Trials That Matter: Minimizing Treatment of Mild, Persistent Asthma

Current guidelines for management of mild, persistent asthma recommend inhaled corticosteroids as first-line therapy (13). Long-term use of these agents in high doses may cause various adverse effects. Therefore, patients may inquire about, and clinicians should consider, alternative management strategies, including low-dose, once-daily inhaled corticosteroids and oral regimens that do not use corticosteroids. Two recently published trials address such approaches (4, 5). What Did These Important Trials Show? The LOCCS (Leukotriene or Corticosteroid or Corticosteroid-Salmeterol) trial involved 500 patients with stable, mild, persistent asthma from 19 centers (4). After receiving open-label inhaled fluticasone propionate (100 g per puff twice daily) for 4 to 6 weeks, adherent patients were randomly assigned to 1 of the following regimens: continued twice-daily fluticasone, nightly inhaled fluticasone (100 g) plus salmeterol (50 g), or nightly oral montelukast (5 or 10 mg). All received placebo inhalers or tablets to mask treatment assignments. The mean age of patients was 31 years; 60% were women, and 35% were African American or Hispanic. Before trial entry, 65% had used short-acting -agonists more than twice weekly, and 45% had used daily inhaled corticosteroids. The average prebronchodilator FEV1 was 86% of predicted at run-in enrollment and 92% of predicted at randomization. Fewer than 7% of monthly follow-up visits during the 16-week intervention period were missed. Treatment failure was defined as hospitalization or an urgent visit for asthma, use of systemic corticosteroids or need for open-label inhaled corticosteroids, predefined decreases in prebronchodilator FEV1 or morning peak expiratory flow rate, daily use of 10 or more puffs of as-needed (rescue) -agonist for 2 consecutive days, or study withdrawal due to patient dissatisfaction with treatment or physician concern over safety. Treatment failure rates for groups receiving twice-daily fluticasone, once-daily fluticasone plus salmeterol, and montelukast were 20.2%, 20.4%, and 30.3%, respectively (hazard ratio for montelukast vs. other groups, 1.6 [95% CI, 1.1 to 2.6]). Almost half of the treatment failures were declines in FEV1; about 10% to 13% were the need for systemic or open-label inhaled corticosteroids or an urgent visit. Patients receiving montelukast used as-needed inhalers more frequently, reported nocturnal awakenings more often, and were less likely to want to continue their assigned treatment after study completion than those receiving twice-daily or once-daily corticosteroid-based treatment. Across groups, similar numbers of patients noted adverse events, although fewer in the montelukast group reported upper respiratory tract or viral respiratory infections. The authors concluded that patients whose mild, persistent asthma was well controlled with a standard, twice-daily inhaled corticosteroid regimen could be switched to a once-daily fluticasonesalmeterol combination inhaler or montelukast. The BEST (Beclomethasone plus Salbutamol Treatment) multinational trial compared symptom-driven use with regular inhaler use (5). A total of 510 potentially eligible patients from 25 centers received open-label inhaled beclomethasone propionate (250 g per puff twice daily) and as-needed albuterol (100 g per puff) for 4 weeks. Of these, 466 adherent patients with stable, mild, persistent asthma were then randomly assigned to 1 of 4 inhalational regimens: 1) as-needed albuterol, 2) as-needed beclomethasone and albuterol combined in a single inhaler, 3) regular use of beclomethasone twice daily and as-needed albuterol, or 4) regular use of combined beclomethasone and albuterol twice daily and as-needed albuterol. All patients received double-dummy inhalers to mask treatment assignments. The mean patient age was about 40 years; approximately 60% of patients were women. The average FEV1 was 88% of predicted. One third of patients had previously used inhaled corticosteroids. Most patients (84%) completed the 6-month trial. Patients receiving as-needed combination therapy, twice-daily beclomethasone therapy, and twice-daily combination therapy had similar mean morning peak expiratory flow rates at 6 months, which were higher than the flow rates of patients receiving as-needed albuterol. Patients receiving as-needed combination therapy had fewer nocturnal awakenings and asthma exacerbations than those receiving as-needed albuterol. The mean cumulative dose of albuterol administered over 6 months was about 10 mg for the as-needed albuterol group and about 7 mg for each of the other 3 groups. Mean cumulative doses of inhaled beclomethasone were lower in the as-needed combination therapy group (approximately 18 mg) than in the regular beclomethasone and regular combination groups (approximately 77 mg for each). Across groups, similar numbers of patients reported