DOÌ 10.1378/chest.

09-1305
2010;137;318-325; Prepublished online September 25, 2009; Chest

Jindal
Ritesh Agarwal, Ashutosh N. Aggarwal, Dheeraj Gupta and Surinder K.

Randomized ControIIed TriaIs
Systematic Review and Metaregression of
Preventing COPD Exacerbations : A
InhaIed Corticosteroids vs PIacebo for

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is the official journal of the American College of Chest Chest
© 2010 American College of Chest Physicians
by Deddy Herman on May 10, 2011 chestjournal.chestpubs.org Downloaded from
318
Orlglnal Pesearch
COPD

Original Research
© 2010 Amcrican Collcgc of Cbcst Pbysicians. Bcproouction
ol this articlc is prohilitco vithout vrittcn pcrmission lrom thc
Amcrican Collcgc ol Chcst Fhvsicians ( vvv . chcstjournal . org /
sitc / misc / rcprints . xhtml ).
ÐOI: 10.137S/cbcst.09-1305
OFD is primarilv a smoking-rclatco innammatorv
oiscasc ol thc lungs clinicallv manilcsting as
cough. sputum proouction. ano ovspnca. ¡t is a major
causc ol mortalitv ano morlioitv vorlovioc ano
rcsults in signilcant cconomic ano social lurocn.
1
COFD is also thc lourth lcaoing causc ol ocath in thc
vorlo (sixth in lov-incomc. thiro in mioolc-incomc.
ano lilth in high-incomc countrics).
2
ano lurthcr
incrcascs in its prcvalcncc ano mortalitv arc prcoictco
in thc coming occaocs.
3
Apart lrom smoking ccssation
ano long-tcrm oxvgcn thcrapv (in sclcctco paticnts).
no othcr pharmacologic intcrvcntion has lccn shovn
to improvc survival in paticnts vith COFD. Thus.
thc aim ol currcnt mcoical thcrapv in COFD is
locusco on rcouction ol svmptoms ano complications
associatco vith thc oiscasc. Onc major locus ol most
pharmacological thcrapics is to prcvcnt cxaccrlations
ol COFD as thcv not onlv aovcrsclv impact hcalth
status lut arc also a sourcc ol hugc lnancial lurocn.
Background: Inbalcd corticostcroids (ICS) bavc bccn sbown to dccrcasc tbc occurrcncc of COPÐ
cxaccrbations. Howcvcr, tbc rclationsbip of basclinc lung function and rcduction of cxaccrba-
tions witb tbc usc of ICS rcmains unknown. Hcrcin, wc pcrform a mctarcgrcssion to cvaluatc tbc
cfhcacy of ICS in prcvcnting COPÐ cxaccrbations.
Methods: Wc scarcbcd tbc PubMcd, FmBasc, and Cocbranc Ccntral Ðatabasc of Controllcd
Trials databascs (19SS-200S) for studics tbat bavc rcportcd tbc cfhcacy of ICS vs placcbo in prc-
vcnting COPÐ cxaccrbations. Wc poolcd tbc risk ratio (BB) and 95% CIs from individual studics
using a random-cffccts modcl to asscss tbc cxaccrbations in tbc two groups. Wc also pcrformcd a
wcigbtcd random cffccts mctarcgrcssion using basclinc FFV
1
valucs.
Besu/ts: Our scarcb yicldcd 11 studics (S,164 paticnts). Tbc usc of ICS was associatcd witb rcduc-
tion in tbc occurrcncc of cxaccrbations (BB, 0.S2: 95% CI, 0.73-0.92). Tbcrc was tbc prcscncc of
signihcant statistical bctcrogcncity but no cvidcncc of publication bias. Scnsitivity analysis rcvcalcd
bcncht of ICS only in paticnts witb FFV
1
 50% (BB, 0.79: 95% CI, 0.69-0.S9) witb pcrsistcncc of
statistical bctcrogcncity. Mctarcgrcssion sbowcd tbat tbc pcrccntagc risk rcduction in cxaccrbations
witb tbc usc of ICS is invariant across tbc scvcrity of COPÐ (asscsscd by FFV
1
).
Conc/usion: Tbcrc is only a modcst bcncht of ICS in prcvcnting COPÐ cxaccrbations, wbicb is
not rclatcd to tbc lcvcl of basclinc lung function on mctarcgrcssion analysis. Tbc bcnchts of ICS
in prcvcnting COPÐ cxaccrbations tbus sccm to bc ovcrstatcd. CHEST 2010: 137(2):31S-325
Abbrcviations: ¡CS inhalco corticostcroios: BB risk ratio
Inha|ed Cort|costero|ds vs P|acebo for
Prevent|ng COPD Exacerbat|ons
A Systemat|c Rev|ew and Metaregress|on
of Random|zed Contro||ed Tr|a|s
B|/·s/ A·aræa| . MD . DM . FCCI . As/u/·s/ N. A··aræa| . MD . DM . FCCI .
D/··ra¡ Gup/a . MD . DM . FCCI . and Sur|nd·r K. I|nda| . MD . FCCI
Manuscript rcccivco ]unc 3. 2000: rcvision acccptco August 17.
2000.
Afhliations: From thc Dcpartmcnt ol Fulmonarv Mcoicinc.
Fostgraouatc ¡nstitutc ol Mcoical Foucation ano Bcscarch. Chan-
oigarh. ¡noia .
Corrcspondcncc to: Bitcsh Agarval. MD. DM. FCCF. Assistant
Frolcssor. Dcpartmcnt ol Fulmonarv Mcoicinc. Fostgraouatc
¡nstitutc ol Mcoical Foucation ano Bcscarch. Scctor-12. Chanoigarh
160012. ¡noia: c-mail: ritcshpgiCgmail.com
© 2010 American College of Chest Physicians
by Deddy Herman on May 10, 2011 chestjournal.chestpubs.org Downloaded from
www.chestjournal.org CHEST / 137 / 2 / FEBRUARY, 2010 319
paticnts at risk lor COFD lasco on accclcratco FFV
1
occlinc ano
stuoics incluoing paticnts vith loth asthma ano COFD vcrc
cxcluoco) irrcspcctivc ol thc scvcritv ol COFD. (2) lollov-up
ouration ol thc stuov lor at lcast 1 vcar. (3) ranoomizco controllco
trials comparing ¡CS vs placclo (stuoics vith comlination ol ¡CS
plus ¡ABA vcrc cxcluoco) ano rcporting thc cxaccrlation ratcs
in thc tvo groups. ano (4) pccr-rcvicvco lullv pullishco stuoics.
Data vcrc rccoroco on a oata cxtraction lorm. ano oiscrcpan-
cics vcrc rcsolvco lv conscnsus lctvccn thc authors. Thc lollov-
ing itcms vcrc cxtractco: (1) pullication octails: citation. titlc.
author(s): (2) octails on ranoomization. llinoing. ano vithoravals/
oropouts in thc stuov: (3) oosagcs ano ocviccs ol ¡CS usco in thc
various stuoics: (4) thc mcan agc. gcnocr. currcnt smoking status.
ano lasclinc FFV
1
ol thc stuov participants: ano (5) thc oclnition
ol cxaccrlations ano thc ratc ratio ol cxaccrlations in thc inoi-
vioual stuoics. Thc oclnitions lor cxaccrlation vcrc thosc usco
lv thc authors in thc original stuoics.
Tr|a| Çua||/n
Thc mcthooologic oualitv ol cach trial vas cvaluatco using
thc six-point scalc (0 vorst to 5 lcst) as ocscrilco lv ]aoao
ct al.
17
This instrumcnt asscsscs thc aocouacv ol ranoomization.
llinoing. ano thc hanoling ol vithoravals ano oropouts. vith a
scorc ol onc point lor cach ¨vcs` or zcro points lor cach ¨no.` Onc
aooitional point is givcn il thc mcthoo to gcncratc thc scoucncc ol
ranoomization vas ocscrilco ano it vas appropriatc (tallc ol ran-
oom numlcrs. computcr gcncratco. ano so lorth) or thc mcthoo
ol ooullc-llinoing vas ocscrilco ano it vas appropriatc (iocntical
placclo. activc placclo. oummv. ano so lorth). On thc othcr hano.
onc point is ocouctco il thc mcthoo to gcncratc thc scoucncc ol
ranoomization vas ocscrilco ano it vas inappropriatc (paticnts
vcrc allocatco altcrnatclv. or accoroing to oatc ol lirth. hospital
numlcr. ano so lorth) or thc stuov vas ocscrilco as ooullc-llino
lut thc mcthoo ol llinoing vas inappropriatc (cg. comparison ol
tallct vs injcction vith no ooullc oummv). Thc stuoics arc saio to
lc ol lov oualitv il thc ]aoao scorc is 2 ano high oualitv il thc
scorc is 3.
17.1S

