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Purpose To evaluate the potential of a Cox marginal structural model (MSM) to estimate the time-varying causal inference of a known clinical trial association where the effectiveness of inhaled corticosteroid- (ICS-) versus non-ICS-containing treatments has been compared in patients with chronic obstructive pulmonary disease (COPD). Methods This retrospective study from 2006 to 2016 used linked data from Clinical Practice Research Datalink-GOLD, Hospital Episode Statistics and Office for National Statistics mortality. A Cox MSM, incorporating a new-user design, was deemed capable of replicating a clinical trial-like pathway. Repeated outcomes for exacerbation events and stabilised weights were used to include time-varying and fixed covariate exposures. Results Of 45,958 patients, 55% were male; 52% had moderate COPD. ICS-treated patients had a higher incidence of comorbid asthma than non-ICS-treated patients. Adjusted hazard risk ratios for any exacerbation event: ICS/long-acting β2-agonist (LABA) versus long-acting muscarinic antagonist (LAMA), 1.07 (95% confidence interval 1.04-1.10); ICS/LABA versus LABA/LAMA, 1.05 (1.00-1.10); ICS/LABA/LAMA versus LAMA, 1.04 (1.01-1.06); ICS/LABA/LAMA versus LABA/LAMA 1.02 (0.97-1.07). Conclusions The Cox MSM was not able to fully demonstrate results consistent with the previously established benefits of ICS-containing treatments seen in clinical trials. Future studies should continue to investigate causal inference methods and their capability to estimate the long-term outcomes of treatment in COPD.

Four long-acting muscarinic antagonists (LAMAs), tiotropium, glycopyrronium, aclidinium, and umeclidinium, are currently available for the treatment of stable chronic obstructive pulmonary disease (COPD). However, no integrated analysis has sought to determine the effectiveness of these LAMAs. Thus, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of LAMA versus placebo in patients with stable COPD.A literature search of relevant randomized control trials that administered LAMA to stable COPD patients was conducted, and the exacerbations, quality of life (QoL), dyspnea score, lung function, and adverse event of patients were evaluated.A total of 33 studies were included in this meta-analysis. LAMA significantly decreased the frequency of exacerbations compared to the placebo (OR 0.75; 95% CI 0.66 to 0.85; P 0.001). The mean changes in the St George's Respiratory Questionnaire score (mean difference, -3.61; 95% CI, -4.27 to -2.95; P 0.00001), transitional dyspnea index score (mean difference 1.00; 95% CI 0.83 to 1.17; P 0.00001), and trough FEVLAMA is superior to placebo due to lower frequency of exacerbations and adverse events, as well as higher trough FEV

Background In symptomatic COPD patients with a history of exacerbations, additional treatment with inhaled corticosteroid (ICS) to long-acting muscarinic antagonist (LAMA) and long-acting beta-agonist (LABA) combination therapy is recommended based on the evidence of low incidence of exacerbations but with a caution for pneumonia. However, ethnic differences may affect the response to drugs. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of this treatment in the Japanese population (PROSPERO: CRD42020191978). Methods We searched relevant randomized control trials and analyzed the exacerbations, quality of life, lung function, and adverse events including pneumonia and mortality as the outcomes of interest. Results We identified a total of three RCTs (N = 632). Treatment with ICS/LAMA/LABA triple therapy significantly decreased the exacerbations (rate ratio, 0.56; 95% CI, 0.38 to 0.85) and improved the trough FEV1 (mean difference, 0.04; 95% CI, 0.01 to 0.07) compared to LAMA/LABA therapy. However, triple therapy showed a significantly higher incidence of pneumonia compared to LAMA/LABA (odds ratio, 3.38; 95% CI, 1.58 to 7.22). Concerning other adverse events including mortality, there were no significant difference between these therapies. Conclusions In the current meta-analysis of the Japanese population, we confirmed that triple therapy causes a higher incidence of pneumonia than LAMA/LABA treatment but is a more preferable treatment since it showed a lower incidence of exacerbations and higher trough FEV1 in patients with symptomatic moderate to severe COPD. However, since the sample sizes were not statistically large enough, further trials involving Japanese patients are needed.

Objective The aim of this study was to evaluate the quality of diagnosis and treatment of COPD using Big Data methodology on the Savana Manager 2.1 clinical platform. Materials and methods A total of 59,369 patients with a diagnosis of COPD were included from a population of 1,219,749 adults over 40 years of age. Results In total, 78% were men. Spirometry data were available for only 26,453 (43.5%) subjects. Disease severity was classified in 18,172 patients: 4396 mild, 7100 moderate, and 6676 severe, although only 27%, 34%, and 28%, respectively, presented obstructive spirometry. The clinical management of COPD is mainly the responsibility of the primary care and pulmonology departments, while internal medicine and, to a lesser extent, geriatrics also participate. Drug treatment was based on bronchodilators and inhaled corticosteroids (ICS). A marked decline in the use of long-acting beta-2 agonists (LABA) in monotherapy and a slight reduction in ICS/LABA combinations, associated with a long-acting anticholinergic (LAMA) in 74% of cases, were observed. All-cause in-hospital mortality among the overall population was 5.6% compared to 1% of the general population older than 40 years. In total, 35% were admitted to hospital, with an average stay of 6.6 days and an in-hospital mortality rate in this group of 10.74%. Discussion This study identifies the main features of an unselected COPD population and the main errors made in the management of the disease.

Long-acting bronchodilators represent the mainstay of maintenance treatment of chronic obstructive pulmonary disease (COPD). This state-of-the-art review summarizes currently available data on the safety, efficacy, and clinical effectiveness of long-acting bronchodilators and describes their role in the management of COPD, as defined by current national and international guidelines. Data from extensive clinical trials and real-life studies have demonstrated that long-acting beta-2 agonists and long-acting muscarinic antagonists can safely reduce the frequency of exacerbations, alleviate symptoms, and improve quality of life, exercise tolerance, and lung function of patients with COPD. They are recommended as first-line maintenance treatment of COPD.

Background Triple therapy combinations of a long-acting muscarinic antagonist (LAMA), a long-acting beta2-agonist (LABA), and an inhaled corticosteroid (ICS) for COPD were studied in randomized trials and observational studies, with variable results. We compared the effectiveness and safety of triple therapy with a LAMA-LABA combination in a real-world clinical practice setting. Methods We identified a cohort of patients with COPD during 2002 through 2015, ≥ 55 years of age, from the UK's Clinical Practice Research Datalink. Patients initiating LAMA-LABA-ICS were matched 4:1 on time-conditional propensity scores with patients initiating LAMA-LABA, and followed for 1 year for the occurrence of a moderate or severe COPD exacerbation and severe pneumonia. Results The cohort included 6,921 initiators of LAMA-LABA-ICS matched to 1,932 initiators of LAMA-LABA. The adjusted hazard ratio (HR) of a COPD exacerbation associated with LAMA-LABA-ICS initiation compared with LAMA-LABA initiation was 0.97 (95% CI, 0.87-1.08). For patients with blood eosinophil counts > 6%, the HR was 0.66 (95% CI, 0.46-0.94). For patients with two or more prior exacerbations, it was 0.83 (95% CI, 0.70-0.98). The incidence of severe pneumonia requiring hospitalization was increased with LAMA-LABA-ICS initiation (HR, 1.46; 95% CI, 1.03-2.06). Conclusions In a real-world setting of COPD treatment, the triple combination of LAMA, LABA, and ICS inhalers is generally as effective as combining LAMA and LABA inhalers in preventing COPD exacerbations. However, with the possible exception of patients with significant eosinophilia or frequent exacerbators, a LAMA-LABA combination without ICS may be preferable because it is associated with fewer severe cases of pneumonia.

