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

Triple therapy may be suitable for patients with moderate to severe COPD and frequent exacerbations, with benefits to outcomes including exacerbation risk, lung function, mortality, and quality of life. However, only some COPD subgroups may achieve a reduction in all-cause mortality from ICS-containing triple therapy, compared to dual bronchodilator combination therapy. Furthermore, ICS-containing regimens could increase the risk of pneumonia, especially among females and those with higher baseline FEV₁ values. Escalation from LABA/LAMA by adding an ICS may be considered for those who are still experiencing persistent COPD symptoms despite optimal LABA/LAMA therapy (see section O4.2.1 ICS/LABA/LAMA vs LABA/LAMA). Similarly, for patients already taking ICS/LABA combination therapy, adding a LAMA may improve quality of life without compromising cardiovascular safety (see section O4.2.2 ICS/LABA/LAMA vs ICS/LABA).

Numerous systematic reviews of RCTs have evaluated 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, Mammen 2020a, Zheng 2018). In a systematic review and Bayesian network meta-analysis of 219 trials involving 228,710 patients with stable COPD, when compared to placebo, all drug classes 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]. A meta-analysis of 11 studies also found triple therapy to reduce the risk of exacerbations compared to dual and monotherapy with a long-acting bronchodilator (relative risk 0.75, 95% CI 0.68 to 0.82); however, ICS/LABA/LAMA also increased the risk of pneumonia (RR 1.48, 95% CI 1.23 to 1.79) (Mammen 2020a) [evidence level I].

Different formulations of single inhaler triple therapy have similar efficacy for reducing exacerbations, as shown in two network meta-analyses (Bourdin 2021, Lee 2021) [evidence level I].