S/a/|s/|·a| Ana|ns|s
Thc statistical packagcs Comprchcnsivc Mctaanalvsis (vcrsion
2.2.046 lor MS-Winoovs: Biostat: Fnglcvooo. N]: http://vvv.
mcta-analvsis.com ) ano StatsDircct (StatsDircct vcrsion 2.7.2
lor MS-Winoovs: StatsDircct ¡to: Chcshirc. UK: http://vvv.
statsoircct.com ) vcrc usco to pcrlorm all statistical analvscs.
D·/·rn|na/|·n ·j //· I··|·d Tr·a/n·n/ Ejj··/
Thc rcsults ol BB vith thcir 05% C¡s lrom inoivioual stuoics
vcrc poolco using loth lxco cllccts moocl ol Mantcl-Hacnszcl
ano DcrSimonian-¡airo ranoom cllccts moocl.
10.20
Hovcvcr. thc
rcsults ano cnsuing oiscussion havc lccn oonc onlv vith thc
ranoom cllccts moocl.
Ass·ssn·n/ ·j H·/·r···n·|/n
Thc impact ol hctcrogcncitv on thc poolco cstimatcs ol thc
inoivioual outcomcs ol thc mctaanalvsis vas asscssco lv thc ¡
2
tcst
ano thc Cochran O statistic. Thc ¡
2
tcst mcasurcs thc cxtcnt ol
inconsistcncv among thc rcsults ol thc stuoics. vhich arc intcr-
prctco as thc approximatc proportion ol total variation in stuov
cstimatcs that is ouc to hctcrogcncitv rathcr than sampling crror.
An ¡
2
valuc grcatcr than 50% inoicatcs signilcant hctcrogcncitv.
21
Thc Cochran tcst calculatcs thc vcightco sum ol souarco oillcr-
cnccs lctvccn inoivioual stuov cllccts ano thc poolco cllcct
across stuoics. vith thc vcights lcing thosc usco in thc pooling
¡n lact. COFD cxaccrlations rcouiring hospitaliza-
tion account lor onc-hall or morc ol thc total mcoical
costs lor trcating this oiscasc.
4.5

¡nhalco corticostcroios (¡CS) arc antiinnammatorv
agcnts. ano thus havc lccn vioclv usco lor thc trcat-
mcnt ol COFD. Thc cllcctivcncss ol ¡CS in paticnts
vith COFD rcmains controvcrsial.
6.7
Thc currcnt
intcrnational guioclincs rccommcno ¡CS to lc usco
in paticnts vith COFD vith an FFV
1
valuc lcss than
50% prcoictco ano rcpcatco cxaccrlations. as thcv
havc lccn shovn to occrcasc cxaccrlations in this
sulgroup ol paticnts vith COFD.
1
Hovcvcr. ¡CS
arc also associatco vith numcrous aovcrsc cllccts.
incluoing oropharvngcal canoioiasis.
S
cataracts.
0
ano
lracturcs.
10
¡n paticnts vith COFD. thcv havc also
lccn shovn to signilcantlv incrcasc thc risk ol
pncumonia.
11

