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First line anti-inflammatory treatment for asthma: Inhaled steroid or leukotriene antagonist?
J ALLERGY CLIN IMMUNOL VOLUME 109, NUMBER 1
7L~ Step-Down Therapy for Asthma With Inhaled Steroids Alone or "l'~il in Combination With a Long Acting ~z-Agonist Stephen Fowler*, Graeme P Currie*, Brian J Lipworth§ *Asthma and Allergy Research Group, University of Dundee, Dundee, UK §University of Dundee, Dundee, UK BACKGROUND: Guidelines for treating moderate to severe asthma suggest achieving optimal initial control with high-dose corticosteroids, then stepping down with inhaled corticosteroid alone or the addition of long acting ~2-agonist. We therefore compared hydrofluoroalkane beclomethasone dipropionate 200gg bid (HFA-BDP) versus fluticasone/salmeterol combination 100/50pg bid (FP/SM) for 8 weeks following initial treatment with dry powder inhaled BDP 1000p.g bid (DPI-BDP) for 4 weeks. METHODS: Thirty-nine uncontrolled moderate to severe asthmatics with severe bronchial hyperresponsiveness were treated with DPI-BDR then randomised to either HFA-BDP (n = 20) or FP/SM (n = 19) in a double blind, double dummy, parallel group design. We measured the provocative dose of methacholine causing a 20% fall in FEV1 (PD20), lung function, surrogate inflammatory markers, diary cards, quality of life (QOL) and safety. RESULTS: There was a 0.9 (95% CI 0.5-1.2) doubling dose improvement in PD20 comparing pre versus post DPI-BDR HFA-BDP maintained this improvement, whilst FP/SM produced a further significant improvement, amounting to a 1.1 (0.2-2.1) doubling dose difference at 8 weeks for SM/FP versus HFA BDE Effects on FEV 1, PEF and QOL were similar to PD20 with a significant difference between SM/FP versus HFA-BDP. Suppression of plasma and urinary cortisol, and serum osteocalcin occurred with DPI-BDE but returned to baseline within one month of HFA-BDP or FP/SM. CONCLUSION: Following high-dose inhaled corticosteroid, stepping down with the combination of a long acting [32-agonist and low-dose inhaled corticosteroid conferred further improvements in bronchoprotection and bronchodilation as compared to monotherapy with double the dose of inhaled corticosteruid.
" T A J ~ First Line Anti-Inflammatory Treatment for Asthma: Inhaled / " t U Steroid or Leukotriene Antagonist? L Jayaram*, M Pizzichini§, P Hussack*, A Efihimiadis*, S Goodwin*, S Chaboillez~,, M Langevin~, C Lemiere~, Andr~ Cartier~q S MantE, E Pizzichini@, FE Hargreave+ *Firestone Institute for Respiratory Health, St Joseph's Healthcare and McMaster University, Hamilton, Canada §University Federal de Santa Catarina, Florinapolis, Brazil ~q-Iospital du Sacre -Coeur de Montreal, Montreal, Canada ~University of Alberta, Edmonton, Canada ~University of Montreal, Montreal, Canada @University Federal de Santa Catarina, Florianopolis, Brazil +The Firestone Institute for Respiratory Health, Hamilton, Canada BACKGROUND: Corticosteroids and leukotriene antagonists, both anti-inflammatory medications, are considered to be suitable first line therapy in the US for the treatment of mild persistent asthma. There are, however, few direct comparisons of the anti-inflammatory effect of these agents. OBJECTIVE: To compare the magnitude of the anti-inflammatory and clinical effects of low dose fluticasone (F) with montelukast (M), in mild persistent asthma. DESIGN: Four centre, randomized, placebo-controlled, parallel group study over eight weeks. PATIENTS: Fifty-five adults with symptomatic steroid-naive asthma and sputum eosinophils of 3.5 % (normal <2). Intervention: Subjects were randomly assigned to receive F 250 mcg daily (n=l 8), M 10mg before bed (n=19) or placebo (P) (n=13). Exacerbations, defined a priori, were treated with open labeled F. M E A S U R E M E N T S : Primary: change in sputum eosinophils. Secondary: change in symptoms score, number of puffs of salbutamol taken as needed, frequency of exacerbations, spirometry, morning and evening peak expiratory flow and blood eosinophils.
