Medium-dose Inhaled Corticosteroids Research Articles

For people with uncontrolled asthma, how does adding long-acting beta2 agonists (LABA) or long-acting muscarinic antagonists (LAMA) to different doses of inhaled corticosteroids (ICS) or doubling the dose of ICS compare with medium-dose ICS?

For people with uncontrolled asthma, how does adding long-acting beta2 agonists (LABA) or long-acting muscarinic antagonists (LAMA) to different doses of inhaled corticosteroids (ICS) or doubling the dose of ICS compare with medium-dose ICS?

Dupilumab Efficacy in Children With Type 2 Asthma Receiving High- to Medium-Dose Inhaled Corticosteroid (VOYAGE)

In phase 3 VOYAGE (NCT02948959), dupilumab showed clinical efficacy with an acceptable safety profile in children (6-11 years) with uncontrolled, moderate-to-severe type 2 asthma (blood eosinophils ≥150 cells/μL or fractional exhaled nitric oxide ≥20 ppb). We analyzed dupilumab's efficacy in children with type 2 asthma by high- or medium-dose inhaled corticosteroids (ICS) at baseline. Children were randomized to receive add-on dupilumab 100/200 mg (by body-weight ≤30 kg/>30 kg) every 2 weeks or placebo for 52 weeks and stratified by high- or medium-dose ICS at baseline. Endpoints were annualized severe exacerbation rate, changes from baseline in percent-predicted forced expiratory volume in 1 second (ppFEV1) and 7-item Asthma Control Questionnaire - Interviewer Administered (ACQ-7-IA) score, proportions of ACQ-7-IA responders (improvement ≥0.5), and biomarker changes. In children receiving high- (n = 152) or medium- (n = 195) dose ICS at baseline, dupilumab versus placebo reduced severe exacerbation rates by 63% (P < .001) and 59% (P = .003), respectively. At week 52, dupilumab improved ppFEV1 by least squares mean difference versus placebo of 5.7 percentage points (P = .02) and 9.35 points (P < .001), and reduced ACQ-7-IA scores by 0.53 points (P < .001) and 0.40 points (P < .001), respectively. No significant treatment interactions between ICS subgroups were detected at week 52. Significant improvements were observed in ACQ-7-IA responder rates and most type 2 biomarker levels. Dupilumab reduced severe exacerbation rates and improved lung function and asthma control in children with uncontrolled, moderate-to-severe type 2 asthma, regardless of ICS dose at baseline.

Urban-rural and socio-economic differences in inhaled corticosteroid treatment for chronic obstructive pulmonary disease: A nationwide register-based cross-sectional study

BackgroundUrban-rural disparities within chronic obstructive pulmonary disease (COPD) have been documented in USA, but not in Europe. Inhaled corticosteroids (ICS) are widely used in COPD despite strict recommendations. We aimed to investigate urban-rural and socioeconomic differences in ICS treatment for COPD. MethodsA Danish nationwide register-based cross-sectional study. All patients alive on the December 31, 2018 with a J44 ICD-10 diagnosis code (COPD) were included (99,057 patients). Daily average ICS dose was calculated from the accumulated ICS use during 2018 based on redeemed prescriptions. Patients were divided into groups: No ICS, low dose ICS, medium dose ICS, high dose ICS. A multinomial logistic regression model including educational level, co-habitation status, age, and sex was performed with “No ICS” as reference group. ResultsCompared to capital municipalities, living in other municipality types was associated with an increased probability of receiving medium and high dose ICS treatment, and increasing odds ratios (ORs) were seen with increasing ICS dose (medium dose ICS: ORs between 1.31 (95 % confidence interval (CI) 1.24–1.38) and 1.35 (95%CI 1.28–1.41), high dose ICS: ORs between 1.73 (95%CI 1.59–1.88) and 1.80 (95%CI 1.68–1.92)). Patients had increased probability of receiving ICS treatment if they were female, were co-habiting, or had completed only primary education. ConclusionPatients with a hospital-registered COPD diagnosis in non-capital municipalities receive more ICS, and in higher doses, compared to patients in capital municipalities. This is the first study to confirm that such urban-rural differences exist in Europe, and further research on this area is warranted.

National Development in the Use of Inhaled Corticosteroid Treatment in Chronic Obstructive Pulmonary Disease: Repeated Cross-Sectional Studies from 1998 to 2018.

Recommendations for the treatment of chronic obstructive pulmonary disease (COPD) have shifted towards a more restrictive use of inhaled corticosteroids (ICS). We aimed to identify the nationwide development over time in the use of ICS treatment in COPD. We conducted a register-based repeated cross-sectional study using Danish nationwide registers. On a yearly basis from 1998 to 2018, we included all patients in Denmark ≥ 40 years of age with an ICD-10 diagnosis of COPD (J44). Accumulated ICS use was calculated for each year based on redeemed prescriptions. Patients were divided into the following groups: No ICS, low-dose ICS, medium-dose ICS, or high-dose ICS. From 1998 to 2018, the yearly proportion of patients without ICS treatment increased (from 50.6% to 57.6%), the proportion of patients on low-dose ICS treatment increased (from 11.3% to 14.9%), and the proportion of patients on high-dose ICS treatment decreased (from 17.0% to 9.4%). We demonstrated a national reduction in the use of ICS treatment in COPD from 1998 to 2018, with an increase in the proportion of patients without ICS and on low-dose ICS treatment and a decrease in the proportion of patients on high-dose ICS treatment.

