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

More data are becoming available on the efficacy of multiple inhaled medications to guide the best combination that will optimise patient’s lung function, improve symptoms and prevent/ reduce exacerbations.

ICS/LABA plus LAMA

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 (2.15 units St George’s Respiratory Questionnaire (SGRQ)) and reduced rescue medications (less than one puff per day) (Frith 2015).

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 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].

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.

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.

Budesonide/formoterol/glycopyrronium: In patients with severe COPD and frequent exacerbations, ICS/LABA/LAMA may be more beneficial than dual therapies ICS/LABA and LAMA/LABA. In the 24-week KRONOS study, triple therapy (ICS/LABA/LAMA – budesonide/formoterol/glycopyrronium MDI) was compared with dual therapies (ICS/LABA – budesonide/formoterol as MDI or DPI, and LAMA/LABA MDI – glycopyrrolate/formoterol) (Ferguson 2018) [evidence level II]. Triple therapy improved lung function compared to budesonide/formoterol and glycopyrrolate/formoterol. The rate of moderate or severe exacerbations was lower in the triple therapy group.

In patients with moderate-to-very-severe COPD who are at risk of exacerbations, triple therapy with a budesonide–glycopyrrolate–formoterol combination MDI (ETHOS Trial) showed significant benefits over dual therapy with a LAMA–LABA or an ICS–LABA combination with respect to the annual rate of moderate or severe COPD exacerbations (Rabe 2020)  [evidence level II]. The rate was significantly lower with 320-μg–budesonide triple therapy than with glycopyrrolate–formoterol (24% lower: rate ratio 0.76; 95% CI 0.69 to 0.83; P<0.001) or budesonide–formoterol (13% lower: rate ratio 0.87; 95% CI 0.79 to 0.95; P=0.003). The rate was significantly lower also with 160-μg–budesonide triple therapy than with glycopyrrolate–formoterol (25% lower: rate ratio 0.75; 95% CI 0.69 to 0.83; P<0.001) or budesonide–formoterol (14% lower: rate ratio 0.86; 95% CI 0.79 to 0.95; P=0.002).

Triple therapy with a 320-μg dose of budesonide also resulted in a 46% lower all-cause mortality than glycopyrrolate–formoterol group [28 vs 49 deaths; hazard ratio 0.54; 95% CI 0.34 to 0.87].

The incidence of any adverse event was similar across the treatment groups (range 61.7 to 64.5%); the incidence of confirmed pneumonia was higher in the groups that included inhaled glucocorticoid (range 3.5 to 4.5%) than the glycopyrrolate–formoterol group (2.3%).

A network meta-analysis of ETHOS, KRONOS, IMPACT, and TRILOGY studies (n = 21,909) comparing triple ICS/LABA/LAMA FDC with dual LABA/LAMA and ICS/LBA FDCs administered via the same inhaler device in COPD patients (Calzetta 2020) found that regardless of the level of blood eosinophil count at baseline, the triple ICS/LABA/LAMA fixed dose combination (FDC) was the most effective treatment in reducing the risk of exacerbation, compared to LABA/LAMA FDC (RR 0.45, 95% CrI 0.32–0.61, P < 0.05) and ICS/LABA FDC (RR 0.73, 95% CI 0.54–0.99, P < 0.05) [evidence level I]. In patients with low level of blood eosinophil count at baseline, LABA/LAMA and ICS/LABA FDCs were equally effective in preventing exacerbations (RR 1.12, 95%CrI 0.83–1.35, P > 0.05). FDCs including an ICS were affected by an increased risk of pneumonia. No increased cardiovascular risk was detected in the FDCs that included two bronchodilators.

The combinations of both beclometasone/formoterol/glycopyrronium and budesonide/formoterol/glycopyrronium are now available in Australia and have been approved for listing as PBS subsidised medications.

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 an Ellipta dry powder 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/μL, 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.

The results described above are further supported by systematic reviews of randomised controlled trials assessing the effects of fixed and separate inhaled triple therapy versus dual therapy (of LABA and LAMA, LABA and ICS, or LAMA and ICS) or monotherapy (LAMA, LABA, or ICS) (Calzetta 2019, Cazzola 2018b, Zheng 2018). In a meta-analysis of 13 randomised controlled trials including 15,519 patients with COPD (Calzetta 2019) [evidence level I], triple therapy was significantly more effective than the ICS/LABA combination in improving trough FEV₁, HRQoL and dyspnoea, and protecting against the risk of moderate or severe exacerbations, without compromising cardiovascular safety. 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 for protection against the risk of a COPD exacerbation was 26.07 (95% CI, 16.79-152.70).

