As-needed budesonide/formoterol for mild persistent asthma may prevent serious exacerbations as well as twice-daily maintenance budesonide

EBM Focus - Volume 13, Issue 22

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Reference: SYGMA 2 trial (N Engl J Med 2018 May 17;378(20):1877) (level 2 [mid-level] evidence)

  • Patients with mild persistent asthma typically use maintenance therapy with regularly administered low-dose inhaled corticosteroids, but patient adherence to such maintenance therapy is low.
  • In the SYGMA 2 noninferiority trial, over 4,000 adolescents and adults with mild persistent asthma were randomized to as-needed combination budesonide/formoterol vs. maintenance budesonide plus as-needed terbutaline for 1 year.
  • As-needed budesonide/formoterol was noninferior to maintenance budesonide with regard to the annualized rate of severe exacerbations (0.11 vs. 0.12), but had a slightly lower likelihood of symptom improvement (in 40.3% vs. 44.3%, p < 0.05).


Regularly administered low-dose inhaled corticosteroids are recommended as maintenance therapy for mild persistent asthma (GINA 2018, Lancet 2018). However, patient adherence to maintenance therapy is low (Curr Opin Pulm Med 2013) and using only an as-needed combined corticosteroid/beta agonist inhaler may be attractive to many patients. In the SYGMA 2 noninferiority trial, 4,215 patients with mild persistent asthma were randomized to as-needed combination budesonide 200 mcg / formoterol 6 mcg inhaler (Symbicort Turbuhaler) vs. maintenance budesonide 200 mcg inhaler (Pulmicort Turbuhaler) twice-daily for 1 year. The as-needed budesonide/formoterol regimen also included twice-daily placebo doses, and the maintenance budesonide regimen also included an as-needed terbutaline 0.5 mg inhaler. The criterion for noninferiority was < 1.2 for the upper limit of the 1-sided 95% CI for the rate ratio for severe exacerbations with as-needed budesonide/formoterol compared to maintenance budesonide. Exacerbations were considered severe if they required systemic corticosteroids for ≥ 3 days, an emergency department visit leading to systemic corticosteroids, or hospitalization. Overall symptom severity was assessed with the Asthma Control Questionnaire-5 score (total score range 0-6), with symptom improvement defined as a ≥ 0.5 point decrease from baseline. Ninety-one percent of patients completed treatment, and 99% were included in the analyses.

Noninferiority for as-needed budesonide/formoterol was met: the annualized rate of severe asthma exacerbations was 0.11 with as-needed budesonide/formoterol vs. 0.12 with maintenance budesonide (rate ratio 0.97, upper limit of 1-sided 95% CI 1.16). The two groups had similar risks of experiencing at least 1 severe exacerbation during the year (in 8.5% vs. 8.8%), proportion of patient-days without using as-needed inhalers (69% vs. 76%), and adherence to maintenance doses (64% vs. 63%). Daily inhaled corticosteroid use was numerically less with as-needed budesonide/formoterol (median 66 vs. 268 mcg), but a statistical comparison was not reported. However, as-needed budesonide/formoterol was associated with a slightly lower likelihood of symptom improvement (in 40.3% vs. 44.3%, p < 0.05). Rates of adverse events were similar between the two groups (in 42.5% vs. 44% of patients), most commonly viral upper respiratory tract infection (7.4% vs. 8%) (statistical comparisons were not reported).

The results from the SYGMA 2 trial demonstrated that, in adolescents and adults with mild persistent asthma, an as-needed budesonide/formoterol inhaler may be an alternative to daily maintenance corticosteroids. There is some uncertainty regarding the noninferiority of as-needed budesonide/formoterol because a per-protocol analysis was not conducted to confirm the results. In secondary analyses, the as-needed regimen also may have reduced inhaled corticosteroid exposure, but it was slightly inferior regarding symptom improvement. Whether or not these differences are clinically relevant may depend on the individual patient. Also, the long-term effects of these differences, particularly with regard to a potential role of corticosteroids in preventing airway remodeling, remain to be seen. On the other hand, an as-needed regimen may be more attractive than a maintenance regimen for many patients. The companion SYGMA 1 trial reported consistent results, and also that as-needed budesonide/formoterol was superior to as-needed terbultaline monotherapy. Finally, it should be noted that the specific formulations used in the SYGMA 2 trial may not be available in every country. While equivalence of similar as-needed budesonide/formoterol formulations is likely, it cannot be guaranteed.

For more information, see the topics Long-acting beta-2 agonists for asthma in adults and adolescents and Inhaled corticosteroids for chronic asthma in adults and adolescents in DynaMed Plus. DynaMed users click here.


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