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

Daniel G Rayner; Dario M Ferri; Gordon H Guyatt; Paul M O’Byrne; Romina Brignardello-Petersen; Farid Foroutan; Bradley Chipps; Kaharu Sumino; Tamara T Perry; Sharmilee Nyenhuis; John Oppenheimer; Elliot Israel; Flavia Hoyte; Katherine Rivera-Spoljaric; Ellen McCabe; Susana Rangel; Lindsay E Shade; Valerie G Press; Lisa Hall; Dia Sue-Wah-Sing; Angel Melendez; Hilarry Orr; Tonya Winders; Donna D Gardner; Kathyrn Przywara; Matthew A Rank; Leonard B Bacharier; Giselle Mosnaim; Derek K Chu

doi:10.1001/jama.2024.22700

. 2024 Oct 28;333(2):143–152. doi: 10.1001/jama.2024.22700

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,^✉

¹Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada

²Department of Medicine, McMaster University, Hamilton, Ontario, Canada

³Capital Allergy & Respiratory Disease Center, Sacramento, California

⁴Department of Medicine, Washington University School of Medicine in St Louis, St Louis, Missouri

⁵Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock

⁶Department of Pediatrics, The University of Chicago, Chicago, Illinois

⁷Department of Internal Medicine, University of Medicine and Dentistry of New Jersey/Rutgers New Jersey Medical School, Newark

⁸Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

⁹Department of Medicine, National Jewish Health, Denver, Colorado

¹⁰Division of Allergy, Immunology, and Pulmonary Medicine, Washington University School of Medicine in St Louis, St Louis, Missouri

¹¹Hunter-Bellevue School of Nursing, Hunter College, New York, New York

¹²Los Angeles General Medical Center, Los Angeles, California

¹³Wake Forest University School of Medicine, Winston-Salem, North Carolina

¹⁴Department of Medicine, The University of Chicago, Chicago, Illinois

¹⁵Bertha, Minnesota

¹⁶Canadian Severe Asthma Network, Toronto, Ontario, Canada

¹⁷El Paso, Texas

¹⁸New Philadelphia, Ohio

¹⁹Global Allergy & Airways Patient Platform, Vienna, Austria

²⁰Allergy & Asthma Network, Fairfax, Virginia

²¹Asthma and Allergy Foundation of America, Arlington, Virginia

²²Department of Internal Medicine, Mayo Clinic, Phoenix, Arizona

²³Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee

²⁴Department of Medicine, Endeavor Health, Evanston, Illinois

Accepted for Publication: October 10, 2024.

Published Online: October 28, 2024. doi:10.1001/jama.2024.22700

^✉

Corresponding Author: Derek K. Chu, MD, PhD, Department of Medicine, Department of Health Research Methods, Evidence, and Impact, McMaster University Medical Centre, 1200 Main St W, HSC-Rm 3H30, Hamilton, ON L8N 3Z5, Canada (chudk@mcmaster.ca).

Author Contributions: Drs Rayner and Chu had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Rayner, Ferri, Guyatt, O’Byrne, Chipps, Sumino, Nyenhuis, Oppenheimer, Hoyte, Rivera-Spoljaric, Shade, Hall, Melendez, Rank, Bacharier, Mosnaim, Chu.

Acquisition, analysis, or interpretation of data: Rayner, Ferri, Guyatt, Brignardello-Petersen, Foroutan, Sumino, Perry, Nyenhuis, Israel, Rivera-Spoljaric, McCabe, Rangel, Press, Hall, Sue-Wah-Sing, Melendez, Orr, Winders, Gardner, Przywara, Rank, Bacharier, Mosnaim, Chu.

Drafting of the manuscript: Rayner, Ferri, O’Byrne, Chipps, Sumino, Oppenheimer, Rivera-Spoljaric, Hall, Melendez, Gardner, Chu.

Critical review of the manuscript for important intellectual content: Ferri, Guyatt, O’Byrne, Brignardello-Petersen, Foroutan, Sumino, Perry, Nyenhuis, Oppenheimer, Israel, Hoyte, Rivera-Spoljaric, McCabe, Rangel, Shade, Press, Hall, Sue-Wah-Sing, Melendez, Orr, Winders, Gardner, Przywara, Rank, Bacharier, Mosnaim, Chu.

Statistical analysis: Rayner, Ferri, Chu.

Obtained funding: Chu.

Administrative, technical, or material support: Ferri, O’Byrne, McCabe, Hall, Melendez, Winders, Gardner, Przywara, Rank, Chu.

Supervision: Guyatt, Chipps, Sumino, Nyenhuis, Israel, Hoyte, Rank, Bacharier, Mosnaim, Chu.

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.

Funding/Support: This work was commissioned and funded by the American Academy of Allergy, Asthma, and Immunology (AAAAI) and American College of Allergy, Asthma and Immunology (ACAAI) through the Joint Task Force on Practice Parameters to inform upcoming guidance on the management of severe asthma.

Role of the Funder/Sponsor: The AAAAI/ACAAI Joint Task Force on Practice Parameters contributed to defining the scope of the review, but otherwise had no role in the design, data collection, data analysis, or data interpretation. The funder was provided a copy of this manuscript at the time of submission. The review team had the ability, but not the obligation, to consider the funders’ feedback.

Data Sharing Statement: See Supplement 2.

Additional Contributions: We thank all patient and family partners and panel members for their input throughout the guideline development process. We are grateful to the McMaster Health Sciences Library Interlibrary Loans team for their help. The authors, editors, and journal take a neutral position with respect to territorial claims in published maps and institutional affiliations.

^✉

Corresponding author.

PMCID: PMC11519786 PMID: 39465893

Key Points

Question

In people with asthma, compared with short-acting β agonists (SABA) alone, is the combination of SABA with inhaled corticosteroids (ICS-SABA) and the combination of formoterol with inhaled corticosteroids (ICS-formoterol) associated with better asthma outcomes?

Findings

In this systematic review and network meta-analysis that included 27 randomized clinical trials (50 496 adult and pediatric patients), compared with SABA alone, ICS-SABA was associated with a 4.7% reduction in risk of severe exacerbations and ICS-formoterol was associated with a 10.3% reduction in severe exacerbations, without an increase in adverse events.

Meaning

Both combined ICS with SABA and ICS with formoterol were associated with lower risks of severe asthma exacerbations compared with SABA alone.

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.

This systematic review and network meta-analysis investigates whether inhaled corticosteroids combined with either short-acting beta agonists or formoterol are more effective than short-acting beta agonists alone in reducing exacerbations and improving control in patients with asthma.

Introduction

Asthma has a global prevalence of 262 million people and is characterized by airway inflammation and variable airflow obstruction.¹ Reliever inhalers, including bronchodilator-only relievers (short-acting β agonists [SABA]), such as albuterol, or inhaled corticosteroids (ICS) with either SABA or formoterol, are indicated for patients with asthma to acutely relieve symptoms of dyspnea, wheezing, or cough.¹ Although the Global Initiative for Asthma (GINA)¹ and the National Asthma Education and Prevention Program² recommend ICS-formoterol as the preferred reliever over SABA alone, the US Food and Drug Administration (FDA) recently approved ICS-SABA as a reliever inhaler; the optimal asthma reliever remains unclear.³ Furthermore, guideline recommendations do not sufficiently differentiate between ICS-SABA and SABA-alone relievers, and the relative benefits of ICS-formoterol compared with ICS-SABA on clinical outcomes remain unclear.^1,2 This systematic review evaluated inhaled relievers for improving outcomes in asthma.

