Efficacy and safety of fluticasone propionate/salmeterol and fluticasone propionate monotherapy in step-up treatment of childhood asthma: A systematic review and meta-analysis.

BACKGROUND: Asthma is a chronic respiratory disease that affects millions of children worldwide and can impair their quality of life and development. Inhaled glucocorticoids are the mainstay of asthma treatment, but some children require step-up therapy with additional drugs to achieve symptom control. Fluticasone propionate and salmeterol (FSC) has been shown to reduce asthma exacerbations and improve lung function in adults. However, the evidence for its efficacy and safety in children is limited. OBJECTIVE: This study aims to provide a comprehensive basis for treatment selection by summarizing existing clinical randomized controlled trials (RCTs) on the efficacy of FSC compared to fluticasone propionate (FP) monotherapy in children with asthma who require step-up treatment. METHODS: Five online databases and three clinical trial registration platforms were systematically searched. The effect size and corresponding 95% confidence interval (CI) were calculated based on the heterogeneity among the included studies. RESULTS: Twelve RCTs were identified and a total of 9, 859 patients were involved. The results of the meta-analysis revealed that the use of FSC was associated with a greater reduction in the incidence of asthma exacerbations than FP alone when the dose of FP was the same or when the duration of treatment exceeded 12 weeks. In addition, FSC resulted in a greater proportion of time with asthma-free and without the use of albuterol compared to FP alone when the duration of treatment exceeded 12 weeks. No significant differences were observed between FSC and FP alone in the incidence of drug-related adverse events and other adverse events. CONCLUSION: Both FSC and FP alone are viable options for the initial selection of step-up treatment in asthmatic children. While, FSC treatment demonstrates a greater likelihood of reducing asthma exacerbations which is particularly important for reducing the personnel, social and economic burden in children requiring step-up asthma treatment.

Bronchodilator reversibility testing in morbidly obese non-smokers: fluticasone/salmeterol efficacy versus salbutamol bronchodilator.

A positive response in reversibility testing is widely used to diagnose patients with airway limitations. However, despite its simple procedure, it doesn't accurately reflect the exact airway irreversibility. This study aimed to investigate the efficacy of a bronchodilation reversibility test using salbutamol and fluticasone/salmeterol combination in obese non-smoker subjects.The study included patients without a history of obstructive lung disease or bronchodilators. A sub-classification of patients based on body mass index (BMI) was carried out into normal (< 24.9 kg/m2), overweight (25-29.9 kg/m2), and obese (BMI ≥ 30). Spirometry measurements were performed before and after salbutamol or fluticasone/salmeterol administration.The study included 415 (49.9% male) patients with a mean age of 40.92 ± 10.86 years. Obese subjects showed a high prevalence of restrictive patterns (23.4%), with non-significantly lower spirometric values compared to normal and overweight subjects (p > 0.05). The magnitude of bronchodilation, as identified by spirometry, following fluticasone/salmeterol was higher in all participants, with a significant increase in obese subjects with a p-value of 0.013, 0.002, and 0.035 for FEV1, FEV1% predicted, and FEV1/FVC, respectively.Fluticasone/salmeterol combination increases FEV1, FEV1% of predicted, and FEV1/FVC ratio than the conventional test using salbutamol inhaler, and it can be a potential candidate for assessment of airway obstruction using reversibility test, especially among the obese population.

Comparative Effectiveness and Safety of Generic Versus Brand-Name Fluticasone-Salmeterol to Treat Chronic Obstructive Pulmonary Disease.

BACKGROUND: In 2019, the U.S. Food and Drug Administration (FDA) approved the first generic maintenance inhaler for asthma and chronic obstructive pulmonary disease (COPD). The inhaler, Wixela Inhub (fluticasone-salmeterol; Viatris), is a substitutable version of the dry powder inhaler Advair Diskus (fluticasone-salmeterol; GlaxoSmithKline). When approving complex generic products like inhalers, the FDA applies a special "weight-of-evidence" approach. In this case, manufacturers were required to perform a randomized controlled trial in patients with asthma but not COPD, although the product received approval for both indications. OBJECTIVE: To compare the effectiveness and safety of generic (Wixela Inhub) and brand-name (Advair Diskus) fluticasone-salmeterol among patients with COPD treated in routine care. DESIGN: A 1:1 propensity score-matched cohort study. SETTING: A large, longitudinal health care database. PATIENTS: Adults older than 40 years with a diagnosis of COPD. MEASUREMENTS: Incidence of first moderate or severe COPD exacerbation (effectiveness outcome) and incidence of first pneumonia hospitalization (safety outcome) in the 365 days after cohort entry. RESULTS: Among 45 369 patients (27 305 Advair Diskus users and 18 064 Wixela Inhub users), 10 012 matched pairs were identified for the primary analysis. Compared with Advair Diskus use, Wixela Inhub use was associated with a nearly identical incidence of first moderate or severe COPD exacerbation (hazard ratio [HR], 0.97 [95% CI, 0.90 to 1.04]) and first pneumonia hospitalization (HR, 0.99 [CI, 0.86 to 1.15]). LIMITATIONS: Follow-up times were short, reflecting real-world clinical practice. The possibility of residual confounding cannot be completely excluded. CONCLUSION: Use of generic and brand-name fluticasone-salmeterol was associated with similar outcomes among patients with COPD treated in routine practice. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute.

Safety and Effectiveness of As-Needed Formoterol in Asthma Patients Taking Inhaled Corticosteroid (ICS)-Formoterol or ICS-Salmeterol Maintenance Therapy.

