A Brief Report on a Systematic Review of Real-World Effectiveness Studies of ICS/LAMA/LABA for Treatment of Adults with Asthma in the US

Abstract

Introduction

Long-acting muscarinic antagonist (LAMA) addition to inhaled corticosteroid/long-acting β₂-agonist (ICS/LABA) dual therapy is recommended for severe asthma, but its real-world effectiveness is not well established.

Methods

A systematic literature review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) to investigate clinical outcomes in US adults with asthma receiving ICS + LABA + LAMA as multiple-/single-inhaler triple therapy (MITT/SITT). Real-world/observational studies published in English in Embase/MEDLINE databases (2014–2024) and conference abstracts presented 2022–2024 were eligible for inclusion.

Results

From 588 identified records, only 8 articles reporting 6 unique studies were included; 2 assessed SITT and 4 assessed MITT, and 4 treatments were investigated. Exacerbation rates reported in two studies were significantly reduced with tiotropium (TIO) + ICS + LABA MITT versus high-dose ICS + LABA within 6 (64% lower) and 12 months (73%), and fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 mcg SITT versus pre-treatment after 12 months (41%). Oral corticosteroid (OCS) use was reported in two studies. The proportion of patients with ≥ 1 rescue OCS dispensing decreased with TIO 1.25 mcg + ICS + LABA MITT, with greatest reductions for MITT ± leukotriene receptor antagonist (pre-treatment: 68.4%, post treatment: 54.2%). Mean number of OCS dispensings/patient/year significantly decreased (29%, p < 0.001) following FF/UMEC/VI 100/62.5/25 mcg SITT initiation. Treatment adherence/persistence was reported in three studies. Mean (standard deviation) proportion of days covered was significantly higher (p < 0.001) for FF/UMEC/VI SITT versus MITT after 6 (0.56 [0.31] versus 0.46 [0.31]) and 12 months (0.46 [0.33] versus 0.35 [0.30]). Persistence at 12 months was 25.9% and 12.0%, respectively. Lung function, clinical remission, quality of life, and safety outcomes were not reported in any study.

Conclusions

This brief communication reports a systematic review that identified few sources of SITT or MITT in US patients with asthma. Although inclusion of observational studies can result in reporting/selection bias, we identified greater clinical benefits with triple therapies versus dual therapies.

Supplementary Information

The online version contains supplementary material available at 10.1007/s41030-025-00288-0.

Key Summary Points

Why carry out this study?

Real-world effectiveness of ICS/LABA/LAMA therapy on clinical outcomes is not well established.

We conducted a systematic literature review to assess the effectiveness of ICS/LAMA/LABA triple therapy for adults with asthma in clinical practice in the US.

What was learned from the study?

From eight articles reporting on six unique studies, exacerbations were reduced with triple therapy compared with dual therapy, oral corticosteroid use was reduced with single-inhaler triple therapy (SITT) and multiple-inhaler triple therapies (MITT) compared with prior treatments, and treatment adherence was improved with SITT versus MITT.

Increased adherence to SITT versus MITT suggests patients are more likely to benefit from these improvements with SITT.

Gaps in the literature around the real-world effectiveness of ICS/LABA/LAMA regarding lung function, quality of life, and clinical remission were identified.

Introduction

The United States (US) Centers for Disease Control and Prevention report that 7.7% of the US population live with asthma, representing approximately 25 million people [1]. A previous real-world study of asthma burden in US patients receiving inhaled corticosteroid/long-acting β₂-agonist (ICS/LABA) therapy showed that half of patients had not-well-controlled or poorly controlled disease. In addition, 81% of patients still experienced symptoms [2], suggesting an unmet need in asthma management.

The Global Initiative for Asthma (GINA) recommends ICS/LABA dual therapy for moderate asthma, with addition of a long-acting muscarinic antagonist (LAMA) for severe disease (step 5) [3]. Triple therapy can be administered either as multiple- or single-inhaler triple therapy (MITT and SITT) [3, 4]. ICS/LAMA/LABA therapies, including beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide and mometasone furoate/indacaterol/glycopyrronium bromide, have shown improved clinical outcomes versus ICS/LABA dual therapy in randomized clinical trials of patients with uncontrolled asthma previously on ICS/LABA [5, 6], though only fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) is licensed for patients with asthma uncontrolled on ICS/LABA in the US [4]. FF/UMEC/VI SITT has been available in the US since 2020 and has shown greater efficacy over FF/VI dual therapy in the CAPTAIN phase 3A clinical trial [4, 7]. However, there is a lack of evidence regarding the impact of ICS/LAMA/LABA versus dual therapy on real-world clinical outcomes.

