O4.2.2 ICS/LABA/LAMA vs ICS/LABA

In a meta-analysis of 21 trials, triple therapy reduced moderate or severe exacerbations compared to ICS/LABA (RR 0.77, 95% CI 0.66 to 0.91) (Zheng 2018) [evidence level I]. Similar findings were observed in a meta-analysis of 13 RCTs including 15,519 patients with COPD, where the number needed to treat to protect against risk of exacerbation for ICS/LABA/LAMA combination versus ICS/LABA was 26.07 (95% CI, 16.79-152.70) (Calzetta 2019) [evidence level I]. Triple therapy was also significantly more effective than the ICS/LABA combination in improving trough FEV₁, HRQoL and dyspnoea. The NNT for a ≥100-mL increase from baseline in trough FEV₁ of ICS/LABA/LAMA combination versus ICS/LABA combination was 3.97 (95% CI, 3.25-5.13) and (Calzetta 2019) [evidence level I].A separate Cochrane systematic review found that combining tiotropium + LABA/ICS versus tiotropium alone showed no significant difference in hospital admission risk (2 studies; 961 participants; OR 0.84, 95% CI 0.53 to 1.33; I² = 0%). However, the quality of evidence for this outcome is low because of the risk of bias in included studies and imprecision of the effect estimates [evidence level I] (Rojas-Reyes 2016) [evidence level I].

There were also significant changes in FEV₁ between the tiotropium + ICS/LABA and tiotropium + placebo groups (4 studies; 1,678 participants; MD 0.06, 95% CI 0.04 to 0.08), though the average benefit observed (60 mL) did not reach the MCID. Compared to tiotropium alone, tiotropium + ICS/LABA-based therapy did not seem to increase adverse effects. 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] (Rojas-Reyes 2016) [evidence level I].

Further, combining tiotropium + LABA/ICS led to a statistically significant but not clinically significant improvement in HRQoL (measured by total SGRQ score) compared to tiotropium alone (mean difference (MD) -3.46, 95% CI -5.05 to -1.87; 4 studies; 1,446 participants) [evidence level I] (Rojas-Reyes 2016) [evidence level I].

Salmeterol/fluticasone propionate + glycopyrronium or tiotropium

A two-year double-blind, double dummy randomised controlled trial comparing tiotropium and combination therapy with fluticasone/salmeterol (500/50μg bd) found that while ICS/LABA + LAMA combination did not decrease exacerbation rates compared to tiotropium alone, it did achieve a small, statistically significant benefit to quality of life and an unexpected benefit of fewer deaths (Wedzicha 2008) [evidence level II].

In the GLISTEN study, adding glycopyrronium or tiotropium to salmeterol/fluticasone propionate demonstrated statistically significant improvements to FEV₁ (101 mL at 12 weeks) compared to the control arm (placebo + salmeterol/fluticasone propionate) and resulted in a statistically but not clinically significant change in health status (2.15 units SGRQ) (Frith 2015) [evidence level II].

Beclomethasone/formoterol/glycopyrronium vs ICS/LABA

In the 52-week RCT TRILOGY study, n=1,368 participants on existing ICS/LABA therapy were escalated to ICS/LABA/LAMA triple therapy in a single inhaler (beclomethasone 100µg/formoterol 6 µg/glycopyrronium 12.5 µg, 2 inhalations twice daily). Participants were eligible if they had COPD, FEV₁ <50% predicted, one or more exacerbations in the last 12 months, and significant dyspnoea and impact of COPD. At week 52, triple therapy 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). Compared to ICS/LABA (beclomethasone/formoterol), triple therapy improved pre-dose FEV₁ by 0.081 L (95% CI 0.052-0.109) at week 26, with no difference in dyspnoea score (Singh 2016a) [evidence level II].

Budesonide/formoterol/glycopyrronium vs ICS/LABA

In the 24-week KRONOS study, participants in the triple therapy group had fewer moderate or severe exacerbations and improved lung function compared to ICS/LABA (budesonide/formoterol MDI or DPI) among people with symptomatic COPD despite receiving 2 or more inhaled maintenance therapies for at least 6 weeks before screening (Ferguson 2018) [evidence level II].

The ETHOS trial evaluated patients with moderate-to-very-severe COPD who are at risk of exacerbations, given either triple therapy (budesonide/formoterol/glycopyrronium MDI including 320 320μg budesonide or 160μg budesonide) or a LABA/LAMA or ICS/LABA combination (Rabe 2020) [evidence level II]. Compared to budesonide/formoterol, the annual rate of moderate to severe exacerbations favoured both 320μg budesonide triple therapy (13% lower: rate ratio 0.87; 95% CI 0.79 to 0.95; P=0.003). and 160μg budesonide triple therapy (14% lower: rate ratio 0.86; 95% CI 0.79 to 0.95; P=0.002) (Rabe 2020) [evidence level II].

