BACKGROUND COPD affects over 5% of the adult population, and it is the only major cause of mortality that is increasing worldwide. Patients with COPD don’t die usually of respiratory failure: indeed lung cancer and cardiovascular diseases are the leading causes of mortality in patients with mild to moderate COPD. Pulmonary and systemic inflammations are prominent. Inhaled corticosteroids have little effect on the rate of decline of lung function, but they reduce the frequency of exacerbations, especially when combined with an inhaled long-acting beta-agonist.
AIM OF THE STUDY The combination of the long-acting beta-agonist salmeterol (SM) and the inhaled corticosteroid fluticasone propionate (FP) would reduce mortality among patients with COPD, as compared with usual care. The primary end-point was the time to death from any cause by 3 years. Secondary end-points were the frequency of exacerbations and health status.
PATIENTS AND METHODS Of 8,554 patients recruited, 6,184 underwent randomization; the mean age was 65 years, and the mean value of postbronchodilator FEV1 was 44% of the predicted value. This double-blind study was conducted in 444 centers of 42 countries. After a 2-week run-in period, eligible patients were randomly assigned to treatment with the combination of SM at a dose of 50 μg and FP at a dose of 500 μg or SM alone at a dose of 50 μg, FP alone at a dose of 500 μg, or placebo, all taken as a dry powder with the use of an inhaler bid for 3 years.
RESULTS There were 875 deaths within 3 years after randomization. The proportions of deaths from any cause at 3 years were 12.6% in the combination therapy group, 15.2% in the placebo group, 13.5% in the SM group, and 16.0% in the FP group. The absolute risk reduction for death in the combination-therapy group as compared with the placebo group was 2.6%, and the hazard ratio was 0.825 (95% confidence interval [CI], 0.681 to 1.002; p = 0.052), corresponding to a reduction in the risk of death at any time in the 3 years of 17.5% (95% CI, –0.2 to 31.9).
DISCUSSION In this trial, the reduction in mortality from any cause did not meet the level of statistical significance (p = 0.052), but the treatment with the combination regimen resulted in significantly fewer exacerbations and improved health status and lung function, as compared with placebo. Mortality could be influenced mainly by factors unresponsive to the study drugs, or it is possible that this study was underpowered to detect this effect. There was also a high withdrawal rate, which was highest among patients in the placebo group.
CONCLUSIONS Even though p = 0.052 is not statistically significant, 126 deaths for every 1,000 treated in the combination-therapy group, after 3 years, instead of 152 in the placebo group, is anyway an important result? Further investigation is needed in future large, prospective trials.
COPD; Mortality; Systemic inflammation; TORCH study.