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Am Fam Physician. 1999;59(8):2293-2294

The American Thoracic Society standards for the treatment of chronic obstructive pulmonary disease (COPD) include both ipratropium and a selective beta2 agonist in patients with daily symptoms. A large multi-center trial, reported by the Combivent Inhalation Aerosol Study Group in 1994, found that use of a metered-dose inhaler (MDI) aerosol containing ipratropium bromide and the beta agonist albuterol sulfate was more effective than either agent alone. While albuterol base and albuterol sulfate are believed to be therapeutically equivalent, albuterol base is the only formulation used in MDI albuterol aerosols marketed in the United States. To further study the effectiveness of a combination aerosol in the treatment of COPD, Campbell and colleagues of the Combivent Inhalation Aerosol Study Group conducted a 29-day trial to directly compare the efficacy of an aerosol of ipratropium bromide and albuterol sulfate with that of the marketed albuterol base aerosol.

The double-blind, parallel-group study included 356 patients who were enrolled at 17 centers. Patients were randomly assigned to receive the combination aerosol (176 patients) or albuterol alone (180 patients). Efficacy was primarily evaluated by comparing the the forced expiratory volume in one second (FEV1) on the first day of treatment and at the end of the trial. Patients were instructed to not use their inhaled medication for at least 12 hours before pulmonary testing. On each day of testing, (FEV1) was determined at baseline and 15, 30 and 60 minutes after treatment with study medication and then hourly for up to six hours. Patients could not use other bronchodilators during the study period, but they could receive theophylline for maintenance if the dosage had been stable for one month. The primary end point was improvement in the FEV1.

On each of the test days, patients in both treatment groups demonstrated a clinically significant response to therapy, with the mean improvement in the (FEV1) being at least 15 percent over baseline. However, compared with albuterol alone, the ipratropium-albuterol aerosol produced a greater overall response to therapy, especially during the first four hours after administration. In addition, the mean peak response for the combination-therapy group was significantly greater than that for the albuterol-only group.

In the group receiving combination therapy, mean peak responses ranged from 26 to 28 percent greater than those in the group receiving albuterol alone. The median time to a peak response was one hour for combination therapy and 30 minutes for albuterol alone. The median duration of action for the combination aerosol ranged from three to four hours; for albuterol alone, it was two hours.

Physician evaluation of improvement in the patients' symptoms revealed that the scores were higher for combination therapy than for albuterol alone, although the difference between the two groups was not statistically significant. However, statistically significant differences in favor of combination therapy were found for improvements in wheezing and shortness of breath throughout the study and for tightness of the chest during the first two weeks of combination therapy. Adverse events were similar in the two groups.

The authors conclude that a fixed-dose combination of ipratropium bromide and albuterol sulfate is more effective than albuterol base alone in the treatment of COPD. The combination aerosol not only resulted in improved pulmonary function but also provided relief in times of increased symptoms, when patients used the combination aerosol for rescue therapy. The authors believe the combination aerosol would provide a useful addition to COPD therapy.

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Copyright © 1999 by the American Academy of Family Physicians.

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