Low-dose Inhaled Corticosteroids Research Articles

S92 Efficacy Of Once-daily Tiotropium Respimat(R) 5 g From Five Phase Iii Trials In Adults With Symptomatic Asthma

Background Recent clinical trials have indicated that the long-acting antimuscarinic agent tiotropium, a once-daily long-acting bronchodilator, may provide benefit to patients with symptomatic asthma. We investigated primary efficacy data (lung function, risk of severe exacerbation and seven-question Asthma Control Questionnaire [ACQ-7] response) from five Phase III, randomised, double-blind, parallel-group trials that evaluated the efficacy and safety of once-daily tiotropium add-on versus placebo add-on (all tiotropium doses delivered via the Respimat ® SoftMist™ inhaler) in adults with symptomatic asthma on inhaled corticosteroid (ICS) ± long-acting β 2 -agonist (LABA) maintenance therapy. Methods Two 48-week trials of tiotropium Respimat ® 5 µg (PrimoTinA-asthma ® : NCT00776984, NCT00772538) in patients on high-dose ICS (≥800 µg budesonide or equivalent) + LABA; two 24-week trials of tiotropium Respimat ® 5 µg and 2.5 µg (MezzoTinA-asthma ® : NCT01172808, NCT01172821) in patients on moderate-dose ICS (400–800 µg budesonide or equivalent); one 12-week trial of tiotropium Respimat ® 5 µg and 2.5 µg (GraziaTinA-asthma ® : NCT01316380) in patients on low-dose ICS (200–400 µg budesonide or equivalent). Results 3476 patients were treated, of whom 1128 received tiotropium Respimat ® 5 µg. Once-daily tiotropium Respimat ® 5 µg significantly improved lung function (Table) in patients with not fully controlled asthma receiving low- to high-dose ICS. In addition, tiotropium Respimat ® 5 µg reduced the risk of severe exacerbations versus placebo (co-primary end point) in patients on high-dose ICS + LABA (hazard ratio 0.79; p = 0.0343), and there was an increase in ACQ-7 responder rate (co-primary end point) with the5 µg dose (odds ratio 1.32; p = 0.0308) compared with placebo in patients on moderate-dose ICS. Conclusion Once-daily tiotropium Respimat ® significantly improves lung function in adult patients with symptomatic asthma receiving a range of doses of ICS, including even high-dose ICS + LABA, suggesting a potential role for this treatment as add-on to ICS in adults with symptomatic asthma.

P231 Once-daily Tiotropium Respimat(R): Safety And Tolerability Results From Five Phase Iii Trials In Adults With Symptomatic Asthma

Background Tiotropium Respimat ® , a once-daily long-acting anticholinergic agent, is effective as add-on to inhaled corticosteroids (ICS) ± a long-acting β2-agonist (LABA) in adults with symptomatic asthma. Safety and tolerability are key issues in the development of new therapies or established therapies in new disease areas. We present key safety data from five Phase III, randomised, double-blind, parallel-group trials that evaluated the efficacy and safety of once-daily tiotropium Respimat ® versus placebo in adults with symptomatic asthma. Methods: Two 48-week trials of tiotropium Respimat ® 5 µg (PrimoTinA-asthma ® : NCT00776984, NCT00772538) in patients on high-dose ICS (≥800 µg budesonide or equivalent) + LABA; two 24-week trials of tiotropium Respimat ® 5 µg and 2.5 µg (MezzoTinA-asthma ® : NCT01172808, NCT01172821) in patients on moderate-dose ICS (400–800 µg budesonide or equivalent); one 12-week trial of tiotropium Respimat ® 5 µg and 2.5 µg (GraziaTinA-asthma ® : NCT01316380) in patients on low-dose ICS (200–400 µg budesonide or equivalent). All tiotropium doses were delivered via the Respimat ® SoftMist™ inhaler. Results: 3476 patients were treated. Incidence of any adverse events (AEs), serious AEs and investigator-defined drug-related AEs was similar across treatment groups within each trial. AEs reported by ≥5% of patients were similar across all treatment groups within each trial (Table). The number of cardiovascular AEs was small in all five studies and comparable between tiotropium Respimat ® and placebo. No deaths occurred in any trial. Conclusion: Once-daily tiotropium Respimat® is well tolerated and comparable with placebo in adult patients with symptomatic asthma receiving at least low- to high-dose ICS.

Addition of antileukotriene agents to inhaled corticosteroids in children with persistent asthma.