Abstracts
$245
RESULTS: Baseline characteristics were similar. F resulted in a significantly greater reduction in sputum eosinophils (median(interquartile range) 9.8(19.0) to 1.4 (1.7) % compared with M(12.5(18.5) to 7.2(12.5)%) and P(15.4(23.7) to 14.8(23.3) %)(p= 0.009), and improvement in FEV1 (mean (standard deviation) 2.7(0.9) to 3.1(0.9) L after F compared with 2.8(0.7) to 2.8 (0.9)L after M and 2.5(0.8) to 2.8(0.8) L after P(p=0.003). The effects of M were not different from R The effect of the three treatments on the other variables was not significantly different. CONCLUSION: Low dose F reduces airway inflammation as measured by sputum eosinophils and improves FEV1 significantly more than M in subjects with mild persistent asthma.The results do not support the use of M for first line anti-inflammatory treatment. Funding: Glaxo Wellcome Inc., Boehringer Ingelheim (Canada) Inc., Father Sean O'Sullivan Research Centre.
747 uct Fluticas°ne Pr°pi°nate/Salmeterol Diskus® C°mbinati°n Prod" Provides Superior Asthma Control Compared With Fluticasone Propionute and Salmeterol Alone in Patients Previously Receivin0 PRN Short-Acting Bctaz-Agonists Alone Richard R Rosenthal*, Kathryn Blake§, Mary Strek~,, Melissa Lange~, Karen W HousetE, Anna K Vandermeer~, Tushar P Shah~ *Laboratory of Applied Immunology, Incorporated, Fairfax, VA §Nemours Children's Clinic, Jacksonvile, FL gUniversity of Chicago, Chicago, IL ~GlaxoSmithKline, RTP, NC Many patients, despite meeting clinical criteria for persistent asthma, are treated with inhaled short-acting beta2-agonists alone, resulting in suboptimal control of their asthma. To address this issue, a randomized, double-blind, parallel-group, 12-week study comparing fluticasone propionate/salmeterol combination (FSC) 100/50 BID, with fluticasone propionate (FP) 100mcg BID and with salmeterol (SALM) 50 mcg BID was conducted in 267 asthma patients aged _>12years with FEV 1 percent predicted of 40-85% at 33 investigational sites, All treatments were administered via Diskus ® and all patients were symptomatic on short-acting beta2-agonists alone at study entry. The primary efficacy variables were area under the serial FEV 1 curve (AUC) at treatment week 12 relative to baseline for FSC versus FP, and mean change from baseline in AM pre-dose FEV 1 at endpoint for FSC versus SALM. After 12 weeks of treatment, patients treated with FSC had significantly greater 12-hour serial FEV 1 AUC relative to baseline (8.38L-hours) than patients receiving FP (7.01L-hours) (p=0.021). At endpoint, the FSC group also had significantly greater improvements in mean morning pre-dose FEV 1 compared with the SALM group (0.51L, 0.38L, respectively; p=0.036). Other efficacy measures are shown below. The overall incidence of adverse events during treatment was comparable across treatment groups. FSC provided superior improvements in pulmonary function and asthma control compared with FP and SALM alone in symptomatic patients previously taking PRN short-acting beta 2agonist therapy alone. These data suggest that treatment of both bronchoconstriction and inflammation was a more effective strategy for the initial maintenance treatment of asthma than treatment with an anti-inflammatory agent alone or a long-acting beta2-agonist alone. Mean change from baseline at endpoint
AM PEF (L/min) PM PEF (L/min) % of rescue-free days % of symptom-free days % of nights with no awakenings *p<0.015 FSC vs FP and SALM.
