundanimprovementinbaselineFEV1andFEV1%predictedinpatientsreceivingICSplusmontelukastcomparedwiththosereceivingICSplusplacebo,butthesedifferenceswerenotsignificant19.Therewasnodifferencebetweenmontelukastandplaceboasadd-ontoICSintheriskofexacerbations19.LimitedavailabledatasuggestthattheproportionofpatientsexperiencingAEswiththeadditionofmontelukasttoICSiscomparablewiththosereceivingplaceboasadd-ontoICS37.TiotropiumimprovedFEV1andFEV1%predictedasadd-ontoICSwithorwithoutadditionalcontrollertherapies21,27,28,38,39,40,41,42.TheproportionofpaediatricpatientswithexacerbationsrequiringOCSwaslowinallstudiesincludedwithinthereviewbyVogelbergetal.35.ThereviewauthorsalsoconcludedthattherewasnoincreaseinthenumberofpatientswithAEsorSAEswithtiotropiumcomparedwithplaceboasadd-ontoICSoradd-ontoICSplusothercontrollers15,21,22,23,25,26,27,28,29,30,31,34.Anadditionalstudyof102patientsaged1–5yearswithpersistentasthmasymptomsreportedsimilarfindings,withthenumberofpatientsreportingAEssimilarinthosewhoreceivedtiotropiumasadd-ontoICStothosewhoreceivedplaceboasadd-on42.TherewerefewerpublishedstudiesontheefficacyandsafetyofLABAs,LTRAsandLAMAsasadd-ontoICSinpatientsaged<5yearscomparedwithstudiesinolderagegroups42,43,44,45.AnRCTof12patientswithasthmaaged2–5yearsreportedthatLABA(formoterol)asadd-ontoICSprovidedrapidandsustainedbronchodilationfor≥8 hcomparedwithplacebo45.A12-weekRCTof689patientswithpersistentasthma(≥3episodesofasthmasymptomsduringthepreviousyear)aged2–5yearsreportedthatLTRA(montelukast)asadd-ontoICS(inatleast50%ofparticipants)improvedmultipleparametersofasthmacontrol,includingdaytimeandovernightasthmasymptomsandthepercentageofdayswithoutasthmasymptomsorasthmacomparedwithplacebo.TherewerenoreporteddifferencesinthefrequencyofreportedAEs44.Similarly,Bisgaardetal.reportedthat,inpatientsaged2–5yearswithintermittentasthma,montelukastsignificantlyreducestherateofasthmaexacerbationsanddelayedthemediantimetofirstexacerbationcomparedwithplaceboover12months.However,patientsinthistrialdidnotreceivemontelukastasadd-ontoICS43.A12-weekRCTof102childrenaged1–5yearsbyVrijlandtetal.reportedthattiotropiumasadd-ontoICSwithorwithoutadditionalcontrollermedicationswasassociatedwithfewerreportedAEsorasthmaexacerbationscomparedwithplacebo.TherewasnosignificantdifferenceinadjustedweeklymeancombineddaytimeasthmasymptomscorebetweenbaselineandWeek12betweenthetiotropiumandplacebogroups42.DiscussionThelong-termaimsofasthmamanagementaresymptomcontrol,reductionofthefutureriskofexacerbationsandairflowlimitation,whileatthesametimeminimisingtreatmentsideeffects9.Althoughmajoradvanceshavebeenmadeinasthmatreatmentandmanagement,therestillremainmanypatientswhohavepoorasthmacontrolandmaintainthepotentialriskofworseningoftheirsymptoms,aswellasanincreasedriskofexacerbations,andunscheduledurgentandemergencycarevisitsandhospitalisations46,47.Foradults,adolescentsandchildren,thereisaneedforeffectiveadd-ontreatmentsasanalternativetoincreasingtheICSdosealone,aslong-term,high-doseICSuseisassociatedwithanincreasedriskofsideeffects9.ThefindingsfromthisliteraturereviewsuggestthatLABAs,LTRAsandtiotropiumhavesimilarsafetyprofilesinbothadultandpaediatricpopulations(Table2).Therefore,comparingthereportedefficacyofthethreeadd-ontreatmentsineachpatientpopulationcouldassistwithdecision-making.GreaterimprovementsinlungfunctionhavebeenreportedwithLABAsandLAMAsvsLTRAsinadults(Figs.3–5).Inaddition,thereappearstobegreaterimprovementsinasthmacontrolandexacerbationswithLABAsandLAMAsasadd-ontherapiesthanwithLTRAsinthispopulation.Muchoftheavailableevidenceforasthmamanagementisbasedonresearchcarriedoutinadults,whichleadstoagreaterrestrictionoflicensingofmedicationinchildren48,creatingadditionaldifficultiesinselectingthemostappropriatetreatmentoptionforpaediatricpatientswithasthma49.Despiteadvancesincare,asthmastillpresentsaburdenwithinthispopulation,withmanychildrenremainingsymptomaticanduncontrolled50.Datainpatientsaged<18yearsarecurrentlylimitedduetoinherentdifficultiesinthestudyofthispopulation;however,availableevidencesuggeststhatLABAsandtiotropiumhavecomparableeffectswithrespecttolungfunction,asthmacontrolandexacerbations.OftheLABAs,LTRAsandLAMAsreviewedhere,theLTRAmontelukastistheonlyadd-ontreatmentthatisindicatedforuseinpatientsaged<4years(asachewabletablet51)andtheonlyadd-ontreatmentrecommendedforuseinpatientsaged≤5yearsasanoptionalcontrollertreatment9.ClinicaltrialsofLTRAsinchildrenaged≤5yearshavenotdemonstratedanysafetyconcerns52.However,in2020,theU.S.FoodandDrugAdministration(FDA)determinedthataboxedwarningfortheLTRAmontelukastwasappropriateduetotheriskofmentalhealthsideeffects,andadvisedthathealthcareprofessionals(HCPs)considerthebenefitsandrisksofmentalhealthsideeffectsbeforeprescribingmontelukast53.Despitelesspublishedevidenceregardinguseofadd-ontherapiesinpaediatricpatients(aged<18years)thaninadultpatients(aged≥18years),currentavailabledatasuggestthatallthreeadd-ontherapieshavecomparablesafetyprofiles,withLABAsandLAMAsprovidinggreaterimprovementsinlungfunctionthanLTRAs.Whenselectingthemostappropriateadd-ontherapyforpaediatricpatients,itisimportanttoconsiderthereportedefficacy,safetydataandsubsequentpost-marketingsafetywarnings(ifapplicable)andtheindicationsoftheseadd-ontherapies,asnotallareappropriateforallageranges(Table1).Whensteppingupasthmatherapyandconsideringadd-ontherapy,itisimportanttoreviewtheoptionsavailable,toinvolvepatientsindecisionsabouttheirtreatmentandtokeepadialoguebetweenpatientsandHCPs46.Anup-to-dateindividualisedasthmaactionplancanhelptokeeparecordofanyattemptedtreatmentapproachesandhelpthepatienttoself-manage54.Theactionplansshouldbediscussedandagreedwithpatientsandreviewedatregularintervalstomakesurethattheyremainuptodateandarefitforpurpose54.Poorasthmacontrolleadstounfavourableoutcomes,morefrequentexacerbations,irreversiblelossoflungfunctionandevenasthma-relateddeaths.Add-ontherapywithLABA,LAMAorLTRAshouldbeconsideredwhenasthmasymptomsremainuncontrolledwithatleastmedium–highICS.Primarycarepractitionerscanandshouldregularlyassesssymptomcontrolfollowingassessmentofadherence,triggers,devicetechniqueandcomorbidities.TherapyshouldbesteppedupasrecommendedinGINAguidelinesinordertoattainoptimalcontrol,consideringindividualsymptoms,lungfunction,comorbidities,inhalertechnique,adherenceandpatientpreferenceasimportantparametersforapersonalisedchoice.Inconclusion,inadults,LAMAsandLABAsappeartoprovideagreaterimprovementinlungfunctionthanLTRAsasadd-ontoICS,althoughtherearenoindividualstudiesthatdirectlycompareLAMAswithLTRAs.LAMAsappeartobeaneffectivealternativetoLABAsforattainingasthmacontrol,optimisinglungfunctionandpreventingexacerbations,withapossiblehigherlungfunctionbenefitofLAMAscomparedwithLABAs.Datainpatientsaged<18yearsarecurrentlylimitedduetoinherentdifficultiesinthestudyofthispopulation.CurrentavailableevidencefromclinicaltrialssuggeststhatLABAs,LTRAsandLAMAshavecomparablesafetyprofiles,withLABAsandLAMAsprovidinggreaterimprovementsinlungfunctionthanLTRAs,yetitshouldbenotedtheFDAhaveadvisedaboxedwarningfortheLTRAmontelukastduetoriskofmentalhealthsideeffects.Asthmashouldbetreatedinaccordancewithcurrentguidelines,withregularchecksmadetoensuresymptomsarecontrolled,aswellasensuringoptimalstrategiesareinplacetopreventexacerbationsandachievebestlungfunction.Ifcontrolisnotachieved,treatmentshouldbesteppedup,ensuringthatfactorsthatmayinfluencecontrol(suchasadherence,administrationtechnique,allergictriggersandcomorbidities)areaddressedforeachindividualpatient.MethodsOurliteraturesearchwasconductedinPubMed.Forthecomparisonofadd-ontherapies,weidentifiedRCTsandmeta-analysesthatcomparedtheLAMAtiotropiumwithLABAsorLTRAs(directlyorwithplacebo)asadd-ontoICSinpatientswithasthma.DatafromRCTsof≥4weeks’durationinallpatientswithasthmaofallagegroups,reportingchangeinFEV1,asthmacontrol,exacerbationsandAEswereincluded.Datawereextractedfrompublishedmanuscriptsandpubliclyavailableonlinedata.Wecheckedthereferencelistsofthesystematicreviewsforreferenceswithanyadditionaldataforendpointsthatwerenotdescribedinthesystematicreviewsandtoensurethatalltrialsmettheinclusioncriteria77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116.SearchstringsaredetailedinSupplementaryMethods.ReportingsummaryFurtherinformationonresearchdesignisavailableintheNatureResearchReportingSummarylinkedtothisarticle. ReferencesGlobalAsthmaNetwork.TheGlobalAsthmaReport2018.http://www.globalasthmareport.org/Global%20Asthma%20Report%202018.pdf(2018).Chapman,K.R.,Boulet,L.P.,Rea,R.M.&Franssen,E.Suboptimalasthmacontrol:prevalence,detectionandconsequencesingeneralpractice.Eur.Respir.J.31,320–325(2008).CAS  Article  PubMed  GoogleScholar  Peters,S.P.,Ferguson,G.,Deniz,Y.&Reisner,C.Uncontrolledasthma:areviewoftheprevalence,diseaseburdenandoptionsfortreatment.Respir.Med.100,1139–1151(2006).Article  PubMed  GoogleScholar  Sapra,S.J.,Broder,M.S.