SABINA + Hong Kong: a territory wide study of prescribing trends and outcomes associated with the use of short-acting ß2 agonists in the Chinese population.

BACKGROUND: Excessive use of short-acting ß2 agonists (SABA) in patients with asthma continues to be a notable concern due to its link to higher mortality rates. Global relevance of SABA overuse in asthma management cannot be understated, it poses significant health risk to patients with asthma and imposes burden on healthcare systems. This study, as part of global SABINA progamme, aimed to describe the prescribing patterns and clinical outcomes associated with SABA use in the Chinese population. METHODS: Retrospective cohort study was conducted using anonymized electronic healthcare records of Clinical Data Analysis and Reporting System (CDARS) from Hong Kong Hospital Authority (HA). Patients newly diagnosed with asthma between 2011 and 2018 and aged ≥12 years were included, stratified by SABA use (≤2, 3-6, 7-10, or ≥11 canisters/year) during one-year baseline period since asthma diagnosis date. Patients were followed up from one-year post-index until earliest censoring of events: outcome occurrence and end of study period (31 December 2020). Cox proportional regression and negative binomial regression were used to estimate the mortality risk and frequency of hospital admissions associated with SABA use respectively, after adjusting for age, sex, Charlson Comorbidity Index (CCI), and inhaled corticosteroid (ICS) dose. Outcomes include all-cause, asthma-related, and respiratory-related mortality, frequency of hospital admissions for any cause, and frequency of hospital admissions due to asthma. RESULTS: 17,782 patients with asthma (mean age 46.7 years, 40.8% male) were included and 59.1% of patients were overusing SABA (≥ 3 canisters per year). Each patient was prescribed a median of 5.61 SABA canisters/year. SABA overuse during baseline period was associated with higher all-cause mortality risk compared to patients with ≤2 canisters/year. Association was dose-dependent, highest risk in those used ≥11 canisters/year (adjusted hazard ratio: 1.42, 95% CI: 1.13, 1.79) and 3-6 canisters/year (adjusted hazard ratio: 1.22, 95% CI: 1.00, 1.50). Higher SABA prescription volume associated with increased frequency of hospital admissions with greatest risk observed in 7-10 canisters/year subgroup (adjusted rate ratio: 4.81, 95% CI: 3.66, 6.37). CONCLUSIONS: SABA overuse is prevalent and is associated with increased all-cause mortality risk and frequency of hospital admissions among the patients with asthma in Hong Kong.

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).

Development and validation of a claims-based algorithm to identify moderate exacerbations in patients with asthma treated in the US.

INTRODUCTION: Definitions of moderate asthma exacerbation have been inconsistent, making their economic burden difficult to assess. An algorithm to accurately identify moderate exacerbations from claims data is needed. METHODS: A retrospective cohort study of Reliant Medical Group patients aged ≥18 years, with ≥1 prescription claim for inhaled corticosteroid/long-acting ß2-agonist, and ≥1 medical claim with a diagnosis code for asthma was conducted. The objective was to refine current algorithms to identify moderate exacerbations in claims data and assess the refined algorithm's performance. Positive and negative predictive values (PPV and NPV) were assessed via chart review of 150 moderate exacerbations events and 50 patients without exacerbations. Sensitivity analyses assessed alternative algorithms and compared healthcare resource utilization (HRU) between algorithm-identified patients (claims group) and those confirmed by chart review (confirmed group) to have experienced a moderate exacerbation. RESULTS: Algorithm-identified moderate exacerbations were: visit of ≤1 day with an asthma exacerbation diagnosis OR visit of ≤1 day with selected asthma diagnoses AND ≥1 respiratory pharmacy claim, excluding systemic corticosteroids, within 14 days after the first claim. The algorithm's PPV was 42%; the NPV was 78%. HRU was similar for both groups. CONCLUSION: This algorithm identified potential moderate exacerbations from claims data; however, the modest PPV underscores its limitations in identifying moderate exacerbations, although performance was partially due to identification of previously unidentified severe exacerbations. Application of this algorithm in future claims-based studies may help quantify the economic burden of moderate and severe exacerbations in asthma when an algorithm identifying severe exacerbations is applied first.

