safetyandefficacy

DOI 10.1378/chest.09-0821 2009;136;1029-1038; Prepublished online July 24, 2009;Chest

Gustavo J. Rodrigo, José A. Castro-Rodriguez and Vicente Plaza Monotherapy for Stable COPD

-AgonistsβCorticosteroids vs Long-Acting -Agonists and InhaledβLong-Acting

Safety and Efficacy of Combined

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Safety and Efficacy of CombinedLong-Acting �-Agonists and InhaledCorticosteroids vs Long-Acting�-Agonists Monotherapy for Stable COPDA Systematic Review

Gustavo J. Rodrigo, MD; Jose A. Castro-Rodriguez, MD, PhD;and Vicente Plaza, MD

Background: Current guidelines recommend the use of inhaled corticosteroids (ICSs) added tolong-acting �2-agonists (LABAs) for treatment of symptomatic patients with severe and verysevere COPD. However, the evidence has been inconclusive. The aim of this review was to assessthe safety and efficacy of LABAs/ICSs compared with LABA monotherapy for patients withmoderate-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 lungfunction, health-related quality of life, and adverse effects.Results: Eighteen randomized controlled trials (12,446 participants) were selected. Therapy withLABAs/ICSs did not decrease the number of severe exacerbations (relative risk [RR], 0.91; 95% CI,0.82 to 1.01; I2 � 1%), or all-cause mortality (RR, 0.90; 95% CI, 0.76 to 1.06; I2 � 0%), respiratorymortality (RR, 0.80; 95% CI, 0.61 to 1.05; I2 � 0%), and cardiovascular mortality (RR, 1.22; 95% CI,0.88 to 1.71; I2 � 0%). To the contrary, the number of moderate exacerbations (RR, 0.84; 95% CI,0.74 to 0.96; I2 � 50%) and the St. George respiratory questionnaire total score (weighted meandifference, �1.88; 95% CI, �2.44 to �1.33; I2 � 29%) were significantly reduced with LABA/ICStherapy. 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 � 20%).Conclusions: Compared with LABA monotherapy, the magnitude of the benefits of LABA/ICStherapy did not reach that of the criteria for predefined clinically important effects and wereassociated 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

COPD is a preventable and treatable disease thatis characterized by airflow limitation that is not

fully reversible.1,2 The main therapeutic goals are toprevent and control symptoms, reduce the frequencyand severity of exacerbations, and improve healthstatus and exercise tolerance. Current guidelines1,2

recommend a stepwise increase in treatment, de-pending on the severity of the disease. Short-actinginhaled bronchodilators (short-acting �2-agonists[SABAs] and anticholinergic agents) are recom-

mended for the relief of symptoms on an as-neededbasis, whereas long-acting inhaled bronchodilators(long-acting �2-agonists [LABAs] or tiotropium) ina regularly scheduled regimen are recommendedas first-line therapy in symptomatic patients withmoderate-to-very severe COPD.

Evidence3 shows that LABA monotherapy is asso-ciated with significant improvements regardingCOPD exacerbations, pulmonary function, qualityof life, and use of rescue medication, with a low

CHEST Original ResearchCOPD

www.chestjournal.org CHEST / 136 / 4 / OCTOBER, 2009 1029



incidence of adverse effects. However, in view of themulticomponent nature of COPD, the use of inhaledcorticosteroids (ICSs), particularly in combinationwith a LABA has obtained widespread acceptanceamong clinicians. In fact, the addition of ICSs inpatients with severe or very severe disease (stages IIIor IV) with repeated exacerbations is recommendedfor decreasing exacerbation rates, and improvinglung function and health status.1,2 Nevertheless, theevidence of the superiority of combination therapy(LABAs/ICSs) over LABA monotherapy has beeninconclusive. While a 2007 review4 failed to demon-strate the superiority of combination therapy overLABA monotherapy in reducing COPD exacerba-tions, others have reported5–7 some benefits of ther-apy with LABAs/ICSs in terms of COPD exacerba-tions, pulmonary function, and quality of life. Evenso, these conclusions might be questionable becausethey are based on a reduced number of selectedstudies and outcomes. Consequently, we performeda systematic review to assess the safety and efficacyof the use of LABAs/ICSs in COPD patients com-pared with LABA monotherapy. The following twospecific questions were identified: (1) what are therisks of adding an ICS to a LABA compared withLABAs monotherapy? and (2) does therapy withLABAs/ICSs provide significant clinical benefitscompared with LABA monotherapy?

