From Pages to Practice

By Leslie Chang, MD

Published July 19, 2022


Asthma is a condition driven by persistent airway inflammation with symptoms resulting from variable airflow limitation. The primary goal of therapy is to optimize symptom control and reduce the risk of exacerbations, which are associated with high morbidity and mortality. Because asthma was initially thought to be a disease primarily of bronchoconstriction, as-needed inhaled short-acting beta-agonists (SABAs) such as albuterol have been the mainstay first-line therapy for many years. The rapid symptom relief and low cost of SABAs reinforced their use. 

Unfortunately, SABAs have minimal effects on underlying airway inflammation. Further, regular SABA use and overuse has been associated with increased risk of exacerbation and overall mortality. This finding prompted a series of randomized-controlled trials to investigate alternative rescue therapies. Combination inhaled corticosteroids (ICS) and long-acting beta-agonists (LABAs) such as formoterol have shown promise for prevention of asthma exacerbations, and a recent Cochrane Review concluded that as-needed ICS-LABA treatment was associated with a reduction in severe exacerbations, as compared with albuterol alone. These data support the recent change in the Global Initiative for Asthma (GINA) guidelines that recommend use of ICS-formoterol as rescue therapy.   

Now, a recent multinational, phase 3, randomized trial published in NEJM examined the efficacy and safety of combination SABA and ICS treatment. Investigators compared combination albuterol-budesonide to albuterol monotherapy in 3123 adults and adolescents with moderate-to-severe asthma. Study participants received as-needed albuterol monotherapy (180 ug), lower-dose combination albuterol-budesonide (180 ug/80 ug), or higher-dose albuterol-budesonide (180 ug/160 ug) in addition to maintenance therapies. At 24-weeks, higher-dose SABA-ICS combination therapy was associated with reduced risk of severe exacerbations, as compared with albuterol monotherapy, with no differences in adverse events among the groups. 

Across the spectrum of asthma severity, as-needed combination ICS-formoterol and ICS-albuterol have been shown to be superior to albuterol alone in reducing severe exacerbations. Although it is easy to reach for as-needed albuterol in the outpatient setting, evidence from this study and a series of prior studies should give providers pause and consider prescribing a combination ICS-LABA or ICS-SABA as rescue therapy instead.

The following NEJM Journal Watch summary provides more details of the study.


A Shift Toward Combining Inhaled Corticosteroids and β-Agonists for Asthma Rescue Therapy

David J. Amrol, MD, reviewing Papi A et al. N Engl J Med 2022 May 15

Overuse of albuterol is associated with excess risk for severe asthma exacerbations. Global Initiative for Asthma (GINA) guidelines. opens in new tab recommend avoiding albuterol for all patients and using inhaled corticosteroids (ICS)/formoterol as a rescue inhaler. Although the National Asthma Education and Prevention Program (NAEPP) guidelines. opens in new tab have not gone that far, they do recommend using as-needed ICS/albuterol for mild asthma.

In a multinational trial, more than 3100 adolescents and adults with uncontrolled moderate-to-severe asthma were randomized to either high- or low-dose albuterol/budesonide (180/160 µg or 180/80 µg) or albuterol alone (180 µg) as a rescue inhaler while continuing their current ICS or ICS/LABA (long-acting β-agonist) therapy. After 24 weeks, severe exacerbations requiring systemic steroids for rescue were significantly less common in the high-dose budesonide/albuterol group than in the albuterol group (annualized rate, 0.45 vs. 0.59). Patients who received inhaled ICS as part of their rescue plan received slightly less total systemic steroid exposure.

Comment: The days of using albuterol monotherapy for rescue therapy in asthma should be numbered. We have excellent data showing that either ICS/formoterol or ICS/albuterol for rescue is superior. This applies to all asthma patients, ranging from those with intermittent asthma who use no controller therapy to those with severe asthma who use high-dose ICS/LABA. ICS/formoterol is expensive and not FDA-approved for rescue indication in the U.S., and we lack a single fixed-dose combination ICS/albuterol inhaler, so new (hopefully affordable) products will be welcome.

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Leslie is a 2021-2022 NEJM Editorial Fellow and a hospitalist at Massachusetts General Hospital. She graduated from Duke University School of Medicine in 2018 and completed her internal medicine residency at Massachusetts General Hospital in 2021.