Real-World Effectiveness of Single-Inhaler Triple Therapy for COPD: Impact of Diabetes Comorbidity.

Type 2 diabetes is a frequent comorbidity in chronic obstructive pulmonary disease (COPD) patients, with the GOLD treatment recommendations asserting that the presence of diabetes be disregarded in the choice of treatment.In a cohort of COPD patients with frequent exacerbations, initiators of single-inhaler triple therapy or dual bronchodilators were compared on the incidence of COPD exacerbation and pneumonia over one year, adjusted by propensity score weighting and stratified by type 2 diabetes.The COPD cohort included 1,114 initiators of triple inhalers and 4,233 of dual bronchodilators (28% with type 2 diabetes). The adjusted hazard ratio (HR) of exacerbation with triple therapy was 1.04 (95% CI: 0.86-1.25) among COPD patients with type 2 diabetes and 0.74 (0.65-0.85) in those without. The incidence of severe pneumonia was elevated with triple therapy among patients with type 2 diabetes (HR 1.77; 1.14-2.75).Triple therapy in COPD is effective among those without, but not those with, type 2 diabetes. Future therapeutic trials in COPD should consider diabetes comorbidity.

Triple therapy for frequent COPD exacerbators is effective in patients without type 2 diabetes but not in those with type 2 diabetes. The impact of comorbidities should be considered in future COPD therapeutic trials.

Real-world treatment trajectories of adults with newly diagnosed asthma or COPD.

BACKGROUND: There is a lack of knowledge on how patients with asthma or chronic obstructive pulmonary disease (COPD) are globally treated in the real world, especially with regard to the initial pharmacological treatment of newly diagnosed patients and the different treatment trajectories. This knowledge is important to monitor and improve clinical practice. METHODS: This retrospective cohort study aims to characterise treatments using data from four claims (drug dispensing) and four electronic health record (EHR; drug prescriptions) databases across six countries and three continents, encompassing 1.3 million patients with asthma or COPD. We analysed treatment trajectories at drug class level from first diagnosis and visualised these in sunburst plots. RESULTS: In four countries (USA, UK, Spain and the Netherlands), most adults with asthma initiate treatment with short-acting ß2 agonists monotherapy (20.8%-47.4% of first-line treatments). For COPD, the most frequent first-line treatment varies by country. The largest percentages of untreated patients (for asthma and COPD) were found in claims databases (14.5%-33.2% for asthma and 27.0%-52.2% for COPD) from the USA as compared with EHR databases (6.9%-15.2% for asthma and 4.4%-17.5% for COPD) from European countries. The treatment trajectories showed step-up as well as step-down in treatments. CONCLUSION: Real-world data from claims and EHRs indicate that first-line treatments of asthma and COPD vary widely across countries. We found evidence of a stepwise approach in the pharmacological treatment of asthma and COPD, suggesting that treatments may be tailored to patients' needs.

Effects of triple therapy on disease burden in patients of GOLD groups C and D: results from the observational COPD cohort COSYCONET.

BACKGROUND: Randomized controlled trials described beneficial effects of inhaled triple therapy (LABA/LAMA/ICS) in patients with chronic obstructive pulmonary disease (COPD) and high risk of exacerbations. We studied whether such effects were also detectable under continuous treatment in a retrospective observational setting. METHODS: Data from baseline and 18-month follow-up of the COPD cohort COSYCONET were used, including patients categorized as GOLD groups C/D at both visits (n = 258). Therapy groups were defined as triple therapy at both visits (triple always, TA) versus its complement (triple not always, TNA). Comparisons were performed via multiple regression analysis, propensity score matching and inverse probability weighting to adjust for differences between groups. For this purpose, variables were divided into predictors of therapy and outcomes. RESULTS: In total, 258 patients were eligible (TA: n = 162, TNA: n = 96). Without adjustments, TA patients showed significant (p < 0.05) impairments regarding lung function, quality of life and symptom burden. After adjustments, most differences in outcomes were no more significant. Total direct health care costs were reduced but still elevated, with inpatient costs much reduced, while costs of total and respiratory medication only slightly changed. CONCLUSION: Without statistical adjustment, patients with triple therapy showed multiple impairments as well as elevated treatment costs. After adjusting for differences between treatment groups, differences were reduced. These findings are compatible with beneficial effects of triple therapy under continuous, long-term treatment, but also demonstrate the limitations encountered in the comparison of controlled intervention studies with observational studies in patients with severe COPD using different types of devices and compounds.

