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, formoterol). 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 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 50 μg twice daily or formoterol 12 μg 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 and formoterol) 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).  In a network meta-analysis of 33 double-blind, multicenter RCTs of LABA monotherapies, no clinically significant differences were noted at 12 or 24 weeks among the different LABAs (Donohue 2017).

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, 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).

A meta-analysis of 16 randomised, double-blinded controlled trials which included 22,872 patients with moderate to severe or very severe COPD with a treatment period ranging from 12 to 52 weeks found that LAMAs were associated with a lower risk of acute exacerbations (OR 0.84, 95% CI 0.74–0.90; P = 0.004) and lower incidence of adverse events (OR 0.92, 95% CI 0.86–0.98; P = 0.007) compared with LABAs (Chen 2017). There were no significant differences between LAMAs and LABAs in terms of changes in lung function, symptom score, health status and serious adverse events. LAMA may be preferable to LABA in patients with stable COPD, especially in those at risk of frequent exacerbations.

A meta-analysis of 24 clinical trials (Xia 2015) of inhaled LABAs (salmeterol, formoterol, indacaterol, vilanterol, olodaterol, aformoterol) for COPD of any severity with at least 3 months follow-up (12,291 received a LABA and 7784 received placebo) found that LABAs were associated with a lower rate of fatal cardiovascular events compared with placebo (RR 0.65, 95% CI 0.50 to 0.86, P = 0.002). This is contradictory to the findings of a meta-analysis of 33 trials lasting from 3 days to 1 year, in which beta2-agonist treatment significantly increased the risk for a cardiovascular event (relative risk [RR], 2.54; 95% CI 1.59 to 4.05) compared to placebo (Salpeter 2004). The RR for sinus tachycardia alone was 3.06 (95% CI 1.70 to 5.50), and for all other events it was 1.66 (95% CI 0.76 to 3.6). Post hoc analysis of the 3-year TORCH dataset found that the probabilities of having a cardiovascular adverse event by 3 years were similar for placebo (24.2%), salmeterol (22.7%), fluticasone propionate (24.3%) and salmeterol-fluticasone propionate combination (20.8%) (Calverley 2010). Cardiac safety of LABAs is less evident when used inappropriately (e.g. overdosing) or in patients with COPD and substantial cardiovascular disease, prolonged QTc interval, or polypharmacy (Lahousse 2016).