Significant variability in response to inhaled corticosteroids for persistent asthma.
BACKGROUND
A clinical model is needed to compare inhaled corticosteroids (ICSs) with respect to efficacy.


OBJECTIVE
The purpose of this investigation was to compare the relative beneficial and systemic effects in a dose-response relationship for 2 ICSs.


METHODS
A 24-week, parallel, open-label, multicenter trial examined the benefit-risk ratio of 2 ICSs in persistent asthma. Benefit was assessed by improvements in FEV(1) and PC(20); risk was assessed by overnight plasma cortisol suppression. Thirty subjects were randomized to either beclomethasone dipropionate (BDP) 168, 672, and 1344 microg/day (n = 15) or fluticasone propionate (FP) 88, 352, and 704 microg/day (n = 15), both administered by means of a metered dose inhaler (MDI) with chlorofluorocarbon propellant via a spacer, in 3 consecutive 6-week intervals; this was followed by 3 weeks of FP dry powder inhaler (DPI) 2000 microg/day.


RESULTS
Maximum FEV(1) response occurred with the low dose for FP-MDI and the medium dose for BDP-MDI and was not further increased by treatment with FP-DPI. Near-maximum methacholine PC(20) improvement occurred with the low dose for FP-MDI and the medium dose for BDP-MDI. Both BDP-MDI and FP-MDI caused dose-dependent cortisol suppression. Responsiveness to ICS treatment was found to vary markedly among subjects. Good (>15%) FEV(1) response, in contrast to poor (<5%) response, was found to be associated with high exhaled nitric oxide (median, 17.6 vs 11.1 ppb), high bronchodilator reversibility (25.2% vs 8.8%), and a low FEV(1)/forced vital capacity ratio (0.63 vs 0.73) before treatment. Excellent (>3 doubling dilutions) improvement in PC(20), in contrast to poor (<1 doubling dilution) improvement, was found to be associated with high sputum eosinophil levels (3.4% vs 0.1%) and older age at onset of asthma (age, 20-29 years vs <10 years).


CONCLUSIONS
Near-maximal FEV(1) and PC(20) effects occurred with low-medium dose for both ICSs in the subjects studied. High-dose ICS therapy did not significantly increase the efficacy measures that were evaluated, but it did increase the systemic effect measure, overnight cortisol secretion. Significant intersubject variability in response occurred with both ICSs. It is possible that higher doses of ICSs are necessary to manage more severe patients or to achieve goals of therapy not evaluated in this study, such as prevention of asthma exacerbations.
Szefler
Stanley J
SJ
National Jewish Medical and Research Center, Department of Pediatrics, Denver, CO 80206, USA.
Martin
Richard J
RJ
King
Tonya Sharp
TS
Boushey
Homer A
HA
Cherniack
Reuben M
RM
Chinchilli
Vernon M
VM
Craig
Timothy J
TJ
Dolovich
Myrna
M
Drazen
Jeffrey M
JM
Fagan
Joanne K
JK
Fahy
John V
JV
Fish
James E
JE
Ford
Jean G
JG
Israel
Elliot
E
Kiley
James
J
Kraft
Monica
M
Lazarus
Stephen C
SC
Lemanske
Robert F
RF
Mauger
Elizabeth
E
Peters
Stephen P
SP
Sorkness
Christine A
CA
D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000730:Androstadienes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy*; D001507:Beclomethasone / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002908:Chronic Disease; D005260:Female; D000068298:Fluticasone; D005541:Forced Expiratory Volume; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D008875:Middle Aged; D011446:Prospective Studies; D016896:Treatment Outcome
D000730:Androstadienes; D018927:Anti-Asthmatic Agents; D016210:Methacholine Chloride; D000068298:Fluticasone; D001507:Beclomethasone; D006854:Hydrocortisone