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. 2024 Oct 28:e2422700.
doi: 10.1001/jama.2024.22700. Online ahead of print.

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

Daniel G Rayner  1 , Dario M Ferri  2 , Gordon H Guyatt  1 , Paul M O'Byrne  2 , Romina Brignardello-Petersen  1 , Farid Foroutan  1 , Bradley Chipps  3 , Kaharu Sumino  4 , Tamara T Perry  5 , Sharmilee Nyenhuis  6 , John Oppenheimer  7 , Elliot Israel  8 , Flavia Hoyte  9 , Katherine Rivera-Spoljaric  10 , Ellen McCabe  11 , Susana Rangel  12 , Lindsay E Shade  13 , Valerie G Press  14 , Lisa Hall  15 , Dia Sue-Wah-Sing  16 , Angel Melendez  17 , Hilarry Orr  18 , Tonya Winders  19 , Donna D Gardner  20 , Kathyrn Przywara  21 , Matthew A Rank  22 , Leonard B Bacharier  23 , Giselle Mosnaim  24 , Derek K Chu  1   2
Affiliations

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

Daniel G Rayner et al. JAMA. .

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr O’Byrne reported receiving grants from AstraZeneca; personal fees from AstraZeneca and Teva during the conduct of the study; grants from GSK, Merck, and Jasper Therapeutics; and personal fees from GSK outside the submitted work. Dr Chipps reported receiving consulting fees from AstraZeneca, Boehringer Ingelheim, Genentech, GSK, Novartis, and Sanofi-Regeneron outside the submitted work. Dr Sumino reported receiving grants from National Institutes of Health (NIH); and personal fees from AstraZeneca and Kyorin Pharmaceutical outside the submitted work. Dr Nyenhuis reported receiving consulting fees from Avillion, GSK, and PRIME Education; grants from NIH and Asthma and Allergy Foundation of America; and book royalties from Wolters Kluwer and Springer outside the submitted work. Dr Israel reported receiving personal fees from Amgen, Arrowhead Pharmaceuticals, AstraZeneca, GSK, Merck, Regeneron, Sanofi, Teva, Apogee Therapeutics, Yuhan, Leerink Partners, Jasper Therapeutics, Generate:Biomedicines, and UpToDate; nonfinancial support from Genentech, Sun Pharma, Laurel Pharmaceuticals, Om Pharma, Nestlé, CSL Behring, and Sanofi-Regeneron; and grants from Genentech, Amgen, GSK, AstraZeneca, Avillion, Gossamer Bio, NIH, and Patient-Centered Outcomes Research Institute outside the submitted work. Dr Oppenheimer reported receiving consulting fees from Aquestive Therapeutics, ARS Pharmaceuticals, and GSK; speaking honoraria from Sanofi-Regeneron; and advisory board honoraria from AstraZeneca, Amgen, Sanofi-Regeneron, and GSK outside the submitted work. Dr Hoyte reported receiving speaker and advisory board honoraria from AstraZeneca and Genentech; advisory board honoraria from Sanofi and Teva; steering committee advisory honoraria from GSK; having family who owns stock in Merck and Amgen; and nonfinancial support from Teva and AstraZeneca for writing assistance outside the submitted work. Dr Press reported receiving grants from NIH (R01 and K24) and Agency for Healthcare Research and Quality (R01); and consulting fees from Humana outside the submitted work. Dr Sue-Wah-Sing reported receiving speaking honoraria from AstraZeneca. Dr Winders reported receiving personal fees from AstraZeneca, GSK, Sanofi-Regeneron, and Roche for serving as a speaker and advisor outside the submitted work. Dr Rank reported receiving grants from National Institute on Minority Health and Health Disparities (2U54MD012388-06) and National Heart, Lung, and Blood Institute (U24 HL138998) outside the submitted work. Dr Bacharier reported receiving personal fees from AstraZeneca, Sanofi-Regeneron, Avillion, Vertex, DBV Technologies, Aravax, GSK, Genentech, Recludix, and Kinaset outside the submitted work; book royalties from Elsevier; and being on the science committee at Global Initiative for Asthma. Dr Mosnaim reported receiving grants from Teva, Novartis, GSK, Sanofi-Regeneron, Genentech, AstraZeneca, and Incyte; personal fees from Teva, Novartis, Sanofi-Regeneron, Genentech, AstraZeneca, Aptar, Abbott, Chiesi, Gemic, and Jasper Therapeutics; and nonfinancial support from Teva, Novartis, GSK, Sanofi-Regeneron, Genentech, and Chiesi outside the submitted work. Dr Chu reported receiving grants from Joint Task Force on Practice Parameters, the Canadian Institutes of Health Research, and McMaster University (all provided full academic and editorial independence for the work) during the conduct of the study. No other disclosures were reported.

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