&Chang,E.AlignmentwiththerevisedNHLBI2007AsthmaGuidelines,ExpertPanelReport3(EPR3)inalargepayerdatabase.J.AllergyClin.Immunol.123,S117(2009).Article  GoogleScholar  Stempel,D.A.,McLaughin,T.P.,Stanford,R.H.&Fuhlbrigge,A.L.Patternsofasthmacontrol:a3-yearanalysisofpatientclaims.J.AllergyClin.Immunol.115,935–939(2005).Article  PubMed  GoogleScholar  Rabe,K.F.etal.Worldwideseverityandcontrolofasthmainchildrenandadults:theglobalasthmainsightsandrealitysurveys.J.AllergyClin.Immunol.114,40–47(2004).Article  PubMed  GoogleScholar  Horne,R.etal.Canasthmacontrolbeimprovedbyunderstandingthepatient’sperspective?BMCPulm.Med.7,8(2007).Article  PubMed  PubMedCentral  GoogleScholar  Kritikos,V.etal.Amultinationalobservationalstudyidentifyingprimarycarepatientsatriskofoverestimationofasthmacontrol.NPJPrim.CareRespir.Med.29,43(2019).Article  PubMed  PubMedCentral  GoogleScholar  GlobalInitiativeforAsthma.Globalstrategyforasthmamanagementandprevention(2020report)https://ginasthma.org/wp-content/uploads/2020/04/GINA-2020-full-report_-final-_wms.pdf(2020).Kew,K.M.,Quinn,M.,Quon,B.S.&Ducharme,F.M.Increasedversusstabledosesofinhaledcorticosteroidsforexacerbationsofchronicasthmainadultsandchildren.CochraneDatabaseSyst.Rev.CD007524(2016).Jackson,D.J.etal.Quintuplinginhaledglucocorticoidstopreventchildhoodasthmaexacerbations.N.Engl.J.Med.378,891–901(2018).CAS  Article  PubMed  PubMedCentral  GoogleScholar  Beasley,R.etal.Inhaledcorticosteroidtherapyinadultasthma.Timeforanewtherapeuticdoseterminology.Am.J.Respir.Crit.CareMed.199,1471–1477(2019).CAS  Article  PubMed  GoogleScholar  Lemanske,R.F.Jretal.Step-uptherapyforchildrenwithuncontrolledasthmareceivinginhaledcorticosteroids.N.Engl.J.Med.362,975–985(2010).CAS  Article  PubMed  PubMedCentral  GoogleScholar  Chauhan,B.F.,Chartrand,C.,NiChroinin,M.,Milan,S.J.&Ducharme,F.M.Additionoflong-actingbeta2-agoniststoinhaledcorticosteroidsforchronicasthmainchildren.CochraneDatabaseSyst.Rev.CD007949(2015).Chauhan,B.F.&Ducharme,F.M.Additiontoinhaledcorticosteroidsoflong-actingbeta2-agonistsversusanti-leukotrienesforchronicasthma.CochraneDatabaseSyst.Rev.CD003137(2014).Ducharme,F.M.,NiChroinin,M.,Greenstone,I.&Lasserson,T.J.Additionoflong-actingbeta2-agoniststoinhaledcorticosteroidsversussamedoseinhaledcorticosteroidsforchronicasthmainadultsandchildren.CochraneDatabaseSyst.Rev.5,CD005535(2010). GoogleScholar  Ducharme,F.,Schwartz,Z.,Hicks,G.&Kakuma,R.Additionofanti-leukotrieneagentstoinhaledcorticosteroidsforchronicasthma.CochraneDatabaseSyst.Rev.CD003133(2004).Anderson,D.E.,Kew,K.M.&Boyter,A.C.Long-actingmuscarinicantagonists(LAMA)addedtoinhaledcorticosteroids(ICS)versusthesamedoseofICSaloneforadultswithasthma.CochraneDatabaseSyst.Rev.CD011397(2015).Castro-Rodriguez,J.A.&Rodrigo,G.J.Theroleofinhaledcorticosteroidsandmontelukastinchildrenwithmild-moderateasthma:resultsofasystematicreviewwithmeta-analysis.Arch.Dis.Child.95,365–370(2010).Article  PubMed  GoogleScholar  Sobieraj,D.M.etal.Associationofinhaledcorticosteroidsandlong-actingmuscarinicantagonistswithasthmacontrolinpatientswithuncontrolled,persistentasthma:asystematicreviewandmeta-analysis.JAMA319,1473–1484(2018).CAS  Article  PubMed  PubMedCentral  GoogleScholar  Kerstjens,H.A.etal.Tiotropiumorsalmeterolasadd-ontherapytoinhaledcorticosteroidsforpatientswithmoderatesymptomaticasthma:tworeplicate,double-blind,placebo-controlled,parallel-group,active-comparator,randomisedtrials.LancetRespir.Med.3,367–376(2015).CAS  Article  PubMed  GoogleScholar  Bateman,E.D.etal.TiotropiumisnoninferiortosalmeterolinmaintainingimprovedlungfunctioninB16-Arg/Argpatientswithasthma.J.AllergyClin.Immunol.128,315–322(2011).CAS  Article  PubMed  GoogleScholar  Paggiaro,P.etal.HighstrengthextrafinepMDIbeclometasone/formoterol(200/6μg)iseffectiveinasthmapatientsnotadequatelycontrolledonmedium-highdoseofinhaledcorticosteroids.BMCPulm.Med.16,180(2016).Article  CAS  PubMed  PubMedCentral  GoogleScholar  Djukanovic,R.etal.Montelukastaddedtofluticasonepropionatedoesnotalterinflammationoroutcomes.Respir.Med.104,1425–1435(2010).Article  PubMed  GoogleScholar  Vaquerizo,M.J.etal.Effectofmontelukastaddedtoinhaledbudesonideoncontrolofmildtomoderateasthma.Thorax58,204–210(2003).CAS  Article  PubMed  PubMedCentral  GoogleScholar  Virchow,J.C.Jr,Prasse,A.,Naya,I.,Summerton,L.