Open-inhaler versus single-inhaler triple therapy (long-acting muscarinic antagonist, inhaled corticosteroid, and long-acting β₂-agonist) in asthma patients: a narrative review

Abstract

Objective

To review the evidence for the use of open-inhaler (inhaled corticosteroid [ICS] plus long-acting β₂-agonist [LABA] with separate add-on long-acting muscarinic antagonist [LAMA]) versus single-inhaler triple therapy (ICS/LABA/LAMA combination) and the merits of add-on LAMA to ICS/LABA in patients with uncontrolled asthma.

Data Sources

Original research articles were identified from PubMed using the search term “triple therapy asthma.” Information was also retrieved from the ClinicalTrials.gov website.

Study Selections

Articles detailing the use of add-on LAMA to ICS plus LABA (open-inhaler triple therapy), and closed triple therapy compared with ICS plus LABA dual therapy, addressing patient symptoms, exacerbations, and health-related quality of life.

Results

Open-inhaler triple therapy was associated with a significantly reduced incidence of hospitalizations and emergency department visits and a decrease in ICS dose, oral corticosteroids use, and antibiotics use. Exacerbations and acute respiratory events were also reduced. Single-inhaler triple therapy showed a greater improvement in lung function, asthma control, and health status and was noninferior to open-inhaler triple therapy for Asthma Quality of Life Questionnaire scores. Single-inhaler triple therapy may also lead to improved therapy adherence.

Conclusion

Add-on LAMA to ICS plus LABA (open- or single-inhaler triple therapy) improves the response in patients who remain symptomatic and provides a reasonable alternative to ICS dose escalation in treatment-refractory patients.

Keywords:

• Asthma
• management
• open-inhaler triple therapy
• single-inhaler triple therapy

Introduction

Asthma affects approximately 26 million physician-diagnosed patients in the United States (US) and more than 358 million individuals of all age groups globally. It is predicted that by 2025, >458 million people will be diagnosed with asthma (1–3). The economic burden of asthma is substantial and has increased in recent years, with predictions of an estimated increase to $963 billion over the next 2 decades (2).

Controlling symptoms and reducing the risk of future exacerbations are the primary targets of appropriate asthma management and preservation of lung function (2). Current treatment recommendations follow a stepwise approach, with inhaled corticosteroids (ICSs) plus formoterol (a long-acting β₂-agonist [LABA]) being the preferred management options (4). Despite optimal treatment adherence, approximately 30%–50% of patients treated with ICS plus LABA have uncontrolled asthma (5). Uncontrolled asthma has been associated with markedly reduced health-related quality of life (HRQoL) and an increase in exacerbations, use of rescue inhalers and systemic corticosteroids, healthcare resource utilization (HCRU), emergency department visits, hospitalizations, and number of deaths compared with well-controlled asthma (5,6). When asthma control is not achieved, increasing the ICS dosage or adding other bronchodilator treatments, such as a long-acting muscarinic antagonist (LAMA), and biologic agents are recommended options (4,7).

ICS dose escalation may not improve asthma control in all asthma patient phenotypes (e.g. those with low eosinophil levels) (8). LAMA as an add-on to ICS plus LABA (triple therapy) is recommended by both the Global Initiative for Asthma (GINA) strategy document and the National Asthma Education and Prevention Program (NAEPP) guidelines before escalating to biologic agents or oral corticosteroids (OCS) (7,9). Use of open triple therapy (i.e. ICS plus LABA with separate add-on LAMA) is supported by evidence demonstrating a reduced number of exacerbations and improved pulmonary function in patients with poorly controlled asthma (9,10). Single-inhaler triple therapy (ICS/LABA/LAMA given in a combined inhaler, also known as closed-inhaler therapy) has shown consistent efficacy on pulmonary function compared with ICS plus LABA, while benefits on exacerbations were less clear and may be dependent on factors such as ICS dose, blood eosinophil count, and lung function reversibility (9).

In this review, we aim to summarize evidence for the use of open-inhaler versus single-inhaler triple therapy and the value of add-on LAMA to ICS/LABA in patients with uncontrolled asthma. Notably, use of LAMA in some of the studies included in this review is not in accordance with US Food and Drug Administration (FDA)-approved labels. The GINA 2022 report and 2020 NAEPP guidelines do not specify the LAMA and dose to be used for asthma treatment; hence, it is recommended that clinicians follow the approved label for each product when prescribing a LAMA to patients with asthma.