BACKGROUND: As-needed low-dose inhaled corticosteroid (ICS)-formoterol reliever is recommended in patients with asthma prescribed maintenance ICS-formoterol. Clinicians often ask whether ICS-formoterol reliever can be used with other maintenance ICS-long-acting ß2-agonists. OBJECTIVE: To evaluate the safety and effectiveness of as-needed formoterol in patients taking maintenance ICS-formoterol or ICS-salmeterol from the RELIEF study. METHODS: RELIEF (SD-037-0699) was a 6-month, open-label study that randomized 18,124 patients with asthma to as-needed formoterol 4.5 µg or salbutamol 200 µg on top of maintenance therapy. This post hoc analysis included patients on maintenance ICS-formoterol or ICS-salmeterol (n = 5436). The primary safety outcome was a composite of serious adverse events (SAEs) and/or adverse events leading to discontinuation (DAEs); the primary effectiveness outcome was time-to-first exacerbation. RESULTS: For both maintenance groups and both relievers, similar numbers of patients had ≥1 SAE and/or DAE. In patients taking maintenance ICS-salmeterol, but not ICS-formoterol, significantly more non-asthma-related and nonserious DAEs occurred with as-needed formoterol versus as-needed salbutamol (P = .0066 and P = .0034, respectively). In patients taking maintenance ICS-formoterol, there was a significantly lower risk in time-to-first exacerbation with as-needed formoterol versus as-needed salbutamol (hazard ratio [HR]: 0.82, 95% confidence interval [CI]: 0.70, 0.95; P = .007). In patients taking ICS-salmeterol maintenance, time-to-first exacerbation was not significantly different between treatment arms (HR: 0.95, 95% CI: 0.84, 1.06; P = .35). CONCLUSIONS: As-needed formoterol significantly reduced exacerbation risk compared with as-needed salbutamol when added to maintenance ICS-formoterol, but not to maintenance ICS-salmeterol. More DAEs were seen with ICS-salmeterol maintenance therapy plus as-needed formoterol. Further research is needed to assess whether this is relevant to as-needed combination ICS-formoterol.

Study on the Effect of Self-Made Lifei Dingchuan Decoction Combined with Western Medicine on Cough Variant Asthma.

Aims: To observe the clinical efficacy of self-made Lifei Dingchuan decoction combined with western medicine in the treatment of cough variant asthma (phlegm-heat accumulation in the lung syndrome). Materials and Methods: The clinical data of 90 patients with cough variant asthma who were hospitalized in the Department of Respiratory Medicine of our hospital from January 2020 to April 2022 were selected as the research objects, and they were equally divided into the observation group and the reference group according to different treatment methods, 45 cases in each group. The group was treated with traditional montelukast sodium chewable tablet and salmeterol fluticasone mixed powder inhalation, and the observation group was treated with self-made Lifei Dingchuan decoction on the basis of the control group, saturation, pH, partial pressure of oxygen in arterial blood, partial pressure of carbon dioxide, length of stay, and hospitalization costs. Results: After the patients underwent self-made Lifei Dingchuan decoction, there were significant differences between the observation group and the reference group in terms of heart rate, respiratory rate, blood oxygen saturation, pH value, arterial blood oxygen partial pressure, carbon dioxide partial pressure, and within the group. There was a statistical difference (P < 0.05). The adverse reactions in patients with cough variant asthma after treatment showed that the red throat, shortness of breath, chest tightness, and dry mouth in the observation group were significantly different from those in the control group (P < 0.05). After investigation, follow-up, and statistics, the hospitalization time, hospitalization cost, asthma exacerbation control time, effective rate, and recurrence rate were compared between the two groups, and the differences between the two groups were statistically significant (P < 0.05). Conclusion: The study on the clinical efficacy and low hospitalization cost of the self-prepared lung and asthma-restorative soup in patients with cough variant asthma significantly improved the patients' arterial oxygen saturation, acid-base value, arterial partial pressure of oxygen, and partial pressure of carbon dioxide and effectively controlled the heart rate and respiratory rate with high safety, which is worth further promotion.

Applying key learnings from the EMAX trial to clinical practice and future trial design in COPD.

Early MAXimisation of bronchodilation for improving COPD stability (EMAX) was a large, multicentre, multi-national, randomised, double-blind, 24-week trial. EMAX evaluated the efficacy and safety of dual bronchodilator therapy with umeclidinium bromide (UMEC)/vilanterol (VI) versus monotherapy with either UMEC or salmeterol (SAL) in symptomatic patients with chronic obstructive pulmonary disease (COPD) at low exacerbation risk who were not taking concomitant inhaled corticosteroid (ICS). EMAX generated evidence covering a wide range of patient-centred endpoints in COPD in addition to measures of lung function, clinical deterioration and safety. In addition, prospective and post hoc secondary analyses have generated clinically valuable information regarding the effects of baseline patient characteristics on treatment outcomes. Importantly, as concomitant ICS use was not permitted in this study, EMAX compared dual long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) therapy with LAMA or LABA monotherapy without potential confounding due to concurrent ICS use or withdrawal. EMAX demonstrated beneficial treatment effects of UMEC/VI over UMEC or SAL monotherapy as maintenance treatment across a range of different patient characteristics, with no forfeit in safety. Thus, the trial provided novel insights into the role of LAMA/LABA versus LABA and LAMA monotherapies as maintenance therapy for patients with symptomatic COPD at low risk of exacerbations. This article will explore the clinical implications of the main findings to date of the EMAX trial and consider the key learnings this trial offers for future trial design in COPD.

Efficacy of salmeterol and magnesium isoglycyrrhizinate combination treatment in rats with chronic obstructive pulmonary disease.