Addition of long-acting beta2 agonists or long-acting muscarinic antagonists versus doubling the dose of inhaled corticosteroids (ICS) in adolescents and adults with uncontrolled asthma with medium dose ICS: a systematic review and network meta-analysis.

Inhaled corticosteroids (ICS) are the mainstay treatment for persistent asthma. Escalating treatment is required when asthma is not controlled with ICS therapy alone, which would include, but is not limited to, adding a long-acting beta2-agonist (LABA) or a long-acting muscarinic antagonist (LAMA) or doubling the dose of ICS. To assess the efficacy and safety of adding a LABA or LAMA to ICS therapy versus doubling the dose of ICS in adolescents and adults whose asthma is not well controlled on medium-dose (MD)-ICS using a network meta-analysis (NMA), and to provide a ranking of these treatments according to their efficacy and safety. We searched the Cochrane Airways Trials Register, CENTRAL, MEDLINE, Embase, Global Health, ClinicalTrials.gov, and the World Health Organization ICTRP for pre-registered randomised controlled trials (RCTs) from January 2008 to 19 December 2022. We searched for studies including adolescents and adults with uncontrolled asthma who had been treated with or were eligible for MD-ICS, comparing it to high-dose (HD)-ICS, ICS/LAMA, or ICS/LABA. We excluded cluster- and cross-over RCTs. Studies were of at least 12 weeks duration. We conducted a systematic review and network meta-analysis according to a previously published protocol. We used Cochrane's Screen4ME workflow to assess search results. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence. The primary outcome is asthma exacerbations (moderate and severe). We included 38,276 participants from 35 studies (median duration 24 weeks (range 12 to 78); mean age 44.1; 38% male; 69% white; mean forced expiratory volume in one second 2.1 litres and 68% of predicted). MD- and HD-ICS/LABA likely reduce and MD-ICS/LAMA possibly reduces moderate to severe asthma exacerbations compared to MD-ICS (hazard ratio (HR) 0.70, 95% credible interval (CrI) 0.59 to 0.82; moderate certainty; HR 0.59, 95% CrI 0.46 to 0.76; moderate certainty; and HR 0.56, 95% CrI 0.38 to 0.82; low certainty, respectively), whereas HD-ICS probably does not (HR 0.94, 95% CrI 0.70 to 1.24; moderate certainty). There is no clear evidence to suggest that any combination therapy or HD-ICS reduces severe asthma exacerbations compared to MD-ICS (low to moderate certainty). This study suggests no clinically meaningful differences in the symptom or quality of life score between dual combinations and monotherapy (low to high certainty). MD- and HD-ICS/LABA increase or likely increase the odds of Asthma Control Questionnaire (ACQ) responders at 6 and 12 months compared to MD-ICS (odds ratio (OR) 1.47, 95% CrI 1.23 to 1.76; high certainty; and OR 1.59, 95% CrI 1.31 to 1.94; high certainty at 6 months; and OR 1.61, 95% CrI 1.22 to 2.13; moderate certainty and OR 1.55, 95% CrI 1.20 to 2.00; high certainty at 12 months, respectively). MD-ICS/LAMA probably increases the odds of ACQ responders at 6 months (OR 1.32, 95% CrI 1.11 to 1.57; moderate certainty). No data were available at 12 months. There is no clear evidence to suggest that HD-ICS increases the odds of ACQ responders or improves the symptom or qualify of life score compared to MD-ICS (very low to high certainty). There is no evidence to suggest that ICS/LABA or ICS/LAMA reduces asthma-related or all-cause serious adverse events (SAEs) compared to MD-ICS (very low to high certainty). HD-ICS results in or likely results in little or no difference in the included safety outcomes compared to MD-ICS as well as HD-ICS/LABA compared to MD-ICS/LABA. The pairwise meta-analysis shows that MD-ICS/LAMA likely reduces all-cause adverse events (AEs) and results in a slight reduction in treatment discontinuation due to AEs compared to MD-ICS (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.77 to 0.96; 4 studies, 2238 participants; moderate certainty; and RR 0.51, 95% CI 0.26 to 0.99; 4 studies, 2239 participants; absolute risk reduction 10 fewer per 1000 participants; moderate certainty, respectively). The NMA evidence is in agreement with the pairwise evidence on treatment discontinuation due to AEs, but very uncertain on all-cause AEs, due to imprecision and heterogeneity. The review findings suggest that MD- or HD-ICS/LABA and MD-ICS/LAMA reduce moderate to severe asthma exacerbations and increase the odds of ACQ responders compared to MD-ICS whereas HD-ICS probably does not. The evidence is generally stronger for MD- and HD-ICS/LABA than for MD-ICS/LAMA primarily due to a larger evidence base. There is no evidence to suggest that ICS/LABA, ICS/LAMA, or HD-ICS/LABA reduces severe asthma exacerbations or SAEs compared to MD-ICS. MD-ICS/LAMA likely reduces all-cause AEs and results in a slight reduction in treatment discontinuation due to AEs compared to MD-ICS. The above findings may assist in deciding on a treatment option during the stepwise approach of asthma management. Longer-term safety of higher than medium-dose ICS needs to be addressed in phase 4 or observational studies given that the median duration of included studies was six months.