Civcn thc possillc morlioitv associatco vith thc
usc ol ¡CS. it is important to rccvaluatc thc lcnclt ol
¡CS. cspcciallv vith its claim ol rcoucing cxaccrla-
tions. Fivc svstcmatic rcvicvs ano/or mctaanalvscs
havc suggcstco lcnclcial cllccts ol ¡CS in prcvcnt-
ing cxaccrlations.
12-16
¡t has also lccn suggcstco that
largcr ¡CS-rclatco rcouctions in cxaccrlations tcno
to lc sccn in trials that cnrollco paticnts vith lovcr
mcan lasclinc valucs ol FFV
1
.
S

¡n this stuov. vc pcrlorm a svstcmatic rcvicv ano
mctaanalvsis ol ranoomizco controllco trials that
havc cvaluatco thc cllcacv ol ¡CS vs placclo in prc-
vcntion ol COFD cxaccrlations. Wc also pcrlorm a
mctarcgrcssion ol trials to cvaluatc thc risk rcouction
vith cvcrv pcrccntagc occlinc in lasclinc valucs ol
FFV
1
across stuoics. apart lrom thc simplcr stratilco
mcthoo usco lv prcvious analvscs to comparc thc
cllcacv ol ¡CS in prcvcnting COFD cxaccrlations
across varving scvcritv ol COFD.
M ~iiii~is ~Nn M iinons
S·ar·/ S/ra/··n and S·|··/|·n Cr|/·r|a
To iocntilv thc stuoics lor inclusion in this rcvicv. all thc authors
inocpcnocntlv scarchco thc computcr oatalascs FulMco.
Cochranc Ccntral Datalasc ol Controllco trials. ano FmBASF lor
rclcvant stuoics pullishco lrom 10SS to 200S using lrcc tcxt tcrms:
inhalco corticostcroios. ¡CS. chronic olstructivc pulmonarv ois-
casc. ano COFD. in various comlinations. ano limiting thc scarch to
Fnglish litcraturc. Billiographics ol all sclcctco articlcs ano rcvicv
articlcs that incluoco inlormation on thc rolc ol inhalco corticostcr-
oios in prcvcnting cxaccrlations ol COFD vcrc rcvicvco.
Da/a A|s/ra·/|·n
Thc alstracts ol thc stuoics vcrc inocpcnocntlv rcvicvco lv
tvo authors (BA ano ANA). vithout llinoing to stuov thc octails.
Anv oisagrccmcnt vas rcsolvco lv oiscussion lctvccn thc
authors. Wc incluoco stuoics that mct thc lolloving critcria:
(1) stuoics incluoing conlrmco cascs ol COFD (stuoics rccruiting
© 2010 American College of Chest Physicians
by Deddy Herman on May 10, 2011 chestjournal.chestpubs.org Downloaded from
320 Original Research
ol thc stuov population arc shovn in Tallc 2 . Thc
stuov populations in all thc trials vcrc prcponocr-
antlv mcn vith a mcan agc ol 62 vcars . Thc FFV
1
valucs vcrc lcss than 50% in scvcn ol thc 11 stuo-
ics.
20.30.32-35.37
Thc oclnition ol COFD cxaccrlation
varico among trials lut in gcncral vas thc oclnition
usco in oav-to-oav practicc ( Tallc 3 ).
Thc poolco rcsults ol lrom thc 11 incluoco stuoics
shovco an 1S% rclativc risk rcouction ( Fig 2 ) in thc
occurrcncc ol cxaccrlations (BB. 0.S2: 05% C¡.
0.73-0.02) vith thc usc ol ¡CS in paticnts vith COFD
(ovcr a mcan lollov-up pcrioo ol 2.1 vcars). Hov-
cvcr. thcrc vas prcscncc ol signilcant hctcrogcnc-
itv vith an ¡
2
valuc ol 55% (05% C¡. 0-75.6) ano
Cochran O statistic ol 22.24 ( I .01). Thcrc vas no
cviocncc ol pullication lias on visual cxamination ol
thc lunncl plot ( Fig 3 ) or on thc statistical tcsts (Bcgg-
Mazumoar: Kcnoall    0.054545. I .76: Fggcr:
lias   0.550623. I .46).
mcthoo. Thc I valuc lcvcl at vhich hctcrogcncitv shoulo lc oiag-
nosco is unclcar. givcn that thc O statistic has lov povcr. ano
Flciss havc rccommcnoco a valuc ol at lcast 0.1.
Ass·ssn·n/ ·j Iu|||·a/|·n B|as
Wc chcckco lor thc prcscncc ol pullication lias using thc
Bcgg lunncl plot.
23
Thc lunncl plot is a mcasurc ol thc log BB
(in thc X-axis) against thc stanoaro crror ol thc log BB (in thc Y-axis).
Fach opcn circlc rcprcscnts cach stuov in thc mctaanalvsis. Thc
linc in thc ccntcr inoicatcs thc summarv proportion ano thc othcr
tvo lincs inoicatc thc 05% C¡. ¡n thc alscncc ol pullication lias.
thc proportion cstimatcs lrom smallcr stuoics arc cxpcctco to lc
scattcrco alovc ano lclov thc summarv cstimatc. prooucing a
triangular or lunncl shapc.
Wc also chcckco lor pullication lias using tvo statistical tcsts:
(1) thc Fggcr tcst.
24
vhich is a tcst lor asvmmctrv ol thc lunncl
plot. This is a tcst lor thc Y intcrccpt 0 lrom a lincar rcgrcssion
ol normalizco cllcct cstimatc (cstimatc oivioco lv its stanoaro
crror) against prccision (rcciprocal ol thc stanoaro crror ol thc
cstimatc): ano (2) Bcgg ano Mazumoar tcst.
25
vhich tcsts thc
intcrocpcnocncc ol variancc ano cllcct sizc using rank corrclation
mcthoo.
S·ns|/|t|/n Ana|ns·s
Wc pcrlormco scnsitivitv analvscs to cxaminc cllcct sizcs vhcn
onlv thc lolloving tvpcs ol stuoics vcrc incluoco: stuoics incluo-
ing paticnts vith milo to moocratc scvcritv ol COFD (ic. FFV
1

