Asthma prescribing trends, inhaler adherence and outcomes: a Real-World Data analysis of a multi-ethnic Asian Asthma population.

Inhaled corticosteroid (ICS) is the mainstay therapy for asthma, but general adherence is low. There is a paucity of real-world inhaler prescribing and adherence data from Asia and at the population level. To address these gaps, we performed a real-world data analysis of inhaler prescribing pattern and adherence in a multi-ethnic Asian asthma cohort and evaluated the association with asthma outcomes. We performed a retrospective analysis of adult asthma patients (aged ≥18 years) treated in the primary and specialist care settings in Singapore between 2015 to 2019. Medication adherence was measured using the medication possession ratio (MPR), and categorised into good adherence (MPR 0.75-1.2), poor adherence (MPR 0.75) or medication oversupply (MPR > 1.2). All statistical analyses were performed using R Studio. 8023 patients, mean age 57 years, were evaluated between 2015 and 2019. Most patients were receiving primary care (70.4%) and on GINA step 1-3 therapies (78.2%). ICS-long-acting beta-2 agonist (ICS-LABA) users increased over the years especially in the primary care, from 33% to 52%. Correspondingly, inpatient admission and ED visit rates decreased over the years. Between 2015 and 2019, the proportion of patients with poor adherence decreased from 12.8% to 10.5% (for ICS) and from 30.0% to 26.8% (for ICS-LABA) respectively. Factors associated with poor adherence included minority ethnic groups (Odds ratio of MPR 0.75-1.2: 0.73-0.93; compared to Chinese), presence of COPD (OR 0.75, 95% CI 0.59-0.96) and GINA step 4 treatment ladder (OR 0.71, 95% CI 0.61-0.85). Factors associated with good adherence were male gender (OR 1.14, 95% CI 1.01-1.28), single site of care (OR 1.22 for primary care and OR 1.76 for specialist care), GINA step 2 treatment ladder (OR 1.28, 95% CI 1.08-1.50). Good adherence was also associated with less frequent inpatient admission (OR 0.91, 95% CI 0.84-0.98), greater SABA overdispensing (OR 1.66, 95% CI 1.47-1.87) and oral corticosteroids use (OR 1.10, 95% CI 1.05-1.14). Inhaled corticosteroid (ICS) adherence has improved generally, however, poor adherence was observed for patients receiving asthma care in both primary and specialist care, and those from the minority ethnicities.

Comparative effectiveness and safety of escalating to triple therapy versus switching to dual bronchodilators after discontinuing LABA/ICS in patients with COPD: a retrospective cohort study.

BACKGROUND: The latest guidelines discourage the use of long-acting beta2-agonists/inhaled corticosteroids (LABA/ICS) for chronic obstructive pulmonary disease (COPD). However, there is a lack of evidence regarding the optimal subsequent treatment after discontinuing LABA/ICS. OBJECTIVES: To compare the effectiveness and safety of switching from LABA/ICS to triple therapy (LABA/long-acting muscarinic antagonists (LAMA)/ICS) or to dual bronchodilators (LABA/LAMA) in COPD patients. DESIGN: This was a new-user, active-comparator, and propensity score-matched cohort study analyzing the Taiwanese nationwide healthcare insurance claims. METHODS: We recruited COPD patients switching from LABA/ICS to triple therapy or to dual bronchodilators from 2015 to 2019. The primary effectiveness outcome was the annual rate of exacerbations, and safety outcomes included severe pneumonia and all-cause mortality. Stratification by prior exacerbations was conducted. RESULTS: After matching, each group comprised 1892 patients, 55% of whom experienced no exacerbations in the prior year. Treatment with LABA/LAMA/ICS versus LABA/LAMA showed comparable annual rate of moderate-to-severe exacerbations (incidence rate ratio, 1.04; 95% confidence interval (CI), 0.91-1.19). However, switching to LABA/LAMA/ICS was associated with increased risks of severe pneumonia (hazard ratio (HR), 1.65; 95% CI, 1.30-2.09) and all-cause death (HR, 1.39; 95% CI, 1.09-1.78). In patients with⩾2 prior exacerbations, LABA/LAMA/ICS versus LABA/LAMA was related to a 21% reduced rate of exacerbations but with a twofold increased pneumonia risk and a 49% elevated risk of all-cause mortality. CONCLUSION: Switching from LABA/ICS to triple therapy versus dual bronchodilators in COPD patients was associated with similar rates of annual exacerbations but was related to elevated risks of severe pneumonia and all-cause mortality. Among frequent exacerbators, triple therapy was associated with lower rates of exacerbation but was accompanied by increased risks of pneumonia and mortality compared to LABA/LAMA. Careful consideration of the examined safety events is necessary when switching from LABA/ICS to triple therapy in COPD management.

Benefit of dual bronchodilator therapy on exacerbations in former and current smokers with chronic obstructive pulmonary disease in real-world clinical practice: a multicenter validation study (TOReTO).