A network meta-analysis of 14 trials found that ICS/LABA/LAMA combination therapy significantly (p<0.001) reduced the risk of moderate or severe COPD exacerbation compared to LABA/LAMA combination therapy (relative effect 0.70, 95% CrI 0.53–0.94) and single long-acting bronchodilator therapy (relative effect 0.62, 95% CrI 0.48–0.80) (Cazzola 2018b). No significant difference was found for the risk of pneumonia when comparing ICS/LABA/LAMA combination therapy with LABA/LAMA combination therapy (relative effect 1.36, 95% CrI 0.84– 2.00) and single long-acting bronchodilator therapy (relative effect 1.31, 95% CrI 0.76–2.32). Females with COPD seemed to be at higher risk of pneumonia and the risk of pneumonia was greater when the value of FEV₁ was high at enrolment.

In a meta-analysis of 21 trials, triple therapy reduced moderate or severe exacerbations compared to LAMA/LABA (rate ratio 0.78, 95% CI 0.70 to 0.88) or ICS/LABA (rate ratio 0.77, 95% CI 0.66 to 0.91) (Zheng 2018) [evidence level I]. A meta-analysis of two 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 health related quality of life (HRQoL) (Zheng 2018).

A systematic review and Bayesian Network meta-analysis of 219 trials involving 228,710 patients with stable COPD, comparing exacerbation, mortality, and adverse events among all regular inhaled drug classes, including ICS/LAMA/LABA, LAMA/LABA, ICS/LABA, LAMA, LABA, ICS, and placebo found that all drug classes showed significant benefits in reducing total exacerbations, compared to placebo (Lee 2019). Triple therapy was the most effective treatment in reducing total exacerbations (odds ratio [OR] = 0.57; 95% credible interval [CrI] 0.50 to 0.64; and all-cause mortality OR = 0.74, 95% CrI 0.59 to 0.93, P[OR>1] = 0.004 compared to placebo. However, ICS combinations had a high probability of pneumonia in comparison to placebo (OR 1.58 (1.26 to 2) for triple therapy and for ICS/LABA 1.59 (1.36 to 1.91). Different formulations of single inhaler triple therapy (ICS/LABA/LAMA) have similar efficacy for reducing exacerbations, as shown in two network meta-analyses (Bourdin 2021, Lee 2021) [evidence level I]. A meta-analysis of 60 RCTs (103,034 patients) suggested that compared with inhaled therapy without ICS, inhaled therapy containing ICS (Peto OR 0.90; 95% CI 0.84-0.97), especially triple therapy (Peto OR, 0.73; 95% CI, 0.59-0.91) was associated with a reduction in all-cause mortality in patients with COPD. Further subgroup analyses revealed that treatment duration ＞6 months (Peto OR 0.90; 95% CI 0.83-0.97), medium-dose (Peto OR 0.71; 95% CI 0.56-0.91), and low-dose ICSs (Peto OR 0.88; 95% CI 0.79-0.97), and budesonide (Peto OR, 0.75; 95% CI 0.59-0.94) were involved in this association. Eosinophil counts ≥200/μL or percentage ≥2%, documented history of ≥2 moderate and/or severe exacerbations in the previous year, GOLD stage III or IV, age＜65 years, and BMI ≥25 were significant predictors, among which eosinophil count ≥200/μL (Peto OR 0.58; 95% CI 0.36-0.95) was the strongest (Chen 2023) [evidence level I].

Reduction in mortality with triple therapy in the IMPACT and ETHOS studies was mainly observed in the first 3 months after randomization. As all the patients recruited for these two trials were frequent exacerbators, and a proportion had ICS ceased prior to randomisation, it is possible that withdrawal from ICS could have been a factor in the observed difference in mortality in those randomised to receive an ICS-containing preparation (Suissa 2022). Therefore, not all patients with COPD will necessarily achieve a reduction in all-cause mortality as a consequence of ICS-containing triple therapy (Chen 2022) [evidence level I].

In summary, triple therapy results in a lower rate of moderate or severe COPD exacerbations, and better lung function and HRQoL than dual therapies. However, triple therapy did not improve patients’ survival, and could increase the risk of pneumonia, when compared with dual bronchodilator therapy. Therefore, triple therapy should be limited to patients with exacerbations and more severe COPD symptoms that cannot be adequately managed by dual therapy, and to patients with COPD phenotypes most likely to respond to the triple therapy. In patients with COPD already on ICS/LABA combination, the therapy can be improved without increase of cardiovascular adverse events when a LAMA is added to the combination. Triple therapy delivered in a single inhaler is convenient for patients and may improve adherence, but it is non-inferior to the use of multiple inhalers in terms of clinical efficacy.

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, for initiation of triple therapy (ICS/LABA/LAMA) subsidised through the PBS, the patient must have experienced at least one severe COPD exacerbation, which required hospitalisation, or two or more moderate exacerbations in the previous 12 months, with significant symptoms despite regular bronchodilator therapy with a long acting muscarinic antagonist (LAMA) and a long acting beta-2 agonist (LABA) or an inhaled corticosteroid (ICS) and a LABA; OR the patient must have been stabilised on a combination of a LAMA, LABA and an ICS for COPD.