O4.2 Inhaled glucocorticoids and long-acting beta-agonists and long-acting anticholinergics in combination

More data is becoming available on the efficacy of multiple inhaled medications to guide the best combination that will optimise patient’s lung function, improve symptoms and reduce exacerbations. A two-year double-blind, double dummy randomised controlled trial comparing tiotropium and combination therapy with fluticasone/salmeterol (500/50μg bd) (Wedzicha et al., 2008) found no difference in exacerbation rates between the groups (the primary aim of the study), but the combination therapy group achieved a small, statistically significant benefit in quality of life as well as the unexpected benefit of fewer deaths [evidence level II]. A systematic review incorporating this study concluded that the high and unbalanced withdrawal rate made interpretation of intervention effects difficult (Welsh et al., 2010).

Studies of “triple therapy” with inhaled glucocorticoids and long-acting beta-agonists and long-acting anticholinergics in combination have revealed conflicting results. A Cochrane systematic review of “triple” therapy studies found uncertainty regarding the long-term benefits and risks of treatment with tiotropium in addition to inhaled glucocorticoid and long-acting beta₂-agonist combination therapy on mortality, hospitalisation, exacerbations of COPD and pneumonia. (Karner and Cates, 2011) The systematic review found that the addition of combination treatment to tiotropium improves health-related quality of life and lung function [evidence level I].  A 12-week study of budesonide/formoterol with or without tiotropium(Welte et al., 2009) [evidence level II] found a significant increase in FEV₁, the primary outcome, with triple therapy, mean difference pre-dosing 128 (95% CI 78, 179) mls. There was a significant benefit in symptom control and also reduction in severe (systemic glucocorticoids and/or hospitalisation/Emergency visit) exacerbations NNT = 9 (95% CI 8, 13). However, a longer term randomised study of one year comparing salmeterol or combined salmeterol/fluticasone in addition to tiotropium (Aaron et al., 2007) did not find “triple” therapy reduced the proportion of patients suffering at least one exacerbation, the primary study endpoint. Despite this, patients receiving “triple” therapy did experience fewer hospitalisations for COPD and for all causes, as well as a clinically significant improvement in their quality of life [evidence level II].

Although RCTs have not found a benefit for triple therapy on mortality, a retrospective cohort study of patients with COPD in the Veterans Affairs health care system found the regimen of tiotropium and inhaled glucocorticoids and long-acting beta-agonists was associated with 40% reduced risk of death (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.45-0.79) compared with inhaled glucocorticoids and long-acting beta-agonists. (Lee et al., 2009) Triple therapy was also associated with reduced rates of COPD exacerbations (HR, 0.84; 95% CI, 0.73-0.97) and COPD hospitalizations (HR, 0.78; 95% CI, 0.62-0.98) (Lee et al, 2009) [evidence level III-2].