The most classic treatment recommended in the current chronic obstructive pulmonary disease (COPD) guidelines is glucocorticoid and ß2 receptor agonist combination, such as salmeterol xinafoate and fluticasone propionate (Sal/Flu), causing many adverse reactions due to hormones. Magnesium isoglycyrrhizinate (MgIG) is an anti-inflammatory glycyrrhizic acid preparation for treating chronic inflammation, contributing to its structure is similar to steroidal anti-inflammatory drugs. In this study, we successfully established COPD rat model by endotracheal-atomized lipopolysaccharide exposure and cigarette smoke induction, as characterized by lung function decline. We discovered that salmeterol xinafoate/MgIG combination could alleviated lung inflammation infiltration, airway wall thickness (AWT) and the secretion of bronchial mucin MUC5AC of COPD rats more than salmeterol xinafoate, MgIG, or salmeterol xinafoate and fluticasone propionate treatment did, as well as reduced inflammatory cells (white blood cells, neutrophils and lymphocytes) accumulation in bronchoalveolar lavage fluid and decreased TNF-α, IL-6 and IL-1ß production in the serum of COPD rats. Finally, we found that Moreover, the mechanism involved might be related to the suppression of JAK/STAT signaling pathway. Overall, our studies suggested that MgIG might be a potential alternative adjuvant drug for fluticasone propionate for the clinical treatment of patients with COPD.

Comparative Efficacy of Umeclidinium/Vilanterol Versus Other Bronchodilators for the Treatment of Chronic Obstructive Pulmonary Disease: A Network Meta-Analysis.

INTRODUCTION: Few randomised controlled trials (RCTs) have directly compared long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) dual maintenance therapies for patients with chronic obstructive pulmonary disease (COPD). This systematic literature review and network meta-analysis (NMA) compared the efficacy of umeclidinium/vilanterol (UMEC/VI) versus other dual and mono-bronchodilator therapies in symptomatic patients with COPD. METHODS: A systematic literature review (October 2015-November 2020) was performed to identify RCTs ≥ 8 weeks long in adult patients with COPD that compared LAMA/LABA combinations against any long-acting bronchodilator-containing dual therapy or monotherapy. Data extracted on changes from baseline in trough forced expiratory volume in 1 s (FEV1), St George's Respiratory Questionnaire (SGRQ) total score, Transitional Dyspnoea Index (TDI) focal score, rescue medication use and moderate/severe exacerbation rate were analysed using an NMA in a frequentist framework. The primary comparison was at 24 weeks. Fixed effects model results are presented. RESULTS: The NMA included 69 full-length publications (including 10 GSK clinical study reports) reporting 49 studies. At 24 weeks, UMEC/VI provided statistically significant greater improvements in FEV1 versus all dual therapy and monotherapy comparators. UMEC/VI provided similar improvements in SGRQ total score compared with all other LAMA/LABAs, and significantly greater improvements versus UMEC 125 µg, glycopyrronium 50 µg, glycopyrronium 18 µg, tiotropium 18 µg and salmeterol 50 µg. UMEC/VI also provided significantly better outcomes versus some comparators for TDI focal score, rescue medication use, annualised moderate/severe exacerbation rate, and time to first moderate/severe exacerbation. CONCLUSION: UMEC/VI provided generally better outcomes compared with LAMA or LABA monotherapies, and consistent improvements in lung function (measured by change from baseline in trough FEV1 at 24 weeks) versus dual therapies. Treatment with UMEC/VI may improve outcomes for symptomatic patients with COPD compared with alternative maintenance treatments.

Bronchodilators are medicines that open the airways, allowing patients with chronic obstructive pulmonary disease (COPD) to breathe more easily. There are two different types of bronchodilators, namely long-acting muscarinic antagonists (LAMAs) and long-acting ß₂-agonists (LABAs), which can be used on their own or combined (LAMA/LABAs). Only a few clinical trials have compared different LAMA/LABA combinations with each other, so it is unclear which LAMA/LABA combination provides the greatest benefits for patients.In this study, we used network meta-analysis to compare a LAMA/LABA combination medicine called umeclidinium and vilanterol (UMEC/VI) with other LAMAs and LABAs used alone or in combination to treat patients with COPD. Network meta-analysis is a way of comparing two or more medicines by analysing data from many studies. We systematically searched for evidence from clinical trials in adult patients with COPD that were at least 8 weeks long and that compared LAMA/LABA combinations with a LAMA, a LABA, or another LAMA/LABA combination. We analysed data from 49 clinical trials that met these criteria.We found that patients treated with UMEC/VI had better lung function than patients treated with alternative LAMA/LABA combinations or bronchodilators used on their own. Patients treated with UMEC/VI had better quality of life than those receiving some other treatments, but not all. All the medicines we compared had similar side effects.Our results suggest that treating patients with COPD with UMEC/VI might improve their lung function and quality of life more than alternative bronchodilators.

Salmeterol-Fluticasone: The Role Revisited.

Apart from the individual diseases, some patients also show overlapping manifestations of asthma and COPD. Nevertheless, the diagnosis of COPD is often delayed due to inaccessibility to spirometry; the prevalence of the asthma COPD overlap phenotype is rather high given the exposure to biomass smoke. Furthermore, the rates of exacerbations are twice as high compared to the patients with either of the diseases. A treatment strategy that would reduce the risk of exacerbations would contribute immensely to the management of such patients. Evidence of eosinophilia (marker of inflammation) in patients with asthma, asthma COPD overlap phenotype or COPD alone should prompt treatment with a combination of inhaled corticosteroids (ICS)/ long-acting ß-agonists (LABA); several studies have shown improvement in the airflow limitation and reduction in the rate of exacerbations with salmeterol-fluticasone combination (SFC). Considering the association of COPD and cardiovascular diseases (CVD), it is critical to determine the cardiovascular safety of the LABA in such patients. Salmeterol is a highly selective partial b-2 agonist; the TORCH study and the studies comparing formoterol and salmeterol infer that there is no increased risk of new cardiovascular adverse events either with Salmeterol or SFC. Furthermore, the combination may provide certain degree of cardio-protection. Since COPD per se increases the risk of CVD, the cardio-safety of salmeterol outweighs its onset of action. SFC has well substantiated benefits in patients with asthma, COPD and high-risk patients such as those with an overlap of COPD and asthma symptoms, patients with elevated eosinophils and pre-existing CVD. An advisory board was hence conducted, which discussed the role of combination of salmeterol and fluticasone (SFC) not only in asthma and COPD but also in asthma COPD overlap phenotype. Based on the panel's clinical experience and the expertise derived thereof, the propositions regarding the place of SFC therapy in patients with stable and uncontrolled asthma, asthma COPD overlap phenotype and COPD has been put forth.

