O1.2.2 Long-acting beta2-agonists (LABA)

Long-acting beta2-agonists cause prolonged bronchodilatation and can be administered once (indacaterol) or twice daily (salmeterol, eformoterol). A systematic review of randomised controlled trials (Appleton 2006b) found that compared to placebo, long-acting beta2-agonists used for at least four weeks produce statistically significant benefits in lung function, quality of life, use of ‘reliever’ short-acting bronchodilators and acute exacerbations. This review compared different drugs and doses independently, the commonest being salmeterol 50 mcg daily which involved up to 3363 participants. It would be necessary to treat 24 (95% CI 14 to 98) patients with salmeterol to prevent one exacerbation.

Treatment using salmeterol 50μg twice daily or formoterol 12μg twice daily has been found to be associated with improved patient quality of life (Kew 2013). LABA treatment has been shown to reduce exacerbations, including those requiring hospitalisation, but the evidence is of moderate quality and confounded by concomitant ICS use. LABAs did not significantly reduce mortality or serious adverse events.

Indacaterol is an inhaled long-acting beta2-agonist that can be given as a once daily maintenance therapy for COPD. Compared to placebo, indacaterol improves dyspnoea, FEV1 and health-related quality of life, and reduces exacerbations (Geake 2015) [evidence level 1]. Compared with twice daily beta-agonists (salmeterol, formoterol and eformoterol) indacaterol did not lead to a clinically significant difference in FEV1, dyspnea or quality of life (Geake 2015).

The bronchodilator effects of indacaterol are at least as good as tiotropium (Donohue 2010). Once-daily treatment with indacaterol via Breezhaler (150 μg) or tiotropium bromide via HandiHaler (18 μg) in patients with severe COPD and a history of exacerbations gave equally effective and clinically relevant improvements in lung function, health status, and breathlessness. Patients receiving indacaterol had a 29% higher annual rate of exacerbations versus patients receiving tiotropium (Decramer 2013).

Olodaterol is another once daily long acting beta2-agonist which improves FEV1 and reduces rescue inhaler use compared with placebo. It appears to be generally safe (although generally asymptomatic increases in plasma creatinine phosphokinase have been reported) and to have similar bronchodilator effects to BD formoterol (Ferguson 2014, Koch 2014) [evidence level II] and once daily indacaterol, although head to head studies with indacaterol have not been reported and the comparisons have been derived through network meta-analysis (Roskell 2014).

The efficacy of long-acting beta2-agonists compared to ipratropium bromide alone, or in combination, have also been combined in a systematic review (Appleton 2006a). Comparisons of monotherapy found a greater increase in FEV1, weighted mean difference = 60 mls (95% CI 0 to 110), and morning PEF, weighted mean difference = 10.96 l/min (95% CI 5.83 to 16.09) for salmeterol over ipratropium bromide. There were no significant differences between interventions for quality of life, functional capacity, symptoms, acute exacerbations or adverse events. Comparisons of the combination of ipratropium bromide and salmeterol with ipratropium bromide alone showed varying effects on lung function and symptoms, but a small, significant reduction in reliever use; weighted mean difference = -0.67 puffs/day (95% CI -1.11 to -0.23).