Multidisciplinary Management of Patients With Chronic Obstructive Pulmonary Disease and Cardiovascular Disease.

Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) frequently coexist, increasing the prevalence of both entities and impacting on symptoms and prognosis. CVD should be suspected in patients with COPD who have high/very high risk scores on validated scales, frequent exacerbations, precordial pain, disproportionate dyspnea, or palpitations. They should be referred to cardiology if they have palpitations of unknown cause or angina pain. COPD should be suspected in patients with CVD if they have recurrent bronchitis, cough and expectoration, or disproportionate dyspnea. They should be referred to a pulmonologist if they have rhonchi or wheezing, air trapping, emphysema, or signs of chronic bronchitis. Treatment of COPD in cardiovascular patients should include long-acting muscarinic receptor antagonists (LAMA) or long-acting beta-agonists (LABA) in low-risk or high-risk non-exacerbators, and LAMA/LABA/inhaled corticosteroids in exacerbators who are not controlled with bronchodilators. Cardioselective beta-blockers should be favored in patients with CVD, the long-term need for amiodarone should be assessed, and antiplatelet drugs should be maintained if indicated.

[Medication management of COPD]. / Prise en charge médicamenteuse de la BPCO.

MEDICATION MANAGEMENT OF COPD. The management of chronic obstructive pulmonary disease (COPD) is based on drug and non-drug measures. Inhaled therapies are the major issues including the use of short-acting bronchodilators for respiratory symptoms. If symptoms are daily, such as disabling dyspnea or frequent exacerbations, daily treatment with a long-acting bronchodilator is proposed: anti-muscarinic (LAMA) or ß2-agonist (LABA). If there is no improvement, escalation to dual and then triple therapy is proposed. Another major issue in the management of COPD is de-escalation in the event of ineffectiveness or side effects of inhaled corticosteroids (ICS). Finally, the role of blood eosinophils and other biomarkers is even more important that biotherapies could expand the therapeutic options for some subtypes of COPD patients.

PRISE EN CHARGE MÉDICAMENTEUSE DE LA BPCO. La prise en charge de la bronchopneumopathie chronique obstructive (BPCO) repose sur des mesures médicamenteuses et non médicamenteuses. Le principe des traitements médicamenteux dans la BPCO comprend des traitements inhalés, et notamment l'utilisation de bronchodilatateurs de courte durée d'action en cas de symptômes respiratoires. Si les symptômes sont quotidiens à type de dyspnée invalidante ou en cas d'exacerbations fréquentes, un traitement de fond quotidien par un bronchodilatateur de longue durée d'action est indiqué : antimuscarinique (LAMA) ou ß2-agoniste (LABA). En l'absence d'amélioration, une escalade est proposée par bithérapie puis trithérapie. Un autre enjeu majeur de la prise en charge de la BPCO est la désescalade thérapeutique en cas d'inefficacité ou d'effets indésirables des corticostéroïdes inhalés (CSI). Enfin, la place du dosage des éosinophiles et autres biomarqueurs sanguins est d'autant plus importante que les biothérapies pourraient venir élargir l'arsenal thérapeutique pour certains soustypes de patients atteints de BPCO.

Treatment pathways, economic burden and clinical outcomes in new users of inhaled corticosteroid/long-acting B2-agonist dual therapy with chronic obstructive pulmonary disease in a primary care setting in England: a retrospective cohort study.