Patient phenotyping and precision medicine

Asthma pathophysiology is often divided into two major pathways: a type 2 high endotype with increased allergic or eosinophilic airway inflammation and a non type 2/type 2 low endotype with either neutrophilic or paucigranulocytic airway inflammation (11). Despite being distinct forms of asthma, allergic and non-allergic asthma phenotypes overlap in the underlying inflammatory process and clinical presentation (11). Regardless of the similarity of clinical symptoms, patients may respond differently to the same treatment (11).

Precision medicine explores specific phenotypes for targeted treatments and consequently better outcomes (12). In asthma patients, there is an urgent need to unveil specific molecular phenotypes (11). Patients with a ≥2% sputum eosinophil level show increases in forced expiratory volume in 1 s (FEV₁) with the use of ICS, whereas those with a low (<2%) eosinophil level may not respond to ICS therapy (13). In the Clinical Study in Asthma Patients Receiving Triple Therapy in a Single Inhaler (CAPTAIN), ICS escalation reduced the exacerbation rate and improved lung function in inadequately controlled moderate or severe asthma patients with elevated baseline eosinophil levels (T2 high endotype), while no improvements were registered for patients with low eosinophil levels (T2 low endotype). Conversely, the improvement in lung function observed with the addition of LAMA seemed to be independent of the patient’s blood eosinophil levels (8,14,15). Thus, ICS dose escalation should be considered according to the patient’s T2 phenotype and the possibility of ICS side effects with little efficacy gain (16). These preliminary results indicate that phenotype stratification in asthma patients can help guide proper treatment (8).

Add-on LAMA to ICS plus LABA (open-inhaler triple therapy) versus ICS plus LABA

The 2022 GINA report recommends low-dose ICS-formoterol as the preferred controller treatment for adults and adolescents at steps 1 and 2 and low-, medium-, and high-dose ICS-formoterol as the preferred controller treatments for adults and adolescents at steps 3, 4, and 5, respectively (4). The GINA report has recommended the use of ICS-formoterol since 2019 as the preferred rescue option for any level of asthma severity, except when patients are using ICS plus LABA in combination as a controller (4). Add-on LAMA is currently recommended for patients at step 5 (4). LAMAs are used for the long-term treatment of asthma. The 2020 NAEPP guidelines recommend LAMAs as add-on to ICS plus LABA and as add-on to ICS controller therapy in patients with uncontrolled persistent asthma (17). A significant proportion of patients with severe asthma remain symptomatic despite recommendation-based treatment with ICS plus LABA (5,11,14,18). A high proportion of patients require more than two OCS rescue treatments annually to manage their exacerbations, predisposing these patients toward an increased incidence of adverse events (19). The use of LAMAs in asthma is supported by the synergistic interaction between LAMAs and LABAs (14). LAMAs inhibit the muscarinic receptors on the smooth muscles; inhibition of the M1 and M3 receptors reduces smooth muscle tone and causes bronchodilation, whereas inhibition of the M2 receptors causes bronchoconstriction (20). Depending on their duration of action (DOA), muscarinic antagonists are classified as short acting (e.g. ipratropium; DOA, 4–8 h) and long acting (e.g. tiotropium, glycopyrronium, and umeclidinium; DOA, ≥24 h) (9,21). LAMAs offer an alternative add-on option for the management of asthma with the convenience of a single daily dose regimen (17). Furthermore, LAMAs plus ICS synergistically enhance the relaxation of passively sensitized medium and small bronchi (14).

Tiotropium as an add-on to ICS plus LABA is currently recommended by the NAEPP Expert Panel before escalation to treatment with biologics (18). The NAEPP Expert Panel conditionally recommends adding a LAMA to ICS plus LABA versus continuing the same dose of ICS plus LABA in uncontrolled persistent asthma patients aged ≥12 years (18). The efficacy of tiotropium as an add-on to ICS plus LABA on lung function and exacerbations was assessed in several clinical trials (Figure 1 and Table 1) (22–25). Tiotropium is currently FDA approved for the long-term, maintenance treatment of asthma in patients ≥6 years of age (26).

Figure 1. Effect of open-inhaler triple therapy versus ICS plus LABA on lung function and symptoms in patients with asthma.

^*Results were statistically significant. Lung function (significance defined by 95% confidence interval (22) and P-value (23)); Exacerbations (significance defined by P-value (20)); Asthma control (significance defined by P-value (20)).

FLU, fluticasone; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; OCS, oral corticosteroids; SAL, salmeterol; TIO, tiotropium.

Table 1. Add-on LAMA to ICS plus LABA (open-inhaler triple therapy) vs ICS plus LABA.