Dupilumab sustains efficacy in patients with moderate-to-severe type 2 asthma regardless of ICS dose.

Dupilumab, a human monoclonal antibody, blocks the shared receptor component for interleukins-4/13, key and central drivers of type 2 inflammation. The TRAVERSE (NCT02134028) open-label extension study demonstrated the long-term safety and efficacy of dupilumab in patients ≥12 years who completed a previous dupilumab asthma study. The safety profile was consistent with that observed in the parent studies. Here, we assess whether dupilumab sustains long-term efficacy in patients regardless of inhaled corticosteroid (ICS) dose at parent study baseline (PSBL). Patients from phase 2b (NCT01854047) or phase 3 (QUEST; NCT02414854) studies receiving high- or medium-dose ICS at PSBL and enrolled in TRAVERSE were included. We analyzed unadjusted annualized severe exacerbation rates, change from PSBL in pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1 ), 5-item asthma control questionnaire, and type 2 biomarkers in patients with type 2 asthma at baseline (blood eosinophils ≥150 cells/μL or fractional exhaled nitric oxide [FeNO] ≥25 ppb), and subgroups defined by baseline blood eosinophils or FeNO. Of patients with type 2 asthma (n = 1666), 891 (53.5%) were receiving high-dose ICS at PSBL. In this subgroup, unadjusted exacerbation rates for dupilumab versus placebo were 0.517 versus 1.883 (phase 2b) and 0.571 versus 1.300 (QUEST) over the parent study (52 weeks) and remained low throughout TRAVERSE (0.313-0.494). Improvements in pre-BD FEV1 were sustained throughout TRAVERSE. Similar clinical efficacy was observed among patients receiving medium-dose ICS at PSBL and biomarker subgroups. Dupilumab showed sustained efficacy for up to 3 years in patients with uncontrolled, moderate-to-severe type 2 asthma on high- or medium-dose ICS.

Association of Inhaled Corticosteroids With All-Cause Mortality Risk in Patients With COPD: A Meta-analysis of 60 Randomized Controlled Trials

Inhaled corticosteroids (ICSs) have been used widely in the maintenance therapy of COPD. However, whether inhaled therapy containing ICSs can reduce the all-cause mortality risk and the possible benefited patient subgroups is unclear. Does inhaled therapy containing ICSs reduce the all-cause mortality risk in patients with COPD compared with other inhaled therapies not containing ICSs? We searched PubMed, Cochrane Library, Embase, and ClinicalTrials.gov for relevant randomized clinical trials (RCTs). Pooled results were calculated using Peto ORs with corresponding 95%CIs. Sixty RCTs enrolling 103,034 patients were analyzed. Inhaled therapy containing ICSs (Peto OR, 0.90; 95%CI, 0.84-0.97), especially triple therapy (Peto OR, 0.73; 95%CI, 0.59-0.91), was associated with a reduction in the all-cause mortality risk among patients with COPD when compared with inhaled therapy without ICSs. Subgroup analyses revealed that treatment duration of > 6months (Peto OR, 0.90; 95%CI, 0.83-0.97), medium-dose ICSs (Peto OR, 0.71; 95%CI, 0.56-0.91), low-dose ICSs (Peto OR, 0.88; 95%CI, 0.79-0.97), and budesonide (Peto OR, 0.75; 95%CI, 0.59-0.94) were involved in this association. The predictors of this association included eosinophil counts of≥ 200/μL or percentage of≥ 2%, documented history of≥ 2 moderate and severe exacerbations in the previous year, Global Initiative for Chronic Obstructive Lung Disease stages III or IV, age younger than 65 years, and BMI of≥ 25kg/m2, among which eosinophil counts of≥ 200/μL (Peto OR, 0.58; 95%CI, 0.36-0.95) were the strongest predictor. Inhaled therapy containing ICSs, especially triple therapy, of longer than 6months was associated with a reduction in the all-cause mortality risk in patients with COPD. The predictors of this association included medication factors and patient characteristics, among which eosinophil counts of≥ 200/μL were the strongest predictor. PROSPERO; No.: CRD42022304725; URL: https://www.crd.york.ac.uk/prospero/.

