O4.2 Inhaled corticosteroids and long-acting beta2-agonists and long-acting antimuscarinics in combination (ICS/LABA/LAMA)

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 (500/50 μg 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 (Rojas-Reyes 2016) that compared tiotropium plus LABA/ICS combination therapy versus tiotropium found no significant difference in risk of hospital admission with the use of tiotropium + LABA/ICS (two studies; 961 participants; OR 0.84, 95% CI 0.53 to 1.33; I2 = 0%); the quality of evidence for this outcome is low because of the risk of bias in included studies and imprecision of the estimates of effect [evidence level I].

Health-related quality of life (HRQoL) 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 (101 ml 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).

ICS/LABA/LAMA – single inhaler triple therapy

Beclometasone/formoterol/glycopyrronium: The TRINITY study evaluated the use of extra-fine beclometasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium bromide BDP/FF/GB (fixed triple) (n=1078) compared to tiotropium, with a free combination of BDP/FF in one inhaler (n=538) and tiotropium (n=1075) in a second inhaler as a control (Vestbo 2017). The rates of moderate to severe COPD exacerbations were 0·46 (0·41–0·51) per patient per year for fixed triple, 0·57 (0·52–0·63) for tiotropium, and 0·45 (0·39–0·52) for open triple. Extra-fine particle fixed triple was superior to tiotropium, with an adjusted rate ratio (RR) of 0·80 (95% CI 0·69–0·92; p=0·0025). The time to first severe exacerbation was prolonged with fixed triple compared with tiotropium (HR 0·70 [95% CI 0·52–0·95]; p=0·0208), and was similar for fixed triple and open triple (1·05 [0·70–1·56]; p=0·82). The adjusted mean changes from baseline in pre-dose FEV1 at week 52 were 0·082 L (95% CI 0·065 to 0·100) for fixed triple, 0·021 L (0·003 to 0·039) for tiotropium and 0·085 L (0·061 to 0·110) for open triple. The incidence of adverse events (55 to 58%), including serious adverse events (13 to 15%) and pneumonia (1 to 2%) were similar across the three groups.

In the TRILOGY study, 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 0.081 L (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.

In the TRIBUTE study of COPD patients with severe airflow obstruction and frequent exacerbations, ICS/LABA/LAMA in a single MDI (beclometasone/formoterol/glycopyrronium, twice daily) was associated with reduced exacerbations over 52 weeks (rate ratio 0·85, 95% CI 0·72–0·99), compared to once daily LABA/LAMA (indacaterol/glycopyrronium) (Papi 2018) [evidence level II]. Pneumonia rates were similar.

Fluticasone furoate/umeclidinium/vilanterol: In a 24-week RCT of 1,810 patients with moderate to severe COPD, once daily fluticasone furoate/umeclidinium/vilanterol in a single inhaler was compared to twice daily budesonide/formoterol (Lipson 2017). Fluticasone furoate/umeclidinium/vilanterol improved FEV1 (mean difference 171 ml, 95% CI 148 to 194) and SGRQ total score (mean difference -2.2 units, 95% CI -3.5 to -1.0), and reduced exacerbation rates (rate ratio 0.65, 95% CI 0.49 to 0.86), supporting some benefits of single inhaler triple therapy.

