CHEST Original Research

COPD

Safety and Efficacy of Combined

Long-Acting ␤-Agonists and Inhaled
Corticosteroids vs Long-Acting
␤-Agonists Monotherapy for Stable COPD
A Systematic Review
Gustavo J. Rodrigo, MD; José A. Castro-Rodriguez, MD, PhD;
and Vicente Plaza, MD

Background: Current guidelines recommend the use of inhaled corticosteroids (ICSs) added to
long-acting ␤2-agonists (LABAs) for treatment of symptomatic patients with severe and very
severe COPD. However, the evidence has been inconclusive. The aim of this review was to assess
the safety and efficacy of LABAs/ICSs compared with LABA monotherapy for patients with
moderate-to-very severe COPD.
Methods: Systematic searches were conducted on MEDLINE, EMBASE, the Cochrane Con-
trolled Trials Register, and the trial registers of manufacturers, without language restriction.
Primary outcomes were COPD exacerbations and mortality. Secondary outcomes included lung
function, health-related quality of life, and adverse effects.
Results: Eighteen randomized controlled trials (12,446 participants) were selected. Therapy with
LABAs/ICSs did not decrease the number of severe exacerbations (relative risk [RR], 0.91; 95% CI,
0.82 to 1.01; I2 ⴝ 1%), or all-cause mortality (RR, 0.90; 95% CI, 0.76 to 1.06; I2 ⴝ 0%), respiratory
mortality (RR, 0.80; 95% CI, 0.61 to 1.05; I2 ⴝ 0%), and cardiovascular mortality (RR, 1.22; 95% CI,
0.88 to 1.71; I2 ⴝ 0%). To the contrary, the number of moderate exacerbations (RR, 0.84; 95% CI,
0.74 to 0.96; I2 ⴝ 50%) and the St. George respiratory questionnaire total score (weighted mean
difference, ⴚ1.88; 95% CI, ⴚ2.44 to ⴚ1.33; I2 ⴝ 29%) were significantly reduced with LABA/ICS
therapy. Although therapy with LABAs/ICSs increases FEV1 significantly (0.06 and 0.04 L, respec-
tively), they were associated with an increased risk of pneumonia (RR, 1.63; 95% CI, 1.35 to 1.98;
I2 ⴝ 20%).
Conclusions: Compared with LABA monotherapy, the magnitude of the benefits of LABA/ICS
therapy did not reach that of the criteria for predefined clinically important effects and were
associated with serious adverse effects. (CHEST 2009; 136:1029 –1038)
Abbreviations: ICS ⫽ inhaled corticosteroid; LABA ⫽ long-acting ␤2-agonist; MI ⫽ myocardial infarction; NNTB ⫽
number needed to treat for benefit; NNTH ⫽ number needed to treat for harm; RR ⫽ relative risk; SABA ⫽ short-acting
␤2-agonist; SGRQ ⫽ St. George respiratory questionnaire; WMD ⫽ weighted mean difference

C isOPDcharacterized
is a preventable and treatable disease that
by airflow limitation that is not
mended for the relief of symptoms on an as-needed
basis, whereas long-acting inhaled bronchodilators
fully reversible.1,2 The main therapeutic goals are to (long-acting ␤2-agonists [LABAs] or tiotropium) in
prevent and control symptoms, reduce the frequency a regularly scheduled regimen are recommended
and severity of exacerbations, and improve health as first-line therapy in symptomatic patients with
status and exercise tolerance. Current guidelines1,2 moderate-to-very severe COPD.
recommend a stepwise increase in treatment, de- Evidence3 shows that LABA monotherapy is asso-
pending on the severity of the disease. Short-acting ciated with significant improvements regarding
inhaled bronchodilators (short-acting ␤2-agonists COPD exacerbations, pulmonary function, quality
[SABAs] and anticholinergic agents) are recom- of life, and use of rescue medication, with a low

