O1.2 Long-acting bronchodilators

Long-acting bronchodilators produce significant improvements in lung function, symptoms and quality of life (Braido 2013), as well as decreasing exacerbations.  These benefits come at a cost of increased adverse effects, which are generally of mild to moderate severity.

O1.2.1 Long-acting muscarinic antagonists (LAMA)

Long-acting muscarinic antagonists (LAMAs) result in bronchodilation with a duration of action of 12 to 24 hours, depending on the agent. A number of LAMAs are available in Australia, which are delivered via a range of devices:

  • aclidinium (Genuair)
  • glycopyrronium (Breezhaler)
  • tiotropium (HandiHaler, Respimat)
  • umeclidinium (Ellipta)

Aclidinium: Aclidinium is a twice daily LAMA. A Cochrane systematic review of 12 RCTs (9,547 participants) showed that, compared to placebo, aclidinium resulted in marginal improvements in quality of life and FEV1, and reduced the number of patients with exacerbations requiring hospitalisation (NNT 77, 95% CI 51 to 233) (Ni 2014) [evidence level I]. Aclidinium has also been shown to reduce the rate of moderate to severe exacerbations (OR 0.80) (Wedzicha 2016a) [evidence level I] without increasing major adverse cardiovascular events (Wise 2019) [evidence level II].

Glycopyrronium: Once daily glycopyrronium demonstrated significant improvement in spirometry and a reduction in the rate of moderate to severe exacerbations, but no difference in quality of life, compared with placebo (D’Urzo 2011, Kerwin 2012) [evidence level II]. In an RCT comparing glycopyrronium to tiotropium, there was no difference in FEV1, dyspnoea, quality of life, exacerbation rate or adverse effects (Chapman 2014) [evidence level II].

Tiotropium: Once daily tiotropium resulted in improved quality of life, and reduced exacerbation rates (OR 0.78, 95% CI 0.70 to 0.87; NNT 16, 95% CI 10 to 36) compared to placebo, in a Cochrane systematic review of 22 studies (23,309 participants) (Karner 2014) [evidence level I]. Tiotropium improved FEV1 (mean difference 119 mL, 95% CI 113 to 125), and there was no overall difference in mortality.  In a 2 year RCT of 841 COPD patients with post-bronchodilator FEV1 >50% predicted, tiotropium resulted in a significantly higher FEV1 (mean difference of 157 ml, 95% CI 123 to 192) and reduced annual decline in post-bronchodilator FEV1 (mean difference 22 ml per year, 95% CI 6 to 37), compared to placebo (Zhou 2017) [evidence level II].  However, there was a high withdrawal rate and 40% were current smokers.

Compared to ipratropium, tiotropium had beneficial effects for quality of life, dyspnoea and exacerbation rates (Yohannes 2011b) [evidence level I]. Compared to LABAs, tiotropium reduced exacerbation rates (Vogelmeier 2011, Decramer 2013) [evidence level II], whereas effects were heterogeneous for quality of life, compared to various LABAs (Chong 2012, Decramer 2013) [evidence level II].

Umeclidinium: Once-daily umeclidinium significantly improved lung function, dyspnoea and quality of life, compared with placebo (Trivedi 2014) [evidence level II]. Umeclidinium resulted in a greater improvement in FEV1 than tiotropium, but there were no significant differences between umeclidinium and tiotropium for dyspnoea, St George’s Respiratory Questionnaire (SGRQ) or COPD Assessment Test (CAT) scores (Feldman 2016) [evidence level II].

Adverse effects of LAMAs include dry mouth, constipation and urinary retention (Halpin 2015). A safety study showed similar rates of death and exacerbations with tiotropium HandiHaler and tiotropium Respimat (Wise 2013) [evidence level II].

Network meta-analyses of LAMAs: A network meta-analysis of LAMAs versus placebo showed that there were no statistically significant differences among LAMAs in preventing moderate-to-severe COPD exacerbations (Oba 2015) [evidence level I]. Tiotropium HandiHaler was the only LAMA formulation which reduced severe exacerbations (HR 0.73; 95% CrI 0.60– 0.86). Another network meta-analysis showed that current LAMAs have similar efficacy for change in FEV1, SGRQ, dyspnoea and rescue medication use (Ismaila 2015) [evidence level I]. However, with few head to head comparisons of LAMAs available, the choice of LAMA and inhaler device depends on patient and clinician preferences.

A meta-analysis of 9 studies of LAMA vs. LABA inhalers (17,120 COPD patients, with tiotropium as the most common LAMA) showed that LAMAs had reduced exacerbation rates (RR 0.88, 95% CI 0.84 to 0.93) and exacerbation-related hospitalisations (RR 0.78, 95% CI 0.69 to 0.87), compared to LABAs (Maia 2017) [evidence level I].