Background: Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and mortality worldwide, yet there are no treatment options available to reduce mortality. Survival rates can improve with smoking cessation in patients with early stage COPD; oxygen supplementation in patients with persistent hypoxemia; and lung-reduction surgery for selected patients with emphysema.
Retrospective studies have reported that there may be a survival benefit for patients with COPD who use inhaled corticosteroids with or without long-acting beta agonists (e.g., salmeterol [Serevent]). The Towards a Revolution in COPD Health trial was conducted to prospectively analyze the effects of corticosteroid and long-acting beta-agonist use on survival in patients with COPD.
The Study: Participants were recruited at centers in 42 countries. Patients who had been diagnosed with COPD and who had at least a 10 pack-year history of smoking were enrolled in the study. The diagnosis of COPD was confirmed with a prebronchodilator forced expiratory volume in 1 second (FEV1) of less than 60 percent of predicted value; a ratio of FEV1 to forced vital capacity of 0.7 or less; and an improvement in FEV1 of less than 10 percent after using a short-acting bronchodilator. Participants were taken off all corticosteroids and long-acting beta-agonist bronchodilators for two weeks; they were then randomly assigned to use 500 mcg of fluticasone propionate (Flovent [withdrawn from the U.S. market]), 50 mcg of salmeterol, a combination of both (Advair Diskus), or placebo twice a day for three years. Participants were evaluated every 12 weeks to confirm vital status, to monitor adherence, and to record any adverse events. They also were assessed by postbronchodilator spirometry every 24 weeks.
Outcomes measured were health status, frequency of COPD exacerbations, and time to death from any cause during the study.
Results: Of the 8,554 patients between 40 and 80 years of age who were initially recruited, 2,370 failed to meet inclusion criteria. The remaining 6,184 patients were randomized to one of the four groups, and 6,112 patients were considered for the efficacy population. During the three-year, double-blind study, 44 percent of patients withdrew from the placebo treatment, which was a significantly higher percentage than in the other groups. The lowest withdrawal rate, occurring in the combination group, was 34 percent. Adherence to treatment was similar in all groups.
Overall, 875 patients died during the study. Patients receiving combination therapy were less likely to die than those receiving only fluticasone, but no other difference in mortality was identified between the treatment groups. However, there was a 17.5 percent relative-risk reduction of death in patients receiving the combination therapy compared with patients receiving placebo, which was just outside the margin for statistical significance (P = .052).
Pneumonia occurred more frequently in the fluticasone and combination groups (18.3 and 19.6 percent, respectively) compared with the salmeterol and placebo groups (13.3 and 12.3 percent, respectively). No significant differences among the groups were found with regard to fracture risk, cardiac events, or the development of cataracts.
The most commonly reported adverse event was COPD exacerbation. Compared with placebo, 25 percent fewer exacerbations occurred in patients receiving the combination therapy, and the number needed to treat to prevent one exacerbation in one year was four. In the combination therapy group, health status and spirometric measurements significantly improved when compared with the other groups. Hospitalization rates were 17 percent lower in the combination and salmeterol groups than in patients receiving placebo.
Conclusion: Combination therapy of fluticasone and salmeterol does not reduce mortality in COPD patients, but it does reduce the number of COPD exacerbations. A greater risk of pneumonia was noted in groups receiving fluticasone, but no difference in the development of eye disorders, fractures, or cardiac events was found during three years of follow-up.