Authors, publication date (patient characteristics)	Intervention, number of patients included during treatment initiation (treatment duration)		Key efficacy endpoints					Key findings
			Lung function (includes PEF, FEV1, and forced vital capacity)		Asthma control (includes ACQ-7 or use of rescue medications or number of exacerbations)		QoL
					Exacerbations	Symptoms
Kerstjens et al, 2012 (22) (adult patients aged 18–75 years with severe asthma) PrimoTinA-asthma 1 (trial 1) NCT00772538 PrimoTinA-asthma 2 (trial 2) NCT00776984	TioR 5 μg^a OD Trial 1: n = 211 Trial 2: n = 198 PboR Trial 1: n = 202 Trial 2: n = 203 (48 weeks)		Peak FEV1 within 3 h of dosing (FEV1(0-3h)),^d mean ± SE at week 24 (mL) TioR vs PboR: difference of 86 ± 34 in trial 1 (P = 0.01) and 154 ± 32 in trial 2 (P < 0.001) Trough FEV1 at week 24^d, mean ± SE (mL) TioR vs PboR: change from baseline of 88 ± 31 in trial 1 (P = 0.01) and 111 ± 30 in trial 2 (P < 0.001)		ACQ-7^c At week 24, the mean difference in scores within the TioR vs PboR groups was significant only in trial 2 (−0.13 [P = 0.06] and −0.2 [P = 0.003] in trials 1 and 2, respectively). MCID was not achieved in either trial	Not reported	AQLQ scores^c: Significant differences between TioR vs PboR were only seen in trial 2 (0.18 units, P = 0.02) (24 weeks) The MCID of 0.5 was not achieved in either trial.	In patients with poorly controlled asthma despite the use of ICS and LABAs, the addition of Tio significantly increased the time to the first severe exacerbation and provided modest sustained bronchodilation
Wang et al, 2015 (23) (adult patients aged 29–43 years with uncontrolled moderate asthma)	Tio 18 µg^a OD, n = 33 Double-dose ICS: salmeterol/fluticasone 50/500 µg BID, n = 30 (add-on treatments for 4 and 12 weeks)		Average diurnal PEF variability^b: No significant difference was observed between treatments PEF variability, mean % ± SEM at the second follow-up Tio: 10.22 ± 2.28 Double-dose ICS: 9.38 ± 1.77		ACT score (mean ± SEM) Tio: 24.44 ± 1.01 Double-dose ICS: 24.88 ± 0.35	Add-on Tio improved patient symptoms	Not reported	Tio in combination with ICS plus LABA showed similar effects compared with double-dose ICS plus LABA, without adverse events, and might be the best option for the optimal control of asthma
Ohta et al, 2015 (24) (adult patients aged 18–75 years with symptomatic asthma) Only the results of the relevant secondary endpoints have been listed NCT01340209	TioR 5 µg^a OD, n = 114 TioR 2.5 µg OD, n = 114 PboR, n = 57 (52 weeks)		Adjusted mean difference vs PboR at week 52 Trough FEV1^c (mL) TioR 5 µg: 112 (95.0% CI, 18 to 207; P = 0.0203) TioR 2.5 µg: 12 (95.0% CI, −82 to 106; P = 0.7971) In-clinic trough PEFR (L/min)^c TioR 5 µg: 34.2 (95.0% CI, 9.9 to 58.4; P = 0.0058) TioR 2.5 µg: 0.50 (95.0% CI, −23.6 to 24.6; P = 0.9677)		ACQ-7 responder rates at week 52^c TioR 5 µg: 76.3% TioR 2.5 µg: 71.1% PboR: 73.2%	Not reported	Not reported	Compared with PboR, TioR 5 μg, but not TioR 2.5 μg, significantly improved lung function and symptoms, supporting the long-term efficacy of the TioR 5 μg dose
Hamelmann et al, 2017 (25) (adolescent patients aged 12–17 years with a ≥3-month history of severe symptomatic asthma) NCT01277523	TioR 5 µg^a OD, n = 130 TioR 2.5 µg OD, n = 127 PboR, n = 135 (12 weeks)	Change in peak FEV1(0-3h) at week 12^b (mL) Adjusted mean difference from PboR: TioR 5 µg: 90 (95.0% CI, −19 to 198; P = 0.104) TioR 2.5 µg: 111 (95.0% CI, 2 to 220; P = 0.046)		Adjusted mean ACQ-7 scores at week 12^c TioR 5 μg vs Pbo, difference: 0.036 (95.0% CI, −0.123 to 0.196) TioR 2.5 μg vs placebo, difference: 0.058 (95.0% CI, −0.102 to 0.219) Severe asthma exacerbations: TioR 2.5 μg vs placebo: 0.79% vs 0.74% TioR 5 μg vs placebo: 1.54% vs 0.74%		Not reported	Not reported	The primary endpoint of efficacy (change from baseline in peak FEV1(0-3h)) was not met, although positive trends for improvements in lung function and asthma control were observed

^a Indicates use of a LAMA (dose or device) without the United States Food and Drug Administration–approved label.

