Dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma: meta-analysis Commentary: Dosage needs systematic and critical

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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 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 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 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 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 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