High Doses Of Inhaled Corticosteroids Research Articles

P29 Impact Of Respiratory Virtual Clinics In Primary Care On Responsible Respiratory Prescribing And Inhaled Corticosteroid Withdrawal In Patients With Copd: A Feasibility Study

Introduction There is considerable variation in accuracy of diagnosis and long-term management of COPD in the UK. High rates of inhaled corticosteroid (ICS) prescribing have been reported, raising concerns about their over use, with less focus on high value interventions like stop smoking support/pulmonary rehabilitation. ICS are indicated in severe COPD patients (FEV 1 2 per year). Primary care data from SE London showed that 38% of COPD patients were over treated with high dose ICS, resulting in 12 additional cases of pneumonia, and costs >£500,000, annually. There is limited guidance on methods and feasibility of withdrawing ICS in these patients. Methods A responsible respiratory prescribing group including CCG medicines management, respiratory pharmacist and integrated respiratory team agreed COPD prescribing guidance across primary/ secondary care. GPs were supported with COPD review templates, written step down protocols and educational events. Virtual clinics with an integrated respiratory consultant/GP respiratory lead were offered to support ICS withdrawal in primary care. Results 45/48 (94%) of CCG practices took part. Data from 372 patients on COPD registers reviewed over 25 virtual clinics is presented. 321 (86%) patients had confirmed COPD (including 33 with COPD and asthma), 34 had asthma, 15 needed more spirometry and 2 had another diagnosis. 279/321 (87%) patients had a recommendation made: 64 (23%) referred for PR, 53 (19%) for spirometry, and 45 (16%) for smoking cessation. Changes to drug therapies were also recommended: 42 (15%) patients had a LAMA recommended, 16 (5%) a LABA, and while 117/321 COPD patients (37%) required no change to ICS therapy, a graduated step down/stop was suggested for 198 (63%). The outcomes associated with this are in Table 1. Overall, from Q4 13/14 prescribing data, there was a 4% decrease in high dose ICS (as proportion of total ICS use) resulting in a saving of £50,000. Conclusion Integrated working through respiratory virtual clinics offers hugescope to improve high value care for COPD patients. Overuse of ICS in COPD is common and GP-led withdrawal of high dose ICS where appropriate is feasible, acceptable and well tolerated by patients.

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.

P252 Gold Category And Optimal Management : A Canadian Perspective

Hypothesis Current Canadian guidelines and GOLD strategy for COPD management provide a treatment algorithm based on current symptoms and exacerbation history. We wished to assess COPD patient current objective, subjective symptoms, quality of life and exacerbation history of a random sample in primary care and office based chest medicine clinics. A convenience sample of 500 was selected. Results We report the characteristics of the first 250 COPD patients from our ongoing 500 patient survey. Basic demographics 55% Male, 45% Female. Mean age patients 68 ± 12 yrs, all patients were previous smokers with 56 ± 10 pkt/yrs smoking history. 34% remain current smokers. Mean FEV1 48% ± 10%, Mean FEV1/FVC ratio 49% ± 10. Median mMRC dyspnea score 2. Mean CAT score 18 ± 10 (Range 0–38). GOLD Stage Classification 13% GOLD Stage A, 67% GOLD Stage B, 1% GOLD Stage C and 19% GOLD Stage D. Current treatment LAMA (long-acting muscarinic antagonist) was prescribed to over 90% of all patients in groups B, C and D whereas monotherapy with LABA (long acting beta-agonist) or dual bronchodilation with LABA/LAMA therapy was prescribed to less than 5%. There was significant overtreatment with ICS/LABA in all categories with high dose ICS (inhaled corticosteroid) being preferred. 20% of patients in GOLD Stage A where receiving Triple therapy (LAMA + ICS/LABA) and a further 20% where receiving monotherapy with ICS/LABA, yet had no history of exacerbations. 30% of patients in GOLD Stage B where receiving Triple therapy (LAMA + ICS/LABA) yet had no history of exacerbations. Conclusion Current Canadian Guidelines and the GOLD strategy focus on symptom relief and striving to prevent exacerbations with step-wise prescription of short and long-acting bronchodilators with individual or combinations of LAMA, LABA, LAMA/LABA or ICS/LABA inhalers. Patients in GOLD Group C are rare. Current prescription choices in our survey does not reflect current evidence or guidelines. We report a heavy reliance on ICS/LABA along with over prescription of triple therapy at all stages of disease.

