Asthma outcomes improve with inhaled corticosteroids plus formoterol, SABA
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Key takeaways:
- The meta-analysis included 27 unique randomized controlled trials and 50,496 patients.
- Combinations improved symptom control and quality of life compared with short-acting beta agonists alone.
BOSTON — Combined treatments were associated with reduced asthma exacerbations compared with short-acting beta agonists alone, based on a review presented at the American College of Allergy, Asthma & Immunology Annual Scientific Meeting.
The prospectively registered systematic network meta-analysis included 27 unique randomized controlled trials (RCTs) published by MEDLINE, Embase and CENTRAL between Jan. 1, 2020, and Sept. 27, 2024.
“There are very few head-to-head trials,” Bradley E. Chipps, MD, medical director of respiratory therapy and the cystic fibrosis center at Sutter Medical Center in Sacramento, California, said during his presentation. “The dots were connected using indirect measures.”
Comparators included inhaled corticosteroids (ICS) with formoterol, ICS with short-acting beta agonists (SABA), SABA alone and formoterol alone.
“Their comparative efficacy is important because there are now inhalers of each type,” Derek K. Chu, MD, PhD, assistant professor in the department of medicine at McMaster University, told Healio.
Outcomes included severe exacerbations, asthma symptom control, asthma-related quality of life and adverse events.
The trials included 50,496 patients with asthma overall.
“As you’d expect, there were more females in the trials,” Chipps said.
The male populations in these studies ranged from 16% to 60% with a median of 41%.
The mean age was 41 years, with individual study means ranging from 10.8 to 49.4 years. Also, cohorts for two of the studies comprised patients aged 18 years and younger entirely.
“Most trials were half a year,” Chipps said.
The median treatment duration was 26 weeks with individual studies ranging from 3 to 65 weeks.
The review included 22 RCTs with 45,117 patients that assessed severe exacerbations. “Compared to SABA alone relievers, anti-inflammatory relievers (those containing ICS) reduced severe asthma exacerbations,” Chu said.
Based on high-certainty evidence, the researchers said, ICS-formoterol had lower risks for severe exacerbations than bronchodilator-only relievers (RR = 0.65; 95% CI, 0.6-0.72), with a risk difference of –10.3% (95% CI, –11.8% to –8.3%).
High-certainty evidence also showed lower risks for severe exacerbations with ICS-SABA (RR = 0.84; 95% CI, 0.73-0.95), with a risk difference of –4.7% (95% CI, –8% to –1.5%) compared with bronchodilator-only relievers as well.
The researchers also noted similar associations between these treatments and asthma-related hospitalizations and ED visits. When the researchers compared ICS-formoterol with ICS-SABA, they said that ICS-formoterol had lower risks for severe exacerbations (RR = 0.78; 95% CI, 0.66-0.92), with a risk difference of –5.5% (95% CI, –8.4% to –2%) among patients on Global Initiative for Asthma (GINA) step 4, based on evidence of moderate certainty.
“There is improvement with ICS-formoterol compared with ICS-SABA almost consistently through the study,” Chipps said.
But among patients with lower risks, absolute risk differences fell, with a risk difference of –1.9% (95% CI, –3% to –0.7%) for patients on GINA step 1.
“The absolute improvements depended on the risk of having a severe exacerbation, with smaller benefits in lower risk populations compared populations at higher risk for exacerbations,” Chu said.
The review additionally included 22 RCTs with 25,233 patients that analyzed symptom control using Asthma Control Questionnaire-5 scores, comparing ICS-formoterol and ICS-SABA with bronchodilator-only relievers.
High-certainty evidence indicated better asthma control with ICS-formoterol (mean difference: –0.09; 95% CI, –0.13 to –0.05), including a risk ratio of 1.07 (95% CI, 1.04-1.1) corresponding to a 0.5-point or more improvement in minimum important difference (MID) in total score, along with a risk difference of 4.1% (95% CI, 2.3%-5.9%).
ICS-SABA also was associated with better asthma control, including a mean difference of –0.12 (95% CI, –0.19 to –0.04; a risk ratio of 1.09 (95% CI, 1.03-1.15) corresponding to a 0.5-point or more improvement in MID in total score; and a risk difference of 5.4% (95% CI, 1.8%-8.5%).
