Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial

BACKGROUND: Inhaled corticosteroids (ICSs) and long-acting beta(2)-agonists (LABAs) are used to treat moderate to severe chronic obstructive pulmonary disease (COPD). OBJECTIVE: To determine whether long-term ICS therapy, with and without LABAs, reduces inflammation and improves pulmonary function in COPD. DESIGN: Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00158847) SETTING: 2 university medical centers in The Netherlands. PATIENTS: 114 steroid-naive current or former smokers with moderate to severe COPD. MEASUREMENTS: Cell counts in bronchial biopsies and sputum (primary outcome); methacholine responsiveness at baseline, 6, and 30 months; and clinical outcomes every 3 months. INTERVENTION: Random assignment by minimization method to receive fluticasone propionate, 500 microg twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 microg twice daily, and salmeterol, 50 microg twice daily, for 30 months (single inhaler; n = 28); or placebo twice daily (n = 29). RESULTS: 101 patients were greater than 70% adherent to therapy. Fluticasone therapy decreased counts of mucosal CD3(+) cells (-55% [95% CI, -74% to -22%]; P = 0.004), CD4(+) cells (-78% [CI, -88% to 60%]; P < 0.001), CD8(+) cells (-57% [CI, -77% to -18%]; P = 0.010), and mast cells (-38% [CI, -60% to -2%]; P = 0.039) and reduced hyperresponsiveness (P = 0.036) versus placebo at 6 months, with effects maintained after 30 months. Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium, with accompanying reductions in sputum neutrophil, macrophage, and lymphocyte counts and improvements in FEV(1) decline, dyspnea, and quality of life. Reductions in inflammatory cells correlated with clinical improvements. Discontinuing fluticasone therapy at 6 months increased counts of CD3(+) cells (120% [CI, 24% to 289%]; P = 0.007), mast cells (218% [CI, 99% to 407%]; P < 0.001), and plasma cells (118% [CI, 9% to 336%]; P = 0.028) and worsened clinical outcome. Adding salmeterol improved FEV(1) level. LIMITATIONS: The study was not designed to evaluate clinical outcomes. Measurement of primary outcome was not available for 24% of patients at 30 months. CONCLUSION: ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD. Adding LABAs does not enhance these effects.