We conducted a systematic literature review (SLR) to assess the real-world benefit of ICS/LABA/LAMA for the treatment of adult patients with asthma in US clinical practice.

Methods

Study Design and Identification of Studies

Predetermined population, intervention, comparison, outcome, and study design (PICOS) criteria were used to determine studies eligible for inclusion (Table 1). In summary, this SLR included adults aged ≥ 18 years diagnosed with asthma of any severity who were receiving triple inhaler therapy (ICS + LABA + LAMA) via SITT or MITT as maintenance treatment.

Table 1.

PICOS study selection criteria

Criteria	Inclusion criteria	Exclusion criteria and descriptiona
Population	Adults (≥ 18 years) diagnosed with asthma of any severityb Mixed populations for which ≥ 75% of the population is of interest	Population not of interest   Studies not evaluating patients with asthma, or not conducted in children or adolescents
Interventions	Triple inhaler therapy (ICS + LABA + LAMA) via a SITT or MITT as maintenance treatment	Intervention not of interest   Studies only evaluating other treatments for asthma (e.g., ICS alone or biologics)   Studies only evaluating ICS + LABA inhalers   Studies evaluating nebulized treatment   Studies on treatment in the acute setting
Comparators	None (single-arm studies) Dual therapy ICS + LABA inhalers Triple therapy ICS + LABA + LAMA inhalers (SITT or MITT)	Nonec   Not applicable
Outcomes	Effectiveness Exacerbations (any, mild, moderate, severe: definition to be captured) Annualized rate Proportion of patients with events  Hospitalized exacerbations Annualized rate   Proportion of patients with events Clinical remission (proportion and definition) OCS use (proportion at baseline, post-treatment, change from baseline) Reduction in OCS dose (change from baseline) Lung function (via spirometry data)  FEV1% predicted (pre- and post-bronchodilator)  FVC  FEV1/FVC Safety/tolerability (proportion of patients):   Total discontinuation   Any adverse event   Any treatment-related adverse event   Any serious adverse event  Nasopharyngitis   Headache   Upper respiratory tract infection   Bronchitis   Back pain   Influenza   Pharyngitis HRQoL based on validated disease specific measures   ACQ (any version)   AQLQ (adult version only)   ACT Adherenced	Outcomes not of interest  No reported outcomes of interest (e.g., costs or resource use other than hospitalization)
Study Design	Journal articles or conference abstracts that present results of real-world evidence/observational studies (e.g., retrospective and prospective cohorts, cross-sectional studies, analyses of claims data, electronic health records, patient registries, chart reviews, or surveys)	Publication type not of interest   Editorial, letters to the editor, erratum, trial protocol, guideline, case report/study, case series, narrative reviews Study design not of interest   In vitro, ex vivo, or animal studies   Clinical trials  SLRsb
Geography	US	Country not of interest   Study is conducted outside the US
Language	English language	Non-English language   Full-text articles not published in English
Time period	Full-text: 2014–2024 Conference abstracts: 2022–2024	Outside of search period   Full-text published prior to 2014   Conference abstract presented prior to 2022

^aReasons for exclusion may be refined during the screening process and any adjustments were documented in the study listing

^bStudies in elderly populations were tagged at screening

^cSLRs from the past 3 years were reviewed for reference checks but were not eligible for inclusion in the review

^dStudies reporting adherence were tagged at screening

ACQ Asthma Control Questionnaire, AQLQ Asthma Quality of Life Questionnaire, ACT Asthma Control Test, FEV₁ forced expiratory volume in 1 s, FVC forced vital capacity, HRQoL health-related quality of life, ICS inhaled corticosteroid, LABA long-acting β₂-agonist, LAMA long-acting muscarinic antagonist, MITT multiple-inhaler triple therapy, OCS oral corticosteroid, SITT single-inhaler triple therapy, SLR systematic literature review

As other triple therapies, such as budesonide/glycopyrronium/formoterol, are not yet approved for use in asthma in the US, these were not eligible for inclusion. For multiple-arm studies, comparators included dual therapy (ICS + LABA) versus MITT or SITT and MITT (ICS + LABA + LAMA) versus SITT, and both effectiveness and safety outcomes were explored. Journal articles and conference abstracts of real-world evidence/observational studies from the US were included.