&Harris,A.Zafirlukastimprovesasthmacontrolinpatientsreceivinghigh-doseinhaledcorticosteroids.Am.J.Respir.Crit.CareMed.162,578–585(2000).Article  PubMed  GoogleScholar  Kerstjens,H.A.etal.Tiotropiuminasthmapoorlycontrolledwithstandardcombinationtherapy.N.Engl.J.Med.367,1198–1207(2012).CAS  Article  PubMed  GoogleScholar  Paggiaro,P.etal.Theeffectoftiotropiuminsymptomaticasthmadespitelow-tomedium-doseinhaledcorticosteroids:arandomizedcontrolledtrial.J.AllergyClin.Immunol.Pract.4,104–113(2016).e102.Article  PubMed  GoogleScholar  Ohta,K.etal.Long-termonce-dailytiotropiumRespimat(R)iswelltoleratedandmaintainsefficacyover52weeksinpatientswithsymptomaticasthmainJapan:arandomised,placebo-controlledstudy.PLoSONE10,e0124109(2015).Article  CAS  PubMed  PubMedCentral  GoogleScholar  Beeh,K.M.etal.TiotropiumRespimat(R)inasthma:adouble-blind,randomised,dose-rangingstudyinadultpatientswithmoderateasthma.Respir.Res.15,61(2014).Article  PubMed  PubMedCentral  GoogleScholar  Timmer,W.etal.Once-dailytiotropiumRespimat((R))5mugisanefficacious24-hbronchodilatorinadultswithsymptomaticasthma.Respir.Med.109,329–338(2015).Article  PubMed  GoogleScholar  AmericanLungAssociationAsthmaClinicalResearchCenters.Clinicaltrialoflow-dosetheophyllineandmontelukastinpatientswithpoorlycontrolledasthma.Am.J.Respir.Crit.CareMed.175,235–242(2007).Article  CAS  GoogleScholar  Peters,S.P.etal.Tiotropiumbromidestep-uptherapyforadultswithuncontrolledasthma.N.Engl.J.Med.363,1715–1726(2010).CAS  Article  PubMed  PubMedCentral  GoogleScholar  Wechsler,M.E.etal.Anticholinergicvslong-actingbeta-agonistincombinationwithinhaledcorticosteroidsinblackadultswithasthma:theBELTrandomizedclinicaltrial.JAMA314,1720–1730(2015).CAS  Article  PubMed  GoogleScholar  Vogelberg,C.etal.Acomparisonoftiotropium,long-actingβ2-agonistsandleukotrienereceptorantagonistsonlungfunctionandexacerbationsinpaediatricpatientswithasthma.Respir.Res.21,19(2020).CAS  Article  PubMed  PubMedCentral  GoogleScholar  Płoszczuk,A.,Bosheva,M.,Spooner,K.,McIver,T.&Dissanayake,S.Efficacyandsafetyoffluticasonepropionate/formoterolfumarateinpediatricasthmapatients:arandomizedcontrolledtrial.Ther.Adv.Respir.Dis.12,1–15(2018).Article  CAS  GoogleScholar  Simons,F.E.etal.Montelukastaddedtobudesonideinchildrenwithpersistentasthma:arandomized,double-blind,crossoverstudy.J.Pediatr.138,694–698(2001).CAS  Article  PubMed  GoogleScholar  Hamelmann,E.etal.Arandomisedcontrolledtrialoftiotropiuminadolescentswithseveresymptomaticasthma.Eur.Respir.J.49,1601100(2017).Article  CAS  PubMed  PubMedCentral  GoogleScholar  Hamelmann,E.etal.Tiotropiumadd-ontherapyinadolescentswithmoderateasthma:a1-yearrandomizedcontrolledtrial.J.AllergyClin.Immunol.138,441–450(2016).e448.CAS  Article  PubMed  GoogleScholar  Szefler,S.J.etal.AphaseIIIrandomizedcontrolledtrialoftiotropiumadd-ontherapyinchildrenwithseveresymptomaticasthma.J.AllergyClin.Immunol.140,1277–1287(2017).CAS  Article  PubMed  GoogleScholar  Vogelberg,C.etal.Tiotropiumadd-ontherapyimproveslungfunctioninchildrenwithsymptomaticmoderateasthma.J.AllergyClin.Immunol.Pract.6,2160.e9–2162.e9(2018).Article  GoogleScholar  Vrijlandt,E.J.L.E.etal.Safetyandefficacyoftiotropiuminchildrenaged1–5yearswithpersistentasthmaticsymptoms:arandomised,double-blind,placebo-controlledtrial.LancetRespir.Med.6,127–137(2018).CAS  Article  PubMed  GoogleScholar  Bisgaard,H.etal.Montelukastreducesasthmaexacerbationsin2-to5-year-oldchildrenwithintermittentasthma.Am.J.Respir.Crit.CareMed.171,315–322(2005).Article  PubMed  GoogleScholar  Knorr,B.etal.Montelukast,aleukotrienereceptorantagonist,forthetreatmentofpersistentasthmainchildrenaged2to5years.Pediatrics108,E48(2001).CAS  Article  PubMed  GoogleScholar  Nielsen,K.G.&Bisgaard,H.Bronchodilationandbronchoprotectioninasthmaticpreschoolchildrenfromformoteroladministeredbymechanicallyactuateddry-powderinhalerandspacer.Am.J.Respir.Crit.CareMed.164,256–259(2001).CAS  Article  PubMed  GoogleScholar  Buhl,R.&Hamelmann,E.Futureperspectivesofanticholinergicsforthetreatmentofasthmainadultsandchildren.Ther.Clin.RiskManag.15,473–485(2019).CAS  Article  PubMed  PubMedCentral  GoogleScholar  Aalbers,R.