Materials and Methods

Search Strategy and Selection Criteria

We identified studies from MEDLINE, EMBASE (January1980 to May 2009), and the Cochrane Controlled Trials Register(second quarter of 2009) databases by using the following MeSH,full text, and keywords terms: (long-acting �2 adrenoceptoragonist OR salmeterol OR formoterol OR inhaled corticoste-roids OR fluticasone OR budesonide OR beclomethasone)AND (COPD OR chronic bronchitis OR emphysema). Also,we performed a search of relevant files from AstraZeneca

(www.astrazenecaclinicaltrials.com) and GlaxoSmithKline (www.gsk-clinicalstudyregister.com) databases. Trials published solelyin abstract form were excluded because the methods and resultscould not be fully analyzed.

The specific inclusion criteria were as follows: (1) stable adultpatients aged � 40 years with COPD satisfying the diagnosticcriteria of the American Thoracic Society/European RespiratorySociety1 or the Global Initiative for Chronic Obstructive LungDisease2; (2) therapy with inhaled LABAs plus ICSs (deliveredvia metered-dose inhaler or dry powder inhaler) as the interven-tion arm compared with therapy with a LABA; (3) study dura-tions of � 1 month; (4) randomized controlled trials (parallel-group design) without language restriction; and (5) primaryoutcomes “severe COPD exacerbation” (requiring hospitalizationor withdrawals) and “moderate COPD exacerbations” (requiringsystemic corticosteroids or antibiotic use), all-cause mortality(deaths for any cause), respiratory deaths (deaths due to arespiratory event such as COPD exacerbation or pneumonia),and cardiovascular mortality (including sudden death) during thetreatment period. Secondary outcome measures were as follows:mean change in FEV1 (pre-bronchodilator therapy and post-bronchodilator therapy); mean change from baseline in the St.George respiratory questionnaire (SGRQ) total score8; end-of-treatment dyspnea score; withdrawals from the study during thetreatment period (overall, due to adverse effects, and due to lackof efficacy); and adverse effects (pneumonia, oropharyngealcandidiasis, viral respiratory infections, and myocardial infarc-tions [MIs]).

Data Abstraction and Validity Assessment

Titles, abstracts, and citations were independently analyzed byall reviewers. From full text, they independently assessed studiesfor inclusion based on the criteria for population, intervention,study design, and outcomes. Three reviewers (G.J.R., J.C.R., andV.P.) were independently involved in all stages of study selection,data extraction, and quality assessment. Any disagreement wasresolved by consensus. In case of multiple published or unpub-lished reports for a particular study, data from the most recentversion were extracted.

Statistical Analysis

Binary outcomes were pooled by using common relative risks(RRs) and 95% CIs. If pooled effect estimates were significantlydifferent between groups, we calculated the number needed totreat for benefit (NNTB) or the number needed to treat for harm(NNTH). For continuous outcomes, the standardized meandifference or weighted mean difference (WMD) and 95% CIswere calculated. Heterogeneity was further measured by usingthe I2 test.9 With low heterogeneity (I2 � 40%), data werecombined by mean of a fixed-effects model10; otherwise, arandom-effects model was used. Publication bias of primaryoutcomes was evaluated by means of the visual inspection offunnel plots.11 A predefined sensitivity analysis of the primaryoutcome of severe COPD exacerbations was conducted to ex-plore the influence of the following factors: concealment alloca-tion12 (adequate vs unclear); trial duration (long-term [� 52weeks] vs short-term [� 52 weeks]); reversibility to SABA (poorlyreversible patients or FEV1 � 15% from baseline vs reversiblepatients or FEV1 � 15% from baseline); choice of LABAs(salmeterol vs formoterol); and the use of ICSs before thepatients were enrolled (� 50% of patients vs � 50% of patients).Subgroups were compared by using the interaction test.13 Ap value of � 0.05 using a two-tailed test was considered toindicate significance. Metaanalyses were performed with using a