BACKGROUND: Dual bronchodilator therapy, consisting of a long-acting beta-agonist (LABA) and a long-acting muscarinic antagonist (LAMA), has proven effective for patients with chronic obstructive pulmonary disease (COPD). However, it remains uncertain whether there are efficacy differences between current and former smokers with COPD. This study aims to explore the effectiveness of LABA/LAMA therapies in both these groups. METHODS: The TOReTO trial assessed lung function, symptoms, health status, the occurrence of exacerbations, clinically significant exacerbations, and the use of LABA/LAMA therapies. These therapies include Tio/Olo, umeclidinium/vilanterol (Umec/Vi), and umeclidinium/vilanterol (Umec/Vi) are used in patients with COPD. The study examined the differences in outcomes between current and former smokers. To balance the baseline characteristics, propensity score matching (PSM) was employed. RESULTS: Data from 967 patients were collected. After PSM, the time to the first acute exacerbation in current smokers was analyzed separately for the three treatment groups and was significantly different between them (p = 0.0457). Among, there are differences in the occurrence of acute exacerbation between treatment and smoking status in Umec/Vi (p = 0.0114). There is no significant difference in the treatment of former smokers among the three different groups of LABA/LAMA fixed-dose combinations (p = 0.3079). COPD-related symptoms remained stable throughout the treatment period. There were no significant differences in symptom scores, including CAT and mMRC, among the three groups at the end of the study. CONCLUSIONS: The three fixed-dose combinations of LABA/LAMA showed no difference in reducing exacerbations in former smokers but did show differences in current smokers. This trend has clinical significance, and future research will be conducted to control influencing variables to validate this point. However, due to the non-randomized study design, these findings should be interpreted with caution.

Left ventricular systolic function after inhalation of beta-2 agonists in healthy athletes.

Inhaled beta-2 adrenoceptor agonists (iß2A) are routinely used as bronchodilators in the treatment of asthma. However, their cardiac effects in athletes are scarcely examined. Thus, the aim of this study was to evaluate the effects of iß2A on left ventricular (LV) systolic function (SF) by echocardiography in healthy, non-asthmatic female and male endurance athletes. A randomized, double-blinded, placebo-controlled, balanced, 4-way complete block cross-over study was conducted. Twenty-four healthy athletes (12f/12m: 22.9 ± 2.7/24.4 ± 4.6 years) randomly completed 4 study arms (placebo; salbutamol; formoterol; formoterol + salbutamol). After inhalation of the study medication, the participants performed a 10-min time trial (TT) on a bicycle ergometer. After each TT an echocardiography was performed to determine LVSF. Blood samples were collected pre, post, 3 h and 24 h post TT. In females, total serum concentrations for salbutamol and formoterol were higher. LV ejection fraction (LVEF) and LV global longitudinal strain (LVendoGLS) showed a treatment effect for the whole study group (p < 0.0001) and a sex effect on LVEF (p = 0.0085). In women, there was a significant treatment effect for all medication arms (at least p ≤ 0.01) both on LVEF and LVendoGLS. In men only formoterol and formoterol + salbutamol displayed a treatment effect on LVEF (p = 0.0427, p = 0.0330; respectively), whereas on LVendoGLS only formoterol + salbutamol was significant (p = 0.0473). The iß2A significantly influenced LVSF after an acute bout of exercise in healthy endurance athletes. These effects were even more pronounced when combining both iß2A that supports a dose-dependent effect on cardiac function. Moreover, female athletes had higher serum concentrations of ß2 agonists and stronger effects on LVSF compared to male athletes. This is mainly explained by differences in body weight and related plasma volume and may indicate a potential risk when increasing dose above the tested concentrations. Trial registration: At the European Union Drug Regulating Authorities Clinical Trials (Eudra CT) with the number 201,500,559,819 (registered prospectively on 09/12/2015) and at the German register for clinical studies (DRKS number 00010574 registered retrospectively on 16/11/2021).

Baseline patient demographics for TETRIS: a prospective, noninterventional study to characterize the use of triple therapy for COPD in Germany.

BACKGROUND: Evidence on how decisions regarding escalation to triple therapy and de- or re-escalation are taken and the rationale on which these decisions are based is currently limited in Germany. OBJECTIVES: The TETRIS study aims to elucidate influences on treatment decisions surrounding triple therapy in a real-world practice setting in Germany. DESIGN: TETRIS is an ongoing, multicenter, prospective, observational cohort study recruiting patients with chronic obstructive pulmonary disease (COPD) with or without asthma who have already been treated with triple therapy for 2-48 weeks. METHODS: For better representation of the treatment reality in Germany, patients are recruited from general practitioners and pulmonologists. Data are collected in two parts. Part 1 involves cross-sectional phenotyping of patients at enrollment. Part 2 involves a 2-year longitudinal follow-up period to monitor/document all visits by the patients during the 24-month observation period per routine clinical practice. Here, we report the demographic and baseline characteristics of 1213 eligible patients recruited to part 1 of the study. RESULTS: The mean patient age was 66.4 years overall, and 29.3% (356/1213) of patients had no comorbidities. The mean CAT score was 19.4; the number of exacerbations and hospitalizations due to exacerbations in the past 3 years before starting triple therapy was 0.6 and 0.1, respectively. Dual bronchodilation with a long-acting muscarinic antagonist (LAMA) plus a long-acting ß-2 agonist (LABA) was the most common therapy for COPD before initiation of triple therapy in 58.3% of patients. CONCLUSION: In this real-world setting in Germany, patients with COPD have a relatively low reported exacerbation rate but high symptom burden, and over 70% are multimorbid. Triple therapy is initiated in patients who are primarily highly symptomatic despite being on LAMA + LABA. Future prospective studies in patients with multimorbidity are warranted to better understand the treatment landscape across the disease spectrum. TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT04657211.