Methods

This prospectively registered systematic review (PROSPERO CRD42023486453) is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (eMethods 1 in Supplement 1).

Search Strategy and Selection Criteria

We systematically searched the MEDLINE, Embase, and CENTRAL databases from January 1, 2020, to September 27, 2024, for published and unpublished randomized clinical trials (RCTs) reported in any language that evaluated eligible inhaled reliever therapies for any type of asthma (see eMethods 2 in Supplement 1 for search strategies used for each database). Additionally, studies included in prior relevant systematic reviews were evaluated for inclusion.^4,5 To identify additional eligible studies, we searched reference lists of included studies and the articles citing them using Web of Science (all databases). Eligible inhaled reliever therapies included: (1) bronchodilator-only relievers (SABA); (2) fast-onset, long-acting β agonist alone; (3) ICS and fast-onset, long-acting β agonist; and (4) ICS and SABA. Eligible trials compared different reliever therapies and had similar levels of maintenance therapy between clinical trial groups (defined by GINA 2024 step classifications).¹

Study Selection and Data Extraction

Two reviewers (D.G.R., D.M.F.) screened titles and abstracts and reviewed full texts independently using Covidence (Veritas Health). Two reviewers (D.G.R., D.M.F.) independently extracted data using standardized and prepiloted extraction forms. Reviewers resolved disagreements through discussion and, if necessary, through discussion with a third reviewer (D.K.C.). We collected study bibliographic information, trial design, patient characteristics, intervention and comparator characteristics, outcomes according to randomized group, and sources of funding. See eMethods 3 in Supplement 1 for additional methods details.

Outcomes

Outcomes were selected and prioritized based on input from a multistakeholder guideline development group, including clinicians (internists, pediatricians, nurse practitioners, physician assistants), asthma experts (allergists-immunologists and pulmonologists), and patient and caregiver partners (people with asthma and their family or caregivers). Outcomes consisted of asthma symptom control, asthma-related quality of life, severe asthma exacerbations (defined as use of systemic corticosteroids, emergency department visits, and/or hospitalizations) and their individual components, adverse events (overall, serious adverse events, treatment discontinuations due to adverse events), and overall mortality.

Risk-of-Bias Assessment

Following a similar approach to the data extraction process, 2 reviewers (D.G.R., D.M.F.) assessed the risk of bias for each outcome of each study using a modified Cochrane Risk of Bias tool version 2 (RoB 2.0) for RCTs.⁶ We further classified assessments with some concerns regarding risk of bias as some concerns, probably high and some concerns, probably low. If at least 1 domain was high or probably high risk for bias, we considered the study outcome to be at high risk of bias. Potential examples for classifying a study outcome as overall high risk of bias included a lack of allocation concealment, high rates of missing data, and the use of subjective outcome measurements in an unblinded setting.

Evaluating Evidence Certainty

We evaluated the certainty (quality) of the evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach,^7,8 with certainty being classified as high, moderate, low, or very low. Evidence from RCTs starts at high certainty and may be rated down for risk of bias, imprecision, inconsistency, indirectness, publication bias, intransitivity (the potential imbalance of effect modifiers among studies forming an indirect comparison), and incoherence (the potential disagreement between direct and indirect evidence).^7,8 Bias was assessed by considering the contribution and consistency of studies at high vs low risk of bias, imprecision and inconsistency were assessed by comparing the individual and pooled estimates and CIs to small effect thresholds established by our linked guideline panel,^7,8,9 and indirectness was assessed by evaluating whether the studies addressed the review question. We evaluated for intransitivity by evaluating for imbalanced distribution of credible effect modifiers comprising comparisons among the networks and comparing estimates from unadjusted models with those produced by models adjusted for covariates (eg, GINA 2024 steps¹). We assessed incoherence by assessing the consistency and contribution of direct and indirect estimates to the network estimates using node-splitting models.

Data Synthesis

We used the R meta package (R Foundation) to calculate pairwise effect estimates for each pairwise comparison using restricted maximum likelihood random-effects meta-analyses (eMethods 3 in Supplement 1). Following GRADE guidance, we used linear transformation to the most commonly used scale if multiple instruments measured the same outcome.⁹

We used the R netmeta package (R Foundation) to perform frequentist random-effects network meta-analyses using restricted maximum likelihood estimators (eMethods 3 in Supplement 1). We calculated absolute risks using the median risk among participants assigned to bronchodilator-only relievers (SABA) and ICS-SABA as baseline risks in the included trials in primary analyses (eMethods 3 in Supplement 1).¹⁰ For severe exacerbation estimates, recognizing the difference in exacerbation risk between groups of patients, we generated absolute risk estimates for different GINA 2024 steps (based on the classification of asthma maintenance therapies in accordance with the GINA 2024 guidelines¹), with GINA step 1 patients representing a lower-risk group and GINA step 4 patients representing a higher-risk group. For all continuous outcomes, we conducted responder analyses by modeling risk differences and 95% CIs for achieving at least the minimum important difference (MID) for each scale (5-item Asthma Control Questionnaire [ACQ-5]: 0.5-point decrease; Asthma Quality of Life Questionnaire [AQLQ]: 0.5-point increase). We calculated the effective sample size for each indirect comparison from the network meta-analysis.¹¹

We assessed publication bias by inspecting funnel plots for small study effects, evaluating the relationship between study findings and funding, and through a review of trial registries (using Cochrane CENTRAL, which includes ClinicalTrials.gov and the World Health Organization’s International Clinical Trials Registry Platform) for completed trials without publication or reporting of results.¹²

eMethods 3 in Supplement 1 details the subgroup (risk of bias, age, therapy intensity [defined by the GINA 2024 step classifications¹], and asthma type [type 2 high vs non–type 2 high, defined using baseline peripheral blood eosinophil count]), with credibility appraised using the Instrument for assessing the Credibility of Effect Modification Analyses¹³ and sensitivity analyses. Sensitivity analyses were based on the use of imputation of missing SDs using established Cochrane guidance (eMethods 3 in Supplement 1), reliever strategies using combined or separate inhalers, and between-study variance estimators.

We used R version 4.3.2 (R Foundation) for pairwise and network meta-analyses and Stata version 18 (StataCorp) for sample size calculations.

Results

The systematic search yielded 3179 unique citations and 201 potentially relevant full articles. Of these, 26 articles^{14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39} reporting 27 unique RCTs (50 496 patients) were included (Figure 1). The Table summarizes characteristics of the included trials. Participants in the 27 RCTs had a mean age of 41.0 years (range of means, 10.8-49.4 years) and the median percentage of male participants was 41% (range, 16%-60%). The treatment duration of the included RCTs was a median of 26 weeks (range, 3-65 weeks). All included RCTs of fast-onset, long-acting β agonists (alone or combined with an ICS) as a reliever therapy evaluated formoterol. Two trials (7%) evaluated patient populations composed entirely of people aged 18 years or younger (pediatrics).^24,38 Consistent associations were found between adult and pediatric studies for all outcomes. All included trials were conducted in outpatient settings. No included clinical trials evaluated levalbuterol. For all RCTs, prescription of oral corticosteroids for severe exacerbations was based on physician discretion.