For the current issue of the Journal, we asked Drs Jimmy Chong and Bhupendrasinh Chauhan to comment on and put into context the Cochrane Review on the efficacy and safety of adding antileukotriene agents (LTRAs) to low-dose inhaled corticosteroids (ICS) in children with persistent asthma (1). In the treatment of children with mild persistent asthma, low-dose ICS are recommended as the preferred monotherapy (referred to as step 2 of therapy). In children with inadequate asthma control on low doses of ICS (step 2), asthma management guidelines recommend adding an LTRA to existing ICS as one of three therapeutic options to intensify therapy (step 3). Trials were identified from the Cochrane Airways Group Specialised Register of Trials, which is derived from systematic searches of bibliographical databases, including the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, AMED and CINAHL, and a manual search of respiratory journals and meeting abstracts, as well as the web-site www.clinicaltrials.gov. The search was conducted until January 2013. Randomized controlled trials (RCTs) that involved children and adolescents one to 18 years of age, with asthma, who remained symptomatic despite the use of a stable maintenance dose of ICS, and in whom LTRAs were added to ICS and compared with the same, an increased or a tapering dose of ICS for at least four weeks were considered for inclusion. Sandard methods outlined by The Cochrane Collaboration were used. Five paediatric (parallel group or cross-over) trials met the inclusion criteria. Two (40%) trials were considered to be at a low risk for bias. Four published trials, representing 559 children (≥6 years of age) and adolescents with mild-to-moderate asthma, contributed data to the review. No trial enrolled preschool-age children. All trials used montelukast as the LTRA, administered for between four and 16 weeks. Three trials evaluated the combination of LTRAs and ICS compared with the same dose of ICS alone (step 3 versus step 2). No statistically significant group difference was observed in the only trial reporting participants with exacerbations requiring oral corticosteroids over four weeks (n=268 participants; RR 0.80 [95% CI 0.34 to 1.91]). There was also no statistically significant difference in percent change in forced expiratory volume in 1 s (FEV1) in this trial, with a mean difference (MD) of 1.3 (95% CI -0.09 to 2.69); however, a significant group difference was observed in the morning and evening peak expiratory flow rates: n=218 participants; MD 9.70 L/min (95% CI 1.27 L/min to 18.13 L/min) and MD 10.70 L/min (95% CI 2.41 L/min to 18.99 L/min), respectively. One trial compared the combination of LTRAs and ICS with a higher dose of ICS (step 3 versus step 3). No significant group difference was observed in this trial for participants with exacerbations requiring rescue oral corticosteroids over a 16-week period (n=182 participants; RR 0.82 [95% CI 0.54 to 1.25]), nor was there any significant difference in exacerbations requiring hospitalization. There was no statistically significant group difference in withdrawals overall or because of any cause with either protocol. No trial explored the impact of adding LTRAs as a means to taper the dose of ICS. The addition of LTRAs to ICS is not associated with a statistically significant reduction in the need for rescue oral corticosteroids or hospital admission compared with the same or an increased dose of ICS in children and adolescents with mild to moderate asthma. Although LTRAs have been licensed for use in children for >10 years, the paucity of paediatric trials, the absence of data regarding preschool-age children and the variability in the reporting of relevant clinical outcomes considerably limit firm conclusions. At present, there is no firm evidence to support the efficacy and safety of LTRAs as add-on therapy to ICS as a step 3 option in the therapeutic arsenal for children with uncontrolled asthma symptoms on low-dose ICS. The full text of the Cochrane Review is available in The Cochrane Library (1).

Risk of congenital malformations for asthmatic pregnant women using a long-acting β2-agonist and inhaled corticosteroid combination versus higher-dose inhaled corticosteroid monotherapy

Current recommendations for managing persistent asthma during pregnancy when low-dose inhaled corticosteroids (ICSs) are insufficient include adding a long-acting β₂-agonist (LABA) or increasing the ICS dose. However, there are no data to help clinicians evaluate the safest regimen during pregnancy. We sought to compare the risk of major congenital malformations in asthmatic women exposed to a LABA plus ICS combination and those exposed to ICS monotherapy at higher doses during the first trimester. A cohort of asthmatic pregnant women exposed to ICSs during the first trimester who delivered between January 1990 and March 2009 was established. The primary outcome was major malformation recorded at birth or during the first year of life. Two subcohorts were established as follows: (1) users of a LABA plus low-dose ICS combination or users of a medium-dose ICS and (2) users of a LABA plus medium-dose ICS combination or users of a high-dose ICS. Generalized estimating equations were used to compare the risk of major malformations between the groups. In one subcohort there were 643 women who used a LABA plus low-dose ICS and 305 who used a medium-dose ICS; the other subcohort included 198 users of a LABA plus medium-dose ICS and 156 users of a high-dose ICS. The prevalence of major malformations was 6.9% and 7.2%, respectively. The adjusted odds ratio for major malformations was 1.1 (95% CI, 0.6-1.9) when a LABA plus low-dose ICS was used compared with a medium-dose ICS and 1.2 (95% CI, 0.5-2.7) when a LABA plus medium-dose ICS was used compared with a high-dose ICS. The risk of major malformations was similar with a LABA plus ICS combination and ICS monotherapy at higher doses, suggesting that both therapeutic options can be considered during pregnancy.

The inverse agonist propranolol confers no corticosteroid-sparing activity in mild-to-moderate persistent asthma.

