Search

Introduction: Chronic Bronchitis (CB) represents a phenotype of chronic obstructive pulmonary disease (COPD). While several definitions have been used for diagnosis, the relationship between clinical definitions and radiologic assessment of bronchial disease (BD) has not been well studied. The aim of this study was to evaluate the relationship between three clinical definitions of CB and radiographic findings of BD in spirometry-defined COPD patients., Methods: A cross-sectional analysis was performed from a COPD phenotyping study. It was a prospective observational cohort. Participants had spirometry-defined COPD and available chest CT imaging. Comparison between CB definitions, Medical Research Council (CB MRC ), St. George's Respiratory Questionnaire (CB SGRQ ), COPD Assessment Test (CB CAT ) and CT findings were performed using Cohen's Kappa, univariate and multivariate logistic regressions., Results: Of 112 participants, 83 met inclusion criteria. Demographics included age of 70.1 ± 7.0 years old, predominantly male (59.0 %), 45.8 ± 30.8 pack-year history, 21.7 % actively smoking, and mean FEV 1 61.5 ± 21.1 %. With MRC, SGRQ and CAT definitions, 22.9 %, 36.6 % and 28.0 % had CB, respectively. BD was more often present in CB compared to non-CB patients; however, it did not have a statistically significant relationship between any of the CB definitions. CB SGRQ had better agreement with radiographically assessed BD compared to the other two definitions., Conclusion: Identification of BD on CT was associated with the diagnoses of CB. However, agreement between imaging and definitions were not significant, suggesting radiologic findings of BD and criteria defining CB may not identify the same COPD phenotype. Research to standardize imaging and clinical methods is needed for more objective identification of COPD phenotypes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DPT has consulted with AstraZeneca, Sunovion, Mylan and Theravance. RGB reports personal consulting fees from Theravance Biopharma/Mylan and GlaxoSmithKline. JEP is employed by AMGEN. CBC reports grants from NIH/NHLBI, NIH Foundation and the COPD Foundation, during the conduct of the study; he also reports personal fees from AstraZeneca, GlaxoSmithKline, Chiesi, NUVAIRA, MGC Diagnostics, Horizon Therapeutics, Respiree, Herbalife, Verona, RS BioTherapeutics, Genentec and Cambridge University Press, outside the submitted work. IZB has consulted with Astra Zeneca, Grifols, Verona Pharma, Takeda, Sanofi/Regeneron, Inhibrx and has received funding from Viatris, Theravance, AMGEN, Takeda and Aerogen. MF, TA, JCF, SCP, FA, and JB have no reportable disclosures., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Chronic obstructive pulmonary disease (COPD) is a preventable, progressive disease and the third leading cause of death worldwide. The epidemiological data of COPD from Gulf countries are very limited, as it remains underdiagnosed and underestimated. Risk factors for COPD include tobacco cigarette smoking, water pipe smoking (Shisha), exposure to air pollutants, occupational dusts, fumes, and chemicals. Inadequate treatment of COPD leads to worsening of disease. The 2024 GOLD guidelines recommend use of inhaled bronchodilators, corticosteroids, and adjunct therapies for treatment and management of COPD patients based on an individual assessment of the severity of symptoms and risk of exacerbations. This article reviews COPD pharmacotherapy in the Gulf countries and explores the role of nebulization in the management of COPD in this region. Methods: To review the COPD pharmacotherapy in the Gulf Countries, literature search was conducted using PubMed, Medline, Cochrane Systematic Reviews, and Google Scholar databases (before December 2022), using search terms such as COPD, nebulization, inhalers/inhalation, aerosols, and Gulf countries. Relevant articles from the reference list of identified studies were reviewed. Consensus statements, expert opinion, and other published review articles were included. Results: In the Gulf countries, pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs), soft mist inhalers, and nebulizers are used for drug delivery to COPD patients. pMDIs and DPIs are most prone to errors in technique and other common device handling errors. Nebulization is another mode of inhalation drug delivery, which is beneficial in certain patient populations such as the elderly and patients with cognitive impairment, motor or neuromuscular disorders, and other comorbidities. Conclusion: There is no major difference between Gulf countries and rest of the world in the approach to management of COPD. Nebulizers should be considered for patients who have difficulties in accessing or using MDIs and DPIs, irrespective of geographical location.

Introduction: Clinical decisions in chronic obstructive pulmonary disease (COPD) treatment often utilize serially assessed physiologic parameters and biomarkers. To better understand the reliability of these tests, we evaluated changes in commonly assessed biomarkers over 3 months in patients with clinically stable COPD., Methods: We performed an observational prospective cohort study of 89 individuals with clinically stable COPD, defined as no exacerbation history within 3 months of enrollment. Biomarkers included lung function and functional performance status, patient-reported outcomes of symptoms and health status, and blood markers of inflammation. The correlation between testing at baseline and at 3-month follow-up was reported as the intraclass correlation coefficient (ICC). "Outliers" had significant variability between tests, defined as >1.645 standard deviations between the two measurements. Differences in clinical features between outliers and others were compared., Results: Participants with COPD (n = 89) were 70.5 ± 6.7 years old, 54 (61%) male, had a 40 pack-year smoking history with 24.7% being current smokers, and postbronchodilator forced expiratory volume in one second (FEV 1 ) 62.3 ± 22.7% predicted. The biomarkers with excellent agreement between the initial and the follow-up measurements were FEV 1 (ICC = 0.96), Saint George's Respiratory Questionnaire (SGRQ) (ICC = 0.98), COPD Assessment Test (CAT) (ICC = 0.93) and C-reactive protein (CRP) (ICC = 0.90). By contrast, parameters showing less robust agreement were 6-minute walking distance (ICC = 0.75), eosinophil count (ICC = 0.77), erythrocyte sedimentation rate (ICC = 0.75) and white blood cell count (ICC = 0.48). Individuals with greater variability in biomarkers reported chronic bronchitis more often and had higher baseline SGRQ and CAT scores., Conclusion: Our study evaluated the stability of commonly assessed biomarkers in clinically stable COPD and showed excellent agreement between baseline and three-month follow-up values for FEV 1 , SGRQ, CAT and CRP. Individuals with chronic bronchitis and more symptomatic disease at baseline demonstrated greater variability in 3-month interval biomarkers., Competing Interests: JP is an employee of Amgen Inc. CBC reports personal fees from PulmonX, GlaxoSmithKline, NUVAIRA and MGC Diagnostics, outside the submitted work. DPT has consulted with AstraZeneca, Sunovion, Mylan and Theravance. IZB has consulted with Astra Zeneca, Grifols, Verona Pharma, Sanofi, Theravance, Viatris, Aerogen and Inhibrx and has received research grants from AMGEN, Aerogen, Theravance and Viatris and GE Healthcare. RGB reports personal fees from Viatris/Theravance Biopharma, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2023 Park et al.)

Background: Bronchodilator responsiveness (BDR) in obstructive lung disease varies over time and may be associated with distinct clinical features., Research Question: Is consistent BDR over time (always present) differentially associated with obstructive lung disease features relative to inconsistent (sometimes present) or never (never present) BDR in tobacco-exposed people with or without COPD?, Study Design and Methods: We retrospectively analyzed data from 2,269 tobacco-exposed participants in the Subpopulations and Intermediate Outcome Measures in COPD Study with or without COPD. We used various BDR definitions: change of ≥ 200 mL and ≥ 12% in FEV 1 (FEV 1 -BDR), change in FVC (FVC-BDR), and change in in FEV 1 , FVC or both (ATS-BDR). Using generalized linear models adjusted for demographics, smoking history, FEV 1 % predicted after bronchodilator administration, and number of visits that the participant completed, we assessed the association of BDR group: (1) consistent BDR, (2) inconsistent BDR, and (3) never BDR with asthma, CT scan features, blood eosinophil levels, and FEV 1 decline in participants without COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 0) and the entire cohort (participants with or without COPD)., Results: Both consistent and inconsistent ATS-BDR were associated with asthma history and greater small airways disease (%parametric response mapping functional small airways disease) relative to never ATS-BDR in participants with GOLD stage 0 disease and the entire cohort. We observed similar findings using FEV 1 -BDR and FVC-BDR definitions. Eosinophils did not vary consistently among BDR groups. Consistent BDR was associated with FEV 1 decline over time relative to never BDR in the entire cohort. In participants with GOLD stage 0 disease, both the inconsistent ATS-BDR group (OR, 3.20; 95% CI, 2.21-4.66; P < .001) and consistent ATS-BDR group (OR, 9.48; 95% CI, 3.77-29.12; P < .001) were associated with progression to COPD relative to the never ATS-BDR group., Interpretation: Demonstration of BDR, even once, describes an obstructive lung disease phenotype with a history of asthma and greater small airways disease. Consistent demonstration of BDR indicated a high risk of lung function decline over time in the entire cohort and was associated with higher risk of progression to COPD in patients with GOLD stage 0 disease., (Published by Elsevier Inc.)