OBJECTIVE: Management of chronic obstructive pulmonary disease (COPD) with inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) improves lung function and health status and reduces COPD exacerbation risk versus monotherapy. This study described treatment use, healthcare resource utilisation (HCRU), healthcare costs and outcomes following initiation of single-device ICS/LABA as initial maintenance therapy (IMT). DESIGN: Retrospective cohort study. SETTING: Primary care, England. DATA SOURCES: Linked data from the Clinical Practice Research Datalink Aurum and Hospital Episode Statistics datasets. PARTICIPANTS: Patients with COPD and ≥1 single-device ICS/LABA prescription between July 2015 and December 2018 were included. PRIMARY AND SECONDARY OUTCOME MEASURES: Treatment pathways, COPD-related HCRU and healthcare costs, COPD exacerbations, time to triple therapy, medication adherence (proportion of days covered ≥80%) and indexed treatment time to discontinuation. Data for patients without prior maintenance therapy history (IMT users) and non-triple users were assessed over a 12-month follow-up period. RESULTS: Of 13 451 new ICS/LABA users, 5162 were IMT users (budesonide/formoterol, n=1056; beclomethasone dipropionate/formoterol, n=2427; other ICS/LABA, n=1679), for whom at 3 and 12 months post-index, 45.6% and 39.4% were still receiving any ICS/LABA. At >6 to ≤12 months, the proportion of IMT users with ≥1 outpatient visit (10.1%) and proportion with ≥1 inpatient stay (12.6%) had increased from those at 3 months (9.0% and 7.4%, respectively). Inpatient stays contributed most to total COPD-related healthcare costs. For non-triple IMT users, at 3 and 12 months post-index, 4.5% and 13.7% had ≥1 moderate-to-severe COPD exacerbation. Time to triple therapy initiation and time to discontinuation of index medication ranged from 45.9 to 50.2 months and 2.3 to 2.8 months between treatments. Adherence was low across all time points (21.5-27.6%). Results were similar across indexed therapies. CONCLUSIONS: In the year following treatment initiation, ICS/LABA adherence was poor and many patients discontinued or switched therapies, suggesting that more consideration and optimisation of treatment is required in England for patients initiating single-device ICS/LABA therapy.

The effect of combining an inhaled corticosteroid and a long-acting muscarinic antagonist on human airway epithelial cells in vitro.

BACKGROUND: Airway epithelial cells (AECs) are a major component of local airway immune responses. Direct effects of type 2 cytokines on AECs are implicated in type 2 asthma, which is driven by epithelial-derived cytokines and leads to airway obstruction. However, evidence suggests that restoring epithelial health may attenuate asthmatic features. METHODS: We investigated the effects of passive sensitisation on IL-5, NF-κB, HDAC-2, ACh, and ChAT in human bronchial epithelial cells (HBEpCs) and the effects of fluticasone furoate (FF) and umeclidinium (UME) alone and in combination on these responses. RESULTS: IL-5 and NF-κB levels were increased, and that of HDAC-2 reduced in sensitised HEBpCs. Pretreatment with FF reversed the effects of passive sensitisation by concentration-dependent reduction of IL-5, resulting in decreased NF-κB levels and restored HDAC-2 activity. Addition of UME enhanced these effects. Sensitized HEBpCs also exhibited higher ACh and ChAT levels. Pretreatment with UME significantly reduced ACh levels, and addition of FF caused a further small reduction. CONCLUSION: This study confirmed that passive sensitisation of AECs results in an inflammatory response with increased levels of IL-5 and NF-κB, reduced levels of HDAC-2, and higher levels of ACh and ChAT compared to normal cells. Combining FF and UME was found to be more effective in reducing IL-5, NF-κB, and ACh and restoring HDAC-2 compared to the individual components. This finding supports adding a LAMA to established ICS/LABA treatment in asthma and suggests the possibility of using an ICS/LAMA combination when needed.

ß2-Adrenergic receptor agonists as a treatment for diabetic kidney disease.

