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Effect of Long-term Salmeterol Therapy Compared With As-Needed Albuterol Use on Airway Hyperresponsiveness^*

Richard R. Rosenthal, MD; William W. Busse, MD; James P. Kemp, MD, FCCP; James W. Baker, MD; Christopher Kalberg, PhD; Amanda Emmett, MS and Kathleen A. Rickard, MD

^* From the Johns Hopkins School of Medicine (Dr. Rosenthal), Baltimore, MD; University of Wisconsin (Dr. Busse), Madison, WI; Allergy and Asthma Medical Group and Research Center (Dr. Kemp), San Diego, CA; Allergy Associates Research Center (Dr. Baker), PC, Portland, OR; and Glaxo Wellcome, Inc (Drs. Kalberg and Rickard, Ms. Emmett), Research Triangle Park, NC. A list of investigators is located in the ^Appendix.

Correspondence to: Richard R. Rosenthal, MD, 8318 Arlington Blvd, Suite 308, Fairfax, VA 22031

Study objectives: To determine the effect of long-term salmeterol aerosol therapy on airway hyperresponsiveness measured by methacholine challenge.

Design: Randomized, double-blind, placebo-controlled, multicenter study.

Setting: Thirty-one clinical centers in the United States.

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

Interventions: Twice-daily salmeterol aerosol, 42 µg, or placebo via metered-dose inhaler for 24 weeks. Backup albuterol was available.

Measurements and 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 ß-agonist salmeterol does not lead to clinical instability or vulnerability to unpredictable asthma attacks.

Key Words: asthma • bronchial hyperresponsiveness • methacholine challenge • salmeterol

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