&Park,H.S.Positioningoflong-actingmuscarinicantagonistsinthemanagementofasthma.AllergyAsthmaImmunol.Res.9,386–393(2017).CAS  Article  PubMed  PubMedCentral  GoogleScholar  Cates,C.J.Currentchallengesinasthma.Br.J.Gen.Pract.57,179–180(2007).PubMed  PubMedCentral  GoogleScholar  Vogelberg,C.Preschoolchildrenwithpersistentasthmaticsymptoms.Ther.Clin.RiskManag.15,451–460(2019).Article  PubMed  PubMedCentral  GoogleScholar  Hossny,E.etal.Theuseofinhaledcorticosteroidsinpediatricasthma:update.WorldAllergyOrgan.J.9,26(2016).Article  CAS  PubMed  PubMedCentral  GoogleScholar  AccordHealthcareLimited.Montelukast10mgfilmcoatedtablets.Summaryofproductcharacteristics.June2019.https://www.medicines.org.uk/emc/product/1243/smpc(2019).Doherty,G.M.Ismontelukasteffectiveandwelltoleratedinthemanagementofasthmainyoungchildren?:PartA:Evidence-basedanswerandsummary.Paediatr.ChildHealth12,307–308(2007).Article  PubMed  PubMedCentral  GoogleScholar  U.S.Food&DrugAdministration.FDArequiresBoxedWarningaboutseriousmentalhealthsideeffectsforasthmaandallergydrugmontelukast(Singulair);advisesrestrictinguseforallergicrhinitis.https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-boxed-warning-about-serious-mental-health-side-effects-asthma-and-allergy-drug(2020).Pinnock,H.Supportedself-managementforasthma.Breathe11,98–109(2015).Article  PubMed  PubMedCentral  GoogleScholar  MerckSharp&DohmeLimited.Singulairpaediatric4mgtablets.Summaryofproductcharacteristics.October2018.https://www.medicines.org.uk/emc/product/6500/smpc(2018).MerckSharp&DohmeLimited.Singulairpaediatric5mgchewabletablets.Summaryofproductcharacteristics.October2018.https://www.medicines.org.uk/emc/product/197/smpc(2018).BoehringerIngelheimLimited.SpirivaRespimat2.5microgram,inhalationsolution.Summaryofproductcharacteristics.April2018.https://www.medicines.org.uk/emc/product/407/smpc(2018).GlaxoSmithKlineUK.SereventAccuhaler.SummaryofProductCharacteristics.October2018.https://www.medicines.org.uk/emc/product/848/smpc(2018).GlaxoSmithKline.HighlightsofprescribinginformationforSEREVENTDISKUS(salmeterolxinafoateinhalationpowder),fororalinhalationuse.December2018.https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Serevent_Diskus/pdf/SEREVENT-DISKUS-PI-MG-IFU.PDF(2018).Merck&CoInc.HighlightsofprescribinginformationforFORADILAEROLIZER(formoterolfumarateinhalationpowder)fororalinhalationonly.November2012.https://www.merck.com/product/usa/pi_circulars/f/foradil/foradil_pi.pdf(2012).NovartisPharmaceuticalsUKLtd.Foradil.Summaryofproductcharacteristics.October2016.https://www.medicines.org.uk/emc/product/1030/smpc(2016).Price,D.B.,Swern,A.,Tozzi,C.A.,Philip,G.&Polos,P.Effectofmontelukastonlungfunctioninasthmapatientswithallergicrhinitis:analysisfromtheCOMPACTtrial.Allergy61,737–742(2006).CAS  Article  PubMed  GoogleScholar  BoheringerIngelheimPharmaceuticsInc.PrescribinginformationforSpiriva®Respimat®(tiotropiumbromide)inhalationspray,fororalinhalation.March2019.https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Spiriva%20Respimat/spirivarespimat.pdf(2019).MerckSharp&DohmeLimited.Singulairpaediatric4mggranules.Summaryofproductcharacteristics.October2018.https://www.medicines.org.uk/emc/product/45/smpc(2018).U.S.Food&DrugAdministration.AdvairDiskus®(fluticasonepropionate/salmeterol):Prescribinginformation.https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021077s029lbl.pdf(2008).AstraZenecaUKLimited.SymbicortTurbohaler100/6,inhalationpowder.Summaryofproductcharacteristics.November2018.https://www.medicines.org.uk/emc/product/1326/smpc(2018).GenericsUKT/AMylan.Sirdupla25microgram/250microgrampermetereddosepressurisedinhalation,suspension.Summaryofproductcharacteristics.February2019.https://www.medicines.org.uk/emc/product/2538/smpc(2019).SandozLimited.AirFluSalMDI25microgram/250microgramperactuationpressurisedinhalation,suspension.Summaryofprocuctcharacteristics.April2019.https://www.medicines.org.uk/emc/product/8785/smpc(2019).U.S.Food&DrugAdministration.BreoEllipta®(fluticasonefuroate/vilanterol):prescribinginformation.https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/204275s017lbl.pdf(2019).U.S.Food&DrugAdministration.Dulera®(mometasone/formoterol):prescribinginformation,https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022518s021lbl.pdf(2017).TevaPharmaBV.AerivioSpiromax50microgram/500micrograminhalationpowder.SummaryofProductCharacteristics.June2017.https://www.medicines.org.uk/emc/product/2482/smpc(2017).TevaPharmaBV.DuoRespSpiromax160micrograms/4.5microgramsinhalationpowder.Summaryofproductcharacteristics.April2019.https://www.medicines.org.uk/emc/product/3323/smpc(2019).ChiesiLimited.Fostair100/6inhalationsolution.Summaryofproductcharacteristics.February2019.https://www.medicines.org.uk/emc/product/6318/smpc(2019).OrionPharma(UK)Limited.FobumixEasyhaler160/4.5inhalationpowder.Summaryofproductcharacteristics.December2017.https://www.medicines.org.uk/emc/product/8706/smpc(2017).NappPharmaceuticalsLimited.Flutiform125microgram/5microgramperactuationpressurisedinhalation,suspension.Summaryofproductcharacteristics.January2019.https://www.medicines.org.uk/emc/product/7649/smpc(2019).Szefler,S.J.,Carlsson,L.G.,Uryniak,T.