Chest
Volume 119, Issue 6, June 2001, Pages 1661-1670
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Clinical Investigations
Bronchodilators
Salmeterol Plus Theophylline Combination Therapy in the Treatment of COPD

https://doi.org/10.1378/chest.119.6.1661Get rights and content

Background

Patients with COPD often require multiple therapies to improve lung function and decrease symptoms and exacerbations. Salmeterol and theophylline are indicated for the treatment of COPD, but the use of these agents in combination has not been extensively studied.

Objectives

To compare the efficacy and safety of salmeterol plus theophylline vs 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 levels, 10 to 20μ g/mL), patients were randomly assigned to receive salmeterol (42μ g bid) plus theophylline, salmeterol (42 μg bid), or theophylline for 12 weeks. Serial pulmonary function tests were completed on day 1 and treatment week 12. Patients kept diary cards and noted their peak flow rates, symptom scores, and albuterol use, and periodically completed quality-of-life and dyspnea questionnaires.

Results

All three groups significantly improved compared with baseline. Combination treatment with salmeterol plus theophylline provided significantly (p ≤ 0.045) greater improvements in pulmonary function; significantly (p ≤ 0.048) greater decreases in symptoms, dyspnea, and albuterol use; and significantly fewer COPD exacerbations (p = 0.023 vs 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 events (p ≤ 0.042) than either treatment that included theophylline. The safety profile (adverse events, vital signs, and ECG findings) of the two 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 events or other adverse sequelae.

Section snippets

Patient Selection

Male and female patients ≥ 45 years old with COPD due to chronic bronchitis or emphysema were recruited to participate from 74 outpatient clinics in the United States. Screening entry criteria required a smoking history of at least 20 pack-years, FEV1 ≥ 0.70 L and ≤ 65% of predicted normal based on standards of Crapo et al,19 and an FEV1/FVC ratio of ≤ 70%. Patients with an FEV1 < 0.70 L were eligible if their percent predicted FEV1 was at least 40% of predicted normal. Patients with a history

Disposition and Demographics

A significant percentage of screened patients (242 of 1,185; 20%) were withdrawn during the open-label theophylline titration period (Fig 1) . Of these, 107 of 242 patients (44%) were withdrawn due to adverse events related to theophylline, and an additional 30 of 242 patient (12%) failed to achieve the target theophylline concentration within the allotted time period. Once randomization to study treatment was complete, 86% (803 of 938) of the patients completed the study. The most common

Discussion

To our knowledge, this is the first study that has compared the efficacy and safety of combination treatment with salmeterol plus theophylline vs either agent alone in patients with COPD. All treatment groups significantly improved compared to baseline in a variety of efficacy measures, showing that both salmeterol and theophylline as single agents provide benefit to patients with COPD. However, combination treatment with salmeterol plus theophylline consistently provided significantly greater

ACKNOWLEDGMENT

We thank Amy Schaberg for assisting with the preparation of this article.

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    Presented in abstract form at the 2000 American Thoracic Society Meeting, Toronto, Canada, May 8, 2000.

    This study was supported by a grant from Glaxo Wellcome Inc, Research Triangle Park, NC.

    Dr. Mahler is a consultant to Glaxo Wellcome Inc.

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