Study objectives: To determine the effect of
long-term salmeterol aerosol therapy on airway hyperresponsiveness
measured by methacholine challenge.
Randomized, double-blind, placebo-controlled, multicenter study.
Setting: Thirty-one clinical centers in the United
Patients: Four hundred eight asthmatic
patients ≥ 12 years of age with baseline FEV1 of ≥ 70%
of predicted values. Patients were not using inhaled
Interventions: Twice-daily salmeterol
aerosol, 42 μg, or placebo via metered-dose inhaler for 24 weeks.
Backup albuterol was available.
results: Pulmonary function tests were performed before, during,
and after treatment. Subjects recorded asthma-related symptoms, morning
and evening peak expiratory flow (PEF) levels, and use of supplemental
albuterol daily on diary cards. Methacholine challenges were performed
10 to 14 h postdose at weeks 4, 12, and 24, and 3 and 7 days
posttreatment. Over 24 weeks of treatment, salmeterol provided
significant (p < 0.001) protection against methacholine-induced
bronchoconstriction of approximately one doubling dose of methacholine
when compared to placebo with no evidence for a progressive decrease in
protection. A rebound increase in airway hyperresponsiveness was not
observed 3 and 7 days after cessation of salmeterol therapy. Salmeterol
treatment resulted in sustained improvements of 0.21 to 0.26 L in
morning premedication FEV1 and an improvement of 26.2 L/min
in morning PEF when compared to placebo (p < 0.001). The use of
salmeterol significantly reduced combined daytime asthma symptoms by
20% when compared to placebo (p = 0.005). A total of 34 and 48
exacerbations, respectively, were reported in the salmeterol and
placebo groups, and no evidence was present for a difference in the
severity of asthma exacerbations between groups. Adverse event profiles
were similar for the salmeterol and placebo groups.
Conclusions: Regular long-term use of salmeterol aerosol
resulted in sustained improvements in pulmonary function and asthma
symptom control over the 24-week treatment period. There was no
increase in bronchial hyperresponsiveness or loss of bronchoprotection
at 24 weeks from that seen following 4 weeks of therapy. There was no
evidence of rebound airway hyperresponsiveness after cessation of
salmeterol treatment. Regular treatment with the long-actingβ
-agonist salmeterol does not lead to clinical instability or
vulnerability to unpredictable asthma