Manuscript received April 2, 2009; revision accepted July 2, 2009.Affiliations: From the Departamento de Emergencia (Dr. Ro-drigo), Hospital Central de las Fuerzas Armadas, Montevideo,Uruguay; the School of Medicine (Dr. Castro-Rodriguez), Pon-tificia Universidad Catolica de Chile, Santiago, Chile; and Serveide Pneumologia (Dr. Plaza), Hospital de la Santa Creu i SantPau, Universitat Autonoma de Barcelona, Barcelona, Spain.Funding/Support: The funding for this study came from salarysupport for Dr. Rodrigo. No sponsorship from institutions orpharmaceutical industry was provided to conduct this study.Correspondence to: Gustavo J. Rodrigo, MD, Departamentode Emergencia, Hospital Central de las Fuerzas Armadas, Av 8de Octubre 3020, Montevideo 11600, Uruguay; e-mail: [email protected]© 2009 American College of Chest Physicians. Reproductionof this article is prohibited without written permission from theAmerican College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).DOI: 10.1378/chest.09-0821

1030 Original Research



statistical software package (Review Manager, version 5.0.20; theNordic Cochrane Centre, the Cochrane Collaboration; Copen-hagen, Denmark).

Results

Of 164 potential relevant citations, 18 randomized,controlled trials14–31 fulfilled the inclusion crit-eria (Fig 1). Five trials were unpublished.27–31 Dataanalysis was restricted to the LABAs/ICSs andLABAs arms of those trials (12,446 patients) [Table1]. Five studies used formoterol/budesonide combi-nation therapy,17,20,26,27 and 13 studies used salmet-erol/fluticasone combination therapy.14–16,18,19,21–31

Seven studies14–16,21,23,24,31 evaluated therapy withinhaled fluticasone in combination with salmeterolat a dosage of 500 �g twice daily, seven stud-ies18,19,22,25,28–30 assessed therapy with fluticasone ata dosage of 250 �g twice daily, and four stud-ies17,20,26,27 evaluated therapy with budesonide at adosage of 320 �g twice daily. All trials used singleinhalers containing both ICSs and LABAs to deliver thecombined therapy. Eleven trials15–21,23–26 reported thata mean of 31% of patients (range, 0 to 55% of patients)had received ICSs before they were enrolled in thestudy. There were 11 long-term trials (ie, � 52

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 mostlystable patients with COPD who met the Global Initia-tive for Chronic Obstructive Lung Disease criteria formoderate-to-very severe COPD exacerbations.2 Themean age of patients was 64 years (72% of patientswere male), with an average baseline FEV1 of 40% ofpredicted normal values. Allocation concealment wasadequate in only 5 studies,16,20,21,23,24 and was unclearin the remaining 13 studies.

Primary Outcomes

Compared with LABA monotherapy, combinationtherapy with LABAs/ICSs did not significantlydecrease the risk of severe COPD exacerbations(11.3% vs 12.5%, respectively) [Table 2]. The posthoc subgroup analysis did not show significant dif-ferences in COPD exacerbations regarding conceal-ment allocation, trial duration, reversibility to SABAuse, LABA choice, and use of ICSs before thepatients were enrolled in the study (Table 3). To thecontrary, the use of LABAs/ICSs was associated witha significantly reduced risk of moderate COPDexacerbations when compared with LABAs alone(17.5% vs 20.1%, respectively), with evidence ofstatistical heterogeneity among trials. The NNTBwas 31 (95% CI, 20 to 93).

Patients receiving therapy with LABAs/ICSs werenot associated with a significant decrease of overallmortality when compared with those receivingLABAs alone (4.5% vs 5.5%, respectively) [Fig 2]. Inthe same way, the metaanalysis did not showsignificant differences between groups regardingthe risk of respiratory deaths (1.8% in the LABAs/ICSs group vs 2.4% in the LABAs group) andcardiovascular mortality (1.6% vs 1.4%, respectively),without evidence of statistical heterogeneity (Fig 2).On visual inspection of the funnel plots (Fig 3),publication bias could be ruled out for all-cause,respiratory, and cardiovascular mortality. To thecontrary, for severe COPD exacerbations, the plotpresented an asymmetrical shape with an absence ofsmall studies showing a group benefit for therapywith LABAs.

