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

Long-acting beta₂-agonists cause prolonged bronchodilatation with a duration of action of 12 to 24 hours.  Indacaterol is available in Australia on PBS as a monocomponent LABA inhaler for the management of COPD. This and other LABAs (salmeterol, formoterol, vilanterol, olodaterol) are also available as combination LAMA/LABA, ICS/LABA or ICS/LABA/LAMA inhalers.

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

Comparison with LAMAs: 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.

Adverse effects: 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 7,784 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 clear when used inappropriately (e.g. overdosing) or in patients with COPD and substantial cardiovascular disease, prolonged QTc interval, or polypharmacy (Lahousse 2016).