Single-day increase in budesonide–formoterol as needed as good as ICS maintenance in preventing exacerbations in mild asthma

For mild asthma, as-needed budesonide–formoterol (ICS-LABA*) significantly reduces the short-term risk of severe exacerbations, even with just a single day of increased use, compared with as needed SABA** — and this protective benefit appears as good as that seen with regular use of maintenance ICS, suggests a post hoc analysis of the SYGMA*** 1 study.

“Our findings challenge past assumptions that long-term daily adherence with maintenance ICS-containing treatment is necessary to reduce a patient’s risk of severe exacerbations,” said the researchers. “Instead, our findings suggest that the timely use of low-dose budesonide–formoterol on even a single day can reduce the risk of severe exacerbation (and need for OCS) in the subsequent days and weeks.”

“The importance of good adherence to maintenance treatment should not be underestimated, but as-needed use of ICS–formoterol every time a reliever is needed differs from poor adherence to maintenance therapy, when patients often revert to SABA-only use for days or weeks at a time,” they pointed out.

The post hoc analysis involved a subset of 3,836 patients from SYGMA 1 who were randomized 1:1:1 to as-needed terbutaline 0.5 mg (SABA), as-needed budesonide-formoterol 200–6 µg (ICS-LABA), or budesonide 200 µg twice daily + as-needed terbutaline (maintenance ICS). [Lancet Respir Med 2021;9:149–58]

The researchers found that increased use of SABA, even for just a single day, in patients with mild asthma was a predictor of increased short-term risk of severe exacerbations in the subsequent 21-day period. The incidence of severe exacerbations was 3.5 percent in patients who used >2 inhalations on the index single day of increased SABA use, which rose to 7.3 percent in those with >4 inhalations in a single day and 7.6 percent in the group with >6 inhalations in a single day.

However, intervention with as-needed budesonide-formoterol significantly reduced the risk of developing severe exacerbations in the following 21 days to an incidence rate of 0.9 percent in patients with >2 inhalations, 1.7 percent in those with >4 inhalations, and 1.0 percent in patients with >6 inhalations of budesonide-formoterol on the index single day.

Of note, the benefit of as-needed budesonide-formoterol was greater in patients with heightened risk of severe exacerbations (indicated by the number of inhalations increased in the index single day): the risk was reduced by 73 percent in patients with >2 inhalations (hazard ratio [HR], 0.27; p=0.0008), by 76 percent in those with >4 inhalations (HR, 0.24; p=0.003), and by 86 percent in those with >6 inhalations on the index single day (HR, 0.14; p=0.057).

In addition, the benefit appeared to be similar to that achieved with maintenance budesonide — with risk reductions of 61 percent in patients with >2 inhalations (HR, 0.39; p=0.0091), by 70 percent in those with >4 inhalations (HR, 0.30; p=0.0065), and by 57 percent in those with >6 inhalations of maintenance budesonide on the index single day (HR, 0.43; p=0.12).

“Use of an anti-inflammatory reliever might reduce the risk of short-term severe exacerbations by the timely provision of increased doses of as-needed ICS and formoterol when symptoms occur,” explained the researchers.

They also pointed out that, however, asthma exacerbations may not necessarily always be characterized by elevated inflammation, and thus, the benefit from ICS-formoterol may be attributed to more than just timely addition of ICS. In fact, as-needed formoterol, with or without maintenance ICS, has previously been shown to reduce the risk of exacerbations vs as-needed SABA.

“These findings are in contrast with previous assumptions that good long-term adherence to regular maintenance ICS is the only treatment approach to protect against severe exacerbations in mild asthma, and suggest that a single day of repeated use of as-needed low-dose ICS–formoterol in patients with mild asthma can protect against development of a severe exacerbation as effectively as taking regular maintenance ICS,” the researchers highlighted.

“These findings support the use of an anti-inflammatory reliever to reduce the risk of severe exacerbations in asthma and to exploit the natural relief-seeking behaviour of patients in such contexts via the rapid provision, when needed, of increased doses of both ICS and formoterol,” they added.

“Our findings also suggest that in asthma action plans for adolescents and adults, use of as-needed ICS–formoterol more than six times in a day should not necessarily prompt quadrupling the ICS dose (if ICS is already prescribed) or starting a course of OCS, as is often recommended when the reliever is SABA,” advised the researchers.

 

*ICS: Inhaled corticosteroid; LABA: Long-acting beta-agonist
**SABA: Short-acting β2-agonist
***SYGMA: SYmbicort Given as needed in Mild Asthma