A Single Inhaler Combining a Corticosteroid and Long-Acting Beta-2 Agonist for Maintenance with Additional Doses for Reliever Therapy (SMART): Obstacles for Asthma Patients in the USA.

A Single Inhaler Combining a Corticosteroid and Long-Acting Beta-2 Agonist for Maintenance with Additional Doses for Reliever Therapy (SMART): Obstacles for Asthma Patients in the USA.

Addition of long-acting beta2 agonists or long-acting muscarinic antagonists versus doubling the dose of inhaled corticosteroids (ICS) in adolescents and adults with uncontrolled asthma with medium dose ICS: a systematic review and network meta-analysis

Addition of long-acting beta2 agonists or long-acting muscarinic antagonists versus doubling the dose of inhaled corticosteroids (ICS) in adolescents and adults with uncontrolled asthma with medium dose ICS: a systematic review and network meta-analysis

THE EFFECT OF TEZEPELUMAB ON EXACERBATIONS IN PATIENTS WITH SEVERE, UNCONTROLLED ASTHMA ACCORDING TO BASELINE INHALED CORTICOSTEROID DOSE: RESULTS FROM THE PHASE 2B PATHWAY STUDY

SESSION TITLE: Updates in the Management of Severe Asthma SESSION TYPE: Original Investigations PRESENTED ON: October 18-21, 2020 PURPOSE: Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, an epithelial cytokine implicated in asthma pathogenesis. In the phase 2b PATHWAY study (NCT02054130), tezepelumab significantly reduced annualized asthma exacerbation rates (AAER) by up to 71% versus placebo in adults with severe, uncontrolled asthma. This post hoc analysis evaluated the effect of tezepelumab on AAER and forced expiratory volume in 1 second (FEV1) in patients from PATHWAY taking medium-dose (MD) or high-dose (HD) inhaled corticosteroids (ICS) at baseline. METHODS: Adults (18–75 years) with severe, uncontrolled asthma were randomized to receive subcutaneous tezepelumab (70mg every 4 weeks [Q4W], 210mg Q4W, 280mg every 2 weeks) or placebo for 52 weeks. AAER and FEV1 were determined in patients taking MD (250–500μg/day of fluticasone propionate [FP] or equivalent) or HD (>500μg/day FP or equivalent) ICS at baseline. Data are reported for tezepelumab 210mg and pooled tezepelumab doses. RESULTS: Overall, 550 patients were randomized to placebo (n=138) or tezepelumab 70mg (n=138), 210mg (n=137) or 280mg (n=137). Patients taking HD ICS (n=269) had more exacerbations in the prior year (mean: 2.6 vs 2.2), higher fractional exhaled nitric oxide levels (median: 24.3 vs 20.5 ppb) and lower post-bronchodilator FEV1 reversibility (median: 287.0 vs 340.0 mL) at baseline than those taking MD ICS (n=281), and higher occurrence of nasal polyps (18.6% vs 11.4%) and maintenance oral corticosteroid (OCS) use (18.6% vs 0.4%). Over 52 weeks, AAER in placebo-treated patients was higher in the HD ICS group than in the MD ICS group (1.12 [95% confidence interval (CI): 0.76–1.66] vs 0.38 [95% CI: 0.24–0.61], respectively). For tezepelumab 210mg, AAER was reduced by 77% (95% CI: 54–89) and 60% (95% CI: 8–83) versus placebo in the HD and MD ICS groups, respectively. Results were similar for pooled tezepelumab doses versus placebo (HD ICS, 74% [95% CI: 57–84]; MD ICS, 52% [95% CI: 12–73]). Compared with placebo, the least squares mean change from baseline in FEV1 at week 52 was 160mL (95% CI: 10–300) and 140mL (95% CI: 0–280) in patients taking HD and MD ICS, respectively, in the tezepelumab 210mg group, and 190mL (95% CI: 70–310) and 120mL (95% CI: 10–230), respectively, in the pooled tezepelumab dose group. CONCLUSIONS: Patients with severe, uncontrolled asthma taking HD ICS had more exacerbations in the prior year and higher baseline maintenance OCS use than those taking MD ICS, which is consistent with patients taking HD ICS having more severe disease. Treatment with tezepelumab reduced exacerbations and improved FEV1 versus placebo in both ICS dose groups, with a trend of greater effects in patients taking HD ICS. CLINICAL IMPLICATIONS: This study further supports the potential benefits of tezepelumab treatment in patients with severe, uncontrolled asthma, irrespective of pre-treatment maintenance ICS dose. DISCLOSURES: Employee relationship with AstraZeneca Please note: >$100000 Added 04/03/2020 by Christopher Ambrose, source=Web Response, value=Salary Employee relationship with AstraZeneca Please note: >$100000 Added 04/15/2020 by gene colice, source=Web Response, value=Ownership interest Employee relationship with AstraZeneca Please note: >$100000 Added 04/15/2020 by gene colice, source=Web Response, value=Salary Advisory Committee Member relationship with AstraZeneca Please note: $1001 - $5000 Added 04/14/2020 by Jonathan Corren, source=Web Response, value=Honoraria Consultant relationship with AstraZeneca Please note: $1001 - $5000 Added 04/14/2020 by Jonathan Corren, source=Web Response, value=Consulting fee Removed 04/14/2020 by Jonathan Corren, source=Web Response Speaker/Speaker's relationship with AstraZeneca Please note: $5001 - $20000 Added 04/14/2020 by Jonathan Corren, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with Genetech Please note: $5001 - $20000 Added 04/15/2020 by Jonathan Corren, source=Web Response, value=Honoraria Research funds relationship with Genetech Please note: $5001 - $20000 Added 04/15/2020 by Jonathan Corren, source=Web Response, value=Grant/Research Support Research funds relationship with AstraZeneca Please note: $5001 - $20000 Added 04/15/2020 by Jonathan Corren, source=Web Response, value=Grant/Research Support Board Member relationship with Novartis Please note: $1001 - $5000 Added 04/15/2020 by Jonathan Corren, source=Web Response, value=Honoraria Research funds relationship with Novartis Please note: $5001 - $20000 Added 04/15/2020 by Jonathan Corren, source=Web Response, value=Grant/Research Support Speaker/Speaker's Bureau relationship with Regeneron/Sanofi Please note: $5001 - $20000 Added 04/15/2020 by Jonathan Corren, source=Web Response, value=Honoraria Board Member relationship with Regeneron/Sanofi Please note: $1001 - $5000 Added 04/15/2020 by Jonathan Corren, source=Web Response, value=Honoraria Research funds relationship with Regeneron/Sanofi Please note: $5001 - $20000 Added 04/15/2020 by Jonathan Corren, source=Web Response, value=Grant/Research Support Employee relationship with Amgen Please note: >$100000 Added 04/23/2020 by Jane Parnes, source=Web Response, value=Salary Employee relationship with Amgen Please note: >$100000 Added 04/23/2020 by Jane Parnes, source=Web Response, value=Stock and stock options Employee relationship with AstraZeneca Pharma Poland Please note: $20001 - $100000 Added 05/26/2020 by Kinga Sałapa, source=Admin input, value=Salary