Secondary Outcomes

Regarding pulmonary function, patients treatedwith LABAs/ICSs showed significantly greater in-creases in the mean change in FEV1 from baseline(pre-bronchodilator therapy and post-bronchodilatortherapy) compared with patients treated with LABAsalone (Table 4); however, both comparisons showedstatistical heterogeneity. Patients receiving therapywith LABAs/ICSs showed a significantly greaterreduction in the SGRQ total score. Finally, at the

Figure 1. Flowchart for identification of studies.




Table 1—Characteristics of Included Studies

StudiesStudy Location/

DurationPatients: No.

(% male)

MeanAge,

yrMean Baseline

FEV1

CurrentSmoker

BronchodilatorResponse, %

Intervention:Dose

AllocationConcealment

Cazzola et al14 Single-center/12 wk S: 20 (90) 65 1.15 L 45 pack-yr � 12 S: 50 �g twiceMDI

Unclear

SF: 40 (92) 64 1.16 L 44 pack-yr � 12 SF: 50/250 or50/500 �gtwice MDI

Mahler et al15 69 centers/24 wk S: 160 (64) 64 40% predicted 46% 21 S: 50 �g twiceDPI

Unclear

SF: 165 (62) 63 41% predicted 46% 21 SF: 50/500 �gtwice DPI

Calverley et al16 196 centers/52 wk S: 372 (70) 63 46% predicted 51% 3.7 S: 50 �g twiceDPI

Adequate

SF: 358 (75) 63 49% predicted 52% 4.0 SF: 50/500 �gtwice DPI

Calverley et al17 109 centers/52 wk F: 255 (75) 63 36% predicted 36% 6 F: 9 �g twiceDPI

Unclear

FB: 254 (78) 64 36% predicted 33% 6 FB: 9/320 �gtwice DPI

Dal Negroet al18

Single-center/52 wk S: 6 (100) 55–78 48% predicted 0% 3 S: 50 �g twiceDPI

Unclear

SF: 5 (83) 53–77 50% predicted 0% 3.5 SF: 50/ 250 �gtwice DPI

Hanania et al19 75 centers/24 wk S: 177 (58) 64 42% predicted 51% 20 S: 50 �g twiceDPI

Unclear

SF:178 (61) 63 41% predicted 43% 19 SF: 50/250 �gtwice DPI

Szafranski et al20 89 centers/52 wk F: 201 (76) 63 36% predicted 38% 6 F: 9 �g twiceDPI

Adequate

FB:208 (76) 64 36% predicted 30% 6 FB: 9/320 �gtwice DPI

Wouters et al21 39 centers/52 wk S: 184 (75) 64 1.41 L 35% 4 S: 50 �g twiceDPI

Adequate

SF: 189 (73) 63 1.41 L 39% 4 SF: 50/500 �gtwice DPI

O’Donnellet al22

21 centers/8 wk S: 59 (75) 65 40% predicted 34% 18 S: 50 �g twiceDPI

Unclear


Calverley et al23 444 centers/156 wk S: 1,521 (76) 65 44% predicted 43% 4 S: 50 �g twiceDPI

Adequate

SF: 1,533 (75) 65 44% predicted 43% 4 SF: 50/500 �gtwice DPI

Kardos et al24 95 centers/ 44 wk S: 487 (78) 64 40% predicted 37% 7 S: 50 �g twiceDPI

Adequate


Ferguson et al25 94 centers/52 wk S: 388 (52) 65 33% predicted 38% NA S: 50 �g twiceDPI

Unclear

SF: 394 (58) 65 33% predicted 40% NA SF: 50/250 �gDPI twice

Tashkin et al26 194 centers/26 wk F: 284 (66) 64 39% predicted 42% NA F: 9 �g twiceDPI

Unclear

FB: 845 (69) 63 39% predicted 44% NA FB: 9/160 �g or320/9 �gtwice MDI

D-5899C0000127

237 centers/52 wk F: 495 (65) 63 34% predicted 41% 16 F: 9 �g twiceDPI

Unclear

FB: 988 (63) 64 34% predicted 36% 16 FB: 9/320 �g or160/9 MDItwice

(Continued)




end of the protocol, patients treated with combina-tion therapy had a significantly lower dyspnea scorecompared with patients treated with LABAs alone,although with evidence of statistical heterogeneityamong the trials (Table 4).