The IMPACT trial (n=10,355) compared triple therapy (ICS/LABA/LAMA – fluticasone furoate, umeclidinium and vilanterol) with dual therapies using the same molecules (ICS/LABA and LAMA/LABA), all administered once-daily via a single-inhaler (Lipson 2018).  This demonstrated a significantly lower rate of moderate or severe COPD exacerbations – 0.91 per year, as compared with 1.07 per year in the fluticasone furoate–vilanterol group (rate ratio with triple therapy, 0.85; 95% CI 0.80 to 0.90; 15% difference; p<0.001) and 1.21 per year in the umeclidinium–vilanterol group (rate ratio with triple therapy, 0.75; 95% CI 0.70 to 0.81; 25% difference; p<0.001).  The annual rate of severe exacerbations (resulting in hospitalisation) in the triple therapy group was 0.13, as compared with 0.19 in the umeclidinium–vilanterol group (rate ratio 0.66; 95% CI 0.56 to 0.78; 34% difference; p<0.001). Overall, the adverse-event profile of triple therapy was similar to that of the dual therapy comparators. Incidence of pneumonia was higher in the ICS groups than in the umeclidinium–vilanterol group, and the risk of clinician-diagnosed pneumonia was also significantly higher with triple therapy than with umeclidinium–vilanterol (hazard ratio 1.53; 95% CI 1.22 to 1.92; p<0.001).

The difference in the mean change in trough FEV1 between the triple therapy and fluticasone furoate–vilanterol groups was 97 ml (95% CI 85 to 109; p<0.001), and the difference between the triple therapy and umeclidinium–vilanterol groups was 54 ml (95% CI 39 to 69; p<0.001). There were significant differences between the triple therapy group and the fluticasone furoate–vilanterol and umeclidinium–vilanterol groups in the mean change from baseline in the SGRQ total score (–1.8 [–2.4 to –1.1] and –1.8 [–2.6 to –1.0], respectively; both p<0.001) and in the percentage of patients who had a response as defined by a decrease in the SGRQ total score of at least 4 points (1.41 [1.29 to 1.55] and 1.41 [1.26 to 1.57], respectively; both p<0.001).  ICS regimens also showed a possible signal toward lower all-cause mortality during treatment than umeclidinium–vilanterol.

In pre-specified secondary analyses of patients with eosinophil levels <150 cells/μL, the annual rate of moderate or severe exacerbations was 0.85 (95% CI 0.80 to 0.91) with triple therapy, 1.06 (95% CI 0.99 to 1.14) with fluticasone furoate–vilanterol and 0.97 (95% CI 0.88 to 1.07) with umeclidinium–vilanterol. Among patients with eosinophil levels of at least 150 cells per microlitre, the annual rate was 0.95 (95% CI 0.90 to 1.01) with triple therapy, 1.08 (95% CI 1.02 to 1.14) with fluticasone furoate–vilanterol, and 1.39 (95% CI 1.29 to 1.51) with umeclidinium–vilanterol.

In Australia, for initiation of triple therapy (ICS/LABA/LAMA) subsidised through the PBS, the patient must have a post-bronchodilator FEV1 <50% of predicted normal prior to therapy, AND must have a history of repeated exacerbations (2 or more) with significant symptoms despite regular bronchodilator therapy with a LAMA/LABA or an ICS/LABA OR the patient must have been stabilised on a combination of a LAMA, LABA and an ICS for COPD.

Harrison et al reviewed inhaled corticosteroid (ICS) prescription in 711 outpatients with spirometry- confirmed COPD at an Australian tertiary hospital and found that 52.4% of patients were prescribed an ICS despite a post-bronchodilator FEV1 ≥ 50% which is inconsistent with COPD-X recommendations (Harrison 2017). The study did not consider other guideline criteria such as recurrent exacerbations. Several UK GP database studies have demonstrated overprescribing of ICS in COPD (Brusselle 2015, Price 2014, White 2013). Price et al examined inhaler use in primary care in UK in over 3,000 patients with spirometry confirmed COPD. Over 50% of patients who did not qualify for ICS based on GOLD guidelines were inappropriately prescribed ICS (Price 2014). Under treatment was reported in 17% of patients. A similar study, also in primary care in the UK reported over prescription of ICS in approximately 35% of patients (White 2013). Conversely, only 8% of patients were under treated. These studies highlight the importance of commencing bronchodilators as initial pharmacological therapy for patients with symptomatic COPD, before considering adding inhaled steroids in patients who have both moderate to severe airflow limitation (FEV1 <50% predicted) and frequent exacerbations (two or more in the past year) (current PBS criteria).