Low-dose Inhaled Corticosteroids Research Articles

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.

Best step-up treatments for children with uncontrolled asthma: a systematic review and network meta-analysis of individual participant data.

There is uncertainty about the best treatment option for children/adolescents with uncontrolled asthma despite inhaled corticosteroids (ICS) and international guidelines make different recommendations. We evaluated the pharmacological treatments to reduce asthma exacerbations and symptoms in uncontrolled patients age <18 years on ICS. We searched MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Embase, Web of Science, National Institute for Health and Care Excellence Technology Appraisals, National Institute for Health and Care Research Health Technology Assessment series, World Health Organization International Clinical Trials Registry, conference abstracts and internal clinical trial registers (1 July 2014 to 5 May 2023) for randomised controlled trials of participants age <18 years with uncontrolled asthma on any ICS dose alone at screening. Studies before July 2014 were retrieved from previous systematic reviews/contact with authors. Patients had to be randomised to any dose of ICS alone or combined with long-acting β2-agonists (LABA) or combined with leukotriene receptor antagonists (LTRA), LTRA alone, theophylline or placebo. Primary outcomes were exacerbation and asthma control. The interventions evaluated were ICS (low/medium/high dose), ICS+LABA, ICS+LTRA, LTRA alone, theophylline and placebo. Of the 4708 publications identified, 144 trials were eligible. Individual participant data were obtained from 29 trials and aggregate data were obtained from 19 trials. Compared with ICS Low, ICS Medium+LABA was associated with the lowest odds of exacerbation (OR 0.44, 95% credibility interval (95% CrI) 0.19-0.90) and with an increased forced expiratory volume in 1 s (mean difference 0.71, 95% CrI 0.35-1.06). Treatment with LTRA was the least preferred. No apparent differences were found for asthma control. Uncontrolled children/adolescents on low-dose ICS should be recommended a change to medium-dose ICS+LABA to reduce the risk for exacerbation and improve lung function.

American College of Allergy, Asthma and Immunology members' preferred steps 1 to 3 asthma maintenance and reliever therapy and incomplete insurance coverage indicated as main practice hurdle

BackgroundNew asthma guidelines (GINA, 2022; NAEPP EPR-4, 2020) include considerable changes in treatment recommendations, specifically regarding anti-inflammatory rescue and Single MAintenance and Reliever Therapy (SMART). ObjectiveTo explore American College of Allergy, Asthma and Immunology members’ preferred treatment and perceived hurdles. MethodsA survey (SurveyMonkey) regarding steps 1 to 3 asthma therapy was e-mailed to American College of Allergy, Asthma and Immunology members. ResultsThe allergists completed 147 surveys (46% with >20 years of experience; 98% from United States; 29% academic, 75% [also] private practice). In addition, 69% follow the National Asthma Education and Prevention Program and 81% the Global Initiative for Asthma recommendations. Of 147 allergists, 117 (80%) indicated correctly what SMART strategy is; 21%/36%/50%/39% would use SMART in step 3 treatment of a below 5-year-old/5- to 11-year-old/12- to 65-year-old/above 65-year-old patient, respectively. In this group, 11% to 14% incorrectly chose inhaled corticosteroid (ICS) plus salmeterol and 9% ICS plus vilanterol for SMART. In a 4-year-old needing step 1 therapy (N = 129), 55% of the respondents would add anti-inflammatory therapy; for step 2 treatment, most would prescribe ICS 100 to 200 µg budesonide equivalent daily; in step 3, 49% would prescribe ICS plus long-acting beta-agonist (LABA). In a 7-year-old needing step 1 treatment (N = 134), 40% would prescribe only short-acting beta-agonist; in step 3, 45% would institute SMART strategy, but only 8 of 135 (6%) chose very-low dose ICS plus formoterol (as recommended in Global Initiative for Asthma); most (39%) use low-dose ICS plus formoterol. As for rescue therapy, 59% is now instituting some form of anti-inflammatory rescue. Finally, in a 25-year-old patient (N = 144): in step 1, 39% would prescribe exclusively short-acting beta-agonist; in step 2, 4% only anti-inflammatory rescue and the rest prescribes ICS maintenance; one-third begins SMART strategy at step 2 and 50% in step 3.Major hurdles for prescribing one's preferred strategy included incomplete insurance coverage, insurance not approving more than one canister of ICS-formoterol per month, and cost. ConclusionAsthma therapy varies among physicians, with respondents suggesting underutilization of the recommended anti-inflammatory rescue and SMART therapy. A major hurdle is lack of insurance coverage of medication in line with the guidelines.

