O4.2.1 ICS/LABA/LAMA vs LABA/LAMA

In a meta-analysis of 21 trials, triple therapy reduced moderate or severe exacerbations compared to LABA/LAMA (RR 0.78, 95% CI 0.70 to 0.88) (Zheng 2018) [evidence level I]. Similar findings were seen in a network meta-analysis of 14 trials, which indicated that ICS/LABA/LAMA combination therapy significantly reduced the risk of moderate or severe COPD exacerbation compared to LABA/LAMA combination therapy (relative effect 0.70, 95% CI 0.53–0.94; p<0.001) and single long-acting bronchodilator therapy (relative effect 0.62, 95% CI 0.48–0.80; p<0.001) (Cazzola 2018b) [evidence level I]. Another systematic review and Bayesian network meta-analysis of 219 trials involving 228,710 patients with stable COPD found that compared to placebo, all drug classes (ICS/LABA/LAMA, LAMA/LABA, ICS/LABA, LAMA, LABA, ICS) showed significant benefits in reducing total exacerbations, though triple therapy had the largest benefit (odds ratio [OR] = 0.57; 95% credible interval [CrI] 0.50 to 0.64) (Lee 2019) [evidence level I].

Although triple therapy reduced the risk of exacerbations compared to dual combination therapy and monotherapy with a long-acting bronchodilator in a meta-analysis of 11 studies (relative risk 0.75, 95% CI 0.68 to 0.82), ICS/LABA/LAMA also increased the risk of pneumonia (RR 1.48, 95% CI 1.23 to 1.79) (Mammen 2020a) [evidence level I]. Similarly, the network meta-analysis of ETHOS, KRONOS, IMPACT, and TRILOGY studies found ICS-containing combinations to be associated with an increased risk of pneumonia (Calzetta 2020) [evidence level I]. In another systematic review and Bayesian network meta-analysis of 219 trials involving 228,710 patients with stable COPD, ICS-containing combinations, including triple therapy, had a higher probability of pneumonia compared to placebo (OR 1.58; 95% CI 1.26 to 2) and ICS/LABA (1.59; 95% CI 1.36 to 1.91) (Lee 2019) [evidence level I]. However, findings from a network meta-analysis of 14 trials found no significant difference to pneumonia risk between the ICS/LABA/LAMA combination therapy and LABA/LAMA (relative effect 1.36, 95% CrI 0.84– 2.00). Females with COPD and participants with high FEV₁ at enrolment seemed to be at higher risk of pneumonia (Cazzola 2018b).

Triple therapy was the most effective treatment in reducing all-cause mortality (OR = 0.74, 95% CrI 0.59 to 0.93, P[OR>1] = 0.004) compared to placebo in a systematic review and Bayesian network meta-analysis of 219 trials involving 228,710 patients with stable COPD (Lee 2019) [evidence level I]. Another 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. Subgroup analyses of the Bayesian network meta-analysis 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 the association between ICS-containing therapy and reduced all-cause mortality. 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]. These findings may help identify which patients with COPD might be more likely to achieve a reduction in all-cause mortality because from ICS-containing triple therapy (Chen 2022) [evidence level I].

ICS-containing regimens in the IMPACT trial showed a possible signal towards lower all-cause mortality during treatment than umeclidinium/vilanterol (Lipson 2018) [evidence level II]. However, reduction in mortality with triple therapy in the IMPACT and ETHOS studies was mainly observed in the first 3 months after randomisation. As all the patients recruited for these 2 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).
A Cochrane systematic review of studies of triple therapy (i.e. adding an ICS to combination LABA/LAMA inhalers) compared with LAMA/LABA (dual bronchodilators) for the treatment of stable COPD found that triple therapy may reduce rates of moderate-to-severe COPD exacerbations compared to combination LABA/LAMA inhalers (rate ratio (RR) 0.74, 95% confidence interval (CI) 0.67 to 0.81; n = 15,397; low-certainty evidence) (VanGeffen 2023) [evidence level I]. There may be a greater reduction in rate of moderate-to-severe COPD exacerbations with triple therapy in participants with high-eosinophils (150/200 eosinophils/µL) (RR 0.67, 95% CI 0.60 to 0.75) compared to low-eosinophils (RR 0.87, 95% CI 0.81 to 0.93). There were no clinically significant changes observed for measures of health-related quality of life. Multiple statistical analyses measuring quality of life were undertaken with varying results.

