Bronchodilation

and/or

Anti-inflammation

inCOPD?ProfessorPeterMACalverleyInstituteofAgeingandChronicDisease

UniversityofLiverpoolUKDisclosuresIhavereceivedresearchgrantsfromGlaxoSmithKline

andTakeda;personalfeesfromAstraZeneca,

BoehringerIngelheim,GlaxoSmithKlineandRecipharm;andnon-financialsupportfromBoehringerIngelheimTopicstocoverImpactofCOPDSymptomsExacerbationsGoalsofCOPDmanagement:ReducesymptomsanddecreaseexacerbationsRoleofbronchodilatorsinstableCOPDDecreasesymptomsReduceexacerbationsRoleofanti-inflammatorydrugsinstableCOPDTreatmentstrategyinstableCOPDImpactofCOPD:SymptomsMiravitllesM,etal.RespirRes2017;18:67.COPDrespiratorysymptomsDiseaseprognosisReductioninphysicalactivityAnxiety/depressionReductioninQoLImpactofCOPD:ExacerbationsWedzichaJAandSeemungalTA.Lancet2007;370:789–796.ExacerbationsReduced

qualityoflifeDecreased

exercise

performanceIncreased

morbidity

andmortalitySignificant

socio-

economic

impactRapid

decline

inlung

functionManagementgoalsinstableCOPDOnceCOPDhasbeendiagnosed,effectivemanagementshouldbebasedonanindividualizedassessmenttoreducebothcurrentsymptomsandfuturerisksofexacerbations.GoalsfortreatmentofstableCOPDPreventdiseaseprogressionPreventandtreatexacerbationsReducemortalityRelievesymptomsImproveexercisetoleranceImprovehealthstatusandREDUCESYMPTOMSREDUCERISK?2017GlobalInitiativeforChronicObstructiveLungDisease.GlobalStrategyfortheDiagnosis,Management,andPreventionofChronicObstructivePulmonaryDisease(GOLD)2017./gold-2017-global-strategy-diagnosis-management-prevention-copd/.AccessedMay2017.Bronchodilatorsare

centraltosymptommanagementTargetairflowlimitation;increasebronchodilationbyalteringairway

smoothmuscletoneImprove

emptying

ofthelungReducedynamichyperinflationatrestandduringexerciseImprove

exercise

performanceWedzichaJA,etal.EurRespirJ2012;40:1545–1554.Combinedbronchodilatorsanddyspnoea*P<0.001comparedwitheithersingleagentalone.TDIfocalscoreRelievermedicationuseTiotropiumSalmeterolbidTiotropium+salmeterolqdTiotropium+salmeterolbid0.00.51.01.52.02.53.03.5TDIfocalscoreMCID**0.00.51.01.52.02.53.03.5Relievermedicationuse(puffs/24hours)**vanNoordJA,etal.RespirMed2010;104:995–1004.OTEMTO2OTEMTO1OTEMTO2OTEMTO1TDIfocalscore(12weeks)vsplaceboT+O5/5T5PlaceboSinghD,etal.RespirMed2015;109:1312–1319.CombinedbronchodilatorsandbreathlessnessResponderrates(%)ImpactofcombiningbronchodilatorsondynamichyperinflationO’DonnellDE,etal.EurRespirJ2017;49:1601348.P<0.0001forT+O2.5/5and5/5μgvsplacebo,T5μgandO5μgat

0minandatisotime.***P<0.0001vsplacebo;+++P<0.0001vsO5μg;??P<0.001vsT5μgforT+O2.5/5and5/5μg***

++?***

+++????P<0.01vsT5μg;++P<0.001vsO5μg;***P<0.0001vsplacebo;+++P<0.0001vsO5μg;???P<0.0001vsT5μg***

++???***

+??3.02.92.82.72.62.52.42.32.22.12.0012345678910Exercisetime(min)Adjustedmean(SE)IC(L)***

+++??PlaceboO5μgT5μgT+O2.5/5μgT+O5/5μg2.44L2.57L2.57L2.66L2.69L2.50L2.69L2.68L2.78L2.77L+P<0.01vsO5μg;++P<0.001vsO5μg;??P<0.001vs

