Mortality associated with tiotropium Respimat; alternative views on causation.
Bronchodilating agents, like tiotropium, are the cornerstone of
symptomatic COPD management. Contrary to the recent reported safety of
tiotropium administered as dry powder, Singh et al. observed such a
dose-dependent hazardous (cardiovascular) effect by soft mist inhalers.
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)
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. Moreover, substantial smoking (>55 packyears) may have a
modifying effect on the cardiovascular benefit obtained from tiotropium
dry powder. In addition, a subgroup analysis revealed that the
mortality reduction by tiotropium dry powder did not apply for patients
that continued to smoke.
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. In other words, do we need to worry specifically
about COPD patients that continue smoking during their bronchodilating
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Competing interests: No competing interests