LABAs/ICSs therapy was associated with a signif-icant decrease of overall withdrawals from the study(Table 4). Furthermore, patients receiving therapywith LABAs/ICSs were associated with a significantlylower rate of withdrawals from the study due to lackof efficacy, but not with significant withdrawals fromthe study due to adverse effects (Table 4). However,the use of LABAs/ICSs was also associated withsignificantly increased rates of pneumonia (63%increase in RR), viral respiratory infections (22%increase in RR), and oropharyngeal candidiasis (59%

increase in RR) compared with the use of LABAsalone. Finally, combined therapy did not show asignificant difference in the rate of MI, comparedwith LABA monotherapy.

Discussion

In the present study, which is the largest system-atic review designed to evaluate the safety andefficacy of the regular use of LABAs/ICSs comparedwith the use of LABAs alone in stable patients withmoderate-to-very severe COPD, we found that treat-ment with LABAs/ICSs did not modify the risks ofoverall mortality, respiratory deaths, and cardiovas-cular mortality (primary outcomes) compared with

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

Outcomes References

LABAs � ICS,No./Total No.

(%)LABAs, No./Total No. (%) Measure (95% CI)

Absolute RiskReduction I2, %

COPD exacerbations(requiringhospitalization orwithdrawal)

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

COPD exacerbationsrequiring systemiccorticosteroids

15–26,29 794/4,532 (17.5) 1,015/5,058 (20.1) RR � 0.84 (0.74–0.96);p � 0.008/NNTB �31 (20–93)

�2.5 (�1.0 to �4.1) 50

All-cause mortality 16,17,20,21,23–26,28–30

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

Respiratory deaths 16,17,20,21,23–26,28–30

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

Cardiovascular mortality 16,21,23–26,28–30

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

Table 1—(Continued)

StudiesStudy Location/

DurationPatients: No.

(% male)

MeanAge,

yrMean Baseline

FEV1

CurrentSmoker

BronchodilatorResponse, %

Intervention:Dose

AllocationConcealment

SCO4004128 31 centers/156 wk S: 94 (63) 66 � 70% predicted NA NA S: 50 �g twiceDPI

Unclear

SF: 92 (63) 65 � 70% predicted NA NA SF: 50/250 �gDPI twice

SCO10025029 98 centers/52 wk S: 403 (57) 65 � 50% predicted � 10 pack-yr NA S: 50 �g twiceDPI

Unclear

SF: 394 (51) 65 � 50% predicted � 10 pack-yr NA SF: 50/250 �gDPI twice

SCO10047030 135 centers/24 wk S: 532 (78) 64 1.68 L 44% NA S: 50 �g twiceDPI

Unclear

SF: 518 (82) 64 1.65 L 42% NA SF: 50/250 �gDPI twice

SCO10492531 11 centers/12 wk S: 38 (79) 64 � 50% predicted � 10 pack-yr NA S: 50 �g twiceDPI

Unclear

SF: 39 (82) 64 � 50% predicted � 10 pack-yr NA SF: 50/500 �gDPI twice

NA � not applicable; S � salmeterol; F � formoterol; SF � salmeterol/fluticasone; FB � formoterol/budesonide; MDI � metered-dose inhaler;DPI � dry powder inhaler.




treatment with LABAs alone. On the contrary, theanalysis of secondary outcomes showed that therapywith LABAs/ICSs significantly increased the risk ofpneumonia, oropharyngeal candidiasis, and viral re-spiratory infections (question 1). However, it isinteresting to point out that these adverse effectswere not accompanied by a concomitant and propor-tional increase in respiratory-related mortality or over-all mortality. Concerning the benefits (question 2), wefound that therapy with LABAs/ICSs significantlydecreased the frequency of moderate COPD exac-erbations independently of concealment allocation,trial duration, reversibility to SABA therapy, LABAchoice, and previous use of ICSs.