Clinical Response and Cost-Savings Associated With Generic Fluticasone Propionate/Salmeterol Multidose, Dry-Powder Inhaler in Asthma Patients Managed in an Ambulatory Care Practice Setting.

BACKGROUND: Fluticasone propionate/salmeterol multidose, dry powder inhaler (MDPI) was the first and only authorized generic inhaled corticosteroid/long-acting beta agonist (ICS/LABA) combination inhaler at the time of this study. This offers the potential for significant prescription cost-savings for both patients and accountable care organizations. The objective of the study was to demonstrate patients' clinical response to generic fluticasone propionate/salmeterol MDPI when switched from one of its brand name competitors. METHODS: The study was approved by the Institutional Review Board at MCPHS University. This was a prospective chart review of a large, multi-center ambulatory care organization in the Greater Boston area. Patients 12 years of age or older who were switched from a brand-name ICS/LABA inhaler to the generic fluticasone/salmeterol MDPI were included in the study. The primary endpoint was worsened asthma control requiring a change in therapy, oral corticosteroid therapy, or hospitalization at or before 12 weeks after the inhaler was switched. RESULTS: In total, 203 patients met inclusion criteria. Of those 203 patients, 35 had a change in therapy due to worsened asthma control (17.2% of patients, 95% CI 12.0% to 22.4%) within 12 weeks. Total projected yearly prescription cost-savings for patients who were switched and remained on the generic inhaler was $581,628. CONCLUSION: Eighty-three percent of patients maintained appropriate asthma control after switching from a brand ICS/LABA inhaler to the generic fluticasone/salmeterol MDPI for 12 weeks. Switching to the generic inhaler resulted in significant prescription cost-savings for the accountable care organization.

Economic Evaluation of Umeclidinium/Vilanterol versus Umeclidinium or Salmeterol in Symptomatic Non-Exacerbating Patients with COPD from a UK Perspective Using the GALAXY Model.

INTRODUCTION: Dual bronchodilators are recommended as maintenance treatment for patients with symptomatic COPD in the UK; further evidence is needed to evaluate cost-effectiveness versus monotherapy. Cost-effectiveness of umeclidinium/vilanterol versus umeclidinium and salmeterol from a UK healthcare perspective in patients without exacerbations in the previous year was assessed using post hoc EMAX trial data. METHODS: The validated GALAXY model was populated with baseline characteristics and treatment effects from the non-exacerbating subgroup of the symptomatic EMAX population (COPD assessment test score ≥10) and 2020 UK healthcare and drug costs. Outputs included estimated exacerbation rates, costs, life-years (LYs), and quality-adjusted LYs (QALYs); incremental cost-effectiveness ratio (ICER) was calculated as incremental cost/QALY gained. The base case (probabilistic model) used a 10-year time horizon, assumed no treatment discontinuation, and discounted future costs and QALYs by 3.5% annually. Sensitivity and scenario analyses assessed robustness of model results. RESULTS: Umeclidinium/vilanterol treatment was dominant versus umeclidinium and salmeterol, providing an additional 0.090 LYs (95% range: 0.035, 0.158) and 0.055 QALYs (-0.059, 0.168) with total cost savings of £690 (£231, £1306) versus umeclidinium, and 0.174 LYs (0.076, 0.286) and 0.204 QALYs (0.079, 0.326) with savings of £1336 (£1006, £2032) versus salmeterol. In scenario and sensitivity analyses, umeclidinium/vilanterol was dominant versus umeclidinium except over a 5-year time horizon (more QALYs at higher total cost; ICER=£4/QALY gained) and at the lowest estimate of the St George's Respiratory Questionnaire treatment effect (fewer QALYs at lower total cost; ICER=£12,284/QALY gained); umeclidinium/vilanterol was consistently dominant versus salmeterol. At willingness-to-pay threshold of £20,000/QALY, probability that umeclidinium/vilanterol was cost-effective in this non-exacerbating subgroup was 95% versus umeclidinium and 100% versus salmeterol. CONCLUSION: Based on model predictions from a UK perspective, symptomatic patients with COPD and no exacerbations in the prior year receiving umeclidinium/vilanterol are expected to have better outcomes at lower costs versus umeclidinium and salmeterol.

Pharmacogenetic studies of long-acting beta agonist and inhaled corticosteroid responsiveness in randomised controlled trials of individuals of African descent with asthma.