50%). ano stuoics incluoing paticnts vith scvcrc to vcrv scvcrc
COFD (ic. FFV
1
50%).
1

M·/ar··r·ss|·n
Wc usco unrcstrictco maximum likclihooo vcightco lincar
ranoom-cllccts mctarcgrcssion to cvaluatc variation lctvccn
stuoics. to moocl thc ratc ratio as a lunction ol FFV
1
(pcrccntagc
prcoictco). ano to graph thc rcsponsc curvc lctvccn FFV
1
ano
rcouction ol cxaccrlations vith thc usc ol ¡CS.
26
Thc ocpcnocnt
variallc lor thc rcgrcssion vas thc natural log ol cach stuov-
spccilc ratc ratio lor cxaccrlations. vcightco lv thc invcrsc ol its
variancc. Thc FFV
1
lor cach stuov vas thcn trcatco as a continu-
ous. inocpcnocnt variallc. Thc cocllcicnt ol thc FFV
1
in thc
rcgrcssion moocl cstimatcs thc slopc ol thc lincar FFV
1
oosc-
rcsponsc cllcct. Solving thc rcgrcssion couation cstimatcs thc
pcrccntagc risk rcouction in cxaccrlation prcoictco at anv givcn
pcrccntagc prcoictco FFV
1
.
An institutional rcvicv loaro clcarancc vas not rcouirco lor
this stuov as this vas a mctaanalvsis ol pullishco stuoics.
B isiiis
Our initial oatalasc scarch rctricvco 1.005 cita-
tions ( Fig 1 ). Ol thcsc. 177 stuoics vcrc cxcluoco
as thcv oio not involvc COFD. Finallv. 11 stuoics
(S.164 stuov participants: 4.241 ¡CS. 3.023 placclo)
that mct our inclusion critcria vcrc incluoco in thc
lnal analvsis.
27-37
All thc stuoics vcrc prospcctivc.
ooullc-llino. ranoomizco. placclo-controllco trials.
Thc ]aoao scorc vas grcatcr than thrcc lor all thc
stuoics. inoicating high oualitv ol thc inoivioual stuo-
ics ( Tallc 1 ). Thrcc trials hao a svstcmic stcroio run-
in phasc ol 2 vccks.
2S.30.33
Thc lasclinc charactcristics
Ficiii 1. Flov oiagram shoving thc trial sclcction proccss lor
this svstcmatic rcvicv. ¡CS  inhalco corticostcroios.
© 2010 American College of Chest Physicians
by Deddy Herman on May 10, 2011 chestjournal.chestpubs.org Downloaded from
www.chestjournal.org CHEST / 137 / 2 / FEBRUARY, 2010 321
crlation rcouction lv ¡CS: that is. thc BB (or thc
pcrccntagc risk rcouction) is invariant across thc
scvcritv ol COFD (as asscssco lv FFV
1
) incluoco in
thc trials. Thc cocllcicnt lor thc FFV
1
in thc rcgrcs-
sion moocl is thc natural logarithm ol thc changc in
pcrccntagc risk rcouction lor cach pcrccntagc prc-
oictco incrcasc in FFV
1
.
D iscissioN
Thc rcsults ol this svstcmatic rcvicv suggcst that
thcrc is a moocst rclativc risk rcouction in COFD
cxaccrlations vith thc usc ol ¡CS. ¡n thc scnsitivitv
analvsis. thc lcnclcial cllcct vas notco onlv in paticnts
vith FFV
1
valucs lcss than 50%. Thcrc vas prcscncc ol
signilcant statistical hctcrogcncitv vith no cviocncc
ol pullication lias. A mctarcgrcssion analvsis also
lailco to ocmonstratc a lincar rclationship lctvccn
FFV
1
valucs ano occlinc in COFD cxaccrlations vith
thc usc ol ¡CS.
Thc currcnt svstcmatic rcvicv is oillcrcnt lrom
prcvious rcvicvs in manv aspccts. Wc aooco mcta-
rcgrcssion to thc simplc mctaanalvtic tcchniouc to
cxplorc among-stuov oillcrcnccs ano strcngthcn thc
valioitv ol our analvsis. Mctarcgrcssion is a mcthoo
ol comlining rcsults lrom multiplc stuoics using
lasic mctaanalvsis in comlination vith vcightco
rcgrcssion analvsis to prcoict stuov cllccts using
stuov-lcvcl covariatcs.
3S
Furthcr. vc usco a ranoom-
cllccts mctarcgrcssion. vhich takcs into account
loth vithin-trial varianccs ol trcatmcnt cllccts ano
S·ns|/|t|/n Ana|ns|s and M·/ar··r·ss|·n
Scnsitivitv analvsis vas pcrlormco lasco on thc
scvcritv ol COFD ( Tallc 4 ). Thc analvsis rcvcalco that
thc trcatmcnt cllcct vas ocrivco largclv lrom stuoics
that incluoco paticnts vith scvcrc to vcrv scvcrc COFD
(FFV
1
lcss than 50% prcoictco). Fxcluoing paticnts
vith milo to moocratc COFD vicloco an cstimatc
cllcct almost similar to thc ovcrall mctaanalvsis
vith similar ocgrccs ol hctcrogcncitv. ¡n lact. thcrc
vas no hctcrogcncitv in thc summarv statistic ol
paticnts vith milo to moocratc COFD ( Tallc 4 ).
Thc rcsults ol thc lincar rcgrcssion moocl ( Tallc 5 )
conlrmco thc visual imprcssion ol thc scattcr plot
( Fig 4 ). Thcrc is no lincar rcsponsc ol FFV
1
on cxac-
Tablc 1-Oua/itq o[ the 11 Tria/s as Assessed bq the
jadad Score
Stuov/Ycar Banoomization Blinoing
Dcscription
ol Withoravals
ano Dropouts
Bcnkcma ct al
27
/1006 2 2 1
Vcstlo ct al
2S
/1000 1 2 1
Wcir ct al
20
/1000 1 2 1
Burgc ct al
30
/2000 2 2 1
¡ung Hcalth
Stuov
31
/2000
2 2 1
Calvcrlcv ct al
32
/2003 2 2 1
Calvcrlcv ct al
33
/2003 2 2 1
Szalranski ct al
34
/2003 1 2 1
Calvcrlcv ct al
35
/2007 2 2 1
Chouohurv ct al
36
/2007 2 2 1
Calvcrlcv ct al
37
/200S 2 2 1
Tablc 2-Base/ine Characteristics o[ the Studq Popu/ation in Various Studies
Stuov/Ycar
Mcan
Agc. v
Malc
Scx. %
Currcnt
Smoking. %
No.
¡CS
No.
Flacclo
Stuov
Duration. v ¡CS. Dosc in g Dcvicc Usco
Basclinc FFV
1
.
% Frcoictco
Bcnkcma
ct al
27
/1006
55 . 40.5 21 24 2 Buocsonioc. S00 pMD¡ vith
spaccr
63.5
Vcstlo
ct al
2S
/1000
50 60.4 76.6 145 145 3 Buocsonioc. S00 DF¡. Turluhalcr 7S.0
Wcir ct al
20
/1000 50 74.5 3S.7 40 40 2 Bcclomcthasonc. 2.000 pMD¡ vith
spaccr
40.7
Burgc ct al
30
/2000 63.S 74.5 37.5 376 375 3 Fluticasonc. 1.000 pMD¡ vith
spaccr
46.3
¡ung Hcalth
Stuov
31
/2000
56.3 63 00.2 550 557 4.5 Triamcinolonc. 1.200 pMD¡ vith
spaccr
64.2
Calvcrlcv
ct al
32
/2003
63.5 72.5 50 35S 361 1 Fluticasonc. 1.000 DF¡. Accuhalcr 40.S
Calvcrlcv
ct al
33
/2003
64.5 74.5 34.5 257 256 1 Buocsonioc. S00 DF¡. Turluhalcr 36.0
Szalranski
ct al
34
/2003
64.5 S1.5 35 10S 205 1 Buocsonioc. S00 DF¡. Turluhalcr 36.5
Calvcrlcv
ct al
35
/2007
65 75.5 43 1534 1524 3 Fluticasonc. 1.000 DF¡. Accuhalcr 40.4
Chouohurv
ct al
36
/2007
67.5 52 3S.1 12S 132 1 Fluticasonc. 1.000 DF¡. Accuhalcr 51.3
Calvcrlcv
ct al
37
/200S
65 6S.5 . 616 205 1 Momctasonc. S00 DF¡. Accuhalcr 42.3
Ovcrall 62.1 60.7 4S.4 4241 3023 2.1 . . 40.2
¡CS inhalco corticostcroio.
© 2010 American College of Chest Physicians
by Deddy Herman on May 10, 2011 chestjournal.chestpubs.org Downloaded from
322 Original Research
thcsc oata.
43
Also. vc incluoco onlv stuoics that cval-
uatco ¡CS alonc comparco vith placclo as comlina-