Long-acting muscarinic antagonist and long-acting ß2-agonist combination for the treatment of maintenance therapy-naïve patients with chronic obstructive pulmonary disease: a narrative review.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Faster lung function impairment occurs earlier in the disease, particularly in mild-to-moderate COPD, highlighting the need for early and effective targeted interventions. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2024 report recommends initial pharmacologic treatment with a long-acting muscarinic antagonist (LAMA) and long-acting ß2-agonist (LABA) combination in group B (0 or 1 moderate exacerbation not leading to hospitalization, modified Medical Research Council score of ⩾2, and COPD Assessment Test™ score of ⩾10) and E (⩾2 moderate exacerbations or ⩾1 exacerbation leading to hospitalization and blood eosinophil count <300 cells/µL) patients. In randomized controlled trials (RCTs), LAMA/LABA combination therapy improved lung function, St. George's Respiratory Questionnaire (SGRQ) total score, and Transitional Dyspnea Index (TDI) focal score and reduced the use of rescue medications, exacerbation risk, and risk of first clinically important deterioration (CID), compared with LAMA or LABA monotherapy. However, there is limited evidence regarding the efficacy and safety of LAMA/LABA combination therapy versus LAMA or LABA monotherapy in maintenance therapy-naïve patients. This review discusses the rationale for the early initiation of LAMA/LABA combination therapy in maintenance therapy-naïve patients with COPD. In post hoc analyses of pooled data from RCTs, compared with LAMA or LABA monotherapy, LAMA/LABA combination therapy improved lung function and quality of life and reduced COPD symptoms, risk of first moderate/severe exacerbation, risk of first CID, and use of rescue medication, with no new safety signals. In a real-world study, patients initiating LAMA/LABA had significantly reduced risk of COPD-related inpatient admissions and rate of on-treatment COPD-related inpatient admissions over 12 months than those initiating LAMA. Consequently, LAMA/LABA combination therapy could be considered the treatment of choice in maintenance therapy-naïve patients with COPD, as recommended by the GOLD 2024 report.

Long-acting bronchodilator combination therapy for the treatment of maintenance therapy­naïve patients with chronic obstructive pulmonary diseaseChronic obstructive pulmonary disease (COPD) is a common lung disease that makes it hard to breathe and is a leading cause of death and disability worldwide. This disease tends to worsen lung function from an early stage, especially in people who only have mild or moderate symptoms. To help stop the loss of lung function and maintain the quality of life for patients with COPD, two main types of long-lasting inhaler medications are used: one type focuses on relaxing the muscles around the airways, and the other type helps open the airways making it easier to breathe. Some medications combine these two types of action and are approved for long-term management of COPD. However, there is not much information on the effectiveness and safety of these combination medications in patients who have never taken long-lasting COPD medication before. Current health guidelines suggest starting these combination medications in patients who are likely to see their symptoms get worse quickly, and who do not have a high level of a specific type of white blood cell. In this review, we discuss the evidence for starting these combination treatments early in patients who have never used long-lasting COPD medications before. There is no strong evidence yet that shows starting treatment early benefits patients with newly diagnosed COPD. However, about 30% of patients in clinical trials designed to study the effectiveness of these combination medications, had never received any long-lasting treatment before. After-the-fact analyses of these patients showed that these combination medications could reduce symptoms such as breathlessness, improve lung function, enhance quality of life, lessen the need for emergency medications, and decrease the risk of severe symptom flare-ups. Overall, the evidence supports using these combination inhaler medications as the first choice of treatment for patients with moderate COPD symptoms who have not previously been treated with long-lasting inhalers.

Clinical reasoning amongst paramedics using nebulised ß2 agonists to treat acute asthma exacerbations: a qualitative study.

