Comparison of the Application of Vibrating Mesh Nebulizer and Jet Nebulizer in Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-analysis.

Objective: To comparison of the application of Vibrating Mesh Nebulizer and Jet Nebulizer in chronic obstructive pulmonary disease (COPD). Research Methods: This systematic review and meta-analysis was conducted following the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statements. The primary outcome measures analyzed included: The amount of inhaler in the urine sample at 30 minutes after inhalation therapy (USAL0.5), The total amount of inhaler in urine sample within 24 hours (USAL24), Aerosol emitted, Forced expiratory volume in 1 second (FEV1), Forced vital capacity (FVC). Results: Ten studies were included with a total of 314 study participants, including 157 subjects in the VMN group and 157 subjects in the JN group. The data analysis results of USAL0.5, MD (1.88 [95% CI, 0.95 to 2.81], P = 0.000), showed a statistically significant difference. USAL24, MD (1.61 [95% CI, 1.14 to 2.09], P = 0.000), showed a statistically significant difference. The results of aerosol emitted showed a statistically significant difference in MD (3.44 [95% CI, 2.84 to 4.04], P = 0.000). The results of FEV1 showed MD (0.05 [95% CI, -0.24 to 0.35], P=0.716), the results were not statistically significant. The results of FVC showed MD (0.11 [95% CI, -0.18 to 0.41], P=0.459), the results were not statistically significant. It suggests that VMN is better than JN and provides higher aerosols, but there is no difference in improving lung function between them. Conclusion: VMN is significantly better than JN in terms of drug delivery and utilization in the treatment of patients with COPD. However, in the future use of nebulizers, it is important to select a matching nebulizer based on a combination of factors such as mechanism of action of the nebulizer, disease type and comorbidities, ventilation strategies and modes, drug formulations, as well as cost-effectiveness, in order to achieve the ideal treatment of COPD.

A placebo-controlled, crossover trial to investigate the efficacy of tiotropium bromide or placebo added to usual care in stable symptomatic post-hematopoietic stem cell transplantation (HSCT) bronchiolitis obliterans syndrome (BOS).

BACKGROUND: Despite the fundamental progress in hematopoietic stem cell transplant, this treatment is also associated with complications. Graft-versus-host disease is a possible complication of HSCT. Bronchiolitis obliterans syndrome (BOS) is the pulmonary form of this syndrome. Due to the high morbidity and mortality rate of BOS, various studies have been conducted in the field of drug therapy for this syndrome, although no standard treatment has yet been proposed. According to the hypotheses about the similarities between BOS and chronic obstructive pulmonary disease, the idea of using tiotropium bromide as a bronchodilator has been proposed. METHOD/DESIGN: A randomized, double-blind, placebo-controlled, and crossover clinical trial is being conducted to evaluate the efficacy of tiotropium in patients with BOS. A total of 20 patients with BOS were randomly assigned (1:1) to receive a once-daily inhaled capsule of either tiotropium bromide (KP-Tiova Rotacaps 18 mcg, Cipla, India) or placebo for 1 month. Patients will receive tiotropium bromide or placebo Revolizer added to usual standard care. Measurements will include spirometry and a 6-min walking test. ETHICS/DISSEMINATION: This study was approved by the Research Ethics Committees of Imam Khomeini Hospital Complex, Tehran University of Medical Science. Recruitment started in September 2022, with 20 patients randomized. The treatment follow-up of participants with tiotropium is currently ongoing and is due to finish in April 2024. The authors will disseminate the findings in peer-reviewed publications, conferences, and seminar presentations. TRIAL REGISTRATION: Iranian Registry of Clinical Trial (IRCT) IRCT20200415047080N3. Registered on 2022-07-12, 1401/04/21.

Characteristics of Users and New Initiators of Single- and Multiple-Inhaler Triple Therapy for Chronic Obstructive Pulmonary Disease in Germany.

