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).

A Cochrane systematic review of six studies (Rojas-Reyes 2016) comprising 1,902 participants with low risk of bias that compared tiotropium plus LABA/ICS combination therapy versus tiotropium alone found that “triple” therapy decreases hospital admissions (all causes) in comparison with tiotropium alone (assumed risk: 156 per 1,000 vs. 101 per 1,000 OR 0.61 (0.40 to 0.92) n = 961; (2 studies)).

Health-related quality of life measured by SGRQ showed a statistically significant but not clinically significant improvement in total scores with the use of tiotropium plus LABA/ICS compared with tiotropium alone (mean difference (MD) -3.46, 95% CI -5.05 to -1.87; four studies; 1,446 participants. Statistically significant changes in FEV1 with the use of tiotropium plus LABA/ICS compared with tiotropium plus placebo were observed (four studies; 1,678 participants; MD 0.06, 95% CI 0.04 to 0.08); however, the difference in treatment effect on FEV1 was 60 mL and did not reach the MCID. Compared with the use of tiotropium alone, tiotropium plus LABA/ICS-based therapy does not seem to increase adverse effects. Evidence is insufficient to support the benefit of “triple” therapy for mortality or exacerbations (low-quality evidence). Not all people included in these studies had COPD that was severe enough to be recommended “triple” therapy according to current guidelines [evidence level I].

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).

Escalation to ICS/LABA/LAMA in a single inhaler, in patients already taking ICS/LABA, was tested in a 52 week RCT of 1,368 COPD patients who had FEV1 <50% predicted, one or more exacerbations in the last 12 months, and significant dyspnoea and impact of COPD (Singh 2016a) [evidence level II]. Compared to ICS/LABA (beclometasone/formoterol), ICS/LABA/LAMA in a single MDI (beclometasone 100µg/formoterol 6 µg/glycopyrronium 12.5 µg, two inhalations twice daily) improved pre-dose FEV1 by 0.081L (95% CI 0.052-0.109) at week 26, with no difference in dyspnoea score. At week 52, beclometasone/formoterol/glycopyrronium was associated with a reduced rate of moderate-severe exacerbations (rate ratio 0.77, 95% CI 0.65-0.92) and increased proportion of patients having a beneficial improvement in SGRQ (rate ratio 1.33, 95% CI 1.06-1.66). In patients with severe COPD and frequent exacerbations, ICS/LABA/LAMA in a single inhaler may be more beneficial than ICS/LABA. The combination of beclometasone/formoterol/glycopyrronium is not currently available in Australia.

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).