SYSTEMIC EFFECTS OF INHALED FLUTICASONE PROPIONATE AND BUDESONIDE IN ADULT PATIENTS WITH ASTHMA

	To the Editor :

We read the article by Dr. Derom and colleagues (1) with interest. However, we find the presumptions underlying the study design debatable. The authors state that patients with asthma might differ from healthy volunteers when estimating the systemic effects of inhaled corticosteroids upon the HPA-axis. Surprisingly, they then state that the maximum impact on the HPA-axis of exogenous corticosteroid occurs after 5 d of treatment and, as a consequence, use treatment periods of 1 wk, referring exclusively to data from healthy volunteers (2). Moreover, this statement has a most weak foundation, considering that the duration of treatment in the studies that are cited is 4 d, 3.5 d, 5 d and 3.5 d. Other results indicate that the time needed for exogenous corticosteroids to exert a fully suppressive effect upon the HPA-axis probably amounts to weeks or even months (6). One could also ask whether the use of corticosteroid-naive patients further compromises the intentions of the study.

We would also like to object to the statement that equi-efficacious doses were applied. The relative difference in efficacy between fluticasone propionate and budesonide have been discussed thoroughly, with data supporting a 1:1 as well as a 2:1 relationship (7). Therefore, it should be self-evident that comparison of efficacy parameters are mandatory when one wishes to compare side effects of equi-efficacious doses. The authors explain this lack of completeness by referring to difficulty in applying the present study design to more severe asthmatics. However, it would seem more appropriate to select a study population and efficacy parameters with the ability to deliver the information pivotal to a proper comparison, and then design the study according to this. In all, we find the basis for the study conclusion to be weak and incomplete.

Departments of Clinical Pharmacology and Respiratory Diseases, Aarhus University Hospital, Aarhus, Denmark

1. Derom, E., J. Van Schoor, W. Verhaeghe, W. Vincken, and R. Pauwels. 1999. Systemic effects of inhaled fluticasone propionate and budesonide in adult asthmatic patients with asthma. Am. J. Respir. Crit. Care Med. 160: 157-161 [Abstract/Free Full Text].

2. Boorsma, M., N. Andersson, P. Larsson, and A. Ullman. 1996. Assessment of the relative systemic potency of inhaled fluticasone propionate and budesonide. Eur. Respir. J. 9: 1427-1432 [Abstract].

3. Grahnén, A., S. Å. Eckernäs, R. M. Brundin, and A. Ling-Andersson. 1994. An assessment of the systemic activity of single dose of inhaled fluticasone propionate in healthy volunteers. Br. J. Clin. Pharmacol. 38: 521-525 [Medline].

4. Donnelley, R., K. M. Williams, A. B. Baker, C.-A. Badcock, R. O. Day, and J. P. Seale. 1997. Effects of budesonide and fluticasone on 24-hour plasma cortisol: a dose-response study. Am. J. Respir. Crit. Care Med. 156: 1746-1751 [Abstract/Free Full Text].

5. Lönnebo, A., A. Grahnén, B. Jansson, R. M. Brundin, A. Ling-Andersson, and S. Å. Eckernäs. 1996. An assessment of the systemic effects of single and repeated doses of inhaled fluticasone propionate and inhaled budesonide in healthy volunteers. Eur. J. Clin. Pharmacol. 49: 459-463 [Medline].

6. Dluhy, R. G.. 1998. Clinical relevance of inhaled corticosteroids and HPA-axis suppression. J. Allergy Clin. Immunol. 101: S447-S450 [Medline].

7. Barnes, N. C., C. Hallett, and T. A. Harris. 1998. Clinical experience with fluticasone propionate in asthma: a meta-analysis of efficacy and systemic activity compared with budesonide and beclomethasone dipropionate at half the microgram dose or less. Respir. Med. 92: 95-104 [Medline].

