Beclometasone

To the Editor:

The method chosen by the investigators in the Gaining Optimal Asthma Control (GOAL) study (1) to measure systemic side effects of mostly high dosages (

When a sensitive measure of hypothalamic-pituitary-adrenal (HPA) axis function is used, the picture is entirely different. For example, in a study for the National Heart Lung and Blood Institute's Asthma Clinical Research Network, using plasma cortisol AUC, a dosage of fluticasone of only 352 µg/day produced 50% adrenal suppression, a considerably greater degree than the equipotent dosage of beclometasone, leaving the authors to conclude that "increasing the dose beyond this point of maximum efficacy ... resulted in increase in systemic effect especially with fluticasone metered dose inhaler with its CFC propellant" (3). Any clinical improvement at higher doses could well be due to the systemic rather than the local effect of this inhaled corticosteroid. Remember that the systemic effect of 1,000 µg/day of fluticasone has been estimated as equivalent to 11 mg of oral prednisolone (4).

The clinical significance of such findings is confirmed by our report that fluticasone was associated with nearly all cases of adrenal crisis due to inhaled corticosteroids in the UK, despite it being the least prescribed (5), and in the Health Canada database, where all nine cases of adrenal insufficiency (including two with adrenal crisis) reported between 1996 and 2002 were associated with the use of fluticasone (6).

Failure to demonstrate "clinical evidence of adrenal suppression" after 1 year's study is neither convincing nor reassuring. Except in some children, the clinical features of adrenal insufficiency are of insidious onset, nonspecific, and difficult to recognize. Also, in our study, 75% of patients developed adrenal crisis more than 1 year after starting fluticasone (5), longer than the duration of this study.

It should cause considerable concern not only that this study involves a large majority of patients ending up on doses of fluticasone double the probable maximum effective dose, but also, once again, the tests used to measure systemic effect are insensitive and unreliable.

Conflict of Interest Statement: G.R.G.T. received lecture fees totaling $12,000 from AstraZeneca in 2002 and he has had no financial relationship with any commercial entity that has an interest in the subject of this letter since then.

G. R. G. TODD

Antrim Area Hospital

Antrim, United Kingdom

References

1. Bateman ED. Boushcy NA, Bousquet J, Busse W, Clark TJM. Paurels RA, Pederser SE, for the GOAL Investigators Group. Can guideline-defined asthma control be achieved? Am J Respir Crit Care Med 2004; 170:836-844.

2. Bollert FGE, Naysmith J, Capsey L, Crompton GK, Honour JW, Greening AP. Variation in dose responses to fluticasone propionate in adult asthmatics [abstract]. Am J Respir Crit Care Med 1997;155:A349.

3. Szefler SJ, Martin RJ, King TS, Boushey HA, Cherniack RM, Chinchilli VM, Craig TJ, Dolovich M, Drazen JM, Pagan JK, et al. Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol 2002;109:410-418.

4. Tan KS, McFarlane LC, Lipworth BJ. Effects of oral and inhaled corticosteroid on lymphocyte beta2-adrenoccptor function in asthmatic patients. Br J Clin Pharmacol 1997;44:565-568.

5. Todd GRG, Acerini CL, Ross-Russell R, Zahra S, Warner JT, McCance D. Survey of adrenal crisis associated with inhaled corticosteroids in the UK. Arch Dis Child 2002;87:457-461.

6. Barton K. Fluticasone and adrenal suppression. Canadian Adverse Reaction Newsletter 2003;13:2.

From the Authors:

Dr. Todd's letter focuses on suppression of the HPA axis caused by high doses of inhaled corticosteroids. His concerns, summarized in the last paragraph of his letter, are of limited relevance to the GOAL study (1).

They suggest that patients ended up on fluticasone propionate at "double the probable maximum effective dose," and cite evidence from dose-response studies in which single measures (usually FEV^sub 1^) serve as the endpoint (2). In GOAL, the dose was individualized (increased at intervals) to obtain the maximal clinical response, and a composite measure, which is more discriminating of control, was used (3). The dose was not excessive as it was increased according to clinical need. The results confirm that some patients only achieve control with the highest dose, at times only after 3 to 6 months. These results raise questions about conventional methods of assessing dose-response relationships of corticosteroids in chronic uncontrolled asthma.

GOAL examined a fundamental question-whether asthma control can be achieved. Practical limitations of design prevented inclusion of dose-minimization strategies (e.g., step-down routines). However, the highest dose of corticosteroids employed was one approved and widely used in adults. The results provide useful evidence on the superiority and steroid-sparing effects of combination treatment. We recognize that the question of how hard to try in individual patients to achieve control (with respect to dose and duration of treatment) remains a challenge. The decision is based upon patient needs and expectations, cost, and potential adverse effects.

A second concern of Dr. Todd is the "insensitive and unreliable" tests of HPA axis function. We accept that 24-hour urinary cortisols are less sensitive than the ACTH stimulation test, but the latter was not a practical option in a large scale outpatient study, and is not without risk. The 24-hour urinary cortisol method is superior to single point measurement of blood cortisol, widely used and accepted by regulatory authorities (4, 5).

The references on adrenal suppression and crisis cited by Dr. Todd are not relevant to GOAL. The second is of unusual design, two involved use of a pressurized metered dose inhaler (MDI) that results in higher systemic exposure to corticosteroid than the Diskus device, and one concerned mainly children. Of the four adults with adrenal crisis, all were on doses higher than used in GOAL. The clinical relevance of the reductions in urinary cortisols in some patients in the GOAL study remains controversial, and must be weighed against the risk of exacerbations, and the "cost" of continued uncontrolled asthma.

Conflict of Interest Statement: E.D.B. received honoraria for speaking at scientific meetings and courses organized and financed by AstraZeneca, Boehringer Ingelheim and GlaxoSmithKline and served on Advisory Boards for the following companies: AstraZeneca, Boehringer Ingelheim, Hoffman le Roche and ClaxoSmithKline. He performed consultancy services for AstraZeneca, Aventis, Altana, Hoffman le Roche and Kyowa Hakko.

ERIC D. BATEMAN

for GOAL Study Steering Committee

University of Cape Town Lung Institute

Cape Town, South Africa

References

1. Bateman ED, Boushey HA, Bousquet J, Busse W, Clark T, Pauwels RA. Pedcrsen SE for the GOAL Investigators Group. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma Control Study. Am J Respir Crit Care Med 2004;170:836-844.

2. Szefler SJ, Martin RJ, King TS, Boushey HA, Cherniak RM, Chincilli VM, Craig TJ, Dolovich M, Drazen JM, Pagan JK, et al. Significant variability in response to corticosteroids for persistent asthma. J Allergy Clin Immunol 2002;109:410-418.

3. Bateman ED, Bousquet J, Braunslein GL. Is overall asthma control being achieved? A hypothesis-generating study. Eur Respir J 2001;17:5890-595.

4. Harrison TW, Wisniewski A, Honour J, Tattersfield AE. Comparison of the systemic effects of fluticasone propionate and budesonide given by dry powder inhaler in healthy and asthmatic subjects. Thorax 2001;56: 186-191.

5. McIntyre HD, Mitchell CA, Bowler SD, Armstrong JG, Wooler JA, Cowley DM. Measuring the systemic effects of inhaled beclomethasone: timed morning urine collections compared with 24 hour urine specimens. Thorax 1995;50:1280-1284.

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