O4.2 Inhaled corticosteroids and long-acting beta2-agonists and long-acting antimuscarinics 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 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 2013).

Studies of “triple therapy” with inhaled corticosteroids and long-acting beta-agonists and long-acting antimuscarinics 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 corticosteroid and long-acting beta2-agonist combination therapy on mortality, hospitalisation, exacerbations of COPD and pneumonia (Karner 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 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. Similar effects on FEV1 were found with the combination of tiotropium and salmeterol/ fluticasone (Hanania 2012Jung 2012).

There was a significant benefit in symptom control and also reduction in severe (systemic corticosteroids and/or hospitalisation/Emergency visit) exacerbations NNT = 9 (95% CI 8, 13). However, a longer term randomised double blind placebo-controlled study of one year comparing salmeterol or combined salmeterol/fluticasone in addition to tiotropium (Aaron 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].

The GLISTEN three arm study compared the addition of glycopyrronium or tiotropium or placebo to salmeterol/fluticasone propionate.  The addition of either of the LAMAs demonstrated statistically significant improvements to FEV1 (101ml at 12 weeks), a statistically but not clinically significant change in health status (2.15units SGRQ) and reduced rescue medications (less than one puff per day) (Frith 2015).

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 corticosteroids 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 corticosteroids and long-acting beta-agonists (Lee 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].

A large UK GP database study found frequent over-prescribing of ‘triple’ therapy in COPD patients without asthma, severe airflow obstruction or history of frequent exacerbations (Brusselle 2015) [evidence level III-2]. This study highlights the importance of commencing bronchodilators as initial pharmacological therapy for patients with symptomatic COPD, before considering adding inhaled steroids (as ICS/LABA inhalers) in patients who have both severe airflow obstruction (FEV1 <50% predicted) AND frequent exacerbations (two or more in the past year) (current PBS criteria).