Inhaled Corticosteroids in Patients with Chronic Obstructive Pulmonary Disease and Risk of Acquiring Streptococcus pneumoniae Infection. A Multiregional Epidemiological Study.

Inhaled corticosteroids (ICS) are associated with an increased risk of clinical pneumonia among patients with chronic obstructive pulmonary disease (COPD). It is unknown whether the risk of microbiologically verified pneumonia such as pneumococcal pneumonia is increased in ICS users. The study population consists of all COPD patients followed in outpatient clinics in eastern Denmark during 2010-2017. ICS use was categorized into four categories based on accumulated use. A Cox proportional hazard regression model was used adjusting for age, body mass index, sex, airflow limitation, use of oral corticosteroids, smoking, and year of cohort entry. A propensity score matched analysis was performed for sensitivity analyses. A total of 21,438 patients were included. Five hundred and eighty-two (2.6%) patients acquired a positive lower airway tract sample withS. pneumoniaeduring follow-up. In the multivariable analysis ICS-use was associated with a dose-dependent risk ofS. pneumoniae as follows:low ICS dose: HR 1.11, 95% CI 0.84 to 1.45, p = 0.5; moderate ICS dose: HR 1.47, 95% CI 1.13 to 1.90, p = 0.004; high ICS dose: HR 1.77, 95% CI 1.38 to 2.29, p < 0.0001, compared to no ICS use. Sensitivity analyses confirmed these results. Use of ICS in patients with severe COPD was associated with an increased and dose-dependent risk of acquiringS. pneumoniae, but only for moderate and high dose. Caution should be taken when administering high dose of ICS to patients with COPD. Low dose of ICS seemed not to carry this risk.

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/.

Expert Opinion on Practice Patterns in Mild Asthma After the GINA 2019 Updates: A Major Shift in Treatment Paradigms from a Long-Standing SABA-Only Approach to a Risk Reduction-Based Strategy with the Use of Symptom-Driven (As-Needed) Low-Dose ICS/LABA.

This expert opinion, prepared by a panel of chest disease specialists, aims to review the current knowledge on practice patterns in real-life management of mild asthma and to address the relevant updates in asthma treatment by The Global Initiative for Asthma (GINA) to guide clinicians for the best clinical practice in applying these new treatment paradigms. On the basis of the emerging body of evidence suggesting the non-safety of short-acting β2-agonists (SABA)-only therapy and comparable efficacy of the as-needed inhaled corticosteroids (ICS)-formoterol combinations with maintenance ICS regimens, GINA recently released their updated Global Strategy for Asthma Management and Prevention Guide (2019). The new GINA 2019 recommendations no longer support the SABA-only therapy in mild asthma but instead includes new off-label recommendations such as symptom-driven (as-needed) low-dose ICS-formoterol and "low dose ICS taken whenever SABA is taken." The GINA 2019 asthma treatment recommendations include a major shift from long-standing approach of clinical practice regarding the use of symptom-driven SABA treatment alone in the management of mild asthma. This expert opinion supports the transition from a long-standing SABA-only approach to a risk reduction-based strategy, with the use of symptom-driven (as-needed) low-dose ICS/LABA in mild asthma patients, particularly in those with poor adherence to controller medications. The thoughtful and comprehensive approach of clinicians to these strategies is important, given that the exact far-reaching impact of this major change in management of mild asthma in the real-world settings will only be clarified over time.