Purpose: To assess patient characteristics of users and new initiators of triple therapy for chronic obstructive pulmonary disease (COPD) in Germany. Patients and Methods: Retrospective cohort study of patients with COPD and ≥1 prescription for single-inhaler triple therapy (SITT; fluticasone furoate/umeclidinium/vilanterol [FF/UMEC/VI] or beclomethasone dipropionate/glycopyrronium bromide/formoterol [BDP/GLY/FOR]) or multiple-inhaler triple therapy (MITT), using data from the AOK PLUS German sickness fund (1 January 2015-31 December 2019). The index date was the first date of prescription for FF/UMEC/VI or BDP/GLY/FOR (SITT users), or the first date of overlap of inhaled corticosteroid, long-acting ß2-agonist, and long-acting muscarinic antagonist (MITT users). Two cohorts were defined: the prevalent cohort included all identified triple therapy users; the incident cohort included patients newly initiating triple therapy for the first time (no prior use of MITT or SITT in the last 2 years). Patient characteristics and treatment patterns were assessed on the index date and during the 24-month pre-index period. Results: In total, 18,630 patients were identified as prevalent triple therapy users (MITT: 17,945; FF/UMEC/VI: 700; BDP/GLY/FOR: 908; non-mutually exclusive) and 2932 patients were identified as incident triple therapy initiators (MITT: 2246; FF/UMEC/VI: 311; BDP/GLY/FOR: 395; non-mutually exclusive). For both the prevalent and incident cohorts, more than two-thirds of patients experienced ≥1 moderate/severe exacerbation in the preceding 24 months; in both cohorts more BDP/GLY/FOR users experienced ≥1 moderate/severe exacerbation, compared with FF/UMEC/VI and MITT users. Overall, 97.9% of prevalent triple therapy users and 86.4% of incident triple therapy initiators received maintenance treatment in the 24-month pre-index period. Conclusion: In a real-world setting in Germany, triple therapy was most frequently used after maintenance therapy in patients with recent exacerbations, in line with current treatment recommendations.

Triple therapy (a combination of three different respiratory inhaled medications) is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience repeated short-term symptom flare-ups when taking dual therapy (a combination of two different respiratory medications). Previously, patients had to take triple therapy using two or three separate inhalers. More recently, single-inhaler triple therapies have been developed, meaning patients can take all three different medications at the same time via one single inhaler. This study assessed the characteristics of patients who were already receiving triple therapy, or who started triple therapy (either via multiple inhalers or a single inhaler), in Germany between January 2015 and December 2019. In total, 18,630 patients who were already receiving triple therapy during the study period, and 2932 patients who newly started using triple therapy were included. The study reported that more than two-thirds of included patients had experienced at least one flare-up of COPD symptoms in the 2 years before starting triple therapy. Most patients had also received another therapy for COPD before starting triple therapy. A small proportion of patients started taking triple therapy after receiving no other therapy for COPD in the previous 2 years. The results of the study suggest that triple therapy for COPD in Germany is most often used in accordance with recommendations (patients already receiving therapy and experiencing repeated symptom flare-ups).

Inhaled Corticosteroids in Subjects with Chronic Obstructive Pulmonary Disease: An Old, Unfinished History.

Chronic obstructive pulmonary disease (COPD) is one of the major causes of disability and death. Maintenance use of inhaled bronchodilator(s) is the cornerstone of COPD pharmacological therapy, but inhaled corticosteroids (ICSs) are also commonly used. This narrative paper reviews the role of ICSs as maintenance treatment in combination with bronchodilators, usually in a single inhaler, in stable COPD subjects. The guidelines strongly recommend the addition of an ICS in COPD subjects with a history of concomitant asthma or as a step-up on the top of dual bronchodilators in the presence of hospitalization for exacerbation or at least two moderate exacerbations per year plus high blood eosinophil counts (≥300/mcl). This indication would only involve some COPD subjects. In contrast, in real life, triple inhaled therapy is largely used in COPD, independently of symptoms and in the presence of exacerbations. We will discuss the results of recent randomized controlled trials that found reduced all-cause mortality with triple inhaled therapy compared with dual inhaled long-acting bronchodilator therapy. ICS use is frequently associated with common local adverse events, such as dysphonia, oral candidiasis, and increased risk of pneumonia. Other side effects, such as systemic toxicity and unfavorable changes in the lung microbiome, are suspected mainly at higher doses of ICS in elderly COPD subjects with comorbidities, even if not fully demonstrated. We conclude that, contrary to real life, the use of ICS should be carefully evaluated in stable COPD patients.