Tiotropium Respimat® add-on therapy to inhaled corticosteroids in patients with symptomatic asthma improves clinical outcomes regardless of baseline characteristics

Despite currently available therapies and detailed treatment guidelines, many patients with asthma remain symptomatic. Tiotropium delivered by the soft mist inhaler Respimat®, as add-on therapy to medium-dose inhaled corticosteroids (ICS), has been shown to improve lung function and asthma control in patients with symptomatic moderate asthma. To determine whether the efficacy of tiotropium Respimat® in asthma differs by patients' study baseline characteristics. Two replicate Phase III, randomized, double-blind, placebo-controlled, parallel-group studies (MezzoTinA-asthma®; NCT01172808 and NCT01172821) of once-daily tiotropium Respimat 5 μg and 2.5 μg add-on to ICS were conducted in patients with symptomatic asthma despite treatment with medium-dose ICS with or without additional controllers. Subgroup analyses of peak forced expiratory volume in 1 s (FEV1), trough FEV1, risk of severe asthma exacerbation and Asthma Control Questionnaire responder rate were performed to determine whether results were influenced by patients' baseline characteristics. In this analysis, 523 patients received placebo while 517 and 519 patients received the 5 μg and 2.5 μg dose of tiotropium Respimat, respectively. The magnitude of the improvements in lung function and asthma control, as well as the reduced risk of severe exacerbation with both doses of tiotropium Respimat versus placebo, was independent of a broad range of baseline characteristics. Once-daily tiotropium Respimat as add-on to ICS is a beneficial treatment option for patients with asthma who remain symptomatic despite at least medium-dose ICS, regardless of baseline characteristics.

Global Initiative for Asthma 2016–derived asthma control with fluticasone propionate and salmeterol: A Gaining Optimal Asthma Control (GOAL) study reanalysis