The murine asthma model shows that switching off airway β2 receptors with an inverse agonist may confer anti-inflammatory effects as well as corticosteroid-sparing activity. We have assessed for any corticosteroid-sparing effects of propranolol, an inverse agonist, added to low-dose inhaled corticosteroid (ICS) compared with higher dose ICS. A randomized double-blind placebo-controlled cross-over trial in mild-to-moderate persistent asthmatic patients was performed. After a run-in (2 weeks) on hydrofluoroalkane-beclometasone dipropionate (HFA-BDP) at 100 μg/day (HFA-BDP100), patients received randomized treatments (4 weeks) with propranolol at 80 mg/day plus HFA-BDP at 100 μg/day compared with placebo plus HFA-BDP at 400 μg/day (HFA-BDP400). Propranolol was up-titrated to 80 mg/day over the initial 2 weeks. Tiotropium was co-administered until 5 days before each histamine challenge (the primary outcome). Sixteen patients completed the study [mean age, 38 years; forced expiratory volume in 1 s (FEV1), 86.4%; histamine provocative concentration causing a 20% fall in FEV1 (PC20), 1.39 mg/ml; ICS dose, 406 μg/day]. Histamine PC20 was unchanged by adding propranolol to HFA-BDP100 compared with baseline (HFA-BDP100) {0.17 doubling dilution (dd) difference [95% confidence interval (CI): -0.58 to 0.92]}, but there was a significant improvement with HFA-BDP400 compared with both baseline [1.05 dd (95% CI: 0.43-1.66); P=0.02], and propranolol+HFA-BDP100 [0.88 dd (95% CI: 0.45-1.30); P=0.006]. Significant improvements were also observed with HFA-BDP400 for exhaled nitric oxide, blood eosinophils, serum eosinophilic cationic protein and asthma quality-of-life questionnaire symptoms compared with propranolol+HFA-BDP100. Salbutamol recovery post-challenge was partially blunted by propranolol (median prolongation 5 min; P=0.002). Domiciliary evening FEV1 also fell with propranolol+HFA-BDP100 [mean reduction from baseline 0.22 litres (95% CI: 0.10-0.34); P=0.012], whereas Asthma Control Questionnaire remained unchanged. In conclusion, the inverse agonist propranolol produced no improvements when given with low-dose ICS, whereas further significant improvements in airway hyper-responsiveness and inflammation were demonstrated with higher dose ICS. Thus, propranolol does not confer corticosteroid-sparing activity in persistent asthma.

Inhaled corticosteroids in children with persistent asthma: dose-response effects on growth.

Inhaled corticosteroids (ICS) are the first-line treatment for children with persistent asthma. Their potential for growth suppression remains a matter of concern for parents and physicians. To assess whether increasing the dose of ICS is associated with slower linear growth, weight gain and skeletal maturation in children with asthma. We searched the Cochrane Airways Group Specialised Register of trials (CAGR) and the ClinicalTrials.gov website up to March 2014. Studies were eligible if they were parallel-group randomised trials evaluating the impact of different doses of the same ICS using the same device in both groups for a minimum of three months in children one to 17 years of age with persistent asthma. Two review authors ascertained methodological quality independently using the Cochrane Risk of bias tool. The primary outcome was linear growth velocity. Secondary outcomes included change over time in growth velocity, height, weight, body mass index and skeletal maturation. Among 22 eligible trials, 17 group comparisons were derived from 10 trials (3394 children with mild to moderate asthma), measured growth and contributed data to the meta-analysis. Trials used ICS (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) as monotherapy or as combination therapy with a long-acting beta2-agonist and generally compared low (50 to 100 μg) versus low to medium (200 μg) doses of hydrofluoroalkane (HFA)-beclomethasone equivalent over 12 to 52 weeks. In the four comparisons reporting linear growth over 12 months, a significant group difference was observed, clearly indicating lower growth velocity in the higher ICS dose group of 5.74 cm/y compared with 5.94 cm/y on lower-dose ICS (N = 728 school-aged children; mean difference (MD)0.20 cm/y, 95% confidence interval (CI) 0.02 to 0.39; high-quality evidence): No statistically significant heterogeneity was noted between trials contributing data. The ICS molecules (ciclesonide, fluticasone, mometasone) used in these four comparisons did not significantly influence the magnitude of effect (X(2) = 2.19 (2 df), P value 0.33). Subgroup analyses on age, baseline severity of airway obstruction, ICS dose and concomitant use of non-steroidal antiasthmatic drugs were not performed because of similarity across trials or inadequate reporting. A statistically significant group difference was noted in unadjusted change in height from zero to three months (nine comparisons; N = 944 children; MD 0.15, 95% CI -0.28 to -0.02; moderate-quality evidence) in favour of a higher ICS dose. No statistically significant group differences in change in height were observed at other time points, nor were such differences in weight, bone mass index and skeletal maturation reported with low quality of evidence due to imprecision. In prepubescent school-aged children with mild to moderate persistent asthma, a small but statistically significant group difference in growth velocity was observed between low doses of ICS and low to medium doses of HFA-beclomethasone equivalent, favouring the use of low-dose ICS. No apparent difference in the magnitude of effect was associated with three molecules reporting one-year growth velocity, namely, mometasone, ciclesonide and fluticasone. In view of prevailing parents' and physicians' concerns about the growth suppressive effect of ICS, lack of or incomplete reporting of growth velocity in more than 86% (19/22) of eligible paediatric trials, including those using beclomethasone and budesonide, is a matter of concern. All future paediatric trials comparing different doses of ICS with or without placebo should systematically document growth. Findings support use of the minimal effective ICS dose in children with asthma.

