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Copyright ©ERS Journals Ltd 2004
From the authors:
Medical Research Institute of New Zealand, Wellington, New Zealand
It is helpful to have the opportunity to respond to the letter of J. Ingelf and colleagues to clarify issues relating to the meta-analysis of the dose-response relationship of budesonide in the treatment of adult asthma 1.
The ideal way to explore the relationship between dose and response amongst individuals with different characteristics, such as severity or duration of disease, would be by meta-analysis of individual patient data. Unfortunately, only summary response data were available; a useful extension of our work would have been possible if our attempts to access individual patient data from AstraZeneca had been successful. This point regarding access to individual patient data held by pharmaceutical companies was made in an accompanying editorial with reference to our work on the doseresponse relationship of fluticasone 2. Pending the analysis and publication of these data, we recommend that physicians should prescribe in accordance with the therapeutic dose range, which has been defined in our meta-analysis based on available scientific data.
In response to the methodological issues, the effect obtained with 1,600 µg·day–1 was considered to be the "maximum effect", as this was the highest dose used in the studies included in the meta-analysis. It will be possible to examine the effects with higher doses if dose-response studies including high doses are undertaken. No attempt was made to determine the dose-response relationship of local side-effects. Indeed, the systemic adverse effects are of considerably greater importance than local adverse effects and, in this respect, we refer back to the study by Aaronson et al. 3 discussed in the manuscript, in which 6 weeks of 3,200 µg·day–1 budesonide treatment led to the suppression of adrenal cortisol production of a magnitude similar to that observed with 10 mg of oral prednisone. With regard to the regression using a quadratic term, this is a standard approach to the modelling of curvature, and was consistent with both the exponential model, fitted numerically, and with the analysis comparing 400 µg·day–1 of budesonide versus higher doses.
The comparison in efficacy of 400 µg·day–1 budesonide versus higher doses addresses an important clinical question: what is the probable magnitude of benefit of increasing the dose of budesonide if the asthmatic patient is not well controlled with budesonide at a dose of 400 µg·day–1? This analysis showed small nonsignificant differences, findings consistent with the other analyses undertaken, indicating that most of the therapeutic benefit is obtained with a 400 µg·day–1 budesonide dose. In terms of the efficacy of doses higher than those included in the meta-analysis, there has been only one randomised double-blind study that compared doses of budesonide >1,600 µg·day–1 4. In this study, there was no therapeutic difference between 8 weeks of treatment with 3,200 and 1,600 µg·day–1, confirming the lack of further benefit at very high doses.
In terms of dose-response studies that have examined either very low (<200 µg·day–1) or very high (>1,600 µg·day–1) doses, we agree that there is little current available literature-based evidence to guide clinicians. This represents a gap in current knowledge and should be a stimulus for further research; however, it does not affect the interpretation of the available literature. Our understanding of the optimal use of inhaled budesonide in asthma will improve with the publication of additional controlled trials and analyses based on individual patient data from existing research, both published and unpublished. AstraZeneca is in an ideal position to contribute to this advancement in knowledge.
Whilst recognising that the relative potency between budesonide and fluticasone is a controversial issue, the budesonide 1 and fluticasone analyses 5 would suggest a 1:2 ratio for their clinical effects.
In summary, our meta-analysis presents the data that are available from scientific studies and have examined the dose-response relationship of inhaled budesonide in adults. Whilst recognising that there is marked individual variability in response to inhaled corticosteroids, which would suggest that some patients may obtain a greater clinical benefit at higher doses, just as some patients may obtain the maximum effect at lower doses, we recommend that physicians should prescribe in accordance with the therapeutic dose range defined in the meta-analysis.
References
- Masoli M, Holt S, Weatherall M, Beasley R. Dose-response relationship of inhaled budesonide in adult asthma: a meta-analysis. Eur Respir J 2004;23:552–558.
[Abstract/Free Full Text] - Herxheimer A. Commentary: dosage needs systematic and critical review. BMJ 2001;323:257.
[Abstract/Free Full Text] - Aaronson D, Kaiser H, Dockhorn R, et al. Effects of budesonide by means of the Turbuhaler on the hypothalamic-pituitary-adrenal axis in asthmatic subjects: a dose-response study. J Allergy Clin Immunol 1998;101:312–319.[CrossRef][Medline] [Order article via Infotrieve]
- Reddel H, Jenkins C, Marks G, et al. Optimal asthma control starting with high doses of inhaled budesonide. Eur Respir J 2000;16:226–235.[Abstract]
- Holt S, Suder A, Weatherall M, Cheng S, Shirtcliffe P, Beasley R. Dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma: meta-analysis. BMJ 2001;323:253–256.
[Abstract/Free Full Text]
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