© 2005 American Thoracic Society
GOAL—Asthma Control, but at What Cost?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 (< 1,000 µg/day) of the inhaled steroid, fluticasone, 24-hour urinary cortisol, is insensitive, unreliable, and not reassuring. Unfortunately, it has already been demonstrated in a study sponsored by the manufacturers of fluticasone that there is no dose/response relationship for this drug and 24-hour urinary cortisol or 0800 hours cortisol (2), the two methods nearly always used in the "extensive safety data." 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.
Antrim Area Hospital, Antrim, United Kingdom FOOTNOTES 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. REFERENCES
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