Combination Inhalers in Asthma: Time to Switch?

Written by Anand Swaminathan
REBEL EM
Medical Category: Thoracic and Respiratory
Asthma, Asthma Exacerbation, Corticosteroids, Inhalers, Pulmonary, Steroids

June 23, 2025

📌 Key Points

- 💨 Most asthma patients still leave the ED with a SABA alone—time for an upgrade.
- 📉 SABA/ICS combo inhalers cut severe exacerbations compared to SABA alone.
- 🏥 Study excluded typical ED patients—few had recent exacerbations.
- 💰 New combo inhaler costs ~$500 and was compared to a weaker treatment.
- 💡 Bottom line: combo inhalers beat SABA alone, but LABA/ICS remains best-in-class.

📝 Introduction

Standard practice in the ED is to discharge stable patients with asthma exacerbations with a short-acting beta agonist (SABA) rescue inhaler. However, organizations like the Global Initiative for Asthma (GINA) now recommend daily corticosteroid-containing inhalers to reduce the risk of severe exacerbations (Reddel 2019). Recent studies have found that formoterol (a long acting beta agonist – LABA)/budesonide (inhaled corticosteroid – ICS) combination inhalers are effective both as rescue and maintenance therapy (Jiang 2021, Crossingham 2021). Data on SABA/ICS combo inhalers is more limited.

🧾 Paper

LaForce C et al. As-Needed Albuterol-Budesonide in Mild Asthma. NEJM 2025. PMID: 40388330

⚙️ What They Did

CLINICAL QUESTION

Does use of an as-needed albuterol/budesonide (SABA/ICS) combo inhaler reduce the time to first severe asthma exacerbation?

STUDY DESIGN

Design: Fully virtual, multicetner, double-blind randomized controlled, superiority trial performed in the US.
Trial Sponsor: Bond Avillion 2 Development and AstraZeneca

POPULATION

Inclusion Criteria:

Patients > 12 years of age with uncontrolled asthma on either a SABA inhaler or a SABA/ICS or SABA/leukotriene receptor antagonist inhaler.

Exclusion Criteria:

Any evidence of significant lung disease other than asthma
Hospitalization due to asthma in the 3 months prior to enrollment or self-reported admission to the Intensive Care Unit with life-threatening asthma at any time in the past
Self-reported use of inhaled Long-Acting Beta-Agonists (LABA), theophylline, inhaled anticholinergic agent, or medium/high dose ICS daily, as regular maintenance asthma therapy in the 3 months prior to enrollment
Self-reported use of systemic corticosteroids (SCS) for the treatment of asthma and any other condition in the 6 weeks prior to enrollment
Participants with a home supply of oral corticosteroids (OCS) to be used in the case of an asthma exacerbation
Receipt of any marketed (eg, omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab, tezepelumab) or investigational biologic for the treatment of asthma at any time in the past
Receipt of bronchothermoplasty
Use of a SABA prophylactically primarily to prevent exercise induced bronchospasm (EIB) and not to treat symptoms
Currently receiving systemic treatment with potent cytochrome P3A4 inhibitors (eg, ketoconazole, itraconazole, and ritonavir)
Judgment by the Investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
Pregnant or breast feeding
Participants without access to a smartphone or the internet.

INTERVENTION & COMPARATOR

Intervention:

Albuterol (180 mcg)/budesonide (160 mcg) inhaled (each inhaler actuation contained ½ dose and participants asked to take 2 puffs/use)

Comparator:

Albuterol 180 mcg inhaled (each inhaler actuation contained ½ dose and participants asked to take 2 puffs/use)

OUTCOMES

Primary Outcome

Time to first severe asthma exacerbation (worsening symptoms resulting in > 3 days of systemic glucocorticoids, an ED or UC visit for asthma, hospitalization due to asthma or death from asthma) based on per-protocol analysis.

Secondary Outcomes

Time to first asthma exacerbation (intention-to-treat analysis)
Rate of severe asthma exacerbations
Total exposure to systemic glucocortocoids

📈 Results

Patient Enrollment

💥 Critical Results

💪 Strengths

- Strengths:
  - Large, multicenter study
  - While adverse events were common in both groups, most of these were infectious in nature (unclear if related to the medication or not) and serious adverse events were uncommon (~ 3% in both groups).
  - Provided analysis of both intention-to-treat and per-protocol data.

