Metered-dose inhalers for asthma, introduced in the 1950s, were a treatment breakthrough, allowing asthmatic patients to keep their inhaled asthma treatment in their pockets, rather than having to carry around bulky nebulisers.
Originally, bronchodilators were the only treatment available in this format, but by the early 1980s, glucocorticoids (to dampen undefined inflammation) also became available in inhaler form for asthma treatment in the United States.
At that time, writes Dr Jeffrey Drazen in The New England Journal of Medicine, we told our patients that inhaled glucocorticoids were meant to be used on a regularly scheduled basis (e.g, twice a day), whereas their bronchodilator inhaler was to be used for “rescue therapy” when needed for asthma symptoms.
With two inhalers for different uses, patients were often confused about which inhaler to use for rescue and which to use on a regular basis. This situation led to common scenarios. When a patient was not having asthma symptoms, they would not use any asthma inhaler. When asthma struck, they could easily use the wrong inhaler for rescue.
Then patient observation taught us something. Although it was not well documented in the literature, we all had patients who, when they started to have asthma symptoms, remembered to take their inhaled glucocorticoids along with their bronchodilators. These patients seemed to do as well as, if not better than, those who stayed on their regularly scheduled inhaled glucocorticoid treatment.
The National Institutes of Health-sponsored Asthma Clinical Research Network picked up on this observation and found that intermittent use of inhaled glucocorticoids – that is, when patients with asthma had symptoms – and scheduled use of these drugs had similar effects on morning peak-flow rates.
The trial authors concluded: “It may be possible to treat mild persistent asthma with short, intermittent courses of inhaled or oral corticosteroids taken when symptoms worsen.”
Papi and colleagues later found that the as-needed use of a single inhaler containing both a glucocorticoid and a bronchodilator prevented asthma exacerbations at rates that were visually identical on a Kaplan–Meier plot to rates among patients using regularly scheduled inhaled glucocorticoid therapy plus an as-needed inhaled bronchodilator.
At the time that this trial was designed, non-inferiority trials were yet to take their place on centre stage in the clinical trials universe, and hence a non-inferiority design was not used.
In the past 18 years, numerous trials, including thousands of patients, have shown the efficacy and effectiveness of a combination inhaler used as rescue treatment for patients with mild-to-moderate asthma symptoms to reduce asthma exacerbations.
In the trials noted, the combination inhalers that were used contained both budesonide, an inhaled glucocorticoid, and formoterol, a rapid-onset, long-acting β2-agonist that can be administered multiple times per day.
On the strength of these data, combination inhalers using budesonide and formoterol are noted as the preferred treatment in the early steps of asthma treatment by the Global Initiative for Asthma (GINA).
The use of formoterol–budesonide combination inhalers has been approved by regulators in many countries for the as-needed treatment of asthma symptoms.
However, in the United States and many other countries, although this combination is approved for “maintenance treatment,” it is not approved for “rescue” relief of acute symptoms, and such use remains “off-label.”
This off-label use of a formoterol–budesonide combination inhaler has left many physicians in a quandary. We know that combination treatment is effective and glucocorticoid sparing, but off-label use has its own set of problems, including prohibitive out-of-pocket costs when insurance will not pay.
In 2022, the publication of the MANDALA trial involving patients with moderate-to-severe asthma who were receiving background inhaled glucocorticoid treatment showed that use of a fixed-dose combination of 180 μg of albuterol (a rapid-onset, short-acting β2-agonist) and 160 μg of budesonide, compared with albuterol alone for rescue treatment, significantly lowered asthma exacerbation risk by 26%.
Although this combination has been approved by the Food and Drug Administration, until now we lacked evidence for its use in the treatment of patients with mild-to-moderate asthma.
Below, LaForce and colleagues report the BATURA trial involving patients with disease that was uncontrolled despite treatment for mild asthma. They evaluated the effect of rescue treatment with albuterol–budesonide in a single inhaler as compared with treatment with an inhaler containing albuterol alone on the incidence of severe asthma exacerbations.