The heterogeneous nature of asthma results in a wide range of presentations during exacerbation. Despite UK pre-hospital management guidelines focusing on ß2 agonists, variables such as cause, severity, underlying health, comorbidities, and drug side effects can often make emergency treatment optimisation difficult. This article examines paramedics' methods of observing, perceiving, interpreting, and treating asthma with ß2 agonists, often acting on limited information in rapidly evolving situations. We recruited paramedics from a single UK National Health Service ambulance Trust for qualitative semi-structured interviews. Responses underwent framework analysis to identify data similarities and differences. Fifteen qualitative interviews with paramedics revealed three main themes affecting patient management: clinician experience of presentation, adaptation of patient management approaches, and severity of side effects. Paramedics felt their ability to manage various asthma presentations was enhanced through guideline adaptation based on their own clinical experience and understanding of ß2 agonist side effects, allowing tailored responses based on a set of reinforcing factors. Inductive analysis revealed additional complexities within these themes, such as anxiety and diabetes, which may influence ß2 agonist administration and result in multiple care pathways being initiated during exacerbation. Paramedic care mirrors asthma's complexity, accounting for a range of characteristics. A dynamic, critically thought approach enables patient management to be based on the presenting conditions rather than strict adherence to a single algorithm. Comprehending the complexities and variables in treatment can be crucial to how paramedics rationalise their treatment and optimise the care provided.

The Real-World Efficacy of Fixed Triple Inhalation Therapy in the Treatment of Moderate COPD Patients (RATIONALE Study).

Purpose: COPD affects more than 300 million people worldwide, requiring inhalation treatment. Novel triple formulations of ICS, LABAs and LAMAs are becoming the mainstay of treatment, however there is still a lack of clinical evidence for personalized therapy. Patients and Methods: RATIONALE was a non-interventional, prospective, 52 week study, assessing the effectiveness of beclometasone/formoterol/glycopyrronium-bromide (BDP/FF/G), in symptomatic COPD patients, with moderate airflow obstruction. The study included 4 visits, where data on demographic parameters, exacerbations, symptoms, quality of life (based on the EQ-5D-3L questionnaire) and lung function were collected. Data on adherence to treatment, based on prescriptions filled was collected from the database of the National Health Insurance Fund, with the patients' consent. The primary objective was the change of adherence to treatment during the study, compared to baseline. Results: Altogether 613 patients had been enrolled. Their average age was 64.56 years and 50.5% were female. The average CAT score was 20.86, and most patients had suffered minimum one exacerbation (82.2%). Average FEV1 was 59.6%. Most patients had some limitation in one or more dimensions of EQ-5D-3L, with an average visual analogue scale score (VAS) of 60.31. After 12 months of treatment, adherence improved significantly - proportion of patients in the highest adherence group increased from 29.8% to 69.7% (p<0.001). The average CAT score improved by 7.02 points (95% CI 5.82-8.21, p<0.001). There was a significant improvement in all dimensions of EQ-5D-3L, with an average increase of 17.91 (95% CI 16.51-19.31, p< 0.001) points in the VAS score. Exacerbation frequency also decreased significantly. Conclusion: Although limitations of observational studies are present, we observed that early introduction of fixed triple combination results in a marked improvement in adherence to treatment, symptom scores, exacerbation frequency and quality of life. The optimal choice of treatment is crucial for reaching the highest possible adherence.

Baseline Characteristics and Maintenance Therapy Choice on Symptom Control, Reliever Use, Exacerbation Risk in Moderate-Severe Asthma: A Clinical Modelling and Simulation Study.

INTRODUCTION: Although some factors associated with asthma symptom deterioration and risk of exacerbation have been identified, these are not yet fully characterised. We conducted a clinical modelling and simulation study to understand baseline factors affecting symptom control, reliever use and exacerbation risk in patients with moderate-severe asthma during follow-up on regularly dosed inhaled corticosteroid (ICS) monotherapy, or ICS/long-acting beta2-agonist (LABA) combination therapy. METHODS: Individual patient data from randomised clinical trials (undertaken between 2001 and 2019) were used to model the time course of symptoms (n = 7593), patterns of reliever medication use (n = 3768) and time-to-first exacerbation (n = 6763), considering patient-specific and extrinsic factors, including treatment. Model validation used standard graphical and statistical criteria. Change in symptom control scores (Asthma Control Questionnaire 5 [ACQ-5]), reduction in reliever use and annualised exacerbation rate were then simulated in patient cohorts with different baseline characteristics and treatment settings. RESULTS: Being a smoker, having higher baseline ACQ-5 and body mass index affected symptom control scores, reliever use and exacerbation risk (p < 0.01). In addition, low forced expiratory volume in 1 s percent predicted, female sex, season and previous exacerbations were found to contribute to a further increase in exacerbation risk (p < 0.01), whereas long asthma history was associated with more frequent reliever use (p < 0.01). These effects were independent from the underlying maintenance therapy. In different scenarios, fluticasone furoate (FF)/vilanterol was associated with greater reductions in reliever use and exacerbation rates compared with FF or fluticasone propionate (FP) alone or budesonide/formoterol, independently from other factors (p < 0.01). CONCLUSIONS: This study provided further insight into the effects of individual baseline characteristics on treatment response and highlighted significant differences in the performance of ICS/LABA combination therapy on symptom control, reliever use and exacerbation risk. These factors should be incorporated into clinical practice as the basis for tailored management of patients with moderate-severe asthma.