Searches were conducted in OVID to identify English language articles published between 2014 and 2024 in Excerpta Medica database (Embase) (Table S1), Medical Literature and Retrieval System Online (MEDLINE), and MEDLINE In-process (Table S2). Gray literature searches identified relevant research from conference meeting abstracts from 2022 to 2024 in the Embase database, conference websites, or other relevant media. Conferences of the American Thoracic Society, American Academy of Allergy Asthma & Immunology, European Respiratory Society, and the American College of Chest Physicians (CHEST) were searched. The searches used a combination of free-text search terms and controlled vocabulary terms specific to each database, as recommended by the Cochrane Collaboration [8]; results were reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The review was not registered. No ethical approval was required for this study as no human participants were recruited or animals used.

Study Selection

Search records were imported, deduplicated, and screened in Nested Knowledge software (AutoLit®). Study titles and abstracts were independently screened by two reviewers with disagreements resolved by a third reviewer, and eligible studies subsequently underwent full-text screening. Identified gray literature were assessed by a single reviewer and validated by a second reviewer.

Data Extraction and Study Quality Assessment

The key PICOS criteria for each eligible study were extracted and validated by a senior researcher. For full-text publications, quality was assessed using the Newcastle–Ottawa Scale (NOS) [9]. The NOS was selected for use in this SLR because it is a validated tool for quality assessment of non-randomized studies in systematic reviews [9]. The NOS scores studies across three domains (selection, comparability, and exposure). Studies are scored from 0 to 9 on the basis of the items met within each domain, with 0–2 indicating poor quality, 3–5 fair quality, and 6–9 good/high quality [10]. Studies with only abstracts available were not assessed for quality due to limited methodology and data reporting. Analysis of heterogeneity between study results and sensitivity analyses were not performed.

Results

Literature Search Results and Quality Assessment

A total of 588 records were identified (Fig. 1). After deduplication, the title and abstracts of 458 records were screened and 31 passed to full-text screening. Overall, eight publications from six unique studies were included in the SLR [11–18]. No additional records were identified from the gray literature search. No major concerns surrounding the quality of the studies were identified (Table 2).

Fig. 1.

PRISMA flow diagram for study inclusion and exclusion. SLR systematic literature review

Table 2.

Quality of included studies

Author, year	Domain			Overall scorea (max: 9)	Quality
	Selection (max: 4)	Comparability (max: 2)	Outcome (max: 3)
Averell, 2019 [11]	4	0	1	5	Fair
Bogart, 2023 [18]	4	1	1	6	Good
Busse, 2022 [14]	4	0	1	5	Fair
Chipps, 2020 [15]	4	0	1	5	Fair
Oppenheimer, 2022 [16]	4	0	1	5	Fair
Spain, 2022 [17]	4	0	1	5	Fair

^aIn the Newcastle–Ottawa Scale, studies are scored from 0 to 9, with 0–2 indicating poor quality, 3–5 fair quality, and 6–9 good/high quality[10]

Results were reported descriptively given the limited number and heterogeneity of the publications identified.

Study and Patient Characteristics

All included studies were retrospective cohort studies; two studies assessed SITT and four studies assessed MITT, with four triple therapy treatments assessed overall. Comparative results were available from two studies, one comparing exacerbation rates with triple versus dual therapy [15] and one comparing adherence with SITT versus MITT [14]. For MITT, assessed treatments were LAMA + ICS + LABA [17], tiotropium (TIO) 1.25 mcg + ICS + LABA versus increased ICS dose + LABA (ICS dose increased from either low to medium/high dose or medium to high dose) [15], TIO 1.25 mcg or TIO 2.5 mcg monotherapy or concomitant with ICS or ICS/LABA with or without leukotriene receptor antagonist (LTRA) [11], and FF 100 mcg + UMEC 62.5 mcg + VI 25 mcg [14]. For SITT, both studies assessed FF/UMEC/VI 100/62.5/25 mcg [12–14, 16].