&Baker,J.W.Budesonideinhalationsuspensionversusmontelukastinchildrenaged2to4yearswithmildpersistentasthma.J.AllergyClin.Immunol.Pract.1,58–64(2013).Article  PubMed  GoogleScholar  Demoly,P.,Annunziata,K.,Gubba,E.&Adamek,L.Repeatedcross-sectionalsurveyofpatient-reportedasthmacontrolinEuropeinthepast5years.Eur.Respir.Rev.21,66–74(2012).CAS  Article  PubMed  GoogleScholar  Fuhlbrigge,A.etal.ThestatusofasthmacontrolintheU.S.adultpopulation.AllergyAsthmaProc.30,529–533(2009).Article  PubMed  GoogleScholar  Reddel,H.K.,Sawyer,S.M.,Everett,P.W.,Flood,P.V.&Peters,M.J.AsthmacontrolinAustralia:across-sectionalweb-basedsurveyinanationallyrepresentativepopulation.Med.J.Aust.202,492–496(2015).Article  PubMed  GoogleScholar  Nunes,C.,Pereira,A.M.&Morais-Almeida,M.Asthmacostsandsocialimpact.AsthmaRes.Pract.3,1(2017).Article  PubMed  PubMedCentral  GoogleScholar  Soriano,J.B.etal.Global,regional,andnationaldeaths,prevalence,disability-adjustedlifeyears,andyearslivedwithdisabilityforchronicobstructivepulmonarydiseaseandasthma,1990–2015:asystematicanalysisfortheGlobalBurdenofDiseaseStudy2015.LancetRespir.Med.5,691–706(2017).Article  GoogleScholar  Allen,D.,Hines,E.W.,Pazdernik,V.,Konecny,L.T.&Breitenbach,E.Four-yearreviewofpresenteeismdataamongemployeesofalargeUnitedStateshealthcaresystem:aretrospectiveprevalencestudy.Hum.Resour.Health16,59(2018).Article  PubMed  PubMedCentral  GoogleScholar  Sullivan,P.W.etal.Therelationshipbetweenasthma,asthmacontrolandeconomicoutcomesintheUnitedStates.J.Asthma51,769–778(2014).Article  PubMed  GoogleScholar  McGeachie,M.J.etal.Patternsofgrowthanddeclineinlungfunctioninpersistentchildhoodasthma.N.Engl.J.Med.374,1842–1852(2016).CAS  Article  PubMed  PubMedCentral  GoogleScholar  Price,D.,Fletcher,M.&vanderMolen,T.Asthmacontrolandmanagementin8,000Europeanpatients:theREcogniseAsthmaandLInktoSymptomsandExperience(REALISE)survey.NPJPrim.CareRespir.Med.24,14009(2014).Article  PubMed  PubMedCentral  GoogleScholar  Wechsler,M.E.Managingasthmainprimarycare:puttingnewguidelinerecommendationsintocontext.MayoClin.Proc.84,707–717(2009).Article  PubMed  PubMedCentral  GoogleScholar  DeSimoni,A.,Horne,R.,Fleming,L.,Bush,A.&Griffiths,C.Whatdoadolescentswithasthmareallythinkaboutadherencetoinhalers?InsightsfromaqualitativeanalysisofaUKonlineforum.BMJOpen7,e015245(2017).Article  PubMed  PubMedCentral  GoogleScholar  FitzGerald,J.M.,Boulet,L.P.,McIvor,R.A.,Zimmerman,S.&Chapman,K.R.AsthmacontrolinCanadaremainssuboptimal:TheRealityofAsthmaControl(TRAC)study.Can.Respir.J.13,253–259(2006).Article  PubMed  PubMedCentral  GoogleScholar  Thomas,M.,Leather,D.&Price,D.High-doseinhaledcorticosteroidsandadd-ontherapyuseinadultswithasthmaintheUKin2003:anobservationalstudy.Prim.CareRespir.J.15,166–172(2006).Article  PubMed  PubMedCentral  GoogleScholar  Thomas,M.,Murray-Thomas,T.,Fan,T.,Williams,T.&Taylor,S.PrescribingpatternsofasthmacontrollertherapyforchildreninUKprimarycare:across-sectionalobservationalstudy.BMCPulm.Med.10,29(2010).Article  PubMed  PubMedCentral  GoogleScholar  Hamelmann,E.,vonMutius,E.,Bush,A.&Szefler,S.J.Addressingtheriskdomaininthelong-termmanagementofpediatricasthma.Pediatr.AllergyImmunol.31,233–242(2020).Article  PubMed  GoogleScholar  Levy,M.L.etal.Summaryofthe2008BTS/SIGNBritishGuidelineonthemanagementofasthma.Prim.CareRespir.J.18,S1–S16(2009).Article  PubMed  PubMedCentral  GoogleScholar  Kaplan,A.&Price,D.Treatmentadherenceinadolescentswithasthma.J.AsthmaAllergy13,39–49(2020).CAS  Article  PubMed  PubMedCentral  GoogleScholar  Koster,E.S.,Philbert,D.,deVries,T.W.,vanDijk,L.&Bouvy,M.L.“Ijustforgettotakeit”:asthmaself-managementneedsandpreferencesinadolescents.J.Asthma52,831–837(2015).Article  CAS  PubMed  GoogleScholar  Shimoda,T.,Obase,Y.,Kishikawa,R.&Iwanaga,T.Influenceofcigarettesmokingonairwayinflammationandinhaledcorticosteroidtreatmentinpatientswithasthma.AllergyAsthmaProc.37,e50–e58(2016).Article  GoogleScholar  Boulet,L.