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© 2009 American College of Chest Physicians
incidence of adverse effects. However, in view of the (www.astrazenecaclinicaltrials.com) and GlaxoSmithKline (www.
multicomponent nature of COPD, the use of inhaled gsk-clinicalstudyregister.com) databases. Trials published solely
in abstract form were excluded because the methods and results
corticosteroids (ICSs), particularly in combination could not be fully analyzed.
with a LABA has obtained widespread acceptance The specific inclusion criteria were as follows: (1) stable adult
among clinicians. In fact, the addition of ICSs in patients aged ⬎ 40 years with COPD satisfying the diagnostic
patients with severe or very severe disease (stages III criteria of the American Thoracic Society/European Respiratory
or IV) with repeated exacerbations is recommended Society1 or the Global Initiative for Chronic Obstructive Lung
Disease2; (2) therapy with inhaled LABAs plus ICSs (delivered
for decreasing exacerbation rates, and improving via metered-dose inhaler or dry powder inhaler) as the interven-
lung function and health status.1,2 Nevertheless, the tion arm compared with therapy with a LABA; (3) study dura-
evidence of the superiority of combination therapy tions of ⬎ 1 month; (4) randomized controlled trials (parallel-
(LABAs/ICSs) over LABA monotherapy has been group design) without language restriction; and (5) primary
inconclusive. While a 2007 review4 failed to demon- outcomes “severe COPD exacerbation” (requiring hospitalization
or withdrawals) and “moderate COPD exacerbations” (requiring
strate the superiority of combination therapy over systemic corticosteroids or antibiotic use), all-cause mortality
LABA monotherapy in reducing COPD exacerba- (deaths for any cause), respiratory deaths (deaths due to a
tions, others have reported5–7 some benefits of ther- respiratory event such as COPD exacerbation or pneumonia),
apy with LABAs/ICSs in terms of COPD exacerba- and cardiovascular mortality (including sudden death) during the
tions, pulmonary function, and quality of life. Even treatment period. Secondary outcome measures were as follows:
mean change in FEV1 (pre-bronchodilator therapy and post-
so, these conclusions might be questionable because bronchodilator therapy); mean change from baseline in the St.
they are based on a reduced number of selected George respiratory questionnaire (SGRQ) total score8; end-of-
studies and outcomes. Consequently, we performed treatment dyspnea score; withdrawals from the study during the
a systematic review to assess the safety and efficacy treatment period (overall, due to adverse effects, and due to lack
of the use of LABAs/ICSs in COPD patients com- of efficacy); and adverse effects (pneumonia, oropharyngeal
candidiasis, viral respiratory infections, and myocardial infarc-
pared with LABA monotherapy. The following two tions [MIs]).
specific questions were identified: (1) what are the
risks of adding an ICS to a LABA compared with
LABAs monotherapy? and (2) does therapy with Data Abstraction and Validity Assessment
LABAs/ICSs provide significant clinical benefits Titles, abstracts, and citations were independently analyzed by
compared with LABA monotherapy? all reviewers. From full text, they independently assessed studies
for inclusion based on the criteria for population, intervention,
study design, and outcomes. Three reviewers (G.J.R., J.C.R., and
V.P.) were independently involved in all stages of study selection,
Materials and Methods data extraction, and quality assessment. Any disagreement was
resolved by consensus. In case of multiple published or unpub-
Search Strategy and Selection Criteria lished reports for a particular study, data from the most recent
version were extracted.
We identified studies from MEDLINE, EMBASE (January
1980 to May 2009), and the Cochrane Controlled Trials Register
(second quarter of 2009) databases by using the following MeSH, Statistical Analysis
full text, and keywords terms: (long-acting ␤2 adrenoceptor
Binary outcomes were pooled by using common relative risks
agonist OR salmeterol OR formoterol OR inhaled corticoste-
(RRs) and 95% CIs. If pooled effect estimates were significantly
roids OR fluticasone OR budesonide OR beclomethasone)
different between groups, we calculated the number needed to
AND (COPD OR chronic bronchitis OR emphysema). Also,
treat for benefit (NNTB) or the number needed to treat for harm
we performed a search of relevant files from AstraZeneca
(NNTH). For continuous outcomes, the standardized mean
difference or weighted mean difference (WMD) and 95% CIs
Manuscript received April 2, 2009; revision accepted July 2, 2009. were calculated. Heterogeneity was further measured by using
Affiliations: From the Departamento de Emergencia (Dr. Ro- the I2 test.9 With low heterogeneity (I2 ⬍ 40%), data were
drigo), Hospital Central de las Fuerzas Armadas, Montevideo, combined by mean of a fixed-effects model10; otherwise, a
Uruguay; the School of Medicine (Dr. Castro-Rodriguez), Pon-
tificia Universidad Católica de Chile, Santiago, Chile; and Servei random-effects model was used. Publication bias of primary
de Pneumologia (Dr. Plaza), Hospital de la Santa Creu i Sant outcomes was evaluated by means of the visual inspection of
Pau, Universitat Autonoma de Barcelona, Barcelona, Spain. funnel plots.11 A predefined sensitivity analysis of the primary
Funding/Support: The funding for this study came from salary outcome of severe COPD exacerbations was conducted to ex-
support for Dr. Rodrigo. No sponsorship from institutions or plore the influence of the following factors: concealment alloca-
pharmaceutical industry was provided to conduct this study. tion12 (adequate vs unclear); trial duration (long-term [ⱖ 52
Correspondence to: Gustavo J. Rodrigo, MD, Departamento weeks] vs short-term [⬍ 52 weeks]); reversibility to SABA (poorly
de Emergencia, Hospital Central de las Fuerzas Armadas, Av 8 reversible patients or FEV1 ⬍ 15% from baseline vs reversible
de Octubre 3020, Montevideo 11600, Uruguay; e-mail: gurodrig@ patients or FEV1 ⱖ 15% from baseline); choice of LABAs
adinet.com.uy
© 2009 American College of Chest Physicians. Reproduction (salmeterol vs formoterol); and the use of ICSs before the
of this article is prohibited without written permission from the patients were enrolled (ⱖ 50% of patients vs ⬍ 50% of patients).
American College of Chest Physicians (www.chestjournal.org/site/ Subgroups were compared by using the interaction test.13 A
misc/reprints.xhtml). p value of ⬍ 0.05 using a two-tailed test was considered to
DOI: 10.1378/chest.09-0821 indicate significance. Metaanalyses were performed with using a