P229 Once-daily Tiotropium Respimat(R) As Add-on To At Least Medium- To High-dose Ics, With Or Without Laba, Improves Lung Function In Patients With Symptomatic Asthma, Independent Of Allergic Status

Background A substantial number of patients have symptomatic asthma despite treatment according to guidelines. Several studies have confirmed that tiotropium Respimat ® , a once-daily long-acting anticholinergic bronchodilator, improves lung function in symptomatic patients receiving at least medium-dose inhaled corticosteroids (ICS) + long-acting β 2 -agonist (LABA) (Kerstjens et al . NEJM 2012;367:1198–207; Bateman et al . JACI 2011;128:315–22). Here we examine whether the atopic and/or allergic status of patients in these trials influenced their response to tiotropium Respimat ® . Method Two 48-week trials of tiotropium Respimat ® 5 µg (PrimoTinA-asthma ® : NCT00776984, NCT00772538) in patients (n = 912) on high-dose ICS + LABA; two 24-week trials of tiotropium Respimat ® 5 µg and 2.5 µg (MezzoTinA-asthma ® : NCT01172808, NCT01172821) in patients (n = 2100) on moderate-dose ICS. Pre-planned analyses (pooled populations) were performed in two subgroups defined at baseline as total serum immunoglobulin E (IgE) ≤ or >430 μg/L or blood eosinophils ≤ or >0.6×10 9 /L or clinical judgement of allergic status (‘No’ or ‘Yes’). All tiotropium doses were delivered via the Respimat ® SoftMist™ inhaler. Results Tiotropium Respimat ® 5 µg or 2.5 µg improved peak and trough forced expiratory volume in 1 second versus placebo (Table) independent of IgE, eosinophil count and clinical judgement. Conclusion Once-daily tiotropium Respimat ® as add-on to ICS or ICS + LABA in patients with moderate to severe symptomatic asthma reduces airflow obstruction, apparently independent of their atopic and/or allergic status.

P230 Once-daily Tiotropium Respimat(R) Improves Lung Function In Patients With Severe Symptomatic Asthma Independent Of Leukotriene Modifier Use

Background Once-daily tiotropium Respimat®, a long-acting anticholinergic bronchodilator, has been shown in a Phase III programme to improve lung function and reduce severe exacerbation risk in patients with severe asthma who remain symptomatic despite using inhaled corticosteroids (ICS) + long-acting β2-agonist (LABA). Use of pre-trial leukotriene receptor antagonists (LTRAs) was not restricted; we analysed whether pre-screening LTRA use affected tiotropium Respimat® efficacy. Methods In two Phase III, replicate, randomised, double-blind, placebo-controlled, parallel-group trials (PrimoTinA-asthma®: [NCT00772538][1], [NCT00776984][2]), symptomatic patients received high-dose ICS + LABA and once-daily tiotropium 5 µg or placebo (both delivered via the Respimat® SoftMist™ inhaler). LTRAs were permitted during run-in and treatment. Co-primary end points were peak and trough forced expiratory volume in 1 second (FEV1) responses (difference from baseline) at 24 weeks. Subgroups were defined by pre-screening LTRA use: ‘Yes’/‘No’. Results Of 912 randomised patients, 205 reported pre-screening LTRA use, 200 reported LTRA use during the treatment period and 187 had efficacy data at Week 24. Baseline characteristics were comparable between groups. Mean body mass index in LTRA ‘Yes’/‘No’ groups was 27.8 kg/m2 and 28.3 kg/m2, respectively. Mean% predicted FEV1 at baseline was 56% in both groups. Lung function responses improved independent of LTRA use: peak FEV1 was 99 ± 50 mL (p = 0.049) in the LTRA ‘Yes’ group and 113 ± 28 mL (p < 0.001) in the LTRA ‘No’ group (peak FEV1 improvements independent of concomitant LTRA use [interaction p value=0.6742]). Trough FEV1 (difference from placebo) was 90 ± 46 mL (p = 0.052) in the LTRA ‘Yes’ group and 93 ± 25 mL (p < 0.001) in the LTRA ‘No’ group (trough FEV1 improvements independent of concomitant LTRA use [interaction p value = 0.5218]). Conclusion Once-daily tiotropium Respimat® added to ICS + LABA improves lung function in patients with severe symptomatic asthma, independent of initial LTRA use. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00772538&atom=%2Fthoraxjnl%2F69%2FSuppl_2%2FA178.1.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00776984&atom=%2Fthoraxjnl%2F69%2FSuppl_2%2FA178.1.atom

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).