Comparative efficacy of inhalers in mild-to-moderate asthma: systematic review and network meta-analysis

The comparative effectiveness of different inhaler therapies in mild-to-moderate asthma remains unclear. To assess this, we performed a systematic review and network meta-analysis of randomized controlled trials on the use of inhalers for mild-to-moderate asthma by searching PubMed, Cochrane, and Embase. A total of 29 trials including 43,515 patients and 12 types of inhaler therapies were included. For the prevention of severe and moderate-to-severe exacerbations, inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) as maintenance and reliever (SMART) showed the highest rank for effectiveness. As-needed ICS/LABA or short-acting β2-agonist (SABA) was similar to low-dose ICS and superior to as-needed SABA or LABA for the prevention of severe and moderate-severe exacerbations. As for lung function (FEV1), low-dose ICS/LABA had the highest rank; as-needed ICS/LABA was inferior to regular low-dose ICS but superior to placebo. Higher-dose ICS had a superior effect on the Asthma Control Questionnaire (ACQ) scores, and as-needed ICS/LABA and as-needed SABA or LABA had lower ranks in p-rankogram than did the regular use of low-dose ICS. As-needed ICS with LABA or SABA was more effective than a similar dose of regular ICS for preventing exacerbation in mild-to-moderate asthma. As-needed ICS showed some weakness in improving lung function and controlling asthma symptoms.

Extrafine Beclometasone Dipropionate/Formoterol NEXThaler on Device Usability, Adherence, Asthma Control and Quality of Life. A Panhellenic Prospective, Non-Interventional Observational Study in Patients with Asthma-The NEXT-Step Study.

Background: The fixed combination of extrafine beclometasone dipropionate 100 μg/formoterol 6 μg (extrafine BDP/F) delivered by NEXThaler has proved to be effective in patients with moderate-to-severe asthma in terms of lung function, symptoms and asthma control. The aim of this study was to investigate the usability/satisfaction of NEXThaler and adherence to treatment in asthma patients not well controlled by low-dose inhaled corticosteroids (ICS). Methods: This was a 6-month prospective, multicenter, open-label, observational study in 661 patients with asthma not well controlled by low-dose ICS according to the physician’s clinical assessment, which have received regular treatment with extrafine BDP/F NEXThaler. Feeling of Satisfaction with Inhaler (FSI), treatment adherence with self-reported Morisky scale, asthma control, lung function and QoL were recorded at baseline, 3 and 6 months after treatment with extrafine BDP/F. Results: The percentage of patients at least “fairly” satisfied with NEXThaler usability (FSI-10 score 40 to 50) was 96.3%. The mean FSI-10 total score was 46.8 ± 4.4 on Visit 2 and increased to 48.1 ± 3.3 on Visit 3 (p < 0.001). Approximately 67% of the patients reported “high adherence” on Visit 2, and 70% of them reported “high adherence” on Visit 3. The percentage of patients with ACQ-6-uncontrolled asthma decreased from 79.1% on Visit 1 to 22.3% on Visit 2 and further decreased to 6.7% on Visit 3. Significant improvements were also observed in the total AQLQ score, predicted FEV1% and reduction in rescue medication use. Conclusions: The NEXThaler device, delivering a combination of BDP/F, achieves satisfaction and high adherence in patients with asthma not well controlled with low-dose ICS. Asthma control, QoL, lung function and rescue medication use were improved in a Greek real-world setting.

Effect of Vitamin D3 Supplementation on Severe Asthma Exacerbations in Children With Asthma and Low Vitamin D Levels: The VDKA Randomized Clinical Trial