Background: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) considers blood eosinophil counts < 100 cells/μL (BEC ≤100 ) in people with COPD to predict poor inhaled corticosteroid (ICS) responsiveness. However, the BEC ≤100 phenotype is inadequately characterized, especially in advanced COPD., Research Question: Are there differences between GOLD group D patients with high BEC and those with low BEC regarding baseline characteristics and longitudinal outcomes?, Study Design and Methods: We used multivariable mixed models and logistic regression to contrast clinical characteristics and outcomes of BEC ≤100 vs BEC > 100 (BEC 100+ ) in all subjects with COPD (n = 1,414) and GOLD group D subjects (n = 185) not receiving ICS., Results: We identified n = 485 with BEC ≤100 (n = 61 GOLD group D) and n = 929 people with BEC 100+ (n = 124 GOLD group D). BEC ≤100 status was stable at 6 weeks and approximately 52 weeks (intraclass correlations of 0.78 and 0.71, respectively). Compared with BEC 100+ , BEC ≤100 comprised more women, with greater current smoking, and less frequent childhood asthma. Among all analyzed participants, the two BEC-defined subsets showed similar rates of lung function decline (mean slope, BEC ≤100 vs BEC 100+ , -50 vs -39 mL/y; P = .140), exacerbations (0.40 vs 0.36/y; P = .098), subsequent ICS initiation (2.5% vs 4.4%; P = .071), and mortality (7.8% vs 8.4%; P = .715). However, in GOLD group D, people with BEC ≤100 showed higher exacerbation rates within 365 days of enrollment (0.62 vs 0.33/y; P = .002) and total follow-up (1.16 vs 0.83/y; P = .014). They also had greater lung function decline (mean slope of -68 mL/y vs -23 mL/y; P = .036) and had greater emphysema at baseline (voxels < 950 Hounsfield units at total lung capacity of 7.46% vs 4.61%; P = .029)., Interpretation: In non-ICS-treated GOLD group D COPD, people with BEC ≤100 had more baseline emphysema, prospective exacerbations, and lung function decline. Our analysis has identified a particularly vulnerable subpopulation of people with COPD, suggesting the need for studies focused specifically on their therapeutic treatment., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT01969344; URL: www., Clinicaltrials: gov., (Copyright © 2023. Published by Elsevier Inc.)

Background: Chronic obstructive pulmonary disease (COPD) is associated with worsened outcomes in COVID-19 (coronavirus disease 2019). However, data remain fraught with heterogeneity and bias from comorbid conditions. Additionally, data on the impact of COPD-specific factors, such as pre-hospital medications and pulmonologist involvement, remain sparse., Objective: We report a single-center analysis of COPD patients hospitalized with COVID-19 compared to those without COPD. Primary outcomes include ICU admission, mechanical ventilation, and in-hospital mortality., Methods: We evaluated all patients ≥40 years admitted with PCR-confirmed COVID-19 between February 2020 and February 2021. COPD was defined by documented ICD-10 diagnosis of COPD, confirmed smoking history, and active bronchodilator use. We compared outcomes between COPD patients and the remainder of the COVID-19 cohort. Multivariable analyses were adjusted for age, sex, smoking status, and comorbid conditions., Results: Of 1537 hospitalized COVID-19 patients, 122 (7.9%) carried a diagnosis of COPD. The COPD cohort was older (74 ± 13 vs 66 ± 15 years, P < 0.001) and more often former smokers (P < 0.001). Comorbid conditions including diabetes, cardiovascular disease, and kidney disease were more prevalent in the COPD group (P < 0.001). After adjusting for comorbid conditions, the COPD cohort had higher severity scores and trended towards fewer hospital-free days. Among patients with COPD, pre-hospital use of aspirin was associated with decreased ICU admissions (aHR 0.56, P = 0.049) and mechanical ventilation (aHR 0.25, P = 0.008), while LAMAs (long-acting muscarinic antagonists) were associated with decreased in-hospital mortality (aHR 0.34, P = 0.047). Involvement of pulmonology in pre-hospital management of COPD was not found to significantly affect outcomes., Conclusion: When corrected for comorbid illnesses, COPD was associated with more severe disease but not with increased ICU admission, mechanical ventilation, or in-hospital mortality rates. Among COPD patients, prehospital treatment with aspirin and COPD-directed therapies were associated with improved outcomes., Competing Interests: Dr Russell G Buhr reports grants from NIH/NCATS, during the conduct of the study; grants from NIH/NHLBI, personal fees from Viatris/Theravance Biopharma, personal fees from Dynamed/American College of Physicians, outside the submitted work; and Dr. Buhr is employed by the Department of Veterans Affairs. The content of this manuscript does not necessarily represent the views or positions of the US Federal Government. Dr Igor Barjaktarevic reports grants, personal fees from Theravance and Viatris, grants from Amgen, personal fees from Astra Zeneca, personal fees from Verona, personal fees from Inhibrx, personal fees from Grifols, personal fees from GSK, personal fees from Aerogen, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2022 Toppen et al.)

Rationale: Chronic obstructive pulmonary disease (COPD) is defined by fixed spirometric ratio, FEV 1 /FVC < 0.70 after inhaled bronchodilators. However, the implications of variable obstruction (VO), in which the prebronchodilator FEV 1 /FVC ratio is less than 0.70 but increases to 0.70 or more after inhaled bronchodilators, have not been determined. Objectives: We explored differences in physiology, exacerbations, and health status in participants with VO compared with reference participants without obstruction. Methods: Data from the SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) cohort were obtained. Participants with VO were compared with reference participants without obstruction. Measurements and Main Results: We assessed differences in baseline radiographic emphysema and small airway disease at study entry, baseline, and change in lung function by spirometry, functional capacity by 6-minute walk, health status using standard questionnaires, exacerbation rates, and progression to COPD between the two groups. All models were adjusted for participant characteristics, asthma history, and tobacco exposure. We assessed 175 participants with VO and 603 reference participants without obstruction. Participants with VO had 6.2 times the hazard of future development of COPD controlling for other factors (95% confidence interval, 4.6-8.3; P  < 0.001). Compared with reference participants, the VO group had significantly lower baseline pre- and post-bronchodilator (BD) FEV 1 , and greater decline over time in post-BD FEV 1 , and pre- and post-BD FVC. There were no significant differences in exacerbations between groups. Conclusions: Significant risk for future COPD development exists for those with pre- but not post-BD airflow obstruction. These findings support consideration of expanding spirometric criteria defining COPD to include pre-BD obstruction. Clinical trial registered with www.clinicaltrials.gov (NCT01969344).

