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Monday, June 20, 2011

The safety of tiotropium

“Safety of tiotropium: Indirect evidence suggests the Respimat inhaler is riskier than the Handihaler.” So states an editorial by Cates (BMJ 2011;342:d2970) that accompanies a recent BMJ article by Singh et al. (BMJ 2011;342:d3215). The authors systematically reviewed the risk of mortality associated with long-term use of tiotropium delivered using a mist inhaler for symptomatic improvement in COPD and found that 5 randomized controlled trials were eligible for inclusion. Tiotropium mist inhaler was associated with a significantly increased risk of mortality. The number needed to treat for a year with the 5 µg dose to see one additional death was estimated to be 151, based on the average control event rate from the long term trials. There is however considerable uncertainty around this estimate (95% confidence interval: 51 to 5556). However, this point estimate is considerably larger than that found for salmeterol in asthma.

Is everything clear? No. The same authors made a previous meta-analysis on tiotropium (Singh et al. JAMA 2008;300:1439-50) and showed that inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD. However, the publication of the large UPLIFT trial (Tashkin et al. N Engl J Med 2008;359:1543-54) did not confirm this meta-analysis. The FDA (Michele et al. N Engl J Med 2010;363(12):1097-9) did not support the conclusions of Singh et al. on tiotropium “because of the strengths of the UPLIFT data, the absence of a strong signal related to stroke or cardiovascular events with tiotropium and the potential methodologic limitations of the Singh meta-analysis.”
However, the conclusions of Cates are ambiguous since he wrote: “An ongoing trial will provide more certainty about the comparative safety of tiotropium inhaler devices” and concludes “if patients have a strong preference for the mist inhaler, the possible increased risk mortality will need to be shared with them.”

We therefore think that you should be warned about this new controversy and we would be delighted to know what you think.