Background Clinical characteristics of the international population with severe asthma are unknown. Intercountry comparisons are hindered by variable data collection within regional and national severe asthma registries. We aimed to describe demographic and clinical characteristics of patients treated in severe asthma services in the United States, Europe, and the Asia-Pacific region. Methods The International Severe Asthma Registry retrospectively and prospectively collected data in patients with severe asthma (≥ 18 years old), receiving Global Initiative for Asthma (GINA) Step 5 treatment or with severe asthma remaining uncontrolled at GINA Step 4. Baseline demographic and clinical data were collected from the United States, United Kingdom, South Korea, Italy, and the Severe Asthma Web-based Database registry (including Australia, Singapore, and New Zealand) from December 2014 to December 2017. Results We included 4,990 patients. Mean (SD) age was 55.0 (15.9) years, and mean (SD) age at asthma onset was 30.7 (17.7) years. Patients were predominantly female (59.3%) and white (72.6%), had never smoked (60.5%), and were overweight or obese (70.4%); 34.9% were at GINA Step 5; and 57.2% had poorly controlled disease. A total of 51.1% of patients were receiving regular intermittent oral corticosteroids, and 25.4% were receiving biologics (72.6% for those at GINA Step 5). Mean (SD) exacerbation rate was 1.7 (2.7) per year. Intercountry variation was observed in clinical characteristics, prescribed treatments, and biomarker profiles. Conclusions Using a common data set and definitions, this study describes severe asthma characteristics of a large patient cohort included in multiple severe asthma registries and identifies country differences. Whether these are related to underlying epidemiological factors, environmental factors, phenotypes, asthma management systems, treatment access, and/or cultural factors requires further study.

This document on COPD from the Latin American Chest Association (ALAT-2019) uses PICO methodology to analyze new evidence on inhaled medication and answer clinical questions. The following key points emerged from this analysis: 1) evidence is lacking on the comparison of short-acting vs. long-acting bronchodilators in patients with mild COPD; patients with moderate-to-severe COPD obtain greater benefit from long-acting bronchodilators; 2) the benefits of monotherapy with long-acting antimuscarinic agents (LAMA) and combined therapy with long-acting β2-agonists and inhaled corticosteroids (LABA/ICS) are similar, although the latter is associated with a greater risk of pneumonia; 3) LABA/LAMA offer greater benefits in terms of lung function and risk of exacerbation than LABA/ICS (the latter involve an increased risk of pneumonia), 4) LAMA/LABA/ICS have greater therapeutic benefits than LABA/LAMA on the risk of moderate-severe exacerbations. With regard to the role of eosinophils in guiding the use of ICS, ICS withdrawal must be considered when the initial indication was wrong or no response is elicited, in patients with side effects such as pneumonia, and in patients with a low risk of exacerbation and an eosinophil blood count of

This paper studies the impact of long-term unemployment on physical activity. We examined the effects 6 and 15 years following a severe business cycle downturn in Finland over the period 1991–1994. The study sample comprised residents of Northern Finland. The unemployed individuals were 23–26 years old during the downturn. Physical activity, measured by MET minutes and meeting WHO guidelines, was higher 15 years later among those people who experienced the longest periods of unemployment in 1991–1994. Physical activity was somewhat lower among people with relatively shorter periods of unemployment. peerReviewed

Background There is little consensus with regards to the most appropriate surgical management for low-grade appendiceal mucinous adenocarcinomas (LAMA), though right hemicolectomy is usually recommended. Methods The SEER database was queried for all patients with non-metastatic LAMA. Disease specific and overall survival was compared by surgery type: 1) appendectomy, 2) formal right hemicolectomy 3) non-formal colectomy (including ileocecectomy). Results A total of 579 patients with non-metastatic LAMA were identified. 133 (23%), 404 (70%), and 42 (7%) of patients had stage I, II, and III disease, respectively. 99 (17.1%) had appendectomy, 87 (15%) had non-formal colectomy, and 302 (52.2%) had formal right hemicolectomy. We observed no significant differences in disease specific or overall survival by surgery type. Controlling for age and stage, surgery type was not a significant predictor of disease specific or overall survival. Conclusion In patients with localized LAMA, right hemicolectomy did not increase disease specific or overall survival. Right hemicolectomy should be reserved for LAMA patients with positive margins post appendectomy.

Objective To assess the incidence and determinants of the triple inhaled therapy in chronic obstructive pulmonary disease (COPD) primary care patients. Methods Data derived from the Health Search Database (HSD) gathering information on 700 Italian general practitioners. A cohort of COPD patients, prescribed for the first time with inhaled treatments, was followed-up between January 2002 and December 2014. The outcome was the first incident prescription of a triple inhaled therapy, namely the combination of inhaled corticosteroids (ICS), long-acting beta agonists (LABA), and long-acting muscarinic antagonists (LAMA). Cox regressions were used to test the association (hazard ratios, HR) between candidate determinants and the outcome. Results Out of 17589 patients (mean age 71.1 ± 11.3 years; 37.4% females), 3693 (21%) were prescribed with a triple inhaled therapy during follow-up. Older age (HR = 1.79 to 2.61), current and former smoking habit (HR = 1.72 and 1.66), higher GOLD stage (HR = 1.45 to 2.79), the number of moderate and severe COPD exacerbations (HR = 1.10 to 2.63), and heart failure (HR = 1.17) resulted statistically significantly associated with an increased incident prescription of the triple inhaled therapy. Female sex (HR = 0.80) and some comorbidities (HR = 0.21 to 0.87) resulted negatively associated with the outcome. Furthermore, patients initially treated with LAMA (HR = 1.5) and LABA/ICS (HR = 1.23) were more likely to escalate to the triple therapy, than those on LABA. Conversely, patients initially treated with ICS presented a negative hazard (HR = 0.72). Conclusions The knowledge of demographic and clinical determinants of the escalation to the triple inhaled therapy in real-world COPD patients may help clinicians to better personalize respiratory pharmacological treatments of their patients, and inform international societies that issue clinical guidelines.

Aclidinium bromide is an inhaled long-acting muscarinic antagonist (LAMA). Although the initial potential increased cardiovascular and mortality risk among users of tiotropium has been ruled out by several observational studies, and clinical trials, there are still concerns related to the use of newer LAMA medications. The current study aimed to evaluate the risk of death among users of aclidinium and other LAMAs.We conducted a cohort and nested case-control study among patients with COPD aged 40 years or older to compare the risk of all-cause mortality among users of aclidinium and other COPD medications with the risk among users of long-acting β2 agonists (LABA), in the Clinical Practice Research Datalink (CPRD) in the United Kingdom (2012-2017).Mortality rates per 1,000 person-years were 32.9 for aclidinium, 43.8 for tiotropium, 38.0 for other LAMA, 47.1 for LABA/ICS, and 38.1 for LABA. The RR of death compared with current use of LABA was 0.54 (confidence interval [95% CI], 0.40-0.72) for aclidinium, 0.96 (95% CI, 0.76-1.21) for tiotropium, 0.76 (95% CI, 0.58-0.99) for other LAMA, and 1.08 (95% CI, 0.90-1.31) for LABA/ICS. Decreased risk for death observed among users of aclidinium was driven by overall current single use (RR = 0.41; 95% CI, 0.22-0.79), which corresponded to 26% of the aclidinium users (15 cases) and not by multiple use (RR = 1.02; 95% CI, 0.71-1.48).Use of aclidinium, tiotropium, other LAMA, or LABA/ICS was not associated with an increased risk of all-cause mortality as compared with the use of LABAs.

