As-Needed Budesonide-Formoterol Reduces Risk of Severe Exacerbation - Post hoc Analysis of SGYMA 1 Study

5 Apr, 21

Introduction

Regular use of medications containing inhaled corticosteroids (ICS) might lower the risk of exacerbations and mortality in asthma. However, patients often rely on short-acting ?₂-agonist (SABA) for symptom relief and the maintenance treatment with ICS is neglected. A combination of budesonide-formoterol has demonstrated reduction in the long-term exacerbation risk compared with as-needed short-acting ?₂-agonist (SABA), with a similar or increased reduction versus maintenance with budesonide plus as-needed SABA, despite a lower budesonide dose. The timely administration of intensified ICS and formoterol doses might treat symptoms, bronchoconstriction and worsening of inflammation, thereby arresting progression to an exacerbation.

Aim

The frequency of reliever use and risk of a severe exacerbation in the 2 days after the first use of more than two, four, six, or eight reliever inhalations in 24 hour in this post-hoc analysis of the SYmbicort Given as needed in Mild Asthma (SYGMA) 1 study.

Patient Profile

Subjects aged >12 years with mild asthma

Method

Study Design

Randomized, double-blind, controlled, 52-week phase 3 trial

Treatment Strategy

The patients entered a run-in period of 2-4 weeks wherein they received as-needed terbutaline
The subjects were required to have evidence of need of GINA step 2 treatment, indicated by the use of as-needed terbutaline on atleast 3 days during the last week of the run-in period and not to have used >6 inhalations of terbutaline on >2 days
The cohort was randomized in 1:1:1 to placebo twice daily plus as-needed terbutaline 0·5 mg, placebo twice daily plus as-needed budesonide-formoterol 200-6 ?g, or budesonide 200 ?g twice daily plus as-needed terbutaline (ie, budesonide maintenance group).

End Points

Frequency of reliever use
Risk of severe exacerbation in the 21 days after first use of more than 2, 4, 6 and 8 as-needed inhalations taken in a single day from reliever index day

Results

Out of the overall cohort of 5721 patients enrolled in SYGMA 1, 3849 were randomized to as-needed terbutaline (n=1280), as-needed budesonide-formoterol (n=1279), or budesonide maintenance (n=1290), of whom 3836 had evaluable data (n=1277 as-needed terbutaline, n=1277 as needed budesonide-formoterol, and n=1282 budesonide maintenance).
Median reliever use was 0·32 (IQR 0·08-0·91) inhalations per day for the as-needed terbutaline group, 0·29 (0·07-0·72) for the as-needed budesonide-formoterol group, and 0·16 (0·04-0·52) for the budesonide maintenance group.
The patients did not use the reliever on 70-77.5% of study days in all the 3 groups
Significantly fewer patients in both the as-needed budesonide-formoterol and budesonide maintenance groups ever used more than 2, 4, 6 or 8 inhalations of reliever in a single day as compared to as-needed terbutaline group (all p=0.0002)
For patients in the as-needed terbutaline group, the risk of severe exacerbation increased after the first reliever index day of more than 4, 6 or 8 inhalations as compared to the first day of more than 2 inhalations
After adjustment for age, sex, randomly assigned treatment, pre-study treatment group, baseline % predicted post-bronchodilator FEV₁, and severe exacerbation in the 12 months before enrolment in the study, the hazard ratio (HR) for severe exacerbation in the 21 days after a single day with more than two as-needed inhalations was 0·27 (p=0·0008) with as-needed budesonide-formoterol and 0·39 (p=0·0091) with budesonide maintenance compared with as-needed terbutaline
Similarly, after a single day of more than four as-needed inhalations the HR was 0·24 (p=0·0030) with as-needed budesonide-formoterol and 0·30 (p=0·0065) with budesonide maintenance
The HR was 0·14 (p=0·057) with as-needed budesonide-formoterol and 0·43 (p=0·12) with budesonide maintenance after a single day of more than six as-needed inhalations.

Conclusions

In mild asthma, even a single day with increased SABA use is an indicator for increased short-term risk of severe exacerbation
As-needed budesonide-formoterol is associated with a reduction in the short-term risk of severe exacerbations after a single day of higher use (more than two as-needed inhalations), even when overall use is infrequent.
The frequency of exacerbations and subsequent risk of sever exacerbations and the need for oral corticosteroids is reduced with as-needed budesonide-formoterol as compared to as-needed SABA.

Lancet Respir Med. 2021 Feb;9(2):149-158. Doi: 10.1016/S2213-2600(20)30416-1.