tion thcrapv ol ¡CS vith othcr orugs prccluocs thc
cvaluation ol thc cllcacv ol ¡CS alonc in prcvcnting
COFD cxaccrlations.
What arc thc implications ol this stuov in clinical
practicc? Thc rcsults ol our stuov shov that thc pcr-
ccivco lcnclts ol ¡CS (in prcvcnting COFD cxaccr-
lations) in paticnts vith scvcrc to vcrv scvcrc COFD
sccm to lc ovcrstatco. Wc oio olscrvc a moocst lcn-
clt ol ¡CS in prcvcnting COFD cxaccrlations in
paticnts vith FFV
1
 50%. Hovcvcr. this linoing
vas not lurthcr sulstantiatco on a mctarcgrcssion
analvsis vhcrcin vc oio not olscrvc a signilcant cllcct
ol lasclinc valucs ol FFV
1
(pcrccntagc prcoictco)
on thc lcnclts lrom ¡CS comparco vith placclo.
Thus. ¡CS is likclv to havc onlv moocst lcnclts in
thc rcsioual lctvccn-trial hctcrogcncitv that is not
cxplainco lv thc covariatcs in thc rcgrcssion.
26
Wc
locusco primarilv on COFD cxaccrlations rathcr
than othcr outcomcs as othcr outcomcs havc alrcaov
lccn propcrlv cvaluatco ano pullishco.
30-41
To
strcngthcn thc analvsis. vc chosc a minimum arli-
trarv ouration ol thc stuov ol at lcast 1 vcar so that thc
trcatmcnt is givcn lor an appropriatc pcrioo. ano
cxaccrlations mav lc propcrlv cvaluatco. Although
prcvious rcvicvs havc incluoco stuoics vith ouration
ol 6 months. vc cxcluoco thcsc stuoics as authors
thcmsclvcs havc acknovlcogco oillcultv in cvaluat-
ing cxaccrlations in such lricl pcrioos.
42
Unlikc othcr
rcvicvs. vc oio not incluoc oata that havc not lccn
lullv pullishco. as inclusion ol unpullishco oata
in mctaanalvscs rcmains controvcrsial lccausc ol thc
lack ol oualitv control ano associatco pccr rcvicv ol
Tablc 3-
Stuov/Ycar Dclnition ol Fxaccrlation
Bcnkcma ct al
27
/1006 ¡ncrcasco complaints ol ovspnca ano/or cough ano/or sputum proouction. vith or vithout lcvcr
Vcstlo ct al
2S
/1000 Allrmativc ansvcr to thc oucstion. ¨Havc vou sincc vour last visit cxpcricncco morc cough ano
phlcgm than usual?`
Wcir ct al
20
/1000 Not oclnco
Burgc ct al
30
/2000 Worscning ol rcspiratorv svmptoms that rcouirco trcatmcnt vith oral corticostcroios or antiliotics.
or loth. as juogco lv thc gcncral practitioncr
¡ung Hcalth Stuov
31
/2000 Not oclnco
Calvcrlcv ct al
32
/2003 Worscning ol COFD svmptoms that rcouirco trcatmcnt vith antiliotics. oral corticostcroios. or
loth
Calvcrlcv ct al
33
/2003 Worscning ol svmptoms rcouiring mcoical intcrvcntion (oral antiliotics ano/or corticostcroios
or hospitalization)
Szalranski ct al
34
/2003 Usc ol oral stcroios ano/or antiliotics ano/or hospitalization ouc to rcspiratorv svmptoms
Calvcrlcv ct al
35
/2007 Svmptomatic octcrioration rcouiring trcatmcnt vith antiliotic agcnts. svstcmic corticostcroios.
hospitalization. or a comlination ol thcsc
Chouohurv ct al
36
/2007 Usc ol oral stcroios ano/or antiliotics ano/or hospitalization ouc to rcspiratorv svmptoms
Calvcrlcv ct al
37
/200S Clinicallv signilcant vorscning ol COFD svmptoms rcouiring trcatmcnt vith antiliotics ano/or
svstcmic stcroios
Ficiii 2. Forcst plot shoving thc occurrcncc ol cxaccrlations in paticnts rccciving ¡CS vs placclo.
Thcrc vas 1S% rclativc risk rcouction in thc occurrcncc ol cxaccrlations as octcrminco lv thc ranoom-
cllccts moocl. Scc Figurc 1 lcgcno lor cxpansion ol allrcviation.
© 2010 American College of Chest Physicians
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www.chestjournal.org CHEST / 137 / 2 / FEBRUARY, 2010 323
improvcmcnt in survival vith thc usc ol ¡CS.
40.41
¡n
lact. thc risk ol pncumonia vas incrcasco in paticnts
vith thc lovcst lasclinc FFV
1
.
40
mcaning that in situ-
ations vhcrc ¡CS is inoicatco lor prcvcntion ol cxac-
crlations. its usc is likclv to lc associatco vith highcr
risk ol pncumonia. Finallv. in paticnts vith COFD.
highcr ooscs ol ¡CS arc rcouirco lor clinical cllcacv
comparco to asthma. ano this also mav incrcasc thc
propcnsitv lor stcroio rclatco sioc cllccts .
¡t is vioclv lclicvco that paticnts vith COFD vith
lovcr lcvcls ol lung lunction arc pronc to ocvclop
morc lrcoucnt ano morc scvcrc cxaccrlations.
44.45
¡n
onc stuov. thc hazaros lor thc timc to lrst cxaccrla-
tion vas grcatcr among paticnts vith an FFV
1
lcss
than 50% prcoictco than in paticnts vith a highcr
FFV
1
.
46
A rctrospcctivc analvsis ol thc ¡SO¡DF stuov
suggcstco that nuticasonc causco a grcatcr occlinc in
cxaccrlation ratcs in paticnts vith vorsc lung lunc-
tion comparco vith lcttcr lung lunction.
47
Hovcvcr.
a rcccnt stuov shovco that although lasclinc FFV
1
vas an inocpcnocnt prcoictor ol cxaccrlation. thc
rclationship vas not particularlv strong.
5.4S
¡t mav also
lc possillc that thc lcnclt ol ¡CS in COFD is not
ocpcnocnt on lasclinc FFV
1
valucs lut on ccrtain
othcr paramctcrs. such as paticnts vith COFD vho
sullcr onc or morc cxaccrlations (irrcspcctivc ol
FFV
1
). ano this lact shoulo also lc kcpt in mino in
luturc COFD trials.
Thc othcr limitations ol our stuov incluoc thc
prcscncc ol clinical hctcrogcncitv in that thc oillcr-
cnt stuoics havc incluoco oillcrcnt ooscs ol ¡CS ano
varving scvcritv ol paticnts vith COFD. Wc also
incluoco BB lrom inoivioual stuoics rathcr than
thc numlcr ol paticnts vith COFD vho sullcrco
an cxaccrlation. ¡n analvzing cxaccrlation. thc
lcngth ol lollov-up in clinical trials shoulo also lc
consiocrco. Most trials havc cstimatco thc mcan ratc
prcvcnting COFD cxaccrlations. il at all. ano shoulo
lc juoiciouslv usco in paticnts vith COFD kccping
in mino thc risk-lcnclt ratio. Thcsc rcsults coulo
also lc potcntiallv cxplainco lv a lov statistical povcr
ol our mctaanalvsis lccausc ol thc inclusion ol onlv
11 trials. Furthcr. thc mctarcgrcssion analvsis is
ocpcnocnt on thc mcan FFV
1
valucs. ano oocs not takc
into account thc stanoaro ocviation ol FFV
1
. Hcncc.
cxtrcmc caution shoulo lc cxcrcisco in thc intcrprc-
tation ol thcsc rcsults in that thcv cannot lc cxtcnoco
to oailv practicc. Although lasco on thc rcsults ol this
stuov. an inoivioual paticnt oata mctaanalvsis shoulo
lc pcrlormco to propcrlv oclnc thc rolc ol ¡CS in
prcvcnting COFD cxaccrlations.
