ICS/formoterol in the management of asthma in the clinical ...

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Instead, the current Global Initiative for Asthma (GINA) Report recommends the use of the combination of inhaled corticosteroids (ICS) with the ... Skiptomaincontent Advertisement SearchallBMCarticles Search ICS/formoterolinthemanagementofasthmaintheclinicalpracticeofpulmonologists:aninternationalsurveyonGINAstrategy DownloadPDF DownloadPDF Research OpenAccess Published:29January2021 ICS/formoterolinthemanagementofasthmaintheclinicalpracticeofpulmonologists:aninternationalsurveyonGINAstrategy ÁlvaroA.Cruz1,SaraBarile2,ElenaNudo2,LauraBrogelli3,PatriciaGuller2&…AlbertoPapi4 Showauthors AsthmaResearchandPractice volume 7,Article number: 1(2021) Citethisarticle 6270Accesses 1Citations 7Altmetric Metricsdetails AbstractBackgroundThetreatmentwithshort-actingbeta-2agonists(SABA)aloneisnolongerrecommendedduetosafetyissues.Instead,thecurrentGlobalInitiativeforAsthma(GINA)Reportrecommendstheuseofthecombinationofinhaledcorticosteroids(ICS)withtherapid/long-actingbeta-2agonistformoterol,althoughtheuseinsteps1and2isstilloff-labelintheEUandinmanycountries.Itisimportanttounderstandclinicians’knowledgeandopinionsontheissuewiththeultimategoaltoencouragetheimplementationofthenewapproachinclinicalpractice.MethodsWeperformedaninternationalsurvey,directedtopulmonologistsinterestedinthemanagementofpatientswithasthma.ResultsMostparticipantsreportedthatSABAaloneshouldnotbeusedinGINAStep1asthmatreatment.As-neededlow-doseICS/formoterolcombinationtopatientsinstep1,andas-neededlow-doseICS/formoterolasrelievertherapyinanystepwerefoundtobeofcurrentuseprescribedintheirreal-lifesettings.SABAalonewasstillprescribedtoaproportionofpatients,althoughthepulmonologists’opinionwasthatitshouldnolongerbeused.ConclusionsMostspecialistsareuptodateandunderstandtherelevanceofthechangesinGINAreportsfrom2019.Nevertheless,disseminationandimplementationofGINAnovelmanagementstrategyisstillneeded. BackgroundTheGlobalInitiativeforAsthma(GINA)criticallyrevisesevidenceonasthmamanagementyearlyandprovidesastructuredsetofrecommendations[1].The2020GINAReportmaintainsamajorchangeinthemanagementrecommendations,whichwereintroducedin2019,inrelationtopharmacologicaltreatment[2].Thetreatmentwithshort-actingbeta-2agonists(SABA)alone,whichhashistoricallybeenthetherapyofchoiceformildpatients(step1),andcommonrelievertreatmentforotherstagesarenolongerrecommendedduetosafetyissues,sincetheriskofexacerbationshasbeenreportedtobeincreasedbytheirregularorfrequentuse[1].UsageofSABAsintheabsenceofeffectiveanti-inflammatorytreatment,wasassociatedwithincreasedriskofasthmaexacerbations,hospitalizationandmortalityduetoasthma[2,3,4,5].Therefore,currentGINAReportrecommendsuseofthecombinationofinhaledcorticosteroids(ICS)withtherapid/long-actingbeta-1agonistformoterolinsteadofSABAalone,includinginsteps1and2oftreatment,wheretheuseiscurrentlystilloff-labelintheEUandmanycountries.InlinewiththesameconceptofincludinganICSintherescuemedication,anothermajorchangethatwasintroducedin2019isthatrelievertherapywithas-neededlow-doseICS/formoterolisnowrecommendedasthepreferredrescueoptionforanyasthmastep,exceptwhenpatientsareusinganotherICS–long-actingbeta-2agonistcombinationasacontroller[2].Evidencefortheserecommendationswasproducedbylargerandomizedcontrolledtrialsandbyreal-worldstudies.Tworandomized,double-blind,placebo-controlledtrialsshowedtheefficacyandsafetyofbudesonide–formoterolasrelievertherapyintheabsenceofregularmaintenancetreatmentinpatientswithmildasthma[6,7].Thethree-waySYGMA1trialincludedpatientsonGINAstep2treatmentandindicatedthatas-neededbudesonide–formoterolcombinationwassuperiortoas-neededSABAandprovidedanon-inferioreffectonannualrateofexacerbationreduction,withalowerexposuretoICSs,whencomparedtoamaintenanceICSregimen[6].TheresultsofSYGMA2trial,includingthesamepatientpopulation,alsoindicatednon-inferiorityoftheas-neededbudesonide–formoterolcombinationcomparedtothemaintenanceICSplusas-neededSABAregimeninreducingtheexacerbationrateinpatientswithmildasthma[7].Morerecently,open-labelrandomizedcontrolledtrialsconfirmedthefindingsoftheSYGMAstudies.TheNovelSTART(NovelSymbicortTurbuhalerAsthmaRelieverTherapy)trial,investigatedbudesonide–formoterolrelievertherapyusedonanas-neededbasisinadultswithmildasthmawhohadbeentreatedwithonlyas-neededSABA,comparedwithICSmaintenancetherapyplusas-neededSABAoras-neededSABAonly.Thiswasanopen-labelstudyintheclinicalpracticesettinganddemonstratedtheexternalvalidityofSYGMA1and2[8].Theopen-label,randomizedPRACTICALstudy,carriedoutin15primarycareorhospital-basedclinicalunitsandprimarycarepractices,showedthatincidenceofsevereexacerbationswaslowerwithas-neededbudesonide–formoterolthanwithmaintenancebudesonideplusterbutalineasneeded[9].AstherecentGINAReportsintroducedlandmarkchangesinrecommendationsforasthmamanagement,itisimportanttounderstandclinicians’knowledgeandopinionsontheissuewiththeultimategoaltoencouragetheimplementationofthenewapproachinclinicalpractice.Inparticular,theseissuesincludetheknowledgeofcurrentevidenceonmildasthmatreatment,theimplementationofguidelinesinclinicalpracticeandtherelateddifferenceacrossdifferentclinicalsettingsorindifferentgeographicareas,withaparticularemphasisontheacceptanceofthechangesinthe2019GINAReportbyclinicians.Assurveysarewidelyusedtoinvestigatephysicians’perspectiveinthemanagementofasthma[10,11,12,13],wehaveperformedaninternationalsurvey,directedtopulmonologistsinterestedinthemanagementofpatientswithasthma,withtheaimtoinvestigatetheiropinion/behavioronthechangesintroducedintheGINAReportfrom2019andtoassesstheexistenceofanydifferenceacrosscountries.ParticipantsandmethodsParticipantselectionPulmonologistsfromdifferentcountries,identifiedinaproprietarydatabase,wereinvitedtoanswerthesurvey.Differentcountrieswereinvolvedtogatherasamplesuitabletoaddresstheresearchquestionwithaglobalapproach.Clinicianscouldbeinvitediftheyhadmorethan5 yearsofclinicalexperienceinrespiratorydisease,patientswithasthmarepresentedatleast25%oftheirpracticeinthelastmonth,andatleast80%oftheirpatientswereadult(≥18 years)subjects.MethodsThesurveywasdevelopedwiththeassistanceofanindependentthirdparty,withbroadexperienceinmarketresearchinthepharmaceuticalsetting(DoxaPharma,Milan,Italy),andthenshareditwiththeauthorsfordiscussionsviaseveralonlinemeetingsuntilafinalagreementwasreached.Thequestionnairewasthendeliveredonlineviaacomputer-assistedwebinterview.Thequestionnairecontained42questions.Openandclosed(multiplechoice,witheithersingleormultiplepermittedanswers)questionswereincluded.Interviewswereanonymous.Thelevelofagreementwasmeasuredby5-pointLikertscale.Datawereanalyzedbydescriptivestatistics.TheEnglishversionofthesurveyquestionnaireispresentedassupplementarymaterial.ResultsSampledescriptionThesurveywasconductedonlinefromJanuarytoFebruary2020.Atotalof160pulmonologistsbasedinItaly,Germany,TheNetherlands,Brazil,ChinaandRussiaansweredthequestionnaire.TenpulmonologistswerefromTheNetherlands,30fromeachoneoftheothercountries.Intotal,59%ofparticipantswereolderthan46 