In the same way, therapy with LABAs/ICSs wasassociated with significant increases in the meanchange in pre-bronchodilator therapy and post-bronchodilator therapy FEV1, the mean change inSGRQ total score, and with a significant decrease inthe end-of-treatment dyspnea score compared withtreatment with LABAs alone. However, given thatthe size of these benefits did not reach the suggestedclinically important minimal differences (FEV1, 0.10to 0.14 L; SGRQ score, 4-unit decrement),32 therelevance of these improvements seems uncertain.In the same way, the 16% decrease in the rate ofmoderate COPD exacerbations was smaller than thesuggested threshold value of 22% for clinical signif-icance.32 Conversely, treatment with LABAs/ICSsfailed to significantly reduce the risk of severeCOPD exacerbations. These facts suggest a limitedextra efficacy when ICSs were added to LABAs forCOPD treatment.

The relative benefits of therapy with LABAs/ICSsmust be weighed against the risks. Thus, the mostconcerning side effect was the increase in the risk ofpneumonia associated with the administration of

ICSs added to LABAs. The precise mechanism isuncertain, but it could be related to the fact thatICSs achieve locally high concentrations in the lung,increasing the risk of pneumonia due to their immu-nosuppressive effects.33 Thus, inhaled fluticasone atdosages of 1,000 �g/d exerts effects on serum corti-sol levels that are equivalent to 10 mg of prednisone,a dose that may double the risk of pneumonia inpatients with arthritis.34 Our analysis showed anincrease in the risk of pneumonia with both moder-ate dosages of fluticasone (500 �g/d; RR, 1.75; 95%CI, 1.16 to 2.64; I2 � 30%) and high dosages offluticasone (1,000 �g/d; RR � 1.64; 95% CI, 1.32 to2.06, I2 � 22%). To the contrary, therapy withLABAs/ICSs was associated with significant de-creases in overall withdrawals and withdrawals dueto lack of efficacy compared with LABA mono-therapy. This finding could be associated with thefact that therapy with LABAs/ICSs significantly re-duces dyspnea with a greater clinical effectivenessperception. Also, this fact could be associated withbetter control of the disease.

When we compared the results of the presentmetaanalysis with those of previous reviews (basedon a limited number of published trials), we foundsome similarities and few differences. For example, aCochrane review5 of 10 studies, reported a signifi-cant RR reduction of moderate COPD exacerbationsof 18% with the combined treatment with LABAs/ICSs compared with treatment with LABAs alone.Also, the combination therapy was more effectivethan that with LABAs alone in improving qualityof life as measured by the SGRQ (�1.64 points),and predose and postdose FEV1 (0.06 and 0.05 L,respectively). While there was no significant dif-ference in terms of overall mortality, pneumoniaoccurred more commonly in patients receiving

Table 3—Sensitivity Analysis. Comparisons Between RR in COPD Exacerbations Requiring Hospitalization orWithdrawal) Stratified by Concealment Allocation (Adequate vs Unclear), Trial Duration (Long-Term > 52 Weeksvs 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), LABAschoice (Salmeterol vs Formoterol), and Use of ICSs Before the Patients Were Enrolled (< 50% of Patients vs < 50%

of Patients)

Subgroup Comparisons RR (95% CI) �I2Interactive Test17

RR (95% CI) p Value

Adequate16,20,21,23,24 vs unclearconcealment14,15,17–19,22,25–31

0.93 (0.82–1.05) �35% vs 0.90 (0.77–1.05) �0% 0.96 (0.79–1.18) 0.74

Long-term16,17,20,21,23,25,27–29 vsshort-term15,19,22,24,26,30

0.93 (0.84–1.03) �1% vs 0.80 (0.59–1.11) �0% 0.86 (0.61–1.19) 0.37

Poorly reversible16,17,20,21,23,24 vsreversible15,19,22,25–30

0.90 (0.80–1.01) �0% vs 0.94 (0.74–1.20) �0% 1.04 (0.79–1.36) 0.75

Salmeterol15,16,19,21–25,28–30 vsFormoterol17,20,26,27

0.94 (0.84–1.05) �0% vs 0.87 (0.73–1.04) �41% 0.92 (0.75–1.14) 0.46

Previous use of ICS (� 50%16, 24,26 vs� 50% of patients15,17–21,23–25)

0.84 (0.65–1.14) �28% vs 0.92 (0.88–1.04), �31% 1.06 (0.79–1.43) 0.65




combined therapy (58% increase in RR). How-ever, another metaanalysis4 that was limited to fiveEnglish-language trials failed to demonstrate thesuperiority of combination treatment over LABAmonotherapy in reducing COPD exacerbations andoverall mortality.