Effect of low dose of inhaled corticosteroid combined with tiotropium bromide on cytokines and pulmonary function of patients with bronchial asthma

Objective To investigate clinical efficacy of low dose of corticosteroid combined with tiotropium bromide on cytokines and pulmonary function of patients with bronchial asthma treated by inhaling.Methods 80 cases of patients with light or moderate asthma were randomly divided into observation group and control group,40 cases for each group.Observation group was treated with inhaling low dose of two beclomethasone dipropionate and tiotropium bromide,control group was treated with high dose of two beclomethasone.The cytokines,pulmonary function and asthma symptom score changes between two groups were compared.Results At post-treatment,the IL-8,IL-10,TNF-α in observation group were significantly lower than those in control group (P ＜ 0.05); the FVC,FEV1,FEV1/FVC (％) in observation group were significantly higher than those in control group (P ＜ 0.05); asthma score was significantly lower than that in control group (P ＜ 0.05); the incidence of adverse reaction was lower than that in control group (P ＜ 0.05).Conclusion Treating bronchial asthma by inhaling low dose of corticosteroid combined with tiotropium bromide has good clinical curative effect,which is safe and reliable,and worthy of clinical application. Key words: Hormone; Tiotropium; Bronchial asthma; Cytokines; Pulmonary function

Variability of methacholine bronchoprovocation and the effect of inhaled corticosteroids in mild asthma

BackgroundThe methacholine challenge test quantifies airway hyper-responsiveness, which is measured by the provocative concentration of methacholine causing a 20% decrease in forced expiration volume in 1 second (PC20). The dose–response effect of inhaled corticosteroids (ICS) on PC20 has been inconsistent and within-patient variability of PC20 is not well established. ObjectiveTo determine the effect of high- vs low-dose ICS on PC20 and within-patient variability in those with repeated measurements of PC20. MethodsA randomized, double-masked, crossover trial was conducted in patients with asthma on controller medications with PC20 of 8 mg/mL or lower (n = 64) to evaluate the effect of high-dose (1,000 μg/d) vs low-dose (250 μg/d) fluticasone for 4 weeks on PC20. In addition, the variability of PC20 was assessed in participants who underwent 2 or 3 PC20 measurements on the same dose of ICS (n = 27) over a 4-week interval. ResultsBecause there was a significant period effect, dose comparison of the change in PC20 was assessed in the first treatment period. There was no significant difference in the change in PC20 for high- vs low-dose ICS (39% vs 30% increase, respectively; P = .87). The within- and between-participant variances for log PC20 were 0.84 and 0.96, respectively, with an intra-class correlation of 0.53, and 37% of participants had more than 2 doubling dose changes in PC20 in those with repeated measurements. ConclusionThe effect of ICS on PC20 is not dose dependent at fluticasone levels of 250 and 1,000 μg/d. Interpersonal variability for PC20 is large. A lack of precise measurements should be taken into account when interpreting any change in PC20.

Potential Masking of Airway Eosinophilic Inflammation by Combination Therapy in Asthma

PurposeLong-acting β2 agonists (LABA) may mask ongoing bronchial inflammation, leaving asthmatic patients at greater risk of severe complications. The aim of this study was to compare the effect of combination therapy using low-dose inhaled corticosteroids (ICS) plus LABA on airway inflammation in asthma to the effect of medium-dose ICS alone.MethodsTwenty-four patients with asthma not controlled by low-dose (400 µg per day) budesonide alone were enrolled in this prospective crossover study. Patients were randomized into 2 treatment phases: one receiving medium-dose (800 µg per day) budesonide (ICS phase), and the other receiving a combination therapy of low-dose budesonide/formoterol (360 µg/9 µg per day) delivered by a single inhaler (LABA phase). Each treatment phase lasted for 6 week, after which patients were crossed over. Asthma symptoms, lung function, and airway inflammation were compared between the 2 phases.ResultsTwenty-three patients completed the study; adequate sputum samples were collected from 17 patients. Asthma symptoms and lung function remained similar between the 2 phases. However, the mean sputum eosinophil percentage was higher in the LABA phase than in the ICS phase (5.07±3.82% vs. 1.02±1.70%; P<0.01). Sputum eosinophilia (≥3%) was more frequently observed in the LABA phase than in the ICS phase (six vs. two).ConclusionAddition of LABA may mask airway eosinophilic inflammation in asthmatic patients whose symptoms are not controlled with low-dose ICS.

