the relationship among copd severity, inhaled ... · the use of inhaled corticosteroids (ics) has...
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LUND UNIVERSITY
PO Box 117221 00 Lund+46 46-222 00 00
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:[email protected]
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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