A New Approach for Treating Patients with Intermittent Mild Asthma

For many years, as-needed albuterol or another short-acting β-agonist (SABA) has been the standard of care for patients with intermittent asthma, with an added daily inhaled corticosteroid (ICS) for patients with mild persistent asthma. The U.S. National Asthma Education and Prevention Program (NAEPP) guideline, last updated in 2007, defines intermittent asthma as symptoms that occur at most twice weekly, nighttime symptoms that occur at most twice monthly, normal lung function, ≤1 severe exacerbation annually, and no substantial impairment in activities. Patients with mild persistent asthma have less-than-daily symptoms, nighttime symptoms less often than weekly, mild limitation of activities, or ≥2 exacerbations annually, along with normal lung function.

Studies have shown that even patients with intermittent asthma can have severe or fatal exacerbations and that ICS can prevent them. In addition, patients who receive early ICS treatment might retain better lung function and require less ICS later. Given these observations, recent studies have been designed to evaluate as-needed ICS in patients with intermittent or mild persistent asthma. Five randomized trials have confirmed that as-needed ICS combined with a bronchodilator (4 with budesonide/formoterol and 1 with beclomethasone/albuterol) are noninferior to daily ICS for preventing exacerbations in patients with mild asthma (at the expense of a small increase in daily symptom scores). The most recent study was a “real world” open-label trial of as-needed budesonide/formoterol versus daily ICS. It showed that as-needed treatment yielded similar symptom scores and was superior at preventing exacerbations (NEJM JW Gen Med Oct 15 2019 and Lancet 2019; 394:919). The well-documented fact that most asthma patients do not use their ICS daily when they are asymptomatic probably explains this outcome.

This new body of evidence has led to a change in the Global Initiative for Asthma (GINA) guideline; GINA is an international collaboration comprised largely of European asthma experts. GINA classifies asthma severity based on the level of therapy needed to control symptoms after several months of therapy: The intermittent classification is no longer used, and asthma controlled with as-needed therapy or daily low-dose ICS is defined as “mild.” Preferred therapy for patients with symptoms less often than twice monthly is either (a) as-needed low-dose ICS/formoterol (formoterol is a long-acting β-agonist [LABA] with a quick onset of action) or (b) as-needed ICS whenever as-needed SABA is used. For patients whose symptoms are more frequent (but still not on most days), preferred therapy is daily low-dose ICS plus as-needed SABA or as-needed low-dose ICS/formoterol. For more-symptomatic patients, more-intensive treatment is recommended. Notably, GINA strongly discourages use of as-needed monotherapy with a SABA (e.g., albuterol), even in patients with only mild symptoms — and that is a major departure from typical U.S. practice.

In support of as-needed ICS/formoterol for patients with mild symptoms, GINA notes that as-needed ICS/formoterol prevents more exacerbations than does as-needed SABA alone. Moreover, as-needed budesonide/formoterol is as good as daily ICS in preventing severe asthma exacerbations and exposes patients to substantially less inhaled steroid over time.

Wrap-Up

So what is a U.S. clinician to do with the new GINA guideline, given that the NAEPP guideline is relatively outdated? In my view, the GINA guideline should inform practice, but we must be aware that its approach is not FDA approved, it does not apply to children younger than 12, and the device studied for as-needed budesonide/formoterol is the dry-powder Turbohaler (in the U.S., only the metered-dose inhaler is available). In addition, salmeterol (the LABA in Advair) cannot be used as a relief medication, because its onset of action is slower than that of formoterol. Vilanterol (the LABA in Breo) has quicker onset than salmeterol, and in theory, mometasone/formoterol (Dulera) should perform similarly to budesonide/formoterol, but studies have not been performed with as-needed use of either medication.

AstraZeneca chose to bring the metered-dose inhaler version of budesonide/formoterol to the U.S. instead of the dry-powder Turbohaler version based on marketing decisions, and no U.S. clinical trial is on the horizon for as-needed budesonide/formoterol in a metered-dose inhaler, but we might see a combined beclomethasone/albuterol inhaler in the U.S. eventually. Until then, for my patients with mild intermittent asthma who would fall into step 1 GINA therapy (rare symptoms, normal lung function, and no history of severe exacerbations), I will continue to prescribe as-needed albuterol, because it is much less expensive than budesonide/formoterol (Symbicort) — generic albuterol is about US$50 versus $300 for a canister of Symbicort. For patients who require step 2 therapy with GINA or for patients with mild persistent asthma based on the older NAEPP guidelines, I have detailed discussions with patients regarding risks and benefits of a daily ICS plus as-needed albuterol versus as-needed ICS/formoterol. More and more often, I end up prescribing as-needed budesonide/formoterol based on patient preference, and I have had very good patient feedback so far.