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Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials

BMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d3215 (Published 14 June 2011) Cite this as: BMJ 2011;342:d3215

Mortality associated with tiotropium Respimat; alternative views on causation.

Bronchodilating agents, like tiotropium, are the cornerstone of
symptomatic COPD management.[1] Contrary to the recent reported safety of
tiotropium administered as dry powder,[2] Singh et al. observed such a
dose-dependent hazardous (cardiovascular) effect by soft mist inhalers.[3]
Both studies are well-designed meta-analyses on rather severe COPD
patients. As tiotropium has an increased systemic uptake by soft mist
inhalation, the disparity in safety profiles was attributed to the
difference in delivery devices, although device differences would be
difficult to untangle from other trial differences and none of the
included studies were primarily designed for analysing (cardiovascular)
mortality.[3;4]

However, baseline cardiovascular disease was not tested for its
effect on outcome, and both studies used different measures for smoking
history which was not analysed for its modifying effect in the Respimat
study.[3] Moreover, substantial smoking (>55 packyears) may have a
modifying effect on the cardiovascular benefit obtained from tiotropium
dry powder.[2] In addition, a subgroup analysis revealed that the
mortality reduction by tiotropium dry powder did not apply for patients
that continued to smoke.[5]

We wonder if part of the reported discrepancies could indeed be the
result of an interaction between bronchodilators and smoking, in which
bronchodilators influence the pulmonary deposition and hence the toxicity
of cigarette smoke.[6] In other words, do we need to worry specifically
about COPD patients that continue smoking during their bronchodilating
treatment?

Reference List

[1] Global Strategy for the Diagnosis, Management and Prevention of
COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD),
updated 2010. www.goldcopd.org. accessed 2011.

[2] Rodrigo GJ, Castro-Rodriguez JA, Nannini LJ, Moral VP, Schiavi
EA. Tiotropium and risk for fatal and nonfatal cardiovascular events in
patients with chronic obstructive pulmonary disease: Systematic review
with meta-analysis. Respir Med 2009.

[3] Singh S, Loke YK, Enright PL, Furberg CD. Mortality associated
with tiotropium mist inhaler in patients with chronic obstructive
pulmonary disease: systematic review and meta-analysis of randomised
controlled trials. BMJ 2011; 342.

[4] Cates CJ. Safety of tiotropium. BMJ 2011; 342.

[5] Tashkin DP, Celli B, Kesten S, Lystig T, Mehra S, Decramer M.
Long-term efficacy of tiotropium in relation to smoking status in the
UPLIFT trial. Eur Respir J 2010; 35(2):287-294.

[6] van Dijk WD, Heijdra Y, Scheepers PT, Lenders JW, van Weel C,
Schermer TR. Interaction in COPD experiment (ICE): A hazardous combination
of cigarette smoking and bronchodilation in chronic obstructive pulmonary
disease. Med Hypotheses 2010; 74(2):277-280.

Competing interests: No competing interests

17 June 2011
Wouter D. van Dijk
PhD student, Family Medicine trainee
L. van den Bemt, T.R.J. Schermer
Radboud University Nijmegen Medical Centre, Department of Primary and Community Care