Over the duration of the studies reviewed, triple therapy statistically but not clinically improved SGRQ compared to combination LABA/LAMA inhalers (mean difference (MD) −1.65, 95% CI −2.15 to −1.15; n = 13,879; high-certainty evidence). The proportion of participants who met the MCID threshold was higher amongst those treated with triple therapy (OR 1.35, 95% CI 1.26 to 1.45; n= 14,070; high-certainty evidence) (VanGeffen 2023) [evidence level I]. This highlights the need for clinical review.
In stable COPD, the risk of diagnosed/confirmed pneumonia was probably higher in those treated with triple therapy compared to combination LABA/LAMA inhalers (OR 1.59, 95% CI 1.33 to 1.89; n = 15,412; moderate-certainty evidence) (VanGeffen 2023) [evidence level I]. All-cause serious adverse events were similar between the triple therapy and the LABA/LAMA combination groups (OR 0.95, 95% CI 0.87 to 1.03; n =15,412; low-certainty evidence).

Beclomethasone/formoterol/glycopyrronium vs LABA/LAMA

The TRIBUTE study investigated efficacy of twice daily triple therapy (beclomethasone/formoterol/glycopyrronium) for patients with COPD with severe airflow obstruction and frequent exacerbations. ICS/LABA/LAMA was associated with reduced exacerbations over 52 weeks (rate ratio 0·85, 95% CI 0·72–0·99), compared to once daily indacaterol/glycopyrronium (Papi 2018) [evidence level II]. Pneumonia rates were also similar between triple therapy and LABA/LAMA groups (Papi 2018) [evidence level II].

Budesonide/formoterol/glycopyrronium vs LABA/LAMA

Among people with symptomatic COPD despite receiving 2 or more inhaled maintenance therapies for at least 6 weeks before screening, those in the triple therapy group had fewer moderate or severe exacerbations and improved lung function compared to LABA/LAMA (glycopyrrolate/formoterol MDI) (Ferguson 2018) [evidence level II]. In the ETHOS trial the annual rate of moderate to severe exacerbations favoured both 320μg budesonide triple therapy (24% lower: rate ratio 0.76; 95% CI 0.69 to 0.83; P<0.001) and 160μg budesonide triple therapy (25% lower: rate ratio 0.75; 95% CI 0.69 to 0.83; P<0.001), compared to glycopyrrolate/formoterol (Rabe 2020) [evidence level II].

All-cause mortality in KRONOS was significantly lower for the 320μg budesonide triple therapy group compared to the glycopyrrolate/formoterol group [28 vs 49 deaths; hazard ratio 0.54; 95% CI 0.34 to 0.87] (Ferguson 2018) [evidence level II].
While the incidence of any adverse events was similar across treatment groups in the KRONOS study (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%) (Ferguson 2018) [evidence level II].

Fluticasone furoate/ umeclidinium/vilanterol vs LABA/LAMA

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 umeclidinium/vilanterol group (1.21 per year; rate ratio 0.75; 95% CI 0.70 to 0.81; 25% difference; p<0.001). The annual rate of severe exacerbations (resulting in hospitalisation) was 0.13 in the triple therapy group, significantly lower than the umeclidinium/vilanterol group (0.19 per year; rate ratio 0.66; 95% CI 0.56 to 0.78; 34% difference; p<0.001). The difference between triple therapy and umeclidinium/vilanterol in mean change for trough FEV₁ was significant at 54 mL (95% CI 39 to 69; p<0.001), as were the differences for SGRQ total score (–1.8; 95% CI –2.6 to –1.0, 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 1.26 to 1.57, p<0.001) (Lipson 2018) [evidence level II].

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) (Lipson 2018) [evidence level II].

A network meta-analysis of ETHOS, KRONOS, IMPACT, and TRILOGY studies (n = 21,909 COPD patients) showed that regardless of the level of blood eosinophil count at baseline, ICS/LABA/LAMA significantly reduced the risk of exacerbations compared to LABA/LAMA (RR 0.45, 95% CrI 0.32–0.61, P < 0.05) or ICS/LABA (RR 0.73, 95% CrI 0.54–0.99, P < 0.05) (Calzetta 2020) [evidence level I]. In patients with low level of blood eosinophil count at baseline, LABA/LAMA and ICS/LABA were equally effective in preventing exacerbations (RR 1.12, 95% CrI 0.83–1.35, P > 0.05).

In pre-specified secondary analyses from the IMPACT trial among participants 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 fluticasone furoate/umeclidinium/vilanterol), 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 (Lipson 2018) [evidence level II]. 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 (Lipson 2018) [evidence level II].

For further information on eosinophil count and inhaled corticosteroids, see section O.4.2.5.