Background: Small airways are known to be affected early in the course of COPD; however, traditional spirometric indices may not accurately identify small airways disease., Research Question: Can forced expiratory volume in 3 s/forced expiratory volume in 6 s (FEV 3 /FEV 6 ) identify early airflow abnormalities and predict future clinically important respiratory-related outcomes, including development of COPD?, Study Design and Methods: The study included 832 current and former smokers with post-bronchodilator FEV 1 /FVC ≥ 0.7 from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Participants were classified as having a reduced pre-bronchodilator FEV 3 /FEV 6 based on lower limit of normal (LLN) values. Repeatability analysis was performed for FEV 3 and FEV 6 . Regression modeling was used to evaluate the relationship between baseline FEV 3 /FEV 6 and outcome measures, including functional small airways disease, on thoracic imaging and respiratory exacerbations. Interval-censored analysis was used to assess progression to COPD., Results: FEV 3 /FEV 6 less than the LLN at baseline, defined as reduced compared with FEV 3 /FEV 6 at or above the LLN, was associated with lower FEV 1 , poorer health status (St. George's Respiratory Questionnaire score), more emphysema, and more functional small airways disease on quantitative imaging. FEV 3 and FEV 6 showed excellent agreement between repeat measurements. A reduced FEV 3 /FEV 6 was associated with increased odds of a severe respiratory exacerbation within the first year of follow-up and decreased time to first exacerbation. A low FEV 3 /FEV 6 was also associated with development of COPD according to spirometry results (post-bronchodilator FEV 1 /FVC < 0.7) during study follow-up., Interpretation: FEV 3 /FEV 6 is a routinely available and repeatable spirometric index that can be useful in the evaluation of early airflow obstruction in current and former smokers without COPD. A reduced FEV 3 /FEV 6 can identify those at risk for future development of COPD and respiratory exacerbations., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT01969344; URL: www., Clinicaltrials: gov: ClinicalTrials.gov., (Copyright © 2021 American College of Chest Physicians. All rights reserved.)

The purpose of this study was to explore the relationships between heart rate variability (HRV) and various phenotypic measures that relate to health and functional status in chronic obstructive pulmonary disease (COPD), and secondly, to demonstrate the feasibility of ascertaining HRV via a chest-worn wearable biosensor in COPD patients. HRV analysis was performed using SDNN (standard deviation of the mean of all normal R-R intervals), low frequency (LF), high frequency (HF), and LF/HF ratio. We evaluated the associations between HRV and COPD severity, class of bronchodilator therapy prescribed, and patient reported outcomes. Seventy-nine participants with COPD were enrolled. There were no differences in SDNN, HF, and LF/HF ratio according to COPD severity. The SDNN in participants treated with concurrent beta-agonists and muscarinic antagonists was lower than that in other participants after adjusting heart rate (beta coefficient -3.980, p = 0.019). The SDNN was positively correlated with Veterans Specific Activity Questionnaire (VSAQ) score ( r = 0.308, p = 0.006) and handgrip strength ( r = 0.285, p = 0.011), and negatively correlated with dyspnea by modified Medical Research Council (mMRC) questionnaire ( r = -0.234, p = 0.039), health status by Saint George's Respiratory Questionnaire (SGRQ) ( r = -0.298, p = 0.008), symptoms by COPD Assessment Test (CAT) ( r = -0.280, p = 0.012), and BODE index ( r = -0.269, p = 0.020). When measured by a chest-worn wearable device, reduced HRV was observed in COPD participants receiving inhaled beta-sympathomimetic agonist and muscarinic antagonists. HRV was also correlated with various health status and performance measures.

Rationale: There is an association between body mass index (BMI) and mortality in chronic obstructive pulmonary disease (COPD), with underweight individuals having higher mortality risk. Mortality and exacerbation risks among individuals with higher BMI are unclear. Objectives: To examine the relationship between BMI and adverse outcomes in COPD. Methods: This post hoc analysis included data from TIOSPIR (Tiotropium Safety and Performance in Respimat) ( N  = 17,116) and tiotropium-treated patients in UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) ( N  = 2,986). BMI classes (underweight [BMI < 20 kg/m 2 ], normal weight [BMI 20 to <25 kg/m 2 ], overweight [BMI 25 to <30 kg/m 2 ], obesity class I [BMI 30 to <35 kg/m 2 ], obesity class II [BMI 35 to <40 kg/m 2 ], and obesity class III [BMI ⩾ 40 kg/m 2 ]) were examined for adjusted associations with mortality, exacerbation, and nonfatal cardiovascular event risk using over 50,000 patient-years of cumulative follow-up data. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression models. Results: In TIOSPIR, obesity prevalence was 22%, overweight 32%, and underweight 12%. The proportion of females was highest in obesity classes II and III. Overweight and obese participants had better baseline lung function versus other BMI classes; underweight participants were more likely to be current smokers. Underweight participants had a significantly higher risk of death (HR, 1.88; 95% CI, 1.62-2.20; P  < 0.0001) and severe exacerbations (HR, 1.31; 95% CI, 1.16-1.47; P  < 0.0001) versus normal-weight participants; however, overweight and obese participants were at lower to no additional risk. Results from UPLIFT were similar to TIOSPIR. Conclusions: These results suggest that there is a strong association between body weight, COPD events, and risk of death. A holistic management approach taking into account respiratory and cardiovascular risk factors and nutritional status is needed to improve the general well-being of patients with COPD.

Inhaled bronchodilators are central for the treatment of chronic obstructive pulmonary disease (COPD), as they can provide symptom relief and reduce the frequency and severity of exacerbations while improving health status and exercise tolerance. In 2017, glycopyrrolate (GLY) delivered via the eFlow® closed system (CS) nebulizer (nebulized GLY; 25 µg twice daily), was approved by the US Food and Drug Administration for maintenance treatment of moderate-to-very-severe COPD. This approval was based largely on results from the replicate, placebo-controlled, Phase III clinical trials- GOLDEN 3 and 4. In this review, we summarize key findings from secondary analyses of the GOLDEN 3 and 4 studies, and provide a comprehensive overview that may assist both pulmonologists and primary-care providers in their treatment decisions. Comorbidities are common among patients with COPD in clinical practice and may impact bronchodilator efficacy. This review highlights outcomes among subpopulations of patients with comorbidities (e.g., anxiety/depression, cardiovascular disease), and their impact on the efficacy of nebulized GLY. In addition, the efficacy and safety of nebulized GLY across various demographics (e.g., age, gender) and baseline disease characteristics (e.g., disease severity, rescue medication use) are discussed. Real-world outcomes with nebulized GLY, including device satisfaction, healthcare resource utilization, and exacerbations, are also presented. These secondary analyses and real-world data complement the primary results with nebulized GLY from Phase III studies and support the need for the inclusion of patients representative of real-world clinical practice in RCTs. In addition, these data suggest that RCTs for COPD therapies should be complemented with real-world observational studies., (© 2021. The Author(s).)

Background: Chronic bronchitis (CB) is one of the conditions that contribute to chronic obstructive pulmonary disease (COPD). Despite its widespread prevalence among patients with COPD and overall negative impact on treatment outcomes, the effect of CB on the efficacy of bronchodilator therapy has not been evaluated. The objective of this post hoc analysis is to assess the effect of nebulized glycopyrrolate (GLY) on lung function and health-related quality of life outcomes in patients with St George's Respiratory Questionnaire (SGRQ)-defined CB at baseline., Methods: Pooled data from the replicate, 12-week GOLDEN 3 and 4 studies (N=861) were grouped by CB status at baseline. The endpoints reported are changes from baseline in trough forced expiratory volume in 1 second (FEV 1 ), SGRQ and EXAcerbations of Chronic Pulmonary Disease Tool-Respiratory Symptoms (EXACT-RS) scores. Safety of GLY was evaluated by monitoring the incidence of adverse events (AEs)., Results: Following 12 weeks of treatment, GLY 25 μg twice-daily (BID) resulted in placebo-adjusted improvements from baseline in FEV 1 of 77.1 mL and 124.4 mL in the CB and non-CB groups, respectively (p<0.0001 vs placebo in both groups). Significant improvements in SGRQ total scores were observed with GLY 25 μg BID compared with placebo, regardless of baseline CB status. Although EXACT-RS improvements were noted in both CB and non-CB groups, significant improvements were observed only in the CB group. GLY 25 μg BID was generally well tolerated through 12 weeks of treatment, with a low incidence of AEs., Conclusion: Treatment with nebulized GLY 25 μg BID for 12 weeks resulted in significant improvements in lung function and SGRQ total scores, compared with placebo. Significant improvements in EXACT-RS total scores were observed only in the CB group. Together, these results support the use of GLY 25 μg BID in patients with COPD, regardless of their CB status., Competing Interests: DPT declares that he has served as a consultant and speaker for Sunovion, AstraZeneca, Innoviva/Theravance, Mylan, and Boehringer-Ingelheim. AOG was an employee of Sunovion Pharmaceuticals Inc at the time of the study and is currently an employee of Alexion Pharmaceuticals. SSh and SSa are employees of Sunovion Pharmaceuticals Inc. The authors report no other conflicts of interest in this work., (© 2021 Tashkin et al.)

