Background: Modern combination maintenance therapy for persistent asthma using inhaled corticosteroids plus long-acting beta2 agonists has improved symptom control and reduced the need for higher doses of steroids. Nevertheless, exacerbations are inevitable, and the optimal relief strategy has not been clearly identified. Rabe and colleagues compared the effectiveness and safety of three reliever strategies: a short-acting beta2 agonist (terbutaline [Brethine]), a rapid-onset long-acting beta2 agonist (formoterol [Foradil]), and a combination of a long-acting beta2 agonist plus inhaled corticosteroids (budesonide/formoterol [Symbicort]).
The Study: They enrolled 3,394 patients older than 12 years who had asthma for at least six months complicated by at least one severe exacerbation. Participants had to meet criteria for forced expiratory volume in one second (FEV1) and be established on a constant daily dose of inhaled corticosteroids for at least four weeks. The eligibility criteria included use of reliever medication on five of the last seven days of the run-in period.
Patients were attendees at clinics in 20 countries. Study visits occurred at the beginning and end of the two-week run-in period and after one, four, eight, and 12 months of treatment. During the run-in period, participants used budesonide/formoterol one inhalation twice daily plus terbutaline inhaler for reliever therapy. After the run-in period, all participants continued maintenance use of the budesonide/formoterol inhaler and were randomly assigned to one of three reliever therapies for up to 12 months.
Of the randomized patients, 1,141 were allocated to terbutaline 0.4 mg as needed; 1,140 to formoterol 4.5 mcg as needed; and 1,113 to budesonide/formoterol 4.5 mcg as needed. Patients were instructed to use the reliever strategy for exacerbations of asthmatic symptoms but not to use more than 10 inhalations daily.
The primary outcome was time to first severe exacerbation. Secondary outcomes included total number of severe exacerbations, time to first emergency treatment or hospitalization, total number of emergency treatments or hospitalizations, morning and evening peak expiratory flow (PEF), asthma symptom scores on standardized questionnaires, and reliever medication use. At every clinic visit, PEF and FEV1 scores were recorded and reviews were conducted of symptoms and adverse effects.
Results: Complete data were analyzed on 1,138 patients using terbutaline reliever strategy; 1,137 using formoterol; and 1,107 using budesonide/formoterol. The time to first severe exacerbation was longer with the budesonide/formoterol strategy compared with the other strategies. This strategy also performed better on several of the secondary outcomes (see accompanying table). Three percent of patients in the budesonide/formoterol group experienced more than one exacerbation, compared with seven in each of the other groups. The rates of asthma-controlled days and nocturnal symptoms were similar in all three groups. All treatments were well tolerated, but serious adverse events were reported by 6.3 percent of patients in the combination group, 4.8 percent of formoterol users, and 5.7 percent of terbutaline users.
|Outcome||Terbutaline (Brethine)||Formoterol (Foradil)||Budesonide/formoterol (Symbicort)|
|Emergency department visit or hospitalizations*||7||5||4|
|Mild exacerbations (days per patient per year)||69||63||57|
|Asthma symptom score†||−0.58||−0.57||−0.69|
|Reliever use per 24 hours†||−0.64||−0.67||−0.84|
|Forced expiratory volume in one second†||−0.02||0.01||0.06|
|Morning peak expiratory flow†||7.90||10.60||15.30|
Conclusion: The authors conclude that all three strategies were effective but that the combination therapy greatly enhanced the protective effect. For monotherapy, formoterol provided greater protection against severe exacerbations than terbutaline.
editor's note: This special edition of The Lancet on asthma includes editorials, research reports, and reviews, many of which challenge contemporary understanding and practices. The general theme is that asthma is not a single disease but a “final common pathway” symptom complex for several different pathophysiologic processes. It is my hope that better understanding of these processes will lead to improved treatments, including preventive strategies.—a.d.w.