⚠️ Limitations

This was not a trial of patients presenting to EDs with asthma exacerbations and, in fact, ED presentations were uncommon in the 12 months prior to enrollment as well as during the trial period.
The primary outcome was designated as time to first exacerbation but risk of exacerbation (a secondary outcome) is reported as the primary outcome. It is unclear why this occurred. Time to exacerbation is shown in figure 2 of the article.
The trial was stopped early after a prespecified interim analysis. Early stoppage of studies tends to overestimate benefits due to the regression to the mean phenomena.
Spectrum bias: Severe exacerbations were uncommon in both groups (< 10% in the albuterol group, ~ 5% in the combo inhaler group).
Selection bias: patients were recruited via social media and completely virtually
Though the study included patients > 12 years old, only 3% of patients were < 18. This data cannot be applied to pediatric patients.
Due to the virtual nature of the trial, there is no data on lung function tests or measures of antiinflammatory properties.
Large percentage of patients were excluded from analysis due to loss to follow up (~ 20%).
Though there was blinding in the study, patients may have been unblinded if they were able to “taste” a difference in the medications. Steroids can have an odd taste and this may have unblinded patients.

🗣️ Discussion

This study provides additional data that clinicians should make prescription of a combo inhaler standard practice but it is hard to extrapolate the data to the ED setting based on the trial setup.
This pharmaceutical sponsored trial compared an expensive new medication to a known inferior treatment.
- AstraZeneca markets a SABA/ICS combo inhaler which retails for $500.
- The researchers demonstrated that a SABA/ICS combo inhaler is superior to SABA alone.
- LABA/ICS combo inhalers are already accepted as standard care (GINA 2019) and this therapy should have been included as the control medication.
- In the absence of superiority data versus a LABA/ICS combo inhaler, this data provides a weak argument to prescribe a SABA/ICS inhaler.
It is unusual to see a per-protocol analysis for the primary outcome.
- Per-protocol looks at ideal circumstances where patients are fully compliant with treatment. An intention to treat analysis may be more reflective of the real world.
- Additionally, per-protocol analysis can introduce a selection bias because it doesn’t follow along with randomization.
- Patients who don’t complete the trial may have a worse prognosis than those who complete the trial and intention to treat analysis provides a more conservative measure.

📘 Author's Conclusion

“As-needed use of albuterol–budesonide resulted in a lower risk of a severe asthma exacerbation than as-needed use of albuterol alone among participants with disease that was uncontrolled despite treatment for mild asthma.“

💬 Our Conclusion

A SABA/ICS combo inhaler reduces asthma exacerbations when compared to a SABA inhaler alone. However, comparison against an inferior treatment modality markedly reduces the utility of this data and makes demonstration of superiority significantly easier.

💡 Potential to Impact Current Practice:

This is further evidence that combination therapy (a beta agonist + an inhaled corticosteroid) is superior to beta agonist therapy alone as rescue therapy in asthma.

🚨 Clinical Bottom Line

Prescribe comb inhalers (LABA/ICS) for rescue therapy to patients with asthma in addition to their maintenance medications. The inhaler of choice may vary based on cost and availability.

📚 References

Jiang P, Zhao L, Yao Z.
Budesonide/formoterol versus salmeterol/fluticasone for asthma in children: an effectiveness and safety analysis.
J Comp Eff Res. 2021; 10(17): 1283-1289.
PMID: 34668718
Crossingham I, Turner S, Ramakrishnan S, et al.
Combination fixed-dose β agonist and steroid inhaler as required for adults or children with mild asthma: a Cochrane systematic review.
BMJ Evid Based Med. 2022;27(3):178-184.
PMID: 34282031
Reddel HK, FitzGerald JM, Bateman ED, et al.
GINA 2019: a fundamental change in asthma management: Treatment of asthma with short-acting bronchodilators alone is no longer recommended for adults and adolescents.
Eur Respir J. 2019; 53(6).
PMID: 3124901

Post Peer Reviewed By: Marco Propersi, DO (Twitter/X: @Marco_propersi), and Mark Ramzy, DO (X: @MRamzyDO)

👤 Associate Editor

Anand Swaminathan

MD

Associate Professor Emergency Medicine, Zucker School of Medicine Staten Island University Hospital / Northwell Health

Meet The Team

🔎 Your Deep-Dive Starts Here

Clinical Conundrum: Should Acute Asthma Exacerbations Be Discharged From the ED With Combination Beta Agonist/Corticosteroid Inhalers?

Bottom Line Up Top: In patients with mild to moderate ...

Thoracic and Respiratory

Cite this article as: Anand Swaminathan, "Combination Inhalers in Asthma: Time to Switch?", REBEL EM blog, June 23, 2025. Available at: https://rebelem.com/combination-inhalers-in-asthma-time-to-switch/.

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