The proportion of female patients ranged from 57% to 69%, and patient age ranged from a mean of 47.8 to 56.1 years (Table 3). Disease severity was reported in three studies, all of which focused on moderate or severe asthma [11, 14, 17]. Prior therapy was reported in two studies, and included dual and triple therapies (ICS/LABA, ICS/LABA + LTRA, LAMA/LABA, MITT), monotherapies (LTRA, ICS), or no prior treatment [11, 12]. Comorbidities were reported in five studies [11, 12, 14–16]; the most commonly reported were allergic rhinitis, metabolic disorders, hypertension, sinusitis, and respiratory tract infections (Table 3).

Table 3.

Study and patient characteristics in included studies

Author, year	Study design	Objective	Sample size (N)	Treatments evaluated	Asthma severity n (%)	Prior treatments n (%)	Mean age (SD), years	Female, n (%)	Comorbiditiesa n (%)
Averell, 2019 [11]	Retrospective cohort study	To understand the real-world use of LAMA by examining patient characteristics and treatment patterns in patients with asthma before and after initiation of treatment with TIO 1.25 mcg and 2.5 mcg, either alone or in combination with other controller medications	465	MITT: TIO 1.25 mcg + ICS + LABA ± LTRA	Moderate: 181 (38.9) Severe: 44 (9.5)	ICS/LABA, ICS/LABA + LTRA, LTRA, no treatment, and ICS	47.8 (13.1)	310 (66.7)	Allergic rhinitis: 316 (68.0) Hypertension, uncomplicated: 137 (29.5) GERD: 112 (24.1) Obstructive sleep apnea: 81 (17.4) Obesity: 70 (15.1)
			607	MITT: TIO 2.5 mcg + ICS + LABA ± LTRA	Moderate: 199 (32.8) Severe: 69 (11.4)	ICS/LABA, ICS/LABA + LTRA, LTRA, no treatment, and ICS	50.0 (12.4)	379 (62.4)	Allergic rhinitis: 341 (56.2) Hypertension, uncomplicated: 173 (28.5) GERD: 149 (24.5) Obstructive sleep apnea: 104 (17.1) Obesity: 89 (14.7)
Bogart, 2022 [13]; Bogart, 2023 [12, 18]	Retrospective, pre-/post-cohort study	To assess rescue medication use and asthma-related exacerbations in patients with asthma before and after initiating SITT FF/UMEC/VI, using administrative claims data	890	SITT: FF/UMEC/VI 100/62.5/25 mcg	NR	ICS/LABA (33.5), leukotriene modifiers (33.0), ICS (5.7), MITT (5.3), and LAMA/LABA (2.5)	52.0 (11.3)	506 (56.9)	Allergic rhinitis: 449 (50.4) Sinusitis: 347 (39.0) Upper respiratory tract infection: 335 (37.6) GERD: 282 (31.7) Obstructive sleep apnea: 207 (23.3)
Busse 2022 [14]	Retrospective cohort study	To compare adherence and persistence among adults with asthma receiving SITT versus MITT FF/UMEC/VI	1396	SITT: FF/UMEC/VI 100/62.5/25 mcg	Moderate/severe: 1396 (100)	NR	52.1 (11.3)	813 (58.2)	Hypertension: 676 (48.4) Obesity: 330 (23.6) Diabetes: 246 (17.6) Cardiac arrhythmias: 157 (11.2) Rheumatoid arthritis/collagen vascular disease: 105 (7.5)
			5115	MITT: FF/UMEC/VI 100/62.5/25 mcg	Moderate/severe: 5115 (100)	NR	49.7 (12.9)	3372 (65.9)	Hypertension: 2133 (41.7) Obesity: 1259 (24.6) Diabetes: 780 (15.2) Cardiac arrhythmias: 649 (12.7) Rheumatoid arthritis/collagen vascular disease: 389 (7.6)
Chipps, 2020 [15]	Retrospective cohort study	To compare the effectiveness of tiotropium 1.25 mg (two puffs once-daily) addition to ICS + LABA versus an increased ICS + LABA dose in a real-world cohort of patients with asthma initiated on ICS + LABA	2619	MITT: TIO 1.25 mcg + ICS + LABA	NR	NR	≥ 12	1802 (69)	Hypertension: 806 (31) GERD: 770 (29) Anxiety/depression: 605 (23) Endocrine/metabolic disorders: 1382 (53)
Oppenheimer, 2022 [16]	Retrospective cohort study	To describe real-world prevalence, outcomes, and treatment patterns associated with MITT	1831	MITT: FF/UMEC/VI 100/62.5/25 mcg	NR	NR	56.1 (14.4)	1221 (66.7)	Other lower respiratory tract disease: 1365 (74.6) Other upper respiratory tract disease: 1257 (68.7) Allergic rhinitis: 1052 (57.5) Cardiovascular disease: 958 (52.3) Hypertension: 901 (49.2)
Spain, 2022 [17]	Retrospective cohort study	To describe how prescribing practices for LAMA addition to ICS + LABA and how biologic therapy have changed with increased treatment options and revised treatment guidelines	277,373	MITT: LAMA + ICS + LABA	Moderate/severe: 277,373 (100)	NR	NR	170,725 (61.6)	NR