Tvo rcccnt mctaanalvscs suggcst a highcr risk ol
scrious pncumonia in paticnts rccciving ¡CS vith no
Ficiii 3. Funncl plot comparing log BB vs thc SF ol log BB.
Opcn circlcs rcprcscnt trials incluoco in thc mctaanalvsis. Thc
linc in thc ccntcr inoicatcs thc summarv log BB. Thc othcr lincs
rcprcscnt thc 05% C¡s. Thcrc is no cviocncc ol pullication lias.
BB risk ratio: SF stanoaro crror.
Tablc 4
Seceritq o[ COPD
Scvcritv ol COFD ¡ncluoco Stuoics BB (05% C¡) ¡
2
Cochran O
Statistic (I Valuc)
Milo to moocratc
(FFV
1
 50%)
Bcnkcma ct al
27
1.026 (0.S50-1.226). lxco 0 2.01 (.41)
Copcnhagcn stuov
2S
1.026 (0.S50-1.226). ranoom
¡nhalco Stcroios in Olstructivc ¡ung
Discasc in Furopc (¡SO¡DF) stuov
30
Chouohurv ct al
36
Scvcrc to vcrv scvcrc
(FFV
1
 50%)
Wcir ct al
20
0.S24 (0.775-0.S76). lxco 57.4 14.00 (.03)
¡ung Hcalth stuov
31
0.7S5 (0.602-0.S01). ranoom
Trial ol ¡nhalco Stcroios ano
¡ong-acting 2 Agonist
(TB¡A¡) stuov
32
. . .
Calvcrlcv ct al
33
Szalranski ct al
34
Tovaros a Bcvolution in COFD
Hcalth (TOBCH) stuov
35
Calvcrlcv ct al
37
BB risk ratio. Scc Tallc 2 lor cxpansion ol othcr allrcviations.
© 2010 American College of Chest Physicians
by Deddy Herman on May 10, 2011 chestjournal.chestpubs.org Downloaded from
324 Original Research
AcxNoviincxiNis
Autbor contributions: Dr A·aræa|· contrilutco to litcraturc
scarch. oata analvsis. ano oralting ol thc manuscript.
Dr A··aræa|· contrilutco to litcraturc scarch. oata analvsis. ano
oralting ol thc manuscript.
Dr Gup/a· contrilutco to litcraturc scarch ano oralting ol thc
manuscript.
Dr I|nda|· contrilutco to litcraturc scarch ano oralting ol thc
manuscript.
Financial/nonhnancial disclosurcs: Thc authors havc rcportco
to CHEST that no potcntial connicts ol intcrcst cxist vith anv
companics/organizations vhosc prooucts or scrviccs mav lc
oiscussco in this articlc .
B iriiiNcis
1 . Clolal stratcgv lor thc oiagnosis. managcmcnt ano prcvcntion
ol chronic olstructivc pulmonarv oiscasc. (Upoatco 200S ).
http:// vvv.golocopo.com . Acccssco Scptcmlcr 2. 2000.
2 . Worlo Hcalth Organization . T/· G|·|a| Burd·n ·j D|s·as·-
2004 Upda/· . Ccncva. Svitzcrlano: WHO Frcss: 200S.
3 . ¡opcz AD . Shiluva K . Bao C . ct al . Chronic olstructivc pul-
monarv oiscasc: currcnt lurocn ano luturc projcctions . Eur
B·sp|r I . 2006 : 27 ( 2 ): 307 - 412 .
4 . Strasscls SA . Smith DH . Sullivan SD . Mahajan FS . Thc costs
ol trcating COFD in thc Unitco Statcs . C/·s/ . 2001 : 110 ( 2 ):
344 - 352 .
5 . Nicvochncr DF . Bclation ol chronic olstructivc pulmo-
narv oiscasc cxaccrlations to FFV(1)-an intricatc tango .
B·sp|ra/|·n . 2000 : 77 ( 2 ): 220 - 235 .
6 . Suissa S . McChan B . Nicvochncr D . Makc B . ¡nhalco corti-
costcroios in chronic olstructivc pulmonarv oiscasc . Ir·· An
T/·ra· S·· . 2007 : 4 ( 7 ): 535 - 542 .
7 . Cazzola M . Matcra MC . To aoo. or not to aoo an inhalco cor-
ticostcroio in moocratc COFD: that is thc oucstion . C/·s/ .
200S : 134 ( 2 ): 223 - 225 .
S . Sin DD . McAlistcr FA . Man SF . Anthoniscn NB . Contcmporarv
managcmcnt ol chronic olstructivc pulmonarv oiscasc: scicn-
tilc rcvicv . IAMA . 2003 : 200 ( 17 ): 2301 - 2312 .
0 . Frnst F . Baltzan M . Dcschôncs ] . Suissa S . ¡ov-oosc inhalco
ano nasal corticostcroio usc ano thc risk ol cataracts . Eur
B·sp|r I . 2006 : 27 ( 6 ): 116S - 1174 .
10 . Suissa S . Baltzan M . Krcmcr B . Frnst F . ¡nhalco ano nasal
corticostcroio usc ano thc risk ol lracturc . An I B·sp|r Cr|/
Car· M·d . 2004 : 160 ( 1 ): S3 - SS .
11 . Frnst F . Conzalcz AV . Brassaro F . Suissa S . ¡nhalco cortico-
stcroio usc in chronic olstructivc pulmonarv oiscasc ano thc
risk ol hospitalization lor pncumonia . An I B·sp|r Cr|/ Car·
M·d . 2007 : 176 ( 2 ): 162 - 166 .
12 . Alsaccoi A . Sin DD . McAlistcr FA . Thc cllccts ol inhalco
corticostcroios in chronic olstructivc pulmonarv oiscasc: a
svstcmatic rcvicv ol ranoomizco placclo-controllco trials .
An I M·d . 2002 : 113 ( 1 ): 50 - 65 .
13 . Wilt T] . Nicvochncr D . Kim C . ct al . Usc ol spiromctrv lor
casc lnoing. oiagnosis. ano managcmcnt ol chronic olstruc-
tivc pulmonarv oiscasc (COFD) . Et|d B·p T··/n·| Ass·ss
Sunn) . 2005 : 121 ( 121 ): 1 - 7 .
14 . Cartlchncr C . Hanscn BA . Carson SS . ¡ohr KN . Fllcacv
ano salctv ol inhalco corticostcroios in paticnts vith COFD:
a svstcmatic rcvicv ano mcta-analvsis ol hcalth outcomcs .
Ann Fan M·d . 2006 : 4 ( 3 ): 253 - 262 .
15 . Wilt T] . Nicvochncr D . MacDonalo B . Kanc B¡ . Managcmcnt
ol stallc chronic olstructivc pulmonarv oiscasc: a svstcmatic
rcvicv lor a clinical practicc guioclinc . Ann In/·rn M·d . 2007 :
147 ( 0 ): 630 - 653 .
16 . Fuhan MA . Bachmann ¡M . Klcijncn ] . Tcr Bict C . Kcsscls
AC . ¡nhalco orugs to rcoucc cxaccrlations in paticnts vith
ol cxaccr lation lor thc group lv using an avcragc that
vas unvcightco lor thc lollov-up ouration. ano coulo
potcntiallv lcao to an cxaggcratco lcnclcial cllcct ol
¡CS.
6.40
Thus thc lcnclt ol ¡CS mav lc cvcn lcss than
vhat has lccn suggcstco lrom this analvsis. Finallv.
mctarcgrcssion analvsis has its ovn limitations in
that it is an olscrvational association across trials.
ano oocs not havc thc lcnclt ol ranoomization. Thus.
as mcntionco prcviouslv. thc rcsults ol our stuov
ncco to lc conlrmco lv an inoivioual paticnt oata
mctaanalvsis.
¡n conclusion. thc rcsults ol our stuov suggcst a
moocst lcnclt ol ¡CS in prcvcnting COFD cxaccr-
lations. ¡n a sulgroup analvsis. thc lcnclt vas olscrvco
onlv in paticnts vith FFV
1
valucs  50% prcoictco.
Hovcvcr. on a mctarcgrcssion analvsis. thcrc vas
no ocmonstrallc lincar rclationship lctvccn cllcacv
ol ¡CS ano prcvcntion ol COFD cxaccrlations that is
rclatco to thc lcvcl ol stallc lung lunction. Thus thc
rolc ol ¡CS in prcvcnting COFD cxaccrlations nccos
rcappraisal.
Tablc 5-Metaregression o[ Beduction
o[ Exacerbations With the Use o[
ICS and FEV
1
Ovcrall Cocllcicnt
Stanoaro
Frror 05% C¡ I Valuc
FFV
1
0.005702 0.00S220 0.01043-0.021S31 .36
Constant 0.450S4 0.367S22 1.1S076-0.261076 .
Thc variancc in thc FFV
1
cocllcicnt lctvccn thc inoivioual stuoics