FSC
FP
SALM
68.1 * 51.0" 52.5* 40.6* 29.8
36.5 30.4 30.8 24.6 21.1
33.0 24.4 35.0 25.6 26.4
7L~ Step-Down Therapy for Asthma With Inhaled Steroids Alone or "l'~il in Combination With a Long Acting ~z-Agonist Stephen Fowler*, Graeme P Currie*, Brian J Lipworth§ *Asthma and Allergy Research Group, University of Dundee, Dundee, UK §University of Dundee, Dundee, UK BACKGROUND: Guidelines for treating moderate to severe asthma suggest achieving optimal initial control with high-dose corticosteroids, then stepping down with inhaled corticosteroid alone or the addition of long acting ~2-agonist. We therefore compared hydrofluoroalkane beclomethasone dipropionate 200gg bid (HFA-BDP) versus fluticasone/salmeterol combination 100/50pg bid (FP/SM) for 8 weeks following initial treatment with dry powder inhaled BDP 1000p.g bid (DPI-BDP) for 4 weeks. METHODS: Thirty-nine uncontrolled moderate to severe asthmatics with severe bronchial hyperresponsiveness were treated with DPI-BDR then randomised to either HFA-BDP (n = 20) or FP/SM (n = 19) in a double blind, double dummy, parallel group design. We measured the provocative dose of methacholine causing a 20% fall in FEV1 (PD20), lung function, surrogate inflammatory markers, diary cards, quality of life (QOL) and safety. RESULTS: There was a 0.9 (95% CI 0.5-1.2) doubling dose improvement in PD20 comparing pre versus post DPI-BDR HFA-BDP maintained this improvement, whilst FP/SM produced a further significant improvement, amounting to a 1.1 (0.2-2.1) doubling dose difference at 8 weeks for SM/FP versus HFA BDE Effects on FEV 1, PEF and QOL were similar to PD20 with a significant difference between SM/FP versus HFA-BDP. Suppression of plasma and urinary cortisol, and serum osteocalcin occurred with DPI-BDE but returned to baseline within one month of HFA-BDP or FP/SM. CONCLUSION: Following high-dose inhaled corticosteroid, stepping down with the combination of a long acting [32-agonist and low-dose inhaled corticosteroid conferred further improvements in bronchoprotection and bronchodilation as compared to monotherapy with double the dose of inhaled corticosteruid.
" T A J ~ First Line Anti-Inflammatory Treatment for Asthma: Inhaled / " t U Steroid or Leukotriene Antagonist? L Jayaram*, M Pizzichini§, P Hussack*, A Efihimiadis*, S Goodwin*, S Chaboillez~,, M Langevin~, C Lemiere~, Andr~ Cartier~q S MantE, E Pizzichini@, FE Hargreave+ *Firestone Institute for Respiratory Health, St Joseph's Healthcare and McMaster University, Hamilton, Canada §University Federal de Santa Catarina, Florinapolis, Brazil ~q-Iospital du Sacre -Coeur de Montreal, Montreal, Canada ~University of Alberta, Edmonton, Canada ~University of Montreal, Montreal, Canada @University Federal de Santa Catarina, Florianopolis, Brazil +The Firestone Institute for Respiratory Health, Hamilton, Canada BACKGROUND: Corticosteroids and leukotriene antagonists, both anti-inflammatory medications, are considered to be suitable first line therapy in the US for the treatment of mild persistent asthma. There are, however, few direct comparisons of the anti-inflammatory effect of these agents. OBJECTIVE: To compare the magnitude of the anti-inflammatory and clinical effects of low dose fluticasone (F) with montelukast (M), in mild persistent asthma. DESIGN: Four centre, randomized, placebo-controlled, parallel group study over eight weeks. PATIENTS: Fifty-five adults with symptomatic steroid-naive asthma and sputum eosinophils of 3.5 % (normal <2). Intervention: Subjects were randomly assigned to receive F 250 mcg daily (n=l 8), M 10mg before bed (n=19) or placebo (P) (n=13). Exacerbations, defined a priori, were treated with open labeled F. M E A S U R E M E N T S : Primary: change in sputum eosinophils. Secondary: change in symptoms score, number of puffs of salbutamol taken as needed, frequency of exacerbations, spirometry, morning and evening peak expiratory flow and blood eosinophils.
