Dual and triple therapy in COPD and asthma care

Long-acting beta-agonist (LABA), long-acting muscarinic antagonist (LAMA) and inhaled corticosteroid (ICS) are standard agents used in management of chronic obstructive pulmonary disease (COPD) and asthma. At the Autumn Respiratory Seminar 2022, Professor Wisia Wedzicha of the Imperial College London, UK, discussed current evidence and recommendations regarding the use of dual bronchodilator therapy with a LABA/LAMA combination in patients with COPD as well as when triple therapy with a LABA/LAMA/ICS combination is appropriate in those with poorly controlled symptomatic COPD or asthma.

LABA/LAMA combination as early maintenance therapy in most COPD patients
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023 Report recognizes the central role of long-acting bronchodilators, specifically initial dual therapy with an inhaled LABA/LAMA combination in patients with COPD. As a combination maintenance therapy, LABA/LAMA helps improve lung function and prevent or reduce COPD symptoms and exacerbations. [GOLD 2023 Report, https://goldcopd.org/2023-goldreport-2/]

“Early optimization of bronchodilation with dual therapy is crucial because baseline forced expiratory volume in the first second [FEV₁] influences subsequent decline in lung function among patients with COPD,” explained Wedzicha. “Thus, we have to treat patients earlier to delay COPD progression.” [Am J Respir Crit Care Med 2016;194:178-184]

Single-inhaler IND/GLY as initial LABA/LAMA therapy
Indacaterol/glycopyrronium (IND/GLY), a LABA/LAMA combination, is associated with improved lung function (ie, increased FEV₁) and reduced symptoms and exacerbations vs placebo and monotherapy with either IND or GLY. [Eur Respir J 2013;42:1484-1494] Importantly, single-inhaler therapy with a once-daily dosing regimen may be more effective and convenient vs multiple inhalers. [GOLD 2023 Report, https://goldcopd.org/2023-goldreport-2/; Am J Respir Crit Care Med 2020;201:e56-e69]

“The efficacy and safety of fixed-dose, once-daily combination of IND/GLY 110/50 μg in a single inhaler was demonstrated in the randomized, multicentre, placebo-controlled BLAZE study that included 247 patients aged ≥40 years with moderate-to-severe COPD,” said Wedzicha. “Using a self-administered computerized version of the Baseline and Transition Dyspnoea Index [SAC-TDI] after 6 weeks, the study showed a significantly higher SAC-TDI total score with IND/GLY [110/50 μg QD] vs placebo [least square mean (LSM) treatment difference, 1.37; p<0.001] and LAMA monotherapy [tiotropium (TIO) 18 μg QD; LSM treatment difference, 0.49; p=0.021]. IND/GLY therapy also significantly improved FEV₁ area under the curve from 0 hours to 4 hours postdose vs TIO and placebo at day 1 and week 6 [p<0.001 for all].” [Eur Respir J 2014;43:1599-1609]

“In the randomized, double-blind, parallel-group SPARK study, IND/GLY [110/50 μg QD; n=741] significantly reduced the rate of moderate-to-severe exacerbations vs GLY monotherapy [50 μg QD; n=742] by 12 percent [rate ratio, 0.88; 95 percent confidence interval (CI), 0.77–0.99; p=0.038] in patients aged ≥40 years with severe or very severe COPD,” said Wedzicha. “The incidence of adverse events [AEs] was similar in all treatment groups.” [Lancet Respir Med 2013;1:199-209]

“Earlier guidelines recommended a LABA/ICS combination as an option for COPD patients at high risk of exacerbations,” she continued. “However, the 52-week, randomized, double-blind, noninferiority FLAME trial demonstrated not only noninferiority, but also superiority, with fixed-dose IND/GLY QD vs salmeterol plus fluticasone [SAL/FLU] BID in reducing the annual rate of all COPD exacerbations [rate ratio, 0.89; 95 percent CI, 0.83–0.96; p=0.003] in patients with a history of ≥1 exacerbation in the previous year.” [N Engl J Med 2016;374:2222-2234]

Elevated blood eosinophil count (BEC) has been recognized as a useful biomarker to help identify COPD patients who are more likely to benefit from an ICS-containing regimen. [GOLD 2023 Report, https://goldcopd.org/2023-gold-report-2/] However, the reduction in COPD exacerbation rates associated with IND/GLY vs SAL/FLU was independent of patients’ baseline BEC in the FLAME trial (BEC <2 percent: rate ratio, 0.80; 95 percent CI, 0.68–0.93; p=0.004) (BEC ≥2 percent: rate ratio, 0.85; 95 percent CI, 0.75–0.96; p=0.01). [N Engl J Med 2016;374:2222-2234]

Despite similar rates of AEs and deaths in both treatment groups in FLAME, pneumonia rate was significantly higher in the SAL/FLU vs IND/GLY group (4.8 percent vs 3.2 percent; p=0.02). Increased risk of pneumonia should thus be anticipated with ICS-containing regimens for COPD. [N Engl J Med 2016;374:2222-2234; GOLD 2023 Report, https://goldcopd.org/2023-gold-report-2/]

Results from these studies support the concept of dual bronchodilation with initial fixed-dose LABA/LAMA combination therapy for COPD. [GOLD 2023 Report, https://goldcopd.org/2023-goldreport-2/; Am J Respir Crit Care Med 2020;201:e56-e69]

Role of ICS in COPD
“There are certain scenarios where adding an ICS to a LABA/LAMA combination may be beneficial in COPD,” Wedzicha commented.

