Meta-Analysis Finds ICS-Formoteral and ICS-SABA Reduces Asthma Exacerbations, Improved Asthma Control

In patients with asthma, reliever inhalers—including bronchodilator-only relievers, such as albuterol—or inhaled corticosteroids (ICS) with either a short-acting β agonist (SABA) or formoteral, are indicated to relieve symptoms of wheezing, cough, or dyspnea. Despite this, guidelines do not effectively differentiate between ICS-SABA and SABA-alone relievers, as well as the benefits of ICS-formoterol compared with ICS-SABA on patients’ clinical outcomes. Authors of a systematic review published in JAMA Network Open evaluated inhaled relievers for improving outcomes in patients with asthma, including asthma exacerbations, hospitalizations because of asthma, adverse events (AEs), and mortality.

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For this review, the authors systematically searched multiple databases (eg, MEDLINE, Embase, and CENTRAL) from January 1, 2020, to September 27, 2024, for both published and unpublished randomized clinical trials (RCTs) that evaluated eligible inhaled reliever therapies for any type of asthma. Additionally, the authors used reference lists to identify eligible studies. These studies compared different reliever therapies—bronchodilator-only relievers; fast-onset, long-acting β agonist (LABA) alone; ICS and fast-onset, LABA; and ICS and SABA—and had similar levels of maintenance therapy between the clinical trial groups.

The outcomes for this review were selected and prioritized based on input from a multistakeholder guideline development group, which included clinicians, asthma experts, as well as patients with asthma and their caregivers. Outcomes consisted of asthma symptom control, asthma-related quality of life, severe asthma exacerbations (defined as use of systemic corticosteroids, emergency department [ED] visits, and/or hospitalizations) and their individual components, AEs (overall, serious AEs, treatment discontinuations because of AEs), and overall mortality.

According to the authors, the systematic search yielded 3179 unique citations and 201 potentially relevant full articles. Of these, 26 articles that reported 27 unique RCTs (N = 50,496 patients) were included. The participants in the 27 RCTs had a mean age of 41.0 years (range: 10.8 to 49.4 years) and the median percentage of male participants was approximately 41% (range: 16% to 60%). Across all RCTs included, treatment duration was a median of 26 weeks (range: 3 to 65 weeks), and all RCTs that evaluated fast-onset, LABAs—whether alone or combined with an ICS—as a reliever therapy evaluated formoterol. Two trials (7%) evaluated patient populations that consisted entirely of patients with asthma who were aged 18 years or younger, resulting in these trials being considered as pediatric trials.

Further, consistent associations were found between adult and pediatric studies for all outcomes, and all included RCTs were conducted in outpatient settings. Levalbuterol was not among the evaluated treatments, and for all RCTs, prescription of oral corticosteroids for severe exacerbations was based on the discretion of the individual patient’s health care professional.

A total of 22 RCTs that included 45,117 patients provided data for the outcome of severe asthma exacerbations. These trials found that compared with bronchodilator-only relievers, 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%]). In addition, 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 a lower risk of severe exacerbations. The authors also observed similar associations for asthma-related hospitalizations and ED visits were observed. 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%]); however, these RDs became smaller in lower-risk patient populations (RD, −1.9% [95% CI, −3.0% to −0.7%]).

A total of 22 RCTs that included 25,233 patients were identified for analyses of asthma symptom control measured using the ACQ-5, in which scores ranged from 0 to 6 and lower scores indicating better asthma control. Compared with bronchodilator-only relievers, the authors observed 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, with low-certainty evidence suggesting little to no difference between the 2 when control asthma. symptoms.

A total of 5 RCTs that included 9688 patients were identified for asthma-related quality of life analyses. 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 compared with bronchodilator-only relievers. Additionally, low-certainty evidence suggested little to no difference between ICS-SABA or ICS-formoterol in asthma-related quality of life.

There were no observed associations of increased risk of harm between inhaler groups. Twelve RCTs consisting of 31,228 patients were included in analyses for any AE, and 23 RCTs (41,933 patients were included in analyses of serious AEs. Among the 15 studies (65%) that reported specific causes of serious AEs, the 2 most reported were cardiovascular events and pneumonia. In addition, 21 RCTs that consisted of 26,539 total patients were included in analyses for inhaler discontinuations due to an AE. Twenty-one RCTs (26,539 patients) were included in analyses for inhaler discontinuations because of an AE, and 15 RCTs (40,425 patients) informed analyses for mortality.

According to the authors, limitations of this review include the lack of direct comparisons between ICS-formoterol and ICS-SABA as reliever inhalers, few of the selected RCTs reported the effects of inhaled reliever therapies on individual outcomes, and only 2 of the included RCTs were limited to pediatric populations. Further, none of the included trials reported on whether ipratropium use was allowed in combination with albuterol.

REFERENCE

Rayner DG, Ferri DM, Guyatt GH, et al. Inhaled Reliever Therapies for Asthma: A Systematic Review and Meta-Analysis. JAMA. Published online October 28, 2024. doi:10.1001/jama.2024.22700