Long-acting beta(2)-agonist in addition to tiotropium versus either tiotropium or long-acting beta(2)-agonist alone for chronic obstructive pulmonary disease

Cochrane Database Syst Rev. 2012 Apr 18;4(4):CD008989. doi: 10.1002/14651858.CD008989.pub2.


Background: Long-acting bronchodilators comprising long-acting beta(2)-agonists and the anticholinergic agent tiotropium are commonly used for managing persistent symptoms of chronic obstructive pulmonary disease. Combining these treatments, which have different mechanisms of action, may be more effective than the individual components. However, the benefits and risks of combining tiotropium and long-acting beta(2)-agonists for the treatment of chronic obstructive pulmonary (COPD) disease are unclear.

Objectives: To assess the relative effects of treatment with tiotropium in addition to long-acting beta(2)-agonist compared to tiotropium or long-acting beta(2)-agonist alone in patients with chronic obstructive pulmonary disease.

Search methods: We searched the Cochrane Airways Group Specialised Register of trials and clinicaltrials.gov up to January 2012.

Selection criteria: We included parallel group, randomised controlled trials of three months or longer comparing treatment with tiotropium in addition to long-acting beta(2)-agonist against tiotropium or long-acting beta(2)-agonist alone for patients with chronic obstructive pulmonary disease.

Data collection and analysis: Two review authors independently assessed trials for inclusion and then extracted data on trial quality and the outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials.

Main results: Five trials were included in this review, mostly recruiting participants with moderate or severe chronic obstructive pulmonary disease. All of them compared tiotropium in addition to long-acting beta(2)-agonist to tiotropium alone, but only one trial additionally compared a combination of the two types of bronchodilator with long-acting beta(2)-agonist (formoterol) alone. Two studies used the long-acting beta(2)-agonist indacaterol, two used formoterol and one used salmeterol.Compared to tiotropium alone (3263 patients), treatment with tiotropium plus long-acting beta(2)-agonist resulted in a slightly larger improvement in the mean health-related quality of life (St George's Respiratory Questionnaire (SGRQ) MD -1.61; 95% CI -2.93 to -0.29). In the control arm, tiotropium alone, the SGRQ improved by falling 4.5 units from baseline and with both treatments the improvement was a fall of 6.1 units from baseline (on average). High withdrawal rates in the trials increased the uncertainty in this result, and the GRADE assessment for this outcome was therefore moderate. There were no significant differences in the other primary outcomes (hospital admission or mortality).The secondary outcome of pre-bronchodilator FEV(1) showed a small mean increase with the addition of long-acting beta(2)-agonist (MD 0.07 L; 95% CI 0.05 to 0.09) over the control arm, which showed a change from baseline ranging from 0.03 L to 0.13 L on tiotropium alone. None of the other secondary outcomes (exacerbations, symptom scores, serious adverse events, and withdrawals) showed any statistically significant differences between the groups. There were wide confidence intervals around these outcomes and moderate heterogeneity for both exacerbations and withdrawals.The results from the one trial comparing the combination of tiotropium and long-acting beta(2)-agonist to long-acting beta(2)-agonist alone (417 participants) were insufficient to draw firm conclusions for this comparison.

Authors' conclusions: The results from this review indicate a small mean improvement in health-related quality of life for patients on a combination of tiotropium and long-acting beta(2)-agonist compared to tiotropium alone, but it is not clear how clinically important this mean difference may be. Hospital admission and mortality have not been shown to be altered by adding long-acting beta(2)-agonists to tiotropium. There were not enough data to determine the relative efficacy and safety of tiotropium plus long-acting beta(2)-agonist compared to long-acting beta(2)-agonist alone. There were insufficient data to make comparisons between the different long-acting beta(2)-agonists when used in addition to tiotropium.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Adrenergic beta-2 Receptor Agonists / therapeutic use*
  • Aged
  • Albuterol / analogs & derivatives
  • Albuterol / therapeutic use
  • Bronchodilator Agents / therapeutic use*
  • Ethanolamines / therapeutic use
  • Formoterol Fumarate
  • Humans
  • Indans / therapeutic use
  • Middle Aged
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Quality of Life
  • Quinolones / therapeutic use
  • Salmeterol Xinafoate
  • Scopolamine Derivatives / therapeutic use*
  • Tiotropium Bromide


  • Adrenergic beta-2 Receptor Agonists
  • Bronchodilator Agents
  • Ethanolamines
  • Indans
  • Quinolones
  • Scopolamine Derivatives
  • Salmeterol Xinafoate
  • indacaterol
  • Albuterol
  • Formoterol Fumarate
  • Tiotropium Bromide