Effect of long-term salmeterol therapy compared with as-needed albuterol use on airway hyperresponsiveness.
OBJECTIVE
To determine the effect of long-term salmeterol aerosol therapy on airway hyperresponsiveness measured by methacholine challenge.


METHODS
Randomized, double-blind, placebo-controlled, multicenter study.


METHODS
Thirty-one clinical centers in the United States.


METHODS
Four hundred eight asthmatic patients > or = 12 years of age with baseline FEV1 of > or = 70% of predicted values. Patients were not using inhaled corticosteroids.


METHODS
Twice-daily salmeterol aerosol, 42 microg, 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-acting beta-agonist salmeterol does not lead to clinical instability or vulnerability to unpredictable asthma attacks.
Rosenthal
R R
RR
Johns Hopkins School of Medicine, Baltimore, MD, USA.
Busse
W W
WW
Kemp
J P
JP
Baker
J W
JW
Kalberg
C
C
Emmett
A
A
Rickard
K A
KA
D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage* / Q000009:adverse effects; D000328:Adult; D000336:Aerosols; D000420:Albuterol / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives*; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy*; D001985:Bronchial Provocation Tests; D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008297:Male; D016210:Methacholine Chloride; D010366:Peak Expiratory Flow Rate; D000068299:Salmeterol Xinafoate
D000318:Adrenergic beta-Agonists; D000336:Aerosols; D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D016210:Methacholine Chloride; D000068299:Salmeterol Xinafoate; D000420:Albuterol