Figure 1. — ^aOne publication reports 2 separate randomized clinical trials.³²

Table. Characteristics of Included Trials in the Systematic Review and Meta-Analysis of Asthma Inhaled Reliever Therapies (N = 27)^a.

Source	Randomized participants, No.	Age, mean (SD) [range], y	No. (%)		Follow-up, wk	GINA step^b	Interventions and comparators (No. randomized per group)
Source	Randomized participants, No.	Age, mean (SD) [range], y	Male	Female	Follow-up, wk	GINA step^b	Interventions and comparators (No. randomized per group)
Israel et al,¹⁴ 2022 (PREPARE)	1201	47.7 (13.7) [18-75]	196 (16)	1005 (84)	65	3	Any SABA (601) Beclomethasone dipropionate, 80 μg + any SABA (600)
Papi et al,¹⁵ 2022 (MANDALA)	3132	49.4 (16.4) [≥4]	1102 (35)	2030 (75)	24	4	Albuterol, 180 μg (1059) Budesonide/albuterol, 180/80-160 μg (2073)
NCT03924635¹⁶	42	49.2 (15.8) [≥18]	15 (36)	27 (64)	24	3	Budesonide/formoterol, 100-200/6 μg (24) Salbutamol, 100 μg (18)
Beasley et al,¹⁷ 2019 (Novel START)	675	35.6 (14.1) [18-75]	307 (46)	368 (54)	52	1	Albuterol, 200 μg (227) Budesonide/formoterol, 200/6 μg (222)
O’Byrne et al,¹⁸ 2018 (SYGMA 1)	3849	39.6 (16.6) [≥12]	1496 (39)	2353 (61)	52	1	Terbutaline, 0.5 mg (1280) Budesonide/formoterol, 200/6 μg (1279)
Lazarinis et al,¹⁹ 2014	66	28.4 (11.1) [≥12]	30 (45)	36 (55)	6	1	Terbutaline, 0.5 mg (22) Budesonide/formoterol, 200/6 μg (23)
Takeyama et al,²⁰ 2014	63	40.0 (NR) [16-80]	23 (37)	40 (63)	48	4	Salbutamol, 100 μg (31) Budesonide/formoterol, 160/4.5 μg (32)
Atienza et al,²¹ 2013 (SAKURA)	2091	45.7 (14.5) [≥16]	677 (32)	1413 (68)	52	3	Terbutaline, 0.4 mg (1042) Budesonide/formoterol, 160/4.5 μg (1049)
Papi et al,²² 2013	1714	48.0 (NR) [≥18]	657 (38)	1057 (62)	48	2	Salbutamol, 100 μg (857) Beclomethasone dipropionate/formoterol, 100/6 μg (857)
Patel et al,²³ 2013 (SMART)	303	42.0 (14.1) [16-65]	94 (31)	209 (69)	24	4	Salbutamol, 100 μg (152) Budesonide/formoterol, 200/6 μg (151)
Martinez et al,²⁴ 2011 (TREXA)	288	10.8 (3.1) [6-18]	159 (55)	129 (45)	44	1 or 2	Albuterol, 180 μg (146) Beclomethasone, 80 μg + albuterol, 180 μg (142)^c
Ställberg et al,²⁵ 2008 (SHARE)	1776	43.5 (NR) [≥12]	733 (41)	1043 (59)	52	3	Terbutaline, 0.25-0.5 mg (456) Budesonide/formoterol, 80-160/4.5 μg (887)
Bousquet et al,²⁶ 2007	2309	39.5 (NR) [≥12]	877 (38)	1432 (62)	24	4	Terbutaline, 0.5 mg (1155) Budesonide/formoterol, 160/4.5 μg (1154)
Kuna et al,²⁷ 2007	3335	NR [≥12]	1415 (42)	1920 (58)	24	3	Terbutaline, 0.5 mg (2228) Budesonide/formoterol, 160/4.5 μg (1107)
Papi et al, 2007²⁸ (BEST)	466	38.8 (13.6) [18-65]	192 (41)	274 (59)	26	1	Albuterol, 100 μg (119) Beclomethasone/albuterol, 250/100 μg (124)
Cheung et al,²⁹ 2006	211	44.7 (13.4) [≥18]	105 (50)	106 (50)	3	2	Salbutamol, 100 μg (211) Formoterol, 4.5 μg (211)
Haahtela et al,³⁰ 2006 (SOMA)	93	35.7 (11.4) [15-63]	28 (30)	65 (70)	24	1	Formoterol, 4.5 μg (48) Budesonide/formoterol, 160/4.5 μg (45)
Rabe et al,³¹ 2006	3394	42.3 (NR) [≥12]	1345 (40)	2049 (60)	52	3	Terbutaline, 0.4 mg (1141) Formoterol, 4.5 μg (1140) Budesonide/formoterol, 160/4.5 μg (1113)
Chuchalin et al,³² 2005 (1)	675	23.5 (NR) [≥6]	402 (60)	273 (40)	52	1	Terbutaline, 0.5 mg (342) Formoterol, 4.5 μg (333)
Chuchalin et al,³² 2005 (2)	455	25.0 (NR) [≥6]	232 (51)	223 (49)	52	2	Terbutaline, 0.5 mg (227) Formoterol, 4.5 μg (228)
O’Byrne et al,³³ 2005	2760	35.7 (NR) [4-80]	1231 (45)	1529 (55)	52	3	Terbutaline, 0.4 mg (909) Budesonide/formoterol, 80/4.5 μg (925)
Vogelmeier et al,³⁴ 2005	2143	45.0 (NR) [≥12]	879 (41)	1264 (59)	54	4	Salbutamol, 100 μg (1076) Budesonide/formoterol, 160/4.5 μg (1067)
Jain et al,³⁵ 2004	60	NR	NR	NR	26	NR	Albuterol, 200 μg (31) Formoterol, 4.5 μg (29)
Pauwels et al,³⁶ 2003 (RELIEF)	18 124	39.0 (NR) [≥6]	7793 (43)	10 331 (57)	24	2	Salbutamol, 200 μg (9060) Formoterol, 4.5 μg (9064)
Ind et al,³⁷ 2002	357	47.0 (NR) [≥18]	143 (40)	214 (60)	12	1	Terbutaline, 0.5 mg (181) Formoterol 4.5 μg (176)
Villa et al,³⁸ 2002	552	NR [6-17]	NR	NR	26	NR	Terbutaline, 0.25 mg (276) Formoterol, 4.5 μg (276)
Tattersfield et al,³⁹ 2001	362	47.0 (NR) [≥18]	157 (43)	205 (57)	12	2	Terbutaline, 0.5 mg (180) Formoterol, 4.5 μg (182)

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Abbreviations: GINA, Global Initiative for Asthma; NR, not reported; SABA, short-acting β agonist.

^{^a}

Smoking status, reported in 10 trials (37%), was 0%-19% current, 8%-42% prior, and 44%-87% never.