In this study we quantified how individual baseline patient characteristics at the start of treatment influence the response to regular maintenance medication. Specifically, using computer modelling and simulations based on data from individual patients enrolled into clinical trials in moderate­severe asthma, we predicted how much reliever inhaler they need, how well they rate their asthma control, and how likely an asthma attack (exacerbation) is to occur within the next 12 months. Simulation scenarios were then implemented to evaluate opportunities to improve and personalise real-life management of patients in clinical practice. Considering symptom control level, reliever use and other patient-specific factors at the start of treatment, we assessed how well maintenance therapy with inhaled corticosteroids/bronchodilators contributes to symptom improvement and/or reduction in the risk of asthma attacks. These scenarios show that current smokers, people with higher asthma symptom scores, who are obese, and have a longer history of asthma tend to use their reliever inhalers more often. Moreover, this was linked to a higher risk of having an asthma attack and worse symptom control. This pattern appears to compensate in most cases for the effect of the same baseline factors on symptom control. Switching patients who are not responding well to initial treatment with the inhaled corticosteroid, fluticasone propionate, to fluticasone furoate/vilanterol resulted in a significantly greater reduction in reliever inhaler use and risk of asthma attack, compared with those switched to budesonide/formoterol. These findings highlight the importance of tailored choices for optimal management of patients with moderate­severe asthma.

Evaluation of Adherence and Persistence to Triple Therapy in Patients with COPD: A German Claims Data Study.

Purpose: Triple therapy (long-acting muscarinic antagonist/long-acting ß2-agonist/inhaled corticosteroid) is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience recurrent exacerbations. Multiple-inhaler triple therapy (MITT) is associated with poor adherence and persistence. This study assessed comparative adherence and persistence to single-inhaler triple therapy (SITT) versus MITT among patients with COPD in a real-world setting in Germany. Patients and Methods: This retrospective analysis using the WIG2 benchmark database identified patients with COPD newly initiating triple therapy with MITT or SITT (fluticasone furoate/umeclidinium/vilanterol [FF/UMEC/VI] or formoterol/beclomethasone/glycopyrronium bromide [FOR/BDP/GLY]) November 2017-June 2019. Eligible patients were ≥35 years with 1 year's continual insurance prior to triple therapy initiation and no previous record of triple therapy. Inverse probability of treatment weighting was used to balance baseline characteristics. Adherence was measured using proportion of days covered (PDC) at 6, 12, and 18 months post-treatment initiation; persistence (time until treatment discontinuation) was measured at 6, 12, and 18 months, with a gap of >30 days used to define non-persistence. Results: Of 5710 patients included in the analysis (mean age 66 years), 71.4% initiated MITT and 28.6% initiated SITT (FF/UMEC/VI: 41.4%; FOR/BDP/GLY: 58.6%). Mean PDC was higher among SITT versus MITT users at all time points; at each time point, mean PDC was highest among FF/UMEC/VI users. During the first 6 months following treatment initiation, higher adherence was exhibited by FF/UMEC/VI (29%) and FOR/BDP/GLY (19%) users versus MITT users. Over the entire observation period, FF/UMEC/VI users had the highest proportion of persistent patients; at 18 months, 16.5% of FF/UMEC/VI users were persistent versus 2.3% of MITT users. Conclusion: Patients initiating SITT in Germany had significantly higher adherence and persistence compared with patients initiating MITT over 6 to 18 months following treatment initiation. Among SITT, FF/UMEC/VI users had the highest proportion of adherence and persistence.

Uncovering patterns of inhaler technique and reliever use: the value of objective, personalized data from a digital inhaler.

Electronic inhalers provide information about patterns of routine inhaler use. During a 12-week study, 360 asthma patients using albuterol Digihaler generated 53,083 inhaler events that were retrospectively analyzed. A total of 41,528 (78%) of the recorded inhalation events were suitable for flow analysis (having a PIF ≥ 18 L/min and <120 L/min). Median PIF, inhalation volume, inhalation duration, and time to PIF for these events steadily decreased between the first and last 10 days of the study, by 5.1%, 12.6%, 15.9%, and 6.4%, respectively. Continuous short-acting beta2-agonist (SABA) overuse, defined as ≥2 SABA inhalations/week throughout the study period, was seen in 29% (n = 104) of patients. Of 260 patients with ≥1 instance of acute short-term SABA overuse, 55 (21%) had a confirmed exacerbation. Electronic recording of real-life inhaler use can capture valuable, objective information that could inform disease management and clinical decision-making.

Retrospective, observational study of different medication regimens and outcome in children with cough variant asthma.