Inpatient Admissions and Re-Admissions in Medicare Beneficiaries Initiating Umeclidinium/Vilanterol or Tiotropium Therapy.

Purpose: Patients with chronic obstructive pulmonary disease (COPD) who are hospitalized are more likely to die from their illness and have increased likelihood of re-admission than those who are not. Subsequent re-admissions further increase the burden on healthcare systems. This study compared inpatient admission rates and time-to-first COPD-related inpatient admission among Medicare beneficiaries with COPD indexed on umeclidinium/vilanterol (UMEC/VI) versus tiotropium (TIO). Patients and Methods: This retrospective study used the All-Payer Claims Database to investigate hospital admission and re-admission outcomes in Medicare beneficiaries with COPD with an initial pharmacy claim for UMEC/VI or TIO from 1 January 2015 to 28 February 2020. Inpatient admissions, baseline, and follow-up variables were assessed in patients indexed on UMEC/VI and TIO after propensity score matching (PSM), with time-to-first on-treatment COPD-related inpatient admission as the primary endpoint. Re-admissions were assessed among patients with a COPD-related inpatient admission in the 30- and 90-days post-discharge. Results: Post-PSM, 7152 patients indexed on UMEC/VI and 7069 on TIO were eligible for admissions analysis. The mean (standard deviation [SD]) time-to-first COPD-related inpatient admission was 46.71 (87.99) days for patients indexed on UMEC/VI and 44.96 (85.90) days for those on TIO (p=0.06). The mean (SD) number of inpatient admissions per patient was 1.24 (2.92) for patients indexed on UMEC/VI and 1.26 (3.05) for those on TIO (p=0.49). Proportion of patients undergoing re-admissions was similar between treatments over both 30 and 90 days, excluding a significantly lower proportion of patients indexed on UMEC/VI than those indexed on TIO for COPD-related re-admissions for hospital stays of 4-7 days and 7-14 days, and all-cause re-admissions for stays of 4-7 days. Conclusion: Patients with COPD using Medicare in the US and receiving UMEC/VI or TIO reported similar time-to-first inpatient admission and similar proportion of re-admissions.

Real-World Disease Burden and Healthcare Resource Utilization Among Patients with COPD and Asthma Using Triple Therapy (FF/UMEC/VI) in the United States.

Purpose: Chronic obstructive pulmonary disease (COPD) and asthma are associated with chronic inflammation of the respiratory tract; despite some overlap of symptoms, they are considered separate disorders. Triple therapy is recommended for patients with COPD and asthma whose symptoms remain uncontrolled despite dual therapy. There are limited real-world studies evaluating outcomes among patients with COPD and asthma who are receiving inhaled triple therapy. This United States (US)-based real-world study aimed to evaluate clinical and economic outcomes among patients with COPD and asthma receiving single-inhaler triple therapy (fluticasone furoate/umeclidinium/vilanterol [FF/UMEC/VI]). Patients and Methods: Retrospective pre-post study using claims data from the Optum Clinformatics® database. Patients with COPD and asthma were indexed on the first date of FF/UMEC/VI prescription (1 October 2017-31 March 2019). Each patient acted as their own control. Patients were required to have continuous health plan enrollment for 12 months prior to (pre-treatment) and following (post-treatment) index. Exacerbations, all-cause and COPD-related healthcare resource utilization, and costs were compared before and after FF/UMEC/VI initiation. Results: Overall, 2743 patients were included (mean age: 71 years; 64% female). Cardiovascular disease was the most prevalent comorbidity during both the pre- and post-treatment periods (90% for both periods). There was a lower proportion of patients with ≥1 COPD exacerbation or ≥1 asthma exacerbation post-treatment versus pre-treatment (51% vs 57%, p<0.0001, and 22% vs 32%, p<0.0001, respectively). Fewer patients had ≥1 all-cause office visit post-treatment versus pre-treatment (99.3% vs 99.7%, p=0.0329); more patients had ≥1 COPD-related office visit post-treatment versus pre-treatment (89.6% vs 87.5%, p=0.0035). Total all-cause healthcare costs were significantly higher post-treatment versus pre-treatment ($72,809 vs $63,734, p<0.0001). The driver of increased costs appeared to be primarily non-COPD-related (COPD-related costs: post-treatment $27,779 vs pre-treatment $25,081, p=0.0062). Conclusion: FF/UMEC/VI reduced exacerbations among patients with COPD and asthma in a real-world setting in the US.

