Thorax 69:598-599 doi:10.1136/thoraxjnl-2014-205155
  • Chest clinic
  • Opinion

Safety of tiotropium through the Handihaler: why did meta-analyses and database studies appear to give a false alarm?

  1. Kourtney J Davis4
  1. 1Respiratory Medical Franchise, GSK, Uxbridge, UK
  2. 2The William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, UK
  3. 3St George's University of London, London, UK
  4. 4GSK, Worldwide Epidemiology, Wavre, Belgium
  1. Correspondence to Professor Neil C Barnes, Respiratory Medical Franchise, GSK, Stockley Park, Uxbridge UB11 1BT, UK; neil.c.barnes{at}
  • Received 23 January 2014
  • Accepted 25 January 2014
  • Published Online First 18 February 2014

Concerns about the safety of long-acting antimuscarinic agents for the treatment of COPD,1 ,2 particularly the use of tiotropium through the Respimat device, led to the TIOSPIR study.3 This large well-conducted randomised study compared the use of tiotropium through the Handihaler (18 µg) with tiotropium at two doses (2.5 µg and 5.0 µg) through the Respimat in over 17 000 patients with COPD. It showed no difference in mortality or efficacy between the two delivery systems, nor even a trend for a mortality difference. It is now worth reviewing the data that led to these concerns and the lessons that may be learned.

Two systematic reviews played a key role in raising concerns over tiotropium. Antimuscarinic agents were generally considered safe and well tolerated until a meta-analysis of trials that included short-acting and long-acting antimuscarinic agents suggested an increase in cardiac events and mortality.1 This led to fears about safety of the whole class, although the analysis was criticised because it combined short-acting and long-acting antimuscarinic agents. Concerns about tiotropium via the Handihaler were addressed by the UPLIFT study4 a large randomised double-blind placebo-controlled trial which compared the addition of tiotropium or placebo to routine treatment for COPD over a 4-year period. Although the primary outcome was rate of decline of lung function, data on deaths and cardiac side effects were collected prospectively. There was a numerical reduction in mortality in the tiotropium-treated group, which in the prespecified statistical evaluation did not reach statistical significance. There was also evidence of a reduction in reported cardiac events in the actively treated group. This led to the view that tiotropium through the Handihaler did not cause an excess of cardiac adverse events. The results were reviewed by the Regulatory Agencies who were in agreement with this.5

Following this, a …

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