Principal findings of systematic reviews for chronic treatment in childhood asthma

Objective: To summarize the principal findings pertaining to most effective long-term pharmacologic treatment of childhood asthma. Methods: Systematic reviews of randomized clinical trials (SRCTs) on pharmacologic chronic treatment in children (1–18 years) with persistent asthma were retrieved through MEDLINE, EMBASE, CINAHL, SCOPUS, and CDSR (up to January2014). Results: One hundred eighty-three SRCTs were searched from databases. Among those, 39 SRCTs were included: two were related to step 1, 24 to step 2, nine to steps 3 and 4, and four to step 5 (according with NAEPP and GINA guidelines). The methodological quality of these SRCTs was determined by using the AMSTAR tool. Results: For step 1: addition of ipatropium bromide to short-acting beta2-agonists does not show any benefit. For step 2: in preschoolers, inhaled corticosteroids (ICSs) reduce severe exacerbations and improve other clinical and lung function parameters. In children, ICSs are superior to leukotriene receptor antagonist (LTRA), cromones, or xantines in reducing severe exacerbations, improving lung function and other clinical outcomes. Fluticasone propionate (FP) is better than beclomethasone dipropionate (BDP) or budesonide only for lung function; but similar to hydrofluoroalkane-BDP or to ciclosenide. Compared to low ICSs doses, moderate doses result in only better lung function, but this is not true for FP. For steps 3 and 4: adding LTRA to ICS confers a small benefit; adding LABA improves lung function but does not reduce exacerbations more than double or higher ICS doses. For step 5: adding omalizumab decreases exacerbations. Conclusions: SRCTs are useful for guiding decisions in chronic childhood asthma treatment.

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 (ICS) and risk of mycobacterium in patients with chronic respiratory diseases: a meta-analysis.

Studies have indicated that therapy with inhaled corticosteroids (ICS) can be associated with a higher risk of pneumonia. However, it is not known whether ICS increases the risk of mycobacterium. Most of these published studies were small, and the conclusions were inconsistent. A meta-analysis was conducted into whether ICS increases the risk of mycobacterium in patients with chronic respiratory diseases. PubMed, OVID, EMBASE and Cochrane Library databases were searched. Five studies involving 4,851 cases and 28,477 controls were considered in the meta-analysis. From the pooled analyses, there was significant association between ICS and risk of mycobacterium in all patients with chronic respiratory diseases [risk ratio (RR) =1.81; 95% confidence interval (CI), 1.23-2.68; P=0.003]. Among patients with chronic respiratory diseases, the relationship between ICS and risk of tuberculosis (TB) was also significant (RR =1.34; 95% CI, 1.15-1.55; P=0.0001). And meta-analysis of four studies in patients with chronic obstructive pulmonary disease (COPD) (RR =1.42; 95% CI, 1.18-1.72; P=0.0003) or two studies in patients who have prior pulmonary TB (RR =1.61; 95% CI, 1.35-1.92; P<0.00001) or three studies in patients with high-dose ICS (RR =1.60; 95% CI, 1.28-1.99; P<0.0001) showed a relationship between ICS and risk of mycobacterium. Significant relationship has been shown between ICS use and risk of mycobacterium in all patients with chronic respiratory diseases. ICS use also increases the risk of TB among the patients with chronic respiratory diseases. Use of ICS increases the risk of mycobacterium in patients with COPD or patients with prior pulmonary TB or patients inhaling high-dose corticosteroids. Further research is required to establish the potential adverse effect of ICS as a therapy for chronic respiratory diseases.

Combination inhaled corticosteroids and long-acting beta2-agonists for children and adults with bronchiectasis.