Background Long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are recommended as initial maintenance treatments for COPD, with their combination (LABA-LAMA) advocated as the disease progresses. Randomized trials comparing the effectiveness of this combination with the alternative combination of LABA with inhaled corticosteroid (LABA-ICS) have reported conflicting data, while there are no real-world comparative effectiveness and safety studies of these regimens in clinical practice settings. Methods We identified a cohort of patients with COPD during 2002-2015, age 55 years or older, from the United Kingdom’s Clinical Practice Research Datalink. Patients initiating LABA-LAMA on the same day (no ICS) were matched on time-conditional high-dimensional propensity scores with patients initiating LABA-ICS on the same day (no LAMA), and monitored for 1 year for the occurrence of a moderate or severe COPD exacerbation and severe pneumonia. Results The cohort included 1,977 initiators of LABA-LAMA matched with 1,977 initiators of LABA-ICS. The hazard ratio (HR) of moderate or severe COPD exacerbation associated with LABA-LAMA initiation, relative to LABA-ICS initiation, was 1.04 (95% CI, 0.90-1.20), while for a severe exacerbation it was 0.94 (95% CI, 0.65-1.36). The incidence of severe pneumonia requiring hospitalization was lower with LABA-LAMA initiation (HR, 0.66; 95% CI, 0.41-1.05), particularly in the on-treatment analysis (HR, 0.66; 95% CI, 0.50-0.87). Conclusions In a real-world clinical practice setting of COPD treatment, combined LABA-LAMA inhalers appear to be as effective as combined LABA-ICS inhalers in preventing COPD exacerbations. However, a LABA-LAMA combination may be preferred because it is associated with fewer severe pneumonias.

Background Inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) combination is commonly prescribed to treat COPD; therefore, we performed a meta-analysis on the effect of adding a long-acting muscarinic receptor antagonist (LAMA) to ICS/LABA combination in COPD. Methods Studies were identified by searching in different databases the randomized controlled trials that investigated the effect of ICS/LABA/LAMA combination in COPD. The primary end points were the effect of triple therapy on trough FEV1, risk of acute exacerbation of COPD (AECOPD), and risk of cardiovascular serious adverse events (SAEs), compared with ICS/LABA combination. The Grading of Recommendations Assessment, Development, and Evaluation system was used to assess the quality of evidence. Results Thirteen randomized controlled trials including 15,519 patients with COPD (ICS/LABA/LAMA combination, 53.1%; ICS/LABA combination, 46.9%) were meta-analyzed. ICS/LABA/LAMA combination improved trough FEV1 (mean difference, +104.86 mL; 95% CI, 86.74-122.99; high quality of evidence) and protected against AECOPD (relative risk, 0.78; 95% CI, 0.71-0.85; high quality of evidence) vs ICS/LABA combination. For every approximately four patients treated with triple therapy, one increased FEV1 > 100 mL, and approximately 26 patients had to be treated for 1 year with ICS/LABA/LAMA combination to prevent one AECOPD, compared with ICS/LABA combination. Adding a LAMA to ICS/LABA therapy did not modulate the risk of cardiovascular SAEs (moderate quality of evidence). Conclusions Triple therapy provides significant clinical benefit in patients with COPD on ICS/LABA combination. ICS/LABA therapy can be escalated to triple therapy without a real risk to increase cardiovascular SAEs when a LAMA is added to the combination. Trial Registry ClinicalTrials.gov; No.: CRD42018095300; URL: www.clinicaltrials.gov.

Little is known about the firm-level dynamics behind trade responses to political tensions. This article reinvestigates variation in the travel pattern of the 14th Dalai Lama to study how political tensions affect trading decisions of Chinese importers. Using monthly trade data from China Customs covering imports of machinery and transport equipment from 173 countries over the 2000–2006 period, our empirical results show a significant reduction of imports in response to foreign government members' meetings with the Dalai Lama. In line with the idea that Chinese importers face a trade-off between bearing costs from suboptimal trade transactions and costs from not accommodating the government, this ‘Dalai Lama Effect’ operates at the intensive margin, i.e., via a decrease in the import volume per importer. Examining differential effects across types of firm ownership, we find that the observed effect is driven by state-owned enterprises (and foreign-invested firms) and not by private companies. Moreover, while direct importers temporarily reduce their trade with Dalai Lama-receiving countries, there is some evidence that trade intermediaries fill the void. Overall, we find the effects to be much more short-lived than previously thought.

Cigarette smoking in patients with asthma leads to poor symptom control. As patients who are current smokers have been excluded from enrollment in many clinical trials on asthma, there are few reports on the treatment in current smokers with asthma. In this study, we aimed to assess how respiratory physicians manage asthma in current smokers in Japan.Respiratory physicians in 16 Japanese hospitals answered a questionnaire on treatment for patients with asthma between December 2014 and February 2015. Medical records were reviewed for 1756 patients with asthma.The mean patient age was 61.1 years, and 62.9% of the patients were female. A total of 102 patients (5.8%) were current smokers, and 546 patients (31.1%) were former smokers. Long-acting muscarinic antagonists (LAMA) were prescribed more frequently for current smokers with asthma than for former smokers and never smokers with asthma (10.8% vs 4.6%, p = 0.01, 10.8% vs 3.8%, p0.01). In contrast, macrolides were prescribed more frequently for former smokers and never smokers with asthma than for current smokers with asthma (7.7% vs 1.0%, p = 0.01, 6.4% vs 1.0%, p = 0.03). Triple therapy, i.e., inhaled corticosteroids, long-acting beta agonists, and LAMA concomitantly, was prescribed for current smokers with asthma more frequently than for former smokers and never smokers with asthma (9.8% vs 4.0%, p = 0.01, 9.8% vs 3.3%, p0.01).According to this survey, current smokers with asthma received more intensive therapy, including LAMA, than did former smokers with asthma.

Introduction The cost-effectiveness of long-acting muscarinic antagonist (LAMA) umeclidinium bromide (UMEC) 62.5 μg as add-on therapy to other maintenance COPD treatments is unknown. Methods This analysis assessed the cost-effectiveness of the following in COPD: UMEC + fluticasone furoate/vilanterol 100/25 μg (FF/VI); UMEC + fluticasone propionate/salmeterol 250/50 μg (FP/SAL); and UMEC + several alternative choices of inhaled corticosteroid/long-acting β2-agonist (ICS/LABA). The model was informed with direct and indirect data from previously published studies, with a UK perspective and a lifetime horizon. Sensitivity analyses were also performed. Results For the lifetime horizon, compared with FF/VI, FP/SAL and ICS/LABAs, addition of UMEC was associated with incremental costs per quality-adjusted life-years (QALY) of £4050, £7210 and £5780, respectively, and incremental costs per life year gain of £3380, £6020 and £4940. All UMEC-containing regimens resulted in numerically lower exacerbation rates versus comparator regimens over a lifetime horizon. Conclusions Addition of UMEC to various ICS/LABA treatments was associated with higher cost than ICS/LABA alone, but was cost-effective in most scenarios.