We have previously shown that the long-acting ß2-adrenergic receptor (ß2-AR) agonist formoterol induced recovery from acute kidney injury in mice. To determine whether formoterol protected against diabetic nephropathy, the most common cause of end-stage kidney disease (ESKD), we used a high-fat diet (HFD), a murine type 2 diabetes model, and streptozotocin, a murine type 1 diabetes model. Following formoterol treatment, there was a marked recovery from and reversal of diabetic nephropathy in HFD mice compared with those treated with vehicle alone at the ultrastructural, histological, and functional levels. Similar results were seen after formoterol treatment in mice receiving streptozotocin. To investigate effects in humans, we performed a competing risk regression analysis with death as a competing risk to examine the association between Veterans with chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD), who use ß2-AR agonists, and Veterans with CKD but no COPD, and progression to ESKD in a large national cohort of Veterans with stage 4 CKD between 2011 and 2013. Veterans were followed until 2016 or death. ESKD was defined as the initiation of dialysis and/or receipt of kidney transplant. We found that COPD was associated with a 25.6% reduction in progression from stage 4 CKD to ESKD compared with no COPD after adjusting for age, diabetes, sex, race-ethnicity, comorbidities, and medication use. Sensitivity analysis showed a 33.2% reduction in ESKD in Veterans with COPD taking long-acting formoterol and a 20.8% reduction in ESKD in Veterans taking other ß2-AR agonists compared with those with no COPD. These data indicate that ß2-AR agonists, especially formoterol, could be a treatment for diabetic nephropathy and perhaps other forms of CKD.NEW & NOTEWORTHY Diabetic nephropathy is the most common cause of ESKD. Formoterol, a long-acting ß2-adrenergic receptor (ß2-AR) agonist, reversed diabetic nephropathy in murine models of type 1 and 2 diabetes. In humans, there was an association with protection from progression of CKD in patients with COPD, by means of ß2-AR agonist intake, compared with those without COPD. These data indicate that ß2-AR agonists, especially formoterol, could be a new treatment for diabetic nephropathy and other forms of CKD.

Inhaled corticosteroids with combination inhaled long-acting beta2-agonists and long-acting muscarinic antagonists for chronic obstructive pulmonary disease.