^aTop five most common comorbidities, as reported in each included study

FF fluticasone furoate, GERD gastroesophageal reflux disease, ICS inhaled corticosteroid, LABA long-acting β₂-agonist, LAMA long-acting muscarinic antagonist, LTRA leukotriene receptor antagonist, MITT multiple-inhaler triple therapy, n number of patients with characteristic, N number of patients evaluated, NR not reported, SD standard deviation, SITT single-inhaler triple therapy, TIO tiotropium, UMEC umeclidinium, VI vilanterol

Outcomes

Exacerbations

Over a 12-month period, treatment with triple therapy inhalers administered either via SITT or MITT was associated with reduction of asthma exacerbations compared with baseline rates. Exacerbation outcomes were reported in two studies, one assessing TIO + ICS + LABA MITT versus high-dose ICS + LABA dual therapy [15], while the other assessed FF/UMEC/VI 100/62.5/25 mcg SITT [12, 18] (Table 4). Treatment with MITT significantly reduced exacerbation rates versus ICS + LABA within 6 months (exacerbation rates per 100 patient-years: 64% lower, p < 0.0001) and 12 months following treatment initiation (73% lower, p < 0.0001) [15]. Treatment with FF/UMEC/VI SITT also significantly reduced exacerbation rates versus the pre-treatment period after 12 months by 41% (rate ratio [RR] [95% confidence interval (CI)]: 0.59 [0.52, 0.67], p < 0.001) [12, 18].

Table 4.

Exacerbation outcomes in included studies

Author, year (data source)	Population (accrual)	Treatment	Sample size (N)	Follow-up	Exacerbation definition	Baseline exacerbations		Follow-up exacerbations
						Proportion n (%)	Annualized rate	Proportion n (%)	Annualized rate
Bogart, 2023 [12, 18] (IQVIA PharMetrics Plus database)	Adults with asthma (18 September 2016‒31 March 2020)	SITT: FF/UMEC/VI 100/62.5/25 mcg	890	12 months	Any: asthma-related inpatient or ED visit or outpatient visit requiring SCS	12 months pre-treatment: 376 (42.2)	12 months pre-treatment: 0.84 PPY	3 months: 106 (11.9) 6 months: 171 (19.2) 9 months: 208 (23.4) 12 months: 247 (27.8)	12 months post-treatment: 0.50 PPY, 41% reduction from baseline (p < 0.001)
					Inpatient/ED visit defined	12 months pre-treatment: 77 (8.7)	12 months pre-treatment: 0.12 PPY	3 months: 18 (2.0) 6 months: 33 (3.7) 9 months: 41 (4.6) 12 months: 50 (5.6)	12 months post-treatment: 0.08 PPY, 30% reduction from baseline (p = 0.032)
					SCS defined	12 months pre-treatment: 339 (38.1)	12 months pre-treatment: 0.73 PPY	3 months: 92 (10.3) 6 months: 151 (17.0) 9 months: 186 (20.9) 12 months: 225 (25.3)	12 months post-treatment: 0.41 PPY, 43% reduction from baseline (p < 0.001)
Chipps, 2020 [15] (IQVIA IMS LifeLink PharMetrics Plus and the EMRClaims +)	Patients with asthma (January 2014‒December 2018)	MITT: TIO 1.25 mcg + ICS + LABA	2619	9.7 months	NR	NR	NR	NR	6 months: 41.4 cases/100 PY 12 months: 15.7 cases/100 PY