OBJECTIVE: This retrospective longitudinal cohort study aimed to explore the best therapeutic regimen and treatment duration of cough variant asthma (CVA) in children. METHODS: A total of 314 children with CVA were divided into receive inhaled corticosteroids (ICS) combined with long-acting beta2-agonist (LABA) group, ICS combined with leukotriene receptor antagonists (LTRA) group, ICS monotherapy group and LTRA monotherapy group. All clinical data were statistically analyzed. Logistic regression model was used to compare the advantages and disadvantages of different treatment schemes at each follow-up time point and the best treatment scheme. The Cox proportional hazard regression model based on inverse probability weighting was used to compare the effects of different medication regimens on adverse outcomes with asthma recurrence or progression as the end point. RESULTS: (1) After comprehensive analysis, ICS + LABA group was the preferred control regimen for CVA within 8 weeks. After 8 weeks of diagnosis, the efficacy of ICS group or LTRA group was comparable to that of ICS + LABA group and ICS + LTRA group. (2) The ICS + LABA group showed a significant improvement in cough at an early stage, particularly at 4 weeks; the symptoms of ICS + LTRA and ICS groups were significantly improved at 36 weeks. The LTRA group alone showed significant improvement at 20 weeks. CONCLUSION: ICS + LABA, ICS + LTRA, ICS alone and LTRA alone can effectively treat CVA. ICS + LABA could improve the symptoms most quickly within 8 weeks after CVA diagnosis, followed by ICS + LATR group. After 8 weeks, it can be reduced to ICS alone to control CVA for at least 36 weeks based on the remission of symptoms in children.

Comparing Costs and Healthcare Resource Utilization (HCRU) Using LAMA versus LABA/ICS at Treatment Initiation for COPD: Findings from CITRUS (Comparing the Incidence of Tiotropium and ICS/LABA in Real-World Use in South Korea) Study.

Background: COPD causes substantial economic burden on healthcare. Alternative treatment strategies for COPD can be associated with different costs dependent upon their relative safety and effectiveness. We compared costs and healthcare resource utilization (HCRU) associated with LAMA or LABA/ICS initiation. Methods: Using the Korean National Health Insurance Service database, we enrolled COPD patients initiating treatment with LAMA or LABA/ICS between January 2005 and April 2015. Propensity score matched individuals were compared on all-cause and COPD-related medical costs and HCRU over a three-year follow-up period. Results: A total of 2444 patients were enrolled in each treatment group. LAMA group was associated with significantly lower costs than LABA/ICS group, both in all-cause (403.08 vs 474.50 USD per patient per month [PPPM], cost ratio 1.18, 95% confidence interval [CI]=1.10-1.26, p<0.0001) and COPD-related (216.37 vs 267.32 USD PPPM, cost ratio 1.24, 95% CI=1.13-1.35, p<0.0001) medical costs. All-cause HCRU was not significantly different between groups, while COPD-related HRCU was higher in LAMA group (0.66 vs 0.60 medical visits PPPM, p<0.0001). Conclusion: COPD patients initiating treatment with LAMA were associated with lower all-cause and COPD-related medical costs than those starting with LABA/ICS despite the similar all-cause HCRU and higher COPD-related HCRU. Initiation with LAMA is a cost-efficient option for the treatment of COPD.

Effects on cerebral blood flow after single doses of the ß2 agonist, clenbuterol, in healthy volunteers and patients with mild cognitive impairment or Parkinson's disease.

AIMS: Cerebral hypometabolism occurs years prior to a diagnosis of neurodegenerative diseases and coincides with reduced cerebral perfusion and declining noradrenergic transmission from the locus coeruleus. In pre-clinical models, ß-adrenoceptor (ß-AR) agonists increase cerebrocortical glucose metabolism, and may have therapeutic potential for neurodegenerative diseases. This study investigated the safety and effects on regional cerebral blood flow (rCBF) of the oral, brain-penetrant ß2-AR agonist, clenbuterol, in healthy volunteers (HV) and patients with mild cognitive impairment (MCI) or Parkinson's disease (PD). METHODS: This study evaluated the safety and effects on cerebral activity of the oral, brain-penetrant, ß2-AR agonist clenbuterol (20-160 µg) in healthy volunteers and patients with MCI or PD. Regional CBF, which is tightly coupled to glucose metabolism, was measured by arterial spin labelling MRI in 32 subjects (25 HV and 8 MCI or PD) across five cohorts. In some cohorts, low doses of nadolol (1-5 mg), a ß-AR antagonist with minimal brain penetration, were administered with clenbuterol to control peripheral ß2-AR responses. RESULTS: Significant, dose-dependent increases in rCBF were seen in multiple brain regions, including hippocampus, amygdala and thalamus, following the administration of clenbuterol to HVs (mean changes from baseline in hippocampal rCBF of -1.7%, 7.3%, 22.9%, 28.4% 3 h after 20, 40, 80 and 160 µg clenbuterol, respectively). In patients with MCI or PD, increases in rCBF following 80 µg clenbuterol were observed both without and with 5 mg nadolol (in hippocampus, 18.6%/13.7% without/with nadolol). Clenbuterol was safe and well-tolerated in all subjects; known side effects of ß2-agonists, including increased heart rate and tremor, were mild in intensity and were blocked by low-dose nadolol. CONCLUSIONS: The effects of clenbuterol on rCBF were evident both in the absence and presence of low-dose nadolol, suggesting central nervous system (CNS) involvement. Concomitant inhibition of the peripheral effects of clenbuterol by nadolol confirms that meaningful ß2-AR antagonism in the periphery was achieved without interrupting the central effects of clenbuterol on rCBF.