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.

Nebulization versus metered-dose inhaler and spacer in bronchodilator responsiveness testing: a retrospective study.

BACKGROUND: The recommended delivery mode for bronchodilators in bronchodilator responsiveness (BDR) testing remains controversial. OBJECTIVE: To compare the efficacy of salbutamol administration using a nebulizer versus a metered-dose inhaler (MDI) with spacer in BDR testing. DESIGN: A retrospective study. METHODS: This study examined the data of patients with chronic obstructive pulmonary disease who completed BDR testing between 1 December 2021 and 30 June 2022, at Xiangya Hospital, Central South University. After administering 400 µg of salbutamol through an MDI with spacer or 2.5 mg using a nebulizer, the changes in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were analyzed in patients with moderate-to-very severe spirometric abnormalities [pre-bronchodilator FEV1 percentage predicted values (FEV1%pred) ⩽59%]. Significant responsiveness was assessed as >12% and >200 mL improvement in FEV1 and/or FVC or >10% increase in FEV1%pred or FVC percentage predicted values (FVC%pred) from pre- to post-bronchodilator administration. RESULTS: Of the enrolled 894 patients, 83.2% were male (median age, 63 years). After propensity score matching, 240 pairs of patients were selected. The increment in FEV1 and increased FEV1 relative to the predicted value (ΔFEV1%pred) were significantly higher in patients <65 years and those with severe spirometric abnormalities in the nebulization group than patients in the MDI group (all p < 0.05). Compared with MDI with spacer, patients who used nebulization had a 30 mL greater increase in ΔFEV1 (95% CI: 0.01-0.05, p = 0.004) and a 1.09% greater increase in ΔFEV1%pred (95% CI: 0.303-1.896, p = 0.007) from baseline. According to the > 12% and >200 mL increase criterion, the significant BDR rate with nebulization was 1.67 times higher than that with an MDI with spacer (OR = 1.67, 95% CI: 1.13-2.47, p = 0.009). CONCLUSION: Salbutamol delivered using a nebulizer may be preferable to an MDI with spacer in certain circumstances. Nebulization has the potential to increase responsiveness to salbutamol in BDR testing.

Nebulization versus metered-dose inhaler and spacer in bronchodilator responsiveness testingBronchodilator responsiveness testing is commonly undertaken as an important part of spirometry testing to determine the degree of volume and airflow improvement after bronchodilator administration. BDR testing results may affect patients' diagnosis and treatment. This study compared the effects of two delivery models (a metered dose inhaler (MDI) with spacer and nebulization) on responsiveness to bronchodilators and the results of bronchodilator responsiveness testing among patients with chronic obstructive pulmonary disease. We found that the increment in forced expiratory volume in one second were significantly higher in patients aged <65 years and in those with severe spirometric abnormalities in the nebulization group than in those in the MDI group. The study provides evidence that salbutamol delivered by a nebulizer is preferable to an MDI with spacer in patients <65 years and in those with severe spirometric abnormalities and could increase positive responsiveness to bronchodilators. The study will assist in clinical decision-making by selecting the appropriate dosing regimen for different patients.

Associations of medication regimen complexity with medication adherence and clinical outcomes in patients with chronic obstructive pulmonary disease: a prospective study.

