Chest
Volume 136, Issue 4, October 2009, Pages 1029-1038
Journal home page for Chest

Original Research
COPD
Safety and Efficacy of Combined Long-Acting β-Agonists and Inhaled Corticosteroids vs Long-Acting β-Agonists Monotherapy for Stable COPD: A Systematic Review

https://doi.org/10.1378/chest.09-0821Get rights and content

Background

Current guidelines recommend the use of inhaled corticosteroids (ICSs) added to long-acting β2-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 Controlled 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 = 1%), or all-cause mortality (RR, 0.90; 95% CI, 0.76 to 1.06; I2 = 0%), respiratory mortality (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 mean difference, −1.88; 95% CI, −2.44 to −1.33; I2 = 29%) were significantly reduced with LABA/ICS therapy. Although therapy with LABAs/ICSs increases FEV1 significantly (0.06 and 0.04 L, respectively), 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/ICS therapy did not reach that of the criteria for predefined clinically important effects and were associated with serious adverse effects.

Section snippets

Search Strategy and Selection Criteria

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, full text, and keywords terms: (long-acting β2 adrenoceptor agonist OR salmeterol OR formoterol OR inhaled corticosteroids 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

Results

Of 164 potential relevant citations, 18 randomized, controlled trials14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 fulfilled the inclusion criteria (Fig 1). Five trials were unpublished.27, 28, 29, 30, 31 Data analysis was restricted to the LABAs/ICSs and LABAs arms of those trials (12,446 patients) [Table 1]. Five studies used formoterol/budesonide combination therapy,17, 20, 26, 27 and 13 studies used salmeterol/fluticasone combination therapy.14, 15, 16, 18, 19, 21,

Discussion

In the present study, which is the largest systematic review designed to evaluate the safety and efficacy of the regular use of LABAs/ICSs compared with the use of LABAs alone in stable patients with moderate-to-very severe COPD, we found that treatment with LABAs/ICSs did not modify the risks of overall mortality, respiratory deaths, and cardiovascular mortality (primary outcomes) compared with treatment with LABAs alone. On the contrary, the analysis of secondary outcomes showed that therapy

Acknowledgments

Author contributions: Dr. Rodrigo (1) has made substantial contributions to conception and design, acquisition of data, and analysis and interpretation of data; (2) has drafted the submitted article and revised it critically for important intellectual content; and (3) has provided final approval of the version of the article to be published. Dr. Castro-Rodriguez (1) has made substantial contributions to conception and design, and interpretation of data; (2) has revised the article critically

References (0)

Cited by (93)

View all citing articles on Scopus

Funding/Support: The funding for this study came from salary support for Dr. Rodrigo. No sponsorship from institutions or pharmaceutical industry was provided to conduct this study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).

View full text