Addition of anti-leukotriene agents to inhaled corticosteroids in children with persistent asthma

In the treatment of children with mild persistent asthma, low-dose inhaled corticosteroids (ICS) are recommended as the preferred monotherapy (referred to as step 2 of therapy). In children with inadequate asthma control on low doses of ICS (step 2), asthma management guidelines recommend adding an anti-leukotriene agent to existing ICS as one of three therapeutic options to intensify therapy (step 3). To compare the efficacy and safety of the combination of anti-leukotriene agents and ICS to the use of the same, an increased, or a tapering dose of ICS in children and adolescents with persistent asthma who remain symptomatic despite the use of maintenance ICS. In addition, we wished to determine the characteristics of people or treatments, if any, that influenced the magnitude of response attributable to the addition of anti-leukotrienes. We identified trials from the Cochrane Airways Group Specialised Register of Trials (CAGR), which were derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, AMED, and CINAHL; and the handsearching of respiratory journals and meeting abstracts, as well as the www.clinicaltrials.gov website. The search was conducted until January 2013. We considered for inclusion randomised controlled trials (RCTs) conducted in children and adolescents, aged one to 18 years, with asthma, who remained symptomatic despite the use of a stable maintenance dose of ICS and in whom anti-leukotrienes were added to the ICS if they were compared to the same, an increased, or a tapering dose of ICS for at least four weeks. We used standard methods expected by The Cochrane Collaboration. Five paediatric (parallel group or cross-over) trials met the inclusion criteria. We considered two (40%) trials to be at a low risk of bias. Four published trials, representing 559 children (aged ≥ six years) and adolescents with mild to moderate asthma, contributed data to the review. No trial enrolled preschoolers. All trials used montelukast as the anti-leukotriene agent administered for between four and 16 weeks. Three trials evaluated the combination of anti-leukotrienes and ICS compared to the same dose of ICS alone (step 3 versus step 2). No statistically significant group difference was observed in the only trial reporting participants with exacerbations requiring oral corticosteroids over four weeks (N = 268 participants; risk ratio (RR) 0.80, 95% confidence interval (CI) 0.34 to 1.91). There was also no statistically significant difference in percentage change in FEV₁ (forced expiratory volume in 1 second) with mean difference (MD) 1.3 (95% CI -0.09 to 2.69) in this trial, but a significant group difference was observed in the morning (AM) and evening (PM) peak expiratory flow rates (PEFR): N = 218 participants; MD 9.70 L/min (95% CI 1.27 to 18.13) and MD 10.70 (95% CI 2.41 to 18.99), respectively. One trial compared the combination of anti-leukotrienes and ICS to a higher-dose of ICS (step 3 versus step 3). No significant group difference was observed in this trial for participants with exacerbations requiring rescue oral corticosteroids over 16 weeks (N = 182 participants; RR 0.82, 95% CI 0.54 to 1.25), nor was there any significant difference in exacerbations requiring hospitalisation. There was no statistically significant group difference in withdrawals overall or because of any cause with either protocol. No trial explored the impact of adding anti-leukotrienes as a means to taper the dose of ICS. The addition of anti-leukotrienes to ICS is not associated with a statistically significant reduction in the need for rescue oral corticosteroids or hospital admission compared to the same or an increased dose of ICS in children and adolescents with mild to moderate asthma. Although anti-leukotrienes have been licensed for use in children for over 10 years, the paucity of paediatric trials, the absence of data on preschoolers, and the variability in the reporting of relevant clinical outcomes considerably limit firm conclusions. At present, there is no firm evidence to support the efficacy and safety of anti-leukotrienes as add-on therapy to ICS as a step-3 option in the therapeutic arsenal for children with uncontrolled asthma symptoms on low-dose ICS.

The risk of asthma exacerbation after stopping low-dose inhaled corticosteroids: A systematic review and meta-analysis of randomized controlled trials

Current asthma guidelines suggest that patients and their providers consider decreasing or stopping controller medications when asthma is stable. We sought to estimate the risk of asthma exacerbation in patients who stop low-dose inhaled corticosteroids (ICSs) compared with those who continue ICSs in randomized controlled trials. We identified relevant trials from a systematic review of English-language and non-English-language articles using MEDLINE, EMBASE, and CENTRAL (inception to January 21, 2012). Articles were screened at the abstract and full-text level by 2 independent reviewers. We included randomized controlled trials with a stable asthma run-in period of 4 weeks or more, an intervention to stop or continue ICSs, and a follow-up period of at least 3 months. We pooled results using a random-effects meta-analysis. The search strategy identified 1798 potential articles, of which 172 were reviewed at the full-text level and 7 met the criteria for inclusion. The relative risk for an asthma exacerbation in patients who stopped ICSs compared with those who continued use was 2.35 (95% CI, 1.88-2.92; P<.001; I(2)=0%), as determined by using data pooled from trials with a mean follow-up of 27 weeks. The pooled absolute risk difference for an asthma exacerbation was 0.23 (95% CI, 0.16-0.30; P<.001; I(2)=44%). Patients who discontinued ICSs also had a decreased FEV1 of 130 mL (95% CI, 40-210 mL; P=.003; I(2)=53%), a decreased mean morning peak expiratory flow of 18L/min (95% CI, 6-29 L/min; P=.004; I(2)=82%), and an increased mean standardized asthma symptom score of 0.43 SDs (95% CI, 0.28-0.58 SDs; P<.001; I(2)=0%). Patients with well-controlled asthma who stop regular use of low-dose ICSs have an increased risk of an asthma exacerbation compared with those who continue ICSs.