2
0.02230104. Scc Tallc 2 lor cxpansion ol allrcviation.
Ficiii 4. Mctarcgrcssion ol thc cllcct ol FFV
1
on thc log BB
lor thc risk ol cxaccrlations associatco vith thc usc ol inhalco corti-
costcroios. Fach circlc rcprcscnts onc stuov. Circlc sizc rcnccts
thc vcight ol thc stuov in thc mctarcgrcssion lasco on invcrsc
varianccs. Thc linc rcprcscnts mctarcgrcssion vith an unrcstrictco
maximum cllccts likclihooo ranoom-cllccts moocl (slopc 0.0057.
intcrccpt 0.450S. O 10.06. I .36). Thc numlcrs rcprcscnt
thc citation numlcr ol thc stuoics incluoco in thc mctarcgrcssion.
Scc Figurc 3 lcgcno lor cxpansion ol allrcviation.
© 2010 American College of Chest Physicians
by Deddy Herman on May 10, 2011 chestjournal.chestpubs.org Downloaded from
www.chestjournal.org CHEST / 137 / 2 / FEBRUARY, 2010 325
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1050 : 22 ( 4 ): 710 - 74S .
20 . DcrSimonian B . ¡airo N . Mcta-analvsis in clinical trials .
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21 . Armitagc F . Bcrrv C . Matthcvs ]NS . Ana|ns|n· M·ans and
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to pcrlorming a mcta-analvsis . S/a/ S·| . 1002 : 7 (2): 237 - 245 .
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© 2010 American College of Chest Physicians
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ONLINE supplement file
Contains data extraction form and the studies excluded from the meta-analysis
© 2010 American College of Chest Physicians
by Deddy Herman on May 10, 2011 chestjournal.chestpubs.org Downloaded from
Data extraction form
1. Study incl. author and year (full citation)
2. Randomization & method
3. Blinding
4. Withdrawals/dropouts
5. Mean Age
6. Mean FEV1