BackgroundIn 2004, the landmark Gaining Optimal Asthma Control (GOAL) study demonstrated that most patients can achieve asthma control through sustained treatment and that adding a long-acting β2-adrenoreceptor agonist to an inhaled corticosteroid (ICS) is more effective than ICS alone in this regard. Definitions of asthma control have since evolved, and the consequent implications for the GOAL study findings are unclear. ObjectiveTo evaluate the efficacy of fluticasone propionate and salmeterol and fluticasone propionate alone in achieving and maintaining asthma control, as derived from the Global Initiative for Asthma (GINA) 2016 report. MethodsIn total, 3416 patients were stratified by prior medication (ICS-naive [stratum 1], low-dose ICS [stratum 2], or medium-dose ICS [stratum 3]) and randomized to receive fluticasone propionate and salmeterol or fluticasone propionate. The primary end point was the proportion of patients achieving well-controlled or partly controlled asthma; secondary end points included the proportion of patients achieving well-controlled asthma. Control was evaluated during the last 4 weeks of each dose titration. ResultsIn all strata, more patients achieved well-controlled or partly controlled asthma with fluticasone propionate and salmeterol vs fluticasone propionate alone (stratum 1: 91% vs 85%; P = .003; stratum 2: 86% vs 82%; P = .07; and stratum 3: 76% vs 66%; P < .001), as well as patients with well-controlled asthma (stratum 1: 64% vs 56%; P = .005; stratum 2: 59% vs 41%; P < .001; and stratum 3: 40% vs 22%; P < .001). ConclusionA markedly higher proportion of patients with uncontrolled asthma in each stratum achieved control according to GINA 2016 criteria compared with the original study criteria. The proportion of patients achieving control remained greater with fluticasone propionate and salmeterol than with fluticasone propionate alone.

A “real-life” study on height in prepubertal asthmatic children receiving inhaled steroids

ABSTRACTIntroduction: Asthma is the most common chronic respiratory disease in children and inhaled corticosteroids (ICS) constitute the first line of treatment for these patients. However, the potential growth-inhibiting effect of ICS has often been a cause of concern for both caregivers as well as physicians, and there still remains conflict regarding their safety profile. Objective: To assess whether the administration of ICS in low or medium doses is associated with height reduction in prepubertal children. Methods: We performed a retrospective study to examine the association between ICS treatment and growth deceleration in children with mild persistent asthma. The comparison of height measurements every 6 months from 3 to 8 years of age was conducted among three groups of patients: patients not receiving ICS, patients being treated with low dose of ICS and patients being treated with medium dose of ICS (GINA Guidelines 2015). Results: This study included 284 patients (198 male, 86 female) aged 3–8 years; 75 patients were not receiving ICS, 63 patients were on low-dose ICS and 146 patients were on medium-dose ICS. The measured height every 6 months did not differ significantly (p > 0.05) among the three groups while the difference remained stable (p > 0.05), even when we evaluated males and females separately. Conclusions: In this “real-life” study we found that long-term treatment with ICS in low or medium doses is not associated with height reduction in prepubertal children with asthma.

A phase III randomized controlled trial of tiotropium add-on therapy in children with severe symptomatic asthma

Studies in adults and adolescents have demonstrated that tiotropium is efficacious as an add-on therapy to inhaled corticosteroids (ICSs) with or without other maintenance therapies in patients with moderate or severe symptomatic asthma. We sought to assess the efficacy and safety of once-daily tiotropium Respimat add-on therapy to high-dose ICS with 1 or more controller medications, or medium-dose ICS with 2 or more controller medications, in the first phase III trial of tiotropium in children with severe symptomatic asthma. In this 12-week, double-blind, placebo-controlled, parallel-group trial, 401 participants aged 6 to 11years were randomized to receive once-daily tiotropium 5μg (2 puffs of 2.5μg) or 2.5μg (2 puffs of 1.25μg), or placebo (2 puffs), administered through the Respimat device as add-on to background therapy. Compared with placebo, tiotropium 5μg, but not 2.5μg, add-on therapy improved the primary end point, peak FEV1 within 3hours after dosing (5μg, 139mL [95% CI, 75-203; P<.001]; 2.5μg, 35mL [95% CI, -28 to 99; P=.27]), and the key secondary end point, trough FEV1 (5μg, 87mL [95% CI, 19-154; P=.01]; 2.5μg, 18mL [95% CI, -48 to 85; P=.59]). The safety and tolerability of tiotropium were comparable with those of placebo. Once-daily tiotropium Respimat 5μg improved lung function and was well tolerated as add-on therapy to ICSwith other maintenance therapies in children with severesymptomatic asthma.

Comparison of early effects of budesonide/formoterol maintenance and reliever therapy with fluticasone furoate/vilanterol for asthma patients requiring step-up from inhaled corticosteroid monotherapy

