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      The safety of long-acting β 2-agonists in the treatment of stable chronic obstructive pulmonary disease

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          Inhaled long-acting bronchodilators are the mainstay of pharmacotherapy for chronic obstructive pulmonary disease (COPD). Both the twice-daily long-acting β 2-adrenoceptor agonists (LABAs) salmeterol and formoterol and the once-daily LABA indacaterol are indicated for use in COPD. This review examines current evidence for the safety of LABAs in COPD, focusing on their effect on exacerbations and deaths.


          We searched PubMed for placebo-controlled studies evaluating long-term (≥24 weeks) use of formoterol, salmeterol, or indacaterol in patients with stable COPD, published between January 1990 and September 2012. We summarized data relating to exacerbations and adverse events, particularly events related to COPD.


          From 20 studies examined (8774 LABA-treated patients), there was no evidence of an association between LABA treatment and increased exacerbations, COPD-related adverse events, or deaths. Where analyzed as an efficacy outcome, LABA treatment was generally associated with significant or numerical reductions in COPD exacerbations compared with placebo. Incidences of COPD-related adverse events were similar for active and placebo treatments. The incidence of adverse events typically associated with the β 2-agonist drug class such as skeletal muscle tremors and palpitations was low (often <1% of patients), and there were no reports of increased incidence of cardiac arrhythmias. The systemic effects of β 2-adrenoceptor stimulation, such as high glucose and potassium levels, were considered minor.


          Current evidence from clinical studies of the safety and tolerability profile of LABAs supports their long-term use in COPD.

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          Most cited references 9

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          Effect of long-acting beta-agonists on the frequency of COPD exacerbations: a meta-analysis.

            Inhaled long-acting beta-agonists have been licensed for the treatment of chronic obstructive pulmonary disease (COPD) since the late 1990s, and they improve lung function and symptoms of dyspnoea. However, the evidence that long-acting beta-agonists alone can reduce the rate of COPD exacerbations is not conclusive. This meta-analysis was performed to evaluate their effect on the frequency of exacerbations. MEDLINE, EMBASE, CINAHL and the Cochrane trials database were searched for the review. Randomized controlled trials of greater than or equal to 24weeks' treatment duration comparing long-acting beta-agonists (LABAs) with placebo were reviewed. Studies were pooled to yield odds ratios (ORs) with 95% confidence intervals (CIs). Seventeen randomized controlled trials (11871 randomized subjects) met the inclusion criteria and were selected for analysis. Salmeterol, formoterol and indacaterol significantly reduced COPD exacerbations compared with placebo. Salmeterol significantly reduced COPD exacerbations with both study arms exposed or not exposed to inhaled corticosteroids (ICS). The summary ORs were 0·79 (95% CI: 0·67-0·92; P<0·01) and 0·80 (95% CI: 0·65-0·99; P=0·04), respectively. However, when both arms were not exposed to ICS, there was no significant reduction in exacerbations with formoterol compared with placebo. The 'summary OR was 0·93 (95% CI: 0·75-1·15; P=0·50). Long-acting beta-agonists reduce the frequency of COPD exacerbations. Salmeterol, formoterol and indacaterol significantly reduced COPD exacerbations compared with placebo. Salmeterol but not formoterol decreased exacerbations significantly in the absence of ICS. © 2011 Blackwell Publishing Ltd.
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            [Dynamic lung hyperinflation and its clinical implication in COPD].

            Static lung hyperinflation is defined as the elevation of end- expiratory lung volume above its predicted value, with no increase in end-expiratory alveolar pressure, which remains equal to atmospheric pressure. Dynamic hyperinflation is the transient increase of this volume above the relaxation volume. In patients with COPD, dynamic hyperinflation is mainly determined by the mechanical properties of the respiratory system. Its measurement relies on plethysmography and, during exercise, inspiratory capacity. During exercise, dynamic hyperinflation attenuates expiratory flow limitation but increases the inspiratory loading and induces functional weakness of the diaphragm. It also has haemodynamic consequences and results in more rapid, shallow breathing and progressive reduction in dynamic lung compliance. These events explain exercise intolerance. Several approaches may help combat dynamic hyperinflation and its deleterious clinical effects: bronchodilators, hyperoxia, helium-oxygen mixtures, lung volume reduction surgery...
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              Safety of long-acting beta-agonists: urgent need to clear the air remains.


                Author and article information

                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                25 January 2013
                : 8
                : 53-64
                [1 ]Respiratory Division, University Hospital, KU Leuven, Belgium
                [2 ]Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, TX, USA
                [3 ]Krefting Research Centre, University of Gothenburg, Gothenburg, Sweden
                [4 ]Department of Research, Olmsted Medical Center, Rochester, MN, USA
                Author notes
                Correspondence: Marc L Decramer Chief Respiratory Division, UZ Leuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium Tel +32 16 346 807 Fax +32 16 346 803 Email marc.decramer@
                © 2013 Decramer et al, publisher and licensee Dove Medical Press Ltd

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.


                Respiratory medicine

                copd, bronchodilator, indacaterol, salmeterol, formoterol, laba


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