Dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma: meta-analysisCommentary: Dosage needs systematic and critical review
BMJ 2001; 323 doi: https://doi.org/10.1136/bmj.323.7307.253 (Published 04 August 2001) Cite this as: BMJ 2001;323:253
Abstract
Objective: To examine the dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma.
Design: Meta-analysis of placebo controlled, randomised clinical trials that presented data on at least one outcome measure of asthma and that used at least two different doses of fluticasone.
Setting: Medline, Embase, and GlaxoWellcome's internal clinical study registers.
Main outcome measures: FEV1, morning and evening peak expiratory flow, night awakenings, β agonist use, and major exacerbations.
Results: Eight studies, with 2324 adolescents and adults with asthma, met the inclusion criteria. Data on doses of >500 µg/day were limited. The dose-response curve for the raw data began to reach a plateau at around 100-200 µg/day and peaked by 500 µg/day. A negative exponential model for the data, without meta-analysis, indicated that 80% of the benefit at 1000 µg/day was achieved at doses of 70-170 µg/day and 90% by 100-250 µg/day. A quadratic meta-regression showed that the maximum achievable efficacy was obtained by doses of around 500 µg/day. The odds ratio for patients remaining in a study at a dose of 200 µg/day, compared with higher doses, was 0.73 (95% confidence interval 0.49 to 1.08). Comparison of the standardised difference in FEV1 for an inhaled dose of 200 µg/day against higher doses showed a difference in FEV1 of 0.13 of a standard deviation (−0.02 to 0.29).
Conclusions: In adolescent and adult patients with asthma, most of the therapeutic benefit of inhaled fluticasone is achieved with a total daily dose of 100-250 µg, and the maximum effect is achieved with a dose of around 500 µg/day. However, these findings were limited by the lack of data on individual patients and by the paucity of dose-response studies that included doses of >500 µg/day.
What is already known on this topic
What is already known on this topic Inhaled corticosteroids are recommended for most patients with asthma, with the dose being increased as required to obtain control
A therapeutic dose range of fluticasone propionate of 200-2000 µg/day is recommended in the British National Formulary for adults with asthma
What this study adds
What this study adds Published data are insufficient to determine with confidence the dose-response relation of inhaled fluticasone at doses of >500 µg/day
The dose-response curve for inhaled fluticasone in moderate to severe asthma in adolescents and adults, for all major clinical outcome measures, including exacerbations, begins to plateau at 100-200 µg/day and peaks at around 500 µg/day
This study partially explains why adding a long acting β agonist to inhaled corticosteroids is more efficacious than increasing the dose of inhaled steroid beyond this dose range
Dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma: meta-analysis
- Shaun Holt, research fellow,
- Aneta Suder, medical student,
- Mark Weatherall, senior lecturer,
- Soo Cheng, biostatistician,
- Philippa Shirtcliffe, research fellow,
- Richard Beasley (beasley{at}wnmeds.ac.nz), professor of medicine
- Wellington Asthma Research Group, Wellington School of Medicine, PO Box 7343, Wellington, New Zealand
- 9 Park Crescent, London N3 2NL
- Correspondence to: R Beasley
Abstract
Objective: To examine the dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma.
Design: Meta-analysis of placebo controlled, randomised clinical trials that presented data on at least one outcome measure of asthma and that used at least two different doses of fluticasone.
Setting: Medline, Embase, and GlaxoWellcome's internal clinical study registers.
Main outcome measures: FEV1, morning and evening peak expiratory flow, night awakenings, β agonist use, and major exacerbations.
Results: Eight studies, with 2324 adolescents and adults with asthma, met the inclusion criteria. Data on doses of >500 µg/day were limited. The dose-response curve for the raw data began to reach a plateau at around 100-200 µg/day and peaked by 500 µg/day. A negative exponential model for the data, without meta-analysis, indicated that 80% of the benefit at 1000 µg/day was achieved at doses of 70-170 µg/day and 90% by 100-250 µg/day. A quadratic meta-regression showed that the maximum achievable efficacy was obtained by doses of around 500 µg/day. The odds ratio for patients remaining in a study at a dose of 200 µg/day, compared with higher doses, was 0.73 (95% confidence interval 0.49 to 1.08). Comparison of the standardised difference in FEV1 for an inhaled dose of 200 µg/day against higher doses showed a difference in FEV1 of 0.13 of a standard deviation (−0.02 to 0.29).
Conclusions: In adolescent and adult patients with asthma, most of the therapeutic benefit of inhaled fluticasone is achieved with a total daily dose of 100-250 µg, and the maximum effect is achieved with a dose of around 500 µg/day. However, these findings were limited by the lack of data on individual patients and by the paucity of dose-response studies that included doses of >500 µg/day.
What is already known on this topic
What is already known on this topic Inhaled corticosteroids are recommended for most patients with asthma, with the dose being increased as required to obtain control
A therapeutic dose range of fluticasone propionate of 200-2000 µg/day is recommended in the British National Formulary for adults with asthma
What this study adds
What this study adds Published data are insufficient to determine with confidence the dose-response relation of inhaled fluticasone at doses of >500 µg/day
The dose-response curve for inhaled fluticasone in moderate to severe asthma in adolescents and adults, for all major clinical outcome measures, including exacerbations, begins to plateau at 100-200 µg/day and peaks at around 500 µg/day
This study partially explains why adding a long acting β agonist to inhaled corticosteroids is more efficacious than increasing the dose of inhaled steroid beyond this dose range
Footnotes
Funding The Wellington Asthma Research Group is supported by grants from the Health Research Council of New Zealand and the New Zealand Guardian Trust.
Competing interests The Wellington Asthma Research Group has received research grants from Astra Draco, Glaxo Wellcome, and Novartis. RB has received fees for consulting and speaking and reimbursement for attending symposiums from Astra Draco and GlaxoWellcome. SH has received reimbursement for attending symposiums from Astra Draco and Novartis.
Commentary: Dosage needs systematic and critical review
- Andrew Herxheimer (Andrew_Herxheimer{at}compuserve.com), emeritus fellow, UK Cochrane Centre
- Wellington Asthma Research Group, Wellington School of Medicine, PO Box 7343, Wellington, New Zealand
- 9 Park Crescent, London N3 2NL
Footnotes
Competing interests None declared