BACKGROUND: High medication burdens are common in patients with chronic obstructive pulmonary disease (COPD). This study aimed to explore the associations of medication regimen complexity index (MRCI) with medication adherence and clinical outcomes among patients with acute exacerbations of COPD (AECOPD) after hospital discharge. METHODS: Data were obtained from a nationwide cohort study of inpatients with AECOPD in China. MRCI scores were calculated using the medication list 30 days after discharge and separated into COPD-specific and non-COPD MRCI scores. Medication adherence was measured by the withdrawal rate of COPD or inhaled long-acting bronchodilators 6 months after discharge. Clinical outcomes included re-exacerbations and COPD-related readmissions during the 30-day to 6-month follow-up period. The associations of MRCI with medication withdrawal and clinical outcomes were evaluated using univariate and multivariate logistic regressions. Potential covariates included sociodemographic factors, year of COPD diagnosis, post-bronchodilator percentage predicted forced expiratory volume in 1 s, mMRC score, CAT score, and comorbidities. RESULTS: Among the 2853 patients included, the median total MRCI score was 7 [interquartile range (IQR), 7-13]. A high MRCI score (>7) was presented in 1316 patients (46.1%). Of the MRCI score, 91% were COPD specific. The withdrawal rates of the COPD and inhaled long-acting bronchodilators were 24.2% and 24.4%, respectively. Re-exacerbation and COPD-related readmission rates were 10.2% and 7.5%, respectively. After adjusting for covariates, patients with high total MRCI scores were less likely to discontinue COPD drugs [odds ratio (OR), 0.62; 95% confidence interval (CI), 0.52-0.74] and inhaled long-acting bronchodilators (OR, 0.68; 95%CI, 0.57-0.81); conversely, these patients were more likely to experience re-exacerbation (OR, 1.64; 95% CI, 1.27-2.11) and readmission (OR, 1.57; 95% CI, 1.17-2.10). CONCLUSION: MRCI scores were relatively low among post-hospitalized patients with AECOPD in China. Higher MRCI scores were positively associated with adherence to COPD or inhaled medications, and risk of re-exacerbation and readmission. REGISTRATION: ClinicalTrials.gov identifier: NCT02657525.

Exacerbations and Real-World Outcomes After Single-Inhaler Triple Therapy of Budesonide/Glycopyrrolate/Formoterol Fumarate, Among Patients with COPD: Results from the EROS (US) Study.

Purpose: Triple therapy to prevent exacerbations from chronic obstructive pulmonary disease (COPD) is associated with improved health compared to single and dual-agent therapy in some populations. This study assessed the benefits of prompt administration of budesonide/glycopyrrolate/formoterol fumarate (BGF) following a COPD exacerbation. Patients and methods: EROS was a retrospective analysis of people with COPD using the MORE2 Registry®. Inclusion required ≥1 severe, ≥2 moderate, or ≥1 moderate exacerbation while on other maintenance treatment. Within 12 months following the index exacerbation, ≥1 pharmacy claim for BGF was required. Primary outcomes were the rate of COPD exacerbations and healthcare costs for those that received BGF promptly (within 30 days of index exacerbation) versus delayed (31-180 days) and very delayed (181-365 days). The effect of each 30-day delay in initiation of BGF was estimated using a multivariable negative binomial regression model. Results: 2409 patients were identified: 434 prompt, 1187 delayed, and 788 very delayed. The rate (95% CI) of total exacerbations post-index increased as time to BGF initiation increased: prompt 1.52 (1.39-1.66); delayed 2.00 (1.92-2.09); and very delayed 2.30 (2.20-2.40). Adjusting for patient characteristics, each 30-day delay in receiving BGF was associated with a 5% increase in the average number of subsequent exacerbations (rate ratio, 95% CI: 1.05, 1.01-1.08; p<0.05). Prompt initiation of BGF was also associated with lower post-index annualized COPD-related costs ($5002 for prompt vs $7639 and $8724 for the delayed and very delayed groups, respectively). Conclusion: Following a COPD exacerbation, promptly initiating BGF was associated with a reduction in subsequent exacerbations and reduced healthcare utilization and costs.

A comparative examination of morphine and fentanyl: unravelling the differential impacts on breathing and airway stability.