BackgroundIf asthma patients fail to achieve symptom control using a medium dose of inhaled corticosteroid (ICS) alone, addition of a long-acting β2 agonist (LABA) is the preferred treatment. Currently, there are several combinations of ICS/LABA that are available, each of which has a different property. Here, we aimed to compare the early effects of budesonide/formoterol (BUD/FM; Symbicort®) for maintenance and reliever therapy (SMART) with a fixed dose of fluticasone furoate/vilanterol (FF/VI; Relvar®). MethodsInadequately controlled asthma patients (defined as having an Asthma Control Questionnaire, 5-item version [ACQ5] score≥1.5) with a fractional exhaled nitric oxide (FeNO) value > 35 ppb, who had been treated with a medium dose of ICS alone, were enrolled. Patients were randomized into two groups and treated with two inhalations twice-daily of BUD/FM 160/4.5 μg plus as-needed BUD/FM (SMART group, n = 15) or one inhalation once-daily of FF/VI 100/25 μg plus as-needed procaterol (FF/VI group, n = 15) for 4 weeks. Outcomes including FeNO, impulse oscillometry (IOS) parameters and ACQ5 scores were measured at 0, 2 and 4 weeks. ResultsBoth groups showed improvement in airway inflammation, pulmonary function and symptoms from baseline to 2 weeks. From 2 to 4 weeks, the SMART group exhibited continuous improvement in most measured parameters, whereas improvement in the FF/VI group seemed to reach a plateau transiently. Consequently, the SMART group showed significant improvement in the FeNO, IOS parameters (resonance frequency and integrated area of low frequency reactance) and ACQ5 score as compared with the FF/VI group at 4 weeks. ConclusionAs compared with the FF/VI group, the SMART group achieved a greater improvement in FeNO, small airway parameters regarding IOS and ACQ score, in patients with airway inflammation and uncontrolled symptoms treated with a medium dose of ICS alone. In this 4-week study, these two ICS/LABA combination therapies showed different treatment outcomes; they must be investigated further to clarify suitable patient characters and the long term efficacies for each combination.

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.

Addition to inhaled corticosteroids of long-acting beta2-agonists versus anti-leukotrienes for chronic asthma.

Asthma patients who continue to experience symptoms despite taking regular inhaled corticosteroids (ICS) represent a management challenge. Long-acting beta2-agonists (LABA) and anti-leukotrienes (LTRA) are two treatment options that could be considered as add-on therapy to ICS. To compare the safety and efficacy of adding LABA versus LTRA to the treatment regimen for children and adults with asthma who remain symptomatic in spite of regular treatment with ICS. We specifically wished to examine the relative impact of the two agents on asthma exacerbations, lung function, symptoms, quality of life, adverse health events and withdrawals. We searched the Cochrane Airways Group Specialised Register until December 2012. We consulted reference lists of all included studies and contacted pharmaceutical manufacturers to ask about other published or unpublished studies. We included randomised controlled trials (RCTs) conducted in adults or children with recurrent asthma that was treated with ICS along with a fixed dose of a LABA or an LTRA for a minimum of four weeks. Two review authors independently assessed the risk of bias of included studies and extracted data. We sought unpublished data and further details of study design when necessary. We included 18 RCTs (7208 participants), of which 16 recruited adults and adolescents (6872) and two recruited children six to 17 years of age (336) with asthma and significant reversibility to bronchodilator at baseline. Fourteen (79%) trials were of high methodological quality.The risk of exacerbations requiring systemic corticosteroids (primary outcome of the review) was significantly lower with the combination of LABA + ICS compared with LTRA + ICS-from 13% to 11% (eight studies, 5923 adults and 334 children; risk ratio (RR) 0.87, 95% confidence interval (CI) 0.76 to 0.99; high-quality evidence). The number needed to treat for an additional beneficial outcome (NNTB) with LABA compared with LTRA to prevent one additional exacerbation over four to 102 weeks was 62 (95% CI 34 to 794). The choice of LTRA, the dose of ICS and the participants' age group did not significantly influence the magnitude of effect. Although results were inconclusive, the effect appeared stronger in trials that used a single device rather than two devices to administer ICS and LABA and in trials of less than 12 weeks' duration.The addition of LABA to ICS was associated with a statistically greater improvement from baseline in lung function, as well as in symptoms, rescue medication use and quality of life, although the latter effects were modest. LTRA was superior in the prevention of exercise-induced bronchospasm. More participants were satisfied with the combination of LABA + ICS than LTRA + ICS (three studies, 1625 adults; RR 1.12, 95% CI 1.04 to 1.20; moderate-quality evidence). The overall risk of withdrawal was significantly lower with LABA + ICS than with LTRA + ICS (13 studies, 6652 adults and 308 children; RR 0.84, 95% CI 0.74 to 0.96; moderate-quality evidence). Although the risk of overall adverse events was equivalent between the two groups, the risk of serious adverse events (SAE) approached statistical significance in disfavour of LABA compared with LTRA (nine studies, 5658 adults and 630 children; RR 1.33, 95% CI 0.99 to 1.79; P value 0.06; moderate-quality evidence), with no apparent impact of participants' age group.The following adverse events were reported, but no significant differences were demonstrated between groups: headache (11 studies, N = 6538); cardiovascular events (five studies, N = 5163), osteopenia and osteoporosis (two studies, N = 2963), adverse events (10 studies, N = 5977 adults and 300 children). A significant difference in the risk of oral moniliasis was noted, but this represents a low occurrence rate. In adults with asthma that is inadequately controlled by predominantly low-dose ICS with significant bronchodilator reversibility, the addition of LABA to ICS is modestly superior to the addition of LTRA in reducing oral corticosteroid-treated exacerbations, with an absolute reduction of two percentage points. Differences favouring LABA over LTRA as adjunct therapy were observed in lung function and, to a lesser extend, in rescue medication use, symptoms and quality of life. The lower overall withdrawal rate and the higher proportion of participants satisfied with their therapy indirectly favour the combination of LABA + ICS over LTRA + ICS. Evidence showed a slightly increased risk of SAE with LABA compared with LTRA, with an absolute increase of one percentage point. Our findings modestly support the use of a single inhaler for the delivery of both LABA and low- or medium-dose ICS. Because of the paucity of paediatric trials, we are unable to draw firm conclusions about the best adjunct therapy in children.