To investigate if supplementation with vitamin D3 would improve the time to a severe exacerbation in children at high risk with vitamin D insufficiency and taking low-dose inhaled corticosteroids (ICSs) for persistent asthma.The participants were recruited from 7 children’s hospitals across the United States. Participants, 6 to 16 years of age, had to have physician-diagnosed asthma for at least 1 year, being treated with low-dose ICSs, and have a serum 25-hydroxyvitamin D level less than 30 ng/mL. They also had to have at least 1 severe asthma exacerbation in the last year (defined as systemic steroids for at least 3 days or an emergency department visit or hospitalization requiring systemic corticosteroids). All participants had to show bronchodilator responsiveness or airway responsiveness to methacholine inhalation. The mean age of the participants was 9.8 years (40% girls). A total of 219 subjects passed screening and entered run-in. A total of 192 subjects were randomly assigned to active drug or placebo capsules.This was a randomized, double-blind, parallel, placebo-controlled clinical trial. Participants initially all received placebo capsules and were maintained on inhaled fluticasone propionate, 176 μg per day (6–11 years) or 220 μg per day (12–16 years) during run-in. They continued the ICSs and then were randomly assigned to daily vitamin D3 4000 IU or continuing placebo for 48 weeks. After 24 weeks, participants dose of fluticasone was reduced by 50%, if asthma was well controlled and spirometry was normal. Serum vitamin D levels and parameters of asthma control were measured every 16 weeks. The primary outcome was the time to a severe asthma exacerbation. Secondary outcomes included the time to a viral-induced severe exacerbation, the proportion of participants in whom the dose of ICS was reduced halfway through the trial, and the cumulative fluticasone dose during the trial.A total of 94% of randomly assigned subjects completed the trial. A total of 36 participants (37.5%) in the vitamin D3 group and 33 (34.4%) in the placebo group had ≥1 severe exacerbations. Compared with the placebo, vitamin D3 supplementation did not significantly improve the time to a severe exacerbation. The mean time to exacerbation was 240 days in the vitamin D3 group versus 253 days in the placebo group (mean group difference: −13.1 days; adjusted hazard ratio: 1.13; P = .63). Vitamin D3 supplementation, compared with the placebo, did not significantly improve the time to a viral-induced severe exacerbation, the proportion of participants whose dose of ICSs was reduced, or the cumulative fluticasone dose during the trial. Serious adverse events were similar in both groups (vitamin D3 group: n = 11; placebo group: n = 9).In children 6 to 16 years old with persistent asthma and low vitamin D levels, vitamin D3 supplementation, compared with a placebo, did not significantly improve the time to a severe asthma exacerbation or ICS dosing.As the authors note, in several observational studies, researchers have linked low serum vitamin D levels to severe asthma exacerbations, lower lung function, and reduced response to corticosteroids. Yet meta-analyses and reviews of vitamin D3 supplementation for severe asthma exacerbations have found insufficient evidence to recommend vitamin D3 supplementation in children. In this study, the authors, looking at a high-risk population for asthma exacerbations, add to that negative body of literature.

The cost-effectiveness of as-needed budesonide-formoterol versus low-dose inhaled corticosteroid maintenance therapy in patients with mild asthma in Canada

BackgroundThe Global Initiative for Asthma recommends the use of as-needed low-dose inhaled corticosteroid (ICS)-formoterol as a preferred controller therapy for patients with mild asthma. These recommendations were based, in part, on evidence from the SYGMA 1 and 2 studies of as-needed budesonide-formoterol. This analysis aimed to compare the cost-effectiveness of as-needed budesonide-formoterol to low-dose maintenance ICS plus as-needed short-acting β2-agonist (SABA) in patients with mild asthma.MethodsA Markov cohort model was designed that included three possible health states (non-exacerbation, severe exacerbation, and death) to compare as-needed budesonide-formoterol 200–6 μg to twice-daily budesonide 200 μg maintenance therapy (low-dose ICS) plus as-needed terbutaline 0.5 mg (SABA). The deterministic base-case analysis used severe exacerbation, adverse event (AE), and healthcare resource use data from SYGMA 2, and was conducted from a Canadian public payer perspective with a 50-year time horizon, and a discount rate of 1.5% per annum. Moderate exacerbation was modelled on data from SYGMA 1 in sensitivity analyses. Utility values were derived from SYGMA 2 quality of life data. All-cause- and asthma-related mortality rates and costs (reported in 2019 Canadian dollars) were based on published data, using Canada-specific values where available. One-way deterministic sensitivity, probabilistic sensitivity, and eight scenario analyses were conducted to examine the robustness of the results.ResultsAs-needed budesonide-formoterol was the dominant treatment option in the base-case analysis, providing incremental cost savings of $9882 per patient and quality-adjusted life year (QALY) gains of 0.002 versus low-dose maintenance ICS plus as-needed SABA over a 50-year time horizon. Using a willingness-to-pay threshold of $50,000/QALY ($100,000/QALY), as-needed budesonide-formoterol had a 94% (95%) probability of being cost-effective compared with maintenance ICS plus as-needed SABA. Cost-saving was mostly driven by lower overall medication and AE-related costs. As-needed budesonide-formoterol remained the dominant treatment in sensitivity and scenario analyses.ConclusionsAs-needed budesonide-formoterol is a cost-saving option for the treatment of mild asthma from the perspective of the Canadian public payer compared with low-dose maintenance ICS plus as-needed SABA.

