Comparison of three combined pharmacological approaches with tiotropium monotherapy in stable moderate to severe COPD: a systematic review

Pulm Pharmacol Ther. 2012 Feb;25(1):40-7. doi: 10.1016/j.pupt.2011.10.006. Epub 2011 Nov 7.


Background: Guidelines recommend the use of inhaled long-acting bronchodilators, inhaled corticosteroids (ICS) and their combinations for maintenance treatment of moderate to severe COPD. However, there are limited data supporting combination therapy.

Methods: This systematic review assessed the efficacy of three therapeutic approaches: tiotropium plus long-acting beta2-agonist (LABA) ("dual" therapy), LABA/ICS ("combined" therapy), and tiotropium plus LABA/ICS ("triple" therapy), all compared with tiotropium monotherapy. Randomized controlled trials were identified after a search of different databases of published and unpublished trials.

Results: Twenty trials (6803 participants) were included. "Dual" therapy showed significant improvements in forced volume in the first second (FEV(1)), health-related quality of life (HRQoL), and dyspnea. However, it failed to reduce the risk of COPD exacerbations. Compared with tiotropium, "combined" therapy presented modest but significant effects on FEV(1), HRQoL, and dyspnea. Again, there was no significant difference in exacerbations, but it was associated with a significant increase of serious adverse effects (SAE) (number need to treat for harm [NNTH] = 20; 95% CI: 11-119). Finally, "triple therapy" increased FEV(1), improved HRQoL (both benefits exceeded minimal important differences) and decrease COPD exacerbations in anon-significant way. (Odds ratio [OR] = 0.57; 95% CI: 0.24 to 1.37, p = 0.21).

Conclusions: "Dual" and "triple" therapy seem like the most promising for patients with moderate to very severe COPD. However, data are still scarce and studies too short to generate a strong recommendation. Future studies should examine long-term efficacy and safety.

Publication types

  • Comparative Study
  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Aged
  • Bronchodilator Agents / administration & dosage
  • Bronchodilator Agents / therapeutic use*
  • Data Collection
  • Data Interpretation, Statistical
  • Female
  • Forced Expiratory Volume
  • Humans
  • Male
  • Middle Aged
  • Odds Ratio
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Quality of Life
  • Randomized Controlled Trials as Topic
  • Research Design
  • Scopolamine Derivatives / administration & dosage
  • Scopolamine Derivatives / therapeutic use*
  • Tiotropium Bromide
  • Treatment Outcome


  • Bronchodilator Agents
  • Scopolamine Derivatives
  • Tiotropium Bromide