years,and53%hadmorethan15 yearsofclinicalexperienceaspulmonologists(Table 1). Table1ParticipantsFullsizetableOnaverage,asthmapatientsrepresented47%ofpatient’svisitseachmonth.Amongpatientswithasthma,27%hadmilddisease,43%moderatedisease,and30%severeasthma,asexpectedinaspecialistcaresetting.Follow-upofpatientswithasthmawasperformedonaverageevery3–4 monthsby45%ofparticipants(withcountryvariationsfrom43%inItalyto57%inGermany),basedonseverity.CurrentpracticeThemostlikelyprescribedtherapyforpatientsinGINAstep1wasas-neededlow-doseICS/formoterolfor44%(upto57%inBrazil)ofclinicians.As-neededlow-doseICS/formoterolwasreportedtobeprescribedtoanaverageof37%ofpatients(upto49%inBrazil),followedbyas-neededlow-doseICS.Amongpatientsinstep1,whowereprescribedlow-doseICS/formoterol,51%receivedaprescriptionofbudesonide–formoterol,and44%receivedaprescriptionofbeclometasonedipropionate–formoterol.Intotal,95%ofphysiciansfollowedthisstrategyproposedbyGINAinstep1,andcheckedpatients’adherencetotheprescribedtherapy,eitherbyaninterviewatfollow-upvisitsorbyaskingpatientstofillinadiary.DiariesaremostoftenusedinChina(67%)andneverusedinTheNetherlands.Therelievertherapymostlikelytobeprescribedinanystepwasas-neededlow-doseICS/formoterolfor61%ofclinicians.Itwascurrentlyprescribedto52%ofpatients(withvariationsfrom36%inTheNetherlandsto74%inBrazil(Fig. 1).Amongpatientsprescribedas-neededlow-doseICS/formoterolasareliever,50%receivedbudesonide–formoteroland48%beclometasonedipropionate–formoterol,whereastheother2%usedotherformulations. Fig.1Low-doseICSformoterolasthemostfrequentprescriptionofareliever:nationalvariationFullsizeimageAs-neededSABAwasprescribedto47%ofpatients,and38%ofphysiciansconsidereditastherelievertherapytheywouldprescribemostoften.Atotalof82%ofpulmonologistsreportedthatidentificationofasthmaphenotypesfromthefirststageofdiagnosiswasimportanttoguidetailoredtherapeuticapproaches.Assessmentofriskfactorsforexacerbationswasreportedtobeperformedby33%ofcliniciansonlywhenanexacerbationoccurs.DriverstotreatmentdecisionSomequestionsinvestigatedcriteriausedbyparticipantstoprescribeatherapeuticregimenforasthma,intheirclinicalpractice.Treatmentdecisionsinasthmapatientswerebasedmainlyonclinicaloutcomes,suchassymptomcontrol,whichwasthemostimportantdriverin48%ofcases.Characteristicsofthedrug,suchassafetyandcost,werealsoimportantcriteria;onthecontrary,patient’scharacteristics,suchasthephysicalfitness,thelevelofadherence,comorbidities,history,andeconomicsituation,wererarelyconsidered(Table 2). Table2MaincriteriausedbyparticipantstoprescribeatherapeuticregimenforasthmaFullsizetableAttitudetowardguidelinesGuidelineswerethemainsourceofreferenceinprescriptionchoice(90%ofpneumologists),followedbypastclinicalexperience(81%)andpublishedevidence(75%)(Fig. 