Both asthma and chronic obstructive pulmonary disease (COPD) are inflammatory chronic respiratory conditions with high rates of morbidity and mortality worldwide. The objectives of this review are to briefly describe the pathophysiology and epidemiology of asthma and COPD, discuss guideline recommendations for uncontrolled disease, and review a new generic option for the treatment of asthma and COPD. Although mild forms of these diseases may be controlled with as-needed pharmacotherapy, uncontrolled or persistent asthma and moderate or severe COPD uncontrolled by bronchodilators with elevated eosinophilia or frequent exacerbations may require intervention with combination therapy with inhaled corticosteroids (ICS) and long-acting beta agonists (LABAs), according to international guidelines. Fixed-dose combinations of ICS/LABA are commonly prescribed for both conditions, with fluticasone propionate (FP) and salmeterol forming a cornerstone of many treatment plans. An oral inhalation powder containing the combination of FP and salmeterol has been available as Advair Diskus® in the United States for almost 20 years, and the first and only substitutable generic version of this product has recently been approved for use: Wixela™ Inhub™. Bioequivalence of Wixela Inhub and Advair Diskus has been established. Furthermore, the Inhub inhaler was shown to be robust and easy to use, suggesting that Wixela Inhub may provide an alternative option to Advair Diskus for patients with asthma or COPD requiring intervention with an ICS/LABA., Competing Interests: In accordance with the disclosure policy and our ethical obligations as researchers, we disclose the following interests fully and have in place an approved plan for managing any potential conflicts arising from these interests: Donald P. Tashkin has been a paid consultant for Innoviva and an advisory board member and paid speaker for AstraZeneca, Boehringer-Ingelheim, Sunovion, and Mylan Inc. Jill A. Ohar has received an investigator-initiated grant from Sunovion and has been a paid consultant for Boehringer-Ingelheim, GlaxoSmithKline, Mylan Inc., Theravance, and Sunovion. Arkady Koltun is a Mylan Inc. employee, stock owner, and shareholder. Richard Allan is a Mylan Pharma UK employee and stock owner. Jonathan K. Ward is a Mylan Pharma UK employee and stock owner., (Copyright © 2021 Donald P. Tashkin et al.)

Bronchodilators, including long-acting β 2 -agonists and long-acting muscarinic antagonists, are the mainstay for treatment of patients with chronic obstructive pulmonary disease (COPD) to prevent exacerbations or reduce symptoms. Formoterol is a highly selective and potent β 2 -agonist that relaxes airway smooth muscle to significantly improve lung function. Inhaled formoterol works within 5 minutes of administration and provides improvements in spirometry measurements over 12 hours. The lipophilicity of formoterol allows it to form a depot within the smooth muscle to provide a prolonged duration of action. Following therapeutic doses, plasma concentrations are very low or undetectable. Determination of the pharmacokinetics of formoterol following high-dose administration to healthy volunteers revealed that the drug was rapidly absorbed and excreted unchanged in the urine with a half-life of 10 hours. Inhaled formoterol, as monotherapy or in combination with other agents, is an effective and safe treatment option for patients with moderate to severe COPD. Clinical studies have demonstrated improvements in lung function and COPD symptoms, particularly dyspnea; reductions in the risk of exacerbations; and improvement in patients' health status. The adverse event profile of inhaled formoterol is similar to that of placebo, with few adverse cardiovascular events. Formoterol is a valuable bronchodilator used in the maintenance treatment of COPD. This review describes the mechanism of action, pharmacodynamics, and pharmacokinetics of inhaled formoterol. It also reviews the results of large, randomized, controlled clinical trials that evaluated the use of formoterol as monotherapy and in combination with inhaled corticosteroids, long-acting muscarinic antagonists, and triple therapy regimens in the treatment of patients with moderate to severe COPD., Competing Interests: DPT serves on advisory boards for AstraZeneca, Sunovion, Mylan, and Theravance/Innoviva and as a speaker for AstraZeneca, Boehringer Ingelheim, and Sunovion. The author reports no other conflicts of interest in this work., (© 2020 Tashkin.)

Analytic epidemiological studies cover a large spectrum of study methodologies, ranging from noninterventional observational studies (population-based, case-control, or cohort studies) to interventional studies (clinical trials). Herein, we review the different research methodologies or study designs and discuss their advantages and disadvantages in the context of chronic obstructive pulmonary disease (COPD) pharmacotherapy. Although randomized controlled trials (RCTs) are considered the "gold standard" for evaluating the efficacy and safety of an intervention, observational studies conducted in a real-world scenario are useful in providing evidence on the effectiveness of the intervention in clinical practice; understanding both efficacy and effectiveness is important from the clinician's perspective. Pragmatic clinical trials that use real-world data while retaining randomization bridge the gap between explanatory RCTs and noninterventional observational studies. Overall, different study designs have their associated advantages and disadvantages; together, findings from all types of studies bring about progress in clinical research as elucidated through examples from COPD research in this paper., Competing Interests: Dr. Tashkin has participated as an advisory board member and speaker for Boehringer Ingelheim, AstraZeneca, and Sunovion. He has also worked as a consultant for Mylan and Innoviva/Theravance. He also reports personal fees from AstraZeneca, outside the submitted work. Dr. Amin has worked as a consultant and/or speaker for Boehringer Ingelheim, Sunovion, BMS, Pfizer, Portola, and AstraZeneca. He also reports personal fees from Boehringer Ingelheim, Sunovion, BMS, Pfizer, Portola, and Astra Zeneca, outside the submitted work. Dr. Kerwin has participated in consulting, advisory boards, and speaker panels for, or has received travel reimbursement from, Amphastar, AstraZeneca, Boehringer Ingelheim, Cipla, GlaxoSmithKline, Mylan, Novartis, Oriel, Pearl, Sunovion, Teva, and Theravance. He has conducted multicenter clinical research trials for approximately 40 pharmaceutical companies. The authors report no other conflicts of interest in this work., (© 2020 Tashkin et al.)