BACKGROUND: Management of chronic obstructive pulmonary disease (COPD) commonly involves a combination of long-acting bronchodilators including beta2-agonists (LABA) and muscarinic antagonists (LAMA). LABA and LAMA bronchodilators are now available in single-combination inhalers. In individuals with persistent symptoms or frequent exacerbations, inhaled corticosteroids (ICS) are also used with combination LABA and LAMA inhalers. However, the benefits and risks of adding ICS to combination LABA/LAMA inhalers as a triple therapy remain unclear. OBJECTIVES: To assess the effects of adding an ICS to combination LABA/LAMA inhalers for the treatment of stable COPD. SEARCH METHODS: We searched the Cochrane Airways Group Register of Trials, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase up to 30 November 2022. We also searched ClinicalTrials.gov and the WHO ICTRP up to 30 November 2022. SELECTION CRITERIA: We included parallel-group randomised controlled trials of three weeks' duration or longer that compared the treatment of stable COPD with ICS in addition to combination LABA/LAMA inhalers against combination LABA/LAMA inhalers alone. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. The primary outcomes were acute exacerbations of COPD, respiratory health-related quality of life, pneumonia and other serious adverse events. The secondary outcomes were symptom scores, lung function, physical capacity, and mortality. We used GRADE to assess certainty of evidence for studies that contributed data to our prespecified outcomes. MAIN RESULTS: Four studies with a total of 15,412 participants met the inclusion criteria. The mean age of study participants ranged from 64.4 to 65.3 years; the proportion of female participants ranged from 28% to 40%. Most participants had symptomatic COPD (COPD Assessment Test Score ≥ 10) with severe to very severe airflow limitation (forced expiratory volume in one second (FEV1) < 50% predicted) and one or more moderate-to-severe COPD exacerbations in the last 12 months. Trial medications differed amongst studies. The duration of follow-up was 52 weeks in three studies and 24 weeks in one study. We assessed the risk of selection, performance, and detection bias to be low in the included studies; one study was at high risk of attrition bias, and one study was at high risk of reporting bias. Triple therapy may reduce rates of moderate-to-severe COPD exacerbations compared to combination LABA/LAMA inhalers (rate ratio (RR) 0.74, 95% confidence interval (CI) 0.67 to 0.81; n = 15,397; low-certainty evidence). Subgroup analysis stratifying by blood eosinophil counts showed there may be a greater reduction in rate of moderate-to-severe COPD exacerbations with triple therapy in participants with high-eosinophils (RR 0.67, 95% CI 0.60 to 0.75) compared to low-eosinophils (RR 0.87, 95% CI 0.81 to 0.93) (test for subgroup differences: P < 0.01) (high/low cut-offs: 150 eosinophils/µL in three studies; 200 eosinophils/µL in one study). However, moderate-to-substantial heterogeneity was observed in both high- and low-eosinophil subgroups. These subgroup analyses are observational by nature and thus results should be interpreted with caution. Triple therapy may be associated with reduced rates of severe COPD exacerbations (RR 0.75, 95% CI 0.67 to 0.84; n = 14,131; low-certainty evidence). Triple therapy improved health-related quality of life assessed using the St George's Respiratory Questionnaire (SGRQ) by the minimal clinically important difference (MCID) threshold (4-point decrease) (35.3% versus 42.4%, odds ratio (OR) 1.35, 95% CI 1.26 to 1.45; n = 14,070; high-certainty evidence). Triple therapy may result in fewer symptoms measured using the Transition Dyspnoea Index (TDI) (OR 1.33, 95% CI 1.13 to 1.57; n = 3044; moderate-certainty evidence) and improved lung function as measured by change in trough FEV1 (mean difference 38.68 mL, 95% CI 22.58 to 54.77; n = 11,352; low-certainty evidence). However, these benefits fell below MCID thresholds for TDI (1-unit decrease) and trough FEV1 (100 mL), respectively. Triple therapy is probably associated with a higher risk of pneumonia as a serious adverse event compared to combination LABA/LAMA inhalers (3.3% versus 1.9%, OR 1.74, 95% CI 1.39 to 2.18; n = 15,412; moderate-certainty evidence). In contrast, all-cause serious adverse events may be similar between groups (19.7% versus 19.7%, OR 0.95, 95% CI 0.87 to 1.03; n = 15,412; low-certainty evidence). All-cause mortality may be lower with triple therapy (1.4% versus 2.0%, OR 0.70, 95% CI 0.54 to 0.90; n = 15,397; low-certainty evidence). AUTHORS' CONCLUSIONS: The available evidence suggests that triple therapy may reduce rates of COPD exacerbations (low-certainty evidence) and results in an improvement in health-related quality of life (high-certainty evidence) compared to combination LABA/LAMA inhalers, but probably confers an increased pneumonia risk as a serious adverse event (moderate-certainty evidence). Triple therapy probably improves respiratory symptoms and may improve lung function (moderate- and low-certainty evidence, respectively); however, these benefits do not appear to be clinically significant. Triple therapy may reduce the risk of all-cause mortality compared to combination LABA/LAMA inhalers (low-certainty evidence). The certainty of the evidence was downgraded most frequently for inconsistency or indirectness. Across the four included studies, there were important differences in inclusion criteria, trial medications, and duration of follow-up. Investigation of heterogeneity was limited due to the small number of included studies. We found limited data on the effects of triple therapy compared to combination LABA/LAMA inhalers in patients with mild-moderate COPD and those without a recent exacerbation history.

[Perioperative Rehabolotation Usefulness in Preventing Complications].

The number of elderly patients in thoracic surgery is increasing. The percentage of patients over the age of 80 in surgical cases of malignant diseases such as lung cancer and mediastinal tumors is increasing every year. It is also true that the indications for surgery have been expanding as surgery itself has become less invasive, such as thoracoscopic and robotic surgery. However, it is not uncommon for patients over 80 years of age to have some organ dysfunction and many comorbidities. Therefore, when performing surgery for lung cancer and other diseases, it is important to assess the patient's ability to tolerate surgery, including respiratory and cardiac functions, and to perform risk management. To prevent postoperative complications and improve the accuracy of perioperative management, respiratory rehabilitation should be conducted before and after surgery, and not only smoking cessation instruction but also inhalation training using incentive spirometry( IS), breathing exercises, and the use of inhalers such as long-acting ß2 agonist (LABA)/long-acting muscaring antagonist (LAMA) for patients with chronic obstructive pulmonary disease( COPD) are useful.

[CQ IN THE LONG-TERM MANAGEMENT OF ADULT ASTHMATIC PATIENTS WHO ARE NOT ADEQUATELY CONTROLLED WITH INHALED CORTICOSTEROIDS MONOTHERAPY, WHICH IS MORE BENEFICIAL: ADDING A LONG ACTING BETA2 AGONIST OR A LONG ACTING MUSCARINIC ANTAGONIST?]

