As-needed Budesonide-formoterol in Mild Asthma

Stephanie Keller, Pharm.D, Coborn’s Pharmacy / CHI St. Gabriel’s Health Family Medical Center

Background: The 2018 Global Initiative for Asthma (GINA) guidelines recommend as-needed short-acting beta agonists (SABAs) with or without low-dose inhaled corticosteroids as maintenance therapy in patients with mild asthma. Similarly, the 2007 National Heart, Lung, and Blood Institute (NHLBI) guidelines prefer low-dose inhaled corticosteroids along with as-needed SABAs for these patients. Many patients rely on SABAs for symptom relief, but these medications do not treat underlying inflammation and overuse is associated with a higher risk of asthma exacerbation. Additionally, poor adherence to maintenance inhaled corticosteroids is a critical issue in clinical practice. Two recent studies have investigated the use of as-needed budesonide-formoterol as an alternative to conventional therapy in adolescent and adult patients with mild asthma.

Evidence: The Symbicort®️ given as needed in mild asthma 1 (SYGMA 1) trial randomized 3,849 participants to one of three regimens: twice-daily placebo plus terbutaline (0.5mg) used as-needed, twice-daily placebo plus budesonide-formoterol (200mcg-6mcg) used as-needed, or twice-daily budesonide (200mcg) plus terbutaline (0.5mg) used as-needed. Subjects were 12 years of age and older with a clinical diagnosis of asthma requiring GINA guideline step two treatment. Inhaler use was measured according to inhaler monitor data, and symptom control was recorded electronically in a daily diary, also serving as an adherence reminder. With respect to percentage of weeks with well-controlled asthma, as-needed budesonide-formoterol was found to be superior to as-needed terbutaline (34.4% vs. 31.1%; OR 1.14 [95% CI 1.00-1.30]; P=0.046), but inferior to budesonide maintenance therapy (34.4% vs. 44.4%; OR 0.64 [95% CI 0.57-0.73]). Additionally, as-needed budesonide-formoterol was associated with a 64% lower rate of severe asthma exacerbations as compared to as-needed terbutaline (RR 0.36 [95% CI 0.27-0.49]). The rate of exacerbations in the as-needed budesonide-formoterol group did not differ significantly from the budesonide maintenance group. When comparing the median daily dose of inhaled glucocorticoid, the as-needed budesonide-formoterol group received 17% of the dose in the budesonide maintenance group.

With a more pragmatic study design eliminating daily adherence reminders, the Symbicort®️ given as needed in mild asthma 2 (SYGMA 2) trial examined whether as-needed budesonide-formoterol would be noninferior to budesonide maintenance therapy in preventing severe asthma exacerbations in patients with mild asthma. The 4,215 participants were randomized to receive either twice-daily placebo plus budesonide-formoterol (200mcg-6mcg) used as-needed, or twice-daily budesonide (200mcg) plus terbutaline (0.5mg) used as-needed. Similar to SYGMA 1, subjects were 12 years of age and older with a clinical diagnosis of asthma that required GINA guideline step two treatment. With regards to the annualized rate of severe exacerbations, budesonide-formoterol used as-needed was noninferior to budesonide maintenance therapy (RR 0.97 [95% CI upper limit, 1.16]), as the confidence interval upper limit remained below the prespecified noninferiority limit of 1.2. There was no significant difference in time to first severe exacerbation between the two groups (P=0.66). Secondary efficacy outcomes assessing asthma symptom control, asthma quality of life, and change in FEV1 from baseline favored the budesonide maintenance group. The as-needed budesonide-formoterol group had a 75% lower median daily dose of inhaled glucocorticoid compared to the budesonide maintenance group.

Discussion: SYGMA 1 demonstrated a 3.3% increase in weeks with well-controlled asthma and a 64% lower rate of severe asthma exacerbation with as-needed budesonide-formoterol as compared to as-needed terbutaline. However, budesonide maintenance therapy was superior to as-needed budesonide-formoterol with a 10% increase in weeks with well-controlled asthma in this study. Both SYGMA 1 and SYGMA 2 trials demonstrated similar rates of severe asthma exacerbations with as-needed budesonide-formoterol and budesonide maintenance therapy. Furthermore, as-needed budesonide-formoterol significantly decreased exposure to inhaled corticosteroids. Although both trials revealed inferior symptom control with as-needed budesonide-formoterol when compared to budesonide maintenance therapy, researchers found adherence rates to maintenance treatment in these trials were much higher than in clinical practice. Interestingly, SYGMA 2 initially aimed to evaluate the superiority of as-needed budesonide-formoterol, but the protocol was modified to test for inferiority due to a pre-specified sample size review of blinded results that confirmed lower exacerbation rates and higher adherence rates than anticipated. Additionally, all groups were required to use twice-daily maintenance inhalers, either budesonide or placebo, which would not be necessary in real-world situations.

Clinical Impact: In patients with mild asthma who qualify for GINA step two treatment, budesonide-formoterol used as-needed may be preferred over SABAs alone and may be used as an alternative to budesonide maintenance therapy in select situations. Clinicians should consider patient preference, medication adherence, and the reason for treating mild asthma when selecting therapy. Although current GINA and NHLBI guidelines have not addressed the results of these new trials, as-needed budesonide-formoterol may be acceptable for the treatment of mild asthma in patients unwilling to use daily maintenance inhaled corticosteroids, those struggling with medication adherence, and when treating to decrease asthma exacerbation risk rather than control symptoms. Moreover, additional studies with more practical study designs are needed to determine the effectiveness of as-needed budesonide-formoterol when compared to maintenance inhaled corticosteroids in a clinical practice setting.

References:

  1. Global initiative for asthma. Global strategy for asthma management and prevention, 2018. Available from:www.ginasthma.org.

  2. National Asthma Education and Prevention Program, Third Expert Panel on the Diagnosis and Management of Asthma. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda (MD): National Heart, Lung, and Blood Institute (US); 2007. Available from: https://www.ncbi.nlm.nih.gov/books/NBK7232/.

  3. O'Byrne PM, FitzGerald JM, Bateman ED, et al. Inhaled combined budesonide-formoterol as needed in mild asthma (SYGMA 1). N Engl J Med. 2018;378(20):1865-1876. doi: 10.1056/NEJMoa1715274.

  4. Bateman ED, Reddel HK, O'Byrne PM, et al. As-needed budesonide-formoterol versus maintenance budesonide in mild asthma (SYGMA 2). N Engl J Med. 2018;378(20):1877-1887. doi: 10.1056/NEJMoa1715275.