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© 2009 American College of Chest Physicians
 weeks)16 –18,20,21,23–25,27–29 and 7 short-term trials (ie,
⬍ 52 weeks).14,15,19,22,26,30,31 Studies enrolled mostly
stable patients with COPD who met the Global Initia-
tive for Chronic Obstructive Lung Disease criteria for
moderate-to-very severe COPD exacerbations.2 The
mean age of patients was 64 years (72% of patients
were male), with an average baseline FEV1 of 40% of
predicted normal values. Allocation concealment was
adequate in only 5 studies,16,20,21,23,24 and was unclear
in the remaining 13 studies.

Primary Outcomes
Compared with LABA monotherapy, combination
therapy with LABAs/ICSs did not significantly
decrease the risk of severe COPD exacerbations
(11.3% vs 12.5%, respectively) [Table 2]. The post
hoc subgroup analysis did not show significant dif-
ferences in COPD exacerbations regarding conceal-
ment allocation, trial duration, reversibility to SABA
use, LABA choice, and use of ICSs before the
patients were enrolled in the study (Table 3). To the
contrary, the use of LABAs/ICSs was associated with
a significantly reduced risk of moderate COPD
exacerbations when compared with LABAs alone
(17.5% vs 20.1%, respectively), with evidence of
Figure 1. Flowchart for identification of studies. statistical heterogeneity among trials. The NNTB
was 31 (95% CI, 20 to 93).
Patients receiving therapy with LABAs/ICSs were
not associated with a significant decrease of overall
statistical software package (Review Manager, version 5.0.20; the mortality when compared with those receiving
Nordic Cochrane Centre, the Cochrane Collaboration; Copen- LABAs alone (4.5% vs 5.5%, respectively) [Fig 2]. In
hagen, Denmark). the same way, the metaanalysis did not show
significant differences between groups regarding
the risk of respiratory deaths (1.8% in the LABAs/
Results ICSs group vs 2.4% in the LABAs group) and
cardiovascular mortality (1.6% vs 1.4%, respectively),
Of 164 potential relevant citations, 18 randomized,
without evidence of statistical heterogeneity (Fig 2).
controlled trials14 –31 fulfilled the inclusion crit-
On visual inspection of the funnel plots (Fig 3),
eria (Fig 1). Five trials were unpublished.27–31 Data
publication bias could be ruled out for all-cause,
analysis was restricted to the LABAs/ICSs and
respiratory, and cardiovascular mortality. To the
LABAs arms of those trials (12,446 patients) [Table
contrary, for severe COPD exacerbations, the plot
1]. Five studies used formoterol/budesonide combi-
presented an asymmetrical shape with an absence of
nation therapy,17,20,26,27 and 13 studies used salmet-
small studies showing a group benefit for therapy
erol/fluticasone combination therapy.14 –16,18,19,21–31
with LABAs.
Seven studies14 –16,21,23,24,31 evaluated therapy with
inhaled fluticasone in combination with salmeterol
Secondary Outcomes
at a dosage of 500 ␮g twice daily, seven stud-
ies18,19,22,25,28 –30 assessed therapy with fluticasone at Regarding pulmonary function, patients treated
a dosage of 250 ␮g twice daily, and four stud- with LABAs/ICSs showed significantly greater in-
ies17,20,26,27 evaluated therapy with budesonide at a creases in the mean change in FEV1 from baseline
dosage of 320 ␮g twice daily. All trials used single (pre-bronchodilator therapy and post-bronchodilator
inhalers containing both ICSs and LABAs to deliver the therapy) compared with patients treated with LABAs
combined therapy. Eleven trials15–21,23–26 reported that alone (Table 4); however, both comparisons showed
a mean of 31% of patients (range, 0 to 55% of patients) statistical heterogeneity. Patients receiving therapy
had received ICSs before they were enrolled in the with LABAs/ICSs showed a significantly greater
study. There were 11 long-term trials (ie, ⱖ 52 reduction in the SGRQ total score. Finally, at the