Breathe easy: Updates on asthma management

Several asthma trials have been published in recent months evaluating key treatments such as long-acting beta-2 agonists (LABAs), inhaled corticosteroids (ICSs), and tiotropium (Spiriva— oehringer Ingelheim, Pfizer). Studies have questioned the recommendation to discontinue LABAs; compared the efficacy of intermittent, symptom-based ICS use with scheduled inhalations in adults with mild to moderate persistent asthma; evaluated the effects of ICS use in children on their adult height; and evaluated the role of tiotropium in the management of uncontrolled asthma.

P2X7-Regulated Protection from Exacerbations and Loss of Control Is Independent of Asthma Maintenance Therapy

The function of the P2X(7) nucleotide receptor protects against exacerbation in people with mild-intermittent asthma during viral illnesses, but the impact of disease severity and maintenance therapy has not been studied. To evaluate the association between P2X(7), asthma exacerbations, and incomplete symptom control in a more diverse population. A matched P2RX7 genetic case-control was performed with samples from Asthma Clinical Research Network trial participants enrolled before July 2006, and P2X(7) pore activity was determined in whole blood samples as an ancillary study to two trials completed subsequently. A total of 187 exacerbations were studied in 742 subjects, and the change in asthma symptom burden was studied in an additional 110 subjects during a trial of inhaled corticosteroids (ICS) dose optimization. African American carriers of the minor G allele of the rs2230911 loss-of-function single nucleotide polymorphism were more likely to have a history of prednisone use in the previous 12 months, with adjustment for ICS and long-acting β(2)-agonists use (odds ratio, 2.7; 95% confidence interval, 1.2-6.2; P = 0.018). Despite medium-dose ICS, attenuated pore function predicted earlier exacerbations in incompletely controlled patients with moderate asthma (hazard ratio, 3.2; confidence interval, 1.1-9.3; P = 0.033). After establishing control with low-dose ICS in patients with mild asthma, those with attenuated pore function had more asthma symptoms, rescue albuterol use, and FEV(1) reversal (P < 0.001, 0.03, and 0.03, respectively) during the ICS adjustment phase. P2X(7) pore function protects against exacerbations of asthma and loss of control, independent of baseline severity and the maintenance therapy.

Once-daily fluticasone furoate is efficacious in patients with symptomatic asthma on low-dose inhaled corticosteroids

BackgroundFluticasone furoate (FF) is an inhaled corticosteroid (ICS) with 24-hour activity in development as a once-daily treatment for the long-term management of asthma. ObjectiveTo assess the efficacy and safety of 4 doses of once-daily FF administered using a dry powder inhaler in patients (≥12 years) with moderate asthma, uncontrolled on low-dose ICS (fluticasone propionate [FP] 200 μg/day or equivalent). MethodsThis double-blind, placebo-controlled, dose-ranging study randomized 622 patients to 1 of 6 treatments: FF (100, 200, 300, or 400 μg) once daily in the evening, FP 250 μg twice daily (active control), or placebo for 8 weeks. The primary endpoint was the change from baseline in predose evening forced expiratory colume in 1 second (FEV1) at week 8. ResultsAt week 8, relative to placebo, all doses of FF once daily and FP twice daily demonstrated significantly (P < .001) greater increases from baseline and greater than 200-mL increases in predose FEV1. There was no evidence of a dose-response relationship between FF doses. Improvement with once-daily FF was similar to or greater than that for twice-daily FP. Secondary efficacy endpoint findings generally supported the efficacy of FF 100 to 400 μg once daily, although statistically significant improvements versus placebo in symptom-free 24-hour periods were only reported for FF 400 μg. There were few withdrawals due to lack of efficacy. Oral candidiasis was reported in 0 to 4% of patients; 24-hour urinary cortisol excretion ratios were similar across active treatment groups and not significantly different from placebo. ConclusionFF 100 to 400 μg once daily in the evening is effective and well tolerated in patients with asthma uncontrolled on low-dose ICS, with 100 μg and 200 μg, considered the most applicable doses in this asthma population. Trial Registrationclinicaltrials.gov Identifier: NCT00603278.

