Background: Patients with COPD frequently require multiple therapies to improve lung function and decrease symptoms and exacerbations.

Background: Patients with COPD frequently require multiple therapies to improve lung function and decrease symptoms and exacerbations. Salmeterol and theophylline are indicated for the treatment of COPD if it were not that the use of these agents in combination has not been extensively studied.

Objectives: To compare the efficacy and safety of salmeterol plus theophylline v either agent alone in COPD

Methods: Randomized, double-blind, double-dummy, parallel-group trial in 943 patients with COPD After an open-label theophylline titration period (serum evens 10 to 20 [micro]g/mL), patients were randomly assigned to receive salmeterol (42 [micro]g bid) plus theophylline, salmeterol (42 [micro]g bid), or theophylline for 12 weeks. Serial pulmonary function examples were completed on day 1 and treatment week 12 Patients kept diary cards and noted their peak emanate rates, symptom scores, and albuterol use, and periodically complet quality-of-life and dyspnea questionnaires.

Results: All three collections significantly improved compared with baseline. Combination treatment with salmeterol plus theophylline provided significantly (p [is les than or equal to] 0045) greater improvements in pulmonary function; significantly (p [is les than or equal to] 0048) greater decreases in symptoms, dyspnea, and albuterol use; and significantly fewer COPD exacerbations (p = 0023 v theophylline). In general, treatment with salmeterol provided greater improvement in lung function and satisfaction with treatment compared with theophylline. Salmeterol treatment was also associated with significantly fewer drug-related adverse ends (p [is less than or equal to] 0042) than either treatment that included theophylline. The safety profile (adverse terminations vital signs, and ECG findings) of the couple treatments that included theophylline were similar.

Conclusion: Patients with COPD may benefit from combination treatment with salmeterol plus theophylline, without a resulting increase in adverse terminations or other adverse sequelae. (CHEST 2001; 119:1661-1670)

[i]clavis[/i] words: chronic bronchitis; combination therapy; COPD; dyspnea; emphysema; exacerbations; [FEVsub1]; quality of life; salmeterol; theophylline

Abbreviations: ANOVA = analysis of variance; AUC = area subordinate to the curve; BDI = baseline dyspnea index; CI = confidence interval; CRDQ = chronic respiratory disease questionnaire; HRQOL = health-related quality of life; MDI = metered-dose inhaler; PEF = peak expiratory flow; PFT = pulmonary function testing; SALM = salmeterol twice daily; SALM + THEO = salmeterol twice daily plus theophylline twice daily; TDI = transitional dyspnea index; THEO = theophylline twice daily

COPD is a progressive disease that is characterized by way of the presence of airflow obstruction proper to chronic bronchitis and/or emphysema.[1,2] general treatments for COPD are aimed at increasing airflow, decreasing respiratory symptoms (particularly dyspnea), decreasing exacerbations, and improving the quality of life. Multiple therapies, including short-acting and long-acting bronchodilators, anticholinergics, methylxanthines, and corticosteroids, are used as single agents or more commonly in combination to treat patients with COPD[12]

Theophylline, a methylxanthine derivative, has been used in the treatment of COPD for many years. Studies[3-8] have shown that theophylline can increase lung function, decrease symptoms, and improve diaphragmatic muscle function that may translate to reducing fatigue and enhancing endurance during activities of daily living.

Salmeterol xinafoate is a long-acting [[Beta].sub.2]-agonist that increases lung function and diminishs dyspnea and other symptoms of COPD[9-18] In addition, patients with COPD who receive salmeterol experience significant improvement in health-related quality of life (HRQOL)[1011] Salmeterol has been approveed as first-line maintenance therapy in the treatment of patients with symptomatic COPD[12]

The end of this randomized, controlled trial was to investigate the combined use of salmeterol and theophylline in the treatment of patients with COPD The hypothesis was that salmeterol and theophylline would provide greater improvements in lung function and greater reductions in breathlessness compared with either agent alone.

MATERIALS AND METHODS

Patient Selection

Male and female patients [is greater than or equal to] 45 years of advanced age with COPD due to chronic bronchitis or emphysema were recruited to participate from 74 outpatient clinics in the United States. Screening hall criteria required a smoking history of at least 20 pack-years, [FEVsub1] [is greater than or equal to] 070 L and [is les than or equal to] 65% of predicted normal based forward standards of Crapo et al,[19] and an [FEVsub1]/FVC ratio of [is les than or equal to] 70% Patients with an [FEVsub1] [is les than] 070 L were eligible if their percent predicted [FEVsub1] was at least 40% of predicted normal. Patients with a history of asthma, a daily continuous oxygen requirement, a modern viral or bacterial pulmonary infection, congestive heart failure, or other clinically active diseases were exclud Patients were not permitted to receive inhaled ipratropium during the contemplation or have any changes in their regular COPD medications within 4 weeks of the screening visit. Stable doses of inhaled corticosteroids and/or oral corticosteroid doses ([is les than or equal to] 10 mg/d of prednisone or equivalent) were allowed.

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