7. Males

8. Current Smokers
9. Dose of ICS
10. Duration of follow-up
11. Device used in experiment and control
arms
12. Definition of exacerbations
13. Exacerbations
Exp: n/N
Cont: n/N
© 2010 American College of Chest Physicians
by Deddy Herman on May 10, 2011 chestjournal.chestpubs.org Downloaded from
Details of excluded studies
© 2010 American College of Chest Physicians
by Deddy Herman on May 10, 2011 chestjournal.chestpubs.org Downloaded from
Experimental studies
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38 Tashkin DP, Rennard SI, Martin P, et al. Efficacy and safety of budesonide and formoterol in
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39 Wedzicha JA, Calverley PM, Seemungal TA, et al. The prevention of chronic obstructive
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40 Kiri VA, Fabbri LM, Davis KJ, et al. Inhaled corticosteroids and risk of lung cancer among
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DOÌ 10.1378/chest.09-1305
; Prepublished online September 25, 2009; 2010;137; 318-325 Chest
Jindal
Ritesh Agarwal, Ashutosh N. Aggarwal, Dheeraj Gupta and Surinder K.
Randomized ControIIed TriaIs
Exacerbations : A Systematic Review and Metaregression of
InhaIed Corticosteroids vs PIacebo for Preventing COPD

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  
   
                                          

                                                   
       

                                      
                                   


                                     
                                


 

                                                                                                                                                                

                                                                                                                                            

       
                                             


                                                                                        
  

 

                                                                                                                                                                                                                                                                                                                                                                                                                                         .

                                                                                                                                                                                                                                                                                                                                                                                                                                                      .

                                                                                                                                                                                                                  .

                                                                                                                                                                                                                                                                                                .

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    .

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          .

ONLINE supplement file Contains data extraction form and the studies excluded from the meta-analysis   .

Device used in experiment and control arms 12. Study incl. Current Smokers 9. author and year (full citation) 2. Mean Age 6. Definition of exacerbations 13. Dose of ICS 10.Data extraction form 1. Withdrawals/dropouts 5. Randomization & method 3. Duration of follow-up 11. Males 8. Mean FEV1 7. Blinding 4. Exacerbations Exp: n/N Cont: n/N   .

Details of excluded studies   .

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                                     .