Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Salmeterol taken twice per day reduced asthma symptoms and improved peak flow compared with albuterol in patients with asthma

ACP J Club. 1993 May-June;118:83. doi:10.7326/ACPJC-1993-118-3-083


Source Citation

Pearlman DS, Chervinsky P, LaForce C, et al. A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma. N Engl J Med. 1992 Nov 12;327:1420-5.


Abstract

Objective

To compare respiratory function and symptoms in patients with asthma who have a baseline forced expiratory volume at 1 second (FEV1) that is 50% to 80% of expected, while on a long-acting (salmeterol) or short-acting (albuterol) β-agonist.

Design

12-week, randomized, double-blind, placebo-controlled trial.

Setting

8 asthma clinics.

Patients

Patients with asthma (American Thoracic Society definition) were included if they were nonsmokers, aged ≥ 12 years, required daily medication for asthma for ≥ 6 months, and had a FEV1 of 50% to 80% of predicted values. 234 patients (mean age 27 y, 150 men) were studied.

Intervention

78 patients were randomized to salmeterol, 42 µg twice a day; 77, to albuterol, 180 µg 4 times/d; and 79, to placebo. All patients could use open-label albuterol for short-term symptomatic relief; patients on inhaled steroid or cromolyn maintained these at constant dose.

Main outcome measures

Patients recorded daily asthma symptoms, night awakenings, and albuterol use. At biweekly visits, vital signs, FEV1, forced vital capacity, forced midexpiratory flow rate, and adverse clinical events were recorded.

Main results

8 patients in the salmeterol group withdrew as did 9 in the albuterol group and 16 in the placebo group. Patients on salmeterol fared better in FEV1 improvement compared with placebo (P < 0.001), but only for the first 4 weeks of the trial compared with albuterol (P < 0.05); in morning peak expiratory flow rate (up 24 L/min compared with down 6 L/min on albuterol and up 1 L/min on placebo [ P < 0.002 for both comparisons]); and in symptom improvement (22% fewer days and 52% fewer nights with symptoms, [ P < 0.05]). The use of supplemental albuterol decreased significantly in both active treatment groups compared with placebo (P < 0.01), but not between the active treatment groups. The groups did not differ for exacerbations (10% of patients on salmeterol, 13% on albuterol, and 15% on placebo). The albuterol and placebo groups did not differ for any comparisons. Adverse reactions were mild, infrequent, and equally common in all 3 groups.

Conclusion

For patients with asthma who have a FEV1 50% to 80% of expected, salmeterol taken twice per day reduced asthma symptoms and improved spirometry when compared with albuterol taken as needed or taken 4 times/d.

Source of funding: Glaxo, Inc.

For article reprint: Dr. D.S. Pearlman, Colorado Allergy and Asthma Clinic, 1450 South Havana Street, Aurora, CO 80012, USA. FAX 303-696-0922


Commentary

Regular bronchodilator therapy has recently come under scrutiny, being linked with increasing asthma morbidity and mortality. In this short (12-week) study by Pearlman and colleagues, salmeterol was more effective than regular albuterol or placebo, indicating that salmeterol may not share the adverse effects of short-acting β-agonists, at least in patients with mild asthma. Regular albuterol was no more effective than use-as-needed.

The study does not address whether improved pulmonary function and reduced symptoms with salmeterol reflected reduced severity of asthma, or merely more effective bronchodilatation, which might mask persistent inflammation. The similar frequency of exacerbations suggests that the intrinsic severity of asthma was not modified by salmeterol. Bronchodilator response to albuterol and salmeterol was maintained, suggesting that smooth muscle tachyphylaxis did not occur (although bronchodilator responsiveness is only 1 indicator of tachyphylaxis). Other studies show that the immediate protective effect of terbutaline against mast-cell stimulation was reduced by regular terbutaline, suggesting mast-cell tachyphylaxis (1), and that protection against methacholine challenge diminished significantly after regular treatment with salmeterol (2).

Adequate anti-inflammatory therapy should minimize the need for β-agonist therapy, but salmeterol may prove useful as a third-line drug in patients with asthma who, despite corticosteroids, have labile but reversible airflow obstruction. This possibility is not addressed by the current study because most patients did not use an inhaled corticosteroid. Given its lack of anti-inflammatory activity, salmeterol is not recommended as monotherapy for asthma.

Malcolm R. Sears, MB, ChB
McMaster UniversityHamilton, Ontario, Canada


References

1. O'Connor BJ, Aitkan SL, Barnes PJ. Tolerance to the nonbronchodilator effects of inhaled β2-agonists in asthma. N Engl J Med. 1992;327:1204-8.

2. Cheung D, Timmers MC, Zwinderman AH, et al. Long-term effects of a long-acting β2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma. N Engl J Med. 1992;327:1198-203.