adverse events. The investigators concluded that symptoms in patients with mild, persistent asthma could be controlled by using symptom-driven administration of a beclomethasonealbuterol combination inhaler. How Do the Trials Advance What We Know? The LOCCS trial showed that patients with mild, persistent asthma whose symptoms are well controlled with a standard, twice-daily inhaled corticosteroid regimen can be managed effectively by using a fluticasonesalmeterol combination inhaler or montelukast once daily. The montelukast therapy, although reasonably effective, had a higher failure rate than once-daily inhaled combination therapy. Regardless, once-daily therapy is simpler and easier to follow than twice-daily regimens. In addition, over the long term, total corticosteroid exposure with once-daily combination therapy is lower and dose-related side effects may be reduced. The risk of stepping down to either an inhaled or an oral once-daily regimen seems small. Similar numbers of patients in the twice-daily and once-daily regimens required systemic corticosteroids, use of an open-label inhaled corticosteroid, or an unscheduled urgent visit. The BEST trial showed that symptoms of patients with mild, persistent asthma can be controlled effectively by symptom-driven use of a combination inhaler incorporating beclomethasone and albuterol. Patients using the as-needed combination inhaler fared as well as those treated with a traditional regimen (regular use of an inhaled corticosteroid plus an as-needed, short-acting -agonist). The study's primary end point for defining control was morning peak flow rather than symptoms. However, secondary end points, including numbers of acute exacerbations and nocturnal awakenings, also improved in the group that used the as-needed combination inhaler compared with the group that used as-needed albuterol. Over the 6-month study, the as-needed combination treatment group received the lowest cumulative dose of corticosteroid. Of note, the study design precluded assessment of any steroid-sparing effect because a relatively high dose of inhaled corticosteroid was used as part of the rescue regimen, and the potential effectiveness of lower doses of regular inhaled corticosteroid was not measured. The attractiveness of the treatment regimen was evident in that more than three quarters of those using the rescue combination inhaler wished to continue the regimen after the trial. What Should Patients and Clinicians Do? Both trials included carefully selected patients with mild, persistent asthma who were clinically stable. Because a large proportion of patients with asthma have mild, persistent disease, the potential impact of an effective, simplified management regimen is substantial. We now know that several such regimens can be used in managing these patients. Choices include once-daily use of a combination corticosteroidlong-acting -agonist inhaler, as-needed administration of a combination corticosteroidshort-acting -agonist for acute symptoms, or a once-daily leukotriene modifier. Unfortunately, the combination corticosteroidshort-acting -agonist inhaler is not yet commercially available in the United States. Clinicians can offer once-daily therapy with an inhaled corticosteroidlong-acting -agonist combination to patients who wish to avoid as-needed inhalations for symptoms, although such use is not yet approved by the U.S. Food and Drug Administration. Although some concern has arisen about increased risk for severe adverse events with long-acting inhaled -agonists (6), use of corticosteroidlong-acting -agonist combination inhalers has not been implicated in increases in morbidity or mortality. This lends some measure of comfort to use of the combination inhaler in minimal doses over the long term. Finally, a leukotriene modifier may be reasonable in patients who prefer an oral agent, particularly in those with an allergic or exercise-related component to their asthma. Patients and clinicians must recognize, however, that this option is associated with a higher failure rate than the others. Several questions about the new treatment options are as yet unaddressed. We do not know whether a once-daily or as-needed inhaled corticosteroid-agonist inhaler, rather than regular, twice-daily, inhaled corticosteroid, will adversely affect the long-term course of mild, persistent asthma. We wonder whether a regimen that does not include long-term use of inhaled corticosteroids will adequately mitigate subclinical airway inflammation and prevent disease progression, which, at this time, remains at least a theoretical concern. Additional studies that incorporate exhaled nitric oxide measurements or sputum eosinophil counts might help in the assessment of these and related questions. In the meantime, we recommend trying once-daily or as-need regimens in carefully selected patients with stable, mild, persistent asthma who want minimal therapy and to go as low as they can.