Summary Background Long-acting β2 agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are the recommended initial maintenance treatment for chronic obstructive pulmonary disease (COPD), with almost all LABAs dispensed in fixed combination with inhaled corticosteroids (LABA-ICS). We compared the effectiveness and safety of LABA-ICS versus LAMA treatment initiation as a function of blood eosinophilia, a potential biomarker of ICS effectiveness, in a real-world setting. Methods In this population-based cohort study, we identified a cohort of patients with COPD initiating treatment with a LAMA or LABA-ICS during 2002–15, age 55 years or older, from the UK's Clinical Practice Research Datalink. We excluded patients who initiated treatment with both bronchodilators on the same date. All patients required at least 1 year of medical history and a measure of blood eosinophil concentration before cohort entry, defined by the date of the first cohort-defining bronchodilator prescription. Patients initiating a LAMA were matched on high-dimensional propensity scores with patients initiating a LABA-ICS. They were followed up for 1 year for the occurrence of a moderate or severe COPD exacerbation and for severe pneumonia. Sensitivity analyses included, among others, repeating the analysis among patients with two blood eosinophil concentration measures and stratification by concurrent asthma and previous exacerbations. Findings The base cohort included 539 643 patients with a prescription for LABAs or LAMAs from Jan 1, 2002, to Dec 31, 2015, of whom 18 500 were initiated on LABA-ICS and 13 870 on LAMAs. Propensity score analysis resulted in 12 366 initiators of LAMAs (mainly tiotropium) matched to 12 366 initiators of LABA-ICS. The hazard ratio (HR) of COPD exacerbation associated with LABA-ICS initiation, relative to LAMA initiation, was 0·95 (95% CI 0·90–1·01). In patients with blood eosinophil concentrations of less than 2% of white blood cell count, the HR was 1·03 (95% CI 0·93–1·13) and for those with eosinophil concentrations of 2–4%, the HR was 1·00 (0·91–1·10). For patients with eosinophil concentrations of more than 4%, the HR was 0·79 (0·70–0·88). The incidence of pneumonia increased with LABA-ICS initiation (HR 1·37 [95% CI 1·17–1·60]) and was similar across all eosinophil concentrations. Sensitivity analyses were consistent with these findings, but the incidence of exacerbation with LABA-ICS among the 2766 (11%) of all 24 732 patients with two or more COPD exacerbations during the baseline year was marginally lower (HR 0·87 [95% CI 0·79–0·97]). Interpretation In this real-world, clinical practice, observational study, initial COPD treatment with LABA-ICS inhalers was only more effective than with LAMAs in patients with high blood eosinophil concentrations (>4%) or counts (>300 cells per μL) and possibly in frequent exacerbators. Because of the increased risk of pneumonia associated with the ICS component, initiation with a LAMA should be preferred in patients with blood eosinophil concentrations of less than 4%. Funding Canadian Institutes of Health Research, Canadian Foundation for Innovation.

COPD is often misdiagnosed and inappropriately treated in many patients. COPD is a distinct disease from adult-onset asthma; however, some patients with COPD may present with several forms of airway disease described as asthma-COPD overlap (ACO). Bronchodilators and inhaled corticosteroids (ICS) both have a place in standard maintenance treatment of COPD and asthma; however, recommendations for use differ widely. In patients with COPD, long-acting bronchodilators are effective initial monotherapy treatment, whereas ICS monotherapy is recommended as initial treatment in patients with asthma. Clinicians need to be confident in their diagnosis to ensure that correct treatment is given because misguided treatment decisions can result in significantly increased safety risks for patients. This review highlights the differences in diagnosis and treatment between COPD, asthma, and ACO and discusses the data supporting guideline recommendations for use of bronchodilators in COPD treatment in contrast to asthma or ACO.

The incidence of chronic obstructive pulmonary disease (COPD) is rising in the United States, and the disease represents a significant source of morbidity and mortality. Primary care providers face many challenges in COPD diagnosis and treatment, as different clinical phenotypes require personalized treatment approaches. Patient adherence and inhaler technique also contribute to treatment outcomes. Around 48% of primary care providers are unaware of guidelines and recommendations for COPD diagnosis and treatment, which may lead to misdiagnosis or undertreatment of COPD symptoms. Inadequately treated COPD can impair patients' quality of life and ability to perform everyday activities. Long-acting bronchodilator therapy is the cornerstone treatment for patients with COPD; combinations of bronchodilators of different pharmacological classes have shown improved efficacy vs monotherapy. We review the rationale behind fixed-dose dual bronchodilator therapy, evidence for the 4 currently Food and Drug Administration-approved long-acting anticholinergic bronchodilators/long-acting β2-agonists fixed combinations, patient suitability for the available inhaler devices, and practical guidance to optimize personalized care for patients with COPD.

Long-acting β2 adrenoceptor agonists (LABAs) in combination with long-acting muscarinic antagonists (LAMAs) can elicit functional and clinical benefits in chronic obstructive pulmonary disease (COPD). LABA/LAMA combinations synergistically relax human isolated airways at the level of the medium and small bronchi. LABAs and LAMAs both modulate the bronchial tone via different pathways localized at the level of presynaptic parasympathetic fibers and airway smooth muscle cells. The exact nature of the interactions between these pathways is not completely understood, but there is cross-talk at many levels in airway smooth muscle cells that is also regulated by the activity of calcium-activated potassium channels and protein tyrosine kinases. While the synergy between LABAs and LAMAs is a class effect, some of the currently available fixed-dose combinations (FDCs) do not induce synergistic interaction because the individual components are not appropriately balanced in the combination. Concerns remain on the cardiovascular safety profile of LABA/LAMA FDCs.

Background Given COPD heterogeneity, we do not know if some LABA/LAMAs are more suitable for some COPD phenotypes. This real-life database study aimed to evaluate retrospectively the 4 LABA/LAMA effectiveness and highlight possible specificities that could better guide us in choosing the right LABA/LAMA to be used. Methods We searched for subjects (1,779) adherent to umeclidinium/vilanterol (UM/VI), indacaterol/glycopyrronium (IND/GLY), aclidinium/formoterol (ACLI/FOR) and tiotropium/olodaterol (TIO/OLO) treatments in our prescribing/dispensing database. Prescriptions for systemic corticosteroids (SC), antibiotics and salbutamol during one year of LABA/LAMA treatment were analyzed. Results A better adherence was found in individuals taking IND/GLY (10.42 ± 1.86 packages/year) compared with UM/VI (10.09 ± 1.9; p = 0.008), ACLI/FOR (9.8 ± 1.8; p = 0.001) and TIO/OLO (10.1 ± 2.1; p = 0.047). The number of patients that were prescribed at least one package of SC/year and their package numbers/year were similar in males/females, across age groups and in “non-frequent exacerbators” with the 4 LABA/LAMAs. More SC were taken by frequent exacerbators, whereas fewer SC/antibiotic packages were prescribed to subjects aged >80 years with all treatments. In patients treated with ACLI/FOR or TIO/OLO, lower risks to having antibiotic prescriptions were observed when UM/VI (0.698[0.516–0.945] and 0.696[0.491–0.985; p = 0.020 and p = 0.041) and IND/GLY (0.597[0.445–0.802] and 0.595[0.423–0.836]; p = 0.001 and p = 0.003) were considered as landmarks. Lower risks for salbutamol prescriptions were detected with UM/VI (0.678[0.480–0.958]; p = 0.027) and TIO/OLO (0.585[0.365–0.937]; p = 0.026) when ACLI/FOR was used as a reference. Conclusion According to our retrospective database study, each LABA/LAMA could have a specific efficacy profile in COPD that might be considered for personalized therapy. However, head-to-head targeted trials aimed to assess the impact of different LABA/LAMAs on COPD are needed to confirm/disprove such results.