This study provides an in-depth analysis of the distinct consequences of the opioid drugs morphine and fentanyl during opioid-induced respiratory depression (OIRD). We explored the physiological implications of both drugs on ventilation and airway patency in anaesthetized mice. Our results revealed a similar reduction in respiratory frequency with equivalent scaled dosages of fentanyl and morphine, though the onset of suppression was more rapid with fentanyl. Additionally, fentanyl resulted in transient airflow obstructions during the inspiratory cycle, which were absent following morphine administration. Notably, these fentanyl-specific obstructions were eliminated with tracheostomy, implicating the upper airways as a major factor contributing to fentanyl-induced respiratory depression. We further demonstrate that bronchodilators salbutamol and adrenaline effectively reversed these obstructions, highlighting the bronchi's contribution to fentanyl-induced airflow obstruction. Our study also uncovered a significant reduction in sighs during OIRD, which were eliminated by fentanyl and markedly reduced by morphine. Finally, we found that fentanyl-exposed mice had reduced survival under hypoxic conditions compared to mice given morphine, demonstrating that fentanyl becomes more lethal in the context of hypoxaemia. Our findings shed light on the distinct and profound impacts of these opioids on respiration and airway stability and lay the foundation for improved opioid use guidelines and more effective OIRD prevention strategies. KEY POINTS: Both morphine and fentanyl significantly suppressed respiratory frequency, but the onset of suppression was faster with fentanyl. Also, while both drugs increased tidal volume, this effect was more pronounced with fentanyl. Fentanyl administration resulted in transient obstructions during the inspiratory phase, suggesting its unique impact on airway stability. This obstruction was not observed with morphine. The fentanyl-induced obstructions were reversed by administering bronchodilators such as salbutamol and adrenaline. This suggests a possible therapeutic strategy for mitigating the adverse airway effects of fentanyl. Both drugs reduced the frequency of physiological sighs, a key mechanism to prevent alveolar collapse. However, fentanyl administration led to a complete cessation of sighs, while morphine only reduced their occurrence. Fentanyl-treated mice showed a significantly reduced ability to survive under hypoxic conditions compared to those administered morphine. This indicates that the impacts of hypoxaemia during opioid-induced respiratory depression can vary based on the opioid used.

Comparative cardiovascular safety of LABA/LAMA FDC versus LABA/ICS FDC in patients with chronic obstructive pulmonary disease: a population-based cohort study with a target trial emulation framework.

BACKGROUND: Use of combinations of long-acting ß2 agonists/long-acting muscarinic antagonists (LABA/LAMA) in patients with chronic obstructive pulmonary disease (COPD) is increasing. Nevertheless, existing evidence on cardiovascular risk associated with LABA/LAMA versus another dual combination, LABA/inhaled corticosteroids (ICS), was limited and discrepant. AIM: The present cohort study aimed to examine comparative cardiovascular safety of LABA/LAMA and LABA/ICS with a target trial emulation framework, focusing on dual fixed-dose combination (FDC) therapies. METHODS: We identified patients with COPD who initiated LABA/LAMA FDC or LABA/ICS FDC from a nationwide Taiwanese database during 2017-2020. The outcome of interest was a hospitalized composite cardiovascular events of acute myocardial infarction, unstable angina, heart failure, cardiac dysrhythmia, and ischemic stroke. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for composite and individual cardiovascular events after matching up to five LABA/LAMA FDC initiators to one LABA/ICS FDC initiator using propensity scores (PS). RESULTS: Among 75,926 PS-matched patients, use of LABA/LAMA FDC did not show a higher cardiovascular risk compared to use of LABA/ICS FDC, with a HR of 0.89 (95% CI, 0.78-1.01) for the composite events, 0.80 (95% CI, 0.61-1.05) for acute myocardial infarction, 1.48 (95% CI, 0.68-3.25) for unstable angina, 1.00 (95% CI, 0.80-1.24) for congestive heart failure, 0.62 (95% CI, 0.37-1.05) for cardiac dysrhythmia, and 0.82 (95% CI, 0.66-1.02) for ischemic stroke. The results did not vary substantially in several pre-specified sensitivity and subgroup analyses. CONCLUSION: Our findings provide important reassurance about comparative cardiovascular safety of LABA/LAMA FDC treatment among patients with COPD.

Efficacy and safety of aclidinium/formoterol versus monotherapies and aclidinium versus placebo in Chinese and other Asian patients with moderate-to-severe COPD: The AVANT Phase 3 study.