2).Physicianswhodidnotrelyonguidelinestrustedpastclinicalexperiencein42%ofcases.PastclinicalexperiencewasmorerelevantforBraziliancliniciansthanforthosefromothercountries.Itwasaprimarydriverofchoiceoftreatmentfor47%ofparticipantsfromBrazil,27%fromItaly,23%fromGermany,13%fromChina,10%fromTheNetherlandsandRussia. Fig.2PointsofreferenceinprescriptionchoiceFullsizeimageGINAReportswereconsideredthemostrelevantandreliablemanagementstrategy(mainlyforItalianandBrazilianpulmonologists,with91and90%ofanswers,respectively).Overall,83%ofparticipantswereawareofupdatesinthe2019GINAReport.TheuseofICS/formoterolinmildasthmawasconsideredasthemainchangeintroducedin2019by34%ofparticipants,whiletherecommendationnottouseSABAinmonotherapywasthemainkeychangefor30%ofclinicians.Overall,91%ofinterviewedpulmonologistswerewillingtofollowthenewrecommendations(Fig. 3).For72%ofparticipants(withawidevariabilityaccordingtocountries,from100%inBrazilto43%inRussia)thenewrecommendationsrepresentedaconfirmationofanestablishedpractice,whileforonly22%ofphysicianstheyrequiredaradicalchangeoftheclinicalapproachtoasthma. Fig.3AttitudetowardsGINAReport.a:ReliabilityofGINAReportversusguidelines;b:AwarenessofupdatestoGINAReport,c:WillingnesstoadheretothenewGINAstrategy,d:AgreementbetweennewGINAstrategyandcurrentclinicalpracticeFullsizeimageSpecifically,prescribingas-neededlow-doseICS/formoteroltothepatientsinGINAstep1wasanestablishedpracticefor76/138(55%)ofpulmonologists(from14%[1/7]inTheNetherlandsto20/30[67%]inBrazil),andarecentchangefortheremaining45%physicians.Inthelattergroupofrespondents,therecentchangeofclinicalbehaviorwasacknowledgedtohavebeenadoptedtoadheretoGINAReportin74%ofcasesandbasedonresultsfrompublishedclinicalstudiesin21%ofcases.Prescribingas-neededlow-doseICS/formoterolasrelievertherapyinanystepwasanestablishedpracticefor59%ofsubjects(from33%inTheNetherlandsto80%inBrazil).Whenaskedabouttheirpatients’attitudetowardasthmatreatment,60%ofphysicians(90%inTheNetherlandsandinBrazil,67%inChina,60%inGermany,40%inItalyand33%inRussia)thoughtthatpatientsinGINAsteps1and2mayadherebettertoICS/formoteroltreatmentwithas-neededtherapythanwitharegulartherapy.Onthecontrary,40%(67%inRussia,60%inItaly,40%inGermany,33%inChina,10%inTheNetherlandsandBrazil)ofrespondentsreportedthatthistherapywouldbebetteradheredifthistreatmentwouldbeprescribedasmaintenance.DiscussionWeconductedaninternationalsurveyamongpulmonologiststoinvestigatetheattitudetowardsthekeychangesinasthmatherapyintroducedinthe2019GINAReportbasedonevidence.Thesespecialistsare,globally,themainreferencefortherapeuticdecisions,withapivotalrole.GPsandotherhealthcareprofessionalsare,indeed,involvedinasthmamanagement,withdifferentrolesaccordingtothecountry’shealthsystem;theywereexcludedtoobtainahomogeneoussample.Inansweringoursurvey,mostparticipantsreportedthatSABAaloneinGINAstep1shouldnotbeused.Thisresultwasinagreementwithpublishedevidence,whichmostcliniciansseemedtobewellacquaintedwith[14].Inaddition,prescribingas-neededlow-doseICS/formoterolcombinationtopatientsinGINAstep1,andas-neededlow-doseICS/formoterolasrelievertherapyinanystepwerefoundtobecurrentuseinthereal-lifesetting.TheuseofICS/formoterolinGINAstep1iscommonlypracticedinItalyandBrazil,lessoftenintheothercountries(Brazil57%,Italy47%,China43%,GermanyandTheNetherlands40%,Russia37%ofparticipants);theriskoflowpatient’sadherenceseemsnottobeabarriertotheuseofICS/formoterolondemand.TheapproachtomildasthmamanagementheredescribedwasinagreementwithavailableevidenceandcliniciansseemedtobeupdatedandtounderstandtherelevanceofnewGINArecommendations[6,7,15,16,17,18].ManypulmonologistsacknowledgedthatGINAReportsweretheirpointofreferenceforclinicaldecision,buttheproportionofphysiciansinthisgroupvariedinthecountrieswithinthesurvey.Nonetheless,evenwhenGINAReportswerenotthemainreference,mostpulmonologistshadadoptedtherecommendedkeychangesintherapychoice,basedeitheronpublishedliteratureoronclinicalexperience.Indeed,thislatteritemcanbeconsideredasacompositeofscientificevidence,personalexperienceandcolleagues’experience.Amongguidelines,theGINAReportisthemostusedoneforpulmonologists,butmanyphysiciansalsorelyonlocalguidelines.Inaddition,pulmonologistsansweredthatattentiontotheGINAReportwouldincreaseinthefuture;suchanattitudemaysuggestthatcliniciansareevaluatingtherecommendations,studyingtheevidenceandimplementingthechange,accordingly;moreover,participationinthesurvey,focusingonrelevantissuesmayitselfhaveaneducationaleffectiveness.Despitethepulmonologists’opinionthatitshouldnolongerbeused,SABAaloneisstillbroadlyused,suggestingthatdisseminationandimplementationofGINAStrategychangesaremuchneeded.Apreviouscross-sectionalstudyinthegeneralpractice,inItaly,hadshownthatalthoughGINAReportswereconsideredrelevantfortreatmentdecision,adherencetotreatmentwaslowforpatientswithmildasthmaandwashigherforpatientswithmoderateorsevereasthma[19].TheseobservationsagreewiththefindingsinoursurveythatpatientsinGINAstep1werenotusuallywillingtoadheretocontinuouscontrollertherapy,suggestingthatpatientswithmilddiseaseoftenunderestimatetheirillnesspotentialtoharmthem.Phenotypeidentificationwasconsideredanearlystepinpatient’sevaluation,andnecessaryfortreatmentdecisioninsevereasthma,sothattherapiescanbebettertargetedtowarddisease-specificfeatures[20,21,22,23,24].Itiscurrentlybelievedthatsuccessfultherapyofasthmarequiresbetterdefinitionofunderlyingpathogenesis,totailorindividualized,evidence-basedandmoreprecisetherapyoptions[21].Finally,answerstothesurveysuggestedthatadherencetoguidelinescanbeimprovedinsomecountries,suchasTheNetherlandsandGermany.Insomeinstances,itmightbeimportanttospreadin-depthinformationaboutthepharmacologicalprofileofdifferentICSs.Inaddition,itisnecessarytofurtherunderstandthebarriersofimplementationofchanges,whichwerefoundthere.Althoughasurveyisausefulmethodforcollectingdataontheneededchanges,ithasalimitationinthepotentialforunderstandingthebarrierstoimplementationofchanges,andanadditionalin-depthqualitativesemi-structuredinterviewwouldbeneeded.Alimitationofoursurveymaybelinkedtodifferentorganizationsinthehealthsystemofthecountriesinvolved;ahomogeneoussampleofpulmonologistswasinterviewed,omittingfamilyphysiciansandnurseswhomayhaverelevantrolesincertaincountriesbutnotinothers.Statisticallyrelevantcomparisonsamongcountrieswerenottheobjectiveofthestudy.Aglobalsampleofpulmonologistswasinvestigatedanddifferencesamongcountriescouldonlybereportedasdescriptivedataonthesample.Inconclusion,thesurveyshowedthatthechangesinGINAStrategyforasthmamanagementfrom2019validatedanestablishedpracticeinsomecountries,whileforaminorityofphysicianstheyrequiredaradicalchangeoftheclinicalapproachtoasthma.MostpulmonologiststakeintoaccountorarewillingtotakeintoaccountintheirpracticethefundamentalchangesproposedbyGINA.1Thegreatestchangeintheapproachtoasthmamanagementintroducedbythe2019GINAReportissupportedbyrelevantevidence,andpulmonologistsappeartoacknowledgethescientificbackgroundofthereportandadoptit. Availabilityofdataandmaterials Thedatasetsusedand/oranalysedduringthecurrentstudyareavailablefromthecorrespondingauthoronreasonablerequest. 