Background Despite passive immunization with palivizumab to select high-risk children under two years of age, the health and economic burden of respiratory syncytial virus (RSV) remains substantial. We evaluated the effectiveness and cost-effectiveness of immunization programs with new generations of RSV prophylactics, including long-acting monoclonal antibodies (LAMA) and maternal vaccines, in terms of reducing hospitalizations in Nunavik, a Canadian Arctic region. Methods We developed an agent-based model of RSV transmission and parameterized it with the demographics and burden of RSV in Nunavik, Quebec. We compared various immunization strategies, taking into account the costs associated with program delivery and calculating the incremental cost-effectiveness ratio (ICER) using quality-adjusted life-years (QALYs) gained as a measure of effectiveness. Scenario analyses included immunization with palivizumab and LAMA for infants under one year of age, and maternal vaccination in mild, moderate, and severe RSV seasons. Data were analysed from November 1, 2019 to May 1, 2021. Findings We found that a Nunavik pilot program with palivizumab which included healthy full-term infants aged 0–2 months in addition to those considered high-risk for complicated RSV disease is not cost-effective, compared to offering palivizumab only to preterm/chronically ill infants under 1 year of age. Using LAMA as prophylaxis produces ICER values of CAD $39,414/QALY (95% Credible Interval [CrI]: $39,314–$40,017) in a mild season (moderately cost-effective) and CAD $5,255/QALY (95% CrI: $5,222–$5,307) in a moderate season (highly cost-effective). LAMA was a dominant (cost-saving with negative incremental costs and positive incremental effects) strategy in a severe RSV season. Maternal vaccination combined with immunization of preterm/chronically ill infants 3–11 months was also a dominant (cost-saving) strategy in all seasons. Interpretation The switch from palivizumab in RSV immunization programs to new prophylactics would lead to significant savings, with LAMA being an effective strategy without compromising benefits in terms of reducing hospitalizations. Funding This work was funded by the Canadian Institutes of Health Research and the Public Health Agency of Canada through the Canadian Immunization Research Network.

Background Previous studies have shown seasonal variation in asthma exacerbations, peaking over the winter months. A single-inhaler triple therapy containing extrafine formulations of the inhaled corticosteroid (ICS) beclomethasone dipropionate (BDP), long-acting β2-agonist formoterol fumarate (FF), and long-acting muscarinic antagonist glycopyrronium (G) is in development for asthma. Objective We sought to evaluate whether calendar season impacted the relative effect of BDP/FF/G versus BDP/FF on moderate and severe asthma exacerbations. Methods TRIMARAN and TRIGGER were double-blind 52-week studies comparing BDP/FF/G with BDP/FF (TRIMARAN medium-dose ICS; TRIGGER high-dose) in adults with uncontrolled asthma (Asthma Control Questionnaire-7 score ≥1.5), prebronchodilator FEV1 less than 80% predicted, history of 1 or more asthma exacerbation, who had been receiving ICS/long-acting β2-agonist for at least 4 weeks before entry. Moderate and severe asthma exacerbations were captured throughout each study. In these post hoc analyses, the annual moderate and severe exacerbation rate was calculated for each month, with rate ratios determined from events grouped by season. Results In patients who received BDP/FF alone, there was a marked seasonal effect on the occurrence of asthma exacerbations, with the rate highest in the winter months. However, the addition of the long-acting muscarinic antagonist component to BDP/FF reduced this seasonal variation, especially during the winter, such that the relative effect of BDP/FF/G versus BDP/FF was greatest in the winter (significant 20.3% reduction [P = .0008]). Reductions in the other seasons ranged between 8.6% and 12.0%. Conclusions These post hoc analyses indicate that inhaled triple therapy with extrafine BDP/FF/G reduces seasonal peaks in moderate and severe exacerbations, and confirm the overall utility of adding long-acting muscarinic antagonist to ICS/long-acting β2-agonist in the management of asthma.

Background COPD frequently coexists with HF with which shares several risk factors. A greater collaboration is required between cardiologists and pulmonologists to better identify and manage concurrent HF and COPD. This observational, retrospective study provides new data regarding the management of these patients. Methods from the Health Search Database which collects information generated by the routine activity of general practitioners, we selected 803 patients suffering from COPD or HF alone or combined analyzing similarities and differences regarding risk factors, diagnostic workup and therapeutic approaches. Main results Statistical analyses have evidenced significant differences regarding exposure to cigarette smoke and the prevalence of diabetes and hypertension in the three groups of patients. As regard to the diagnostic workup, it has been found that the 63,9% of COPD patients and the 57,1% of COPD + HF patients performed a spirometry vs the 95,4% of HF patients and the 95,2% of COPD + HF patients that performed an ECG. Regarding the pharmacologic treatment, the 47% of COPD patients was treated with an ICS/LABA association and the 22% with ICS/LABA + LAMA. In the COPD + HF group, 47% of patients were treated with ICS/LABA association, while 32% of these patients were treated with ICS/LABA + LAMA. The pharmacologic treatment most prescribed in HF was β-blockers (68%), diuretics (92.8%), antiplatelet therapy (55.6%) and ACE inhibitors (38.1%). In the COPD + HF group, β-blockers (40.1%), diuretics (89.8%), antiplatelet therapy (57.1%) and ACE inhibitors (44.9%) were prescribed. Conclusion this study has evidenced a disparity in performing instrumental diagnosis between COPD and HF groups that persists when both conditions coexist. Moreover, the pharmacological treatment of the two conditions shows a consistent under treatment with bronchodilators in COPD patients and with β-blockers in HF patients.

Introduction The 2017 update to the Global Initiative for Obstructive Lung Disease (GOLD) strategy document includes recommendations for treatment intensification or step-down in chronic obstructive pulmonary disease (COPD), although recognises that limited supporting information is available. DACCORD is an ongoing observational, non-interventional study, recruiting patients following COPD maintenance treatment change or initiation, a subset of whom were receiving a long-acting β2-agonist (LABA) plus a long-acting muscarinic antagonist (LAMA) fixed-dose combination (FDC) on entry. Since there were no requirements in terms of prior medication (and no washout before commencing LABA/LAMA FDC), this provides an opportunity to generate ‘real world’ data to test the GOLD 2017 recommendations. Methods To reduce heterogeneity, the current analyses include patients receiving indacaterol/glycopyrronium at baseline, and who, prior to the study, were receiving no COPD maintenance medication (‘none’), LABA or LAMA monotherapy (‘mono’), LABA plus inhaled corticosteroid (ICS; ‘LABA/ICS’), or triple therapy (‘triple’). At the baseline visit, data collected included: demographic and disease characteristics; COPD Assessment Test (CAT); and exacerbations in the 6 months prior to entry. At 3, 6, 9 and 12 months data on exacerbations were collected, with CAT recorded at 3 and 12 months. Results A total of 2724 patients were included in the baseline analyses: 795, 954, 598 and 377 in the ‘none’, ‘mono’, ‘LABA/ICS’ and ‘triple’ subgroups, respectively. There were no clinically relevant differences in baseline demographics between the four groups. In terms of disease characteristics, the ‘triple’ group had the highest proportion of patients with a disease duration of more than 1 year since diagnosis and with severe/very severe airflow limitation, but a similar percentage of non-exacerbators compared to the ‘none’ group. Over the 1-year follow-up, the majority of patients in all four subgroups did not exacerbate (exacerbation rates 0.16, 0.19, 0.21, and 0.26 in the ‘none’, ‘mono’, ‘LABA/ICS’ and ‘triple’ groups, respectively). At 12 months, 61.4%, 65.0%, 71.0% and 52.4% of patients had a clinically relevant improvement in CAT score. Conclusions Overall, the results support the GOLD recommendations in suggesting that a switch from a mono-bronchodilator or LABA plus ICS to LABA/LAMA FDC is a valid treatment option for patients with COPD. The results also validate the use of a LABA/LAMA FDC as initial maintenance treatment for COPD, and provide first ‘real world’ evidence to support the newly added ‘step down’ recommendation (from triple to LABA/LAMA FDC).