^{^b}

GINA step is based on the classification of asthma maintenance therapies in accordance with the GINA 2024 guidelines.¹ GINA steps range from 1 to 5, with higher steps representing more intense asthma maintenance therapies.

^{^c}

Interventions administered using separate inhalers.

Of 138 assessments of risk of bias for study outcomes, 113 (82%) had a low overall risk of bias (eResults 1 and 2 in Supplement 1). Visual inspection of funnel plots, comparison of direct and indirect estimates, and evaluation of potential effect modifier distributions across studies showed no strong evidence of small study effects, network incoherence, or intransitivity (eResults 3-5 in Supplement 1). Network plots and league tables are shown in eResults 5 and 6 in Supplement 1.

Outcomes

Severe Exacerbations

A total of 22 RCTs,^{14,15,16,17,18,20,21,22,23,24,25,26,27,28,31,32,33,34,36,37,39} including 45 117 patients, provided data for the outcome of severe asthma exacerbations (Figures 2 and 3; eResults 7 in Supplement 1). Compared with bronchodilator-only relievers, high-certainty evidence showed that ICS-formoterol was associated with lower risk of severe exacerbations (risk ratio [RR], 0.65 [95% CI, 0.60-0.72]; risk difference [RD], −10.3% [95% CI, −11.8% to −8.3%]). High-certainty evidence demonstrated that ICS-SABA (RR, 0.84 [95% CI, 0.73-0.95]; RD, −4.7% [95% CI, −8.0% to −1.5%]) was associated with lower risk of severe exacerbations. Similar associations for asthma-related hospitalizations and emergency department visits were observed (eResults 5 in Supplement 1). Compared with ICS-SABA, moderate-certainty evidence showed that ICS-formoterol was associated with lower risk of severe exacerbations (RR, 0.78 [95% CI, 0.66-0.92]; RD, −5.5% [95% CI, −8.4% to −2.0%]; GINA step 4). However, these absolute RDs became smaller in lower-risk patient populations (RD, −1.9% [95% CI, −3.0% to −0.7%]; GINA step 1) (Figure 4).

Figure 2. — 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. — 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. — 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.¹ 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.

Asthma Symptom Control

A total of 22 RCTs,^{14,15,16,17,18,19,20,21,22,23,24,26,27,28,29,30,31,32,33,34,39} including 25 233 patients, were identified for analyses of asthma symptom control measured using the ACQ-5 (scores range from 0-6, with lower scores indicating better asthma control). Compared with bronchodilator-only relievers, high-certainty evidence showed ICS-formoterol (mean difference, −0.09 [95% CI, −0.13 to −0.05]; RR corresponding to ≥0.5-point improvement [MID] in total score, 1.07 [95% CI, 1.04-1.10]; RD, 4.1% [95% CI, 2.3%-5.9%]) and ICS-SABA (mean difference, −0.12 [95% CI, −0.19 to −0.04]; RR corresponding to ≥0.5-point improvement [MID] in total score, 1.09 [95% CI, 1.03-1.15]; RD, 5.4% [95% CI, 1.8%-8.5%]) were associated with improvements in asthma symptom control. These effect sizes were small and potentially unimportant to patients. Low-certainty evidence suggested little to no difference between ICS-SABA and ICS-formoterol in asthma symptom control (Figure 4).

Asthma-Related Quality of Life

A total of 5 RCTs,^{15,18,24,27,34} including 9688 patients, were identified for asthma-related quality of life analyses. As measured using the AQLQ (scores range from 1-7, with higher scores indicating better quality of life), compared with bronchodilator-only relievers, moderate-certainty evidence showed ICS-formoterol (mean difference, 0.04 [95% CI, −0.04 to 0.13]; RR corresponding to ≥0.5-point improvement [MID] in total score, 1.03 [95% CI, 0.97-1.10]; RD, 1.6% [95% CI, −1.6% to 5.2%]) and ICS-SABA (mean difference, 0.07 [95% CI, −0.06 to 0.19]; RR corresponding to ≥0.5-point improvement [MID] in total score, 1.05 [95% CI, 0.95-1.15]; RD, 2.8% [95% CI, −2.4% to 7.6%]) were likely associated with greater asthma-related quality of life. These point estimates are likely consistent with improvements in asthma-related quality of life, albeit by small amounts that may be unimportant to patients. Low-certainty evidence suggested little to no difference between ICS-SABA and ICS-formoterol in asthma-related quality of life (Figure 4).

Safety Outcomes

There were no associations of increased risk of harm between inhaler groups (Figure 4). Twelve RCTs (31 228 patients)^{15,16,17,18,19,21,22,29,32,33,36} were included in these analyses for any adverse event (moderate certainty). Twenty-three RCTs (41 933 patients)^{14,15,16,17,18,19,21,22,23,24,27,28,30,31,32,33,34,35,36,37,38,39} were included in analyses of serious adverse events (ICS-formoterol vs SABA alone, high certainty; ICS-SABA vs SABA alone, moderate certainty). Among the 15 studies (65%)^{14,15,17,18,21,22,23,24,27,28,30,31,36,37,39} that reported specific causes of serious adverse events, the 2 most commonly reported were cardiovascular events (ICS-formoterol vs SABA alone: RD, −0.2% [95% CI, −0.5% to 0.1%]; ICS-SABA vs SABA alone: RD, −0.2% [95% CI, −0.7% to 0.4%]) and pneumonia (ICS-formoterol vs SABA alone: RD, 0.1% [95% CI, −0.1% to 0.2%]; ICS-SABA vs SABA alone: RD, 0.2% [95% CI, −0.5% to 0.8%]) (eResults 8 in Supplement 1). Twenty-one RCTs (26 539 patients)^{15,17,18,19,21,22,23,25,26,27,28,29,30,31,32,33,34,37,38,39} were included in analyses for inhaler discontinuations due to an adverse event (ICS-formoterol vs SABA alone: RD, −0.7% [95% CI, −1.2% to −0.3%], high certainty; ICS-SABA vs SABA alone: RD, 0.3% [95% CI, −0.8% to 1.4%], moderate certainty). A total of 15 RCTs (40 425 patients)^{14,15,17,18,19,21,22,23,26,27,31,32,34,36} informed analyses for mortality (ICS-formoterol vs SABA alone: RD, 0% [95% CI, −0.1% to 0.1%], high certainty; ICS-SABA vs SABA alone: RD, 0.1% [95% CI, −0.3% to 0.4%], high certainty).

Other Analyses

In subgroup analyses, results were consistent by risk of bias, patient age, therapy intensity, and asthma type (eResults 9 in Supplement 1). Results were consistent using different imputation methods, data analysis approaches, and inhaler type (combined vs separate) (eResults 9 in Supplement 1).

Discussion

This systematic review and meta-analysis of 27 RCTs including 50 496 adult and pediatric patients with asthma provided high-certainty evidence that, compared with bronchodilator-only relievers, anti-inflammatory reliever treatment with ICS-formoterol and ICS-SABA (combined or separate inhalers) was associated with reduced risks of severe exacerbations and modest improvements in asthma symptom control. Compared with bronchodilator-only relievers, both anti-inflammatory reliever strategies were associated with no statistically significant difference in adverse event risk. Compared with ICS-SABA, ICS-formoterol was likely associated with lower risks of severe exacerbations, but may not be associated with improvements in asthma symptoms or asthma-related quality of life.