^b Indicates primary endpoints of the trial.

^c Indicates secondary endpoints of the trial.

^d Indicates coprimary endpoints of the trial.

ACQ-7, Asthma Control Questionnaire 7; ACT, Asthma Control Test; AQLQ, Asthma Quality of Life Questionnaire; BID, two times each day; CI, confidence interval; FEV₁, forced expiratory volume in 1 s; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; MCID, minimal clinically important difference; OD, once a day; PboR, Placebo Respimat®; PEF, peak expiratory flow; PEFR, peak expiratory flow rate; QoL, quality of life; SE, standard error; SEM, standard error of mean; Tio, tiotropium; TioR, Tiotropium Respimat®.

Real-world evidence shows that LAMAs have been prescribed by primary care physicians—mostly as add-on therapy in older patients with poorly controlled asthma in the United Kingdom since 2002 (14). Add-on tiotropium, a LAMA, is associated with a significantly reduced incidence of hospitalizations and emergency department visits and a decrease in ICS dose, OCS use, and antibiotics use (14). Exacerbations and acute respiratory events were also reduced across various age groups (14,27). In the two replicate, randomized placebo-controlled trials, (PrimoTinA-asthma® 1 and 2) improvements were observed in peak FEV₁ from baseline and predose trough FEV₁ from baseline to week 24 of treatment in the tiotropium 5 µg group compared with placebo in patients with poorly controlled asthma (22). In the tiotropium group, improvements in peak FEV₁ tended to be higher in patients with a lower FEV₁ as a percentage of the predicted value in men and in former smokers with a history of less than 10 pack-years (22). The average daily diurnal peak expiratory flow (PEF) variability improved at 4 and 12 weeks after add-on tiotropium therapy in patients with symptomatic moderate asthma (23), while double-dose ICS demonstrated no significant differences in PEF variability. However, patients receiving double-dose ICS presented with a higher pneumonia risk (23). Similar results were observed with lower tiotropium doses (2.5 µg and 5 µg) at 24 weeks in patients with moderate symptomatic asthma, in ex-smokers or those without a smoking history (28).

Tiotropium therapy (5 µg) was also associated with a 21% reduction in the risk of severe exacerbations in adult patients (22). Conversely, no statistically significant improvement in peak FEV₁ (0–3 h) was observed with once-daily tiotropium Respimat® 5 µg add-on to ICS plus one or more controller therapies in adolescents aged 12–17 years with severe symptomatic asthma, despite numerical improvements (25). An increase in Asthma Control Questionnaire-7 (ACQ-7) responder rates was observed for tiotropium (both 5 and 2.5 µg) compared with placebo after 24 weeks of treatment in adults (24,28); however, at 52 weeks, responder rates were similar across treatment groups (24). Although no significant difference was observed in the response of both ACQ-6 and ACQ-7 scores between tiotropium and placebo after 12 weeks of treatment, statistically significant benefits in peak FEV₁ (0–3 h) response were seen with tiotropium 2.5 μg compared with placebo (111 mL; P = 0.046) (25).

Although effective, patients using multiple inhalers have suboptimal adherence to medication (29). It should be noted that two different inhaler types requiring different inhaler techniques could contribute to further complications (29). Treatment with a single inhaler increases adherence and reduces the risk of asthma-related emergency department/inpatient events, as well as reduces the use of rescue medication, which might indicate superior symptom control (30–32).