GINA 2019 - step 1 and 2 treatment in asthma: Updates with reasons behind

Asthma is a heterogeneous lung disease characterized by chronic airway inflammation. It was suggested that patients with mild asthma symptoms could be managed with as-needed short-acting β2-agonists (SABA) in previous years. In 2019, GINA made a radical change and recommended that SABA should not be used as monotherapy in patients with mild asthma, but instead as-needed low-dose inhaled corticosteroid (ICS)-formoterol or "additional low-dose ICS taken whenever SABA is taken" treatments should be commenced to relieve and control symptoms. The approach emerged in the light of the studies that indicate the increased risk of severe exacerbation and asthma-related death due to overuse of SABA. The present article aimed to enlighten the updates in GINA 2019 step 1 and 2 treatment, the grounds for these updates with the supportive studies.

Budesonide-Formoterol as Needed for The Treatment of Mild Persistent Asthma

Objective: To summarize literature assessing the safety and efficacy of budesonide/formoterol, a low dose inhaled corticosteroid (ICS) and long-acting beta agonist (LABA) used as needed for the treatment of adult patients with mild persistent asthma requiring step 2 therapy compared to low dose inhaled corticosteroid (ICS) plus short-acting beta agonist (SABA) and SABA monotherapy. Data Sources: A literature search of PubMed (1966-October 2020), EMBASE (1973-October 2020) and clinicaltrials.gov was conducted using the following search terms: budesonide, formoterol, as needed, and mild asthma. Study selection and data extraction: Randomized, controlled trials with data describing as needed use of budesonide-formoterol in the treatment of mild, persistent asthma were included. Data synthesis: Current trials demonstrate a reduced risk of exacerbation and an improvement in symptom control in patients receiving budesonide/formoterol as needed when compared to as needed SABA alone. However, when compared to scheduled budesonide maintenance, patients receiving budesonide/formoterol as needed experienced worse symptom control and mixed exacerbation results. Relevance to patient care and clinical practice: This review evaluates the efficacy and safety of budesonide/formoterol as needed for patients with mild asthma. The Global Initiative for Asthma (GINA), a global strategy for asthma management and prevention adopted this change in 2019, and the most recent updated Expert Panel Report 4 of the National Asthma Education and Prevention Program (NAEPP) did not address this area. Conclusions: Based on this review of the literature, further study is needed to determine the place in therapy for budesonide/formoterol as needed in the treatment of mild persistent asthma. Low-dose ICS should remain the standard of therapy in patients with mild asthma requiring Step 2 therapy.

Effect of inhaled corticosteroids on bone mineral density in asthmatic children

Background: There is a rise in prevalence of asthma world-over. This study was undertaken as there are controversies regarding the effect of long term inhaled-corticosteroids (ICS) on bone mineral density (BMD).Methods: Asthmatic children belonging to 5-18 year age-group as per the global initiative for asthma guidelines (GINA) guidelines, who were on ICS for a minimum period of 6 months were studied. This study was conducted at a tertiary-care teaching hospital in Mysuru. 60 asthmatic children were compared with 60 non-asthmatic controls. Dual-energy x-ray absorptiometry at 6 sites was used for estimating the BMD and vitamin D levels were measured.Results: 0.771±0.114 g/cm2 was the mean total BMD among children on low dose ICS, while it was 0.613±0.192 and 0.564±0.104 g/cm2 respectively for those on medium and high dose ICS, with p value of 0.026. Children on low dose ICS did not have any impact on BMD, while 18.9% of those on medium and high dose ICS had a reduced total BMD. Trochanteric region was a useful predictor site for monitoring BMD in children on long term ICS with 38.7% and 68.9% being affected when on ICS for 6-12 months and more than 12 months respectively (p=0.018).Conclusions: The ICS of medium and high dose, for a duration of more than 6 months had a reduced total BMD. However, no effect was seen with low dose. Trochanter is a useful site for long term monitoring of BMD in children. There was no correlation between vitamin D levels and control of asthma.