Real-World Treatment Patterns and Patient-Reported Outcomes in Chronic Obstructive Pulmonary Disease in Japan: The REMIND Study.

INTRODUCTION: Symptom status and treatment changes among patients with chronic obstructive pulmonary disease (COPD) using inhaler treatment in real-world clinical settings are not well understood, particularly according to class of treatment. We investigated the proportion of symptomatic patients among those with COPD using inhaler treatment, based on COPD Assessment Test (CAT) scores in clinical practice, and changes in inhaler treatments and symptoms at 1-year follow-up. METHODS: This was a retrospective analysis of data from a multicenter, prospective cohort study conducted at medical institutions with respiratory specialists in Japan. The primary endpoint was the proportion of patients with CAT scores ≥ 10 or < 10 in each inhaler treatment group at registration. RESULTS: Of 414 patients in the full analysis set, 76 (18.4%), 261 (63.0%), and 77 (18.6%) were using long-acting muscarinic antagonist (LAMA), LAMA + long-acting ß2-agonist (LABA), and inhaled corticosteroids (ICS) + LABA, respectively, at registration. The proportions of patients with CAT scores ≥ 10 or < 10 per inhaler treatment group at registration, respectively, were 32.9% and 67.1% in the LAMA group, 55.0% and 45.0% in the LAMA + LABA group, and 50.0% and 50.0% in the ICS + LABA group. Most patients (> 75%) in each inhaler treatment group showed no change in inhaler treatment at 1 year, regardless of their CAT score at registration. Approximately 70-80% of patients with CAT scores ≥ 10 at registration still had CAT scores ≥ 10 at 1 year; 10-30% of patients with CAT scores < 10 at registration had CAT scores ≥ 10 at 1 year. CONCLUSION: In real-world Japanese clinical practice, a considerable proportion of patients have persistent symptoms (CAT score ≥ 10) despite using mono or dual inhaler treatment; > 75% of symptomatic patients with COPD using inhaler treatment did not undergo treatment escalation at 1-year follow-up and remained symptomatic. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT05903989.

Advances in inhaler therapy for asthma and chronic obstructive pulmonary disease: a comprehensive review of Fostair™ and Trimbow™.

The management of asthma and chronic obstructive pulmonary disease (COPD) poses considerable challenges due to the intricate nature of these respiratory conditions. Fostair™ and Trimbow™, two pressurized metered dose inhalers, have emerged as noteworthy therapeutic options for treating both asthma and COPD. Fostair combines an inhaled corticosteroid, specifically beclometasone dipropionate, with a long-acting beta2-agonist, formoterol fumarate dihydrate, offering a dual-action approach to mitigate airway inflammation and bronchoconstriction. Conversely, Trimbow integrates a tri-particulate formulation consisting of beclometasone dipropionate, formoterol fumarate dihydrate, and glycopyrronium bromide, providing a comprehensive strategy to target the pathophysiology of COPD and asthma. Recent clinical trials have underscored Trimbow's superior efficacy compared with Fostair, particularly in terms of reducing exacerbation rates and enhancing lung function. However, despite their therapeutic promise, both inhalers encounter challenges, including limited generalizability of study findings and a disparity between in vitro and human trial results. This literature review offers an in-depth analysis of Fostair and Trimbow, delving into their mechanisms of action, clinical applications, and outcomes in human studies for asthma and COPD. Additionally, the review discusses the role of combination therapy in managing respiratory diseases and underscores the necessity for further research to address existing knowledge gaps and optimize therapeutic outcomes.

Extrafine single inhaler triple therapy effectiveness in COPD patients previously treated with multiple-inhaler triple therapy: the TRIWIN study.