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 Table 1—Characteristics of Included Studies

Mean
Study Location/ Patients: No. Age, Mean Baseline Current Bronchodilator Intervention: Allocation
Studies Duration (% male) yr FEV1 Smoker Response, % Dose Concealment

Cazzola et al14 Single-center/12 wk S: 20 (90) 65 1.15 L 45 pack-yr ⬍ 12 S: 50 ␮g twice Unclear

MDI
SF: 40 (92) 64 1.16 L 44 pack-yr ⬍ 12 SF: 50/250 or
50/500 ␮g
twice MDI
Mahler et al15 69 centers/24 wk S: 160 (64) 64 40% predicted 46% 21 S: 50 ␮g twice Unclear
DPI
SF: 165 (62) 63 41% predicted 46% 21 SF: 50/500 ␮g
twice DPI
Calverley et al16 196 centers/52 wk S: 372 (70) 63 46% predicted 51% 3.7 S: 50 ␮g twice Adequate
DPI
SF: 358 (75) 63 49% predicted 52% 4.0 SF: 50/500 ␮g
twice DPI
Calverley et al17 109 centers/52 wk F: 255 (75) 63 36% predicted 36% 6 F: 9 ␮g twice Unclear
DPI
FB: 254 (78) 64 36% predicted 33% 6 FB: 9/320 ␮g
twice DPI
Dal Negro Single-center/52 wk S: 6 (100) 55–78 48% predicted 0% 3 S: 50 ␮g twice Unclear
et al18 DPI
SF: 5 (83) 53–77 50% predicted 0% 3.5 SF: 50/ 250 ␮g
twice DPI
Hanania et al19 75 centers/24 wk S: 177 (58) 64 42% predicted 51% 20 S: 50 ␮g twice Unclear
DPI
SF:178 (61) 63 41% predicted 43% 19 SF: 50/250 ␮g
twice DPI
Szafranski et al20 89 centers/52 wk F: 201 (76) 63 36% predicted 38% 6 F: 9 ␮g twice Adequate
DPI
FB:208 (76) 64 36% predicted 30% 6 FB: 9/320 ␮g
twice DPI
Wouters et al21 39 centers/52 wk S: 184 (75) 64 1.41 L 35% 4 S: 50 ␮g twice Adequate
DPI
SF: 189 (73) 63 1.41 L 39% 4 SF: 50/500 ␮g
twice DPI
O’Donnell 21 centers/8 wk S: 59 (75) 65 40% predicted 34% 18 S: 50 ␮g twice Unclear
et al22 DPI
SF: 62 (69) 63 42% predicted 42% 18 SF: 50/250 ␮g
twice DPI
Calverley et al23 444 centers/156 wk S: 1,521 (76) 65 44% predicted 43% 4 S: 50 ␮g twice Adequate
DPI
SF: 1,533 (75) 65 44% predicted 43% 4 SF: 50/500 ␮g
twice DPI
Kardos et al24 95 centers/ 44 wk S: 487 (78) 64 40% predicted 37% 7 S: 50 ␮g twice Adequate
DPI
SF: 507 (74) 64 40% predicted 37% 6 SF: 50/500 ␮g
twice DPI
Ferguson et al25 94 centers/52 wk S: 388 (52) 65 33% predicted 38% NA S: 50 ␮g twice Unclear
DPI
SF: 394 (58) 65 33% predicted 40% NA SF: 50/250 ␮g
DPI twice
Tashkin et al26 194 centers/26 wk F: 284 (66) 64 39% predicted 42% NA F: 9 ␮g twice Unclear
DPI
FB: 845 (69) 63 39% predicted 44% NA FB: 9/160 ␮g or
320/9 ␮g
twice MDI
D-5899C0 237 centers/52 wk F: 495 (65) 63 34% predicted 41% 16 F: 9 ␮g twice Unclear
000127 DPI
FB: 988 (63) 64 34% predicted 36% 16 FB: 9/320 ␮g or
160/9 MDI
twice
(Continued)

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 Table 1—(Continued)

Mean
Study Location/ Patients: No. Age, Mean Baseline Current Bronchodilator Intervention: Allocation
Studies Duration (% male) yr FEV1 Smoker Response, % Dose Concealment

SCO4004128 31 centers/156 wk S: 94 (63) 66 ⬍ 70% predicted NA NA S: 50 ␮g twice Unclear