“Virtually the same results,” Chipps said.
However, the researchers called these effect sizes small and potentially unimportant for patients and added that the difference between ICS-SABA and ICS-formoterol was small to non-existent for asthma symptom control based on evidence with low certainty.
The researchers further analyzed five RCTs with 9,688 patients for asthma-related quality of life, again comparing ICS-formoterol and ICS-SABA with bronchodilator-only relievers.
Moderate-certainty evidence indicated improvements with ICS-formoterol, including a mean difference of 0.04 (95% CI, –0.04 to 0.13), a risk ratio of 1.03 (95% CI, 0.97-1.1) corresponding to a 0.5-point or more improvement in MID in total score and a risk difference of 1.6% (95% CI, –1.6% to 5.2%).
Improvements for ICS-SABA included a mean difference of 0.07 (95% CI, –0.06 to 0.19), a risk ratio of 1.05 (95% CI, 0.95-1.15) corresponding to a 0.5-point or more improvement in MID in total score, and a risk difference of 2.8% (95% CI, –2.4% to 7.6%).
Twelve RCTs with 31,228 patients indicated no associations between increased risks for any adverse event and ICS-formoterol or ICS-SABA use compared with bronchodilator-only relievers with moderate certainty.
In 23 RCTs with 41,933 patients, there were no associations between increased risks for serious adverse events when ICS-formoterol (with high certainty) and ICS-SABA (with moderate certainty) were compared with SABA alone.
Cardiovascular events and pneumonia were the most common causes of serious adverse events in the 15 studies that examined them.
In the cardiovascular events, ICS-formoterol had a risk difference of –0.2% (95% CI, –0.5% to 0.1%) and ICS-SABA had a risk difference of –0.2% (95% CI, –0.7% to 0.4%) compared with SABA alone.
In the pneumonia events, ICS-formoterol had a risk difference of 0.1% (95% CI, –0.1% to 0.2%) and ICS-SABA had a risk difference of 0.2% (95% CI, –0.5% to 0.8%) compared with SABA alone.
There were 21 studies with 26,539 patients that analyzed adverse events that caused inhaler discontinuations. Compared with SABA alone, risk differences included –0.7% (95% CI, –1.2% to –0.3%) for ICS-formoterol and 0.3% (95% CI, –0.8% to 1.4%) for ICS-SABA, with moderate certainty.
In 15 RCTs with 40,425 patients and high certainty, risk differences for mortality included 0% (95% CI, –0.1% to 0.1%) for ICS-formoterol and 0.1% (95% CI, –0.3% to 0.4%) for ICS-SABA compared with SABA alone.
“The safety outcomes are virtually the same,” Chipps said. “We looked at all of these outcomes and found that it’s pretty similar.”
Based on these findings, Chipps and Chu both called anti-inflammatory relievers superior to bronchodilators as independent entities in reducing severe exacerbations and improving asthma control.
“ICS-formoterol is likely superior to ICS-SABA in reducing severe exacerbations, and ICS-SABA is a preferred choice of patients on other maintenance therapies that include drugs on the U.S. market that are not formoterol, so salmeterol, vilanterol and olodaterol,” Chipps said.
“These results show the superiority of anti-inflammatory relievers – ICS-SABA and ICS-formoterol – over SABA-alone relievers, which only relieve asthma symptoms without addressing the underlying inflammation that ultimately drives asthma,” Chu said. Chipps also noted that patient values and preferences may drive asthma management and that treatment should balance key benefits and harms.
“Clinical guidelines and insurance coverage should be updated to reflect the superiority of anti-inflammatory relievers over SABA alone,” Chipps said.
“The findings have potential major implications for practice and policy,” Chu said.
The AAAAI/ACAAI Joint Task Force on Practice Parameters: Severe and Difficult to Control Asthma Guideline Development Group is now developing guidelines for severe asthma, including the use of these relievers.
“These guidelines will be again addressed in great detail in the upcoming guidelines that should be ready, most likely in 2025,” Chipps said.
Reference:
For more information:
Derek K. Chu, MD, PhD, can be reached at chudk@mcmaster.ca.