Comparative safety of long-acting inhaled bronchodilators: a cohort study using the UK THIN primary care database

Drug Saf. 2007;30(12):1151-60. doi: 10.2165/00002018-200730120-00007.


Background: Use of a long-acting inhaled bronchodilator, either an anticholinergic or a beta-adrenergic receptor agonist (beta-agonist), is recommended for maintenance treatment of chronic obstructive pulmonary disease (COPD). In COPD, the organ system most frequently requiring medical care, other than the respiratory system, is the cardiac system.

Objectives: To compare the risk of total mortality and certain respiratory and cardiac adverse events among users of the two types of recommended long-acting bronchodilators, we conducted a cohort study. Specifically, the study compared the safety of the only approved long-acting anticholinergic, tiotropium bromide, with the single-ingredient long-acting beta-agonists (LABAs) salmeterol or formoterol in a broad population of users.

Methods: We used automated general practitioner data from the UK THIN (The Health Information Network) database as the data source for this study. We used Cox proportional hazards models to compute hazard ratio (HR) estimates and 95% CI controlling for propensity scores comprising various baseline demographic variables, medical therapies and illnesses.

Results: The 1061 tiotropium users and 1801 LABA users were similar with regard to risk of total mortality (HR 0.93; 95% CI 0.59, 1.44) and most cardiac events, including angina (HR 0.77; 95% CI 0.37, 1.59), atrial fibrillation or flutter (HR 0.60; 95% CI 0.25, 1.42), myocardial infarction (HR 1.29; 95% CI 0.45, 3.66) and tachycardia (HR 0.66; 95% CI 0.29, 1.51). Though imprecise, there was evidence of a decreased risk of heart failure (HR 0.65; 95% CI 0.37, 1.12) in tiotropium users. As regards respiratory endpoints, the risk of COPD exacerbation (HR 1.15; 95% CI 0.79, 1.67) and pneumonia (HR 1.11; 95% CI 0.38, 3.26) were similar among users of each type of drug, although there was a decreased risk of asthma exacerbation (HR 0.41; 95% CI 0.26, 0.64) in tiotropium users compared with LABA users.

Conclusions: Users of tiotropium and single-ingredient LABA had similar risk of total mortality and cardiovascular endpoints. The decreased risk of asthma exacerbations with tiotropium may be due to residual confounding by indication. Confidence limits for most events include reduced risks for tiotropium and also small increases in risk. Nevertheless, the point estimates suggest that tiotropium was associated with a lower risk of each cardiac event except myocardial infarction. However, the small number of cases means that further studies are needed to confirm these results.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intranasal
  • Adult
  • Aged
  • Aged, 80 and over
  • Albuterol / adverse effects
  • Albuterol / analogs & derivatives*
  • Albuterol / therapeutic use
  • Bronchodilator Agents / adverse effects*
  • Bronchodilator Agents / therapeutic use
  • Cardiovascular Diseases / chemically induced
  • Cohort Studies
  • Databases, Factual
  • Delayed-Action Preparations
  • Ethanolamines / adverse effects*
  • Ethanolamines / therapeutic use
  • Female
  • Formoterol Fumarate
  • Humans
  • Male
  • Medical Records Systems, Computerized
  • Middle Aged
  • Primary Health Care
  • Pulmonary Disease, Chronic Obstructive / drug therapy
  • Salmeterol Xinafoate
  • Scopolamine Derivatives / adverse effects*
  • Scopolamine Derivatives / therapeutic use
  • Tiotropium Bromide
  • United Kingdom


  • Bronchodilator Agents
  • Delayed-Action Preparations
  • Ethanolamines
  • Scopolamine Derivatives
  • Salmeterol Xinafoate
  • Albuterol
  • Formoterol Fumarate
  • Tiotropium Bromide