-P.&Nair,P.Inhaledcorticosteroidsandadultasthma.Am.J.Respir.Crit.CareMed.200,1556–1557(2019).Article  PubMed  PubMedCentral  GoogleScholar  GlobalInitiativeforAsthma.Difficult-to-treat&severeasthmainadolescentandadultpatients–diagnosisandmanagement.https://ginasthma.org/wp-content/uploads/2019/04/GINA-Severe-asthma-Pocket-Guide-v2.0-wms-1.pdf(2019).Turner,S.etal.Long-actingβ-agonistincombinationorseparateinhalerasstep-uptherapyforchildrenwithuncontrolledasthmareceivinginhaledcorticosteroids.J.AllergyClin.Immunol.Pract.5,99–106(2017).e103.Article  PubMed  GoogleScholar  Virchow,J.C.etal.Singleinhalerextrafinetripletherapyinuncontrolledasthma(TRIMARANandTRIGGER):twodouble-blind,parallel-group,randomised,controlledphase3trials.Lancet394,1737–1749(2019).Article  PubMed  GoogleScholar  Rodrigo,G.J.&Castro-Rodriguez,J.A.Safetyoflong-actingbetaagonistsforthetreatmentofasthma:clearingtheair.Thorax67,342–349(2012).Article  PubMed  GoogleScholar  Cazzola,M.,Page,C.P.,Rogliani,P.&Matera,M.G.Beta2-agonisttherapyinlungdisease.Am.J.Respir.Crit.CareMed.187,690–696(2013).CAS  Article  PubMed  GoogleScholar  Busse,W.W.etal.Combinedanalysisofasthmasafetytrialsoflong-actingβ2-agonists.N.Engl.J.Med.378,2497–2505(2018).CAS  Article  PubMed  GoogleScholar  Xia,Y.etal.Safetyoflong-actingbetaagonistsandinhaledcorticosteroidsinchildrenandadolescentswithasthma.Ther.Adv.DrugSaf.4,254–263(2013).CAS  Article  PubMed  PubMedCentral  GoogleScholar  Khalid,F.,Aftab,A.&Khatri,S.Theassociationbetweenleukotriene-modifyingagentsandsuicidality:areviewofliterature.Psychosomatics59,19–27(2018).Article  PubMed  GoogleScholar  Kerstjens,H.A.etal.Tiotropiumimproveslungfunction,exacerbationrate,andasthmacontrol,independentofbaselinecharacteristicsincludingage,degreeofairwayobstruction,andallergicstatus.Respir.Med.117,198–206(2016).Article  PubMed  GoogleScholar  Casale,T.B.etal.TiotropiumRespimatadd-onisefficaciousinsymptomaticasthma,independentofT2phenotye.J.AllergyClin.Immunol.Pract.6,923–935(2018).Article  PubMed  GoogleScholar  Szefler,S.J.etal.Tiotropiumisefficaciousin6-to17-year-oldswithasthma,independentofT2phenotype.J.AllergyClin.Immunol.Pract.7,2286–2295(2019).Article  PubMed  GoogleScholar  Hamelmann,E.&Szefler,S.J.Efficacyandsafetyoftiotropiuminchildrenandadolescents.Drugs78,327–338(2018).CAS  Article  PubMed  PubMedCentral  GoogleScholar  Aalbers,R.,Vogelmeier,C.&Kuna,P.AchievingasthmacontrolwithICS/LABA:areviewofstrategiesforasthmamanagementandprevention.Respir.Med.111,1–7(2016).Article  PubMed  GoogleScholar  Lin,J.etal.Symbicort®MaintenanceandRelieverTherapy(SMART)andtheevolutionofasthmamanagementwithintheGINAguidelines.ExpertRev.Respir.Med.12,191–202(2018).CAS  Article  PubMed  GoogleScholar  Dahl,R.Systemicsideeffectsofinhaledcorticosteroidsinpatientswithasthma.Respir.Med.100,1307–1317(2006).Article  PubMed  GoogleScholar  Gruffydd-Jones,K.Unmetneedsinasthma.Ther.Clin.RiskManag.15,409–421(2019).CAS  Article  PubMed  PubMedCentral  GoogleScholar  NovartisPharmaceuticalsUKLtd.Xolair150mgSolutionforInjection.Summaryofproductcharacteristics.January2019.https://www.medicines.org.uk/emc/product/4725/smpc(2019).GlaxoSmithKlineUK.Nucala100mgpowderforsolutionforinjection.Summaryofproductcharacteristics.June2019.https://www.medicines.org.uk/emc/product/1938/smpc(2019).AstraZenecaUKLimited.Fasenra30mgsolutionforinjectioninpre-filledsyringe.Summaryofproductcharacteristics.July2019.https://www.medicines.org.uk/emc/product/8918/smpc(2019).TevaPharmaLtd.Cinqaero(reslizumab)10mg/mLconcentrateforsolutionforinfusion.Summaryofproductcharacteristics.https://www.medicines.org.uk/emc/product/4370/smpc(2018).DownloadreferencesAcknowledgementsMedicalwritingassistance,intheformofthepreparationandrevisionofthedraftmanuscript,wassupportedfinanciallybyBoehringerIngelheimandprovidedbyRosieRobsonofMediTechMediaundertheauthors’conceptualdirectionandbasedonfeedbackfromtheauthors.BoehringerIngelheimwasgiventheopportunitytoreviewthemanuscriptforfactualaccuracyonly.AuthorinformationAuthorsandAffiliationsFamilyPhysicianAirwaysGroupofCanada,UniversityofToronto,Toronto,ON,CanadaAlanKaplanCentreforLungHealth,VancouverCoastalHealthResearchInstitute,Vancouver,BC,CanadaJ.MarkFitzGeraldPulmonaryDepartment,JohannesGutenbergUniversityMainz,Mainz,GermanyRolandBuhlDepartmentofPediatricPulmonologyandAllergy,UniversityHospitalCarlGustavCarus,TechnicalUniversityofDresden,Dresden,GermanyChristianVogelbergKlinikfürKinderundJugendmedizin,EvangelischesKlinikumBethel,Bielefeld,GermanyEckardHamelmannAllergyCenteroftheRuhrUniversity,Bochum,GermanyEckardHamelmannAuthorsAlanKaplanViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJ.MarkFitzGeraldViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarRolandBuhlViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarChristianVogelbergViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarEckardHamelmannViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarContributionsTheauthorstakefullresponsibilityforthescope,direction,contentandeditorialdecisionsrelatingtothemanuscript,wereinvolvedatallstagesofdevelopmentandhaveapprovedthesubmittedmanuscript.A.K.isaguarantorofthiswork.CorrespondingauthorCorrespondenceto AlanKaplan.Ethicsdeclarations Competinginterests A.K.isontheadvisoryboardand/orspeakersbureauforAstraZeneca,Behring,BoehringerIngelheim,Covis,Grifols,GSK,MerckFrosst,Novartis,NovoNordisk,Pfizer,Purdue,Sanofi,TevaandTrudell;andisamemberofHealthCanadaSectiononAllergyandRespiratoryTherapeutics;co-chairofOntarioHealthQuality,OntarioQualityStandardsforCOPD;memberofOntarioHealthQuality,OntarioQualityStandardsAsthmaChairperson,FamilyPhysicianAirwaysGroupofCanada;honoraryprofessorofRespiratoryMedicineoftheObservationalandPragmaticResearch,Singapore;vicepresidentoftheRespiratoryEffectivenessGroupandmedicalleadatLungHealthPortal,MDBriefcase.J.M.F.isontheadvisoryboardand/orspeakersbureauforAstraZeneca,BoehringerIngelheim,GSK,Novartis,Regeneron,SanofiandTheravance;receivespeer-reviewfundingfromAllerGen,NIH,andCIHR;researchfundingfromAstraZeneca,GSK,NovartisandSanofi-Regeneron,allpaiddirectlytoUBC;isamemberofthesteeringcommitteefortheInternationalSevereAsthmaRegistryandPIforCanadianSevereAsthmaRegistryandisamemberoftheGINAScienceandExecutiveCommittees.R.B.reportsgrantstoMainzUniversityandpersonalfeesfromBoehringerIngelheim,GlaxoSmithKline,NovartisandRoche,aswellaspersonalfeesfromAstraZeneca,Chiesi,Cipla,SanofiandTeva,andisamemberoftheGINAScienceCommittee.C.V.isontheadvisoryboardand/orspeakersbureauforALK,AllergoPharma,Bencard,BoehringerIngelheim,DBVTechnology,HALAllergy,NovartisandSanofi;isPresidentoftheSocietyofPediatricAllergologyandEnvironmentalMedicine(GPA);heisco-authoroftheGermanNationalManagementGuidelineforAsthma(NVLAsthma)andheisreceivinggrantsfromtheGermanResearchFoundation(DFG).E.H.isontheadvisoryboardand/orspeakersbureauforALK,AllergoPharma,Bencard,BoehringerIngelheim,GSK,Novartis,Nutricia,SanofiandStallergenes;isPresidentoftheGermanAsthmaNet(GAN)e.V.,Vice-PresidentoftheGermanAllergySociety(DGAKI)andco-chairoftheasthmasectionoftheGermanPediatricPneumologySociety(GPP);heiscoordinatoroftheGermanguidelineforsevereasthmainchildrenandco-authoroftheGermanNationalManagementGuidelineforAsthma(NVLAsthma)andheisreceivinggrantsfromtheGermanMinistryofEducationandResearch(BMBF). 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ReprintsandPermissionsAboutthisarticleCitethisarticleKaplan,A.,FitzGerald,J.M.,Buhl,R.etal.ComparingLAMAwithLABAandLTRAasadd-ontherapiesinprimarycareasthmamanagement. npjPrim.CareRespir.Med.30,50(2020).https://doi.org/10.1038/s41533-020-00205-9DownloadcitationReceived:01April2020Accepted:03September2020Published:11November2020DOI:https://doi.org/10.1038/s41533-020-00205-9SharethisarticleAnyoneyousharethefollowinglinkwithwillbeabletoreadthiscontent:GetshareablelinkSorry,ashareablelinkisnotcurrentlyavailableforthisarticle.Copytoclipboard ProvidedbytheSpringerNatureSharedItcontent-sharinginitiative DownloadPDF Advertisement Explorecontent Researcharticles Reviews&Analysis News&Comment Collections FollowusonTwitter Signupforalerts RSSfeed Aboutthejournal Aims&Scope JournalInformation Contenttypes AbouttheEditors Contact OpenAccess MeetingAbstracts ArticleProcessingCharges AboutthePartner Editorialpolicies JournalMetrics CallsforPapers TranslatedContent 5QuestionswithOurNewEditor-in-Chief Publishwithus ForAuthors&Referees Submitmanuscript Search Searcharticlesbysubject,keywordorauthor Showresultsfrom Alljournals Thisjournal Search Advancedsearch Quicklinks Explorearticlesbysubject Findajob Guidetoauthors Editorialpolicies Closebanner Close SignupfortheNatureBriefingnewsletter—whatmattersinscience,freetoyourinboxdaily. 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