Comparison of the effects of budesonide/formoterol maintenance and reliever therapy with fluticasone/salmeterol fixed-dose treatment on airway inflammation and small airway impairment in patients who need to step-up from inhaled corticosteroid monotherapy

BackgroundIf asthma patients fail to achieve symptom control using a medium dose of inhaled corticosteroid (ICS) alone, adding a long-acting β2 agonist (LABA) is the preferred treatment. We aimed to compare the effect of two widely available ICS/LABA combinations in these patients in real-life conditions: budesonide/formoterol (BUD/FM; Symbicort®) for maintenance and reliever therapy (SMART) and a fixed dose of fluticasone propionate/salmeterol (FP/SM). MethodsInadequately controlled asthma patients treated with a medium dose of ICS alone, with an Asthma Control Questionnaire (ACQ) score >0.75 and using a short-acting β2-agonist (SABA) 2–6 occasions/week, were enrolled. Patients were randomized into two groups and treated with two inhalation twice-daily BUD/FM 160/4.5 μg plus as-needed BUD/FM (SMART group, n = 15) or one inhalation twice-daily FP/SM 250/50 μg plus as-needed procaterol (FP/SM group, n = 15) for 8 weeks. ResultsBoth groups showed significant improvement in airway inflammation, pulmonary functions and symptoms from baseline. The SMART group showed significant improvement in the fraction of nitric oxide, ACQ score, rescue medication use and small airway parameter R5–R20 measured by impulse oscillometry compared with the FP/SM group. ConclusionFor stepping up treatment from ICS alone to an ICS/LABA combination, SMART is preferable for controlling asthma symptoms by suppressing airway inflammation and improving small airway impairment compared with a fixed dose of FP/SM. It may be achieved by the property of BUD/FM itself and as-needed use, but the degree of each contribution must be investigated further.

Tiotropium: a new therapeutic option in asthma.

Although bronchial hyperresponsiveness to cholinergic agents is a main feature of asthma, the role of anticholinergic drugs in chronic asthma management has been largely underestimated. Several single-dose studies comparing acute bronchodilation induced by ipratropium bromide with salbutamol have shown that salbutamol is more effective than ipratropium in treating asthma. Recently, tiotropium has been studied in asthma, when added to low-medium dose inhaled corticosteroids (ICS) in unselected moderate asthmatics or in patients with uncontrolled asthma, or with COPD and history of asthma. Later, studies on patients with Arg/Arg beta2-receptor polymorphism demonstrated a similar efficacy of tiotropium in comparison with salmeterol, when both were added to ICS. More recently, pivotal long-term studies have been performed on severe asthmatics uncontrolled under ICS/LABA combination, showing the efficacy of tiotropium in improving lung function and in increasing the time until the first severe asthma exacerbation. These data support the use of tiotropium on top of ICS/LABA combination in moderate-severe asthmatic patients. New studies are going to be published on the use of tiotropium in mild and moderate asthmatics, when added to low or medium dose ICS, in comparison with ICS alone or with ICS/LABA combination. These data might extend the indication for using tiotropium in asthma. Therefore, tiotropium represents now a valid therapeutic option, in addition to the current therapy available for severe asthmatics, and in alternative to LABA in selected asthma populations. The specific asthma phenotype which may be appropriate for tiotropium treatment should still be defined.

The β-2 agonist debate

To present an evidence-based review of the US Food and Drug Administration (FDA) recommendations for long-acting β agonist (LABA) use in asthma. The FDA recommendation contraindicating the use of LABAs without a concomitant asthma-controller medication such as an inhaled corticosteroid (ICS) is supported, with the caveat that concomitant use of an asthma-controller medication applies only to ICS therapy and not other asthma controller medications (such as leukotriene receptor antagonist therapy or theophylline). The recommendation that LABA therapy be stopped once asthma control is achieved is restrictive. Although downtitration of therapy should be considered in patients with asthma, who are well controlled, other options such as reducing the dose of ICS may be preferable to stopping LABA therapy. In patients who are at risk of unstable asthma or severe exacerbations, maintaining the ICS/LABA therapy without downtitration may be required. The recommendation against LABA use in patients whose asthma is adequately controlled with a low or medium dose ICS is supported. The recommendation that fixed-dose combination ICS/LABA products should be the only form in which LABAs are prescribed in adolescents and paediatric patients should be extended to all asthma patients. The current β agonist debate focuses on the optimal management approaches for the use of LABA therapy to both minimize risk and maximize clinical efficacy.