Background Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder characterized by usually progressive development of airflow obstruction that is not fully reversible. While most patients will experience symptoms throughout the day or in the morning upon awakening, many patients do not experience their symptoms as constant but report variability in symptoms during the course of the day or over time. Symptom variability adversely affects patients' health status and increases the risk of COPD exacerbations. Methods We examined data from the literature on symptom variability and control in patients with COPD, with focus on the use of inhaled bronchodilator therapy with long-acting muscarinic antagonist agents (LAMA) plus long-acting β 2 -agonists (LABA); in particular twice-daily fixed-dose combination LAMA/LABA therapy with aclidinium/formoterol. Results Correct diagnosis and assessment of COPD requires comprehensive clinical and functional evaluation and consideration of individual needs to support the clinical decisions necessary for effective long-term management. Combining bronchodilators from different and complementary pharmacological classes with distinct mechanisms of action can increase the magnitude of bronchodilation as opposed to increasing the dose of a single bronchodilator. Conclusions The use of inhaled bronchodilator therapy with LAMA/LABA fixed-dose combinations in patients with stable COPD is supported by current evidence. This treatment approach provides robust effects on lung function and symptom control and may improve patients' adherence to treatment. Administration of the long-acting bronchodilators aclidinium and formoterol as twice daily fixed-dose aclidinium/formoterol 400/12 μg has the potential to control symptoms throughout the 24 h in patients with stable moderate-to-severe COPD.

The main objectives of this study, based on a large cohort of German COPD patients, were to assess the level of non-persistence (NP) and non-adherence (NA) with long-acting COPD inhaler treatment and to describe factors that may be associated with NP and NA.This was a retrospective cohort analysis based on claims data provided by a German statutory health insurance fund (years 2010-2012). NP was analyzed for treatment-naïve patients only; it was defined as a gap of90 days in medication availability. With regard to NA, first the overall yearly medication possession ratio (MPR) was analyzed, NA was defined as MPR80%. Secondly, adherence was explored only for the period in which a patient continued therapy with a long-acting COPD agent (no gap90 days).45,937 COPD patients who received at least one prescription of any long-acting COPD agent were identified (mean age 71.4 years; 45.2% female). Among these, 22,276 (42.4%) were classified as newly treated. The percentage of NP patients after 12 months was 65.3% on an overall patient level. Agent-specific NP rates were: 58.5% for LABA, 47.9% for LAMA, 78.0% for ICS, and 69.4% for single-device LABA/ICS combination treatment. The overall 12-month MPR across all agent classes on a patient level was 57.9% (70.0% of patients classified as non-adherent). During periods of general treatment continuation, the mean MPR/NA rates were 85.0%/30.1% (patient level across all agents), 89.3%/28.2% (LABA), 92.1%/16.2% (LAMA), 84.2%/43.8% (ICS) and 84.1%/42.8% (LABA/ICS combination). In the Cox regression analyses, several factors like female gender, higher CCI or lower number of specialist' visits were associated with earlier discontinuation of therapy. In comparison to LABA therapy, LAMA therapy was less likely to be associated with early NP, whereas patients who initiated ICS therapy or a single-device LABA/ICS combination therapy faced a higher NP risk.In German COPD patients, persistence and adherence with respect to long-acting bronchodilator therapy is poor. Approximately two thirds of patients fail to continue treatment after 12 months. In addition, about one third implement their treatment poorly during periods of general therapy continuation.

Background Patients with poor asthma control may receive oral corticosteroid (OCS) therapy despite the risk for adverse effects. Objective We assessed OCS use frequency and treatment patterns in patients with persistent asthma in the United States (US). Methods We used the IBM® MarketScan® Commercial Claims and Encounters, Medicare Supplemental, and Medicaid Multistate Claims research databases to identify patients from January 1, 2012, to December 31, 2017, who were ≥12 years old, met the 2-year Healthcare Effectiveness Data and Information Set criteria for persistent asthma, and were continuously enrolled ≥6 months before (baseline) and ≥24 months after (follow-up) the persistent asthma index date. Patients were classified as high OCS use (defined as ≥450 mg of OCS prescribed within a 90-day period during follow up), low use (use OCS but not meeting high use criteria), or no OCS use. Results We identified 435,675 patients, of whom 65% used OCS and 19% were classified as high OCS users at some point during follow-up. Annual prevalence of high OCS use ranged from 5.3% in 2013 to 7.6% in 2017. During the entire follow-up, high and low OCS users filled an average of 2.2 and 0.8 OCS prescriptions and received an average daily dosage of 2.2 mg and 0.3 mg, respectively. Once becoming high OCS users, the average daily OCS dosage was relatively stable (5.1-7.1 mg) over 3 years. Conclusion Patients with persistent asthma in the US have substantial exposure to OCS. OCS therapy should be considered carefully to avoid associated adverse effects.

The Société de Pneumologie de Langue Française proposes a decision algorithm on long-term pharmacological COPD treatment. A working group reviewed the literature published between January 2009 and May 2016. This document lays out proposals and not guidelines. It only focuses on pharmacological treatments except vaccinations, smoking cessation treatments and oxygen therapy. Any COPD diagnosis, based on pulmonary function tests, should lead to recommend smoking cessation, vaccinations, physical activity, pulmonary rehabilitation in case of activity limitation, and short-acting bronchodilators. Symptoms like dyspnea and exacerbations determine the therapeutic choices. In case of daily dyspnea and/or exacerbations, a long-acting bronchodilator should be suggested (beta-2 agonist, LABA or anticholinergics, LAMA). A clinical and lung function reevaluation is suggested 1 to 3 months after any treatment modification and every 3-12 months according to the severity of the disease. In case of persisting dyspnea, a fixed dose LABA+LAMA combination improves pulmonary function (FEV1), quality of life, dyspnea and decreases exacerbations without increasing side effects. In case of frequent exacerbations and a FEV1≤70%, a fixed dose long-acting bronchodilator combination or a LABA+ inhaled corticosteroids (ICS) combination can be proposed. A triple combination (LABA+LAMA+ICS) is indicated when exacerbations persist despite one of these combinations. Dyspnea in spite of a bronchodilator combination or exacerbations in spite of a triple combination should lead to consider other pharmacological treatments (theophylline if dyspnea, macrolides if exacerbations, low-dose opioids if refractory dyspnea).

Background This study formed part of the dose selection for a glycopyrrolate (GP)/formoterol fumarate (FF) fixed-dose combination formulated using novel Co-Suspension™ Delivery Technology and delivered via a metered dose inhaler (GFF MDI). The study aimed to confirm the optimal dose of GP to formulate with FF 9.6 μg in the fixed-dose combination product, GFF MDI. Methods This multicenter, randomized, double-blind, chronic-dosing, balanced incomplete block, crossover study (NCT01587079) compared five doses of GFF MDI (18/9.6, 9/9.6, 4.6/9.6, 2.4/9.6 and 1.2/9.6 μg, twice daily [BID]) with its monocomponents FF MDI 9.6 μg and GP MDI 18 μg (both BID) and open-label tiotropium (18 μg once daily) as the active control. The primary efficacy endpoint was change from baseline in forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV 1 AUC 0–12 ) on Day 7. Results In total, 159 patients were randomized to treatment and 132 patients (52.2% male, mean age 62.8 years) were included in the intent-to-treat population. All doses of GFF MDI (except 1.2/9.6 μg) resulted in statistically significant improvements in FEV 1 AUC 0–12 versus monocomponents and open-label tiotropium. GFF MDI 18/9.6 μg consistently showing the greatest improvement over monocomponents and open-label tiotropium. Adverse events for each GFF MDI dose were similar versus GP MDI 18 μg, FF MDI 9.6 μg and open-label tiotropium. Conclusions These findings further support selection of GP 18 μg as the optimal dose to combine with FF MDI 9.6 μg for advancement into Phase III clinical trials of GFF MDI.