T5μg;***P<0.0001vsplacebo;???P<0.0001vsT5μgSE,standarderror;L,litresBronchodilatorspreventexacerbationsUPLIFTTiotropiumTORCHSalmeterolLABDsvsPBOProbabilityofCOPDexacerbationHazardratio=0.86,(95%CI,0.81–0.91)P<0.001(log-ranktest)MonthTiotropiumControlTashkinDP,etal.NEnglJMed2008;359:1543–1554.Exacerbationreduction:

LABA+ICS–ExacerbationratebyGOLDstageJenkinsCR,etal.RespirRes2009;10:59.Rateofmoderate/severeexacerbations≥50%FEV1atbaseline1.791.240.821.401.080.711.530.990.681.540.910.570.00.20.40.60.81.01.21.41.61.82.0<30%30–50%PlaceboSalmeterolFluticasonepropionateSalmeterol–fluticasonepropionateBronchodilatorspreventexacerbationsUPLIFTTiotropiumTORCHSalmeterolLABDsvsPBOLAMAvsLABAPOETTiotropiumvs.SalmeterolCOPD:EffectofLAMAvsLABAonexacerbations(POET-COPD?study)POET-COPD?,PreventionOfExacerbationswithTiotropiuminCOPD.VogelmeierC,etal.NEnglJMed2011;364:1093–1103.17%reductioninriskwithtiotropiumversussalmeterolP<0.001(log-ranktest)BronchodilatorspreventexacerbationsUPLIFTTiotropiumLABDscanpreventexacerbationLAMAissuperiorthanLABATORCHSalmeterolLABDsvsPBOLAMAvsLABAPOETTiotropiumvs.SalmeterolBeehKM,etal.AmJRespirCritCareMed2016;196:139–149.PotentialeffectofAchandmuscarinicantagonists(tiotropium)oninflammatorycellsBatemanED,etal.PulmPharmacolTher2009;22:533–542.*P<0.05,significantdifferencesbetweenindicatedsamples.InhibitionofchemotacticactivitybytiotropiuminMonoMac6cellsChAT-likeimmunoreactivityisfoundinmanyinflammatorycellsthatexpressmuscarinicreceptorsInflammatorycellsreleasechemotacticmediatorsafterincubationwithAchinvitroInarecentstudy,tiotropiumsuppressedsecretion

ofLTB4bymorethan70%atthetimeofAchstimulationTiotropiumhasbeenshowntoreduceinflammationinaguinea-pigmodelofallergen-inducedbronchoconstrictionAchmayinduceinflammatorymediatorsfrommostinflammatorycellsviaamuscarinic-mediatedmechanismthatmaybeinhibitedbytiotropiumRelativemigration,%WithoutAchAchAch+TIOTIOUPLIFT?subgroup

GOLDStageII:RateofdeclineinFEV1*P<0.0001vscontrol.RepeatedmeasureANOVAwasusedtoestimatemeans.Estimatedmeansareadjustedforbaselinemeasurements.Month0valuesareobservedmeans.Patientswith≥3acceptablePFTsafterday30wereincludedintheanalysis.Tiotropium:Month0,n=1196;Month48,n=923;Control:Month,0n=1140;Month,48n=853*Day30(steadystate)********061218243036424801Month*********Post-bronchFEV1

=52–82mLPre-bronchFEV1

=100–119mL

Rateofdeclineinpost-bronchFEV1

=6mL,P=0.02DecramerMetal.Lancet.2009;374:1171-8.Anti-inflammatorydrugsinstableCOPDInhaled/oralcorticosteroidsPDE-4inhibitorsAntibiotics:Azithromycin,erythromycinMucolytics/antioxidantsOther:Simvastatin?ActasatherapytopreventexacerbationHavesomeimpactonairwayinflammationProducesmallchangesinFEV1AreadditiveineffecttobronchodilatorsMaymodifydiseaseprogressionReduceexacerbations,especiallyrecurrenteventsInflammationinCOPDMainlypulmonary–SUMMITwasnegativeMaycauselungdamageorresultfromit–

orbothGeneticbasisstillunsureexceptforsomespecificrarepolymorphismsKeycellmaybeneutrophil,macrophage…oreosinophil.MagnifieslunginsultsExacerbationsmaybeofdifferenttypesVI63mL,p<0.001SUMMIT:RateofFEV1decline

