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The Relationship among COPD Severity, Inhaled Corticosteroid Use, and the Risk ofPneumonia.

Rennard, Stephen I; Sin, Donald D; Tashkin, Donald P; Calverley, Peter M; Radner, Finn

Published in:Annals of the American Thoracic Society

DOI:10.1513/AnnalsATS.201506-391LE

2015

Document Version:Peer reviewed version (aka post-print)

Link to publication

Citation for published version (APA):Rennard, S. I., Sin, D. D., Tashkin, D. P., Calverley, P. M., & Radner, F. (2015). The Relationship among COPDSeverity, Inhaled Corticosteroid Use, and the Risk of Pneumonia. Annals of the American Thoracic Society,12(10), 1587-1589. https://doi.org/10.1513/AnnalsATS.201506-391LE

Total number of authors:5

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1

TherelationshipbetweenCOPDseverity,

inhaledcorticosteroiduseandtheriskof

pneumonia

StephenI.Rennard,MD,1DonaldD.Sin,MD,FRCPC,2DonaldP.Tashkin,MD,3PeterM.

Calverley,DSc,4FinnRadner,PhD5

1DivisionofPulmonary,CriticalCare,SleepandAllergy,UniversityofNebraskaMedical

Center,Omaha,NE,USA;2UniversityofBritishColumbia,Vancouver,BC,Canada;3David

GeffenSchoolofMedicineatUCLA,LosAngeles,CA,USA;4UniversityofLiverpool,Liverpool,

UK;5DepartmentofRespiratoryMedicine&Allergology,SkaneUniversityHospital,Lund,

Sweden

Correspondingauthor:

StephenRennard,MD.DivisionofPulmonary,CriticalCare,SleepandAllergy,985910

NebraskaMedicalCenter,Omaha,Nebraska68198-5910,USA

Tel:402-559-7313;Fax:402-559-4878;E-mail:srennard@unmc.edu

Runninghead:COPDseverity,ICSuseandtheriskofpneumonia

Keywords:COPD,severity,inhaledcorticosteroid,pneumonia

Statementoffunding:AstraZeneca

2

AbbreviationsList

COPD–chronicobstructivepulmonarydisease

FEV1–forcedexpiratoryvolumein1second

GOLD–GlobalInitiativeforChronicObstructiveLungDisease

ICS–inhaledcorticosteroids

3

TotheEditor:

Theuseofinhaledcorticosteroids(ICS)hasbeenassociatedwithanincreasedriskof

pneumoniawhenadministeredtopatientswithchronicobstructivepulmonarydisease

(COPD).1,2However,thereisevidencetosuggestthattheriskofpneumoniamayvary

dependingonwhichICSisprescribed.3Ameta-analysisofsevenstudiescomparedinhaled

budesonide,administeredwithorwithoutthelong-actingβ2-agonist,formoterol,witha

non-ICScontrolanddidnotfindanincreasedriskofpneumoniainpatientswithCOPD

treatedwithbudesonide.4Pneumoniabecomesmorecommonasairflowobstruction

worsens5andanytreatment-relatedincreaseintheriskofpneumoniashouldbemost

evidentinpatientswiththeworstairflowobstruction.1Inthisanalysiswedeterminedthe

relationshipofbudesonidetoincidentpneumoniaaccordingtotheseverityofairflow

limitationinpatientswithCOPD.

Methods.Aspreviouslydescribed,4sevenstudiesofinhaledbudesonide,withorwithout

formoterol,versusanon-ICScontrolregimen(formoterolorplacebo)inpatientswithstable

COPDandatleast6monthsoffollow-upwereidentified.Resultsofaneighthtrialthat

fulfilledtheinclusioncriteriawerealsoincludedinthiscurrentpooledanalysis.6Durationof

treatmentrangedfrom6to36monthsinpatientswithmild-to-very-severeCOPD.The

analysiswasrightcensoredto12monthssinceonlytwotrialswereoflongerduration.In

threeoftheeightstudies,patientsreceivedeitherbudesonide(640–1280μg/day)or

placebo.Intheremainingfivestudies,patientsreceivedeitherbudesonide/formoterol

(320/18or640/18μg/day),budesonide(640μg/day),formoterol(18μg/day)orplacebo.

4

Pneumoniaadverseeventsorseriousadverseevents,whichstartedeitherduring,orwithin

15daysofcompletionof,randomisedtreatment,wererecorded.Forthepurposesofthis

analysis,pneumoniaadverseeventswereidentifiedasanyadverseeventcodedtothe

MedDRA(version9)preferredterms“Pneumonia”,“Bronchopneumonia”,“Lobar

pneumonia”,“Lunginfection”,“Pneumoniastaphylococcal”or“Pneumoniapneumococcal”.