Single-inhaler triple therapy versus open triple therapy and ICS plus LABA

Recently, several triple combinations of ICS plus LABA plus LAMA in a single inhaler providing different dosages and more personalized treatment have become commercially available both in the Europe and the US (16). Single-inhaler triple therapy (fluticasone furoate plus umeclidinium plus vilanterol) is widely approved as a once-daily treatment for chronic obstructive pulmonary disease (8). Results of recent clinical trials also support its use in asthma with approval for this indication received in several countries including the US (Figure 2) (8,33,34). Single-inhaler triple therapy reported in the Triple in Asthma With Uncontrolled Patients on Medium Strength of ICS/LABA (TRIMARAN) and Triple in Asthma High Strength Versus ICS/LABA HS and Tiotropium (TRIGGER) studies reduced the rate of moderate and severe exacerbations and significantly improved predose FEV₁ versus ICS plus LABA (Table 2) (34). In TRIGGER, there was no significant difference in predose FEV₁ and rate of moderate and severe exacerbations between the single-inhaler and open-inhaler triple therapy groups (34). Similarly, results of the ARGON study showed that single-inhaler triple therapy was noninferior to open-inhaler triple therapy for Asthma Quality of Life Questionnaire scores but showed greater improvement in lung function, asthma control, and health status (35). In the IRIDIUM study, single-inhaler triple therapy significantly improved trough FEV₁ versus ICS plus LABA in patients with inadequately controlled asthma (36). In CAPTAIN, triple therapy significantly improved lung function (change from baseline in trough FEV₁ at 24 weeks of treatment) and symptoms (as measured by ACQ-7 and St George’s Respiratory Questionnaire) but did not reduce moderate and/or severe exacerbations versus ICS plus LABA in patients with uncontrolled moderate or severe asthma on ICS plus LABA (Table 2) (8). This could possibly be explained by the fact that the population under study had a lower risk than assumed in the power calculation; further, the statistical limitations did not allow for exploring the effect of LABA in reducing exacerbations (8). The CAPTAIN study also concluded that single-inhaler triple therapy is an effective treatment option with a favorable risk-benefit profile in this patient population (8). A systematic review analyzing both observational and interventional clinical studies showed that single-inhaler use was associated with decreased HCRU and improved cost-effectiveness versus multiple-inhaler use (30).

Figure 2. Effect of single-inhaler triple therapy versus ICS plus LABA on lung function and symptoms in patients with asthma.

^*Results were statistically significant. Lung function (significance defined by 95% CI (8) and P-value (36)); Exacerbations (significance defined by 95% CI (34)); Asthma control (significance defined by P-value (36)).

BDP, beclomethasone dipropionate; CI, confidence interval; FF, fluticasone furoate; FLU, fluticasone; GLY, glycopyrronium; ICS, inhaled corticosteroid; IND, ­indacaterol; LABA, long-acting β2-agonist; MF, mometasone furoate; SAL, salmeterol; UMEC, umeclidinium; VI, vilanterol.

Table 2. Single-inhaler triple therapy vs ICS/LABA.