EstablishINg the best STEp-up treatments for children with uncontrolled asthma despite INhaled corticosteroids (EINSTEIN): protocol for a systematic review, network meta-analysis and cost-effectiveness analysis using individual participant data (IPD)

IntroductionAsthma affects millions of children worldwide—1.1 million children in the UK. Asthma symptoms cannot be cured but can be controlled with low-dose inhaled corticosteroids (ICSs) in the majority of individuals....

A multicenter, prospective, observational study on montelukast monotherapy or montelukast-based combinations treating cough variant asthma.

BackgroundEvidence of treatment against cough variant asthma (CVA) is insufficient for the clinical practice in China. We aimed at evaluating the real-world effectiveness of montelukast (MONT) alone or in combination with low-dose inhaled corticosteroids (ICS) and low-dose ICS plus long-acting beta-2-agonists (LABA) for Chinese CVA patients in a multicentre, prospective, cohort study.MethodsAdult patients diagnosed with CVA defined as chronic cough >8 weeks with a positive bronchial provocation test and normal chest X-ray findings were enrolled at respiratory clinics. Study treatment followed routine clinical practice. The investigators initiated MONT by 10 mg/day alone or in combination with a low-dose ICS +/− LABA and followed up treatment outcomes for 4 weeks. The primary outcome measure was the change in cough score (CS) from baseline.ResultsThe study enrolled 247 patients (MONT =146, MONT + ICS =38, MONT + ICS/LABA =63). In the primary analysis, the mean change (95% CI) in CS at the end of the study was −1.2 (−1.6, −0.9), −0.9 (−1.5, −0.4), and −1.3 (−1.7, −0.8) in the three groups, respectively. MONT monotherapy had a satisfactory rate of weekly asthma control at the end of the study (83.5%, 95% CI: 75.1%, 89.4%) in the per-protocol analysis. Rates of weekly asthma control were similar in two MONT-based combination regimens (83.9%, 81.4%). Short-acting beta-2-agonist (SABA) user (≥2 times per week) was 16.8% in the MONT group.ConclusionsThe real-world effectiveness of MONT alone or in combination with ICS or ICS and LABA was acceptable for CVA short-term control.

Cost-effectiveness analysis of double low-dose budesonide and low-dose budesonide plus montelukast among pediatric patients with persistent asthma receiving Step 3 treatment in China

Aims For children aged 1–5 years with persistent asthma, double low-dose inhaled corticosteroids (ICS) are recommended as the preferred Step 3 treatment and low-dose ICS plus leukotriene receptor antagonists (LTRA) as an alternative. Budesonide inhalation suspension (0.5 mg daily) and montelukast (4.0 mg daily) are commonly used low-dose ICS and LTRA, respectively, among children in China. This study compared the cost-effectiveness of double low-dose budesonide vs. low-dose budesonide plus montelukast from a Chinese healthcare payer’s perspective. Methods A Markov model was constructed with four health states (i.e. no exacerbation, mild exacerbation, moderate-to-severe exacerbation, and death). Transition probabilities were estimated based on exacerbation rates, case-fatality of hospitalized patients due to exacerbation, and natural mortality. Treatment adherence was considered and assumed to impact both drug costs and exacerbation rates. Costs (in 2019 Chinese Yuan [¥]) included drug costs and exacerbation management costs. Cost inputs and utilities for each health state were obtained from a public database and the literature. In-depth interviews were conducted with a health economics expert to validate the model, and a clinical expert to verify inputs and assumptions related to clinical practice. Costs and quality-adjusted life-years (QALYs) were estimated over a year. Deterministic and probabilistic sensitivity analyses were performed. Results Compared with low-dose budesonide plus montelukast, double low-dose budesonide was associated with lower costs (¥1,534 vs. ¥2,327), fewer exacerbation events (0.43 vs. 1.67) and slightly better QALYs (0.98 vs. 0.97). Sensitivity analyses supported the robustness of the results and the generalizability of findings across geographic regions in China. Conclusion The cost-effectiveness analysis suggests that double low-dose budesonide is a dominant Step 3 treatment strategy compared with low-dose budesonide plus montelukast for patients aged 1–5 years with persistent asthma in China.

Comparison of Two Therapies on Asthma Control in Children.