BACKGROUND: The extrafine single inhaler triple therapy (efSITT) containing beclomethasone dipropionate/formoterol fumarate/glycopyrronium 87/5/9 µg has proved to be efficacious in patients with chronic obstructive pulmonary disease (COPD) in randomized control trials. OBJECTIVE: TRIWIN study evaluated the effectiveness of efSITT delivering beclomethasone dipropionate/formoterol fumarate/glycopyrronium 87/5/9 µg in COPD patients previously treated with multiple-inhaler triple therapy (MITT) in a real-world study in Greece. DESIGN: Prospective, multicenter, observational, non-interventional study was conducted over 24 weeks. METHODS: A total of 475 eligible patients had moderate-to-severe COPD, an indication for treatment with efSITT, and were symptomatic despite receiving MITT. COPD Assessment Test (CAT) score, pulmonary function parameters, use of rescue medication, and adherence to inhaler use were recorded at baseline (Visit 1), 3 (Visit 2), and 6 months (Visit 3) after treatment. RESULTS: Mean CAT score decreased from 21.4 points at Visit 1, to 16.6 at Visit 2 and 15.1 at Visit 3 (p < 0.001 for all pair comparisons). At Visit 3, 79.8% of patients reached a CAT improvement exceeding minimal clinically important difference (⩾2), compared to baseline. Mean forced expiratory volume in 1 s (%pred.) increased from 55.4% at Visit 1 to 63.5% at the end of study period (p < 0.001), while mean forced vital capacity (%pred.) increased from 71.1% at Visit 1, to 76.7% at Visit 3 (p < 0.001). The mean Test of Adherence to Inhalers score increased from 42.5 to 45.3 and 46.3 points, for the three visits, respectively (p < 0.001 comparing Visits 1/2 and Visits 1/3; p = 0.006 comparing Visits 2/3). The percentage of patients showing good adherence rose from 33.7% at baseline to 58.3% at Visit 3. The percentage of patients using rescue medication during the last month dropped from 16.2% to 7.4% at the end of study period (p < 0.001). Pulmonary function parameters also improved. CONCLUSION: The TRIWIN results suggest that extrafine beclomethasone dipropionate/formoterol fumarate/glycopyrronium is effective in improving health status, pulmonary function, and adherence and in reducing rescue medication use in COPD patients previously treated with MITT, in a real-world setting in Greece.

ROS-mediated regulation of ß2AR function: Does oxidation play a meaningful role towards ß2-agonist tachyphylaxis in airway obstructive diseases?

ß2-adrenergic receptor (ß2AR) agonists are the clinical gold standard for treatment and prophylaxis of airway constriction in pulmonary obstructive diseases such as asthma and COPD. Inhaled ß2-agonists elicit rapid bronchorelaxation of the airway smooth muscle, yet, clinical tachyphylaxis to this response can occur over repeated and chronic use, which reduces the bronchodilatory effectiveness. Several mechanisms have been proposed to impart ß2-agonist tachyphylaxis, most notably ß2AR desensitization. However, airway tissue is known to be highly oxidative, particularly in obstructive disease states where reactive oxygen species (ROS) generation is upregulated and ROS degradation is suboptimal yielding a large oxidative burden. Recent evidence demonstrates that ß2AR can regulate ROS generation and that ROS can post-translationally alter ß2AR cysteine residues via oxidation, leading to distinct functional receptor outcomes. Herein, we discuss the growing evidence for ß2AR mediated ROS generation in airway cells and the role of ROS in regulating ß2AR via cysteine-oxidation of the receptor. Given the functional consequence of the ß2AR-ROS signaling axis in the airways, we also discuss the potential role of ROS in mediating ß2-agonist tachyphylaxis.

Comparative effectiveness and safety of triple therapy and non-triple therapy interventions for COPD: an overview of systematic reviews.

BACKGROUND: Some systematic reviews (SRs) on triple therapy (consisting of long-acting ß2-agonist, long-acting muscarinic antagonist, and inhaled corticosteroid, LABA/LAMA/ICS) for chronic obstructive pulmonary disease (COPD) have reported conflicting results. As the number of syntheses increases, the task of identifying and interpreting evidence becomes increasingly complex and demanding. OBJECTIVES: To provide a comprehensive overview of the efficacy and safety of triple therapy for COPD. DESIGN: Overview of SRs. METHODS: Two independent reviewers conducted comprehensive searches in PubMed, Embase, Web of Science, and the Cochrane Library to identify relevant SRs that compared triple therapy with any non-triple therapy for COPD, from the inception of these databases until 1 June 2023. The AMSTAR 2 and GRADE tools were utilized to assess the quality of the included studies and the evidence for each outcome. RESULTS: Eighteen SRs encompassing 30 original studies and involving 47,340 participants were analyzed. The overall AMSTAR 2 rating revealed that 3 SRs were of low quality, 13 SRs were of critically low quality, and 2 SRs were of high quality. No high-certainty evidence revealed a significant advantage of triple therapy in improving lung function or reducing acute exacerbations. However, all evidence, including one high certainty, supported the benefits of improving quality of life. Regarding all-cause mortality, no significant difference was found when compared to LAMA or ICS/LABA; however, high-certainty evidence confirmed its effectiveness when compared with LABA/LAMA. Notably, high-certainty evidence indicated that triple therapy was associated with a significant increase in the risk of pneumonia compared to LABA/LAMA. CONCLUSION: Triple therapy demonstrated notable benefits in improving lung function, reducing exacerbations, improving quality of life, and reducing all-cause mortality. However, it is important to note that it may also significantly increase the risk of pneumonia. TRIAL REGISTRATION: This overview protocol was prospectively registered with PROSPERO (No. CRD42023431548).