ED emergency department, FF fluticasone furoate, ICS inhaled corticosteroid, LABA long-acting β₂-agonist, MITT multiple-inhaler triple therapy, NR not reported, PY patient year, PPY per patient year, SCS systemic corticosteroid, SD standard deviation, SITT single-inhaler triple therapy, TIO tiotropium, UMEC umeclidinium, VI vilanterol

Oral Corticosteroid Use

Treatment with triple therapy inhalers led to reduced dependence on oral corticosteroids (OCS) in patients with asthma. There were significant reductions in OCS dispensings observed in patients using SITT compared with the pre-treatment period. By contrast, the reductions for MITT were not statistically significant and larger reductions were reported for dual and monotherapy groups. OCS use was reported in two studies, assessing the TIO 1.25 or 2.5 mcg monotherapy versus TIO 1.25 or 2.5 mcg + ICS + LABA MITT with or without LTRA [11] and FF/UMEC/VI 100/62.5/25 mcg SITT [12, 13] (Table 5). With TIO 1.25 mcg-containing MITT, lower proportions of patients had ≥ 1 rescue OCS dispensing in the post- versus pre-treatment period, with the greatest reduction in the triple therapy with or without LTRA group (pre-treatment: 68.4%, post treatment: 54.2%), though over half of patients still required OCS use [11]. With FF/UMEC/VI SITT, the mean number of OCS dispensing per patient per year was 29% lower in the post- versus pre-treatment period (RR [95% CI]: 0.71 [0.65, 0.77], p < 0.001) [12, 13].

Table 5.

Use of OCS in included studies

Author, year (data source)	Population (accrual)	Treatment	Sample size (N)	Follow-up Mean (SD)	Baseline OCS use		Follow-up OCS use
					Proportion n (%)	Mean/median	Proportion n (%)	Mean/median
Averell, 2019 [11] (IQVIA Health Plan Claims Data)	Adults with asthma (January 2014‒December 2018)	MITT: TIO 1.25 mcg + ICS + LABA ± LTRA	465	201.8 (71.7) days	Maintenance OCS: 0 (0.0) Rescue OCS: 318 (68.4)	NR	Maintenance OCS: 2 (0.4) Rescue OCS: 252 (54.2)	NR
		MITT: TIO 2.5 mcg + ICS + LABA ± LTRA	607	271.9 (108.5) days	Maintenance OCS: 0 (0.0) Rescue OCS: 375 (61.8)	NR	Maintenance OCS: 6 (1.0) Rescue OCS: 356 (58.6)	NR
Bogart, 2022 [13]; Bogart, 2023 [12] (IQVIA PharMetrics Plus database)	Adults with asthma (18 September 2016‒31 March 2020)	SITT: FF/UMEC/VI 100/62.5/25 mcg	890	12 months	OCS exposure: Low (> 0–6 mg/day): 605 (68.0) Medium (> 6–12 mg/day): 35 (3.9) High (> 12 mg/day): 13 (1.5) Chronic OCS use: Maintenance use with mean daily dose ≥ 5 mg: 29 (3.3) Maintenance use with mean daily dose ≥ 10 mg: 26 (2.9)	Mean number of OCS dispensings per person per year: 2.3	OCS exposure: Low (> 0–6 mg/day): 466 (52.4) Medium (> 6–12 mg/day): 30 (3.4) High (> 12 mg/day): 10 (1.1) Chronic OCS use: Maintenance use with mean daily dose ≥ 5 mg: 35 (3.9) Maintenance use with mean daily dose ≥ 10 mg: 27 (3.0)	Mean number of OCS dispensings per person per year: 1.6