Frequency and economic burden of exacerbations in inhaled corticosteroid/long-acting beta-agonist-treated patients with asthma: A retrospective US claims study.

INTRODUCTION: Despite adherence to inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) therapy, many patients with asthma experience moderate exacerbations. Data on the impact of moderate exacerbations on the healthcare system are limited. This study assessed the frequency and economic burden of moderate exacerbations in patients receiving ICS/LABA. METHODS: Retrospective, longitudinal study analyzed data from Optum's de-identified Clinformatics® Data Mart Database recorded between October 1, 2015, and December 31, 2019. Eligibility criteria included patients ≥18 years of age with ≥1 ICS/LABA claim and ≥1 medical claim for asthma in the 12 months pre-index (first ICS/LABA claim). Primary objectives included describing moderate exacerbation frequency, and associated healthcare resource utilization (HRU) and costs. A secondary objective was assessing the relationship between moderate exacerbations and subsequent risk of severe exacerbations. Patients were stratified by moderate exacerbation frequency in the 12 months post index. Moderate exacerbations were identified using a newly developed algorithm. RESULTS: In the first 12 months post index 61.6% of patients experienced ≥1 moderate exacerbation. Mean number of asthma-related visits was 4.1 per person/year and median total asthma-related costs was $3544. HRU and costs increased with increasing exacerbation frequency. Outpatient and inpatient visits accounted for a similar proportion of these costs. Moderate exacerbations were associated with an increased rate and risk of future severe exacerbations (incidence rate ratio, 1.56; hazard ratio, 1.51 [both p < 0.001]). CONCLUSIONS: This study highlighted that a high proportion of patients continue to experience moderate exacerbations despite ICS/LABA therapy and subsequently experience increased economic burden and risk of future severe exacerbations.

A network meta-analysis of the association between patient traits and response to regular dosing with ICS plus short-acting ß2-agonist reliever or ICS/formoterol reliever only in mild asthma.

INTRODUCTION/BACKGROUND: Mild asthma treatment recommendations include intermittent inhaled corticosteroid (ICS)/formoterol dosing or regular ICS dosing with short-acting ß2-agonist reliever. Due to the heterogeneity of asthma, identification of traits associated with improved outcomes to specific treatments would be clinically beneficial. AIMS/OBJECTIVES: To assess the impact of patient traits on treatment outcomes of regular ICS dosing compared with intermittent ICS/formoterol dosing, a systematic literature review (SLR) and network meta-analysis (NMA) was conducted. Searches identified randomised controlled trials (RCTs) of patients with asthma aged ≥12 years, containing ≥1 regular ICS dosing or intermittent ICS/formoterol dosing treatment arm, reporting traits and outcomes of interest. RESULTS: The SLR identified 11 RCTs of mild asthma, of 14,516 patients. A total of 11 traits and 11 outcomes of interest were identified. Of these, a feasibility assessment indicated possible assessment of three traits (age, baseline lung function, smoking history) and two outcomes (exacerbation rate, change in lung function). The NMA found no significant association of any trait with any outcome with regular ICS dosing relative to intermittent ICS/formoterol dosing. Inconsistent reporting of traits and outcomes between RCTs limited analysis. CONCLUSIONS: This is the first systematic analysis of associations between patient traits and differential treatment outcomes in mild asthma. Although the traits analysed were not found to significantly interact with relative treatment response, inconsistent reporting from the RCTs prevented assessment of some of the most clinically relevant traits and outcomes, such as adherence. More consistent reporting of respiratory RCTs would provide more comparable data and aid future analyses.

Baseline Characteristics and ICS/LAMA/LABA Response in Asthma: Analyses From the CAPTAIN Study.