Authors, publication year (patient characteristics)	Intervention, number of patients (treatment duration)	Key efficacy endpoints				Key findings
		Lung function (includes PEF, FEV1, and forced vital capacity)	Asthma control (includes Asthma Control Questionnaire 7 or use of rescue medications or number of exacerbations)		QoL
			Exacerbations	Symptoms
Virchow et al, 2019 (34) (adult patients aged 18–75 years with uncontrolled asthma) NCT02676076 TRIMARAN NCT02676089 TRIGGER	TRIMARAN BDP 100 µg/FF 6 µg/GLY 10 µg^a, 2 inhalations BID via pressurized metered-dose inhaler, n = 579 BDP 100 µg/FF 6 µg, 2 inhalations BID via pressurized metered-dose inhaler, n = 576 TRIGGER BDP 200 µg/FF 6 µg/GLY 10 µg^a, 2 inhalations BID, n = 573 BDP 200 µg/FF 6 µg, 2 inhalations BID via pressurized metered-dose inhaler, n = 576 BDP 200 µg/FF 6 µg, 2 inhalations BID via pressurized metered-dose inhaler plus Tio 2.5 μg^a 2 inhalations OD via a soft mist inhaler Respimat^® n = 288 (52 weeks)	Morning predose FEV1 at week 26^d (mL): Adjusted mean difference vs ICS plus LABA vs ICS plus LABA plus LAMA TRIMARAN: 57 (95.0% CI, 15 to 99; P = 0.008) TRIGGER: 73 (95.0% CI, 26 to 120; P = 0.0025)	Annualized rate of moderate and severe exacerbations^d: Adjusted rate ratio vs ICS plus LABA vs ICS plus LABA plus LAMA TRIMARAN: 0.85 (95.0% CI, 0.73 to 0.99; P = 0.033) TRIGGER: 0.88 (95.0% CI, 0.75 to 1.03; P = 0.11)	Asthma symptoms^c: An improvement from baseline in asthma symptoms, in all five groups over the duration of the studies, with similar improvements seen in TRIMARAN for both the BDP/FF/GLY and BDP/FF groups and an improvement seen in TRIGGER for the BDP/FF/GLY group compared with the BDP/FF group in terms of asthma symptom-free days and asthma control days from week 13 onwards	Not reported	In uncontrolled asthma, addition of a LAMA to ICS plus LABA treatment improved lung function and reduced exacerbations
Gessner et al, 2020 (35) (adult patients aged ≥18 years with symptomatic asthma) NCT03158311 ARGON	All treatments were administered using a dry powder inhaler IND 150 μg/GLY 50 μg^a/MF 80 μg OD, n = 474 IND 150 μg/GLY 50 μg^a/MF 160 μg OD, n = 476 SAL 50 μg/FLU 500 μg BID plus TioR 5 μg^a OD, n = 476 (24 weeks)	Change from baseline between single-inhaler triple therapy high-dose vs SAL/FLU high-dose plus TioR: Morning PEF (L/min)^e: 9.561 (95.0% CI, 2.829 to 16.293; P = 0.005) Evening PEF (L/min)^e: 9.145 (95.0% CI, 2.573 to 15.717; P = 0.006)	Moderate exacerbations^e: The annualized rate decreased by 43.0% (P = 0.042) with IND/GLY/MF high-dose versus SAL/FLU high-dose plus TioR Mild and Severe exacerbations: A reduction comparable among all treatment groups was observed	Not reported	The AQLQ score^b: Single-inhaler triple therapy was noninferior to SAL/FLU high-dose BID plus TioR OD via 2 inhalers for the AQLQ scores	IND/GLY/MF high- and medium-dose OD in a single inhaler were noninferior to SAL plus FLU high dose BID plus TioR OD via 2 inhalers for AQLQ scores IND plus GLY plus MF high-dose OD improved lung function and health status vs SAL/FLU high-dose plus TioR
Kerstjens et al, 2020 (36) (adult patients, aged 18–75 years with symptomatic asthma) NCT02571777 IRIDIUM	All treatments were administered using a dry powder inhaler MF 80 μg/IND 150 μg/GLY 50 μg^a OD, n = 620 MF 160 μg/IND 150 μg/GLY 50 μg^a OD, n = 619 MF 160 μg/IND 150 μg OD, n = 617 MF 320 μg/IND 150 μg OD, n = 618 FLU 500 μg/SAL 50 μg BID, n = 618 (52 weeks)	Change from baseline in trough FEV1 at week 26^b (mL) Both doses of single-inhaler triple therapy significantly improved trough FEV1 vs ICS plus LABA Least squares mean treatment difference: MF 80 μg/IND 150 μg/GLY 50 μg vs MF 160 μg/IND 150 μg: 76 (95.0% CI, 41 to 111; P < 0.001) MF 160 μg/IND 150 μg/GLY 50 μg vs MF 320 μg/IND 150 μg: 65 (95.0% CI, 31 to 99; P < 0.001) MF 80 μg/IND 150 μg/GLY 50 μg vs FLU 500 μg/SAL 50 μg: 99 (95.0% CI, 64 to 133; P < 0.001) MF 160 μg/IND 150 μg/GLY 50 μg vs FLU 500 μg/SAL 50 μg: 119 (95.0% CI, 85 to 154; P < 0.001)	Annualized rate of exacerbations at week 52^c: Reduction in moderate/severe exacerbations: MF/IND/GLY medium dose vs MF/IND medium dose: 13.0% (P = 0.17) MF/IND/GLY high dose vs MF/IND high dose: 15.0% (P = 0.12) Reduction in severe exacerbations: MF/IND/GLY vs MF/IND medium dose: 7.0% (P = 0.53) MF/IND/GLY vs MF/IND high dose: 22.0% (P = 0.05) Reduction in all exacerbations: MF/IND/GLY vs MF/IND medium dose: 13.0% (P = 0.16) MF/IND/GLY vs MF/IND high dose: 21.0% (P = 0.016)	Reductions in total daily asthma symptom scores^c, percentage of asthma symptom-free days^c, and percentage of nights with no nighttime awakenings^c were similar across all treatment groups over 52 weeks	AQLQ-S scores^c: Clinically meaningful improvements in the standardized AQLQ-S scores from baseline were observed for all treatment groups over 52 weeks, with no meaningful differences between the treatments	Single inhaler MF plus IND plus GLY OD improved lung function vs ICS plus LABA combinations (MF plus IND and FLU plus SAL) in patients with inadequately controlled asthma
Lee et al, 2021 (8) (patients aged ≥ 18 years with inadequately controlled asthma [ACQ-6 score of ≥ 1.5] despite treatment with ICS plus LABA) NCT02924688 CAPTAIN	All treatments were administered using a dry powder inhaler FF 100 μg/VI 25 μg, n = 407 FF 100 μg/UMEC 31.25 μg^a/VI 25 μg, n = 405 FF 100 μg/UMEC 62.5 μg/VI 25 μg, n = 406 FF 200 μg/VI 25 μg, n = 406 FF 200 μg/UMEC 31.25 μg^a/VI 25 μg, n = 404 FF 200 μg/UMEC 62.5 μg/VI 25 μg, n = 408 (24–52 weeks)	Change from baseline in clinical trough FEV1 at week 24^b: Least squares mean change from baseline difference vs ICS plus LABA FF 100 μg/UMEC 62.5 μg/VI 25 μg vs FF 100 μg /VI 25 μg was 110 mL (95% CI, 66 to 153; P < 0.0001) FF 200 μg/UMEC 62.5 μg/VI 25 μg vs FF 200 μg /VI 25 μg was 92 mL (95.0% CI, 49 to 135; P < 0.0001) FF 100 μg/UMEC 31.25 μg/VI 25 μg vs FF 100 μg/VI 25 μg was 96 mL (95.0% CI, 52 to 139; P < 0.0001) FF 200 μg/UMEC 31.25 μg/VI 25 μg vs FF 200 μg/VI 25 μg was 82 mL (95.0% CI, 39 to 125; P = 0.0002)	Pooled analysis of annualized rate of moderate and/or severe asthma exacerbations^c: Adjusted rate ratio (95.0% CI; P value) FF 100 µg/VI vs FF/UMEC 31.25 µg/VI: 0.88 (0.68 to 1.13; P = 0.32) FF 100 µg/VI vs FF/UMEC 62.5 µg/VI: 0.78 (0.61 to 1.01; P = 0.060) FF 200 µg/VI vs FF/UMEC 31.25 µg/VI: 1.08 (0.82 to 1.42; P = 0.60) FF 200 µg/VI vs FF/UMEC 62.5 µg/VI: 0.97 (0.73 to 1.28; P = 0.80)	Not reported	SGRQ total score^c: (change from baseline analyses at week 24) Least squares mean change from baseline (95.0% CI) FF/VI pooled groups: −11.39 (−12.35 to −10.42; n = 766) FF/UMEC 31.25 µg/VI pooled groups: −10.29 (−11.26 to −9.32; n = 753) FF/UMEC 62.5 µg/VI pooled groups: −11.69 (−12.64 to −10.73; n = 777)	OD single inhaler FF plus UMEC plus VI reduced airflow obstruction and improved asthma control, effectively reducing risk in patients whose asthma was inadequately controlled on ICS plus LABA