FF fluticasone furoate, ICS inhaled corticosteroid, LABA long-acting β₂-agonist, MITT multiple-inhaler triple therapy, NR not reported, OCS oral corticosteroid, SITT single-inhaler triple therapy, UMEC umeclidinium, VI vilanterol

Adherence

Treatment with SITT resulted in better adherence and persistence to inhaler use than MITT in patients with asthma. Treatment adherence or persistence was reported in three studies, two of which assessed ICS + LAMA + LABA MITT [16, 17], and one of which assessed FF/UMEC/VI treatment, comparing SITT versus MITT [14] (Table 6). Following FF/VI + UMEC MITT initiation, the mean standard deviation (SD) proportion of days covered (PDC) was 0.31 (0.27) after 12 months of therapy [16]. Mean (SD) PDC was significantly higher (p < 0.001) in those treated with FF/UMEC/VI SITT versus MITT at 3 months (SITT: 0.68 [0.27]; MITT: 0.59 [0.30]), 6 months (SITT: 0.56 [0.31]; MITT: 0.46 [0.31]), and 12 months post-treatment initiation (SITT: 0.46 [0.33]; MITT: 0.35 [0.30]) [14]. There was a greater likelihood of persistence with SITT versus MITT after 12 months of treatment (adjusted hazard ratio [95% CI]: 1.49 [1.36, 1.60]) with MITT persistence at 15.1% after 12 months compared with 25.9% with SITT [14]. Persistence with MITT after 12 months was also found to be as low as 12% [16]. Probability of LAMA discontinuation with ICS + LAMA + LABA MITT was 40.5% after 3 months of treatment [17].

Table 6.

Medication adherence and persistence outcomes from included studies

Author, year	Population	Treatment	Sample size (N)	Timepoint (months)	Adherence		Persistence
					Measure	Results	Measure	Results
Busse, 2022 [14]	Patients with moderate/severe asthma	SITT: FF/UMEC/VI 100/62.5/25 mcg	1396	3	Proportion of days covered	Mean (SD) [median]: 0.68 (0.27) [0.67]
				6		Mean (SD) [median]: 0.56 (0.31) [0.58]
				12		Mean (SD) [median]: 0.46 (0.33) [0.41]
				NR			Persistence duration	Median: 131 days 12 months: aHR 1.49 (95% CI 1.36, 1.60) [reference: MITT]
		MITT: FF/UMEC/VI 100/62.5/25 mcg	5115	3	Proportion of days covered	Mean (SD) [median]: 0.59 (0.30) [0.60]
				6		Mean SD [median]: 0.46 (0.31) [0.37]
				12		Mean (SD) [median]: 0.35 (0.30) [0.25]
				NR			Persistence duration	Median: 66 days
Oppenheimer, 2022 [16]	Patients with asthma	MITT: FF/UMEC/VI 100/62.5/25 mcg	1831	12	Proportion of days covered	Mean (SD): 0.31 (0.27)	Persistence	12%
Spain, 2022 [17]	Patients with moderate/severe asthma	MITT: LAMA + ICS + LABA	277,373	3			Probability of discontinuation (LAMA)	40.5%

aHR adjusted hazard ratio, CI confidence interval, FF fluticasone furoate, ICS inhaled corticosteroid, LABA long-acting β₂-agonist, LAMA long-acting muscarinic antagonist; MITT multiple-inhaler triple therapy, NR not reported, SD standard deviation, SITT single-inhaler triple therapy, UMEC umeclidinium, VI vilanterol

Additional Outcomes

Data on lung function, clinical remission, quality of life, and safety outcomes that were of interest in the SLR (Table 1) were not reported by any of the identified studies.

Discussion

The SLR identified eight articles from six different real-world studies on outcomes related to treatment with triple therapy for asthma in the US. Overall, exacerbation rates were reduced following triple therapy initiation compared with ICS/LABA dual therapy [12, 15], OCS use was reduced with SITT and LAMA-containing MITT compared with prior treatments [11, 13], and adherence to treatment was significantly improved with SITT versus MITT [14, 16]. More evidence was available for MITT compared with SITT, with only two studies reporting data for SITT [12–14] and one comparing MITT and SITT [14], likely due to the relatively recent approval of SITT in the US (September 2020) [4] and the publication lag for real-world studies following this approval.