More recently, Sobieraj et al7 on the basis of sevenstudies reported that therapy with LABAs/ICSs de-creased the risk of moderate COPD exacerbations(relative reduction risk of 18%), decreased theSGRQ total score (�1.98 points), and increased therisk of pneumonia (32% increase in RR) compared

with therapy with LABAs alone. Additionally, com-bined therapy also showed a reduced risk in overallwithdrawals (17% increase in RR), and withoutdifference in the rate of overall mortality betweengroups. Another systematic review35 has found noevidence that therapy with LABAs alone is moreeffective than combined therapy with LABAs/ICSs.In the same study, a subgroup analysis showed that,when added to LABAs, ICSs significantly reducedthe number of exacerbations in patients with FEV1� 40% predicted. However, these conclusions areuncertain because the review was based on only

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




seven studies15–17,19,20,23,24 (6,376 patients withCOPD). Finally, Singh et al36 showed a significantlyincreased risk of pneumonia with combined therapycompared with LABA monotherapy (32% increase inRR) without a significantly increased risk of death.Interestingly, the risk of pneumonia could be specif-ically attributed to the use of ICSs because the riskfor pneumonia associated with ICS use was similarwhen therapy with ICSs were compared with pla-cebo or when ICSs were added to therapy withLABAs and compared with LABA therapy alone. Inthe same way, a recent trial37 comparing therapywith inhaled tiotropium with therapy with salmet-erol/fluticasone in patients with COPD showed anincreased hazard ratio for time to reported pneumo-nia for combined therapy of � 2 years (94% increasein RR).

This review was performed according to the meth-odological criteria suggested for scientific reviews.38

The fact that there was low evidence of clinical andstatistical heterogeneity between studies increasedthe confidence of our findings. Furthermore, therewas no evidence of publication bias in the majority ofprimary outcomes. However, our metaanalysis had

several potential limitations that came from thequality of the reported data. Thus, the trials did notconsistently use similar definitions of COPD exacer-bations or pneumonia. In particular, we recognizedthat the severity of exacerbations is a complex con-cept constituted by several factors, and that this factcould modify our results. Also, most of the studieswere not specifically designed to monitor outcomesas all-cause, respiratory, or cardiovascular mortality.Additionally, the risk of bias was unclear in 13 trialsin the analysis. Also, the fact that 80% of thereviewed patients were men limits the applicabilityof the results since COPD is suspected to affect menand women equally.

This metaanalysis confirms and extends data fromprevious reviews. The main results of our review areas follows: LABAs/ICSs did not decrease the risk ofall-cause, respiratory, and cardiovascular mortality;however, therapy with LABAs/ICSs increases therisk of pneumonia, oropharyngeal candidiasis, andviral respiratory infections. The use of LABAs/ICSswas associated with a lower incidence of moderateCOPD exacerbations (but not of severe exacerba-tions), increased pulmonary function, improved dys-

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).




pnea, and health-related quality-of-life total scores.However, the magnitude of these benefits did notreach the recent predefined criteria to be clinicalimportant.32

Current guidelines1,2 recommend the use ofICSs in combination with LABAs to reduce thefrequency of exacerbations in symptomatic pa-tients with severe and very severe COPD. Further-more, some authors39 have suggested that, in COPDpatients as in asthma patients, concomitant ICStherapy is preferable over LABA monotherapy. Nev-ertheless, this review suggests that combinationtherapy with LABAs/ICSs presents a borderlinestatistical and limited clinical significance comparedwith LABA monotherapy. Moreover, combinationtherapy offers no statistically significant additionalsurvival benefit and increased the risk of seriousadverse effects. Even so, this last issue requiresfurther prospective evaluation in large studies usingobjective definitions of pneumonia. It is likely thatmost patients with COPD with these levels of sever-ity should be treated only with LABA monotherapy.However, it is possible also that a future definition ofdifferent COPD phenotypes will allow us to knowwhich patients can benefit from ICSs, and whichshould only be treated with LABAs. Thus, patientswho benefit from combination therapy with LABAs/ICSs could be those patients with steroid-responsiveeosinophilic bronchitis.