Long-acting beta2-agonists (LABA) are preferred add-on treatment for adult asthmatic patients whose symptoms cannot be controlled with inhaled corticosteroids (ICS) alone. However, over the last decade, long-acting muscarinic antagonists (LAMA) have gained approval for use in treating asthma, and their efficacy is anticipated. Therefore, we conducted a systematic review to investigate whether the addition of LABA or LAMA is more beneficial for the long-term management of adult asthmatic patients poorly controlled on ICS monotherapy. We extracted eight relevant randomized controlled trials (represented in 18 articles) conducted by June 2022 form the corresponding Cochrane review and additional searches through medical databases (CINAHL, Cochrane Library, EMBASE, MEDLINE, PsycINFO, and ICHUSHI (https://www.jamas.or.jp/)). While the LAMA add-on group showed a significantly better improvement in some respiratory function tests, the difference between groups did not exceed the minimum clinically important difference (MCID). On the other hand, the Asthma Quality of Life Questionnaire, a quality of life metric, was significantly higher in the LABA add-on group, but the difference also did not surpass the MCID. Because no outcomes exceeded the MCID, we could not determine whether adding LABA or LAMA on ICS is more beneficial in the long-term management of adult asthmatic patients. Given that no significant differences were found in the incidence of adverse events (including serious ones), when specific adverse events associated with one treatment occur, switching to the other treatment (from LABA to LAMA, or vice versa) can be considered as an option.

Advances in adrenergic receptors for the treatment of chronic obstructive pulmonary disease: 2023 update.

INTRODUCTION: Strong scientific evidence and large experience support the use of ß2-agonists for the symptomatic alleviation of COPD. Therefore, there is considerable effort in discovering highly potent and selective ß2-agonists. AREAS COVERED: Recent research on novel ß2-agonists for the treatment of COPD. A detailed literature search was performed in two major databases (PubMed/MEDLINE and Scopus) up to September 2023." EXPERT OPINION: Compounds that preferentially activate a Gs- or ß-arrestin-mediated signaling pathway via ß- adrenoceptors (ARs) are more innovative. Pepducins, which target the intracellular region of ß2-AR to modulate receptor signaling output, have the most interesting profile from a pharmacological point of view. They stabilize the conformation of the ß2-AR and influence its signaling by interacting with the intracellular receptor-G protein interface. New bifunctional drugs called muscarinic antagonist-ß2 agonist (MABA), which have both muscarinic receptor (mAChR) antagonism and ß2-agonist activity in the same molecule, are a new opportunity. However, all tested compounds have been shown to act predominantly as mAChR antagonists or ß2-agonists. An intriguing idea is to utilize allosteric modulators that bind to ß2-ARs at sites different than those bound by orthosteric ligands to augment or reduce the signaling transduced by the orthosteric ligand.

Overuse of long-acting ß2-agonist/inhaled corticosteroids in patients with chronic obstructive pulmonary disease: time to rethink prescribing patterns.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality globally. In the major revision of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023 report, the scientific committee concluded that the use of long-acting ß2-agonist/inhaled corticosteroids (LABA/ICS) is not encouraged in patients with COPD. However, current prescribing patterns reveal significant use of LABA/ICS. In this paper, the evidence behind the current practice and the latest treatment recommendations is reviewed. We compare the efficacy and safety of combination therapy with long-acting muscarinic antagonist (LAMA) and LABA vs LABA/ICS and note that LAMA/LABA combinations have reduced the annual rate of moderate/severe exacerbations, delayed the time to first exacerbation, and increased post-dose FEV1 vs ICS-based regimens. The GOLD 2023 report recommends treatment with LABA and LAMA combination (preferably as a single inhaler) in patients with persistent dyspnea, with initiation of ICS in patients based on the symptoms (dyspnea and exercise intolerance as indicated by modified Medical Research Council [mMRC] score ≥ 2 and COPD Assessment Test [CAT™] > 20), blood eosinophil count (≥ 300 cells/µL), and exacerbation history (history of hospitalizations for exacerbations of COPD and ≥ 2 moderate exacerbations per year despite appropriate long-acting bronchodilator maintenance therapy). We describe practical recommendations for primary care physicians to optimize therapy for their patients and prevent overuse of ICS-based regimens. We advocate adherence to current recommendations and a greater focus on effective treatments to successfully control symptoms, minimize exacerbation risk, preserve lung function, maximize patient outcomes, and reduce the burden of drug-related adverse events.