Objective: Bronchodilator responsiveness (BDR) is prevalent in COPD, but its clinical implications remain unclear. We explored the significance of BDR, defined by post-bronchodilator change in FEV 1 (BDR FEV1 ) as a measure reflecting the change in flow and in FVC (BDR FVC ) reflecting the change in volume., Methods: We analyzed 2974 participants from a multicenter observational study designed to identify varying COPD phenotypes (SPIROMICS). We evaluated the association of BDR with baseline clinical characteristics, rate of prospective exacerbations and mortality using negative binomial regression and Cox proportional hazards models., Results: A majority of COPD participants exhibited BDR (52.7%). BDR FEV1 occurred more often in earlier stages of COPD, while BDR FVC occurred more frequently in more advanced disease. When defined by increases in either FEV 1 or FVC, BDR was associated with a self-reported history of asthma, but not with blood eosinophil counts. BDR FVC was more prevalent in subjects with greater emphysema and small airway disease on CT. In a univariate analysis, BDR FVC was associated with increased exacerbations and mortality, although no significance was found in a model adjusted for post-bronchodilator FEV 1 ., Conclusion: With advanced airflow obstruction in COPD, BDR FVC is more prevalent in comparison to BDR FEV1 and correlates with the extent of emphysema and degree of small airway disease. Since these associations appear to be related to the impairment of FEV 1 , BDR FVC itself does not define a distinct phenotype nor can it be more predictive of outcomes, but it can offer additional insights into the pathophysiologic mechanism in advanced COPD., Clinical Trials Registration: ClinicalTrials.gov: NCT01969344T4., Competing Interests: IB has received research grants from AMGEN and GE Healthcare; and reports personal fees from Astra Zeneca, GSK, Boehringer Ingelheim, GE Healthcare, Theravance, Mylan, GRIFOLS, CSL Behring, Verona Pharma and Fisher & Pykel Healthcare. SPB is supported by NIH Grant K23HL133438 and he has served on an advisory board for Sunovion and reports grants from NIH, personal fees from Sunovion, personal fees from GlaxoSmithKline, outside the submitted work. JLC is supported by Merit Review award I01 CX000911 from the Department of Veterans Affairs, and reports grants the Department of Defense, the National Institutes of Health, and from MedImmune Corporation, Ltd., and reports grants from NIH/NHLBI, during the conduct of the study; grants from NIH/NIAID, grants from Department of Veterans Affairs, grants from Department of Defense, outside the submitted work. MKH has consulted for GSK, Boehringer Ingelheim and AstraZeneca, has received research support from Novartis and Sunovion and reports grants from NIH, during the conduct of the study; and Consulting for GSK, BI, Mylan and AstraZeneca, research support from Sunovion and Novartis. FJM reports grants from NHLBI, National Institutes of Health, personal fees from Continuing Education, personal fees from Forest Laboratories, Janssen, GlaxoSmithKline, Nycomed/Takeda, AstraZeneca, Boehringer Ingelheim, Bellerophon (formerly Ikaria), Genentech, Novartis, Pearl, Roche, Sunovion, Theravance, CME Incite, Annenberg Center for Health Sciences at Eisenhower, Integritas, InThought, National Association for Continuing Education, Paradigm Medical Communications, LLC, PeerVoice, UpToDate, Haymarket Communications, Western Society of Allergy and Immunology, Proterixbio (formerly Bioscale), Unity Biotechnology, ConCert Pharmaceuticals, Lucid, Methodist Hospital, Columbia University, Prime Healthcare Ltd, WebMD, PeerView Network, California Society of Allergy and Immunology, Chiesi, Puerto Rico Thoracic Society, outside the submitted work, and reports personal fees from Afferent/Merck, personal fees from American Thoracic Society, grants, personal fees, non-financial support from AstraZeneca, personal fees from Bayer, non-financial support from Boehringer Ingelehim, personal fees from ProTerrix Bio, personal fees from Bridge Biotherapeutics, personal fees, non-financial support from Chiesi, personal fees from Gala, personal fees, non-financial support, personal fees from Genentech, grants, personal fees, non-financial support from GlaxoSmithKline, grants, personal fees from Nitto, personal fees from ProMedior, personal fees from ProMetic, personal fees from Patara/Respivant, personal fees from Biogen, personal fees, non-financial support from Sunovion, personal fees, non-financial support from Teva, personal fees from Veracyte, during the conduct of the study. NH reports grants and personal fees from AstraZeneca, GSK, Boehringer Ingelheim, grants from NIH, COPD Foundation, outside the submitted work. GB has grants from the NIH, Foundation for the NIH, COPD Foundation and Alpha-1 Foundation, and reports grants, personal fees from AstraZeneca, grants from Boehringer Ingelheim, grants from NIH, grants from COPD Foundation, personal fees from Mylan, outside the submitted work. JMW has received grant support from the NIH, contracts to conduct research from GSK, Bayer, MereoBioPharma,Quintiles, and reports grants from NIH/NHLBI, during the conduct of the study; grants from NIH/NCATS, grants from Bayer, grants, personal fees from GSK, personal fees from Boehringer Ingelheim, grants, personal fees from Mereo BioPharma, personal fees from Quintiles, outside the submitted work. EAH a founder and shareholder of VIDA Diagnostics, a company commercializing lung image analysis software developed, and reports personal fees from VIDA Diagnostics, during the conduct of the study. VK has consulted for Boehringer Ingelheim, Gala Therapeutics and AstraZeneca and received personal fees from ABIM, and reports personal fees from Medscape, personal fees from Gala Therapeutics, personal fees from ABIM Critical Care Testwriting Committee, personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, outside the submitted work. MTD reports receiving grants from the NIH, the Department of Defense, and the American Heart Association; consulting fees from Boehringer Ingelheim, GlaxoSmithKline, Novartis, Astra Zeneca, Yungjin, PneumRx/BTG, Pulmonx, Genentech, Boston Scientific, Quark Pharmaceuticals, Mereo and received grants from American Lung Association and NIH, and reports grants from NIH, during the conduct of the study; personal fees from Boehringer Ingelheim, personal fees from AstraZeneca, personal fees from GlaxoSmithKline, personal fees from Boston Scientific, grants from American Lung Association, grants from Department of Defense, grants from Department of Veterans Affairs, personal fees from Mereo, personal fees from Quark, outside the submitted work. MBD has received research grants from the NIH and reports personal fees from Boehringer-Ingelheim, GlaxoSmithKline, AstraZeneca, and Mylan-Theravance, outside the submitted work, and reports grants from NIH-NHLBI, during the conduct of the study; grants, personal fees from Boehringer-Ingelheim, personal fees from GlaxoSmithKline, personal fees from AstraZeneca, personal fees from Mylan-Theravance, grants from Department of Defense, personal fees from Novavax, personal fees from Parion, personal fees from Midmark, personal fees from Philips, outside the submitted work. SAC reports personal fees from AstraZeneca, GSK, Amgen, Glenmark, Sunovion, UpToDate, and received personal fees and non-financial support from Genentech, grants from MedImmune, outside the submitted work, and reports personal fees from AstraZeneca, personal fees from GlaxoSmithKline, personal fees from Amgen, personal fees from Glenmark, personal fees from Sunovion, personal fees from Genentech, non-financial support from Medimmune, outside the submitted work. JAK has received research grants from NIH and the Patient Centered Outcomes Research Institute. DPT reports personal fees from Boehringer-Ingelheim, AstraZeneca, Sunovion, Theravance/Innoviva, Mylan, outside the submitted work, and reports personal fees from AstraZeneca, personal fees from Sunovion, during the conduct of the study; personal fees from AstraZeneca, personal fees from Sunovion, personal fees from Boehringer-Ingelheim, personal fees from Mylan, outside the submitted work. CBC has consulted with PulmonX, has received research funding from Equinox Fitness Clubs, Amgen and is employed part-time by the GlaxoSmithKline Global Respiratory Franchise, and reports personal fees from GlaxoSmithKline, outside the submitted work. DC has grants from the NIH, reports grants from NHLBI, grants from COPD Foundation, during the conduct of the study and no other conflicts. RB served on the advisory boards (GlaxoSmithKline, Boehringer Ingelheim, and Mylan Pharmaceuticals) and received research grants from GlaxoSmithKline and Boehringer Ingelheim, and reports personal fees from GlaxoSmithKline, personal fees from Boehringer Ingelheim, personal fees from Mylan Pharmaceuticals, grants from GlaxoSmithKline, grants from Boehringer Ingelheim, outside the submitted work. RP reports grants from NHLBI, grants from COPD Foundation, NHLBI and Department of Veterans Affairs, outside the submitted work. RGB received personal fees from GlaxoSmithKline, grants from NIH/National Center for Advancing Translational Sciences, grants from NIH/NHLBI, and reports grants from NIH/NCATS, during the conduct of the study; personal fees from GlaxoSmithKline, grants from NIH/NHLBI, outside the submitted work; and Dr. Buhr is employed part-time by the Veterans Health Administration; the content of this manuscript does not necessarily reflect the views of the US Department of Veterans Affairs. RJK received grants and personal fees from Genentech, Boehringer Ingelheim, Medimmune/Astra Zeneca, and Gilead and reports grants from NIH, during the conduct of the study; grants, personal fees from Boehringer Ingelheim, grants, personal fees from Roche/Genentech, outside the submitted work. GC reports grants from Boehringer- Ingelheim, Novartis, Astra Zeneca, Respironics, MedImmune, Actelion, Forest, Pearl, Ikaria, Aeris, PneumRx, Pulmonx, personal fees from HGE Health Care Solutions, Inc, Amirall, Boehringer- Ingelheim, Holaira. NB reports grants from NIH, outside the submitted work. PW reports personal fees from Glenmark Pharmaceuticals, personal fees from GSK, personal fees from NGM Pharma, personal fees from Amgen, nothing from Regeneron, nothing from 23andMe, nothing from Theravance, nothing from AstraZeneca, outside the submitted work. CMD reports grants from NIH, during the conduct of the study. SP reports grants from MIH, HNLBI, during the conduct of the study. The authors report no other conflicts of interest in this work., (© 2019 Barjaktarevic et al.)