-38mL/yrp=0.019-46mL/yrSymbolsrepresentadjustedmeansfromtheRMmodelandlinescomefrommodelforslopesDifferenceinChgfromBLDay360:FF/VI89mL,p<0.0011550160016501700175018000907201080Time(Days)FEV1(mL)180270360450540630810900990-38mL/yrp=0.026-47mL/yrp=0.6543800PlaceboNwithoutevent:3782356333963279267821971858149811719497364863866VI2538303658355434382813234719711612130010438315423912FF/VI100/253883373136103505286423911997163312901035827545VestboJ,etal.Lancet2016;387:1817–1826.FF49mL,p<0.0013879FF1003866VI2538583830368836583580355434523438277728132311234719361971156916121246130010011043792831528542LancetRespirMed2013TheLancetRespiratoryMedicine2013Exacerbationratereduction:

TiotropiumversusLABA+ICS

Wedzicha

JA,etal.AmJRespirCritCareMed.2008;177:19–26.59%62%1.321.28TiotropiumHandiHaler?

18μgSFCTiotropiumHandiHaler?18μgSFCRatiorates0.967,(95%CI,0.836–1.119),P=0.656Nodifferencebetweenexacerbationrates/yearOver2years,%patientswith≥1exacerbationrequiringtreatmentinterventionEstimatedoverallratesofexacerbationperyearFLAME:TimetofirstexacerbationWedzichaJA,etal.NewEnglJMed2016;374:2222–2234.MagnussenH,etal.NEnglJMed2014;371:1285?1294.MagnussenH,etal.EurRespirJ2016;47:651–654.Timetofirstmoderateorsevereon-treatmentCOPDexacerbationbysubgroupHazardratio1.0581.0801.0041.0410.9511.1921.0610.9421.1741.0540.9641.0751.0151.0950.9931.1451.0341.1140.9501.1200.9961.1461.0101.0311.110FactorsTotalICSatscreening*YesNoAgegroup,years<55≥55and<65≥65and<75≥75Xanthinesatscreening*YesNoChronicbronchitis(eCRF)*YesNoGOLDstageatscreening*34GOLDcategoriesatbaseline*CDPreviouscoursesofantibioticsorsteroids*<2≥2BaselineBMI,kg/m2<20≥20and<25≥25and<30≥30SexMaleFemaleSmokingstatusEx-smokerCurrentsmokerPatients,n2441172471734594588326856718741548891149193481916121537903368912771390201043116308111.00.5FavoursICSwithdrawalFavoursICS2.0*Post-hocanalysesTheeosinophilstorySuzukiM,etal.AmJRespirCritCareMed2016:194:1358–1365.PosthocanalysisofLABA/ICSversusLABAstudiesfoundabenefitofICSifthebloodeosinophilswheremorethan2%Norelationshipbetweenthe2%eosinophillevel(150cells/cu.ml)andexacerbationsinWISDOM

irrespectiveoftheuseofICSEosinophilsandCOPDPascoeetalLancetRespirMed2015EXACERBATIONRATEBYBLOODEOSINOPHILIATheriskofrelapseonICSwithdrawalbyeosinophilsubgroup

WatzH,etal.LancetRespirMed2016;4:390–398.EosinophilsandICS:OnepreviousexacerbationCalverleyPMA,etal.AmJRespirCritCareMed2017[ArticleinPress].Copyright?2017bytheAmericanThoracicSocietyEosinophilsandICS:TwoormorepreviousexacerbationsCalverleyPMA,etal.AmJRespirCritCareMed2017[ArticleinPress].withdrawalCopyright?2017bytheAmericanThoracicSocietyThechangingroleofcorticosteroids

instable