Aseriousadverseeventwasdefinedasanadverseeventthatresultedindeathor

hospitalization.Patientswhoexperiencedmorethanoneadverseeventwerecountedonly

once.

PneumoniariskwasstratifiedaccordingtoGlobalInitiativeforChronicObstructiveLung

Disease(GOLD)grade(grade1:mild,post-bronchodilatorforcedexpiratoryvolumein1

second[FEV1]≥80%predicted;grade2:moderate,FEV1≥50%to<80%predicted;grade3:

severe,FEV1≥30%to<50%predicted;grade4:verysevere,FEV1<30%predicted),7for

patientsreceivingbudesonideversusnon-ICScontrol(formoterolorplacebo).Patientswho

receivedbudesonide/formoterolwereincludedwithinthebudesonidetreatmentgroup.

OverallrelativeriskwascalculatedusingaMantel-Haenszelapproach,stratifiedbystudy

andadjustedfortreatmentexposure.ResultswereexpressedasthepooledMantel-

Haenszelrelativeriskand95%confidenceintervals(CIs).

Results.Datawereavailablefor8260patients;4616patientswhoreceivedinhaled

budesonide(3394patient-yearsofexposure)and3644patientswhoreceivednon-ICS

control(2646patient-yearsofexposure).Mean(±standarddeviation)ageofparticipants

was62±10yearsandmean(±standarddeviation)post-bronchodilatorFEV1was49±18%

predicted;69%ofpatientsweremaleand49%werecurrentsmokersatenrolment.Overall,

5

34%ofpatients(n=2825)wereclassifiedasGOLDgrade1or2,48%(n=3987)GOLDgrade3,

and17%(n=1426)GOLDgrade4.GOLDgradewasnotavailablefor12patientswhoreceived

budesonideand10patientswhoreceivednon-ICScontrol;however,nopneumoniaevents

werereportedinthesepatients.

Theincidenceofpneumoniaincreasedwithincreasingseverityofairflowlimitationfor

patientswhoreceivedbudesonideoranon-ICScontrol,intermsofbothpneumoniaAEsper

100treatment-yearsandpneumoniaseriousadverseeventsper100treatment-years(Table

1).Nostatisticallysignificantdifferenceintheriskofpneumoniawithbudesonideornon-ICS

controlwasobservedinthetotalpopulationorinanyseveritysubgroup(Figure1,Table1).

Theoverallrelativeriskforpneumoniaadverseeventsandseriousadverseeventswas1.12

(95%CI:0.89,1.42)and1.01(95%CI:0.72,1.42),respectively.

ThisanalysisevaluatedwhethertherewasanyeffectofCOPDseverityonpneumoniarisk

frombudesonide.Pneumoniaassessedaseitheranadverseeventorseriousadverseevent

increasedwithincreasingseverityofCOPDWhiletherewerenumericaldifferencesfor

pneumoniareportedasanadverserisk,riskofpneumoniawasnotsignificantlydifferentin

patientstreatedwitheitherbudesonide,withorwithoutformoterol,oranon-ICScontrol

acrossallCOPDseverities.Thisisconsistentwiththefindingsoftheaforementionedmeta-

analysis,whichincludeddatafromsevenoftheeightstudiesinvestigatedhere.4Other

inhaledglucocorticoidshavebeenassociatedwithincreasedriskofpneumoniathat

increaseswithGOLDgrade.8Whybudesonidediffersinunknown;however,adatabase

studysuggeststhattheriskofpneumoniainCOPDpatientsisrelatedtotherelativeeffective

doseofadministeredICS.3

6

Ourresultshaveanumberoflimitations.Firstly,theanalysiswasstratifiedbytheGOLD

spirometricclassificationofairflowlimitationonly(post-bronchodilatorFEV1≥50%versus

≥30%to<50%versus<30%predicted),whichisonlyonedimensionoftheGOLDseverity

grade.OthermeasuresofCOPDseverityincludesymptoms,exacerbationhistory,presence

andextentofemphysema,presenceofchronicbronchitis,hypoxemia,functionalstatusand

associatedco-morbidities,noneofwhichwereassessedinthecurrentanalysis.9Secondly,

theeightstudiesinvestigatedwerenotspecificallypoweredtodetectpneumonia.Thirdly,

pneumoniawasidentifiedasanadverseeventoraseriousadverseeventfromreports

submittedbyinvestigators;however,theseeventswerenotsystematicallyvalidated.

Fourthly,ouranalysiscensoredpatientdataat12monthsdespitedatabeingavailablefrom

studiesextendinguptothreeyears.Therefore,thelong-termeffectsofinhaledbudesonide

(>12months)ontheriskofpneumoniawerenotassessed.