BACKGROUND: Findings from CAPTAIN (NCT02924688) suggest that treatment response to fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) differs according to baseline type 2 inflammation markers in patients with moderate to severe asthma. Understanding how other patient physiologic and clinical characteristics affect response to inhaled therapies may guide physicians toward a personalized approach for asthma management. OBJECTIVE: To investigate, using CAPTAIN data, the predictive value of key demographic and baseline physiologic variables in patients with asthma (lung function, bronchodilator reversibility, age, age at asthma onset) on response to addition of the long-acting muscarinic antagonist UMEC to inhaled corticosteroid/long-acting ß2-agonist combination FF/VI, or doubling the FF dose. METHODS: Prespecified and post hoc analyses of CAPTAIN data were performed using categorical and continuous variables of key baseline characteristics to understand their influence on treatment outcomes (lung function [trough FEV1], annualized rate of moderate/severe exacerbations, and asthma control [Asthma Control Questionnaire]) following addition of UMEC to FF/VI or doubling the FF dose in FF/VI or FF/UMEC/VI. RESULTS: Adding UMEC to FF/VI led to greater improvements in trough FEV1 versus doubling the FF dose across all baseline characteristics assessed. Doubling the FF dose was generally associated with numerically greater reductions in the annualized rate of moderate/severe exacerbations compared with adding UMEC, independent of baseline characteristics. Adding UMEC and/or doubling the FF dose generally led to improvements in Asthma Control Questionnaire scores irrespective of baseline characteristics. CONCLUSIONS: Unlike previous findings with type 2 biomarkers, lung function, bronchodilator reversibility, age and age at asthma onset do not appear to predict response to inhaled therapy.

The Association Between Short-Acting ß2-Agonist Over-Prescription, and Patient-Reported Acquisition and Use on Asthma Control and Exacerbations: Data from Australia.

INTRODUCTION: In Australia, short-acting ß2-agonists (SABA) are available both over the counter (OTC) and on prescription. This ease of access may impact SABA use in the Australian population. Our aim was to assess patterns and outcome associations of prescribed, acquired OTC and reported use of SABA by Australians with asthma. METHODS: This was a cross-sectional study, using data derived from primary care electronic medical records (EMRs) and patient completed questionnaires within Optimum Patient Care Research Database Australia (OPCRDA). A total of 720 individuals aged ≥ 12 years with an asthma diagnosis in their EMRs and receiving asthma therapy were included. The annual number of SABA inhalers authorised on prescription, acquired OTC and reported, and the association with self-reported exacerbations and asthma control were investigated. RESULTS: 92.9% (n = 380/409) of individuals issued with SABA prescription were authorised ≥ 3 inhalers annually, although this differed from self-reported usage. Of individuals reporting SABA use (n = 546) in the last 12 months, 37.0% reported using ≥ 3 inhalers. These patients who reported SABA overuse experienced 2.52 (95% confidence interval [CI] 1.73-3.70) times more severe exacerbations and were 4.51 times (95% CI 3.13-6.55) more likely to have poor asthma control than those who reported using 1-2 SABA inhalers. Patients who did not receive SABA on prescription (43.2%; n = 311/720) also experienced 2.71 (95% CI 1.07-7.26) times more severe exacerbations than those prescribed 1-2 inhalers. Of these patients, 38.9% reported using OTC SABA and other prescription medications, 26.4% reported using SABA OTC as their only asthma medication, 13.2% were prescribed other therapies but not SABA OTC and 14.5% were not using any medication. CONCLUSION: Both self-reported SABA overuse and zero SABA prescriptions were associated with poor asthma outcomes. The disconnect between prescribing authorisation, OTC availability and actual use, make it difficult for clinicians to quantify SABA use.

Effects of R-salbutamol on the inflammatory response and acute lung injury in endotoxemic mice.