This systematic review differs from previous reviews^4,5 in the following ways: first, compared with prior reviews, the current review used a comprehensive search strategy to identify relevant RCTs evaluating inhaled reliever therapies, included 12 trials^{16,19,24,28,29,32,35,36,37,38,39} not covered in previous reviews, and included clinical trials for the recently FDA-approved ICS-SABA studies.^14,15 Second, this review selected clinical trials that compared different reliever strategies with the same maintenance strategies in the compared groups. Third, this review assessed patient-important outcomes. Fourth, this review did not include surface under the cumulative ranking curve for its conclusions. Surface under the cumulative ranking curve results may be less valid than the analyses used for these results. Full elaboration of the implications of the study results to clinical practice, policy, and asthma mechanistic understanding is beyond the scope of this meta-analysis.

Limitations

This review has limitations. First, none of the identified RCTs directly compared ICS-formoterol with ICS-SABA (combined or separate inhalers) as reliever inhalers. Estimate imprecision reduced certainty about these results and findings reported here could change with a large RCT directly comparing these 2 inhalers. Second, although the included RCTs evaluated severe exacerbations as a composite of asthma-related hospitalizations, asthma-related emergency department visits, and oral corticosteroid use, few clinical trials (9 of 22) reported the effects of inhaled reliever therapies on the individual outcomes. Estimates from the small number of RCTs that reported each component separately were consistent with results for the composite outcome. Third, only 2 of the included RCTs were limited to pediatric populations.^24,38 Fourth, none of the included trials reported on whether ipratropium use was allowed in combination with albuterol. Fifth, similar to other reviews, assessing publication bias involved the assessment of funnel plots. Using funnel plots, which assess for small study effects, to infer publication bias without additional data relies on untestable assumptions.

Conclusions

In this 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.

Supplement 1.

eMethods 1. Completed PRISMA 2020 and PRISMA NMA checklists.

eMethods 2. Search strategies – from January 1st, 2020 to September 27th, 2024.

eMethods 3. Summary of author contact attempts and responses.

eResults 1. Risk of bias assessments.

eResults 2. GRADE assessments for network meta-analysis estimates.

eResults 3. Network intransitivity assessments.

eResults 4. Funnel plots.

eResults 5. Comparative effects, network plots, and incoherence assessments, of bronchodilator only reliever or anti-inflammatory relievers (inhaled corticosteroids with either SABA or formoterol) for each asthma outcome.

eResults 6. Pairwise forest plots for each comparison and outcome.

eResults 7. Definitions of severe exacerbations used in the included trials.

eResults 8. Analysis of commonly reported serious adverse events in the included trials.

eResults 9. Subgroup and sensitivity analyses.

eDiscussion 1. Sample size calculations.

jama-e2422700-s001.pdf^{(4.3MB, pdf)}

Supplement 2.