	From the Authors:

Drs. Nielsen and Dahl have pointed out that the time needed for exogenous corticosteroids to exert a fully suppressive effect upon the HPA-axis might exceed the 7 d used in our study (1). Admittedly, the exact time needed for inhaled corticosteroids to reach a steady state in patients with asthma was not known at the time the study was conducted. Neither is it known, if the time to reach the steady state varies depending on the severity of the asthma. But it is quite improbable that the time needed to reach a steady state would be different for different corticosteroids. Even if the absolute steady state has not been reached in our patients, we still believe that our conclusions remain relevant, as what we did was a comparison between different inhaled corticosteroids at a given point of time. Interestingly, data concerning this issue have been presented at the 1999 ERS meeting. These indicate that the degree of serum cortisol suppression measured over 24 h, obtained after 1 wk in asthma patients treated with inhaled fluticasone or mometasone is comparable with that measured after 2, 3, and 4 wk (2). This confirms previous data obtained by Nikolaizik (3), cited in our paper.

We agree that accepting a 1:1 or a 2:1 relationship with respect to the effectiveness of the two treatments inserts a bias in the study. It will only be possible to place our data in a proper perspective once the relative efficacy of inhaled fluticasone and budesonide has been estimated in an appropriately designed study (4). The recently published meta-analysis of the relative efficacy and safety of beclomethasone, fluticasone, and budesonide has, however, several methodological flaws, and may be considered as an example of how a meta-analysis should not be performed (5).

As mentioned in the DISCUSSION, we were unable to draw conclusions about the efficacy of the treatments in our study, as patients with more severe asthma could not be included. These individuals would never have tolerated the 3-wk steroid-free washout period or the 4-wk steroid-free run-in period. We believe that it is not ethically justifiable to submit patients who need high doses of inhaled corticosteroids or intermittent courses of oral corticosteroids to a steroid-free period. Our study clearly indicates that it is almost impossible to simultaneously assess clinical efficacy and systemic effects of inhaled corticosteroids in patients with more severe asthma, making it necessary to conduct separate studies to answer questions in this regard. This is in line with the suggestions recently published by the Canadian Thoracic Society (6).

ERIC DEROM

ROMAIN PAUWELS

Department of Respiratory Diseases

University Hospital Ghent

Ghent, Belgium

1. Derom, E., J. Van Schoor, W. Verhaeghe, W. Vincken, and R. Pauwels. 1999. Systemic effects of inhaled fluticasone propionate and budesonide in adult patients with asthma. Am. J. Respir. Crit. Care Med. 160: 157-161 .

2. Affrime, M. B., T. Kosoglou, and C. M. Thonoor. 1999. Comparison of hypothalamic-pituitary-adrenal (HPA) axis suppression by mometasone furoate (MF) with that by fluticasone propionate (FP). Eur. Respir. J. 14(Suppl. 30):196s.

3. Nikolaizik, W. H., M. A. Preece, J. O. Warner, One, and year follow-up study of endocrine and lung function of asthmatic children on inhaled budesonide. 1997. Eur. Respir. J. 10: 2596-2601 [Abstract].

4. Barnes, P., S. Pedersen, and W. W. Busse. 1998. Efficacy and safety of inhaled corticosteroids: new developments. Am. J. Respir. Crit. Care Med. 157(Suppl.): S1-S53 [Free Full Text].

5. Barnes, N. C., C. Hallet, and T. A. Harris. 1998. Clinical experience with fluticasone in asthma: a meta-analysis of efficacy, and systemic activity compared with budesonide and beclomethasone dipropionate at the half microgram dose or less. Respir. Med. 92: 95-104 .

6. Boulet, L. P., D. W. Cockroft, J. Toogood, Y. Lacasse, J. Baskerville, and F. E. Hargraeve. 1999. Comparative assessment of safety and efficacy of inhaled corticosteroids: report of a committee of the Canadian Thoracic Society. Eur. Respir. J. 11: 1194-1210 .