Airway inflammation is a major contributing factor in both asthma and chronic obstructive pulmonary disease (COPD) and represents an important target for treatment. Inhaled corticosteroids (ICS) as monotherapy or in combination therapy with long-acting β 2 -agonists or long-acting muscarinic antagonists are used extensively in the treatment of asthma and COPD. The development of ICS for their anti-inflammatory properties progressed through efforts to increase topical potency and minimise systemic potency and through advances in inhaled delivery technology. Budesonide is a potent, non-halogenated ICS that was developed in the early 1970s and is now one of the most widely used lung medicines worldwide. Inhaled budesonide's physiochemical and pharmacokinetic/pharmacodynamic properties allow it to reach a rapid and high airway efficacy due to its more balanced relationship between water solubility and lipophilicity. When absorbed from the airways and lung tissue, its moderate lipophilicity shortens systemic exposure, and its unique property of intracellular esterification acts like a sustained release mechanism within airway tissues, contributing to its airway selectivity and a low risk of adverse events. There is a large volume of clinical evidence supporting the efficacy and safety of budesonide, both alone and in combination with the fast- and long-acting β 2 -agonist formoterol, as maintenance therapy in patients with asthma and with COPD. The combination of budesonide/formoterol can also be used as an as-needed reliever with anti-inflammatory properties, with or without regular maintenance for asthma, a novel approach that is already approved by some country-specific regulatory authorities and currently recommended in the Global Initiative for Asthma (GINA) guidelines. Budesonide remains one of the most well-established and versatile of the inhaled anti-inflammatory drugs. This narrative review provides a clinical reappraisal of the benefit:risk profile of budesonide in the management of asthma and COPD.

Spirometry is the current gold standard for diagnosing and monitoring the progression of Chronic Obstructive Pulmonary Disease (COPD). However, many current and former smokers who do not meet established spirometric criteria for the diagnosis of this disease have symptoms and clinical courses similar to those with diagnosed COPD. Large longitudinal observational studies following individuals at risk of developing COPD offer us additional insight into spirometric patterns of disease development and progression. Analysis of forced expiratory maneuver changes over time may allow us to better understand early changes predictive of progressive disease. This review discusses the theoretical ability of spirometry to capture fine pathophysiologic changes in early airway disease, highlights the shortcomings of current diagnostic criteria, and reviews existing evidence for spirometric measures which may be used to better detect early airflow impairment., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Smoking continues to be a major risk factor for COPD and may impact the efficacy of COPD treatments, with guidelines supporting the crucial importance for current smokers of smoking cessation. A post-hoc analysis of the FLIGHT1 and FLIGHT2 studies assessed the impact of smoking status on the efficacy and safety of indacaterol/glycopyrrolate (IND/GLY) 27.5/15.6 μg twice daily versus its monocomponents or placebo in patients with COPD., Methods: This post-hoc analysis of pooled data from the replicate, 12-week, placebo-controlled FLIGHT1 and FLIGHT2 studies compared the efficacy and safety of IND/GLY with that of IND, GLY, and placebo in patients with moderate-to-severe COPD. Baseline data from 2038 patients were pooled and grouped by smoking status (52% were current smokers and 48% were ex-smokers). The effects of treatment on lung function, patient-reported outcomes (PROs), and safety were evaluated by baseline smoking status., Results: Treatment with IND/GLY resulted in significant improvements in lung function measurements compared with placebo, irrespective of smoking status. Improvements in St George's Respiratory Questionnaire and transition dyspnea index were significantly greater than placebo in both current and ex-smokers, whereas changes in COPD assessment test were significant only among current smokers. Improvements in lung function and PROs were greater with IND/GLY compared with its monocomponents in current and ex-smokers. The incidences of AEs and SAEs were similar between current and ex-smokers., Conclusions: IND/GLY demonstrated significant improvements in lung function and PROs, independent of baseline smoking status. The safety profile of IND/GLY did not differ between current and ex-smokers., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Use of inhaled corticosteroids (ICS) increases the risk of pneumonia in chronic obstructive pulmonary disease (COPD), but the magnitude of risk with different ICS remains unclear., Methods: A post hoc analysis of the 4-year UPLIFT® trial to assess whether pneumonia risk differed by type of ICS (fluticasone propionate [FP], other ICS, or no ICS) in permanent users (defined by use until end of study) or in users at baseline (sensitivity analysis)., Results: For the permanent-users analysis, 825 patients receiving FP throughout the trial, 825 patients receiving other ICS and 825 patients not receiving ICS were matched on relevant baseline features 1:1:1. A significantly greater risk of pneumonia was observed for FP versus no ICS: the hazard ratio (HR) for risk of pneumonia was 1.33 (95% confidence interval [CI] 1.00, 1.75; p = 0.046) and the rate ratio (RR) was 1.58 (95% CI 1.05, 2.37; p = 0.028). A greater risk was also found for FP versus other ICS: HR 1.28 (95% CI 0.97, 1.68; p = 0.078) and RR 1.48 (95% CI 1.00, 2.19; p = 0.049). A higher proportion of patients on FP were hospitalized with pneumonia (7.9%) versus other ICS (6.7%) or no ICS (5.9%). Whilst other ICS use was associated with the highest number of fatal pneumonia events, the total number of fatal pneumonia incidents was low. A similar pattern was observed in the sensitivity analyses, which included 4002 patients on different treatments at baseline (FP, other ICS, and no ICS) and considered potential switches during the study., Conclusion: The results support existing evidence of an increased pneumonia risk with FP use compared with other ICS and no ICS use in patients with COPD. Healthcare professionals should evaluate the risk-benefit ratio of using ICS when making treatment decisions with their patients., Trial Registration: Post hoc analysis of UPLIFT®. ClinicalTrials.gov number: NCT00144339 . Retrospectively registered September 2, 2005.

Inhaled corticosteroids (ICSs) are a mainstay of COPD treatment for patients with a history of exacerbations. Initial studies evaluating their use as monotherapy failed to show an effect on rate of pulmonary function decline in COPD, despite improvements in symptoms and reductions in exacerbations. Subsequently, ICS use in combination with long-acting β 2 -agonists (LABAs) was shown to provide improved reductions in exacerbations, lung function, and health status. ICS-LABA combination therapy is currently recommended for patients with a history of exacerbations despite treatment with long-acting bronchodilators alone. The presence of eosinophilic bronchial inflammation, detected by high blood eosinophil levels or a history of asthma or asthma-COPD overlap, may define a population of patients in whom ICSs may be of particular benefit. Prospective clinical studies to determine an appropriate threshold of eosinophil levels for predicting the beneficial effects of ICSs are needed. Further study is also required in COPD patients who continue to smoke to assess the impact of cell- and tissue-specific changes on ICS responsiveness. The safety profile of ICSs in COPD patients is confounded by comorbidities, age, and prior use of systemic corticosteroids. The risk of pneumonia in patients with COPD is increased, particularly with more advanced age and worse disease severity. ICS-containing therapy also has been shown to increase pneumonia risk; however, differences in study design and the definition of pneumonia events have led to substantial variability in risk estimates, and some data indicate that pneumonia risk may differ by the specific ICS used. In summary, treatment with ICSs has a role in dual and triple therapy for COPD to reduce exacerbations and improve symptoms. Careful assessment of COPD phenotypes related to risk factors, triggers, and comorbidities may assist in individualizing treatment while maximizing the benefit-to-risk ratio of ICS-containing COPD treatment., Competing Interests: Disclosure DPT has served on advisory boards for AstraZeneca, Novartis, and Sunovion; as a speaker for Boehringer Ingelheim, AstraZeneca, and Sunovion; and as a consultant for Theravance/Innoviva. CS has current, past, or pending grants in COPD from Adverum, the Alpha-1 Foundation, BTG, CSL Behring, Grifols, MatRx, NIH, Novartis, PneumRx, and Shire. He consults for Abeona, AstraZeneca, CSA Medical, CSL Behring, GlaxoSmithKline, Grifols, and Uptake Medical on COPD. The authors report no other conflicts of interest in this work.