DPI
SF: 92 (63) 65 ⬍ 70% predicted NA NA SF: 50/250 ␮g
DPI twice
SCO10025029 98 centers/52 wk S: 403 (57) 65 ⬍ 50% predicted ⬎ 10 pack-yr NA S: 50 ␮g twice Unclear
DPI
SF: 394 (51) 65 ⬍ 50% predicted ⬎ 10 pack-yr NA SF: 50/250 ␮g
DPI twice
SCO10047030 135 centers/24 wk S: 532 (78) 64 1.68 L 44% NA S: 50 ␮g twice Unclear
DPI
SF: 518 (82) 64 1.65 L 42% NA SF: 50/250 ␮g
DPI twice
SCO10492531 11 centers/12 wk S: 38 (79) 64 ⬍ 50% predicted ⬎ 10 pack-yr NA S: 50 ␮g twice Unclear
DPI
SF: 39 (82) 64 ⬍ 50% predicted ⬎ 10 pack-yr NA SF: 50/500 ␮g
DPI twice
NA ⫽ not applicable; S ⫽ salmeterol; F ⫽ formoterol; SF ⫽ salmeterol/fluticasone; FB ⫽ formoterol/budesonide; MDI ⫽ metered-dose inhaler;
DPI ⫽ dry powder inhaler.

end of the protocol, patients treated with combina- increase in RR) compared with the use of LABAs
tion therapy had a significantly lower dyspnea score alone. Finally, combined therapy did not show a
compared with patients treated with LABAs alone, significant difference in the rate of MI, compared
although with evidence of statistical heterogeneity with LABA monotherapy.
among the trials (Table 4).
LABAs/ICSs therapy was associated with a signif-
icant decrease of overall withdrawals from the study Discussion
(Table 4). Furthermore, patients receiving therapy
with LABAs/ICSs were associated with a significantly In the present study, which is the largest system-
lower rate of withdrawals from the study due to lack atic review designed to evaluate the safety and
of efficacy, but not with significant withdrawals from efficacy of the regular use of LABAs/ICSs compared
the study due to adverse effects (Table 4). However, with the use of LABAs alone in stable patients with
the use of LABAs/ICSs was also associated with moderate-to-very severe COPD, we found that treat-
significantly increased rates of pneumonia (63% ment with LABAs/ICSs did not modify the risks of
increase in RR), viral respiratory infections (22% overall mortality, respiratory deaths, and cardiovas-
increase in RR), and oropharyngeal candidiasis (59% cular mortality (primary outcomes) compared with

Table 2—Analysis of Primary Outcomes (LABAs/ICSs vs LABA)

LABAs ⫹ ICS,
No./Total No. LABAs, No./ Absolute Risk
Outcomes References (%) Total No. (%) Measure (95% CI) Reduction I2, %
COPD exacerbations 15–17,19–30 757/6,685 (11.3) 704/5,612 (12.5) RR ⫽ 0.91 (0.82–1.01) ⫺1.2 (⫺2.4 to 0.0) 1
(requiring
hospitalization or
withdrawal)
COPD exacerbations 15–26,29 794/4,532 (17.5) 1,015/5,058 (20.1) RR ⫽ 0.84 (0.74–0.96); ⫺2.5 (⫺1.0 to ⫺4.1) 50
requiring systemic p ⫽ 0.008/NNTB ⫽
corticosteroids 31 (20–93)
All-cause mortality 16,17,20,21, 240/5,292 (4.5) 261/4,721 (5.5) RR ⫽ 0.90 (0.76–1.06) ⫺1.0 (⫺1.8 to 0.0) 0
23–26,28–30
Respiratory deaths 16,17,20,21, 94/5,292 (1.8) 114/4,721 (2.4) RR ⫽ 0.80 (0.61–1.05) ⫺0.6 (⫺1.2 to 0.0) 0
23–26,28–30
Cardiovascular mortality 16,21,23–26, 72/5,856 (1.6) 63/5,299 (1.4) RR ⫽ 1.22 (0.88–1.71) 0.2 (⫺0.3 to 0.7) 0
28–30

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 Table 3—Sensitivity Analysis. Comparisons Between RR in COPD Exacerbations Requiring Hospitalization or
Withdrawal) Stratified by Concealment Allocation (Adequate vs Unclear), Trial Duration (Long-Term > 52 Weeks
vs Short-Term < 52 Weeks), Reversibility to SABAs (Poorly Reversible Patients or FEV1 < 15% From Baseline vs
Reversible Patients or FEV1 > 15%), Baseline Severity (Moderate to Severe vs Severe to Very Severe), LABAs
choice (Salmeterol vs Formoterol), and Use of ICSs Before the Patients Were Enrolled (< 50% of Patients vs < 50%
of Patients)
Interactive Test17
Subgroup Comparisons RR (95% CI) 关I2兴 RR (95% CI) p Value

