Current issues of ACP Journal Club are published in Annals of Internal Medicine


Review: Corticosteroids plus long-acting β-agonists reduce exacerbations more than long-acting β-agonists alone in COPD


ACP J Club. 2008 Mar-Apr;148:49. doi:10.7326/ACPJC-2008-148-2-049

Related Content in this Issue
• Companion Abstract and Commentary: Review: Long-acting inhaled therapies and pulmonary rehabilitation are effective in stable COPD

Clinical Impact Ratings

GIM/FP/GP: 6 stars

Pulmonology: 6 stars

Source Citation

Nannini L, Cates C, Lasserson T, Poole P. Combined corticosteroid and long-acting beta-agonist in one inhaler versus long-acting beta-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2007;(4):CD006829. [PubMed ID: 17943918]



In patients with stable chronic obstructive pulmonary disease (COPD), how do inhaled corticosteroids (ICSs) combined with long-acting β-agonists (LABAs) compare with LABAs alone?


Data sources: MEDLINE, EMBASE/Excerpta Medica, Cochrane Central Register of Controlled Trials, Cochrane Library (issue 1, 2007), Cochrane Airways Group Specialized Register, 4 other databases, reference lists, and conference abstracts.

Study selection and assessment: Randomized, double-blind, controlled trials (RCTs) comparing combination therapy of ICSs plus LABAs with LABAs alone in patients > 45 years of age with stable COPD and no exacerbation for 1 month before study entry, including those with partial reversibility on pulmonary function testing. Studies of patients who had asthma, bronchiectasis, cystic fibrosis, or other lung diseases were excluded. Quality assessment of individual studies was based on the 5-point Jadad scale. 10 RCTs (n = 7598) met the selection criteria: 8 compared fluticasone plus salmeterol with salmeterol alone, and 2 compared budesonide plus formoterol with formoterol. Jadad scores ranged from 3 to 5.

Outcomes: Exacerbations, death, and pneumonia. Secondary outcomes included rescue medication use, quality of life (St. George's Respiratory Questionnaire and Chronic Respiratory Disease Questionnaire), and adverse events.

Main results

Meta-analysis showed that combination therapy reduced exacerbations more than did LABAs alone; groups did not differ for death (Table). Combination therapy improved quality of life but increased pneumonia compared with LABAs alone (Table); groups did not differ for change in rescue medication use. Adverse events associated with fluticasone plus salmeterol included candidiasis and upper respiratory tract infection.


Combined inhaled corticosteroids plus long-acting β-agonists reduce exacerbations more than long-acting β-agonists alone in patients with stable chronic obstructive pulmonary disease.

Source of funding: Not stated.

For correspondence: Dr. L.J. Nannini, Hospital G. Baigorria, Santa Fe-Rosario, Argentina. E-mail

Table. Combined long-acting β-agonists (LABAs) plus inhaled corticosteroid (ICSs) vs LABAs alone in stable chronic obstructive pulmonary disease at 8 to 156 weeks*

Outcomes Number of trials (n) Weighted event rate RRR (95% CI) NNT
Mortality 6 (6747) 6.4% 7.1% 10% (−7.4 to 26) Not significant
Pneumonia 7 (7173) 9.9% 6.4% 56% (32 to 83) 29 (19 to 50)
Rate ratio (CI)
Exacerbations 5 (5696) 0.82 (0.78 to 0.88)
Weighted mean difference (CI)
Change in SGRQ score 4 (4700) −1.6 (−2.3 to −1.0)†
Change in CRDQ score 2 (680) 2.8 (0.2 to 5.4)‡

*CRDQ = Chronic Respiratory Disease Questionnaire; SGRQ = St. George's Respiratory Questionnaire; other abbreviations defined in Glossary. RRR, RRI, NNT, NNH, and CI calculated from control event rates and odds ratios using a fixed-effects model.
†Lower scores indicate better quality of life.
‡Higher scores indicate better quality of life.


In managing stable COPD, physicians aim to reduce symptoms and improve quality of life. Given the significant effect of exacerbations of COPD on quality of life, decline in lung function, and mortality, treatments that lessen their effect are of profound importance. Long-acting anticholinergics, LABAs, and ICSs are effective in reducing exacerbation rates in COPD. Positive effects on health-related quality of life are reported in most studies.

Combination therapy with inhaled LABAs plus CSs is effective in reducing exacerbations, but the reviews by Wilt and colleagues and by Nannini and colleagues differ in their conclusions about the efficacy of combination therapy compared with its monoconstituents. In the review and another recent meta-analysis by Nannini and colleagues, combination therapy was more effective than either monocomponent for reducing exacerbations, whereas Wilt and colleagues found no additional benefit for combination therapy compared with its monocomponents. The differing findings relate to variations in analyses of exacerbation rates and inclusion of different studies in the meta-analyses. Wilt and colleagues reported exacerbation rates as the proportion of patients having an exacerbation, while Nannini and colleagues reported their results as mean exacerbation rates for each group. Both methods appear to be valid, but Aaron and colleagues (1), who reviewed the difficulties surrounding counting, analyzing, and reporting exacerbations in COPD trials, argue that future studies should report results using mean exacerbations per patient-year as the primary outcome. As they contend, methods of defining and analyzing exacerbation rates in COPD differ greatly among trials, and such differences can lead to marked variations in assessments of treatment effects.

Nannini and colleagues included the Towards a Revolution in COPD Health (TORCH) trial (2) in their assessment of overall efficacy of combination therapy and excluded a study by Mahler (3), in which patients were withdrawn after exacerbation. Wilt and colleagues included the Mahler study in their analysis but excluded the TORCH trial because of their chosen method of reporting exacerbations. Future trials should aim for more consistency in both definition and reporting of results. In the meantime, the meta-analysis by Nannini and colleagues, which used exacerbation rate per group as an endpoint and included results of the TORCH trial, concludes that combination therapy is probably more effective at reducing exacerbations than its monocomponents.

Combination therapy also has marginally greater benefits on quality of life and FEV1 than its monocomponents. Combination therapy with fluticasone and salmeterol appears to reduce mortality compared with placebo or fluticasone alone, although not compared with salmeterol. As ICSs appear to be associated with increased incidence of pneumonia (although not with hospitalizations or deaths), increased clinician vigilance and patient education about prompt treatment of infections when these drugs are used seem prudent.

Christine McDonald, MBBS (Hons), PhD, FRACP
Austin Hospital
Heidelberg, Victoria, Australia


1. Aaron SD, Fergusson D, Marks GB, et al. Counting, analyzing and reporting exacerbations of COPD in randomized, controlled trials. Thorax. 2007. [PubMed ID: 17702790]

2. Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775-89. [PubMed ID: 17314337]

3. Mahler DA, Wire P, Horstman D, et al. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2002;166:1084-91. [PubMed ID: 12379552]