Chest
Volume 133, Issue 5, May 2008, Pages 1079-1087
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Original Research: COPD
Safety of Long-Acting β-Agonists in Stable COPD

https://doi.org/10.1378/chest.07-1167Get rights and content

Background

Some studies have suggested that use of long-acting β2-agonists (LABAs) leads to an increased risk for adverse events in patients with stable COPD. The purpose of this review was to assess the safety, and secondarily the efficacy of LABAs.

Methods

The authors conducted a systematic review with metaanalysis of randomized clinical trials (≥ 1 month in duration) in the published literature that have compared LABAs with placebo or anticholinergics in stable poorly reversible and reversible COPD.

Results

MEDLINE, EMBASE, CINAHL, and the Cochrane Controlled Trials Register were searched to identify 27 studies. LABAs reduced severe exacerbations compared with placebo (relative risk [RR], 0.78; 95% confidence interval [CI], 0.67 to 0.91). There was no significant difference between LABA and placebo groups in terms of respiratory deaths (RR, 1.09; 95% CI, 0.45 to 2.64). Use of LABAs with inhaled corticosteroids reduced the risk of respiratory death compared with LABAs alone (RR, 0.35; 95% CI, 0.14 to 0.93). Patients receiving LABAs showed significant benefits in airflow limitation measures, health-related quality of life, and use of rescue medication. Finally, tiotropium decreased the incidence of severe COPD exacerbations compared with LABAs (RR, 0.52; 95% CI, 0.31 to 0.87).

Conclusion

This review supports the beneficial effects of the use of LABAs in patients with stable moderate-to-severe COPD, and did not confirm previous data about an increased risk for respiratory deaths. Also, our analysis suggests the superiority of tiotropium over LABAs for the treatment of stable COPD patients.

Section snippets

Search Strategy and Selection Criteria

The search was conducted using three strategies. Firstly, we queried MEDLINE (1966 to April 2007), EMBASE (1974 to April 2007), and CINAHL (1982 to April 2007) databases using the following medical subject headings, full text, and key word terms: long-acting β2 adrenoceptor agonist OR salmeterol OR formoterol OR eformoterol AND COPD OR COPD OR chronic bronchitis OR emphysema. Secondly, a search of the Cochrane Controlled Trials Register (CENTRAL; first quarter 2007) was completed using the

Data Analysis

Binary outcomes were pooled using common relative risks (RRs) and 95% confidence intervals (CIs). Trials that reported no respiratory deaths were included in an analysis of the absolute risk difference. If pooled-effect estimates for dichotomous outcomes were significantly different between groups, we calculated the number needed to treat (NNT). For continuous outcomes, the weighted mean difference (WMD) [for variables using the same unit of measure] and 95% CI were calculated. The results of

Results

A total of 27 randomized controlled trials13141516171819202122232425262728293031323334353637383940 met inclusion criteria and were selected for analysis (Fig 1). Two studies4142 were excluded from analysis because they included results for patients enrolled in previous trials. Thus, Brusasco et al16 presented combined results of Donohue et al41 and a similar unpublished trial, and van Noord et al37 reported the same data from the study of Rutten van Molken et al.42 All trials were of good

Exacerbations

Fourteen studies comparing LABA with placebo evaluated the incidence of severe COPD exacerbations. The overall cumulative incidence was 7.5% in the LABA group and 10.8% in the placebo group, with a significant exacerbation rate reduction of 3.3% (95% CI, 1.9 to 4.8) [Fig 2]. The RR reduction was similar with a fixed model (RR, 0.78; 95% CI, 0.67 to 0.91) or a random model (RR, 0.80; 95% CI, 0.69 to 0.92). The NNT was 30 (95% CI, 20 to 52). The fail-safe N test, which is the number of

Mortality

Thirteen studies141617203032333435 reported all-cause mortality during the length of protocol. The analysis of the trials that reported one or more deaths did not show significant differences between LABA and placebo (RR, 0.90; 95% CI, 0.76 to 1.06; p = 0.20; I2 = 0%; fixed-effects model). When trials23272931 that did not report any death were incorporated in the analysis, LABAs patients presented an absolute risk reduction of 1.6% (95% CI, 0.8 to 2.4) [LABAs mortality rate, 4.9%; placebo,

Secondary Outcomes

Thirteen studies showed that the mean change from baseline of postbronchodilator FEV1 was greater in patients treated with LABAs (WMD, 0.13 L; 95% CI, 0.10 to 0.15; p = 0.0001, I2 = 92%; random-effect model) compared with placebo. Patients reversible to salbutamol who were treated with salmeterol showed a significantly greater increase in mean change FEV1 from baseline compared with poorly reversible patients treated with the same agent (0.18 L; 95% CI, 0.14 to 0.22; vs 0.10 L; 95% CI, 0.07 to

Discussion

This review found that compared with placebo, LABAs reduced severe exacerbations by 21% (NNT = 30). More important, LABAs patients did not differ in all-cause mortality rate, and contrary to a previous review4 they did not present differences in the rate of all and respiratory mortality, compared with placebo patients (98 reported respiratory deaths in 4,316 patients in the LABA-treated group and 88 deaths in of 3,733 patients in the placebo group). The analysis including those studies without

Strengths and Shortcomings

This study met most of the methodologic criteria suggested for scientific reviews.45 All of the included studies were randomized and double blinded, and combined with quite homogeneous clinical characteristics of the studied samples (namely GOLD stages 3 and 4). We also used the fail-safe N test to adjust for publication bias. Thus, it is unlikely that 23 studies and 14 studies (number of negative studies that would be required to reverse our conclusions regarding COPD exacerbations and

Clinical Implications

This review supports the beneficial effects of the use of LABAs in patients with stable moderate and severe COPD. This benefit was evident in both poorly reversible and reversible patients. Compared to placebo, inhaled LABAs (salmeterol, 50 to 100 μg; formoterol, 4.5 to 18 μg bid) produce a 21% reduction of severe COPD exacerbations. Unlike a previous review,4 our analysis did not confirm an increased risk for respiratory deaths. Furthermore, this current study showed significant changes in

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

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

    Dr. Rodrigo has participated as a lecturer and speaker in scientific meetings and courses under the sponsorship of Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, and Dr. Esteve SA, and consulted for CYDEX Inc. and Discovery Laboratories. Dr. Nannini has participated as a lecturer and speaker in scientific meetings and courses under the sponsorship of AstraZeneca and Altana. Dr. Rodriguez-Roisin has participated as a lecturer and speaker in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Pfizer; consulted with several pharmaceutical companies with relevance to the topics discussed in the present article (Altana, AstraZeneca, Aventis, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Laboratorios Dr. Esteve SA, Novartis, Pfizer, Viechi and Zambon); serves on advisory boards for Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, and Procter & Gamble; has been sponsored for several clinical trials; and has received laboratory research support from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Laboratorios Dr Esteve SA, and Pfizer.

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