Clinical Year in Review III

A significant proportion of children with asthma who are treated with low-dose inhaled corticosteroids (ICS) continue to experience suboptimal disease control and exacerbations. Despite this, the best approach for escalating therapy in these children remains unclear. In the BADGER (Best Add-On Therapy Giving Effective Responses) trial (1), Lemanske and colleagues assessed therapeutic response to three different strategies of escalating therapy beyond low-dose ICS: (1) increasing the dose of the ICS from 100 mg twice daily to 250 mg twice daily; (2) adding montelukast, either 5 or 10 mg daily, to fluticasone, 100 mg twice daily; or (3) adding salmeterol, 50 mg twice daily, to fluticasone, 100 mg twice daily. These strategies were compared in a three-way crossover trial with the primary outcome being a composite of asthma exacerbations, asthma control days, and FEV1. Subjects had mild or moderate persistent asthma according to guidelines, and were eligible to proceed to randomization if they had symptoms 2 days per week on average during a 2-week period, utilized a rescue bronchodilator greater than or equal to 2 puffs/day, or had peak flows less than 80% of predicted during treatment with fluticasone (100 mg twice daily). After 16 weeks of treatment, 98% of participants demonstrated differential response to the three treatment strategies, with the greatest proportion of children responding most favorably to the addition of the long-acting b-agonist. The authors investigated predictors of favorable response to the various regimens, and found that an Asthma Control Test score greater than 19 predicted a favorable response to the addition of the longacting b-agonist. White race also predicted better responsiveness to the addition of the long-acting b-agonist, with black race being associated with a lower likelihood of a favorable response to leukotriene receptor antagonist and equivalent response to long-acting b-agonist or and inhaled steroid increase. The authors concluded that almost all participants demonstrated differential response to the three escalation strategies, with longacting b-agonist add-on therapy significantly more likely to provide the best response when compared with either increasing the dose of inhaled steroid or adding a leukotriene receptor antagonist. Nevertheless, approximately 25% of participants demonstrated a best response to either increasing the dose of inhaled steroid or adding a leukotriene receptor antagonist, suggesting that a substantial minority of patients may do as well or better with step-up therapies other than the addition of a long-acting b-agonist.

Is low dose inhaled corticosteroid therapy as effective for inflammation and remodeling in asthma? A randomized, parallel group study

BackgroundWhile most of the clinical benefits of inhaled corticosteroid (ICS) therapy may occur at low doses, results of dose-ranging studies are inconsistent. Although symptom/lung function response to low and high dose ICS medication is comparable, it is uncertain whether low dose ICSs are as effective as high dose in the treatment of inflammation and remodeling.Methods22 mild or moderate asthmatic adult subjects (corticosteroid free for > 2 months) participated in a randomized, parallel group study to compare effects of fluticasone propionate (FP) 200 mcg/day and 1000 mcg/day. Alveolar macrophage (AM)-derived cytokines and basement membrane thickness (BMT) were measured at baseline and after 7 weeks treatment while symptoms, spirometry, exhaled nitric oxide (eNO) and airway hyperresponsiveness (AHR) to mannitol at baseline and 6 weeks.ResultsFP improved spirometry, eNO, symptoms and AHR with no difference between low and high dose FP. Both high and low dose FP reduced GM-CSF, TNF-alpha and IL-1ra, with no change in BMT and with no differences between low and high dose FP.Conclusions200 μg/day of FP was as effective as 1000 μg/day in improving asthma control, airway inflammation, lung function and AHR in adults in the short term. Future studies should examine potential differential effects between low and high dose combination therapy (ICS/long acting beta agonist) on inflammation and airway remodeling over longer treatment periods.

Risk Factors for Montelukast Treatment Failure in Step-Down Therapy for Controlled Asthma

Background. Leukotriene receptor antagonists including montelukast are an option for step-down therapy for mild asthmatics controlled on low-dose inhaled corticosteroids (ICS). Because some patients fail montelukast step-down therapy, it would be helpful for clinicians to be able to predict the risk of treatment failure. Objectives. To determine patient characteristics associated with montelukast treatment failure and develop a clinical index to predict the risk of montelukast treatment failure. Methods. Using the 165 participants in the Leukotriene or Corticosteroid or Corticosteroid-Salmeterol Study (LOCCS) trial who were stepped down from low-dose ICS to montelukast, we determined associations between enrollment variables and treatment failure. We constructed a montelukast failure index to predict the risk of montelukast treatment failure during step-down. To assess its specificity for montelukast, index performance was evaluated in the other LOCCS treatment groups. Results. Characteristics independently associated with montelukast treatment failure included age of asthma onset <10 years old (OR = 2.39; 95% CI = 1.17–5.02; p = .018), need for steroid burst in the last year (OR = 2.39; 95% CI = 1.13–5.09; p = .022), and pre-bronchodilator forced expiratory volume in 1 s (FEV1) (OR = 1.44 per 10% lower % predicted; 95% CI = 1.07–1.97; p = .016). A montelukast failure index was generated from these three variables (range: −5 to 7 points). Scores <0 predicted low risk (<0.20) of treatment failure, whereas scores >5 predicted high risk (>0.60) of treatment failure. Conclusion. Early asthma onset, worse asthma control in the last year, and lower pre-bronchodilator FEV1 are associated with montelukast treatment failure. A montelukast failure index is proposed to quantify the risk of failure prior to treatment initiation.