BACKGROUND: Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we sought to understand the pharmacogenetic mechanisms regulating therapeutic responsiveness in individuals of African descent. METHODS: We did ancestry-based pharmacogenetic studies of children (aged 5-11 years) and adolescents and adults (aged 12-69 years) from the Best African Response to Drug (BARD) trials, in which participants with asthma uncontrolled with low-dose ICS (fluticasone propionate 50 µg in children, 100 µg in adolescents and adults) received different step-up combination therapies. The hierarchal composite outcome of pairwise superior responsiveness in BARD was based on asthma exacerbations, a 31-day difference in annualised asthma-control days, or a 5% difference in percentage predicted FEV1. We did whole-genome admixture mapping of 15 159 ancestral segments within 312 independent regions, stratified by the two age groups. The two co-primary outcome comparisons were the step up from low-dose ICS to the quintuple dose of ICS (5 × ICS: 250 µg twice daily in children and 500 µg twice daily in adolescents and adults) versus double dose (2-2·5 × ICS: 100 µg twice daily in children, 250 µg twice daily in adolescents and adults), and 5 × ICS versus 100 µg fluticasone plus a LABA (salmeterol 50 µg twice daily). We used a genome-wide significance threshold of p<1·6 × 10-4, and tested for replication using independent cohorts of individuals of African descent with asthma. FINDINGS: We included 249 unrelated children and 267 unrelated adolescents and adults in the BARD pharmacogenetic analysis. In children, we identified a significant admixture mapping peak for superior responsiveness to 5 × ICS versus 100 µg fluticasone plus salmeterol on chromosome 12 (odds ratio [ORlocal African] 3·95, 95% CI 2·02-7·72, p=6·1 × 10-5) fine mapped to a locus adjacent to RNFT2 and NOS1 (rs73399224, ORallele dose 0·17, 95% CI 0·07-0·42, p=8·4 × 10-5). In adolescents and adults, we identified a peak for superior responsiveness to 5 × ICS versus 2·5 × ICS on chromosome 22 (ORlocal African 3·35, 1·98-5·67, p=6·8 × 10-6) containing a locus adjacent to TPST2 (rs5752429, ORallele dose 0·21, 0·09-0·52, p=5·7 × 10-4). We replicated rs5752429 and nominally replicated rs73399224 in independent African American cohorts. INTERPRETATION: BARD is the first genome-wide pharmacogenetic study of LABA and ICS response in clinical trials of individuals of African descent to detect and replicate genome-wide significant loci. Admixture mapping of the composite BARD trial outcome enabled the identification of novel pharmacogenetic variation accounting for differential therapeutic responses in people of African descent with asthma. FUNDING: National Institutes of Health, National Heart, Lung, and Blood Institute.

Efficacy and safety of salmeterol/fluticasone compared with montelukast alone (or add-on therapy to fluticasone) in the treatment of bronchial asthma in children and adolescents: a systematic review and meta-analysis.

BACKGROUND: Despite the recommendation of inhaled corticosteroids (ICSs) plus long-acting beta 2-agonist (LABA) and leukotriene receptor antagonist (LTRA) or ICS/LTRA as stepwise approaches in asthmatic children, there is a lack of published systematic review comparing the efficacy and safety of the two therapies in children and adolescents aged 4 to 18 years. This study aimed to compare the safety and efficacy of salmeterol/fluticasone (SFC) vs. montelukast (MON), or combination of montelukast and fluticasone (MFC) in children and adolescents aged 4 to 18 years with bronchial asthma. METHODS: A systematic search was conducted in MEDLINE, EMBASE, the Cochrane Library, China BioMedical Literature Database, Chinese National Knowledge Infrastructure, VIP Database for Chinese Technical Periodical, and Wanfang for randomized controlled trials (RCTs) published from inception to May 24, 2021. Interventions are as follows: SFC vs. MON, or combination of MFC, with no limitation of dosage or duration. Primary and secondary outcome measures were as follows: the primary outcome of interest was the risk of asthma exacerbation. Secondary outcomes included risk of hospitalization, pulmonary function, asthma control level, quality of life, and adverse events (AEs). A random-effects (I2 ≥ 50%) or fixed-effects model (I2 < 50%) was used to calculate pooled effect estimates, comparing the outcomes between the intervention and control groups where feasible. RESULTS: Of the 1006 articles identified, 21 studies met the inclusion criteria with 2643 individuals; two were at low risk of bias. As no primary outcomes were similar after an identical treatment duration in the included studies, meta-analysis could not be performed. However, more studies favored SFC, instead of MON, owing to a lower risk of asthma exacerbation in the SFC group. As for secondary outcome, SFC showed a significant improvement of peak expiratory flow (PEF)%pred after 4 weeks compared with MFC (mean difference [MD]: 5.45; 95% confidence interval [CI]: 1.57-9.34; I2 = 95%; P = 0.006). As for asthma control level, SFC also showed a higher full-controlled level (risk ratio [RR]: 1.51; 95% CI: 1.24-1.85; I2 = 0; P < 0.001) and higher childhood asthma control test score after 4 weeks of treatment (MD: 2.30; 95% CI: 1.39-3.21; I2 = 72%; P < 0.001) compared with MFC. CONCLUSIONS: SFC may be more effective than MFC for the treatment of asthma in children and adolescents, especially in improving asthma control level. However, there is insufficient evidence to make firm conclusive statements on the use of SFC or MON in children and adolescents aged 4 to 18 years with asthma. Further research is needed, particularly a combination of good-quality long-term prospective studies and well-designed RCTs. PROSPERO REGISTRATION NUMBER: CRD42019133156.

A non-interventional switch study in adult patients with asthma or COPD on clinical effectiveness of salmeterol/fluticasone Easyhaler® in routine clinical practice.