Salbutamol, which consists of an R-isomer and S-isomer, is an effective and widely used ß2 adrenoreceptor agonist that may possess anti-inflammatory properties in addition to its bronchodilator activity. Whether the salbutamol R-isomer has advantages over its racemic mixture and effectiveness in treating endotoxemia and endotoxin-induced lung injury has not been well studied. In this study, we investigated the preventive and therapeutic effects of R-salbutamol (R-sal), S-salbutamol (S-sal), and their racemic mixture (Rac-sal) on a mouse model of lipopolysaccharide (LPS)-induced endotoxemia. Dexamethasone (Dex) was used for comparison. The results showed that R-sal markedly improved the 7-day survival rate of endotoxic mice when administered before and after LPS treatment. Dex was toxic and accelerated the death of endotoxic mice when administered before LPS injection. Histological examination of the lungs revealed that the LPS challenge resulted in acute lung damage, including inflammatory cell infiltration, thickened alveolar septa, and congestion. R-sal pre-treatment effectively inhibited these changes, accompanied by markedly reduced lung myeloperoxidase levels, serum cytokine levels, and lactate release, significant restoration of lymphocyte count, and reduction of monocyte count. This may have occurred through inhibition of M1 macrophage inflammatory responses by enhancement of ß-arrestin2 expression and suppression of NF-κB activation. Rac-sal exhibited diminished effects compared to that of R-sal, while S-sal showed enhanced release of some inflammatory cytokines. In addition, R-sal pre-treatment showed a better improvement in prognostic pulmonary function on day 4 compared to that by Rac-sal. Collectively, our results indicate the potential benefits of R-sal in regulating inflammatory responses to endotoxemia and endotoxin-induced lung injury.

Prescription Patterns of New Use of Fixed-Dose Combination Inhalers in Patients with Chronic Obstructive Pulmonary Disease: Long-Acting ß2 Agonists Plus Long-Acting Muscarinic Antagonists versus Long-Acting ß2 Agonists Plus Inhaled Corticosteroids.

Background: The clinical guideline recommends use of long-acting ß2 agonists/long-acting muscarinic antagonists (LABA/LAMA) or long-acting ß2 agonists/inhaled corticosteroids (LABA/ICS) combination therapies for patients with severe chronic obstructive pulmonary disease (COPD). The fixed-dose combination (FDC) inhalers of LABA/LAMA and LABA/ICS were reimbursed in Taiwan in 2015 and in 2002, respectively. This study aimed to examine prescription patterns of new use of either FDC therapy in real-world practice. Methods: We identified COPD patients who initiated LABA/LAMA FDC or LABA/ICS FDC between 2015 and 2018 from a population-based Taiwanese database with 2 million, randomly sampled beneficiaries enrolled in a single-payer health insurance system. We compared number of LABA/LAMA FDC and LABA/ICS FDC initiators in each calendar year, from different hospital accreditation levels, and cared for by different physician specialties. We also compared baseline patient characteristics between LABA/LAMA FDC and LABA/ICS FDC initiators. Results: A total of 12,455 COPD patients who initiated LABA/LAMA FDC (n=4019) or LABA/ICS FDC (n=8436) were included. Number of LABA/LAMA FDC initiators increased apparently (n=336 in 2015 versus n=1436 in 2018), but number of LABA/ICS FDC initiators decreased obviously (n=2416 in 2015 versus n=1793 in 2018) over time. The preference of use of LABA/LAMA FDC varied across clinical environments. The proportions of LABA/LAMA FDC initiators were more than 30% in the setting of non-primary care clinics (eg, medical centers) and in the services of chest physicians; but were only less than 10% in primary care clinics and non-chest physicians' services (eg, family medicine physicians). LABA/LAMA FDC initiators appeared to be older, male, to have more comorbidities, and to utilize resources more frequently compared to LABA/ICS FDC initiators. Conclusion: This real-world study found evident temporal trends, variations in healthcare provider, and differences in patient characteristics among COPD patients who initiated LABA/LAMA FDC or LABA/ICS FDC.

