Rational timing of combination therapy with tiotropium and formoterol in moderate and severe COPD

Respir Med. 2008 Dec;102(12):1701-7. doi: 10.1016/j.rmed.2008.07.012. Epub 2008 Aug 28.


Aim: To determine which timing of therapy with formoterol (FOR) and/or tiotropium (TIO) shows the greater and more continuous functional improvement during 24 h in patients with moderate to severe COPD.

Methods: In this randomised, blind, crossover study 80 patients with stable COPD (40 moderate and 40 severe) received 5 different bronchodilator 30-day treatments in a random order. Treatments (Tr) were: Tr1: TIO 18 microg once-daily (8 am); Tr2: TIO 18 microg (8 am) + FOR 12 microg (8 pm); Tr3: FOR 12 microg twice-daily (8 am and 8 pm); Tr4: TIO 18 microg (8 am) + FOR 12 microg twice-daily (8 am and 8 pm); Tr5: FOR 12 microg twice-daily (8 am and 8 pm) + TIO 18 microg (8 pm). Spirometries were performed during 24 h (13 steps) on Day1 and Day30. End-points were: gain of FEV(1) (DeltaFEV(1)) from baseline of the Day1 and Day30, AUC (Area Under Curve), Dyspnoea Index, and as-needed use of salbutamol.

Results: Sixty-eight patients completed all treatments. The greater and continuous daily functional improvement was showed during Tr4 and Tr5 (Day1 +135.8 mL and +119.1 mL; Day30 +160.2 mL, and +160.5 mL, respectively). Daily means of DeltaFEV(1) were significantly different between single-drug treatments and combination therapy. Dyspnoea was greater in single-drug treatments. Less use of rescue salbutamol was reported in Tr4 (0.80 puffs/die) and Tr5 (0.71 puffs/die).

Conclusions: In patients with moderate to severe COPD, combination therapy with tiotropium administered in the morning (Tr4) was the most effective; in patients with prevailing night-symptoms, treatment with tiotropium in the evening (Tr5) reduced symptoms and use of salbutamol. Tr5 showed less variability of FEV(1) during the 24 h (CV=0.256). These results are relevant for opening new ways in clinical practice.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Bronchodilator Agents / administration & dosage*
  • Cross-Over Studies
  • Double-Blind Method
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Dyspnea / drug therapy
  • Dyspnea / etiology
  • Ethanolamines / administration & dosage*
  • Female
  • Forced Expiratory Volume / drug effects
  • Formoterol Fumarate
  • Humans
  • Male
  • Middle Aged
  • Pulmonary Disease, Chronic Obstructive / complications
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • Scopolamine Derivatives / administration & dosage*
  • Tiotropium Bromide
  • Treatment Outcome


  • Bronchodilator Agents
  • Ethanolamines
  • Scopolamine Derivatives
  • Formoterol Fumarate
  • Tiotropium Bromide