Combining individual drugs in a single inhaler is the most convenient way to deliver triple therapy. A long-acting muscarinic receptor antagonist (LAMA) added to an inhaled corticosteroid (ICS)/long-acting β2-adrenoceptor agonist (LABA) fixed-dose combination (FDC) can improve efficacy of pharmacological treatment of patients with chronic obstructive pulmonary disease (COPD). New inhaled ICS/LABA/LAMA FDCs, including fluticasone furoate/vilanterol/umeclidinium, budesonide/formoterol/glycopyrronium and beclometasone/formoterol/glycopyrronium, are in Phase III of clinical development for COPD. Triple inhaled therapy might be particularly useful in patients with severe to very severe COPD, above all in those with peripheral blood or sputum eosinophilia, asthma-COPD overlap syndrome (ACOS) or frequent exacerbators. Future prospective studies should assess efficacy and safety of triple ICS/LABA/LAMA therapy in selected COPD phenotypes.

Bronchodilators (BDs) are the cornerstone of COPD treatment. However, their underuse has been reported in real-life studies. PUMA is a primary-care study from Argentina, Colombia, Venezuela and Uruguay that could help understand the BD use in terms of frequency for long-acting (LA-BD) and short-acting (SA-BD) BDs alone or associated with corticosteroids (CS), and the use as-needed or on regular basis.This is a multicentre, multinational, cross-sectional, non-interventional study including no randomised primary-care centres from each country (total 57 centres) without connection with respiratory specialists. Subjects attending routine visits, at-risk for COPD (≥40 years, current or former smokers or exposed to biomass) completed a questionnaire and performed spirometry. COPD was defined as post-BD FEV1/FVC0.70 and by the lower limit of normal (LLN). Prior physician diagnosis of emphysema, chronic bronchitis or COPD was also determined.1743 patients were interviewed, 1540 completed spirometry, 309 had COPD by post-BD FEV1/FVC0.70, 226 by LLN, and 102 had prior medical diagnosis. A total of 77/309 COPD patients by spirometry (24.9%) used BD (3.6% LA-BDs), 15.2% used BD + CS (13.6% LA-BD + CS). Among these patients, SA-BDs (monotherapy) were the most commonly used medication both as-needed (4.5%) and on a regular basis (17.5%). Similar findings were observed using the LLN criteria. In those with prior medical diagnosis, 66/102 (64.7%) used BDs (9.8% LA-BD), and 25.6% used BD + CS (13.6% LA-BD + CS); among them SA-BDs were the most commonly medication used as-needed (9%) and on a regular basis (48.1%). Having health insurance with medication coverage increased the use of BDs.Up to 60% of COPD patients by spirometry and 10% of those with prior medical diagnosis attending a primary care sample of four Latin American countries did not use BDs. LA-BDs are widely underused on a regular-basis (2.6% and 8.3% of patients with spirometric and medical-diagnosis, respectively) This represents a considerable gap between guideline recommendations and BD prescribing pattern in these centres.

Purpose Dual bronchodilator therapy with a long-acting muscarinic antagonist (LAMA) and a long-acting β2-agonist (LABA) is recommended in the pharmacological management of chronic obstructive pulmonary disease (COPD) according to the Global Initiative for Chronic Obstructive Lung Disease. To better understand the evidence supporting use of LAMA+LABA therapy in COPD and evaluate consistency within and across clinical research study types, we systematically reviewed and analyzed data from both randomized controlled trials (RCTs) and real-world studies. Methods We searched PubMed from inception until April 4, 2019, for phase 2/3/4 RCTs of ≥24 weeks’ duration and real-world studies in which the efficacy and/or safety of LAMA+LABAs were compared with monotherapies, other LAMA+LABAs, LABA+inhaled corticosteroid (ICS), or triple therapy (LAMA+LABA+ICS). We extracted primary and key secondary outcomes data from relevant articles for descriptive purposes. Results Overall, 24 RCTs and 8 real-world studies were included in the analysis based on predefined inclusion criteria. LAMA+LABAs improved lung function and health-related quality of life, and reduced exacerbation rates and dyspnea when compared with monotherapies, LABA+ICS, or triple therapy in both RCTs and real-world studies. Importantly, all LAMA+LABAs were well tolerated, with their safety profiles comparable to those of respective monotherapies, and had lower incidences of pneumonia than ICS-containing regimens. Conclusion Results of RCTs and real-world studies are largely consistent; demonstrate that LAMA+LABAs improve lung function and health-related quality of life and reduce exacerbation rates and dyspnea relative to other available pharmacotherapies; and reinforce the position of LAMA+LABAs in the pharmacological management of COPD.

A molecular genetic protocol for distinguishing pure and hybrid South American camelids was developed to provide strong, quantifiable, and unbiased species identification. We detail the application of the approach in the context of a criminal case in the Andes Mountains of central Chile where the defendants were alleged to have illegally hunted three wild guanacos (Lama guanicoe), as opposed to hybrid domestic llama (Lama glama)/wild guanaco crosses, which are unregulated. We describe a workflow that differentiates among wild, domestic and hybrid South American camelids (Lama versus Vicugna) based on mitochondrial cytochrome b genetic variation (to distinguish between Lama and Vicugna), and MC1R and exon 4 variation of the ASIP gene (to differentiate wild from domestic species). Additionally, we infer the population origin and sex of each of the three individuals from a panel of 15 autosomal microsatellite loci and the presence or absence of the SRY gene. Our analyses strongly supported the inference that the confiscated carcasses corresponded with 2 male and 1 female guanacos that were hunted illegally. Statistical power analyses suggested that there was an extremely low probability of misidentifying domestic camelids as wild camelids (an estimated 0 % Type I error rate), or using more conservative approached a 1.17 % chance of misidentification of wild species as domestic camelids (Type II error). Our case report and methodological and analytical protocols demonstrate the power of genetic variation in coat color genes to identify hybrids between wild and domestic camelid species and highlight the utility of the approach to help combat illegal wildlife hunting and trafficking.

Introduction Global Initiative for Asthma (GINA) recommends medium- or high-dose inhaled corticosteroid-long-acting β2-agonist (ICS-LABA) as preferred treatments for patients with moderate-to-severe asthma. Limited data is available on how step 4/5 patients respond to ICS-LABA and how they step up/down in clinical practice. Methods This retrospective cohort study assessed the characteristics, control status, treatment pathways, and healthcare resource utilization in patients with asthma during one year after initiating medium- or high-dose ICS-LABA. Data from the United Kingdom Clinical Practice Research Datalink were analysed between January 01, 2006 and February 28, 2016. Results Overall, 29,229 and 16,575 patients initiated medium- and high-dose ICS-LABA, and 35.1% and 45.7% of patients, respectively, remained uncontrolled. The proportions of patients who were adherent to treatment (Medication Possession Ratio ≥80%) were 37.8% and 49.1% in the medium- and high-dose ICS-LABA cohorts, respectively. Among these adherent patients, 63.8% in the medium- and 70% in the high-dose cohorts remained uncontrolled. In patients who stepped up therapy in the medium-dose cohort (19.0%), the common step-up choices were add-on leukotriene receptor antagonist (LTRA) (42.2%), long-acting muscarinic antagonist (LAMA) (23.3%), and increase in ICS dose (22.9%). In patients who stepped up therapy in the high-dose cohort (26.1%), the common step-up choices were add-on LAMA (43.8%) and LTRA (42.1%). Healthcare resource utilization was higher in uncontrolled patients, regardless of the ICS-LABA dose. Conclusions Many patients remain uncontrolled on both medium- or high-dose ICS-LABA, highlighting the need for timely assessment of asthma control to increase treatment intensity, following evidence-based treatment pathways.

