On Demand as Effective as Maintenance Therapy for Mild Asthma

Jennifer Garcia

May 16, 2018

On-demand treatment is as effective for mild asthma as twice-daily maintenance therapy and reduces overall drug exposure according to two double-blind, multicenter trials published online today in the New England Journal of Medicine.

In the first trial, Symbicort Given as Needed in Mild Asthma (SYGMA 1), researchers randomly assigned 3836 patients with mild asthma into one of 3 treatment groups: placebo plus as-needed terbutaline 0.5 mg (n = 1277), placebo plus as-needed budesonide (200 μg) with formoterol (6 μg) (n = 1277), and maintenance therapy with twice-daily budesonide 200 μg (n = 1282). Patients were followed for 52 weeks, using electronic monitors and diaries to track symptoms, exacerbations, and interventions.

The researchers found that patients in the budesonide-formoterol group achieved a greater percentage of weeks with well-controlled asthma compared with those in the terbutaline group (34.4% vs 31.1%; odds ratio [OR], 1.14; 95% confidence interval [CI], 1.00-1.30; P = .046), but the budesonide-formoterol group had fewer weeks of well-controlled symptoms compared with budesonide maintenance therapy (34.4% vs 44.4%; OR, 0.64; 95% CI, 0.57-0.73). Exacerbation rates were similar between both budesonide groups, but were lower than exacerbation rates seen in the terbutaline group.

Importantly, as-needed budesonide-formoterol therapy also resulted in lower median metered daily glucocorticoid dose (57 μg) compared with the budesonide maintenance group (340 μg).

In the second trial, SYGMA 2, 4176 patients with mild asthma were randomly assigned to either an on-demand treatment group using budesonide-formoterol (n = 2089) or a maintenance group using twice-daily budesonide (n = 2087). Patients in this trial were also followed for 52 weeks, using electronic monitors and diaries to track symptoms, exacerbations, and interventions.

The researchers found that use of on-demand budesonide-formoterol (200 μg budesonide and 6 μg formoterol) was noninferior to twice-daily budesonide (200 μg) maintenance therapy for control of severe asthma exacerbations. The annualized rates of severe exacerbations were 0.11 (95% CI, 0.10-0.13) in the as-needed group vs 0.12 (95% CI, 0.10-0.14) in the maintenance therapy group. In addition, the time to first exacerbation was similar between the 2 groups (hazard ratio, 0.96; 95% CI, 0.78-1.17).

However, again, the median daily metered dose of budesonide was lower in the on-demand group compared with the maintenance group (66 vs 267 μg, respectively).

Despite the similar primary outcomes, the study authors note that secondary outcomes, including quality of life and spirometric assessments, were better among patients in the daily budesonide group.

"These two trials show persuasively that treatment with budesonide–formoterol on an as-needed basis prevented the most serious outcomes of poorly controlled asthma — exacerbations and loss of lung function — but was less effective at mitigating symptoms," writes Stephen C. Lazarus, MD, from the University of California at San Francisco, in an accompanying editorial.

"Not only does this reduce the potential for glucocorticoid side effects and improve the acceptability of the treatment regimen to glucocorticoid-averse patients, but it also has the potential to reduce costs dramatically," he continues. With approximately 18.4 million adults with asthma in the United States, and a monthly average cost for a glucocorticoid inhaler at $218, he estimates that the cost savings could be close to $1 billion annually.

For some patients, however, a reduction in exacerbations may not be enough, particularly "for patients who are unhappy with any symptoms or a need for rescue inhaler use, but many others may prefer to accept occasional mild symptoms and inhaler use if it frees them from daily use of inhaled glucocorticoids while preventing loss of lung function and exacerbations."

Funding for both studies was provided by AstraZeneca, and multiple authors reported financial relationships with the company outside of the submitted work. In addition, several authors report multiple types of financial relationships with numerous other pharmaceutical and biomedical companies. For the full list of disclosures, please see the journal website. The editorialist has reported no relevant financial disclosures.

N Engl J Med. 2018;378:1865-1887, 1940-1942. SYGMA 1, SYGMA 2, Editorial

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