Adequate 16,20,21,23,24
vs unclear 0.93 (0.82–1.05) 关35%兴 vs 0.90 (0.77–1.05) 关0%兴 0.96 (0.79–1.18) 0.74
concealment14,15,17–19,22,25–31
Long-term16,17,20,21,23,25,27–29 vs 0.93 (0.84–1.03) 关1%兴 vs 0.80 (0.59–1.11) 关0%兴 0.86 (0.61–1.19) 0.37
short-term15,19,22,24,26,30
Poorly reversible16,17,20,21,23,24 vs 0.90 (0.80–1.01) 关0%兴 vs 0.94 (0.74–1.20) 关0%兴 1.04 (0.79–1.36) 0.75
reversible15,19,22,25–30
Salmeterol15,16,19,21–25,28–30 vs 0.94 (0.84–1.05) 关0%兴 vs 0.87 (0.73–1.04) 关41%兴 0.92 (0.75–1.14) 0.46
Formoterol17,20,26,27
Previous use of ICS (ⱖ 50%16, 24,26 vs 0.84 (0.65–1.14) 关28%兴 vs 0.92 (0.88–1.04), 关31%兴 1.06 (0.79–1.43) 0.65
⬍ 50% of patients15,17–21,23–25)

treatment with LABAs alone. On the contrary, the ICSs added to LABAs. The precise mechanism is
analysis of secondary outcomes showed that therapy uncertain, but it could be related to the fact that
with LABAs/ICSs significantly increased the risk of ICSs achieve locally high concentrations in the lung,
pneumonia, oropharyngeal candidiasis, and viral re- increasing the risk of pneumonia due to their immu-
spiratory infections (question 1). However, it is nosuppressive effects.33 Thus, inhaled fluticasone at
interesting to point out that these adverse effects dosages of 1,000 ␮g/d exerts effects on serum corti-
were not accompanied by a concomitant and propor- sol levels that are equivalent to 10 mg of prednisone,
tional increase in respiratory-related mortality or over- a dose that may double the risk of pneumonia in
all mortality. Concerning the benefits (question 2), we patients with arthritis.34 Our analysis showed an
found that therapy with LABAs/ICSs significantly increase in the risk of pneumonia with both moder-
decreased the frequency of moderate COPD exac- ate dosages of fluticasone (500 ␮g/d; RR, 1.75; 95%
erbations independently of concealment allocation, CI, 1.16 to 2.64; I2 ⫽ 30%) and high dosages of
trial duration, reversibility to SABA therapy, LABA fluticasone (1,000 ␮g/d; RR ⫽ 1.64; 95% CI, 1.32 to
choice, and previous use of ICSs. 2.06, I2 ⫽ 22%). To the contrary, therapy with
In the same way, therapy with LABAs/ICSs was LABAs/ICSs was associated with significant de-
associated with significant increases in the mean creases in overall withdrawals and withdrawals due
change in pre-bronchodilator therapy and post- to lack of efficacy compared with LABA mono-
bronchodilator therapy FEV1, the mean change in therapy. This finding could be associated with the
SGRQ total score, and with a significant decrease in fact that therapy with LABAs/ICSs significantly re-
the end-of-treatment dyspnea score compared with duces dyspnea with a greater clinical effectiveness
treatment with LABAs alone. However, given that perception. Also, this fact could be associated with
the size of these benefits did not reach the suggested better control of the disease.
clinically important minimal differences (FEV1, 0.10 When we compared the results of the present
to 0.14 L; SGRQ score, 4-unit decrement),32 the metaanalysis with those of previous reviews (based
relevance of these improvements seems uncertain. on a limited number of published trials), we found
In the same way, the 16% decrease in the rate of some similarities and few differences. For example, a
moderate COPD exacerbations was smaller than the Cochrane review5 of 10 studies, reported a signifi-
suggested threshold value of 22% for clinical signif- cant RR reduction of moderate COPD exacerbations
icance.32 Conversely, treatment with LABAs/ICSs of 18% with the combined treatment with LABAs/
failed to significantly reduce the risk of severe ICSs compared with treatment with LABAs alone.
COPD exacerbations. These facts suggest a limited Also, the combination therapy was more effective
extra efficacy when ICSs were added to LABAs for than that with LABAs alone in improving quality
COPD treatment. of life as measured by the SGRQ (⫺1.64 points),
The relative benefits of therapy with LABAs/ICSs and predose and postdose FEV1 (0.06 and 0.05 L,
must be weighed against the risks. Thus, the most respectively). While there was no significant dif-
concerning side effect was the increase in the risk of ference in terms of overall mortality, pneumonia
pneumonia associated with the administration of occurred more commonly in patients receiving