Background/objectives There have been controversies about whether inhaled bronchodilators could increase the risk of clinically important tachyarrhythmias. We investigated the association between inhaled bronchodilators and the development of tachyarrhythmias, including atrial fibrillation and other paroxysmal tachyarrhythmias in real practice. Methods We conducted a nested case–control study with the use of the nationwide insurance claims database of the Health Insurance Review and Assessment Service (Seoul, Republic of Korea). Overall, 3312 cases with newly developed tachyarrhythmias including atrial fibrillation and other paroxysmal tachyarrhythmias and 9732 matched (up to 1:5) controls were identified from 545,508 subjects without acute major cardiovascular events in the past year between January 1, 2011 and December 31, 2011. Conditional logistic regression analysis adjusted by comorbidities, cardiovascular drugs and healthcare utilization was performed. Results In various multivariate models, the use of inhaled long-acting muscarinic antagonists (LAMAs) or long-acting inhaled β2 agonists (LABAs) was significantly associated with tachyarrhythmias. Statistically significant effects of LAMAs on tachyarrhythmias were found only in the non-users of β-blockers. We did not find a statistically significant difference in the impact of a LABA without a LAMA vs a LAMA without a LABA (aOR, 0.93; 95% CI, 0.74–1.18), or a multiplicative or additive interaction between a LABA and a LAMA. Conclusions Inhaled LAMAs and LABAs were significantly and comparably associated with an increased risk of tachyarrhythmias.

BACKGROUND: Umeclidinium (UMEC; long-acting muscarinic antagonist [LAMA])/vilanterol (VI; long-acting beta2-agonist [LABA]) and fluticasone propionate/salmeterol (FP/SAL) (inhaled corticosteroid/LABA) are approved maintenance therapies for chronic obstructive pulmonary disease (COPD). Two studies compared efficacy and safety of UMEC/VI with FP/SAL in patients with moderate-to-severe COPD with no exacerbations in the previous year. METHODS: In these 12-week, multicenter, double-blind, parallel-group, double-dummy trials, randomized (1:1) patients received once-daily UMEC/VI 62.5/25 mcg or twice-daily FP/SAL 250/50 mcg (DB2114930 n = 353 and 353; DB2114951 n = 349 and 348, respectively; intent-to-treat). Endpoints included 0-24 h weighted mean (wm) forced expiratory volume in 1 s (FEV1) (Day 84; primary), trough FEV1 (Day 85; secondary), other lung function endpoints, dyspnea, quality of life (QoL) and safety. RESULTS: UMEC/VI demonstrated statistically significant, clinically meaningful improvements in lung function measures versus FP/SAL. For 0-24 h wmFEV1 (Day 84), improvements with UMEC/VI versus FP/SAL were 74 mL (95% confidence interval [CI]: 38-110; DB2114930) and 101 mL (63-139; DB2114951) (both p 1 unit) and QoL (St George's Respiratory Questionnaire Total score >4-unit decrease) in both studies with no statistical differences between treatments. Adverse event rates were similar: 26 and 30% UMEC/VI; 27 and 31% FP/SAL. CONCLUSIONS: Once-daily UMEC/VI 62.5/25 mcg over 12 weeks resulted in statistically significant, clinically meaningful improvements in lung function versus twice-daily FP/SAL 250/50 mcg in patients with moderate-to-severe COPD with infrequent exacerbations. Both treatments improved dyspnea and QoL. CLINICAL TRIAL REGISTRATION: DB2114930/NCT01817764; DB2114951/NCT01879410.

Background: This study investigated the effects on 24-h lung function and lung volume of a once-daily fixed-dose combination (FDC) of the long-acting muscarinic antagonist tiotropium and the long-acting beta(2)-agonist olodaterol in patients with chronic obstructive pulmonary disease. Methods: This was a randomised, double-blind, placebo-controlled, Phase III trial with an incomplete crossover design. Patients received four of the following six treatment options for 6 weeks each: placebo, olodaterol 5 mu g, tiotropium 2.5 mu g, tiotropium 5 mu g, tiotropium + olodaterol FDC 2.5/5 mu g and tiotropium + olodaterol FDC 5/5 mu g, all delivered via the Respimat (R) inhaler. The primary end point was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 24 h (AUC(0-24)) response after 6 weeks of treatment; key secondary end points were FEV1 AUC from 0 to 12 h and AUC from 12 to 24 h, and further end points included lung-volume parameters measured using body plethysmography (subset of patients), measures of peak and trough FEV1, and incidence of adverse events. Results: A significant improvement in FEV1 AUC(0-24) response was observed with tiotropium + olodaterol 5/5 mu g and 2.5/5 mu g versus placebo and monotherapies after 6 weeks of treatment; mean response with tiotropium + olodaterol 5/5 mu g versus placebo was 0.280 L (p < 0.0001). Differences to monotherapies with tiotropium + olodaterol 5/5 mu g were 0.115 L versus olodaterol 5 mu g, 0.127 L versus tiotropium 2.5 mu g and 0.110 L versus tiotropium 5 mu g (p < 0.0001 for all comparisons). Secondary end points supported these data. No safety concerns were identified. Conclusions: Overall, this study demonstrated improvements in lung function over 24 h with an FDC of tiotropium + olodaterol over tiotropium or olodaterol alone, with no observed difference in tolerability. ClinicalTrials.gov number: NCT01559116.

Background Roflumilast is used in severe chronic obstructive pulmonary disease (COPD) patients with frequent exacerbations. However, limited information is available on its impact in a “real-life” population that may be receiving triple therapy. Objective This study aimed to evaluate the effectiveness and safety of roflumilast in COPD patients already receiving triple therapy (long-acting β -agonist/inhaled corticosteroids and long-acting muscarinic antagonist). Methods Prospective registry that included COPD patients who were prescribed roflumilast added to triple therapy. The yearly rate of all COPD exacerbations before and after roflumilast and side effects related to the drug were registered. Results Among 55 patients prescribed 500 mg of roflumilast. Only 50.9% ( n = 28) completed 1 year of therapy (roflumilast group). A reduction of all exacerbations with roflumilast was observed (2.75 ± 0.29 vs. 3.57 ± 0.26; P = 0.022), with a particular benefit in patients with ≥4 exacerbations prior to initiating therapy (3.55 ± 0.51 vs. 5.00 ± 0.30; P = 0.034). Side effects (mainly gastrointestinal) and treatment discontinuation occurred in 69.1% and 49.1% of the overall population, respectively. Conclusions Roflumilast, when added to triple therapy, reduces exacerbations in a “real-life” population of severe COPD patients with frequent exacerbations. However, side effects are more common and lead more frequently to discontinuation of therapy than has been reported in trials.

BACKGROUND: A simple rule based on short-acting inhaled β2-agonist (SABA) use could identify patients with chronic obstructive pulmonary disease (COPD) at increased risk of exacerbations and signal the need for maintenance therapy change, similar to asthma "Rules of Two(®)". METHODS: Associations between SABA use, COPD exacerbations, and health care costs over 1 year were examined retrospectively using de-identified patient data from the Optum Research Database (ORD; N = 56,581) and the Impact National Benchmark Database (IMPACT™; N = 9423). Nebulized and metered-dose inhaler (MDI) SABA doses were normalized to 2.5 mg and 90 mcg albuterol equivalents, respectively. RESULTS: The GOLD initiative establishes ≥2 exacerbations/year as indicative of increased risk in COPD. We identified a correlation (p