The trial was stopped early for efficacy after exacerbation events had occurred in 5.3% and 9.4%, respectively, of the intention-to-treat population. These data now provide the strong evidence needed for physicians to prescribe this regimen for patients with mild asthma and, more importantly, an observation of efficacy that insurers cannot ignore.
I think there are trials that still need to be done. We need non-inferiority trials, involving patients across the spectrum of mild-to-severe asthma, that compare rescue treatment with single inhalers containing the formoterol–budesonide combination with single inhalers containing albuterol–budesonide.
Formoterol has the theoretical advantage in that it is a rapid-acting and long-lasting selective β2-agonist, whereas albuterol is a rapid-acting selective β2-agonist but with a shorter duration of action.
As we gather data to support our choice of one combination inhaler as compared with another, we should be working toward a world in which all patients with asthma are easily able to leave home with a combination inhaler in their pocket!
Study details
As-Needed Albuterol–Budesonide in Mild Asthma
Craig LaForce, Frank Albers, Anna Danilewicz, Alberto Papi et al for the BATURA Investigators*
Published in The New England Journal of Medicine on 19 May 2025
Abstract
Background
As-needed use of albuterol–budesonide has been shown to result in a significantly lower risk of severe asthma exacerbation than as-needed use of albuterol alone among patients with moderate-to-severe asthma. Data on albuterol–budesonide in mild asthma are needed.
Methods
We conducted a fully virtual, decentralised, phase 3b, multicentre, double-blind, event-driven trial involving people 12 or older with disease that was uncontrolled despite treatment for mild asthma with a short-acting β2-agonist (SABA) with or without a low-dose inhaled glucocorticoid or leukotriene-receptor antagonist. Participants were randomly assigned in a 1:1 ratio to a fixed-dose combination of 180 μg of albuterol and 160 μg of budesonide (with each dose consisting of two inhaler actuations of 90 μg and 80 μg, respectively) or 180 μg of albuterol (with each dose consisting of two inhaler actuations of 90 μg) on an as-needed basis for up to 52 weeks. The primary end point was the first severe asthma exacerbation, assessed in a time-to-event analysis, in the on-treatment efficacy population, and the key secondary end point was the first severe exacerbation in the intention-to-treat population. Secondary end points included the annualised rate of severe asthma exacerbations and exposure to systemic glucocorticoids.
Results
A total of 2516 participants underwent randomisation; 1797 (71.4%) completed the trial. Of 2421 participants in the full analysis population (1209 assigned to the albuterol-budesonide group and 1212 to the albuterol group), 97.2% were 18 or older; 74.4% used a SABA alone at baseline. The trial was stopped for efficacy at a prespecified interim analysis. A severe exacerbation occurred in 5.1% of the participants in the albuterol-budesonide group and in 9.1% of those in the albuterol group in the on-treatment efficacy population (hazard ratio, 0.53; 95% confidence interval [CI], 0.39 to 0.73) and in 5.3% and 9.4%, respectively, in the intention-to-treat population (hazard ratio, 0.54; 95% CI, 0.40 to 0.73) (P<0.001 for both comparisons). The annualised rate of severe asthma exacerbations was lower with albuterol-budesonide than with albuterol (0.15 vs. 0.32; rate ratio, 0.47; 95% CI, 0.34 to 0.64), as was the mean annualised total dose of systemic glucocorticoids (23.2 vs. 61.9 mg per year). Adverse events were similar in the two treatment groups.
Conclusions
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. (Funded by Bond Avillion 2 Development and AstraZeneca; BATURA ClinicalTrials.gov number, NCT05505734.)
NEJM article – As-Needed Albuterol–Budesonide in Mild Asthma (Open access)
NEJM article – Your Combination Asthma Inhaler — Don’t Leave Home without It!
See more from MedicalBrief archives:
As-needed combo-drug inhaler a viable treatment solution in mild asthma
Major German guidelines revision shifts asthma treatment focus
Urgent need to improve asthma control worldwide – global study
Three-in-one inhaler therapy improves lung function and reduces exacerbations