Short-acting ß2-agonist prescription patterns in patients with asthma in Turkey: results from SABINA III.

BACKGROUND: Over-reliance on short-acting ß2-agonists (SABAs) is associated with poor asthma outcomes. However, the extent of SABA use in Turkey is unclear owing to a lack of comprehensive healthcare databases. Here, we describe the demographics, disease characteristics and treatment patterns from the Turkish cohort of the SABA use IN Asthma (SABINA) III study. METHODS: This observational, cross-sectional study included patients aged ≥ 12 years with asthma from 24 centres across Turkey. Data on sociodemographics, disease characteristics and asthma treatments were collected using electronic case report forms. Patients were classified by investigator-defined asthma severity (guided by the 2017 Global Initiative for Asthma [GINA]) and practice type (primary/specialist care). The primary objective was to describe SABA prescription patterns in the 12 months prior to the study visit. RESULTS: Overall, 579 patients were included (mean age [standard deviation; SD]: 47.4 [16.1] years; 74.3% female), all of whom were treated by specialists. Most patients had moderate-to-severe asthma (82.7%, GINA steps 3-5), were overweight or obese (70.5%), had high school or university/post-graduate education (51.8%) and reported fully reimbursed healthcare (97.1%). The mean (SD) asthma duration was 12.0 (9.9) years. Asthma was partly controlled/uncontrolled in 56.3% of patients, and 46.5% experienced ≥ 1 severe exacerbation in the preceding 12 months. Overall, 23.9% of patients were prescribed ≥ 3 SABA canisters in the previous 12 months (considered over-prescription); 42.9% received no SABA prescriptions. As few patients had mild asthma, only 5.7% were prescribed SABA monotherapy. Therefore, most patients (61.5%) were prescribed SABA in addition to maintenance therapy, with 42.8% receiving ≥ 3 SABA canisters in the previous 12 months. Inhaled corticosteroids (ICS), ICS + a long-acting ß-agonist fixed-dose combination and oral corticosteroids were prescribed to 14.5%, 88.3% and 28.5% of all patients, respectively. Additionally, 10.2% of patients purchased SABA over the counter, of whom 27.1% purchased ≥ 3 canisters in the preceding 12 months. CONCLUSIONS: Despite all patients being treated by specialists and most receiving fully reimbursed healthcare, nearly a quarter of patients received prescriptions for ≥ 3 SABA canisters in the previous 12 months. This highlights a public health concern and emphasizes the need to align clinical practices with the latest evidence-based recommendations.

Revisión narrativa de la terapia inhalatoria en la EPOC / COPD inhaled therapy narrative review

La terapia inhalada con broncodilatadores de acción larga es la base del tratamiento farmacológico de la EPOC. Con el fin conocer los que ofrecen un mejor control, se realizó una búsqueda en Medline (Pubmed). Se analizaron los estudios comparativos de terapia inhaladora en pacientes con EPOC. Tras la comparación entre la combinación fija LABA/LAMA frente LABA/CI en pacientes no exacerbadores, se concluye que hay un mejor control con LABA/LAMA. Dentro de las combinaciones LABA/CI, la combinación budesonida/formoterol ofreció un mejor control. En la terapia LAMA no hay grandes diferencias, pero comparada con LABA ofreció un mayor control. La triple terapia en un único dispositivo se muestra superior a la doble terapia y a la triple terapia en dos dispositivos, no habiendo diferencias relevantes entre las combinaciones disponibles (AU)

Inhaled therapy with long-acting bronchodilators is the base of pharmacological treatment in COPD. In order to find out those that offer better control, a search was carried out in Medline (Pubmed). Comparative studies of inhaler therapy in COPD patients were analyzed. The comparison between the fixed combination LABA/LAMA versus LABA/CI in non-exacerbating patients, revealed a better control with LABA/LAMA. Within the LABA/CI combinations, budesonide/formoterol combination offered better control. LAMA inhalers revealed no great differences, but when compared to LABA, it offered a better control. Regarding triple therapy in a single device, was superior to double therapy and to triple therapy in two devices, with no relevant differences among the available combinations(AU)

Ambulatory electrocardiography, heart rate variability, and pharmacologic stress testing in cats with subclinical hypertrophic cardiomyopathy.

