By David Fiore, MD

Professor of Family Medicine, University of Nevada, Reno

Dr. Fiore reports no financial relationships relevant to this field of study.

SYNOPSIS: In two randomized, double-blind, multicenter trials, symptom-triggered, twice-daily dosing of budesonide-formoterol was as effective in preventing severe asthma attacks as scheduled twice-daily dosing of budesonide-terbutaline, but not as effective in relieving symptoms.

SOURCES: O’Byrne PM, et al. Inhaled combined budesonide-formoterol as needed in mild asthma. N Engl J Med 2018;378:1865-1876.

Bateman ED, et al. As-needed budesonide-formoterol versus maintenance budesonide in mild asthma. N Engl J Med 2018;378:1877-1887.

Asthma is a disease with worldwide prevalence that affects approximately 300 million people and is increasing by 50% every decade.1 The guidelines from the National Asthma Education and Prevention Program Expert Panel Report 3 (EPR-3) stress the importance of both symptom control and the prevention of severe exacerbations.2 For mild persistent asthma, EPR-3 recommendations include a short-acting beta-agonist (SABA) and an inhaled corticosteroid (ICS) to both reduce symptoms and reduce the risk of a severe exacerbation. Although not incorporated into the guidelines, a 2013 Cochrane review demonstrated the safety (no increase in severe exacerbations) and benefit (decreased annual steroid dose) of intermittent vs. scheduled ICS use.3 The two studies published in the May 17, 2018, issue of The New England Journal of Medicine concern whether using an ICS plus a long-acting beta-agonist (LABA) is as effective as continuous use of an ICS for reducing symptoms and exacerbations in patients with mild asthma.

In the Symbicort Given as Needed in Mild Asthma (SYGMA) 1 trial, O’Byrne et al performed a 52-week, double-blind, multicenter, randomized study in asthmatics > 12 years of age who experienced mild persistent asthma. A run-in period was used before randomization to ensure that patients met EPR-3 criteria for Step 2 treatment (SABA plus ICS). The three regimens assessed were twice-daily placebo plus terbutaline (0.5 mg) used as needed (terbutaline group), twice-daily placebo plus budesonide-formoterol (200 μg of budesonide and 6 μg of formoterol) used as needed (budesonide-formoterol group), or twice-daily budesonide (200 μg) plus terbutaline used as needed (budesonide maintenance group). A total of 3,836 patients were followed throughout the study. The amount of time (percent of weeks) that the asthma was well-controlled (the primary outcome) was highest in the budesonide maintenance group (44.4%) compared to the budesonide-formoterol group (34.4%) and the terbutaline group (31.1%). The rates of severe exacerbations were similar in both budesonide groups and lower compared to the terbutaline group (annual rate of 7% in the budesonide-formoterol group, 9% in the budesonide maintenance group, and 20% in the terbutaline group). The authors also found that the median metered daily dose of inhaled glucocorticoid in the budesonide-formoterol group (57 μg) was 17% of the dose in the budesonide maintenance group (340 μg). In the SYGMA 2 trial, Bateman et al used similar inclusion and exclusion criteria as well as a run-in period. The authors randomly assigned 4,215 patients to receive twice-daily placebo plus budesonide-formoterol (200 μg of budesonide and 6 μg of formoterol) used as needed or budesonide maintenance therapy with twice-daily budesonide (200 μg) plus terbutaline (0.5 mg) used as needed. The primary outcome was the annualized rate of severe exacerbations with symptom scores as secondary outcomes. The authors found that budesonide-formoterol used as needed was non-inferior to budesonide maintenance for preventing severe exacerbations but was not as successful in reducing symptoms. The total steroid dose was reduced 75%.

COMMENTARY

It is challenging to figure out how to use the results of these two studies, which suggest that as-needed budesonide-formoterol is not inferior to maintenance budesonide in preventing severe asthma exacerbations. However, the results also suggest that when it comes to symptom control, the as-needed combination is less effective than maintenance budesonide but more effective than terbutaline alone. These results are consistent with the findings of previous studies and a 2013 Cochrane review that also found the combination of budesonide-formoterol is effective when used intermittently as guided by symptoms.4,5 Before delving into some of the strengths and limitations of these two studies, it is important to note that not only were these studies sponsored by AstraZeneca, the manufacturer of the medications used (some of which are still on patent), but also that trial data “were analyzed by employees of the sponsor, AstraZeneca” and that the sponsor was involved in all stages of manuscript preparation. I am concerned that the authors (and AstraZeneca) set up a straw man comparison by choosing to use terbutaline vs. formoterol when terbutaline has been shown to be inferior to formoterol for controlling asthma, probably due to its shorter half-life.5 It must also be noted that although the as-needed regimen did not result in increased severe exacerbations, it did not give the same degree of relief from asthma symptoms as the scheduled dose of ICS. Some patients may accept this trade-off, while others may find the persistent symptoms troubling or bothersome. However, given these concerns, the studies were well-conducted and add to the body of literature that in mild asthmatics it is safe to use a controller agent such as an inhaled corticosteroid on an “intermittent” basis, expanding it to an as-needed basis for the ICS/LABA combination used here.

I have been telling my mild asthmatics that they should use their ICS for a week or so when they have a cold or allergies or any other reason they suspect their asthma may worsen. These studies add to this advice, with the ability to use a combination ICS/LABA as needed without worrying about increased severe exacerbations.

REFERENCES

  1. Braman SS. The global burden of asthma. Chest 2006;130(1 Suppl):4S-12S.
  2. National Asthma Education and Prevention Program. Expert panel report 3 (EPR-3): Guidelines for the diagnosis and management of asthma-summary report 2007. J Allergy Clin Immunol 2007;120(5 Suppl):S94-138.
  3. Chauhan BF, et al. Intermittent versus daily inhaled corticosteroids for persistent asthma in children and adults. Cochrane Database Syst Rev 2013;(2):CD009611.
  4. Kew KM, et al. Combination formoterol and budesonide as maintenance and reliever therapy versus combination inhaler maintenance for chronic asthma in adults and children. Cochrane Database Syst Rev 2013;(12):CD009019.
  5. Ekström T, et al. A 3-month comparison of formoterol with terbutaline via turbuhaler. A placebo-controlled study. Ann Allergy Asthma Immunol 1998;81:225-230.