Using prn inhaled steroids/b-agonists in mild asthma

Two drug company sponsored articles appeared in a recent New England Journal highlighting the benefit of as-needed budesonide/formoterol (brand name Symbicort), a combination inhaled corticosteroid (ICS) and long-acting beta-agonist (LABA) in patients with mild asthma.
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The 1^st article compared as-needed ICS/LABA twice-daily with ICS maintenance twice-daily (see asthma mild LABA-ics2 nejm2018 in dropbox, or DOI: 10.1056/NEJMoa1715275)

Details:
-- 4215 patients >12 years old with mild asthma who were appropriate for treatment with low-dose maintenance ICS.
-- Mean age 41, 62% female, 3% current smokers, 8 years since diagnosis of asthma, ACQ–5 score (see below) 1.5, FEV1 pre-bronchodilator was 84% of predicted increasing to 96% after bronchodilator with 15% bronchodilator reversibility, number of severe exacerbations 12 months: 78% zero, 17% one, 5% more.
-- Patients were randomized in this multicenter trial (354 sites in 25 countries) to budesonide 200µg/formoterol 6µg twice-daily as-needed vs budesonide 200µg twice-daily maintenance. Terbutaline was used as a short acting beta agonist (SABA) as needed. Followed 52 weeks, from 2014-2017
-- 46% of the patients had asthma uncontrolled with a SABA alone
-- exclusion criteria were: current or former smoker with a history of 10 or more pack years, history of life-threatening asthma, worsening asthma (including use of systemic steroids prior 30 days)
-- Primary analysis: comparing budesonide/formoterol as-needed with budesonide maintenance therapy, assessing annualized rate of severe exacerbations
-- symptoms were assessed using the Asthma Control Questionnaire–5 (ACQ–5), with a scale of 0 (no impairment) to 6 (maximum impairment), minimal clinically significant difference is 0.5 units

Results:
-- adherence rate was 64% for each therapy
-- the annualized rate of severe exacerbations (needing systemic steroids for >2 days, hospitalization) was 0.11 (0.10-0.13) in those on the prn ICS/LABA combination, and 0.12 (0.10-0.14) for those on maintenance ICS: non-signficant
-- percentage of days of ICS use was lower with budesonide/formoterol (30.5%) prn vs maintenance budesonide (67.9%)
-- the median daily dose of ICS was lower in the budesonide/formoterol group (66 µg) vs the budesonide maintenance group (267 µg)
-- time to 1^st exacerbation was similar in the 2 groups, HR 0.96 (0.78-1.17)
-- median number of days with systemic steroid treatment was 6 in each group
-- change in the ACQ–5 score showed a difference of 0.11 units (0.07-.15) in favor of budesonide maintenance, though this did not meet the criterion for minimal clinically significant difference
-- change in baseline FEV1 was less in the budesonide/formoterol group by 32.6 mL before bronchodilator use and 23 mL after
-- adverse events similar the 2 groups. There was one death in each group. The one in the budesonide maintenance group was felt to be asthma-related, the one in the budesonide/formoterol group was cardiorespiratory arrest felt to be not related to asthma

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 the 2nd article compared prn budesonide/formoterol​ to both prn terbutaline (SABA) as well as to maintenance budesonide (see asthma mild LABA-ics nejm2018 in dropbox, or DOI: 10.1056/NEJMoa1715274)

Details:
-- 3836 patients >12 years old with mild asthma were randomized to terbutaline 0.5 mg used as needed, budesonide/formoterol 200 µg/6 µg twice-daily as needed, or budesonide 200 µg twice-daily maintenance and terbutaline as needed. 52 week trial, from 2014-2017
-- age 40, 61% female, 6.4 years since asthma diagnosis, a ACQ–5 score 1.5, FEV1 84% of predicted/after bronchodilator 96%, bronchodilator reversibility 15%, asthma uncontrolled with short-acting bronchodilator alone 45%, severe exacerbations in previous 12 months 20%
-- similar inclusion criteria as to the above study