BACKGROUND: Selection of the most appropriate device for a switch from one inhaler to an equivalent product is known to have a major impact on clinical outcomes in patients with asthma or chronic obstructive pulmonary disease (COPD). Salmeterol/fluticasone propionate (S/F) Easyhaler® has been demonstrated to be therapeutically equivalent with a reference product. However, no data on real-life effectiveness are currently available for patients switching to S/F Easyhaler from another S/F inhaler. METHODS: The aim of this prospective, open, multicenter, non-interventional study was to assess clinical effectiveness of propionate S/F Easyhaler in adult asthma and COPD patients switched from another inhaler. The primary endpoints were Asthma Control Test (ACT) and COPD Assessment Test (CAT). Secondary endpoints included assessments of patient satisfaction and preference and physician/nurse perception on S/F Easyhaler use. The study included three visits during a 12-week follow-up. RESULTS: A total of 211 patients (160 with asthma; 51 with COPD) were included in the analyses. In patients with asthma, there was a statistically significant increase in the mean ACT score at week 12 (20.2 ± 3.9) compared with the baseline (18.6 ± 4.1), with a mean increase of 1.6 (±3.5) points (p < 0.0001). In patients with COPD, CAT score persisted from baseline (19.9 ± 8.6) to week 12 (19.6 ± 7.0). Patients were significantly more satisfied with Easyhaler and most patients preferred Easyhaler over their previous inhaler. The physicians/nurses reported that it was 'very easy' to teach the use of Easyhaler and the training took less than 5 minutes in most cases. CONCLUSION: The results from this prospective real-life clinical study indicate better or at least similar treatment control of asthma and COPD after switching to S/F Easyhaler from another S/F inhaler. This study also shows that S/F Easyhaler was favored by the patients and that it is easy to teach, learn and use in a real-life setting.The reviews of this paper are available via the supplemental material section.

Medications for chronic obstructive pulmonary disease: a historical non-interventional cohort study with validation against RCT results.

BACKGROUND: Chronic obstructive pulmonary disease treatment is informed by randomised controlled trial results, but it is unclear if these findings apply to people excluded from these trials. We used data from the TORCH (TOwards a Revolution in COPD Health) randomised controlled trial to validate non-interventional methods for assessing the clinical effectiveness of chronic obstructive pulmonary disease treatment in the UK Clinical Practice Research Datalink, before applying these methods to the analysis of people who would have been excluded from TORCH. OBJECTIVES: To validate the use of non-interventional Clinical Practice Research Datalink data and methods for estimating chronic obstructive pulmonary disease treatment effects against trial results, and, using validated methods, to determine treatment effects in people who would have been excluded from the TORCH trial. DESIGN: A historical non-interventional cohort design, including validation against randomised controlled trial results. SETTING: The UK Clinical Practice Research Datalink. PARTICIPANTS: People aged ≥ 18 years with chronic obstructive pulmonary disease registered in Clinical Practice Research Datalink GOLD between January 2000 and January 2017. For objective 1, we prepared a cohort that was analogous to the TORCH trial cohort by applying TORCH trial inclusion/exclusion criteria followed by individual matching to TORCH trial participants. For objectives 2 and 3, we prepared cohorts that were analogous to the TORCH trial that, nevertheless, would not have been eligible for the TORCH trial because of age, asthma, comorbidity or mild disease. INTERVENTIONS: The long-acting beta-2 agonist and inhaled corticosteroid combination product Seretide (GlaxoSmithKline plc) [i.e. fluticasone propionate plus salmeterol (FP-SAL)] compared with (1) no FP-SAL exposure or (2) exposure to salmeterol (i.e. the long-acting beta-2 agonist) only. MAIN OUTCOME MEASURES: Exacerbations, mortality, pneumonia and time to treatment change. RESULTS: For objective 1, the exacerbation rate ratio was comparable to that in the TORCH trial for FP-SAL compared with salmeterol (0.85, 95% confidence interval 0.74 to 0.97, vs. TORCH trial 0.88, 95% confidence interval 0.81 to 0.95), but not for FP-SAL compared with no FP-SAL (1.30, 95% confidence interval 1.19 to 1.42, vs. TORCH trial 0.75, 95% confidence interval 0.69 to 0.81). Active comparator results were also consistent with the TORCH trial for mortality (hazard ratio 0.93, 95% confidence interval 0.65 to 1.32, vs. TORCH trial hazard ratio 0.93, 95% confidence interval 0.77 to 1.13) and pneumonia (risk ratio 1.39, 95% confidence interval 1.04 to 1.87, vs. TORCH trial risk ratio 1.47, 95% confidence interval 1.25 to 1.73). For objectives 2 and 3, active comparator results were consistent with the TORCH trial for exacerbations, with the exception of people with milder chronic obstructive pulmonary disease, in whom we observed a stronger protective association (risk ratio 0.56, 95% confidence interval 0.46 to 0.70, vs. TORCH trial risk ratio 0.85, 95% confidence interval 0.74 to 0.97). For the analysis of mortality, we saw a lack of association with being prescribed FP-SAL (vs. being prescribed salmeterol), with the exception of those with prior asthma, for whom we observed an increase in mortality (hazard ratio 1.49, 95% confidence interval 1.21 to 1.85, vs. TORCH trial-analogous HR 0.93, 95% confidence interval 0.64 to 1.32). CONCLUSIONS: Routinely collected electronic health record data can be used to successfully measure chronic obstructive pulmonary disease treatment effects when comparing two treatments, but not for comparisons between active treatment and no treatment. Analyses involving patients who would have been excluded from trials mostly suggests that treatment effects for FP-SAL are similar to trial effects, although further work is needed to characterise a small increased risk of death in those with concomitant asthma. LIMITATIONS: Some of our analyses had small numbers. FUTURE WORK: The differences in treatment effects that we found should be investigated further in other data sets. Currently recommended chronic obstructive pulmonary disease inhaled combination therapy (other than FP-SAL) should also be investigated using these methods. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 51. See the NIHR Journals Library website for further project information.

