Reference: N Engl J Med 2018 May 17 (level 2 [mid-level] evidence)
Asthma is classified as mild in 50%-75% of patients that are diagnosed and yet is very often poorly controlled even with the many medication treatment options that are available today(Allergy. 2007 Jun). Up to 30-40% of asthma exacerbations in patients with mild asthma will be severe enough to warrant treatment in the emergency department or admission to the hospital (Respiration. 2018). The Global Initiative for Asthma (GINA) guidelines recommend that patients with mild persistent asthma receive regular low-dose inhaled glucocorticoids as a controller medication to help minimize symptoms and use a short acting beta agonist (SABA) as needed for relief of acute symptoms when they occur.
Studies have shown that many patients with mild asthma often use SABAs as needed to control symptoms, but adherence to maintenance medications is generally poor and on average about 35% compliance is seen (J Allergy Clin Immunol. 2006 Oct). Given this low compliance, there is clinical value in determining if the use of a combination LABA/inhaled low dose glucocorticoid on an as needed basis is non-inferior to current recommended maintenance therapy with a low dose inhaled glucocorticoid and as needed SABA.
The SYGMA 2 trial compared the use of Symbicort (budesonide/formoterol) as needed to budesonide daily plus the use of terbutaline, a SABA, as-needed for prevention of severe exacerbations in patients with mild asthma (N Engl J Med. 2018 May 17). The trial included 4,215 outpatients aged 12 years or older diagnosed within the last 6 months and determined to need Step 2 treatment according the Global Initiative for Asthma criteria. Patients were randomized to twice-daily placebo plus as-needed inhaled budesonide 200 μg/formoterol 6 μg or twice-daily inhaled budesonide 200 μg plus as-needed inhaled terbutaline 0.5 mg for 1 year. Patients with worsening asthma (defined as a change in medication therapy or use of systemic glucocorticoids in the last 30 days), persons with history of current or former smoking with a greater than 10-year pack history, and patients with a history of life-threatening asthma were excluded from the trial.
Though initially begun as a superiority trial, the authors reverted to a primary analysis for non-inferiority after a prespecified sample-size review showed a lower than anticipated overall exacerbation rate (0.1 exacerbations annually rather than 0.14) and a higher adherence rate; the change occurred prior to the last patient’s enrollment. Non-inferiority of budesonide/formoterol was defined as a rate ratio of
< 1.2 severe exacerbations annually compared to maintenance budesonide plus as-needed terbutaline at a limit of a one-sided 95% CI. A severe exacerbation is defined as peak expiratory flow (PEF) reduced to ≤50 percent predicted. Despite the switch to non-inferiority analysis, the authors did not report per-protocol results which is the standard for such comparisons. Secondary outcomes included clinically meaningful symptom improvement defined as an at least 0.5-point decrease on Asthma Control Questionnaire-5 score (ACQ-5; ranges from 0-6 points with a score of 6 indicating maximum impairment).
As-needed budesonide/formoterol was shown to have an annual exacerbation rate of 0.11 compared to 0.12 with maintenance budesonide plus as-needed terbutaline (rate ratio 0.97, 95% CI NA to 1.16, non-inferiority criteria met). Overall, 8.5% of patients in the budesonide/formoterol group and 8.8% of the maintenance budesonide plus as-needed terbutaline had at least one severe exacerbation (no p value reported). There was no significant difference in time until the first severe exacerbation after initiation of therapy. Compared to the budesonide maintenance group, the median daily dose of inhaled glucocorticoid was 75% lower in the budesonide/formoterol group, and the number of days with inhaled glucocorticoid use was 37.5% lower (no p values reported for either comparison). Clinically meaningful symptom improvement occurred in 40.3% of the budesonide/formoterol group, which was significantly lower than the 44.3% of the maintenance budesonide group, but the confidence interval includes differences that may not be clinically important (odds ratio 0.86, 95% CI 0.75-0.99). Improvement in lung function was seen in both groups with increased forced expiratory volume in 1 second (FEV1) from baseline both before and after bronchodilator use. There was greater improvement in the budesonide maintenance group (between group difference of -32.6 ml, 95% CI -53.7 ml to -11.4 ml before bronchodilator use and -23.1 ml, 95% CI -41.9 to -4.2 ml after bronchodilator use). Serious adverse event rates were comparable between groups, occurring in 3.2% of the budesonide/formoterol group and 3.5% of the maintenance group (no p value reported).
As needed budesonide-formoterol may be as effective as maintenance therapy with budesonide and as needed SABA at limiting severe exacerbations. The budesonide/formoterol group was also associated with improved lung function and symptoms from baseline, though not when compared to maintenance budesonide. The SYGMA 1 trial had similar findings that showed budesonide-formoterol as needed was superior to terbutaline as needed for asthma control and reducing exacerbation while being non-inferior to budesonide maintenance therapy with regards to exacerbation reduction (
N Engl J Med. 2018 May 17). When looking at these two trials together, we can see that as needed relief is at least non-inferior in reducing severe outcomes. This is something that is beneficial for both providers, patients and the healthcare system as it may reduce cost and prevent deaths. Though there is not sufficient data to show non-inferiority when comparing symptomatic relief, one can argue that this would overall be a huge benefit. (N Engl J Med. 2018 May) Patients that seek more symptomatic relief could still be placed on maintenance therapy after discussion with their provider. One limitation of this study is increased adherence to the regimen, roughly 60%, which is significantly higher than is encountered in clinical practice. Another limitation is the lack of markers tested that would compare the effect on inflammatory response as a decrease in inflammatory response could predispose a patient to fewer exacerbations. This is something that can be addressed in future studies. Further studies could also assess potential differences in long term complications of asthma among patients in the two treatment groups. Given these results, as needed budesonide-formoterol may be a viable alternative asthma management therapy when compared to standard maintenance with budesonide and as needed SABA.
For more information, see the Long-acting Beta-2 Agonists for Asthma in Adults and Adolescents in DynaMed.
TALHA RAMZAN
A second-year resident at Memorial Health University Medical Center’s Family Medicine Program in Savannah, Georgia. He is originally from Islamabad, Pakistan but grew up in Wichita Falls, Texas. He completed his undergraduate training at Midwestern State University and obtained his Masters from the UNT Health Science Center Graduate school of Biomedical Sciences. He attended medical school at Lake Erie College of Osteopathic Medicine and then matched at Memorial’s family medicine program. He is very passionate about Inpatient Medicine and plans to work as a hospitalist back in Texas when he completes his training.