Data Sharing Statement

jama-e2422700-s002.pdf^{(12.7KB, pdf)}

References

1.Global Initiative for Asthma . 2024. GINA report, global strategy for asthma management and prevention. September 25, 2024. Accessed September 28, 2024. https://ginasthma.org/2024-report/
2.Cloutier MM, Dixon AE, Krishnan JA, Lemanske RF Jr, Pace W, Schatz M. Managing asthma in adolescents and adults: 2020 asthma guideline update from the National Asthma Education and Prevention Program. JAMA. 2020;324(22):2301-2317. doi: 10.1001/jama.2020.21974 [DOI] [PubMed] [Google Scholar]
3.Krings JG, Beasley R. The role of ICS-containing rescue therapy versus SABA alone in asthma management today. J Allergy Clin Immunol Pract. 2024;12(4):870-879. doi: 10.1016/j.jaip.2024.01.011 [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Rogliani P, Ritondo BL, Ora J, Cazzola M, Calzetta L. SMART and as-needed therapies in mild-to-severe asthma: a network meta-analysis. Eur Respir J. 2020;56(3):2000625. doi: 10.1183/13993003.00625-2020 [DOI] [PubMed] [Google Scholar]
5.Sobieraj DM, Weeda ER, Nguyen E, et al. Association of inhaled corticosteroids and long-acting β-agonists as controller and quick relief therapy with exacerbations and symptom control in persistent asthma: a systematic review and meta-analysis. JAMA. 2018;319(14):1485-1496. doi: 10.1001/jama.2018.2769 [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Higgins JPT, Thomas J, Chandler J, et al. Cochrane Handbook for Systematic Reviews of Interventions. 2nd ed. John Wiley & Sons; 2019. doi: 10.1002/9781119536604 [DOI] [Google Scholar]
7.Chu DK, Golden DBK, Guyatt GH. Translating evidence to optimize patient care using GRADE. J Allergy Clin Immunol Pract. 2021;9(12):4221-4230. doi: 10.1016/j.jaip.2021.09.035 [DOI] [PubMed] [Google Scholar]
8.Izcovich A, Chu DK, Mustafa RA, Guyatt G, Brignardello-Petersen R. A guide and pragmatic considerations for applying GRADE to network meta-analysis. BMJ. 2023;381:e074495. doi: 10.1136/bmj-2022-074495 [DOI] [PubMed] [Google Scholar]
9.Guyatt GH, Thorlund K, Oxman AD, et al. GRADE guidelines: 13. preparing summary of findings tables and evidence profiles—continuous outcomes. J Clin Epidemiol. 2013;66(2):173-183. doi: 10.1016/j.jclinepi.2012.08.001 [DOI] [PubMed] [Google Scholar]
10.Guyatt GH, Oxman AD, Santesso N, et al. GRADE guidelines: 12. preparing summary of findings tables—binary outcomes. J Clin Epidemiol. 2013;66(2):158-172. doi: 10.1016/j.jclinepi.2012.01.012 [DOI] [PubMed] [Google Scholar]
11.Thorlund K, Mills EJ. Sample size and power considerations in network meta-analysis. Syst Rev. 2012;1:41. doi: 10.1186/2046-4053-1-41 [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Guyatt GH, Oxman AD, Montori V, et al. GRADE guidelines: 5. rating the quality of evidence—publication bias. J Clin Epidemiol. 2011;64(12):1277-1282. doi: 10.1016/j.jclinepi.2011.01.011 [DOI] [PubMed] [Google Scholar]
13.Schandelmaier S, Briel M, Varadhan R, et al. Development of the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN) in randomized controlled trials and meta-analyses. CMAJ. 2020;192(32):E901-E906. doi: 10.1503/cmaj.200077 [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Israel E, Cardet JC, Carroll JK, et al. Reliever-triggered inhaled glucocorticoid in Black and Latinx adults with asthma. N Engl J Med. 2022;386(16):1505-1518. doi: 10.1056/NEJMoa2118813 [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Papi A, Chipps BE, Beasley R, et al. Albuterol-budesonide fixed-dose combination rescue inhaler for asthma. N Engl J Med. 2022;386(22):2071-2083. doi: 10.1056/NEJMoa2203163 [DOI] [PubMed] [Google Scholar]
16.AstraZeneca. An exploratory study to characterise changes in airway inflammation, symptoms, lung function and reliever use in adult asthma patients. January 18, 2023. Accessed June 20, 2024. https://clinicaltrials.gov/study/NCT03924635
17.Beasley R, Holliday M, Reddel HK, et al. ; Novel START Study Team . Controlled trial of budesonide-formoterol as needed for mild asthma. N Engl J Med. 2019;380(21):2020-2030. doi: 10.1056/NEJMoa1901963 [DOI] [PubMed] [Google Scholar]
18.O’Byrne PM, FitzGerald JM, Bateman ED, et al. Inhaled combined budesonide-formoterol as needed in mild asthma. N Engl J Med. 2018;378(20):1865-1876. doi: 10.1056/NEJMoa1715274 [DOI] [PubMed] [Google Scholar]
19.Lazarinis N, Jørgensen L, Ekström T, et al. Combination of budesonide/formoterol on demand improves asthma control by reducing exercise-induced bronchoconstriction. Thorax. 2014;69(2):130-136. doi: 10.1136/thoraxjnl-2013-203557 [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Takeyama K, Kondo M, Tagaya E, et al. Budesonide/formoterol maintenance and reliever therapy in moderate-to-severe asthma: effects on eosinophilic airway inflammation. Allergy Asthma Proc. 2014;35(2):141-147. doi: 10.2500/aap.2014.35.3729 [DOI] [PubMed] [Google Scholar]
21.Atienza T, Aquino T, Fernández M, et al. Budesonide/formoterol maintenance and reliever therapy via Turbuhaler versus fixed-dose budesonide/formoterol plus terbutaline in patients with asthma: phase III study results. Respirology. 2013;18(2):354-363. doi: 10.1111/resp.12009 [DOI] [PubMed] [Google Scholar]
22.Papi A, Corradi M, Pigeon-Francisco C, et al. Beclometasone-formoterol as maintenance and reliever treatment in patients with asthma: a double-blind, randomised controlled trial. Lancet Respir Med. 2013;1(1):23-31. doi: 10.1016/S2213-2600(13)70012-2 [DOI] [PubMed] [Google Scholar]
23.Patel M, Pilcher J, Pritchard A, et al. ; SMART Study Group . Efficacy and safety of maintenance and reliever combination budesonide-formoterol inhaler in patients with asthma at risk of severe exacerbations: a randomised controlled trial. Lancet Respir Med. 2013;1(1):32-42. doi: 10.1016/S2213-2600(13)70007-9 [DOI] [PubMed] [Google Scholar]
24.Martinez FD, Chinchilli VM, Morgan WJ, et al. Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial. Lancet. 2011;377(9766):650-657. doi: 10.1016/S0140-6736(10)62145-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Ställberg B, Ekström T, Neij F, et al. ; SHARE trial group . A real-life cost-effectiveness evaluation of budesonide/formoterol maintenance and reliever therapy in asthma. Respir Med. 2008;102(10):1360-1370. doi: 10.1016/j.rmed.2008.06.017 [DOI] [PubMed] [Google Scholar]
26.Bousquet J, Boulet LP, Peters MJ, et al. Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs high-dose salmeterol/fluticasone. Respir Med. 2007;101(12):2437-2446. doi: 10.1016/j.rmed.2007.07.014 [DOI] [PubMed] [Google Scholar]
27.Kuna P, Peters MJ, Manjra AI, et al. Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations. Int J Clin Pract. 2007;61(5):725-736. doi: 10.1111/j.1742-1241.2007.01338.x [DOI] [PMC free article] [PubMed] [Google Scholar]
28.Papi A, Canonica GW, Maestrelli P, et al. ; BEST Study Group . Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N Engl J Med. 2007;356(20):2040-2052. doi: 10.1056/NEJMoa063861 [DOI] [PubMed] [Google Scholar]
29.Cheung D, van Klink HC, Aalbers R; OZON study group . Improved lung function and symptom control with formoterol on demand in asthma. Eur Respir J. 2006;27(3):504-510. doi: 10.1183/09031936.06.00006805 [DOI] [PubMed] [Google Scholar]
30.Haahtela T, Tamminen K, Malmberg LP, et al. Formoterol as needed with or without budesonide in patients with intermittent asthma and raised NO levels in exhaled air: a SOMA study. Eur Respir J. 2006;28(4):748-755. doi: 10.1183/09031936.06.00128005 [DOI] [PubMed] [Google Scholar]
31.Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG. Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study. Lancet. 2006;368(9537):744-753. doi: 10.1016/S0140-6736(06)69284-2 [DOI] [PubMed] [Google Scholar]
32.Chuchalin A, Kasl M, Bengtsson T, Nihlen U, Rosenborg J. Formoterol used as needed in patients with intermittent or mild persistent asthma. Respir Med. 2005;99(4):461-470. doi: 10.1016/j.rmed.2004.09.012 [DOI] [PubMed] [Google Scholar]
33.O’Byrne PM, Bisgaard H, Godard PP, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med. 2005;171(2):129-136. doi: 10.1164/rccm.200407-884OC [DOI] [PubMed] [Google Scholar]
34.Vogelmeier C, D’Urzo A, Pauwels R, et al. Budesonide/formoterol maintenance and reliever therapy: an effective asthma treatment option? Eur Respir J. 2005;26(5):819-828. doi: 10.1183/09031936.05.00028305 [DOI] [PubMed] [Google Scholar]
35.Jain A, Raghuram J. Randomized controlled study of the safety and efficacy of PRN formoterol compared to PRN albuterol for the management of asthma. American Thoracic Society 100th International Conference; May 21-26, 2004; Orlando, Florida. [Google Scholar]
36.Pauwels RA, Sears MR, Campbell M, et al. ; RELIEF Study investigators . Formoterol as relief medication in asthma: a worldwide safety and effectiveness trial. Eur Respir J. 2003;22(5):787-794. doi: 10.1183/09031936.03.00055803 [DOI] [PubMed] [Google Scholar]
37.Ind PW, Villasante C, Shiner RJ, et al. Safety of formoterol by Turbuhaler as reliever medication compared with terbutaline in moderate asthma. Eur Respir J. 2002;20(4):859-866. doi: 10.1183/09031936.02.00278302 [DOI] [PubMed] [Google Scholar]
38.Villa J, Kuna P, Egner J, Brander R. The safety and efficacy profiles of Oxis (formoterol) Turbuhaler as needed and Bricanyl (terbutaline) Turbuhaler as needed in children with asthma on anti-inflammatory treatment. Eur Respir J. 2002. Accessed October 15, 2024. https://www.astrazenecaclinicaltrials.com/study/SD-037-0695/
39.Tattersfield AE, Löfdahl CG, Postma DS, et al. Comparison of formoterol and terbutaline for as-needed treatment of asthma: a randomised trial. Lancet. 2001;357(9252):257-261. doi: 10.1016/S0140-6736(00)03611-4 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eMethods 1. Completed PRISMA 2020 and PRISMA NMA checklists.

eMethods 2. Search strategies – from January 1st, 2020 to September 27th, 2024.

eMethods 3. Summary of author contact attempts and responses.

eResults 1. Risk of bias assessments.

eResults 2. GRADE assessments for network meta-analysis estimates.

eResults 3. Network intransitivity assessments.

eResults 4. Funnel plots.

eResults 6. Pairwise forest plots for each comparison and outcome.

eResults 7. Definitions of severe exacerbations used in the included trials.

eResults 8. Analysis of commonly reported serious adverse events in the included trials.

eResults 9. Subgroup and sensitivity analyses.

eDiscussion 1. Sample size calculations.

jama-e2422700-s001.pdf^{(4.3MB, pdf)}

Supplement 2.

