Four trials ended the case for treating mild asthma with a reliever inhaler alone

For decades, mild asthma was treated with a short-acting reliever inhaler used when symptoms appeared, and nothing else. Four randomised trials between 2018 and 2019 dismantled that approach by testing the alternative directly: a combination inhaler containing an inhaled corticosteroid alongside a fast-acting bronchodilator, taken as needed instead of the reliever. Against reliever-alone treatment, the combination cut severe exacerbations by roughly half — an annualised rate of 0.195 versus 0.400 in one trial, a relative rate of 0.49 (95% CI 0.33 to 0.72, P<0.001) [s3].

The reason this mattered is set out in the trials' own framing of the problem: patients with mild asthma often rely on short-acting beta-2 agonists for symptom relief and have poor adherence to maintenance therapy [s2]. A reliever-only regimen leaves the inflammatory component of the disease untreated unless a daily preventer is taken as well, and adherence data are the reason that assumption does not hold.

SYGMA 1: the effect against a plain reliever

SYGMA 1 was a 52-week double-blind trial in patients aged 12 and over with mild asthma, randomised to three arms: twice-daily placebo plus as-needed terbutaline 0.5 mg; twice-daily placebo plus as-needed budesonide-formoterol (200 µg budesonide, 6 µg formoterol); or twice-daily budesonide 200 µg plus as-needed terbutaline [s1]. Of 3,849 randomised, 3,836 entered the analysis [s1].

On the primary outcome — electronically recorded weeks with well-controlled asthma — the as-needed combination beat terbutaline (34.4% versus 31.1% of weeks; odds ratio 1.14, 95% CI 1.00 to 1.30, P=0.046) and lost to daily budesonide (34.4% versus 44.4%; odds ratio 0.64, 0.57 to 0.73) [s1]. Both results are worth reading carefully: the win over terbutaline was marginal, and the loss to maintenance therapy was not.

Severe exacerbations told a different story. The annual rate was 0.20 with terbutaline, 0.07 with budesonide-formoterol and 0.09 with budesonide maintenance — a rate ratio of 0.36 (0.27 to 0.49) for the combination against terbutaline, and 0.83 (0.59 to 1.16) against maintenance budesonide [s1]. Adherence in the maintenance arm was 78.9%, far above what routine care achieves [s1]. And the median metered daily inhaled glucocorticoid dose in the as-needed group was 57 µg, 17% of the 340 µg in the maintenance group [s1].

SYGMA 2: the non-inferiority question

SYGMA 2 tested the same as-needed combination against daily budesonide directly, in 4,215 randomised patients aged 12 and over, with a prespecified noninferiority limit of 1.2 on the annualised rate of severe exacerbations [s2].

It met it. The annualised severe exacerbation rate was 0.11 (95% CI 0.10 to 0.13) with as-needed budesonide-formoterol and 0.12 (0.10 to 0.14) with maintenance budesonide — rate ratio 0.97, upper one-sided 95% confidence limit 1.16 [s2]. Time to first exacerbation was similar (hazard ratio 0.96, 0.78 to 1.17) [s2]. Median daily metered inhaled glucocorticoid dose was 66 µg against 267 µg, about a quarter [s2].

The trade-off appeared in symptoms: the change in Asthma Control Questionnaire-5 score differed by 0.11 units (0.07 to 0.15) in favour of maintenance therapy [s2]. The trial's own conclusion is that as-needed treatment was noninferior for severe exacerbations but inferior for symptom control [s2].

Novel START and PRACTICAL: the open-label versions

Both SYGMA trials were double-blind, which means every patient took a twice-daily inhaler, including those assigned to as-needed therapy. That design measures the drug and hides the behaviour. Two open-label trials tested it as it would actually be used.

Novel START randomised 675 adults with mild asthma to albuterol as needed, budesonide 200 µg twice daily plus as-needed albuterol, or as-needed budesonide-formoterol, with electronic inhaler monitoring, and analysed 668 [s3]. The annualised exacerbation rate was 0.195 with budesonide-formoterol against 0.400 with albuterol (relative rate 0.49, 0.33 to 0.72, P<0.001), and did not differ significantly from budesonide maintenance at 0.175 (relative rate 1.12, 0.70 to 1.79, P=0.65) [s3]. Severe exacerbations were fewer with the as-needed combination than with either comparator: 9 versus 23 for albuterol (relative risk 0.40, 0.18 to 0.86) and 9 versus 21 for maintenance budesonide (0.44, 0.20 to 0.96) [s3]. Mean inhaled budesonide dose was 107±109 µg per day against 222±113 µg [s3].

PRACTICAL, a 52-week open-label superiority trial in New Zealand, randomised 890 adults aged 18-75 with mild to moderate asthma and analysed 885 [s4]. Severe exacerbations per patient per year were 0.119 with as-needed budesonide-formoterol against 0.172 with maintenance budesonide plus as-needed terbutaline (relative rate 0.69, 95% CI 0.48 to 1.00, p=0.049) [s4]. That result sits exactly on the conventional threshold, with a confidence interval touching 1.00 — a superiority claim that only just holds.

PRACTICAL's authors state the guideline context plainly: the findings support the 2019 Global Initiative for Asthma recommendation that inhaled-corticosteroid-formoterol reliever therapy is an alternative regimen to daily low-dose inhaled corticosteroid for patients with mild asthma [s4].

What this does not settle

Symptom control was better on daily maintenance therapy in both SYGMA trials, and better on daily budesonide in SYGMA 1 by a clear margin [s1] [s2]. So the case for as-needed combination therapy is not that it is better on everything; it is that it achieves comparable exacerbation protection at a fraction of the steroid exposure, in a regimen people will actually follow. SYGMA 1's 78.9% maintenance adherence is the number that quietly makes the comparison generous to daily therapy [s1].

None of these trials establishes anything about severe asthma, about children under 12, or about a specific individual's regimen. Inhaler regimens are prescribed, and changing one — including stopping a preventer — is a clinical decision, not one this evidence makes on anyone's behalf.

Sources

• Inhaled Combined Budesonide-Formoterol as Needed in Mild Asthma — New England Journal of Medicine, 2018-05-16
• As-Needed Budesonide-Formoterol versus Maintenance Budesonide in Mild Asthma — New England Journal of Medicine, 2018-05-16
• Controlled Trial of Budesonide-Formoterol as Needed for Mild Asthma — New England Journal of Medicine, 2019-05-19
• Budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild to moderate asthma (PRACTICAL) — The Lancet, 2019-08-23