Szefler SJ, Martin RJ, King TS, et al. J Allergy Clin Immunol. 2002;109:410–418
Purpose of the Study.
Clinical studies have suggested that considerable variability exists among individuals with asthma in both their responsiveness to inhaled corticosteroids (ICS) and side effects from such drugs. A clinical model is needed to compare various ICS with respect to efficacy and safety, as no standardized model has yet been developed.
Study subjects were corticosteroid-naive individuals with mostly moderate persistent asthma who were 18 to 55 years of age. The study was designed as a feasibility study rather than a comparative trial.
Thirty subjects were randomized to receive either beclomethasone dipropionate (BDP) 168, 672, and 1344 μg/day (n = 15) or fluticasone propionate (FP) 88, 352, and 704 μg (n = 15) via metered-dose inhaler (MDI) with chlorofluorocarbon propellant and OptiChamber (Respironics, Cedar Grove, NJ) spacer in 3 consecutive 6-week intervals. Compliance was monitored with a Doser CT (Meditrack Products, Hudson, MA) device. All subjects then received 3 weeks of FP dry powder inhaler (DPI) 2000 μg/day. The primary outcome variable for assessing comparative efficacy was forced expiratory volume in 1 second (FEV1). Secondary outcomes were methacholine PC-20, exercise-induced change in FEV1, exhaled nitric oxide (eNO), and induced sputum eosinophilia. Overnight cortisol suppression was measured by collecting hourly blood samples from 7 pm to 7 am.
Maximum FEV1 response occurred with the lowest dose of FP and the medium dose of BDP and was not further increased by high-dose FP-DPI. Near-maximum improvement in methacholine PC-20 occurred with low-dose FP and medium-dose BDP. Responsiveness to ICS varied markedly among subjects. Good (>15%) FEV1 response was associated with high eNO, high pretreatment bronchodilator reversibility, and low pretreatment forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) when compared with poor (<5%) FEV1 response. Both BDP and FP caused dose-dependent cortisol suppression.
Near-maximum improvements in FEV1 and methacholine PC-20 occurred with low doses of FP and medium doses of BDP in these subjects with moderate persistent asthma. Higher doses did not improve efficacy but directly increased systemic side effect, as measured by overnight cortisol secretion. When comparing different ICS in future studies, larger numbers of subjects will be necessary to better define dose-response relationships for both efficacy and side effects.
Despite considerable interest and some scrutiny, it is unclear if any given ICS has a truly superior therapeutic index. Yet, one thing is apparent. ICS dose-response curves are fairly flat, and low doses of these drugs should suffice for the vast majority of patients that pediatricians will be treating primarily. Furthermore, children treated with medium or high doses of ICS should have pulmonary function monitoring. FP is a particularly potent ICS, and higher doses delivered to less obstructed—or unobstructed—airways might very well be associated with greater systemic risk than that posed by some other ICS. Finally, although ICS are widely thought to be the most effective controllers used in asthma therapy, it appears that there are roughly equal numbers of nonresponders among persistent asthmatics receiving ICS as there are among such patients receiving montelukast.