🧭 REBEL Rundown
📌 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
📈 Results
- 5221 patients were screened across 54 sites in the US
- 2516 patients underwent randomization
- 2421 patients were included in the full analysis population
- 1797 (71.4%) patients completed the trial
- 480 (~ 20%) patients were lost to follow up
💥 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
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