Long-acting muscarinic antagonists (LAMAs), along with long-acting β 2 -agonists (LABAs), are the mainstay for treatment of patients with COPD. Glycopyrrolate, or glycopyrronium bromide, like other LAMAs, inhibits parasympathetic nerve impulses by selectively blocking the binding of acetylcholine to muscarinic receptors. Glycopyrrolate is unusual in that it preferentially binds to M 3 over M 2 muscarinic receptors, thereby specifically targeting the primary muscarinic receptor responsible for bronchoconstriction occurring in COPD. Inhaled glycopyrrolate is slowly absorbed from the lungs and rapidly eliminated from the bloodstream, most likely by renal excretion in its unmetabolized form, limiting the potential for systemic adverse events. Inhaled glycopyrrolate is a fast-acting, efficacious treatment option for patients with moderate-severe COPD. It improves lung function, reduces the risk of exacerbations, and alleviates the symptoms of breathlessness, which in turn may explain the improvement seen in patients' quality of life. Inhaled formulations containing glycopyrrolate are well tolerated, and despite being an anticholinergic, few cardiovascular-related events have been reported. Inhaled glycopyrrolate is thus of value as both monotherapy and in combination with other classes of medication for maintenance treatment of COPD. This review covers the mechanism of action of inhaled glycopyrrolate, including its pharmacokinetic, pharmacodynamic, and safety profiles, and effects on mucus secretion. It also discusses the use of inhaled glycopyrrolate in the treatment of COPD, as monotherapy and in fixed-dose combinations with LABAs and inhaled corticosteroid-LABAs, including a triple therapy recently approved in Europe., Competing Interests: Disclosure DPT serves on advisory boards for AstraZeneca, Sunovion, Mylan, and Theravance/Innoviva, and as a speaker for AstraZeneca, Boehringer-Ingelheim, and Sunovion. NJG has no conflicts of interest.

Background: Cigarette smoking is the strongest risk factor for COPD. Smoking burden is frequently measured in pack-years, but the relative contribution of cigarettes smoked per day versus duration towards the development of structural lung disease, airflow obstruction and functional outcomes is not known., Methods: We analysed cross-sectional data from a large multicentre cohort (COPDGene) of current and former smokers. Primary outcome was airflow obstruction (FEV 1 /FVC); secondary outcomes included five additional measures of disease: FEV 1 , CT emphysema, CT gas trapping, functional capacity (6 min walk distance, 6MWD) and respiratory morbidity (St George's Respiratory Questionnaire, SGRQ). Generalised linear models were estimated to compare the relative contribution of each smoking variable with the outcomes, after adjustment for age, race, sex, body mass index, CT scanner, centre, age of smoking onset and current smoking status. We also estimated adjusted means of each outcome by categories of pack-years and combined groups of categorised smoking duration and cigarettes/day, and estimated linear trends of adjusted means for each outcome by categorised cigarettes/day, smoking duration and pack-years., Results: 10 187 subjects were included. For FEV 1 /FVC, standardised beta coefficient for smoking duration was greater than for cigarettes/day and pack-years (P<0.001). After categorisation, there was a linear increase in adjusted means FEV 1 /FVC with increase in pack-years (regression coefficient β=-0.023±SE0.003; P=0.003) and duration over all ranges of smoking cigarettes/day (β=-0.041±0.004; P<0.001) but a relatively flat slope for cigarettes/day across all ranges of smoking duration (β=-0.009±0.0.009; P=0.34). Strength of association of duration was similarly greater than pack-years for emphysema, gas trapping, FEV 1 , 6MWD and SGRQ., Conclusion: Smoking duration alone provides stronger risk estimates of COPD than the composite index of pack-years., Trial Registration Number: Post-results; NCT00608764., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

COPD is a significant cause of morbidity and mortality. In some patients with COPD, eosinophils contribute to inflammation that promotes airway obstruction; approximately a third of stable COPD patients have evidence of eosinophilic inflammation. Although the eosinophil threshold associated with clinical relevance in patients with COPD is currently subject to debate, eosinophil counts hold potential as biomarkers to guide therapy. In particular, eosinophil counts may be useful in assessing which patients may benefit from inhaled corticosteroid therapy, particularly regarding exacerbation prevention. In addition, several therapies targeting eosinophilic inflammation are available or in development, including monoclonal antibodies targeting the IL5 ligand, the IL5 receptor, IL4, and IL13. The goal of this review was to describe the biologic characteristics of eosinophils, their role in COPD during exacerbations and stable disease, and their use as biomarkers to aid treatment decisions. We also propose an algorithm for inhaled corticosteroid use, taking into consideration eosinophil counts and pneumonia history, and emerging eosinophil-targeted therapies in COPD., Competing Interests: Disclosure DPT has served on advisory boards for AstraZeneca, Novartis, and Sunovion, as a speaker for Boehringer-Ingelheim, and as a consultant for Theravance/Innoviva. MEW has served as a consultant for Ambit Bioscience, AstraZeneca, Boehringer-Ingelheim, BSCI, Genentech, Gilacure, GlaxoSmithKline, Meda, Mylan, Neurotronic, Novartis, Regeneron, Sanofi, Sunovion, Teva, Theravance, Tunitas, and Vectura, received research funding from Sanofi, served on an advisory board for Teva, was a DSMB member for Sentien, and received honoraria from BSCI. The authors report no other conflicts of interest in this work.