The utility of ambulatory electrocardiography (AECG) to evaluate cats with subclinical hypertrophic cardiomyopathy (HCM) for arrhythmias and heart rate variability (HRV) is not well defined but may provide information regarding risk stratification. This prospective study used AECG to evaluate ectopy and HRV in subclinical HCM cats compared to healthy controls and is the first to implement a pharmacologic cardiac stress test. Twenty-three purpose-bred, Maine coon cross cats (16 HCM, 7 control) underwent 48-h of continuous AECG. Terbutaline (0.2-0.3 mg/kg) was administered orally at 24 and 36 h. Heart rate, ectopy frequency and complexity and HRV parameters, including standard deviation of normal R-R intervals (SDNN), were compared pre-terbutaline and post-terbutaline and across phenotype, genotype and sex. Genotype for an HCM-causative mutation was significantly associated with the frequency of supraventricular (P = 0.033) and ventricular (P = 0.026) ectopy across all cats. Seven HCM cats and zero healthy cats had a sinus arrhythmia. Mean heart rate was significantly higher post-terbutaline (p < 0.0001). HCM cats had significantly greater HRV compared to controls (SDNN: p = 0.0006). Male cats had significantly higher HRV (SDNN: p = 0.0001) and lower mean heart rates (p = 0.0001). HRV decreased post-terbutaline (SDNN: p = 0.0008) and changes in HRV observed between sexes were attenuated by terbutaline.

A scintigraphy study of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler in patients with moderate-to-very severe chronic obstructive pulmonary disease.

BACKGROUND: Triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting ß2-agonists (ICS/LAMA/LABA) is recommended for patients with chronic obstructive pulmonary disease (COPD) with continued symptoms or exacerbations, despite treatment with LAMA/LABA or ICS/LABA. The pulmonary, extrathoracic, and regional lung deposition patterns of a radiolabeled ICS/LAMA/LABA triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate (BGF 320/18/9.6 µg), delivered via a single Aerosphere metered dose inhaler (MDI) were previously assessed in healthy volunteers and showed good deposition to the central and peripheral airways (whole lung deposition: 37.7%). Here, we report the findings assessing BGF in patients with moderate-to-very severe COPD. METHODS: This phase I, single-dose, open-label gamma scintigraphy imaging study (NCT03906045) was conducted in patients with moderate-to-very severe COPD. Patients received two actuations of BGF MDI (160/9/4.8 µg per actuation) radiolabeled with technetium­99­pertechnetate, not exceeding 5 MBq per actuation. Immediately following each inhalation, patients performed a breath-hold of up to 10 s, then exhaled into an exhalation filter. Gamma scintigraphy imaging of the anterior and posterior views of the lungs and stomach, and a lateral head and neck view, were performed immediately after exhalation. The primary objective of the study was to assess the pulmonary deposition of BGF. Secondary objectives assessed the deposited dose of radiolabeled BGF in the oropharyngeal and stomach regions, on the actuator, and on the exhalation filter in addition to regional airway deposition patterns in the lungs. RESULTS: The mean BGF emitted dose deposited in the lungs was 32.1% (standard deviation [SD] 15.6) in patients with moderate-to-very severe COPD, 35.2% (SD 12.8) in patients with moderate COPD, and 28.7% (SD 18.4) in patients with severe/very severe COPD. Overall, the mean normalized outer/inner ratio was 0.55 (SD 0.19), while the standardized central/peripheral ratio was 2.21 (SD 1.64). CONCLUSIONS: Radiolabeled BGF 320/18/9.6 µg was efficiently delivered and deposited throughout the entire lung, including large and small airways, in patients with moderate-to-very severe COPD, with similar deposition in patients with moderate COPD and patients with severe/very severe COPD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03906045. Registered 8 April 2019, https://clinicaltrials.gov/ct2/show/NCT03906045.