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 Figure 2. Pooled RR for overall mortality, respiratory deaths, and cardiovascular mortality (with 95%
CIs) of eligible studies comparing inhaled LABAs/ICSs with LABAs.

combined therapy (58% increase in RR). How- with therapy with LABAs alone. Additionally, com-
ever, another metaanalysis4 that was limited to five bined therapy also showed a reduced risk in overall
English-language trials failed to demonstrate the withdrawals (17% increase in RR), and without
superiority of combination treatment over LABA difference in the rate of overall mortality between
monotherapy in reducing COPD exacerbations and groups. Another systematic review35 has found no
overall mortality. evidence that therapy with LABAs alone is more
More recently, Sobieraj et al7 on the basis of seven effective than combined therapy with LABAs/ICSs.
studies reported that therapy with LABAs/ICSs de- In the same study, a subgroup analysis showed that,
creased the risk of moderate COPD exacerbations when added to LABAs, ICSs significantly reduced
(relative reduction risk of 18%), decreased the the number of exacerbations in patients with FEV1
SGRQ total score (⫺1.98 points), and increased the ⱕ 40% predicted. However, these conclusions are
risk of pneumonia (32% increase in RR) compared uncertain because the review was based on only

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Figure 3. Funnel plots of LABAs/ICSs vs LABAs comparing COPD severe exacerbations (A), all-cause mortality (B), respiratory deaths (C),
and cardiovascular mortality (D).

seven studies15–17,19,20,23,24 (6,376 patients with several potential limitations that came from the
COPD). Finally, Singh et al36 showed a significantly quality of the reported data. Thus, the trials did not
increased risk of pneumonia with combined therapy consistently use similar definitions of COPD exacer-
compared with LABA monotherapy (32% increase in bations or pneumonia. In particular, we recognized
RR) without a significantly increased risk of death. that the severity of exacerbations is a complex con-
Interestingly, the risk of pneumonia could be specif- cept constituted by several factors, and that this fact
ically attributed to the use of ICSs because the risk could modify our results. Also, most of the studies
for pneumonia associated with ICS use was similar were not specifically designed to monitor outcomes
when therapy with ICSs were compared with pla- as all-cause, respiratory, or cardiovascular mortality.
cebo or when ICSs were added to therapy with Additionally, the risk of bias was unclear in 13 trials
LABAs and compared with LABA therapy alone. In in the analysis. Also, the fact that 80% of the
the same way, a recent trial37 comparing therapy reviewed patients were men limits the applicability
with inhaled tiotropium with therapy with salmet- of the results since COPD is suspected to affect men
erol/fluticasone in patients with COPD showed an and women equally.
increased hazard ratio for time to reported pneumo- This metaanalysis confirms and extends data from
nia for combined therapy of ⬎ 2 years (94% increase previous reviews. The main results of our review are
in RR). as follows: LABAs/ICSs did not decrease the risk of
This review was performed according to the meth- all-cause, respiratory, and cardiovascular mortality;
odological criteria suggested for scientific reviews.38 however, therapy with LABAs/ICSs increases the
The fact that there was low evidence of clinical and risk of pneumonia, oropharyngeal candidiasis, and
statistical heterogeneity between studies increased viral respiratory infections. The use of LABAs/ICSs
the confidence of our findings. Furthermore, there was associated with a lower incidence of moderate
was no evidence of publication bias in the majority of COPD exacerbations (but not of severe exacerba-
primary outcomes. However, our metaanalysis had tions), increased pulmonary function, improved dys-

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© 2009 American College of Chest Physicians
 Table 4 —Analysis of Secondary Outcomes (LABAs/ICSs vs LABAs)