In patients with dyspnoea or exercise intolerance despite dual therapy with a LABA/LAMA combination, the American Thoracic Society conditionally recommends triple therapy with LABA/LAMA/ICS if the patients also experienced ≥1 exacerbation in the past year requiring antibiotics, oral steroids or hospitalization. [Am J Respir Crit Care Med 2020;201:e56-e69]

Patients with BEC ≥300 cells/μL in conjunction with other factors (eg, former smokers, ≥2 moderate exacerbations or ≥1 severe exacerbation in the prior year) are also likely to benefit from the addition of ICS to bronchodilation for exacerbation prevention. [GOLD 2023 Report, https://goldcopd.org/2023-gold-report-2/; Eur Respir J 2020;55:2000881; Am J Respir Crit Care Med 2020;201:e56-e69] Factors to consider when adding an ICS in COPD management are summarized in the Table.

“Since there are several factors [eg, smoking] to consider regarding the addition of ICS to long-acting bronchodilator maintenance therapy in patients with COPD, treatment decisions should be individualized,” stressed Wedzicha. (Table)

“Matching the appropriate inhaler device especially in elderly patients, as well as understanding the relationship between drug formulation and delivery should also be considered to optimize bronchodilation therapy before adding ICS,” she commented.

LABA/LAMA/ICS reduces exacerbations vs LABA/ICS in uncontrolled asthma
Triple therapy containing fixed-dose IND/GLY/mometasone furoate (MF) (150/50/160 μg) QD in a single inhaler is currently approved by the European Commission for use in adults with severe asthma uncontrolled with medium- or high-dose LABA/ICS, and recommended by the Global Initiative for Asthma (GINA) 2022 Report. [GINA 2022 Report, https://ginasthma.org/gina-reports/; Expert Rev Respir Med 2022;16:183-195] The indication and recommendation are supported by results of the phase III IRIDIUM and ARGON trials. [Lancet Respir Med 2020;8:1000-1012; Respir Med 2020;170:106021]

The randomized, double-blind, double-dummy, parallel-group phase III IRIDIUM study assessed the efficacy and safety of medium- or high-dose IND/GLY/MF (80/150/50 μg; 150/50/160 μg QD) vs medium- or high-dose IND/MF (160/150 μg; 320/150 μg QD) and high-dose SAL/FLU (50/500 μg BID) in 3,092 adult patients with inadequately controlled asthma despite medium- or high-dose LABA/ICS who had ≥1 exacerbation in the previous year and <80 percent of predicted FEV₁. [Lancet Respir Med 2020;8:1000-1012]

At week 26, both medium- and high-dose IND/GLY/MF demonstrated superior improvements in trough FEV₁ vs corresponding IND/MF doses (medium-dose group: treatment difference, 76 mL; p<0.001) (high-dose group: treatment difference, 65 mL; p<0.001) and vs SAL/FLU (medium-dose group: treatment difference, 99 mL; p<0.001) (high-dose group: treatment difference, 119 mL; p<0.001).

“IND/GLY/MF also significantly reduced exacerbation rates vs SAL/FLU after 1 year across asthma severities,” added Wedzicha. (Figure) The incidence of AEs was well balanced across the treatment groups. Seven deaths reported during the study were not considered to be related to the treatment or study.

In the randomized, phase IIIb, noninferiority ARGON study, the efficacy and safety of fixed-dose combinations of medium- and high-dose IND/GLY/MF QD were compared with high-dose SAL/FLU BID plus TIO (5 μg QD; added separately) for 24 weeks in adult patients with uncontrolled asthma (Asthma Control Questionnaire-7 score, ≥1.5) despite treatment with medium- or high-dose LABA/ICS. [Respir Med 2020;170:106021]

Results showed that medium- and high-dose IND/GLY/MF regimens were noninferior to SAL/FLU plus TIO for Asthma Quality of Life Questionnaire score (treatment differences: -0.038 and 0.073, respectively; p<0.001 for both comparisons). High-dose IND/GLY/MF significantly improved lung function, with a 96 mL increase in trough FEV₁ vs SAL/FLU plus TIO at week 24 (p<0.001).

“Importantly, there was a significant 43 percent reduction in annualized rate of moderate exacerbations associated with high-dose IND/GLY/MF vs SAL/FLU plus TIO [p=0.042],” highlighted Wedzicha.

These results show that triple LABA/LAMA/ICS combination may be an effective and safe option for patients with severe asthma inadequately controlled with a LABA/ICS combination.

Summary
Dual bronchodilation with a LABA/LAMA combination (eg, fixed-dose IND/GLY in a single inhaler) is an effective and safe initial strategy in most patients with COPD, demonstrating efficacy in improving lung function and symptoms and preventing exacerbations. Triple therapy with a LABA/LAMA/ICS combination may be considered for reducing exacerbation risk in certain patients with COPD, specifically those with elevated BEC and severe disease. Meanwhile, a single-inhaler containing fixed-dose LABA/LAMA/ICS (ie, IND/GLY/MF) may be effective in reducing exacerbations among patients with uncontrolled asthma despite LABA/ICS therapy.