Efficacy of umeclidinium/vilanterol according to the degree of reversibility of airflow limitation at screening: a post hoc analysis of the EMAX trial.

BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD), the relationship between short-term bronchodilator reversibility and longer-term response to bronchodilators is unclear. Here, we investigated whether the efficacy of long-acting bronchodilators is associated with reversibility of airflow limitation in patients with COPD with a low exacerbation risk not receiving inhaled corticosteroids. METHODS: The double-blind, double-dummy EMAX trial randomised patients to umeclidinium/vilanterol 62.5/25 µg once daily, umeclidinium 62.5 µg once daily, or salmeterol 50 µg twice daily. Bronchodilator reversibility to salbutamol was measured once at screening and defined as an increase in forced expiratory volume in 1 s (FEV1) of ≥ 12% and ≥ 200 mL 10-30 min post salbutamol. Post hoc, fractional polynomial (FP) modelling was conducted using the degree of reversibility (mL) at screening as a continuous variable to investigate its relationship to mean change from baseline in trough FEV1 and self-administered computerised-Transition Dyspnoea Index (SAC-TDI) at Week 24, Evaluating Respiratory Symptoms-COPD (E-RS) at Weeks 21-24, and rescue medication use (puffs/day) over Weeks 1-24. Analyses were conducted across the full range of reversibility (-850-896 mL); however, results are presented for the range -100-400 mL because there were few participants with values outside this range. RESULTS: The mean (standard deviation) reversibility was 130 mL (156) and the median was 113 mL; 625/2425 (26%) patients were reversible. There was a trend towards greater improvements in trough FEV1, SAC-TDI, E-RS and rescue medication use with umeclidinium/vilanterol with higher reversibility. Improvements in trough FEV1 and reductions in rescue medication use were greater with umeclidinium/vilanterol compared with either monotherapy across the range of reversibility. Greater improvements in SAC-TDI and E-RS total scores were observed with umeclidinium/vilanterol versus monotherapy in the middle of the reversibility range. CONCLUSIONS: FP analyses suggest that patients with higher levels of reversibility have greater improvements in lung function and symptoms in response to bronchodilators. Improvements in lung function and rescue medication use were greater with umeclidinium/vilanterol versus monotherapy across the full range of reversibility, suggesting that the dual bronchodilator umeclidinium/vilanterol may be an appropriate treatment for patients with symptomatic COPD, regardless of their level of reversibility.

SMART for the treatment of asthma: A network meta-analysis of real-world evidence.

A large proportion of asthmatic patients are treated with protocols resulting from data obtained by randomized controlled trials (RCTs) for which they would not have been eligible. Therefore, the aim of this study was to undertake a quantitative synthesis on real-world evidence comparing single inhaled corticosteroid (ICS)/formoterol maintenance and reliever therapy (SMART) and maintenance ICS/long-acting ß2-adrenoceptor agonist (LABA) + as-needed short-acting ß2-adrenoceptor agonist (SABA). A network meta-analysis of real-world studies was performed to compare SMART with ICS/LABA + as-needed SABA therapies in asthmatic patients. The surface under the cumulative ranking curve analysis was used to rank efficacy. The posterior probability distribution was reported as 95% credible interval (95%CrI). Data of 11,360 asthmatic patients were extracted from 6 studies. SMART including an ICS at medium-dose (MD) was more effective than MD ICS/LABA FDC + as-needed SABA (RR 0.54 95%CrI 0.42-0.69; P < 0.001) and low-dose (LD) SMART (RR 0.82 95%CrI 0.70-0.95; P < 0.05) against severe asthma exacerbation. MD SMART improved the Asthma Control Questionnaire score more than MD ICS/LABA FDC + as-needed SABA (delta effect -0.33 95%CrI -0.62 to -0.01; P < 0.05). The efficacy rank was: MD SMART > LD SMART > ICS + LABA free combination + as-needed SABA > ICS/LABA FDC + as-needed SABA > MD ICS/LABA FDC + as-needed SABA. The findings of this network meta-analysis of real-world evidence, and concordance with the effect estimates resulting from previous meta-analyses of RCTs, suggest that SMART may represent the preferred therapeutic option to reduce the risk of severe exacerbation in adults with moderate to severe asthma.