Fluticasone furoate/ umeclidinium/vilanterol vs ICS/LABA

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) for moderate to severe COPD, administered by once daily via an Ellipta dry powder single inhaler (Lipson 2018) [evidence level II]. Triple therapy demonstrated a significantly lower rate of moderate or severe COPD exacerbations (0.91 per year) compared to the fluticasone furoate/vilanterol group (1.07 per year; rate ratio 0.85; 95% CI 0.80 to 0.90; 15% difference; p<0.001). The difference in mean change for trough FEV₁ between triple therapy and fluticasone furoate/vilanterol was 97 mL (95% CI 85 to 109; p<0.001). There was also a significant differences between the triple therapy group and the fluticasone furoate/vilanterol group in the mean change from baseline in the SGRQ total score (–1.8; 95% CI –2.4 to –1.1, 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; 95% CI 1.29 to 1.55, p<0.001) (Lipson 2018) [evidence level II]. The adverse event profile of triple therapy was similar to that of the dual therapy comparators, though incidence of pneumonia was higher in the ICS groups than in the umeclidinium/vilanterol group.

Similar findings are seen from the 24-week FULFIL RCT, where 1,810 patients with moderate to severe COPD were either given once daily fluticasone furoate/umeclidinium/vilanterol in a single inhaler or twice daily budesonide/formoterol (Lipson 2017). Once daily triple therapy fluticasone furoate/umeclidinium/vilanterol reduced exacerbation rates (rate ratio 0.65, 95% CI 0.49 to 0.86), 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) compared to twice daily budesonide/formoterol (Lipson 2017) [evidence level II].

O4.2.3 Fixed vs open triple therapy

More data are becoming available on different drug combinations and regimens, including open triple therapy (multiple inhalers collectively containing ICS, LAMA, and LABA) and fixed triple therapy (a fixed-dose single triple therapy inhaler containing ICS/LABA/LAMA).

The TRINITY study evaluated the fixed triple therapy (extra-fine beclomethasone dipropionate, formoterol fumarate and glycopyrronium bromide; n=1078) against open triple therapy (tiotropium with combination beclomethasone dipropionate and formoterol fumarate; n=538) and tiotropium alone (n=1075 control) (Vestbo 2017) [evidence level II]. The adjusted mean changes from baseline in pre-dose FEV₁ at week 52 of TRINITY 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 (Vestbo 2017) [evidence level II]. 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, meaning fixed triple was superior to tiotropium (adjusted RR 0·80, 95% CI 0·69 to 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 to 0·95; p=0·0208) and was similar for fixed triple and open triple (1·05 [0·70–1·56]; p=0·82) (Vestbo 2017) [evidence level II]. The incidence of adverse events (55 to 58%), serious adverse events (13 to 15%) and pneumonia (1 to 2%) were similar across the fixed triple, open triple, and control groups (Vestbo 2017) [evidence level II]. A meta-analysis of 2 trials (Bremner 2018, Vestbo 2017) directly comparing fixed triple therapy with separate triple therapy found no statistically significant associations for all the outcomes, including exacerbations of COPD, lung function, adverse events and HRQoL (Zheng 2018).

O4.2.4 Prescribing and availability

Triple therapy prescribing has been increasing since 2016. Retrospective analysis of de-identified administrative data from the US between 2013 and 2018 found that almost three-quarters of patients with COPD who were prescribed triple therapy did not meet guideline recommendations pertaining to prior maintenance therapy and/or exacerbations. Relative to patients prescribed open triple therapy (multiple inhalers collectively containing ICS, LAMA, and LABA), those prescribed closed triple therapy (a fixed-dose single triple therapy inhaler containing fluticasone furoate/umeclidinium/vilanterol) were more likely not to have used ICS, LAMA or LABA and/or their combinations (i.e. maintenance inhaler naïve) and to have no evidence of at least 2 moderate or one severe exacerbation prior to initiating triple therapy. This guideline-discordant prescribing behaviour occurred more often among generalist-specialty prescribers than pulmonologists. Increasing prescriber awareness of guideline recommendations is warranted to counter the continuing overprescribing of triple therapy in individuals with COPD (Bhatt 2022) [evidence level III-2].

In Australia, the fixed-dose triple therapy combination ICS/LABA/LAMA that are subsidised through the PBS (also eligible for 60-day prescriptions) include:

However, access to these subsidised medications on the PBS are subject to certain criteria. To be eligible for PBS-subsidised triple therapy (ICS/LABA/LAMA), patients must have experienced:

  • at least one severe COPD exacerbation, which required hospitalisation, or 2 or more moderate exacerbations in the previous 12 months, with significant symptoms despite regular bronchodilator therapy with a LAMA and a LABA or an ICS and a LABA:
    OR
  • the patient must have been stabilised on a combination of a LAMA, LABA and an ICS for COPD.