Long-acting muscarinic antagonist (LAMA)/long-acting beta2-agonist (LABA)/inhaled corticosteroid (ICS) versus LAMA/LABA in patients with symptomatic COPD

Long-acting muscarinic antagonist (LAMA)/long-acting beta2-agonist (LABA)/inhaled corticosteroid (ICS) versus LAMA/LABA in patients with symptomatic chronic obstructive pulmonary disease (COPD)

Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2024 strategy report recommends (1)

• a stepwise approach to pharmacologic treatment, starting with a long-acting muscarinic antagonist (LAMA) or long-acting beta2-agonist (LABA) for most patients with COPD, and escalating to dual bronchodilation as the next step.
• for patients who are highly symptomatic (eg, COPD Assessment Test score >20) and have a history of exacerbations (≥2 moderate exacerbations or ≥1 leading to hospitalisation), LAMA/LABA dual therapy is recommended as initial treatment
• recommends triple therapy with LAMA/LABA/ICS as initial treatment for patients who are at an increased risk of exacerbations and have blood eosinophil levels ≥300 cells/microlitre and as follow-up for patients with increased exacerbation risk despite treatment with LABA/ICS or LAMA/LABA and with blood eosinophil levels ≥100 cells/microlitre.

There is study evidence of a lower mortality rate during treatment with long-acting muscarinic antagonist (LAMA)/long-acting beta2-agonist (LABA)/inhaled corticosteroid (ICS) versus LAMA/LABA in patients with symptomatic chronic obstructive pulmonary disease (COPD) and a history of exacerbations (2,3):

• analysis of the IMPACT (Informing the Pathway of Chronic Obstructive Pulmonary Disease Treatment) trial (2)
  • this study demonstrated a significant reduction in all-cause mortality (ACM) risk with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus UMEC/VI in patients with chronic obstructive pulmonary disease (COPD) at risk of future exacerbations
  • secondary analysis of an efficacy outcome from the IMPACT trial, once-daily single-inhaler FF/UMEC/VI triple therapy reduced the risk of ACM versus UMEC/VI in patients with symptomatic COPD and a history of exacerbations
• study compared triple fixed-dose of an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting beta2-agonist (LABA) for chronic obstructive pulmonary disease (COPD) - study examined use of inhaled glucocorticoid at two dose levels (3)
  • showed triple therapy with twice-daily budesonide, glycopyrrolate, and formoterol resulted in a lower rate of moderate or severe COPD exacerbations than glycopyrrolate-formoterol or budesonide-formoterol
• was noted by Miravitlles et al that "..neither of these trials were designed or powered for mortality; furthermore, they only enrolled patients with highly symptomatic COPD and a high risk of future exacerbations and, as such, they are not representative of the majority of patients, who have moderate COPD and are infrequent exacerbators.."

A pooled analysis of over 6000 patients with mild-to-very-severe COPD and predominantly low exacerbation risk showed no differences in mortality with LAMA/LABA versus LAMA/LABA/ICS, suggesting that the survival benefit of triple therapy seen in some recent studies may be specific to a high-risk population (4)

• this supports current Global Initiative for Chronic Obstructive Lung Disease recommendations that triple therapy should be reserved for the subpopulations of patients who need it the most (eg, those with an eosinophilic phenotype and a high risk of exacerbations) to avoid ICS overuse

Reference:

1. Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2024. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease
2. Lipson DA, Crim C, Criner GJ, et al. Reduction in all-cause mortality with fluticasone furoate/umeclidinium/vilanterol in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2020;201(12):1508–1516. doi: 10.1164/rccm.201911-2207OC
3. Rabe KF, Martinez FJ, Ferguson GT, et al. Triple inhaled therapy at two glucocorticoid doses in moderate-to-very-severe COPD. N Engl J Med. 2020;383(1):35-48. doi: 10.1056/NEJMoa1916046
4. Miravitlles M, Verhamme K, Calverley PMA, Dreher M, Bayer V, Gardev A, de la Hoz A, Wedzicha J, Price D. A Pooled Analysis of Mortality in Patients with COPD Receiving Dual Bronchodilation with and without Additional Inhaled Corticosteroid. Int J Chron Obstruct Pulmon Dis. 2022 Mar 11;17:545-558.