LABAs ⫹ ICSs,
No./Total No. LABAs, No./ Absolute Risk
Outcomes References (%) Total No. (%) Measure (95% CI) 关p Value兴 Reduction I2, %
Mean change in 14–16,19,21–27, 5,613 5,082 WMD ⫽ 0.06 (0.04–0.07) 82
pre-bronchodilator 29–30 关0.0001兴
therapy FEV1, L
Mean change in 14–16,19,22, 3,455 2,501 WMD ⫽ 0.04 (0.02–0.05) 64
post-bronchodilator 23,26,27 关0.0001兴
therapy FEV1, L
Mean change in 16,17,20, 4,617 4,040 WMD ⫽ ⫺1.88 (⫺2.44 to ⫺1.33) 29
SGRQ 23–26,30 关0.0001兴
End-of-treatment 15,16,19,21,22, 3,216 2,643 SMD ⫽ ⫺0.20 (⫺0.25 to ⫺0.15) 82
dyspnea score 24–26,30 关0.0001兴
Total withdrawals 14–17,19–31 1,731/5,919 (29.2) 1,731/5,919 (29.2) RR ⫽ 0.87 (0.82–0.92) 关0.0001兴; ⫺1.6 (⫺0.2 to ⫺3.0) 0
NNTB ⫽ 25 (18–41)
Withdrawals due to 15,16, 19–21, 680/5,381 (12.6) 654/4,803 (13.6) RR ⫽ 0.93 (0.84–1.03) 关0.26兴 ⫺1.0 (⫺0.3 to 2.3) 0
adverse effects 23–26,28–30
Withdrawals due to 15,16,23,25, 63/3,362 (1.9) 117/3,376 (3.5) RR ⫽ 0.54 (0.40–0.72) 关0.0001兴; ⫺1.6 (⫺0.8 to ⫺2.4) 0
lack of efficacy 29,30 NNTB ⫽ 73 (56–120)
Pneumonia 15,16,19,21, 263/5,212 (5.0) 153/4,540 (3.4) RR ⫽ 1.63 (1.35–1.98) 关0.0001兴; 1.7 (0.9 to 2.5) 20
23–26,28–31 NNTH ⫽ 40 (26–72)
Oropharyngeal 16,19,21,22, 292/3,521 (8.4) 200/2,741 (7.2) RR ⫽ 1.59 (1.07–2.37) 关0.002兴; 1.2 (0.1 to 2.3) 65
candidiasis 24,26,27,29 NNTH ⫽ 22 (10–179)
Viral respiratory 15–17,19,22,23, 441/4,844 (9.1) 342/4,362 (7.8) RR ⫽ 1.22 (1.07–1.39) 关0.004兴; 1.3 (0.1 to 2.4) 0
infections 25,27,29,30 NNTH ⫽ 57 (33–179)
MI 16,23–25,28,29 34/3,278 (1.0) 33/3,265 (1.0) RR ⫽ 1.03 (0.64–1.64) 关0.91兴 0 (⫺0.5 to 0.5) 13
SMD ⫽ standardized mean difference.

pnea, and health-related quality-of-life total scores. Acknowledgments

However, the magnitude of these benefits did not
Author contributions: Dr. Rodrigo (1) has made substantial
reach the recent predefined criteria to be clinical contributions to conception and design, acquisition of data, and
important.32 analysis and interpretation of data; (2) has drafted the submitted
Current guidelines1,2 recommend the use of article and revised it critically for important intellectual content;
ICSs in combination with LABAs to reduce the and (3) has provided final approval of the version of the article to
frequency of exacerbations in symptomatic pa- be published. Dr. Castro-Rodriguez (1) has made substantial
contributions to conception and design, and interpretation of
tients with severe and very severe COPD. Further- data; (2) has revised the article critically for important intellectual
more, some authors39 have suggested that, in COPD content; and (3) has provided final approval of the version to be
patients as in asthma patients, concomitant ICS published. Dr. Plaza (1) has made substantial contributions to
therapy is preferable over LABA monotherapy. Nev- conception and design, and interpretation of data; (2) has revised
ertheless, this review suggests that combination the article critically for important intellectual content; and (3) has
provided final approval of the version to be published.
therapy with LABAs/ICSs presents a borderline Financial/nonfinancial disclosures: Dr. Rodrigo has partici-
statistical and limited clinical significance compared pated as a lecturer and speaker in scientific meetings and courses
with LABA monotherapy. Moreover, combination under the sponsorship of Boehringer Ingelheim, GlaxoSmithKline,
therapy offers no statistically significant additional AstraZeneca, Dr. Esteve SA, and Merck Sharp and Dome. Dr.
survival benefit and increased the risk of serious Castro-Rodriguez has participated as a lecturer and speaker in
scientific meetings and courses under the sponsorship of Merck
adverse effects. Even so, this last issue requires Sharp and Dohme, GlaxoSmithKline, and Grunenthal; and as
further prospective evaluation in large studies using member of the advisory board for GlaxoSmithKline. Dr. Plaza has
objective definitions of pneumonia. It is likely that participated as a lecturer and speaker in scientific meetings and
most patients with COPD with these levels of sever- courses under the sponsorship of AstraZeneca, GlaxoSmithKline,
ity should be treated only with LABA monotherapy. Dr. Esteve SA, and Merck Sharp and Dohme.
However, it is possible also that a future definition of
different COPD phenotypes will allow us to know
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1038 Original Research

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 Safety and Efficacy of Combined Long-Acting β-Agonists and Inhaled
Corticosteroids vs Long-Acting β-Agonists Monotherapy for Stable
COPD : A Systematic Review
Gustavo J. Rodrigo, José A. Castro-Rodriguez and Vicente Plaza
Chest 2009;136; 1029-1038; Prepublished online July 24, 2009;
DOI 10.1378/chest.09-0821
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