Background: Childhood asthma carries significant morbidity. Aim/Objectives: Aim of the study was to compare efficacy of 2 commonly used therapies for asthma control in children with asthma. Methods: This was a 1-year, prospective cohort study at a tertiary care children's hospital. Patients were referred by their primary care physicians (PCPs) for asthma control. All patients were on low-dose inhaled corticosteroids (ICSs) at baseline. They were either switched to medium-dose ICS (ICS group) or medium-dose ICS and long-acting beta agonist (ICS+LABA group). Results were compared over time and between both groups. Results: Our cohort included 163 children (ages 2-18 years) with mean age of 5.62 ± 3.61 years. Mean Asthma Control Test (ACT) score at baseline was 15.9 ± 5.4. Mean ACT and percent predicted forced expiratory volume in one second improved (P < 0.0001 for both) in both groups. Median emergency department visits, short courses of oral steroids, and unscheduled PCP visits for acute asthma significantly decreased (P < 0.001 for all) in both groups. Similarly, days/month with wheezing, nighttime cough, and missed school days significantly decreased in both groups (P < 0.001 for all). Patients in ICS group were more likely to fail to achieve asthma control compared to patients in ICS+LABA group. Conclusion: Our study suggests that in children with uncontrolled asthma on low-dose ICS, switching to either medium-dose ICS or medium-dose ICS+LABA resulted in better symptom control, ACT improvement, and less asthma exacerbations over time. ICS+LABA had the additional benefit of less risk of treatment failure when compared to medium-dose ICS.

Once-daily mometasone plus indacaterol versus mometasone or twice-daily fluticasone plus salmeterol in patients with inadequately controlled asthma (PALLADIUM): a randomised, double-blind, triple-dummy, controlled phase 3 study

Fixed-dose combinations (FDCs) of inhaled corticosteroids (ICS) and long-acting β2-adrenoceptor agonists (LABA) are considered safe and efficacious in asthma management. Most available FDCs require twice-daily dosing to achieve optimum therapeutic effect. The objective of the PALLADIUM study was to assess the efficacy and safety of once-daily FDC of mometasone furoate plus indacaterol acetate (MF-IND) versus mometasone furoate (MF) monotherapy in patients with inadequately controlled asthma. This 52-week, double-blind, triple-dummy, parallel-group, phase 3 study recruited patients from 316 centres across 24 countries. Patients aged 12 to 75 years with a documented diagnosis of asthma for at least 1 year, percentage of predicted FEV1 of 50-85%, and an Asthma Control Questionnaire 7 score of at least 1·5 despite treatment with medium-dose or high-dose ICS or low-dose ICS plus LABA were included. A history of asthma exacerbations was not a study requirement. Participants were randomily assigned (1:1:1:1:1) via interactive response technology to receive one of the following treatments for 52 weeks: high-dose MF-IND (320 μg, 150 μg) or medium-dose MF-IND (160 μg, 150 μg) once daily via Breezhaler; high-dose MF (800 μg [400 μg twice daily]) or medium-dose MF (400 μg once daily) via Twisthaler; or high-dose fluticasone propionate-salmeterol xinafoate (FLU-SAL; 500 μg, 50 μg) twice daily via Diskus. Participants received placebo via inhalation through the Breezhaler, Twisthaler, or Diskus devices in the mornings and evenings, as appropriate. The primary endpoint was improvement in trough FEV1 with high-dose and medium-dose MF-IND versus respective MF doses from baseline at 26 weeks, analysed in the full analysis set by means of a mixed model for repeated measures. High-dose MF-IND once daily was compared with high-dose FLU-SAL twice daily for non-inferiority on improving trough FEV1 at week 26 with a margin of -90 mL using mixed model for repeated measures as one of the secondary endpoints. Safety was assessed in all patients who had received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02554786, and is completed. Between Dec 29, 2015, and May 4, 2018, 2216 patients were randomly assigned (high-dose MF-IND, n=445; medium-dose MF-IND, n=439; high-dose MF, n=442; medium-dose MF, n=444; high-dose FLU-SAL, n=446), of which 1973 (89·0%) completed the study treatment and 234 (10·6%) prematurely discontinued study treatment. High-dose MF-IND (treatment difference [Δ] 132 mL [95% CI 88 to 176]; p<0·001) and medium-dose MF-IND (Δ 211 mL [167 to 255]; p<0·001) showed superiority in improving trough FEV1 over corresponding MF doses from baseline at week 26. High-dose MF-IND was non-inferior to high-dose FLU-SAL in improving trough FEV1 from baseline at week 26 (Δ 36 mL [-7 to 80]; p=0·101). Overall, the incidence of adverse events was similar across the treatment groups. Once-daily FDC of ICS and LABA (MF-IND) significantly improved lung function over ICS monotherapy (MF) at week 26; high-dose MF-IND was non-inferior to twice-daily combination of ICS and LABA (high-dose FLU-SAL) for improvement in trough FEV1. The combination of MF-IND provides a novel once-daily dry powder option for asthma control. Novartis Pharmaceuticals.