^a Indicates use of a LAMA (dose or device) without the United States Food and Drug Administration–approved label.

^b Indicates primary endpoints of the trial.

^c Indicates secondary endpoints of the trial.

^d Indicates coprimary endpoints of the trial.

^e Indicates exploratory endpoints of the trial.

AQLQ, Asthma Quality of Life Questionnaire; AQLQ-S, Standardized Asthma Quality of Life Questionnaire; BDP, beclomethasone dipropionate; BID, two times each day; CI, confidence interval; FEV₁, forced expiratory volume in 1 s; FF, fluticasone furoate; FLU, fluticasone; GLY, glycopyrronium; ICS, inhaled corticosteroid; IND, indacaterol; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; MF, mometasone furoate; OD, one time each day; PEF, peak expiratory flow; QoL, quality of life; SAL, salmeterol; SGRQ, St George’s Respiratory Questionnaire; TioR, tiotropium Respimat®; UMEC, umeclidinium; VI, vilanterol.

A recent meta-analysis showed that triple therapy, including high-dose ICS, has greater beneficial impact than medium-dose single-inhaler triple therapy and both medium- and high-dose single-inhaler ICS plus LABA in reducing the risk of moderate-to-severe exacerbations in patients with uncontrolled asthma (37). However, single-inhaler therapies can also be associated with higher costs and reduced flexibility in independent dose adjustments (16).

Type 2 inflammatory asthma and LAMAs

There is currently limited evidence that LAMAs possess anti-inflammatory activity (38). The anti-inflammatory and anti-proliferative (39,40) effects of LAMA in reducing airway remodeling induced by allergens (41) has been demonstrated in animal models; however, these effects in humans have not been definitively demonstrated (42). Pharmacological interactions between muscarinic antagonists, ICS, and/or LABAs support the use of LAMAs in asthma (14). In the CAPTAIN study, the addition of umeclidinium (62.5 μg) to ICS plus LABA as a single-inhaler triple therapy improved FEV₁ in patients across a range of blood eosinophil and fractional exhaled nitric oxide levels; however, the effect of LAMAs on inflammatory biomarkers in this study may have been confounded by the concurrent use of ICS (8). As such, without concomitant ICS, LAMA monotherapy is linked to an increased risk of severe asthma exacerbations since it has minimal anti-inflammatory effects and is not advised for treating asthma (43,44).