Triple therapy reduced exacerbation burden for patients compared with previous treatment over a 12-month period. Compared with pre-treatment, during which the majority of patients were taking ICS/LABA dual therapy, SITT significantly reduced exacerbation rates [12], and MITT significantly reduced exacerbation rates versus high-dose ICS/LABA dual therapy [15]. This aligns with the results from the pivotal CAPTAIN phase 3A trial, which demonstrated numerical reductions in exacerbation rate with triple versus dual therapy in patients with uncontrolled asthma previously on ICS/LABA [7].

Reduction of OCS use is a key treatment goal for asthma due to the associated adverse effects [3]. Triple therapies were associated with reduced OCS use compared with previous dual therapy treatments [11], with significant reductions in OCS use following initiation of SITT [13]. For MITT, reductions were not statistically significant and over half of patients still required OCS use, indicating that their asthma was not well controlled [11]. This may be due to poorer adherence when using multiple inhalers (as shown in this SLR).

Adherence was the most commonly reported outcome, assessed in three of the six studies [14, 16, 17]. Greater treatment adherence and persistence with SITT versus MITT after 12 months of treatment was reported [14, 16]. Since low adherence is associated with poor symptom control and exacerbations [3, 19], and because there is also increased risk of poor adherence when multiple inhalers are used [3], SITT is likely to provide improved clinical outcomes over MITT. Indeed, previous systematic reviews have shown that patient education and physical demonstrations are required for patients to minimize errors in their inhaler technique, and inhaler errors are associated with poorer health outcomes, including asthma symptom control, lung function, exacerbations, and quality of life [20, 21].

The strengths of this study consist of the inclusion of real-world data, which reflects a generalizable population of patients with asthma undergoing treatment across the US, the systematic nature of the review, and the use of a dual independent screening approach. In addition, included studies contained representative patient cohorts and comparator groups drawn from the same source, and outcomes were evaluated from medical claims data rather than using patient self-reporting or interviews. Limitations of this study include potential reporting and selection bias that is inherent to observational and retrospective studies. Reporting bias in this SLR originated from the lack of data on certain outcomes, which may have been available but not reported in the publications. The analysis of observational data in this SLR revealed gaps in the literature regarding the impact of LAMA addition to ICS/LABA dual therapy on real-world clinical outcomes, as no study provided data to enable assessment of lung function, clinical remission, quality of life, or safety. The limited number of studies identified means only a narrative summary is presented, however, our findings highlight important gaps in the literature and opportunities for future research, particularly in addressing the unmet needs of patients with asthma in the US.

Conclusions

This SLR provides evidence of the clinical benefit of adding a LAMA to existing ICS/LABA dual therapy, either as a SITT or MITT, in adult patients with asthma in the US. Overall, triple therapies showed greater clinical benefits for patients with asthma compared with previous non-LAMA containing therapies. Patients may also experience greater potential benefits with SITT versus MITT due to greater treatment adherence. Evidence on the real-world effectiveness of triple therapies in asthma is currently limited, with data primarily available for MITT. Therefore, further research is needed to understand real-world effectiveness of SITT compared with ICS/LABA dual therapy.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Stephen G. Noorduyn, Kejsi Begaj, Sergio Forero-Schwanhaeuser, Alison Moore, and Rosirene Paczkowski contributed to study concept or design and data analysis and interpretation. Amber Martin and Kassandra Schaible contributed to study concept or design and data acquisition, analysis, and interpretation.

Funding

This study was funded by GSK (GSK Study 222898). The study sponsor was involved in several aspects of the research, including the study design, interpretation of data, and writing of the manuscript-style report. The journal’s Rapid Service Fee was funded by GSK.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Stephen G. Noorduyn, Sergio Forero-Schwanhaeuser, Alison Moore, and Rosirene Paczkowski are employees of GSK and hold financial equities in GSK. Kejsi Begaj is an employee of GSK contracted through the Rutgers Health Outcomes, Policy, and Economic (HOPE) program, and does not hold any financial equities in GSK. Amber Martin and Kassandra Schaible are employees of Evidera Inc., a part of Thermo Fisher Scientific, which received funding from GSK to conduct the study.

Ethical Approval

No ethical approval was required for this study as no human participants were recruited or animals used.