Data Sharing Statement

jama-e2422700-s002.pdf^{(12.7KB, pdf)}

[joi240127r1] 1.Global Initiative for Asthma . 2024. GINA report, global strategy for asthma management and prevention. September 25, 2024. Accessed September 28, 2024. https://ginasthma.org/2024-report/

[joi240127r2] 2.Cloutier MM, Dixon AE, Krishnan JA, Lemanske RF Jr, Pace W, Schatz M. Managing asthma in adolescents and adults: 2020 asthma guideline update from the National Asthma Education and Prevention Program. JAMA. 2020;324(22):2301-2317. doi: 10.1001/jama.2020.21974 [DOI] [PubMed] [Google Scholar]

[joi240127r3] 3.Krings JG, Beasley R. The role of ICS-containing rescue therapy versus SABA alone in asthma management today. J Allergy Clin Immunol Pract. 2024;12(4):870-879. doi: 10.1016/j.jaip.2024.01.011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi240127r4] 4.Rogliani P, Ritondo BL, Ora J, Cazzola M, Calzetta L. SMART and as-needed therapies in mild-to-severe asthma: a network meta-analysis. Eur Respir J. 2020;56(3):2000625. doi: 10.1183/13993003.00625-2020 [DOI] [PubMed] [Google Scholar]

[joi240127r5] 5.Sobieraj DM, Weeda ER, Nguyen E, et al. Association of inhaled corticosteroids and long-acting β-agonists as controller and quick relief therapy with exacerbations and symptom control in persistent asthma: a systematic review and meta-analysis. JAMA. 2018;319(14):1485-1496. doi: 10.1001/jama.2018.2769 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi240127r6] 6.Higgins JPT, Thomas J, Chandler J, et al. Cochrane Handbook for Systematic Reviews of Interventions. 2nd ed. John Wiley & Sons; 2019. doi: 10.1002/9781119536604 [DOI] [Google Scholar]

[joi240127r7] 7.Chu DK, Golden DBK, Guyatt GH. Translating evidence to optimize patient care using GRADE. J Allergy Clin Immunol Pract. 2021;9(12):4221-4230. doi: 10.1016/j.jaip.2021.09.035 [DOI] [PubMed] [Google Scholar]

[joi240127r8] 8.Izcovich A, Chu DK, Mustafa RA, Guyatt G, Brignardello-Petersen R. A guide and pragmatic considerations for applying GRADE to network meta-analysis. BMJ. 2023;381:e074495. doi: 10.1136/bmj-2022-074495 [DOI] [PubMed] [Google Scholar]

[joi240127r9] 9.Guyatt GH, Thorlund K, Oxman AD, et al. GRADE guidelines: 13. preparing summary of findings tables and evidence profiles—continuous outcomes. J Clin Epidemiol. 2013;66(2):173-183. doi: 10.1016/j.jclinepi.2012.08.001 [DOI] [PubMed] [Google Scholar]

[joi240127r10] 10.Guyatt GH, Oxman AD, Santesso N, et al. GRADE guidelines: 12. preparing summary of findings tables—binary outcomes. J Clin Epidemiol. 2013;66(2):158-172. doi: 10.1016/j.jclinepi.2012.01.012 [DOI] [PubMed] [Google Scholar]

[joi240127r11] 11.Thorlund K, Mills EJ. Sample size and power considerations in network meta-analysis. Syst Rev. 2012;1:41. doi: 10.1186/2046-4053-1-41 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi240127r12] 12.Guyatt GH, Oxman AD, Montori V, et al. GRADE guidelines: 5. rating the quality of evidence—publication bias. J Clin Epidemiol. 2011;64(12):1277-1282. doi: 10.1016/j.jclinepi.2011.01.011 [DOI] [PubMed] [Google Scholar]

[joi240127r13] 13.Schandelmaier S, Briel M, Varadhan R, et al. Development of the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN) in randomized controlled trials and meta-analyses. CMAJ. 2020;192(32):E901-E906. doi: 10.1503/cmaj.200077 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi240127r14] 14.Israel E, Cardet JC, Carroll JK, et al. Reliever-triggered inhaled glucocorticoid in Black and Latinx adults with asthma. N Engl J Med. 2022;386(16):1505-1518. doi: 10.1056/NEJMoa2118813 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi240127r15] 15.Papi A, Chipps BE, Beasley R, et al. Albuterol-budesonide fixed-dose combination rescue inhaler for asthma. N Engl J Med. 2022;386(22):2071-2083. doi: 10.1056/NEJMoa2203163 [DOI] [PubMed] [Google Scholar]

[joi240127r16] 16.AstraZeneca. An exploratory study to characterise changes in airway inflammation, symptoms, lung function and reliever use in adult asthma patients. January 18, 2023. Accessed June 20, 2024. https://clinicaltrials.gov/study/NCT03924635

[joi240127r17] 17.Beasley R, Holliday M, Reddel HK, et al. ; Novel START Study Team . Controlled trial of budesonide-formoterol as needed for mild asthma. N Engl J Med. 2019;380(21):2020-2030. doi: 10.1056/NEJMoa1901963 [DOI] [PubMed] [Google Scholar]

[joi240127r18] 18.O’Byrne PM, FitzGerald JM, Bateman ED, et al. Inhaled combined budesonide-formoterol as needed in mild asthma. N Engl J Med. 2018;378(20):1865-1876. doi: 10.1056/NEJMoa1715274 [DOI] [PubMed] [Google Scholar]

[joi240127r19] 19.Lazarinis N, Jørgensen L, Ekström T, et al. Combination of budesonide/formoterol on demand improves asthma control by reducing exercise-induced bronchoconstriction. Thorax. 2014;69(2):130-136. doi: 10.1136/thoraxjnl-2013-203557 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi240127r20] 20.Takeyama K, Kondo M, Tagaya E, et al. Budesonide/formoterol maintenance and reliever therapy in moderate-to-severe asthma: effects on eosinophilic airway inflammation. Allergy Asthma Proc. 2014;35(2):141-147. doi: 10.2500/aap.2014.35.3729 [DOI] [PubMed] [Google Scholar]

[joi240127r21] 21.Atienza T, Aquino T, Fernández M, et al. Budesonide/formoterol maintenance and reliever therapy via Turbuhaler versus fixed-dose budesonide/formoterol plus terbutaline in patients with asthma: phase III study results. Respirology. 2013;18(2):354-363. doi: 10.1111/resp.12009 [DOI] [PubMed] [Google Scholar]