Unmet needs and future directions

Patients with uncontrolled asthma have fewer treatment options in the context of medium/high doses of ICS plus LABA therapy. The use of LAMA as an add-on therapy to ICS plus LABA has shown significant improvements in asthma control and reduction of airflow obstruction without major safety concerns, with effectiveness being independent of type 2 inflammatory biomarkers (8). Triple therapy can represent a new therapeutic option for these specific asthma patient populations, but further studies confirming the differentiating effect of biomarkers of type 2 inflammation on treatment outcomes and precision medicine for asthma patients are required.

The effects of LAMA add-on therapy and ICS escalation appear to be influenced by patient Th2 levels and choice of outcome measures (e.g. exacerbations versus symptoms), indicating that different clinical symptoms respond to different treatment options. This highlights the need for reliable disease biomarkers that can foster precision medicine and personalized treatments in asthma patients (8). Most of the clinical studies assessing LAMA add-on therapy (i.e. ICS plus LAMA and triple therapy) have included the adult population, leading to a restriction in medication licensing for children and underscoring the need to assess both efficacy and safety in pediatric populations (45).

Asthma severity can change over time, and therapy escalation and/or de-escalation might be needed (45). However, de-escalating from triple to dual bronchodilator therapy may be problematic in some patients who are well-controlled on this regimen and may be reluctant to review/change their medication (46). Consequently, direction and education from bodies including the GINA and NAEPP on the best approach to de-escalate patients who no longer require triple therapy may be helpful (46).

Conclusions

The evidence presented in this review supports the use of triple therapy with LAMAs as an add-on in asthma patients (open-inhaler triple therapy) as well as the inclusion of LAMAs as part of a single-inhaler (closed-inhaler) triple therapy regimen. Open-inhaler triple therapy with add-on LAMA to ICS plus LABA or triple therapy with a single inhaler improves the response in patients who remain symptomatic despite receiving ICS plus LABA therapy. Compared with multiple inhaler use, single inhaler use showed improvement in HCRU. Add-on LAMA provides a reasonable alternative to ICS escalation in patients who do not respond to low- or medium-dose ICS. Single-inhaler therapy may potentially increase treatment compliance and reduce treatment costs, leading to better asthma management and increased patient HRQoL. Triple therapy offers an additional strategy to improve response in patients who are symptomatic despite standard ICS plus LABA therapy; further studies are required to determine whether open- versus closed-inhaler approaches are optimal for the management of uncontrolled asthma and more importantly, for specific subsets of patients.

Acknowledgements

Writing, editorial support, and formatting assistance was provided by Sandra Brasil and Shruti Muralidharan of Cactus Life Sciences (part of Cactus Communications), which was contracted and compensated by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) for these services. BIPI was given the opportunity to review the manuscript for medical and scientific accuracy, as well as intellectual property considerations. To ensure independent interpretation of clinical study results and enable authors to fulfill their role and obligations under the ICMJE criteria, BIPI grants all external authors access to relevant clinical study data. In adherence with the BIPI Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript in a peer-reviewed journal, regulatory activities are complete, and other criteria are met. Researchers should use the https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information.

Supplementary information

Additional file 1: A podcast of the review article – Podcast.

Disclosure statement

Dr. Wechsler reports grants and personal fees from Cohero Health, Novartis, and Sanofi; personal fees from Regeneron, Genentech, GlaxoSmithKline plc (GSK), Sentien, Restorbio, Equillium, and Genzyme; grants, personal fees, and nonfinancial support from Teva and AstraZeneca; and personal fees and nonfinancial support from Boehringer Ingelheim Pharmaceuticals, Inc. outside the submitted work. Dr. Wechsler also has received consulting, advisory, or speaking honoraria from Amgen, AstraZeneca, Avalo Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Cerecor, Cohero Health, Cytoreason, Eli Lilly, Equillium, GSK, Incyte, Kinaset, Novartis, Om Pharma, Phylaxis, Pulmatrix, Rapt Therapeutics, Regeneron, Restorbio, Roche/Genentech, Sanofi/Genzyme, Sentien, Sound Biologics, Tetherex Pharmaceuticals, Teva, and Upstream Bio. Dr. Oppenheimer reports to have served on adjudication committees/data- and safety-monitoring boards for AstraZeneca, GSK, Novartis AG, and Sanofi.

Additional information

Funding

Medical writing support was funded by Boehringer Ingelheim Pharmaceuticals, Inc.