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DownloadreferencesAcknowledgementsEditorialassistancewasprovidedbyAashniShah(PolistudiumSRL,Milan,Italy).ThisassistancewassupportedbyDoxaPharma.FundingThesurveyandthedevelopmentofthemanuscriptwerecarriedoutbytheresearchcompany,DoxaPharmaandfundedbythepharmaceuticalcompany,Chiesi.AuthorinformationAuthorsandAffiliationsFundaçãoProARandFederalUniversityofBahia,Salvador,BrazilÁlvaroA.CruzChiesiFarmaceuticiSpA,Parma,ItalySaraBarile, ElenaNudo & PatriciaGullerPolistudiumsrl,Milan,ItalyLauraBrogelliUniversityofFerrara,Ferrara,ItalyAlbertoPapiAuthorsÁlvaroA.CruzViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarSaraBarileViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarElenaNudoViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarLauraBrogelliViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarPatriciaGullerViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarAlbertoPapiViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarContributionsAACandAPsupervisedthequestionnairepreparation.SB,EN,andPGplannedtheresearch,andimplementedthesurvey.LBdevelopedthemanuscript.Allauthorsanalyzedandinterpreteddata,revisedandapprovedthemanuscript.CorrespondingauthorCorrespondenceto ÁlvaroA.Cruz.Ethicsdeclarations Ethicsapprovalandconsenttoparticipate Notapplicable. Consentforpublication Notapplicable. Competinginterests AACreportsgrants,personalfeesornon-financialsupportfromGlaxoSmithKline,AstraZeneca,BoehringerIngelheim,Chiesi,Sanofi,Novartis,Mylan,EurofarmaandMantecorp.APreportsgrants,personalfees,non-financialsupportfromGlaxoSmithKline,AstraZeneca,BoehringerIngelheim,ChiesiFarmaceuticiTEVAandSanofi/Regeneron;personalfees,non-financialsupportfromMundipharma,Zambon,Novartis;grants,personalfeesandnon-financialsupportfromMenarini;personalfeesfromRoche,grantsfromFondazioneMaugeri,grantsfromFondazioneChiesi,personalfeesfromEdmondpharma.SB,PGandENareemployedinChiesiFarmaceuticiSpA,Italy.LBhasnoconflictofinteresttodeclare. 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ReprintsandPermissionsAboutthisarticleCitethisarticleCruz,Á.A.,Barile,S.,Nudo,E.etal.ICS/formoterolinthemanagementofasthmaintheclinicalpracticeofpulmonologists:aninternationalsurveyonGINAstrategy. asthmaresandpract7,1(2021).https://doi.org/10.1186/s40733-021-00067-zDownloadcitationReceived:02November2020Accepted:12January2021Published:29January2021DOI:https://doi.org/10.1186/s40733-021-00067-zSharethisarticleAnyoneyousharethefollowinglinkwithwillbeabletoreadthiscontent:GetshareablelinkSorry,ashareablelinkisnotcurrentlyavailableforthisarticle.Copytoclipboard ProvidedbytheSpringerNatureSharedItcontent-sharinginitiative KeywordsInhaledcorticosteroidShort-actingbeta-2agonistLong-actingbeta-2agonistAsthma DownloadPDF Advertisement AsthmaResearchandPractice ISSN:2054-7064 Contactus Submissionenquiries:AccesshereandclickContactUs Generalenquiries:[email protected]



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