Bronchiectasis is a major contributor to chronic respiratory morbidity and mortality worldwide. Wheeze and other asthma-like symptoms and bronchial hyperreactivity may occur in people with bronchiectasis. Physicians often use asthma treatments in patients with bronchiectasis. To assess the effects of inhaled long-acting beta2-agonists (LABA) combined with inhaled corticosteroids (ICS) in children and adults with bronchiectasis during (1) acute exacerbations and (2) stable state. The Cochrane Airways Group searched the the Cochrane Airways Group Specialised Register of Trials, which includes records identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and other databases. The Cochrane Airways Group performed the latest searches in October 2013. All randomised controlled trials (RCTs) of combined ICS and LABA compared with a control (placebo, no treatment, ICS as monotherapy) in children and adults with bronchiectasis not related to cystic fibrosis (CF). Two review authors extracted data independently using standard methodological procedures as expected by The Cochrane Collaboration. We found no RCTs comparing ICS and LABA combination with either placebo or usual care. We included one RCT that compared combined ICS and LABA with high-dose ICS in 40 adults with non-CF bronchiectasis without co-existent asthma. All participants received three months of high-dose budesonide dipropionate treatment (1600 micrograms). After three months, participants were randomly assigned to receive either high-dose budesonide dipropionate (1600 micrograms per day) or a combination of budesonide with formoterol (640 micrograms of budesonide and 18 micrograms of formoterol) for three months. The study was not blinded. We assessed it to be an RCT with overall high risk of bias. Data analysed in this review showed that those who received combined ICS-LABA (in stable state) had a significantly better transition dyspnoea index (mean difference (MD) 1.29, 95% confidence interval (CI) 0.40 to 2.18) and cough-free days (MD 12.30, 95% CI 2.38 to 22.2) compared with those receiving ICS after three months of treatment. No significant difference was noted between groups in quality of life (MD -4.57, 95% CI -12.38 to 3.24), number of hospitalisations (odds ratio (OR) 0.26, 95% CI 0.02 to 2.79) or lung function (forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)). Investigators reported 37 adverse events in the ICS group versus 12 events in the ICS-LABA group but did not mention the number of individuals experiencing adverse events. Hence differences between groups were not included in the analyses. We assessed the overall evidence to be low quality. In adults with bronchiectasis without co-existent asthma, during stable state, a small single trial with a high risk of bias suggests that combined ICS-LABA may improve dyspnoea and increase cough-free days in comparison with high-dose ICS. No data are provided for or against, the use of combined ICS-LABA in adults with bronchiectasis during an acute exacerbation, or in children with bronchiectasis in a stable or acute state. The absence of high quality evidence means that decisions to use or discontinue combined ICS-LABA in people with bronchiectasis may need to take account of the presence or absence of co-existing airway hyper-responsiveness and consideration of adverse events associated with combined ICS-LABA.

Chronic obstructive pulmonary disease treated with inhaled medium- or high-dose corticosteroids: a prospective and randomized study focusing on clinical efficacy and the risk of pneumonia.

PurposeComplications of pneumonia development in patients with chronic obstructive pulmonary disease (COPD) receiving inhaled corticosteroid (ICS) therapy have been documented. The aim of this study was to focus on clinical efficacy and the incidence of pneumonia between COPD patients receiving medium and high doses of ICS.Patients and methodsThis prospective, randomized study included COPD patients identified from three tertiary medical centers from 2010 to 2012. The patients were randomized into two groups: high dose (HD; fluticasone 1,000 μg + salmeterol 100 μg/day) and medium dose (MD; fluticasone 500 μg + salmeterol 100 μg/day). Lung function with forced expiratory volume in 1 second (FEV1), forced vital capacity, and COPD-assessment test (CAT) were checked every 2 months. The frequency of acute exacerbations and number of pneumonia events were measured. The duration of the study period was 1 year.ResultsIn total, 237 COPD patients were randomized into the two treatment arms (115 in the HD group, 122 in the MD group). The FEV1 level was significantly improved in the patients in the HD group compared with those in the MD group (HD 103.9±26.6 mL versus MD 51.4±19.7 mL, P<0.01) at the end of the study. CAT scores were markedly improved in patients using an HD compared to those using an MD (HD 13±5 versus MD 16±7, P=0.05). There was a significant difference in the percentage of annual rates in acute exacerbations (HD 0.16 versus MD 0.34, P<0.01) between the two groups. The incidence of pneumonia was similar in the two groups (HD 0.08 versus MD 0.10, P=0.38).ConclusionCOPD patients treated with high doses of ICS had more treatment benefits and no significant increases in the incidence in pneumonia. Higher-dose ICS treatment may be suitable for COPD therapy.

Comparative efficacy of inhaled corticosteroid and long-acting beta agonist combinations in preventing COPD exacerbations: a Bayesian network meta-analysis.

BackgroundA combination therapy with inhaled corticosteroid (ICS) and a long-acting beta agonist (LABA) is recommended in severe chronic obstructive pulmonary disease (COPD) patients experiencing frequent exacerbations. Currently, there are five ICS/LABA combination products available on the market. The purpose of this study was to systematically review the efficacy of various ICS/LABA combinations with a network meta-analysis.MethodsSeveral databases and manufacturer’s websites were searched for relevant clinical trials. Randomized control trials, at least 12 weeks duration, comparing an ICS/LABA combination with active control or placebo were included. Moderate and severe exacerbations were chosen as the outcome assessment criteria. The primary analyses were conducted with a Bayesian Markov chain Monte Carlo method.ResultsMost of the ICS/LABA combinations reduced moderate-to-severe exacerbations as compared with placebo and LABA, but none of them reduced severe exacerbations. However, many studies excluded patients receiving long-term oxygen therapy. Moderate-dose ICS was as effective as high-dose ICS in reducing exacerbations when combined with LABA.ConclusionICS/LABA combinations had a class effect with regard to the prevention of COPD exacerbations. Moderate-dose ICS/LABA combination therapy would be sufficient for COPD patients when indicated. The efficacy of ICS/LABA combination therapy appeared modest and had no impact in reducing severe exacerbations. Further studies are needed to evaluate the efficacy of ICS/LABA combination therapy in severely affected COPD patients requiring long-term oxygen therapy.