[joi240127r22] 22.Papi A, Corradi M, Pigeon-Francisco C, et al. Beclometasone-formoterol as maintenance and reliever treatment in patients with asthma: a double-blind, randomised controlled trial. Lancet Respir Med. 2013;1(1):23-31. doi: 10.1016/S2213-2600(13)70012-2 [DOI] [PubMed] [Google Scholar]

[joi240127r23] 23.Patel M, Pilcher J, Pritchard A, et al. ; SMART Study Group . Efficacy and safety of maintenance and reliever combination budesonide-formoterol inhaler in patients with asthma at risk of severe exacerbations: a randomised controlled trial. Lancet Respir Med. 2013;1(1):32-42. doi: 10.1016/S2213-2600(13)70007-9 [DOI] [PubMed] [Google Scholar]

[joi240127r24] 24.Martinez FD, Chinchilli VM, Morgan WJ, et al. Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial. Lancet. 2011;377(9766):650-657. doi: 10.1016/S0140-6736(10)62145-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi240127r25] 25.Ställberg B, Ekström T, Neij F, et al. ; SHARE trial group . A real-life cost-effectiveness evaluation of budesonide/formoterol maintenance and reliever therapy in asthma. Respir Med. 2008;102(10):1360-1370. doi: 10.1016/j.rmed.2008.06.017 [DOI] [PubMed] [Google Scholar]

[joi240127r26] 26.Bousquet J, Boulet LP, Peters MJ, et al. Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs high-dose salmeterol/fluticasone. Respir Med. 2007;101(12):2437-2446. doi: 10.1016/j.rmed.2007.07.014 [DOI] [PubMed] [Google Scholar]

[joi240127r27] 27.Kuna P, Peters MJ, Manjra AI, et al. Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations. Int J Clin Pract. 2007;61(5):725-736. doi: 10.1111/j.1742-1241.2007.01338.x [DOI] [PMC free article] [PubMed] [Google Scholar]

[joi240127r28] 28.Papi A, Canonica GW, Maestrelli P, et al. ; BEST Study Group . Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N Engl J Med. 2007;356(20):2040-2052. doi: 10.1056/NEJMoa063861 [DOI] [PubMed] [Google Scholar]

[joi240127r29] 29.Cheung D, van Klink HC, Aalbers R; OZON study group . Improved lung function and symptom control with formoterol on demand in asthma. Eur Respir J. 2006;27(3):504-510. doi: 10.1183/09031936.06.00006805 [DOI] [PubMed] [Google Scholar]

[joi240127r30] 30.Haahtela T, Tamminen K, Malmberg LP, et al. Formoterol as needed with or without budesonide in patients with intermittent asthma and raised NO levels in exhaled air: a SOMA study. Eur Respir J. 2006;28(4):748-755. doi: 10.1183/09031936.06.00128005 [DOI] [PubMed] [Google Scholar]

[joi240127r31] 31.Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG. Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study. Lancet. 2006;368(9537):744-753. doi: 10.1016/S0140-6736(06)69284-2 [DOI] [PubMed] [Google Scholar]

[joi240127r32] 32.Chuchalin A, Kasl M, Bengtsson T, Nihlen U, Rosenborg J. Formoterol used as needed in patients with intermittent or mild persistent asthma. Respir Med. 2005;99(4):461-470. doi: 10.1016/j.rmed.2004.09.012 [DOI] [PubMed] [Google Scholar]

[joi240127r33] 33.O’Byrne PM, Bisgaard H, Godard PP, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med. 2005;171(2):129-136. doi: 10.1164/rccm.200407-884OC [DOI] [PubMed] [Google Scholar]

[joi240127r34] 34.Vogelmeier C, D’Urzo A, Pauwels R, et al. Budesonide/formoterol maintenance and reliever therapy: an effective asthma treatment option? Eur Respir J. 2005;26(5):819-828. doi: 10.1183/09031936.05.00028305 [DOI] [PubMed] [Google Scholar]

[joi240127r35] 35.Jain A, Raghuram J. Randomized controlled study of the safety and efficacy of PRN formoterol compared to PRN albuterol for the management of asthma. American Thoracic Society 100th International Conference; May 21-26, 2004; Orlando, Florida. [Google Scholar]

[joi240127r36] 36.Pauwels RA, Sears MR, Campbell M, et al. ; RELIEF Study investigators . Formoterol as relief medication in asthma: a worldwide safety and effectiveness trial. Eur Respir J. 2003;22(5):787-794. doi: 10.1183/09031936.03.00055803 [DOI] [PubMed] [Google Scholar]

[joi240127r37] 37.Ind PW, Villasante C, Shiner RJ, et al. Safety of formoterol by Turbuhaler as reliever medication compared with terbutaline in moderate asthma. Eur Respir J. 2002;20(4):859-866. doi: 10.1183/09031936.02.00278302 [DOI] [PubMed] [Google Scholar]

[joi240127r38] 38.Villa J, Kuna P, Egner J, Brander R. The safety and efficacy profiles of Oxis (formoterol) Turbuhaler as needed and Bricanyl (terbutaline) Turbuhaler as needed in children with asthma on anti-inflammatory treatment. Eur Respir J. 2002. Accessed October 15, 2024. https://www.astrazenecaclinicaltrials.com/study/SD-037-0695/

[joi240127r39] 39.Tattersfield AE, Löfdahl CG, Postma DS, et al. Comparison of formoterol and terbutaline for as-needed treatment of asthma: a randomised trial. Lancet. 2001;357(9252):257-261. doi: 10.1016/S0140-6736(00)03611-4 [DOI] [PubMed] [Google Scholar]

PERMALINK

Inhaled Reliever Therapies for Asthma

Daniel G Rayner, MSc

Dario M Ferri, MD

Gordon H Guyatt, MD

Paul M O’Byrne, MD

Romina Brignardello-Petersen, PhD

Farid Foroutan, PhD

Bradley Chipps, MD

Kaharu Sumino, MD

Tamara T Perry, MD

Sharmilee Nyenhuis, MD

John Oppenheimer, MD

Elliot Israel, MD

Flavia Hoyte, MD

Katherine Rivera-Spoljaric, MD

Ellen McCabe, PhD

Susana Rangel, MSN

Lindsay E Shade, PA

Valerie G Press, MD

Lisa Hall

Dia Sue-Wah-Sing, MS

Angel Melendez, MHL

Hilarry Orr, BSE

Tonya Winders, MBA

Donna D Gardner, DrPH

Kathyrn Przywara, BSE

Matthew A Rank, MD

Leonard B Bacharier, MD

Giselle Mosnaim, MD

Derek K Chu, MD, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Data Sources

Study Selection

Data Extraction and Synthesis

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Search Strategy and Selection Criteria

Study Selection and Data Extraction

Outcomes

Risk-of-Bias Assessment

Evaluating Evidence Certainty

Data Synthesis

Results

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

Table. Characteristics of Included Trials in the Systematic Review and Meta-Analysis of Asthma Inhaled Reliever Therapies (N = 27)a.

Outcomes

Severe Exacerbations

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

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

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

Asthma Symptom Control

Asthma-Related Quality of Life

Safety Outcomes

Other Analyses

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases

Table. Characteristics of Included Trials in the Systematic Review and Meta-Analysis of Asthma Inhaled Reliever Therapies (N = 27)^a.

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

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

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