AVANT was a Phase 3, 24-week, randomized, parallel-group, double-blind, double-dummy, placebo-controlled study to assess the efficacy and safety of aclidinium/formoterol 400 µg/12 µg combination vs monotherapies and aclidinium vs placebo (1:1:1:1) in Asian patients (∼70% of whom were Chinese) with moderate-to-severe stable chronic obstructive pulmonary disease. Endpoints were analyzed hierarchically to incorporate type I error control. At Week 24, aclidinium/formoterol demonstrated improvements from baseline in 1-h morning post-dose forced expiratory volume in 1 s (FEV1) vs aclidinium (least squares [LS] mean 92 mL; 95% confidence interval [CI] 60, 124 mL; p < 0.001), and in trough FEV1 vs formoterol (LS mean 85 mL; 95% CI 53, 117 mL; p < 0.001). Furthermore, aclidinium provided improvements in trough FEV1 vs placebo (LS mean 134 mL; 95% CI 103, 166 mL; p < 0.001). There was an improvement in transition dyspnea index focal score at Week 24 for aclidinium/formoterol vs placebo (LS mean 0.8; 95% CI 0.2, 1.3; p = 0.005) but not for aclidinium vs placebo (LS mean 0.4; 95% CI -0.1, 1.0; p = 0.132). Improvements in St George's Respiratory Questionnaire total scores occurred for aclidinium/formoterol vs placebo (LS mean -4.0; 95% CI -6.7, -1.4; p = 0.003) and aclidinium vs placebo (LS mean -2.9; 95% CI -5.5, -0.3; p = 0.031). Aclidinium/formoterol and aclidinium were well tolerated and safety findings were consistent with known profiles; rates of treatment-emergent adverse events (AEs) (aclidinium/formoterol: 54.8%; aclidinium: 47.4%; placebo: 53.9%), serious AEs (7.2, 7.9, and 7.8%, respectively), and AEs leading to discontinuation of study medication (2.3, 1.5, and 2.2%, respectively) were similar between groups.

Patterns and Trends in the Use of Medications for COPD Control in a Cohort of 9476 Colombian Patients, 2017-2019.

Purpose: Chronic obstructive pulmonary disease (COPD) affects approximately 174 million people worldwide. The objective was to determine the trends of COPD medication use in a group of Colombian patients. Patients and Methods: This was a retrospective study on prescription patterns of bronchodilators and other medications used in COPD from a population database with follow-up at 12 and 24 months. Patients older than 18 years of age of any sex with a COPD diagnostic code between 2017 and 2019 were included. Sociodemographic variables, medications, treatment schedules for COPD, comorbidities, comedications, and the specialty of the prescriber were considered. Results: Data from 9476 people with COPD was evaluated. The mean age was 75.9 ± 10.7 years, 50.1% were male, and 86.8% were prescribed by a general practitioner. A total of 57.9% had comorbidities, most often hypertension (44.4%). At the baseline measurement, on average, they received 1.6 medications/patient, mainly short-acting antimuscarinics (3784; 39.9%), followed by short-acting ß-agonists (2997, 31.6%) and inhaled corticosteroids (ICS) (2239, 23.6%); more than half (5083, 53.6%) received a long-acting bronchodilator. Prescription of triple therapy (antimuscarinic, ß-agonist, and ICS) went from 645 (6.8%) at baseline to 1388 (20.6%) at the 12-month mark. Conclusion: This group of patients with COPD treated in Colombia frequently received short-acting bronchodilators and ICS, but a growing proportion are undergoing controlled therapy with long-acting bronchodilators, a situation that can improve the indicators of morbidity, exacerbations, and hospitalization.

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.

Chronic Obstructive Pulmonary Disease Exacerbations and Pneumonia Hospitalizations Among New Users of Combination Maintenance Inhalers.

