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.


METHODS
Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00158847)


METHODS
2 university medical centers in The Netherlands.


METHODS
114 steroid-naive current or former smokers with moderate to severe COPD.


METHODS
Cell counts in bronchial biopsies and sputum (primary outcome); methacholine responsiveness at baseline, 6, and 30 months; and clinical outcomes every 3 months.


METHODS
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.


CONCLUSIONS
The study was not designed to evaluate clinical outcomes. Measurement of primary outcome was not available for 24% of patients at 30 months.


CONCLUSIONS
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. .
Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
Thérèse S
TS
Lapperre
Jiska B
JB
Snoeck-Stroband
Margot M E
MM
Gosman
Désirée F
DF
Jansen
Annemarie
A
van Schadewijk
Henk A
HA
Thiadens
Judith M
JM
Vonk
H Marike
HM
Boezen
Nick H T
NH
Ten Hacken
Jacob K
JK
Sont
Klaus F
KF
Rabe
Huib A M
HA
Kerstjens
Pieter S
PS
Hiemstra
Wim
W
Timens
Dirkje S
DS
Postma
Peter J
PJ
Sterk
D000280:Administration, Inhalation; D000368:Aged; D000420:Albuterol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000730:Androstadienes / Q000008:administration & dosage*; D001980:Bronchi / Q000473:pathology; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D002452:Cell Count; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D000068298:Fluticasone; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D008168:Lung / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D000068299:Salmeterol Xinafoate; D012907:Smoking; D013183:Sputum / Q000166:cytology; D016896:Treatment Outcome
D000730:Androstadienes; D001993:Bronchodilator Agents; D000068299:Salmeterol Xinafoate; D000068298:Fluticasone; D000420:Albuterol