Risk of a severe exacerbation following higher reliever use: post-hoc analysis of SYGMA 1 in mild asthma

Introduction In mild asthma, as-needed budesonide/formoterol (BUD/FORM) reduces long-term severe exacerbation risk vs. terbutaline as-needed, with similar reduction as maintenance BUD + terbutaline as-needed. In a post-hoc analysis of SYGMA 1 (NCT02149199; OʼByrne et al. NEJM 2018;378(20):1865 – 1876) we examined the short-term risk of a severe exacerbation after a single day with various levels of reliever use, comparing terbutaline as-needed, BUD/FORM as-needed, and maintenance BUD + terbutaline as-needed.

Methods In the SYGMA 1 study, 3836 patients with mild asthma were randomised to placebo twice daily (bid) + terbutaline 0.5 mg as-needed, placebo bid + BUD/FORM 200/6 µg as-needed, or maintenance BUD 200 µg bid + terbutaline as-needed. For patients with > 2, > 4, > 6 or > 8 reliever inhalations on any day, the proportions who had a severe exacerbation during the next 21 days were compared.

Results The proportion of patients with > 4, > 6 or > 8 as-needed inhalation use days was lower with BUD/FORM as-needed vs. terbutaline as-needed and maintenance BUD + terbutaline as-needed, with reduced risk of severe exacerbation during the next 21 days vs. terbutaline as-needed ([Fig. 1]; [Table 1]). The safety of BUD/FORM as-needed was consistent across all inhalation groups, with no new safety findings.

Kaplan-Meier plots showing time to first severe exacerbation in the 21 days following first day with > 2, > 4, > 6 and > 8 reliever inhalations.

Tab. 1 Number of patients with a severe exacerbation in the 21 days following first day with > 2, > 4, > 6, and > 8 reliever inhalations.

	As-needed terbutaline 0.5 mg (n = 1277)	As-needed BUD/FORM 200/6 µg (n = 1277)	BUD maintenance 200 µg bid + as-needed terbutaline (n = 1282)
*  Hazard ratios not calculated in view of low exacerbation rates in the as-needed BUD/FORM group.
> 2 “as-needed” inhalations
Patients with > 2 reliever inhalations on ≥ 1day, n (%)	936 (73.3)	850 (66.6)	758 (59.1)
Patients with severe exacerbations within 21 days, n (%)	37 (4.0)	10 (1.2)	11 (1.5)
Hazard ratio (95% CI)	Reference group	0.30 (0.15, 0.61) p = 0.001	0.37 (0.19, 0.73) p = 0.004
	3.33 (1.65, 6.69) p = 0.001	Reference group	1.24 (0.53, 2.91) p = 0.63
> 4 “as-needed” inhalations
Patients with > 4 reliever inhalations on ≥ 1day, n (%)	526 (41.2)	303 (23.7)	311 (24.3)
Patients with severe exacerbations within 21 days, n (%)	40 (7.6)	5 (1.7)	9 (2.9)
Hazard ratio (95% CI)	Reference group	0.24 (0.09, 0.60) p = 0.002	0.41 (0.20, 0.84) p = 0.015
	4.24 (1.67, 10.75) p = 0.002	Reference group	1.73 (0.58, 5.15) p = 0.328
> 6 “as-needed” inhalations
Patients with > 6 reliever inhalations on ≥ 1day, n (%)	281 (22.0)	102 (8.0)	142 (11.1)
Patients with severe exacerbations within 21 days, n (%)	22 (7.8)	1 (1.0)	6 (4.2)
Hazard ratio (95% CI)	Reference group	–	0.61 (0.25, 1.51) p = 0.287
> 8 “as-needed” inhalations*
Patients with > 8 reliever inhalations on ≥ 1day, n (%)	170 (13.3)	49 (3.8)	67 (5.2)
Patients with severe exacerbations within 21 days, n (%)	15 (8.8)	0 (0.0)	2 (3.0)

Conclusions In mild asthma, anti-inflammatory reliever therapy with BUD/FORM as-needed reduces higher reliever use days and reduces exacerbations within the next 21 days vs. terbutaline as-needed.