Budesonide/formoterol maintenance and reliever therapy in primary care asthma management: effects on bronchial hyperresponsiveness and asthma control

The management of asthma has changed since the introduction of budesonide/formoterol (Symbicort®) as both maintenance and reliever therapy (SMART). SMART and its effects on bronchial hyperresponsiveness (BHR) have not been studied in primary care. To compare the effects of SMART and guideline-driven usual care (UC) on BHR and clinical asthma severity in primary care practice. Patients with mild-to-moderate stable asthma were randomised to receive SMART treatment (n=54) (budesonide/formoterol 80/4.5 μg Turbuhaler®, two puffs once daily and extra inhalations as needed) or UC treatment (n=48) for 12 months. Diary data, Asthma Control Questionnaire scores, forced expiratory volume in 1 second (FEV1), and peak expiratory flow (PEF) measurements were collected during run-in and after 1, 3, 6, and 12 months of treatment. BHR, measured as the dose of histamine provoking a fall in FEV1 of 20% (PD20-histamine), was determined at randomisation and after 12 months. One hundred and two patients with asthma participated in the study. The change in PD20-histamine during the study was not significantly different between the SMART and UC groups (p=0.26). The mean inhaled corticosteroid (ICS) dose was 326 μg beclomethasone dipropionate (BDP) equivalents/day (95% CI 254 to 399) with SMART, which was significantly lower (p<0.0001) than the mean ICS dose with UC treatment (798 μg BDP equivalents/day (95% CI 721 to 875). Morning and evening PEF values increased significantly with SMART treatment compared with UC; FEV1, symptoms and asthma control did not differ. Despite a 59% lower dose of ICS, BHR and other clinical outcomes remained stable during SMART treatment while PEF values improved.

Cost Effectiveness of Leukotriene Receptor Antagonists versus Long-Acting Beta-2 Agonists as Add-On Therapy to Inhaled Corticosteroids for Asthma

Information is lacking on the relative effectiveness and cost effectiveness--in a real-life primary-care setting--of leukotriene receptor antagonists (LTRAs) and long-acting beta2 adrenergic receptor agonists (beta2 agonists) as add-on therapy for patients whose asthma symptoms are not controlled on low-dose inhaled corticosteroids (ICS). To estimate the cost effectiveness of LTRAs compared with long-acting beta2 agonists as add-on therapy for patients whose asthma symptoms are not controlled on low-dose ICS. An economic evaluation was conducted alongside a 2-year, pragmatic, randomized controlled trial set in 53 primary-care practices in the UK. Patients aged 12-80 years with asthma insufficiently controlled with ICS (n = 361) were randomly assigned to add-on LTRAs (n = 176) or long-acting beta2 agonists (n = 185). The main outcome measures were the incremental cost per point improvement in the Mini Asthma Quality of Life Questionnaire (MiniAQLQ), per point improvement in the Asthma Control Questionnaire (ACQ) and per QALY gained from perspectives of the UK NHS and society. Over 2 years, the societal cost per patient receiving LTRAs was pounds sterling 1157 versus pounds sterling 952 for long-acting beta2 agonists, a (significant, adjusted) increase of pounds sterling 214 (95% CI 2, 411) [year 2005 values]. Patients receiving LTRAs experienced a non-significant incremental gain of 0.009 QALYs (95% CI -0.077, 0.103). The incremental cost per QALY gained from the societal (NHS) perspective was pounds sterling 22,589 (pounds sterling 11,919). Uncertainty around this point estimate suggested that, given a maximum willingness to pay of pounds sterling 30,000 per QALY gained, the probability that LTRAs are a cost-effective alternative to long-acting beta2 agonists as add-on therapy was approximately 52% from both societal and NHS perspectives. On balance, these results marginally favour the repositioning of LTRAs as a cost-effective alternative to long-acting beta2 agonists as add-on therapy to ICS for asthma. However, there is much uncertainty surrounding the incremental cost effectiveness because of similarity of clinical benefit and broad confidence intervals for differences in healthcare costs. UK National Research Register N0547145240; Controlled Clinical Trials ISRCTN99132811.

Changes in Airway Inflammation and Hyperresponsiveness after Inhaled Corticosteroid Cessation in Allergic Asthma

Background: Most patients with asthma are currently controlled by pharmacotherapeutic means such as inhaled corticosteroid (ICS). However, whether ICS actually induces remission of asthma remains unknown. The present study evaluates changes in airway inflammation and hyperresponsiveness in adult patients with asthma after stopping ICS. Methods: We enrolled 11 patients with allergic asthma (7 males and 4 females; mean age, 52.3 years) who had been asymptomatic and had no exacerbation by low-dose ICS. Airway hyperresponsiveness (AHR) was assessed using methacholine challenge, and induced sputum was evaluated before and every 3 months after ICS cessation during the 1-year follow-up. Results: Among the 11 asthmatics, AHR increased in 10 (90.9%) and asthma clinically relapsed in 4 (36.4%) within 1 year of ICS cessation. AHR increased in all 7 asthmatics that were sensitized to Dermatophagoides farinae and asthma clinically relapsed in 4 (57.1%) of them. Furthermore, eosinophil numbers and IL-4 concentrations in the sputum significantly increased after ICS cessation. Conclusions: Remission with normal airway response to methacholine (no AHR) might be rare in adult patients with allergic asthma, and sensitization to house dust mites appears to play an important role in relapse. Therefore, ICS cessation should be carefully considered in patients sensitive to house dust mites. Serial determination of eosinophil counts or IL-4 concentrations in sputum might be appropriate for monitoring and preventing asthma relapse in adults.