Abstracts
$245
RESULTS: Baseline characteristics were similar. F resulted in a significantly greater reduction in sputum eosinophils (median(interquartile range) 9.8(19.0) to 1.4 (1.7) % compared with M(12.5(18.5) to 7.2(12.5)%) and P(15.4(23.7) to 14.8(23.3) %)(p= 0.009), and improvement in FEV1 (mean (standard deviation) 2.7(0.9) to 3.1(0.9) L after F compared with 2.8(0.7) to 2.8 (0.9)L after M and 2.5(0.8) to 2.8(0.8) L after P(p=0.003). The effects of M were not different from R The effect of the three treatments on the other variables was not significantly different. CONCLUSION: Low dose F reduces airway inflammation as measured by sputum eosinophils and improves FEV1 significantly more than M in subjects with mild persistent asthma.The results do not support the use of M for first line anti-inflammatory treatment. Funding: Glaxo Wellcome Inc., Boehringer Ingelheim (Canada) Inc., Father Sean O'Sullivan Research Centre.
747 uct Fluticas°ne Pr°pi°nate/Salmeterol Diskus® C°mbinati°n Prod" Provides Superior Asthma Control Compared With Fluticasone Propionute and Salmeterol Alone in Patients Previously Receivin0 PRN Short-Acting Bctaz-Agonists Alone Richard R Rosenthal*, Kathryn Blake§, Mary Strek~,, Melissa Lange~, Karen W HousetE, Anna K Vandermeer~, Tushar P Shah~ *Laboratory of Applied Immunology, Incorporated, Fairfax, VA §Nemours Children's Clinic, Jacksonvile, FL gUniversity of Chicago, Chicago, IL ~GlaxoSmithKline, RTP, NC Many patients, despite meeting clinical criteria for persistent asthma, are treated with inhaled short-acting beta2-agonists alone, resulting in suboptimal control of their asthma. To address this issue, a randomized, double-blind, parallel-group, 12-week study comparing fluticasone propionate/salmeterol combination (FSC) 100/50 BID, with fluticasone propionate (FP) 100mcg BID and with salmeterol (SALM) 50 mcg BID was conducted in 267 asthma patients aged _>12years with FEV 1 percent predicted of 40-85% at 33 investigational sites, All treatments were administered via Diskus ® and all patients were symptomatic on short-acting beta2-agonists alone at study entry. The primary efficacy variables were area under the serial FEV 1 curve (AUC) at treatment week 12 relative to baseline for FSC versus FP, and mean change from baseline in AM pre-dose FEV 1 at endpoint for FSC versus SALM. After 12 weeks of treatment, patients treated with FSC had significantly greater 12-hour serial FEV 1 AUC relative to baseline (8.38L-hours) than patients receiving FP (7.01L-hours) (p=0.021). At endpoint, the FSC group also had significantly greater improvements in mean morning pre-dose FEV 1 compared with the SALM group (0.51L, 0.38L, respectively; p=0.036). Other efficacy measures are shown below. The overall incidence of adverse events during treatment was comparable across treatment groups. FSC provided superior improvements in pulmonary function and asthma control compared with FP and SALM alone in symptomatic patients previously taking PRN short-acting beta 2agonist therapy alone. These data suggest that treatment of both bronchoconstriction and inflammation was a more effective strategy for the initial maintenance treatment of asthma than treatment with an anti-inflammatory agent alone or a long-acting beta2-agonist alone. Mean change from baseline at endpoint
AM PEF (L/min) PM PEF (L/min) % of rescue-free days % of symptom-free days % of nights with no awakenings *p<0.015 FSC vs FP and SALM.
FSC
FP
SALM
68.1 * 51.0" 52.5* 40.6* 29.8
36.5 30.4 30.8 24.6 21.1
33.0 24.4 35.0 25.6 26.4