Chronic obstructive pulmonary disease affects 3 million people in the UK and is characterised by breathing difficulties that get worse over time, with sudden acute symptoms (exacerbations), possibly requiring hospitalisation. The evidence for use of medicines for treating chronic obstructive pulmonary disease comes from randomised controlled trial results. Randomised controlled trials generally include younger people with severe disease who do not have any other illnesses apart from chronic obstructive pulmonary disease, meaning that the effectiveness of these trials in all people with chronic obstructive pulmonary disease is unknown. Very large databases of anonymous electronic health records captured during NHS consultations can be used to study patients excluded from trials. However, confidence in results from studies using these data can be low because of fears of unaccounted bias, as patients are not randomised to treatment. In this project, we selected a group of patients from a very large electronic health record database called the Clinical Practice Research Datalink who were very similar to participants in a well-known large chronic obstructive pulmonary disease randomised controlled trial [the TORCH (TOwards a Revolution in COPD Health) trial]. When we analysed data from these patients, we found very similar results to the TORCH trial in relation to the reduction of exacerbations, development of pneumonia and time until death, when comparing one chronic obstructive pulmonary disease treatment with another. Having shown that our methods could be trusted to produce valid results when comparing one chronic obstructive pulmonary disease treatment with another, we then went on to analyse patients in the Clinical Practice Research Datalink who would have been excluded from the TORCH trial for the following reasons: aged > 80 years, having asthma as well as chronic obstructive pulmonary disease, or having only mild chronic obstructive pulmonary disease. For exacerbations, we found that, for people with milder chronic obstructive pulmonary disease, one of the treatments we studied seemed to work better than in the trial. For the analysis of mortality, we found that, for people with asthma as well as chronic obstructive pulmonary disease, one of the treatments seemed not to work so well, with more people dying. Future studies are needed in different populations (such as in a database from another country) to confirm these results.

Treatment of COPD with Long-Acting Bronchodilators: Association Between Early and Longer-Term Clinically Important Improvement.

INTRODUCTION: This post hoc analysis of the "Early MAXimization of bronchodilation for improving COPD stability" (EMAX) trial investigated whether patients achieving early clinically important improvement (CII) sustained longer-term improvements and lower risk of clinically important deterioration (CID). METHODS: Patients were randomized to umeclidinium/vilanterol, umeclidinium, or salmeterol for 24 weeks. The patient-reported outcomes (PROs) Transition Dyspnea Index (TDI), Evaluating Respiratory Symptoms, St George's Respiratory Questionnaire (SGRQ) and COPD Assessment Test (CAT) were assessed. CII, defined as attaining minimum clinically important differences (MCID) in ≥2 PROs, was assessed at Weeks 4, 12 and 24. CID was defined as a deterioration in CAT, SGRQ, TDI by the MCID and/or a moderate/severe exacerbation from Day 30. RESULTS: Of 2425 patients, 50%, 53% and 51% achieved a CII at Weeks 4, 12 and 24, respectively. Patients with a CII at Week 4 versus those without had significantly greater odds of achieving a CII at Weeks 12 and 24 (odds ratio: 5.57 [95% CI: 4.66, 6.66]; 4.09 [95% CI: 3.44, 4.86]). The risk of a CID was higher in patients who did not achieve a CII at Week 4 compared with patients who did (hazard ratio [95% CI]: 2.09 [1.86, 2.34]). Patients treated with umeclidinium/vilanterol versus either monotherapy had significantly greater odds of achieving CII at Weeks 4, 12 and 24. CONCLUSION: Achieving a CII at Week 4 was associated with longer-term improvement in PROs and a reduced risk of deterioration. Further research is required to investigate the importance of an early response to treatment on the long-term disease course.

Comparison of the effect of fluticasone combined with salmeterol and fluticasone alone in the treatment of pediatric asthma.

INTRODUCTION: A systematic review and meta-analysis was performed to investigate the effect of fluticasone + salmeterol and fluticasone alone in the treatment of pediatric asthma. EVIDENCE ACQUISITION: Studies meeting specific selection criteria were selected from online databases, including Pubmed, Embase, and the Cochrane Library. The quality of randomized controlled trials was assessed using the Cochrane Library. Weighted mean difference (WMD) and 95% CI were used to evaluate the effect size of continuous variables, while rate ratio (RR) and 95% CI were used for dichotomous variables. EVIDENCE SYNTHESIS: A total of 11 studies, including 8272 pediatric asthma patients, were included in this meta-analysis. Among these, 4133 patients were in the salmeterol + fluticasone group. The changes in forced expiratory volume in 1 second in children with asthma in the salmeterol + fluticasone and fluticasone alone groups were significantly different (fixed effects model, WMD=3.26, 95% CI: 1.52-5.00, P=0.0002). Asthma exacerbation between two groups were significantly different (fixed effects model, RR=0.85, 95% CI: 0.73-0.98, Z=2.18, P=0.03). There was no difference in the incidence of adverse events between salmeterol + fluticasone and fluticasone alone in the treatment of pediatric asthma (P>0.05). When the control group was treated with double dose fluticasone, the difference of changes in FEV1 and asthma exacerbation in children with asthma between the two groups was not significant. CONCLUSIONS: The efficacy of salmeterol + fluticasone is better than fluticasone alone, and the efficacy of salmeterol + fluticasone is equal to doubling the dose of fluticasone in the treatment of pediatric asthma.

Comparison of fractional exhaled nitric oxide in asthmatics with and without allergic rhinitis.