Results:
-- percent of weeks with well-controlled asthma:
    -- budesonide/formoterol prn was superior to terbutaline, 34.4% vs 31.1%, odds ratio 1.14 (1.00-1.30), p=0.046. The odds of having a week with well-controlled asthma was 14% higher with budesonide/formoterol over the year.
    -- budesonide/formoterol prn was inferior to budesonide maintenance therapy, 34.4% vs 44.4%, odds ratio 0.64 (0.57-0.73)
-- annual rate of severe exacerbations
    -- terbutaline, 0.20
    -- budesonide/formoterol prn, 0.07 (ie, a 64% reduction over terbutaline alone, and a 60% decrease in moderate to severe exacerbations)
    -- maintenance budesonide, 0.09 (not significantly different from budesonide/formoterol prn)
-- adherence in the budesonide maintenance group was 78.9%
    --additional inhaled or systemic steroids for asthma were prescribed in fewer patients on budesonide/formoterol prn (13%) vs on terbutaline (27%) or budesonide maintenance (15%)
-- median daily dose of inhaled steroids in the budesonide/formoterol group was 57 µg, 17% of the 340 µg in the budesonide maintenance group  
-- ACQ-5: no clinically meaningful differences between the groups, but slight edge of budesonide over budesonide/formoterol over terbutaline
-- adverse events: 43% terbutaline, 38% with budesonide/formoterol, 40% with budesonide maintenance
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Commentary:
-- current guidelines suggest using maintenance low-dose ICS for most patients with mild asthma, with SABA for further symptom relief. However studies have documented that adherence to such a regimen is quite poor, below 35%. Patients typically use just SABA. As a result, patients are at higher risk of severe exacerbations and death.
-- “mild” asthma is an important public health issue, comprising 50 to 75% of patients with asthma as well as 30 to 40% of those with severe asthma exacerbations which lead to emergency consultations
-- formoterol is an unusual long-acting b-agonist because it has a rapid onset of action, allowing it to be used prn for symptoms
-- from these 2 studies:
    --in general the prn use of budesonide/formoterol was noninferior to maintenance low-dose budesonide, even though there was less than one quarter of the total exposure to ICS
    --budesonide/formoterol was equally effective to maintenance budesonide in preventing clinically important asthma exacerbations, but was inferior in achieving electronically recorded weeks with well-controlled asthma. BUT, the patients were exposed to less than 1/5 the amount of inhaled steroids
    ​--maintenance budesonide was better than prn budesonide/formoterol but only in the average number of weeks without asthma symptoms
--it should be emphasized that in the latter study, there was no difference in severe exacerbations if use the prn ICS/LABA, except for symptom control.  To me, the big issue really is preventing severe exacerbations because:
    --there is still a significant morbidity and mortality to these severe exacerbations
    --even if there are more symptoms with prn meds and the patient needs to use some extra puffs, that is still less than daily puffs in the maintenance group, the above assessment of the patient’s symptoms by the asthma control questionnaire (ACQ-5) showed no difference between groups, and it may be easier and more accepting by patients just to use a prn med to get adequate symptom control
    --unlike initial conceptions, there is no physiological benefit in terms of long-term lung function/mechanics to using aggressive daily ICS.
    --so, if symptoms can be controlled easily with the prn ICS/LABA, that might well be a much better approach for many patients, with not much downside

So,
-- it seems to me that the approach of trying budesonide/formoterol as-needed for patients with mild asthma is reasonable and dramatically decreases the amount of inhaled steroids used. One issue here is that mild asthma can be very different from one person to another. so, if the individual patient is really having lots more weeks of uncontrolled asthma, and this affects them to the point that they would like to be taking more inhaled steroids, it seems reasonable to prescribe maintenance inhaled steroids. 

My one over-riding clinical concern about prn budesonide/formoterol is that many patients are currently using SABAs for short-term relief (eg albuterol or terbutaline), and it might be confusing having them use budesonide/formoterol as needed but no more than twice a day (ie, the habit of just using their current prn inhaler many times to control symptoms, as done with a SABA, puts them at risk of a potentially fatal b-agonist overdose if they are switched to the ICS/LABA combo). so it only makes sense to use the prn budesonide/formoterol​ if the patient understands not to use any other prn inhaler, but to call or be seen if they do not get adequate symptom relief