The cost-effectiveness of as-needed budesonide/formoterol versus low-dose inhaled corticosteroid maintenance therapy in patients with mild asthma in the UK

BackgroundAs-needed budesonide/formoterol is effective in patients with mild asthma for whom low-dose inhaled corticosteroid (ICS) maintenance therapy is appropriate. We assessed the cost-effectiveness of this regimen versus maintenance low-dose ICS plus as-needed short-acting β2-agonist (SABA). MethodsA probabilistic Markov cohort model was developed that simulated time within/outside severe asthma exacerbations, conducted from a UK NHS perspective with a 70-year time horizon. Clinical efficacy inputs were derived from the SYGMA 2 trial. Patients with mild asthma eligible for low-dose maintenance ICS therapy received as-needed budesonide/formoterol 200/6 μg or twice-daily budesonide 200 μg maintenance therapy plus as-needed terbutaline 0.5 mg. A severe exacerbation was defined as worsening asthma requiring systemic corticosteroid use alone/in combination with an emergency department visit, or hospitalisation for acute asthma. Utility values were derived from SYGMA 2 EQ-5D-5L data, and all-cause- and asthma-related mortality, reduction in utility of an exacerbation, and costs were based on published data. The base-case analysis discount rate was 3.5%. Model robustness was evaluated with one-way sensitivity, probabilistic sensitivity, and two scenario analyses. ResultsOn average, as-needed budesonide/formoterol was associated with a £292.99 cost saving and quality-adjusted life year (QALY) gains of 0.001 versus ICS + SABA. At a willingness-to-pay of £20,000/QALY, as-needed budesonide/formoterol had >85% probability of being cost-effective versus ICS + SABA. Key drivers were budesonide/formoterol and budesonide maintenance annual exacerbation rates, mean daily budesonide/formoterol inhalations, and costs and outcomes discount rates. ConclusionsFrom a UK healthcare payer perspective, as-needed budesonide/formoterol is a cost-effective option for the treatment of mild asthma versus regular ICS.

Higher Omega-3 Index Is Associated with Better Asthma Control and Lower Medication Dose: A Cross-Sectional Study

Asthma is a chronic inflammatory airway disease, associated with systemic inflammation. Omega-3 polyunsaturated fatty acids (n-3 PUFA) have established anti-inflammatory effects, thus having potential as an adjunct therapy in asthma. This study aimed to compare erythrocyte n-3 PUFA in adults with (n = 255) and without (n = 137) asthma and determine the relationship between erythrocyte n-3 PUFA and clinical asthma outcomes. Subjects had blood collected, lung function measured and Juniper Asthma Control Questionnaire (ACQ) score calculated. Fatty acids were measured in erythrocyte membranes by gas chromatography, and the omega-3 index (O3I) was calculated (% eicosapentaenoic acid + % docosahexaenoic acid). O3I was similar in subjects with and without asthma (p = 0.089). A higher O3I was observed in subjects with controlled or partially controlled asthma (ACQ < 1.5) compared to subjects with uncontrolled asthma (ACQ ≥ 1.5) (6.0% (5.4–7.2) versus 5.6% (4.6–6.4) p = 0.033). Subjects with a high O3I (≥8%) had a lower maintenance dose of inhaled corticosteroids (ICS) compared to those with a low O3I (<8%) (1000 μg (400–1000) versus 1000 μg (500–2000) p = 0.019). This study demonstrates that a higher O3I is associated with better asthma control and with lower ICS dose, suggesting that a higher erythrocyte n-3 PUFA level may have a role in asthma management.