PURPOSE OF THE STUDY: The aim of this study was to measure the concentration of FeNO in asthmatics with and without allergic rhinitis (AR) and to determine usefulness of the test in the assessment of asthma control in the Polish population. The next objective of this study was to estimate the cut-off point of FeNO which might be a good indicator of uncontrolled asthma. MATERIALS AND METHODS: The measurements were taken using the Hyp'Air FeNO in 303 adult patients with asthma, AR, comorbid AR and asthma, and non-diseased volunteers. RESULTS: FeNO level in healthy adults was similar to the FeNO concentration in AR as well as controlled asthmatic patients without and with AR. Patients with partly controlled and uncontrolled asthma with and without AR had higher FeNO (>60 ppb) levels when compared to adults with controlled disease. The optimal cut-off point of FeNO > 46 ppb and FeNO > 33 ppb was estimated for identification of uncontrolled asthmatics without and with AR, respectively. CONCLUSION: In conclusion, we found a significant correlation between the FeNO concentration and the level of asthma symptom control in asthmatic patients with and without AR.

Efficacy and safety of salmeterol/fluticasone compared with montelukast alone (or add-on therapy to fluticasone) in the treatment of bronchial asthma in children and adolescents: a systematic review and meta-analysis / 中华医学杂志(英文版)

BACKGROUND@#Despite the recommendation of inhaled corticosteroids (ICSs) plus long-acting beta 2-agonist (LABA) and leukotriene receptor antagonist (LTRA) or ICS/LTRA as stepwise approaches in asthmatic children, there is a lack of published systematic review comparing the efficacy and safety of the two therapies in children and adolescents aged 4 to 18 years. This study aimed to compare the safety and efficacy of salmeterol/fluticasone (SFC) vs. montelukast (MON), or combination of montelukast and fluticasone (MFC) in children and adolescents aged 4 to 18 years with bronchial asthma.@*METHODS@#A systematic search was conducted in MEDLINE, EMBASE, the Cochrane Library, China BioMedical Literature Database, Chinese National Knowledge Infrastructure, VIP Database for Chinese Technical Periodical, and Wanfang for randomized controlled trials (RCTs) published from inception to May 24, 2021. Interventions are as follows: SFC vs. MON, or combination of MFC, with no limitation of dosage or duration. Primary and secondary outcome measures were as follows: the primary outcome of interest was the risk of asthma exacerbation. Secondary outcomes included risk of hospitalization, pulmonary function, asthma control level, quality of life, and adverse events (AEs). A random-effects (I2 ≥ 50%) or fixed-effects model (I2 < 50%) was used to calculate pooled effect estimates, comparing the outcomes between the intervention and control groups where feasible.@*RESULTS@#Of the 1006 articles identified, 21 studies met the inclusion criteria with 2643 individuals; two were at low risk of bias. As no primary outcomes were similar after an identical treatment duration in the included studies, meta-analysis could not be performed. However, more studies favored SFC, instead of MON, owing to a lower risk of asthma exacerbation in the SFC group. As for secondary outcome, SFC showed a significant improvement of peak expiratory flow (PEF)%pred after 4 weeks compared with MFC (mean difference [MD]: 5.45; 95% confidence interval [CI]: 1.57-9.34; I2 = 95%; P = 0.006). As for asthma control level, SFC also showed a higher full-controlled level (risk ratio [RR]: 1.51; 95% CI: 1.24-1.85; I2 = 0; P < 0.001) and higher childhood asthma control test score after 4 weeks of treatment (MD: 2.30; 95% CI: 1.39-3.21; I2 = 72%; P < 0.001) compared with MFC.@*CONCLUSIONS@#SFC may be more effective than MFC for the treatment of asthma in children and adolescents, especially in improving asthma control level. However, there is insufficient evidence to make firm conclusive statements on the use of SFC or MON in children and adolescents aged 4 to 18 years with asthma. Further research is needed, particularly a combination of good-quality long-term prospective studies and well-designed RCTs.@*PROSPERO REGISTRATION NUMBER@#CRD42019133156.

[Systematic review and Meta-analysis on efficacy and safety of Liujunzi Decoction combined with Western medicine for stable chronic obstructive pulmonary disease].

To systematically review the efficacy and safety of Liujunzi Decoction combined with Western medicine in the treatment of stable chronic obstructive pulmonary disease(COPD). Three English databases and four Chinese databases were systematically searched from the database establishment to April 1, 2020. We screened randomized controlled trial(RCT) according to the pre-determined inclusion and exclusion criteria, then extracted data. Methodological quality of included studies was assessed with Cochrane bias risk evaluation tool. Data were analyzed by using RevMan 5.3. A total of 401 articles were retrieved and finally 17 RCTs were included in this study, involving 1 447 patients, and the overall quality of the included studies was not high. Meta-analysis showed that, in reducing traditional Chinese medicine symptom score, Liujunzi Decoction combined with conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation was superior to conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In reducing the grade of modified medical research council(mMRC), Liujunzi Decoction combined with Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation was superior to Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In reducing COPD assessment test(CAT) score, Liujunzi Decoction combined with conventional Western medicine was superior to conventional Western medicine alone. In delaying the decline of forced expiratory volume in one second(FEV_1) or % in the expected value, Liujunzi Decoction combined with conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation was superior to conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In delaying the decline of ratio of FEV_1 to forced vital capacity(FEV_1/FVC), Liujunzi Decoction combined with conventional Western medicine was superior to conventional Western medicine alone, but there was no statistical difference between Liujunzi Decoction combined with Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation and Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In reducing acute exacerbation rate, there was no statistical difference between Liujunzi Decoction combined with Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation and Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. On the other outcome measures of Liujunzi Decoction combined with other Western medicine, Meta-analysis could not be conducted and conclusions due to the inclusion of only one study. In terms of the occurrence of adverse reactions, some studies did not mention, so the safety of Liujunzi Decoction combined with Wes-tern medicine could not be determined in this paper. Due to the limitations of the quality and quantity of inclu-ded studies, the efficacy of Liujunzi Decoction combined with Western medicine for COPD still needs more high-quality studies for confirmation, and its safety needs to be further verified.