Meta-analysis on dose-response relationship of inhaled steroids must be done in homogenous asthma populations

To the Editor:

We would like to draw the readers' attention to the results of the meta-analysis of dose-response of inhaled budesonide in the recent article by Masoli et al. 1, as we think these should be interpreted with great caution.

The dose-response relationship of inhaled steroids in asthma continues to be a topic of discussion, and even after 20 yrs there is no consensus on exactly which dose to use for an individual asthma patient. However, one of the experiences we, and certainly others, have gained is that the dose-response curves differ greatly in different asthma populations and are very much dependent on both the severity of the disease and also on asthma duration. In the latter case, the shorter the duration the lower the dose needed. Although Masoli et al. 1 have excluded studies if they were not placebo-controlled or involved oral steroid-dependent patients, this does not mean that the rest of the asthma population in their meta-analysis is homogenous. Thus the overall approach for the dose-response exercise taken by Masoli et al. 1 needs careful scrutiny, and the dose ranges found may indeed mislead the prescribing physician to use standardised, instead of individualised, doses.

In addition, there are concerns regarding the methodology used for the dose calculations in Masoli et al. 1. First, the suggested efficacy maximum for budesonide Turbuhaler® or Nebuhaler® was arbitrarily chosen to be 1,600 µg·day⁻¹ without giving any reason. Secondly, the use of a meta-regression approach to compare the effect of change in dose is less than ideal, as this model implies that a local maximal effect is achieved, which we know is not the case with inhaled steroids because they reach an efficacy plateau. Thirdly, a further weakness in the analysis is the approach of comparing the 400 µg·day⁻¹ dose with the nearest higher dose. Most of our experience tells us that no difference in clinical efficacy will be detected, for example, when doubling the dose of inhaled steroids.

Regarding the relationship between budesonide and other inhaled steroids, even more caution is required when evaluating clinical findings. It is not possible to compare the results of the meta-analysis performed on fluticasone 2 with the study by Masoli et al. 1, again with the differences in patient populations in mind. In Holt et al. 2 there is also an overall flaw seen by the consistent use of lower doses of fluticasone in the analysed studies. Ideally, the budesonide studies should have included more dose-steps in the range of 100–200 µg, but regrettably such data is not available. However, this reflects the changes in treatment strategies over time and not necessarily any potency differences.

In order to get valid data for the dose-response relationships of inhaled steroids, we believe in performing more studies in defined populations and ideally using several doses of each drug. Also, dose-reduction studies can be used, especially when comparing different steroids or steroid-device combinations. Hopefully most readers are aware that we have used such designs both for the relationship between budesonide Turbuhaler versus the pressurised metered dose inhaler 3, as well as for the relationship between budesonide Turbuhaler and fluticasone Diskhaler and Diskus 4, 5, an approach that was very much endorsed in an editorial in the European Respiratory Journal 3 yrs ago 6.