G94 Characteristics of children with asthma when treatment is stepped up – a real-life observation study of 17256 episodes

BackgroundThe aim of this study was to determine whether patient characteristics were influencing clinicians’ decision making for “step 3” treatment options.MethodsData between 1990–2011 were collected from the Clinical Practice Research...

Meta-Review: Adverse Effects of Inhaled Corticosteroids Relevant to Older Patients

In recent years, clinical trials and observational studies have raised concerns about the potential adverse effects of inhaled corticosteroids (ICS) such as pneumonia, cataract, fractures and hyperglycaemia, which are of particular concern for older patients. We conducted a meta-review by searching electronic databases (MEDLINE, EMBASE, PubMed) for systematic reviews and meta-analyses of ICS use and the adverse effects of interest. We also evaluated new primary studies that reported information beyond that available from previously published meta-analyses. Two reviewers independently extracted data on measures of associated harm with ICS use. We identified five relevant meta-analyses for inclusion in this meta-review, and also three new studies of ICS and pneumonia. We found consistent evidence of a dose-response relationship between ICS use and serious adverse effects such as fractures and pneumonia. The estimated number needed to treat for harm due to fracture with ICS was 83 with 3-years use, and 60 per year for pneumonia. Both asthma and chronic obstructive pulmonary disease (COPD) users of ICS were at risk of pneumonia, with fluticasone appearing to confer higher risk than budesonide. There is also some suggestion that ICS use is associated with cataracts in a dose-response manner but the evidence is less robust here. Equally, the influence of ICS on diabetes mellitus remains uncertain. In view of the dose-response relationship seen between ICS use and important adverse effects such as fractures and pneumonia, clinicians needs to carefully balance the benefits of ICS versus the harms in older patients receiving long-term high-dose ICS.

Pediatric Asthma – do we need more innovation for treatment?

Pediatric Asthma – do we need more innovation for treatment?

Changes to inhaled corticosteroid dose when initiating combination inhaler therapy in long-acting β agonist-naïve patients with asthma: a retrospective database analysis

Retrospective prescribing data were obtained from 46 general practice surgeries in NHS Scotland. Patients with asthma who were naïve to previous long-acting β agonist therapy and initiated combination inhaler therapy...

P162 Effect of adding propranolol or increased inhaled corticosteroid dose in persistent asthma

Introduction and ObjectivesChronic propranolol does not improve airway hyper-responsiveness (AHR) in persistent asthmatics taking medium dose inhaled corticosteroid (ICS), 440µg/day1. We wished to assess for any putative corticosteroid-sparing effect of...

Effects of nebulized high‐dose budesonide on moderate‐to‐severe acute exacerbation of asthma in children: A randomized, double‐blind, placebo‐controlled study

The efficacy of inhaled corticosteroids (ICS) in asthma exacerbation are yet to be clarified. The aim of this study was to investigate the efficacy of nebulized ICS in children with moderate-to-severe acute exacerbation of asthma in an emergency room setting in order to elucidate the potential use of ICS as the first-line therapy in the management of acute exacerbation of asthma. This was a prospective, randomized, double-blind, placebo-controlled study. Paediatric patients with moderate-to-severe acute exacerbation of asthma in emergency room were randomized to receive nebulized salbutamol and ipratropium bromide, with the addition of nebulized high-dose budesonide (BUD group, n = 60) or normal saline (control group, n = 58), three doses in the first hour. The improvement in forced expiratory volume in 1 s was similar in both groups at 0 h after three doses of nebulization, but there was significantly further improvement at 1 and 2 h in the BUD group (0.095 ± 0.062 L and 0.100 ± 0.120 L, respectively) compared with the control group (0.059 ± 0.082 L and 0.021 ± 0.128 L, respectively), P = 0.013 and 0.001, respectively. Complete remission rate was significantly higher (84.7% vs 46.3%, P = 0.004) and need for oral corticosteroids was significantly lower (16.9% vs 46.3%, P = 0.011) in BUD group than in control group. On the basis of nebulized short-acting bronchodilators, addition of nebulized high-dose budesonide resulted in clinical improvement in children with moderate-to-severe acute exacerbation of asthma, suggesting that nebulized high-dose ICS can be used as first-line therapy for non-life-threatening acute exacerbation of asthma in children.