Importance: Clinical guidelines on chronic obstructive pulmonary disease (COPD) recommend inhalers containing long-acting muscarinic antagonists (LAMAs) and long-acting ß-agonists (LABAs) over inhalers containing inhaled corticosteroids (ICSs) and LABAs. However, data from randomized clinical trials comparing these combination inhalers (LAMA-LABAs vs ICS-LABAs) have been conflicting and raised concerns of generalizability. Objective: To assess whether LAMA-LABA therapy is associated with reduced COPD exacerbations and pneumonia hospitalizations compared with ICS-LABA therapy in routine clinical practice. Design, Setting, and Participants: This was a 1:1 propensity score-matched cohort study using Optum's Clinformatics Data Mart, a large commercial insurance-claims database. Patients must have had a diagnosis of COPD and filled a new prescription for a combination LAMA-LABA or ICS-LABA inhaler between January 1, 2014, and December 31, 2019. Patients younger than 40 years were excluded, as were those with a prior diagnosis of asthma. The current analysis was performed from February 2021 to March 2023. Exposures: Combination LAMA-LABA inhalers (aclidinium-formoterol, glycopyrronium-formoterol, glycopyrronium-indacaterol, tiotropium-olodaterol, or umeclidinium-vilanterol) and combination ICS-LABA inhalers (budesonide-formoterol, fluticasone-salmeterol, fluticasone-vilanterol, or mometasone-formoterol). Main Outcome: The primary effectiveness outcome was first moderate or severe COPD exacerbation, and the primary safety outcome was first pneumonia hospitalization. Propensity score matching was used to control for confounding between the 2 groups. Logistic regression analysis was used to estimate propensity scores. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models stratified on matched pairs. Results: Among 137 833 patients (mean [SD] age, 70.2 [9.9] years; 69 530 [50.4%] female) (107 004 new ICS-LABA users and 30 829 new LAMA-LABA users), 30 216 matched pairs were identified for the primary analysis. Compared with ICS-LABA use, LAMA-LABA use was associated with an 8% reduction in the rate of first moderate or severe COPD exacerbation (HR, 0.92; 95% CI, 0.89-0.96) and a 20% reduction in the rate of first pneumonia hospitalization (HR, 0.80; 95% CI, 0.75-0.86). These findings were robust across a range of prespecified subgroup and sensitivity analyses. Conclusion: In this cohort study, LAMA-LABA therapy was associated with improved clinical outcomes compared with ICS-LABA therapy, suggesting that LAMA-LABA therapy should be preferred for patients with COPD.

Navafenterol for chronic obstructive pulmonary disease therapy.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a prevalent disease of the airways in which inhaled bronchodilators can be given as monotherapy or fixed dose combination, in order to better control disease symptoms and to reduce its morbidity. A novel bronchodilator approach is represented by bifunctional molecules such as navafenterol, which exert dual synergic bronchodilator effects as a monotherapy. Navafenterol is currently being investigated for COPD. AREAS COVERED: This review summarizes the preclinical data regarding navafenterol synthesis and in vitro and in vivo testing. Clinical data coming from phase I and II studies are also discussed. Navafenterol was found to improve lung function, dyspnea, and cough severity and was well tolerated, and its effect was comparable with that of fixed-dose combinations in patients with moderate-to-severe COPD. EXPERT OPINION: Despite clinical evidence of efficacy for navafenterol is still limited, the existing data prompts further clinical evaluation and also consideration of other inhalation approaches such as pressure metered-dose inhalers (pMDIs) or nebulization. Other interesting approach would be combination with another bifunctional molecule such as ensifentrine.

Ultrasound assessment of diaphragmatic dynamics in patients with chronic obstructive pulmonary disease after treatment with indacaterol/glycopyrronium.

INTRODUCTION: Air trapping is one of the main determinants of dyspnea in patients with chronic obstructive pulmonary disease (COPD). An increase in air trapping leads to a change in the normal diaphragmatic configuration with associated functional impairment. Said deterioration improves with bronchodilator therapy. Chest ultrasound (CU) has been used to assess changes in diaphragmatic motility after short-acting bronchodilator therapy, but there are no previous studies on these changes after long-acting bronchodilator treatment. MATERIAL AND METHODS: Interventional prospective study. Patients with COPD and moderate to very severe ventilatory obstruction were included in the study. Diaphragm motion and thickness were assessed by CU before and after 3 months of treatment with indacaterol/glycopirronium 85/43 mcg. RESULTS: Thirty patients were included (56.6% men, mean age: 69.4 ± 6.2 years). Pre- and post-treatment diaphragmatic mobility measured during resting breathing, deep breathing, and nasal sniffing were 19.9 ± 7.1 mm and 26.4 ± 8.7 mm (p < 0.0001); 42.5 ± 14.1 mm and 64.5 ± 25.9 mm (p < 0.0001); and 36.5 ± 17.4 mm and 46.7 ± 18.5 mm (p = 0.012), respectively. A significant improvement was also found in the minimum and maximum diaphragm thickness (p < 0.05), but there were no significant changes in the diaphragmatic shortening fraction after treatment (p = 0.341). CONCLUSIONS: Treatment with indacaterol/glycopyrronium 85/43 mcg every 24 hours for 3 months improved diaphragmatic mobility in patients with COPD with moderate to very severe airway obstruction. CU may be useful for assessing the response to treatment in these patients.