Chronic obstructive pulmonary disease (COPD) is a common disease of the lungs associated with continued respiratory symptoms and airflow limitation. COPD causes symptoms such as breathlessness, cough, and production of phlegm, and, if not properly managed, these symptoms may get worse and result in flare-ups, also termed exacerbations. COPD management includes controlling symptoms while reducing the risk of exacerbations. COPD treatments include bronchodilators and inhaled corticosteroids (ICS). Bronchodilators help by widening the airways, making it easier to breathe. The two types of bronchodilators are long-acting muscarinic antagonists (LAMAs; these drugs prevent closing of the airways) and long-acting ß₂-agonists (LABAs; these drugs relax the muscles around the airways to help keep the airways open for a longer time). ICS may reduce swelling in the airways in some patients with COPD. However, the use of ICS-based regimens as the first treatment choice has been linked to health risks and is not in keeping with the recent national and international recommendations. In this narrative review, we examine why the use of ICS-based regimens is still growing and explore, based on available evidence, and why this treatment course may not be optimal for most patients with COPD. We discuss how the treatment for COPD has changed over time, and our findings support the use of LAMA and LABA as the first course of therapy in many patients with COPD. We conclude that greater adherence to the treatment guidelines can help to improve treatment outcomes for many patients with COPD.

Rational use of inhaled corticosteroids for the treatment of COPD: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: Inhaled corticosteroids (ICS) are a type of medication delivered via an inhaler device that are commonly used in the treatment of asthma. ICS can also be used to treat chronic obstructive pulmonary disease (COPD), a progressive respiratory condition in which the lungs become worse over time. However, unlike in asthma, ICS are only effective in a small proportion of people with COPD. ICS can cause significant side effects in people with COPD, including pneumonia. Because of this, guidelines written by COPD experts recommend that ICS should largely be prescribed to people with COPD whose symptoms flare up frequently and become difficult to manage (episodes known as exacerbations). Despite this guidance, records collected from routine clinical practice suggest that many healthcare professionals prescribe ICS to people with COPD who do not have frequent exacerbations, putting them at unnecessary risk of side effects. The over-prescription of ICS in COPD may partly be due to the recent introduction of single-inhaler combination therapies, which combine ICS with other medicines (bronchodilators). This 'one inhaler for all' approach is a concerning trend as it goes against global COPD treatment guidelines, which recommend ICS use in only a small proportion of people. This is a plain language summary of a review article originally published in the journal NPJ Primary Care Respiratory Medicine. In this review, we investigate the benefits and risks of ICS use in COPD. Using data from both randomized controlled trials (RCTs) and observational studies, we explain which people benefit from ICS use, and why health regulatory bodies have concluded that ICS do not help people with COPD to live longer. Lastly, we provide practical guidance for doctors and people with COPD regarding when ICS should be prescribed and when they should be withdrawn.

How can the findings of the EMAX trial on long-acting bronchodilation in chronic obstructive pulmonary disease be applied in the primary care setting?

This review addresses outstanding questions regarding initial pharmacological management of chronic obstructive pulmonary disease (COPD). Optimizing initial treatment improves clinical outcomes in symptomatic patients, including those with low exacerbation risk. Long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) dual therapy improves lung function versus LAMA or LABA monotherapy, although other treatment benefits have been less consistently observed. The benefits of dual bronchodilation in symptomatic patients with COPD at low exacerbation risk, and its duration of efficacy and cost effectiveness in this population, are not yet fully established. Questions remain on the impact of baseline symptom severity, prior treatment, degree of reversibility to bronchodilators, and smoking status on responses to dual bronchodilator treatment. Using evidence from EMAX (NCT03034915), a 6-month trial comparing the LAMA/LABA combination umeclidinium/vilanterol with umeclidinium and salmeterol monotherapy in symptomatic patients with COPD at low exacerbation risk who were inhaled corticosteroid-naïve, we describe how these findings can be applied in primary care.

