Treatment of chronic obstructive pulmonary disease (COPD) aims to control symptoms and prevent exacerbations while improving respiratory function and general health status. Inhaled long-acting beta₂ agonists have been proved effective, but the role of inhaled corticosteroids is less established. Corticosteroids have been associated with improvement in postbronchodilator forced expiratory volume in one second (FEV₁), a reduced number of exacerbations, and a slowing of the general decline in health status. Calverley and colleagues hypothesized that the combination of the two medications might be synergistic.

They studied the effect of combining the beta₂ agonist salmeterol with the corticosteroid fluticasone in a study of 1,465 patients with COPD attending hospital clinics in 25 countries. Patients had to have a baseline FEV₁ of 25 to 70 percent of predicted, an increase in FEV₁ of less than 10 percent 30 minutes after inhaling 400 mcg of albuterol, and a prebronchodilator FEV₁/forced vital capacity (FVC) ratio of 70 percent or less. All patients had histories of at least 10 pack-years of cigarette use (20 cigarettes per day for 10 years), chronic bronchitis, and at least one acute COPD episode that required treatment with oral corticosteroids or antibiotics in each of the preceding three years. Patients were excluded if they had other respiratory disorders, required regular oxygen therapy, or had taken antibiotics or high dosages of corticosteroids in the four weeks immediately before the study began.

After a two-week run-in period, patients were randomly assigned to twice-daily treatment with 50 mcg of salmeterol (372 patients), 500 mcg of fluticasone (374 patients), both medications (358 patients), or placebo (361 patients). Existing therapy with anticholinergics, mucolytics, and theophylline was continued, and inhaled albuterol was available for treatment of acute symptoms. Patients were treated for one year and monitored regularly by clinic visits during the study and two weeks after finishing treatment. The principal outcome measured was FEV₁ after at least six hours' abstinence from bronchodilator therapy. At each clinic visit, FVC and FEV₁ were measured before and after bronchodilator treatment. Patients recorded symptoms and daily medication use. The study also monitored acute exacerbations, hospital admissions, adverse effects of medications, cortisol levels, and electrocardiograms. Health status questionnaires were completed at baseline and five times during the study.

The groups were comparable in all relevant respects. Significantly fewer patients withdrew from the combination and corticosteroid-treated groups than from the other groups. By the second week of treatment, patients in all three treatment groups showed significant improvements in pretreatment FEV₁ compared with patients in the placebo group. The improvements were sustained throughout the study and were significantly greater in the combination group than in the other treatment groups. After one year, FEV₁ had increased 10 percent in the combination group and 2 percent in the single-therapy groups, with similar results in other measures of lung function. FEV₁ declined by 3 percent in the placebo group. Results were not affected by changes in smoking status. The number of exacerbations was significantly lower in all three treated groups than in the placebo group, with the greatest reduction in the combination group (25 percent), followed by the salmeterol group (20 percent), and the fluticasone group (19 percent).

Treatment was most effective in patients with the worst baseline lung function. Compared with other treatments, combination therapy significantly improved symptoms, and patients in this group were the only ones with significant improvements in cough and overall health status. Between 12 and 19 percent of patients in each group—including the placebo group—reported adverse events, but these were generally well tolerated.

The authors conclude that combination therapy with an inhaled long-acting beta2 agonist plus a corticosteroid controls symptoms of COPD significantly better than either treatment alone and with no greater risk of adverse effects. The benefit was apparent early in treatment and was sustained for at least one year. The authors speculate that one mechanism for the synergistic effect could be upregulation of beta receptors by corticosteroids, but they stress that the mechanism or mechanisms of the synergistic effect are unknown.