Acknowledgments

Author contributions: Dr. Rodrigo (1) has made substantialcontributions to conception and design, acquisition of data, andanalysis and interpretation of data; (2) has drafted the submittedarticle and revised it critically for important intellectual content;and (3) has provided final approval of the version of the article tobe published. Dr. Castro-Rodriguez (1) has made substantialcontributions to conception and design, and interpretation ofdata; (2) has revised the article critically for important intellectualcontent; and (3) has provided final approval of the version to bepublished. Dr. Plaza (1) has made substantial contributions toconception and design, and interpretation of data; (2) has revisedthe article critically for important intellectual content; and (3) hasprovided final approval of the version to be published.Financial/nonfinancial disclosures: Dr. Rodrigo has partici-pated as a lecturer and speaker in scientific meetings and coursesunder the sponsorship of Boehringer Ingelheim, GlaxoSmithKline,AstraZeneca, Dr. Esteve SA, and Merck Sharp and Dome. Dr.Castro-Rodriguez has participated as a lecturer and speaker inscientific meetings and courses under the sponsorship of MerckSharp and Dohme, GlaxoSmithKline, and Grunenthal; and asmember of the advisory board for GlaxoSmithKline. Dr. Plaza hasparticipated as a lecturer and speaker in scientific meetings andcourses under the sponsorship of AstraZeneca, GlaxoSmithKline,Dr. Esteve SA, and Merck Sharp and Dohme.

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Table 4—Analysis of Secondary Outcomes (LABAs/ICSs vs LABAs)

Outcomes References

LABAs � ICSs,No./Total No.

(%)LABAs, No./Total No. (%) Measure (95% CI) �p Value

Absolute RiskReduction I2, %

Mean change inpre-bronchodilatortherapy FEV1, L

14–16,19,21–27,29–30

5,613 5,082 WMD � 0.06 (0.04–0.07)�0.0001

82

Mean change inpost-bronchodilatortherapy FEV1, L

14–16,19,22,23,26,27

3,455 2,501 WMD � 0.04 (0.02–0.05)�0.0001

64

Mean change inSGRQ

16,17,20,23–26,30

4,617 4,040 WMD � �1.88 (�2.44 to �1.33)�0.0001

29

End-of-treatmentdyspnea score

15,16,19,21,22,24–26,30

3,216 2,643 SMD � �0.20 (�0.25 to �0.15)�0.0001

82

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) �0.0001;NNTB � 25 (18–41)

�1.6 (�0.2 to �3.0) 0

Withdrawals due toadverse effects

15,16, 19–21,23–26,28–30

680/5,381 (12.6) 654/4,803 (13.6) RR � 0.93 (0.84–1.03) �0.26 �1.0 (�0.3 to 2.3) 0

Withdrawals due tolack of efficacy

15,16,23,25,29,30

63/3,362 (1.9) 117/3,376 (3.5) RR � 0.54 (0.40–0.72) �0.0001;NNTB � 73 (56–120)

�1.6 (�0.8 to �2.4) 0

Pneumonia 15,16,19,21,23–26,28–31

263/5,212 (5.0) 153/4,540 (3.4) RR � 1.63 (1.35–1.98) �0.0001;NNTH � 40 (26–72)

1.7 (0.9 to 2.5) 20

Oropharyngealcandidiasis

16,19,21,22,24,26,27,29

292/3,521 (8.4) 200/2,741 (7.2) RR � 1.59 (1.07–2.37) �0.002;NNTH � 22 (10–179)

1.2 (0.1 to 2.3) 65

Viral respiratoryinfections

15–17,19,22,23,25,27,29,30

441/4,844 (9.1) 342/4,362 (7.8) RR � 1.22 (1.07–1.39) �0.004;NNTH � 57 (33–179)

1.3 (0.1 to 2.4) 0

MI 16,23–25,28,29 34/3,278 (1.0) 33/3,265 (1.0) RR � 1.03 (0.64–1.64) �0.91 0 (�0.5 to 0.5) 13

SMD � standardized mean difference.




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DOI 10.1378/chest.09-0821; Prepublished online July 24, 2009; 2009;136; 1029-1038Chest

Gustavo J. Rodrigo, José A. Castro-Rodriguez and Vicente PlazaCOPD

-Agonists Monotherapy for StableβCorticosteroids vs Long-Acting -Agonists and InhaledβSafety and Efficacy of Combined Long-Acting

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