Inconclusion,thecurrentanalysisextendsthepreviousevaluationassessingpneumoniarisk

inCOPDpatients.AnoverallincreasedriskforpneumoniawithCOPDseverityassessedby

FEV1wasdemonstrated.However,foreachGOLDseveritygroup,nodifferencein

pneumoniariskwasdemonstratedwithbudesonidetreatment.

Acknowledgements

MedicalwritingassistancewasprovidedbyClairThomasofinScienceCommunications,

SpringerHealthcareandfundedbyAstraZeneca.ThisanalysiswasfundedbyAstraZeneca.

7

References

1. CrimC,CalverleyPM,AndersonJA,etal.PneumoniariskinCOPDpatientsreceivinginhaled

corticosteroidsaloneorincombination:TORCHstudyresults.TheEuropeanrespiratory

journal.Sep2009;34(3):641-647.

2. CalverleyPM,StockleyRA,SeemungalTA,etal.ReportedpneumoniainpatientswithCOPD:

findingsfromtheINSPIREstudy.Chest.Mar2011;139(3):505-512.

3. SuissaS,PatenaudeV,LapiF,ErnstP.InhaledcorticosteroidsinCOPDandtheriskofserious

pneumonia.Thorax.Nov2013;68(11):1029-1036.

4. SinDD,TashkinD,ZhangX,etal.Budesonideandtheriskofpneumonia:ameta-analysisof

individualpatientdata.Lancet.Aug292009;374(9691):712-719.

5. ManninoDM,DavisKJ,KiriVA.Chronicobstructivepulmonarydiseaseandhospitalizations

forpneumoniainaUScohort.Respiratorymedicine.Feb2009;103(2):224-229.

6. SharafkhanehA,SouthardJG,GoldmanM,UryniakT,MartinUJ.Effectof

budesonide/formoterolpMDIonCOPDexacerbations:adouble-blind,randomizedstudy.

Respiratorymedicine.Feb2012;106(2):257-268.

7. GlobalInitiativeforChronicObstructiveLungDisease.2014;

http://www.goldcopd.org/uploads/users/files/GOLD_Report2014_Feb07.pdf.

8. JenkinsCR,JonesPW,CalverleyPM,etal.Efficacyofsalmeterol/fluticasonepropionateby

GOLDstageofchronicobstructivepulmonarydisease:analysisfromtherandomised,

placebo-controlledTORCHstudy.RespirRes.2009;10:59.

9. ThomashowB,CrapoJ,YawnB,etal.TheCOPDFoundationPocketConsultantGuide.JCOPD

F.2014;1(1):83-87.

8

Table

Table1

PneumoniaasAEsandSAEsper100treatmentyearsandrelativeriskforpneumoniaAEsandSAEsinpatientswhoreceivedbudesonideversus

non-ICScontrol

GOLDgrade

Budesonide Non-ICS Relativerisk(95%CI)aN Treatment

yearsPneumoniaAE

per100treatmentyears

PneumoniaSAEper100

treatmentyears

N Treatmentyears

PneumoniaAEper100

treatmentyears

PneumoniaSAEper100

treatmentyears

PneumoniaAEsforbudesonidevs

non-ICS

PneumoniaSAEsforbudesonidevs

non-ICSN/Ab 12 7 - - 10 3 - - - -GOLD1+2 1499 1218 4.3 1.1 1326 1085 3.4 1.0 1.19(0.77,1.83) 0.92(0.42,2.06)GOLD3 2277 1630 5.6 2.6 1710 1192 5.2 2.6 1.06(0.76,1.48) 1.03(0.64,1.67)GOLD4 828 540 6.7 4.8 598 365 5.8 4.7 1.12(0.65,1.92) 0.95(0.51,1.78)Allpatients 4616 3395 5.3 2.4 3644 2645 4.5 2.2 1.12(0.89,1.42) 1.01(0.72,1.42)

aRelative risk and exact confidence intervals for pneumonia events (budesonide vs non-ICS) as calculated using StatXact 8.0.0 (Cytel® Inc,

Cambridge,USA).

bGOLDgradewasnotavailablefor12patientswhoreceivedbudesonideand10patientswhoreceivednon-ICScontrol;nopneumoniaevents

werereportedinthesepatients.

9

FigureLegend

Pneumoniareportedasadverseevents(PanelA)orSeriousadverseevents(PanelB)forsubjectstreatedwithbudesonide(blue)orplacebo

(red) separated by GOLD Spirometry Severity. No differences for budesonide vs non-ICS reached statistical signifance. See Table 1 for

confidenceintervals.

Figure1

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