Predicting the duration of action of ß2-adrenergic receptor agonists: Ligand and structure-based approaches.

Agonists of the ß2 adrenergic receptor (ADRB2) are an important class of medications used for the treatment of respiratory diseases. They can be classified as short acting (SABA) or long acting (LABA), with each class playing a different role in patient management. In this work we explored both ligand-based and structure-based high-throughput approaches to classify ß2-agonists based on their duration of action. A completely in-silico prediction pipeline using an AlphaFold generated structure was used for structure-based modelling. Our analysis identified the ligands' 3D structure and lipophilicity as the most relevant features for the prediction of the duration of action. Interaction-based methods were also able to select ligands with the desired duration of action, incorporating the bias directly in the structure-based drug discovery pipeline without the need for further processing.

2023 Canadian Thoracic Society Guideline on Pharmacotherapy in Patients With Stable COPD.

Chronic obstructive pulmonary disease patient care must include confirming a diagnosis with postbronchodilator spirometry. Because of the clinical heterogeneity and the reality that airflow obstruction assessed by spirometry only partially reflects disease severity, a thorough clinical evaluation of the patient should include assessment of symptom burden and risk of exacerbations that permits the implementation of evidence-informed pharmacologic and nonpharmacologic interventions. This guideline provides recommendations from a comprehensive systematic review with a meta-analysis and expert-informed clinical remarks to optimize maintenance pharmacologic therapy for individuals with stable COPD, and a revised and practical treatment pathway based on new evidence since the 2019 update of the Canadian Thoracic Society (CTS) Guideline. The key clinical questions were developed using the Patients/Population (P), Intervention(s) (I), Comparison/Comparator (C), and Outcome (O) model for three questions that focuses on the outcomes of symptoms (dyspnea)/health status, acute exacerbations, and mortality. The evidence from this systematic review and meta-analysis leads to the recommendation that all symptomatic patients with spirometry-confirmed COPD should receive long-acting bronchodilator maintenance therapy. Those with moderate to severe dyspnea (modified Medical Research Council ≥ 2) and/or impaired health status (COPD Assessment Test ≥ 10) and a low risk of exacerbations should receive combination therapy with a long-acting muscarinic antagonist/long-acting ẞ2-agonist (LAMA/LABA). For those with a moderate/severe dyspnea and/or impaired health status and a high risk of exacerbations should be prescribed triple combination therapy (LAMA/LABA/inhaled corticosteroids) azithromycin, roflumilast or N-acetylcysteine is recommended for specific populations; a recommendation against the use of theophylline, maintenance systemic oral corticosteroids such as prednisone and inhaled corticosteroid monotherapy is made for all COPD patients.

Study protocol: A comparison of mobile and clinic-based spirometry for capturing the treatment effect in moderate asthma.

Several inefficiencies in drug development trial implementation may be improved by moving data collection from the clinic to mobile, allowing for more frequent measurements and therefore increased statistical power while aligning to a patient-centric approach to trial design. Sensor-based digital health technologies such as mobile spirometry (mSpirometry) are comparable to clinic spirometry for capturing outcomes, such as forced expiratory volume in 1 s (FEV1); however, the impact of remote spirometry measurements on the detection of treatment effect has not been investigated. A protocol for a multicenter, single-arm, open-label interventional trial of long-acting beta agonist (LABA) therapy among 60 participants with uncontrolled moderate asthma is described. Participants will complete twice-daily mSpirometry at home and clinic spirometry during weekly visits, alongside continuous use of a wrist-worn wearable and regular completion of several diaries capturing asthma symptoms as well as participant- and site-reported satisfaction and ease of use of mSpirometry. The co-primary objectives of this study are (A) to quantify the treatment effect of LABA therapy among participants with moderate asthma, using both clinical spirometry (FEV1c ) and mSpirometry (FEV1m ); and (B) to investigate whether FEV1m is as accurate as FEV1c in detecting the treatment effect using a mixed-effect model for repeated measures. Study results will help inform whether the deployment of mSpirometry and a wrist-worn wearable for remote data collection are feasible in a multicenter setting among participants with moderate asthma, which may then be generalizable to other populations with respiratory disease.

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.