Inhaled Reliever Therapies for Asthma: A Systematic Review and Meta-Analysis

Abstract

Importance: The optimal inhaled reliever therapy for asthma remains unclear.

Objective: To compare short-acting β agonists (SABA) alone with SABA combined with inhaled corticosteroids (ICS) and with the fast-onset, long-acting β agonist formoterol combined with ICS for asthma.

Data sources: The MEDLINE, Embase, and CENTRAL databases were searched from January 1, 2020, to September 27, 2024, without language restrictions.

Study selection: Pairs of reviewers independently selected randomized clinical trials evaluating (1) SABA alone, (2) ICS with formoterol, and (3) ICS with SABA (combined or separate inhalers).

Data extraction and synthesis: Two reviewers independently extracted data and assessed risk of bias. Random-effects meta-analyses synthesized outcomes. GRADE (Grading of Recommendations Assessment, Development, and Evaluation) was used to evaluate the certainty of evidence.

Main outcomes and measures: Asthma symptom control (5-item Asthma Control Questionnaire; range, 0-6, lower scores indicate better asthma control; minimum important difference [MID], 0.5 points), asthma-related quality of life (Asthma Quality of Life Questionnaire; range, 1-7, higher scores indicate better quality of life; MID, 0.5 points), risk of severe exacerbations, and risk of serious adverse events.

Results: A total of 27 randomized clinical trials (N = 50 496 adult and pediatric patients; mean age, 41.0 years; 20 288 male [40%]) were included. Compared with SABA alone, both ICS-containing relievers were associated with fewer severe exacerbations (ICS-formoterol risk ratio [RR], 0.65 [95% CI, 0.60-0.72]; risk difference [RD], -10.3% [95% CI, -11.8% to -8.3%]; ICS-SABA RR, 0.84 [95% CI, 0.73-0.95]; RD, -4.7% [95% CI, -8.0% to -1.5%]) with high certainty. Compared with SABA alone, both ICS-containing relievers were associated with improved asthma control (ICS-formoterol RR improvement [MID] in total score, 1.07 [95% CI, 1.04-1.10]; RD, 4.1% [95% CI, 2.3%-5.9%]; ICS-SABA RR, 1.09 [95% CI, 1.03-1.15]; RD, 5.4% [95% CI, 1.8%-8.5%]) with high certainty. In an indirect comparison with ICS-SABA, ICS-formoterol was associated with fewer severe exacerbations (RR, 0.78 [95% CI, 0.66-0.92]; RD, -5.5% [95% CI, -8.4% to -2.0%]) with moderate certainty. Compared with SABA alone, ICS-formoterol (RD, -0.6% [95% CI, -1.3% to 0%]) was not associated with increased risk of serious adverse events (high certainty) and ICS-SABA (RD, 0% [95% CI, -1.1% to 1.2%]) was not associated with increased risk of serious adverse events (moderate certainty).

Conclusions and relevance: In this network meta-analysis of patients with asthma, ICS combined with formoterol and ICS combined with SABA were each associated with reduced asthma exacerbations and improved asthma control compared with SABA alone.

Figure 1.. Study Selection and Flowchart for Systematic Review and Meta-Analysis of Asthma Relievers

^aOne publication reports 2 separate randomized clinical trials.

Figure 2.. Network Meta-Analysis Map for Severe Exacerbation Outcomes With Bronchodilator-Only Reliever or Anti-Inflammatory Relievers^a

Graphical representation of network for all included RCTs. Connecting lines represent head-to-head comparisons between reliever therapies, indicated by nodes. The thickness of lines between nodes is proportional to the number of RCTs comparing the treatments. The size of the nodes is proportional to the number of patients in each treatment. ICS indicates inhaled corticosteroids; RCTs, randomized clinical trials; and SABA, short-acting β agonists. ^aICS with either SABA or formoterol.

Figure 3.. Network Meta-Analysis Results for Severe Exacerbation Outcomes With Bronchodilator-Only Reliever or Anti-Inflammatory Relievers^a

Severe asthma exacerbations defined as use of systemic corticosteroids, emergency department visits, and/or hospitalizations. The network risk ratio incorporates data from both direct and indirect evidence and thus the network risk ratio may have a larger effective sample size than what is listed in the columns. High-certainty evidence indicates that a large randomized trial is unlikely to change the interpretation. Moderate-certainty evidence indicates that a large randomized trial may importantly change the estimate. ICS indicates inhaled corticosteroids; and SABA, short-acting β agonists. ^aICS with either SABA or formoterol. ^bValues represent the number of contributing trials in the network and a conservative estimate of the effective sample size.

Figure 4.. Summary of Network Meta-Analysis Comparisons of Bronchodilator-Only Reliever or Anti-Inflammatory Relievers^a and Asthma Outcomes

The network estimates incorporate data from both direct and indirect evidence and thus the estimates may have a larger effective sample size than what is listed in the columns. Baseline risks for comparators were derived using the median risk among participants assigned to the comparator in the included trials. The risks of severe exacerbations stratified by GINA 2024 steps reflect a continuum of severity; however, many factors beyond GINA 2024 step classification, including recent history of severe exacerbation, contribute to the future risk of exacerbation. As a result, some patients may be classified in 1 category, but their absolute risk and absolute treatment effects may be optimally reflected by another estimate. Thus, the absolute treatment effects presented should not be rigidly interpreted and should be considered as a spectrum of potential risks. GINA steps are based on the classification of asthma maintenance therapies in accordance with the GINA 2024 guidelines. GINA steps range from 1 to 5, with higher GINA steps representing more intense asthma maintenance therapies. ACQ-5 indicates 5-item Asthma Control Questionnaire; AQLQ, Asthma Quality of Life Questionnaire; GINA, Global Initiative for Asthma; ICS, inhaled corticosteroids; and SABA, short-acting β agonists. ^aICS with either SABA or formoterol. ^bValues represent the number of contributing trials in the network and a conservative estimate of the effective sample size. ^cThe ACQ-5 is a patient-reported questionnaire measuring asthma symptom control. Scores range from 0 to 6, with lower scores indicating greater asthma control. The minimum important difference for the ACQ-5 is 0.5 points. ^dDirectionality is reversed compared with other outcomes, as larger values favor the intervention. ^eThe AQLQ is a patient-reported questionnaire measuring asthma-related quality of life. Scores range from 1 to 7, with higher scores indicating greater quality of life. The minimum important difference for the AQLQ is 0.5 points. ^foveal adverse events defined as any adverse event reported by trial authors. ^gSerious adverse events, defined by the US Food and Drug Administration, are adverse events that led to (1) death, (2) life-threatening states, (3) hospitalization, (4) disability or permanent damage, (5) congenital anomalies or birth defects, or (6) required intervention to prevent permanent impairment or damage.