Switching to nebulised short acting bronchodilators does not increase the risk of arrhythmia in patients hospitalized with a COPD exacerbation.

If short acting ß2-agonists and muscarinic antagonists (SABA/SAMA) may have proarrhythmic effects during acute COPD exacerbations (AECOPD) is still unknown. The primary objective of the study was to investigate the incidence of new onset arrhythmias in hospitalized patients shifted to SABA/SAMA during an AECOPD compared with continuing chronic inhaled therapy. Secondary objectives were to assess the clinical characteristics of patients shifted to SABA/SAMA and risk factors for arrhythmia. This was a retrospective, observational, study enrolling consecutive patients hospitalized with an AECOPD. Incidence of arrhythmias was obtained reviewing digital records. Patients with chronic arrhythmias or home-treated with SABA/SAMA were excluded. 235 patients (63.8% males) were included, and 10/182 patients shifted to SABA/SAMA experienced arrhythmias, while no events were observed in patients on chronic inhaled therapy (p = 0.122). Shifted patients had a more severe AECOPD and history of paroxysmal atrial fibrillation was an independent risk factor for arrhythmia (OR 14.010, IC95%: 2.983-65.800; p = 0.001). In conclusion, shifting patients to SABA/SAMA appears not to increase the risk for arrhythmia during severe AECOPD. However, the pharmacological approach in patients with a history of paroxysmal arrhythmia should be carefully evaluated and monitored.

Inhaled Beta2-Agonists Increase In-Hospital Mortality in ICU Patients with Heart Failure.

The impact of beta2-agonists (B2As) on heart failure (HF) remains controversial. This study aimed to investigate whether inhaled B2As increased in-hospital mortality in ICU patients with HF.The Multiparameter Intelligent Monitoring in Intensive Care III database was initially searched to identify adult patients (≥ 18 years old) with HF in ICU. Then, patients using or not using inhaled B2As were matched using propensity score matching on a 1:1 basis to control for baseline confounders. In-hospital mortality was compared between the two groups, and logistic regression analysis was performed to assess the association between B2As and in-hospital mortality.The initial search retrieved 2345 eligible patients with HF from the database. After propensity score matching, 705 pairs of patients were included in the final analysis. Patients using B2As had markedly higher in-hospital mortality than those not using B2As (4.68% versus 2.27%; P = 0.013). In the multivariate logistic regression analysis, B2A use (odd ratios (OR), 2.471; 95% confidence interval (CI), 1.289-4.734; P = 0.006), stroke (OR, 4.581; 95% CI, 1.621-12.948; P = 0.004), and simplified acute physiology score II (SAPS-II) scores (OR, 1.090; 95% CI, 1.064-1.116; P < 0.001) were significantly associated with increased risk of in-hospital mortality, whereas renin angiotensin system inhibitor use (OR, 0.396; 95% CI, 0.202-0.778; P = 0.007) was significantly associated with decreased risk of in-hospital mortality. Subgroup analysis further indicated that the association between B2A use and mortality was significant only in patients with HF without chronic pulmonary disease (OR, 2.427; 95% CI, 1.351-4.362; P = 0.003), but not in those with chronic pulmonary disease (OR, 2.094; 95% CI, 0.582-7.537; P = 0.258).In ICU patients with HF but without chronic pulmonary disease, the use of inhaled B2As is associated with increased in-hospital mortality.