Background: Prevention of exacerbations is a primary goal for chronic obstructive pulmonary disease (COPD) therapy. This randomized, double-blind, double-dummy, parallel-group, multicenter study evaluated the effect of budesonide/formoterol pressurized metered-dose inhaler (pMDI) versus formoterol dry powder inhaler (DPI) on reducing COPD exacerbations., Methods: 1219 patients aged ≥40 years with moderate-to-very-severe COPD (per lung function) and a history of ≥1 COPD exacerbation received budesonide/formoterol pMDI 320/9 μg twice daily (BID) during a 4-week run-in. Patients were then randomized 1:1 to receive budesonide/formoterol pMDI 320/9 μg BID (n = 606) or formoterol DPI 9 μg BID (n = 613) for 26 weeks. Exacerbations were identified using predefined criteria for symptom worsening and treatment with systemic corticosteroids and/or antibiotics and/or hospitalization. The primary endpoint was annual rate of exacerbations., Results: Budesonide/formoterol pMDI resulted in a 24% reduction in annual rate of exacerbations (0.85 vs 1.12; rate ratio: 0.76 [95% CI: 0.62, 0.92]; P = 0.006), and a significant risk reduction for time to first exacerbation (hazard ratio: 0.78 [95% CI: 0.64, 0.96]; P = 0.016) versus formoterol DPI. The most commonly reported adverse events (AEs; ≥3%) in budesonide/formoterol and formoterol groups were COPD (4.5% vs 8.6%) and nasopharyngitis (5.0% vs 5.2%). Pneumonia AEs were reported in 0.5% and 1.0% of budesonide/formoterol-treated and formoterol-treated patients, respectively., Conclusions: Budesonide/formoterol pMDI is an effective treatment option for reducing exacerbation rates in COPD patients with moderate-to-very-severe airflow limitation and history of exacerbations. No increase in pneumonia was observed with budesonide/formoterol; safety data were consistent with its established profile., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Present treatment strategies to stratify exacerbation risk in patients with chronic obstructive pulmonary disease (COPD) rely on a history of two or more events in the previous year. We aimed to understand year to year variability in exacerbations and factors associated with consistent exacerbations over time., Methods: In this longitudinal, prospective analysis of exacerbations in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort, we analysed patients aged 40-80 years with COPD for whom 3 years of prospective data were available, identified through various means including care at academic and non-academic medical centres, word of mouth, and existing patient registries. Participants were enrolled in the study between Nov 12, 2010, and July 31, 2015. We classified patients according to yearly exacerbation frequency: no exacerbations in any year; one exacerbation in every year during 3 years of follow-up; and those with inconsistent exacerbations (individuals who had both years with exacerbations and years without during the 3 years of follow-up). Participants were characterised by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric category (1-4) on the basis of post-bronchodilator FEV 1 . Stepwise logistic regression was used to compare factors associated with one or more acute exacerbations of COPD every year for 3 years versus no exacerbations in the same timeframe. Additionally, a stepwise zero-inflated negative binomial model was used to assess predictors of exacerbation count during follow-up in all patients with available data. Baseline symptom burden was assessed with the COPD assessment test. This trial is registered with ClinicalTrials.gov, number NCT01969344., Findings: 2981 patients were enrolled during the study. 1843 patients had COPD, of which 1105 patients had 3 years of complete, prospective follow-up data. 538 (49%) of 1105 patients had at least one acute exacerbation during the 3 years of follow-up, whereas 567 (51%) had none. 82 (7%) of 1105 patients had at least one acute exacerbation each year, whereas only 23 (2%) had two or more acute exacerbations in each year. An inconsistent pattern (both years with and without acute exacerbations) was common (456 [41%] of the group), particularly among GOLD stages 3 and 4 patients (256 [56%] of 456). In logistic regression, consistent acute exacerbations (≥1 event per year for 3 years) were associated with higher baseline symptom burden, previous exacerbations, greater evidence of small airway abnormality on CT, lower interleukin-15 concentrations, and higher interleukin-8 concentrations, than were no acute exacerbations., Interpretation: Although acute exacerbations are common, the exacerbation status of most individuals varies markedly from year to year. Among patients who had any acute exacerbation over 3 years, very few repeatedly had two or more events per year. In addition to symptoms and history of exacerbations in the year before study enrolment, we identified several novel biomarkers associated with consistent exacerbations, including CT-defined small airway abnormality, and interleukin-15 and interleukin-8 concentrations., Funding: National Institutes of Health, and National Heart, Lung, and Blood Institute., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: COPD exacerbations are associated with accelerated lung function decline, but whether they are causal is unknown. We evaluated the effect of a single exacerbation on rate of lung function change using data from the 4-year Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT ® ) trial., Methods: Retrospective analysis of annual rates of decline in FEV 1 and FVC before and after a single (and the only) moderate-to-severe exacerbation in patients during UPLIFT ® (exacerbator subgroup), compared with changes between the first and second half of the study in a non-exacerbator subgroup. A sensitivity analysis examined annual rates of decline in matched pairs of exacerbators and non-exacerbators., Results: Following the single moderate-to-severe exacerbation, mean annual decline in post-bronchodilator lung function increased compared with the rate of decline before the exacerbation (FEV 1 76.5 vs. 39.1 mL/year, p = 0.003; FVC 106.5 vs. 34.7 mL/year, p = 0.011). In non-exacerbators, there were no differences in rates of decline between the first and second halves of the study (post-bronchodilator FEV 1 38.2 vs. 41.8 mL/year, FVC 45.3 vs. 43.9 mL/year. Before the single (moderate-to-severe) exacerbation in the exacerbator subgroup, declines in post-bronchodilator FEV 1 or FVC were similar to non-exacerbators in the first half of the study; after the single exacerbation they were significantly higher than for non-exacerbators in the second half of the study. The sensitivity analysis showed similar results., Conclusion: A single COPD exacerbation may result in significant increase in the rate of decline in lung function., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Rationale: Ever-smokers without airflow obstruction scores greater than or equal to 10 on the COPD Assessment Test (CAT) still have frequent acute respiratory disease events (exacerbation-like), impaired exercise capacity, and imaging abnormalities. Identification of these subjects could provide new opportunities for targeted interventions., Objectives: We hypothesized that the four respiratory-related items of the CAT might be useful for identifying such individuals, with discriminative ability similar to CAT, which is an eight-item questionnaire used to assess chronic obstructive pulmonary disease impact, including nonrespiratory questions, with scores ranging from 0 to 40., Methods: We evaluated ever-smoker participants in the Subpopulations and Intermediate Outcomes in COPD Study without airflow obstruction (FEV 1 /FVC ≥0.70; FVC above the lower limit of normal). Using the area under the receiver operating characteristic curve, we compared responses to both CAT and the respiratory symptom-related CAT items (cough, phlegm, chest tightness, and breathlessness) and their associations with longitudinal exacerbations. We tested agreement between the two strategies (κ statistic), and we compared demographics, lung function, and symptoms among subjects identified as having high symptoms by each strategy., Results: Among 880 ever-smokers with normal lung function (mean age, 61 yr; 52% women) and using a CAT cutpoint greater than or equal to 10, we classified 51.8% of individuals as having high symptoms, 15.3% of whom experienced at least one exacerbation during 1-year follow-up. After testing sensitivity and specificity of different scores for the first four questions to predict any 1-year follow-up exacerbation, we selected cutpoints of 0-6 as representing a low burden of symptoms versus scores of 7 or higher as representing a high burden of symptoms for all subsequent comparisons. The four respiratory-related items with cutpoint greater than or equal to 7 selected 45.8% participants, 15.6% of whom experienced at least one exacerbation during follow-up. The two strategies largely identified the same individuals (agreement, 88.5%; κ = 0.77; P < 0.001), and the proportions of high-symptoms subjects who had severe dyspnea were similar between CAT and the first four CAT questions (25.9% and 26.8%, respectively), as were the proportions reporting impaired quality of life (66.9% and 70.5%, respectively) and short walking distance (22.4% and 23.1%, respectively). There was no difference in area under the receiver operating characteristic curve to predict 1-year follow-up exacerbations (CAT score ≥10, 0.66; vs. four respiratory items from CAT ≥7 score, 0.65; P = 0.69). Subjects identified by either method also had more depression/anxiety symptoms, poor sleep quality, and greater fatigue., Conclusions: Four CAT items on respiratory symptoms identified high-risk symptomatic ever-smokers with preserved spirometry as well as the CAT did. These data suggest that simpler strategies can be developed to identify these high-risk individuals in primary care.

Background: The long-term safety and efficacy of a novel Co-Suspension™ Delivery Technology glycopyrrolate (GP)/formoterol fumarate (FF) 18/9.6 μg fixed-dose combination metered dose inhaler (GFF MDI) were investigated in a 28-week safety extension study (PINNACLE-3, NCT01970878) of two randomized controlled Phase III trials (PINNACLE-1 and -2; NCT01854645 and NCT01854658) in subjects with moderate-to-very severe chronic obstructive pulmonary disease (COPD)., Methods: Subjects completing 24 weeks' treatment with GFF MDI, GP MDI, FF MDI (all twice-daily) or open-label tiotropium 18 μg (once-daily) in PINNACLE-1 or -2 were randomly selected to continue treatment for 28 weeks. The target enrollment for PINNACLE-3 was 850 subjects. Safety and efficacy were evaluated over 52 weeks., Results: Of 3274 subjects randomized to active treatment in PINNACLE-1 or -2, 892 entered PINNACLE-3. Incidences of adverse events, serious adverse events and major adverse cardiovascular events were similar across treatment groups with no unexpected safety findings. For change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV 1 ), treatment differences for GFF MDI versus GP MDI, FF MDI and open-label tiotropium over 52 weeks were 57, 65 and 25 mL, respectively (p ≤ 0.0117). Average daily rescue medication use was significantly reduced for GFF MDI versus GP MDI and open-label tiotropium (p ≤ 0.0002). Statistically significant improvements were observed with GFF MDI versus monocomponents in Self-Administered Computerized Transition Dyspnea Index focal score, and in St George's Respiratory Questionnaire total score versus GP MDI., Conclusions: Results confirmed the long-term safety and tolerability of GFF MDI 18/9.6 μg twice-daily in subjects with moderate-to-very severe COPD. Improvements in efficacy endpoints were also sustained over 52 weeks., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Improving health-related quality of life (HRQoL) in COPD patients is an important pharmacotherapeutic objective. This study investigated the extent, consistency, and durability of tiotropium maintenance therapy impact on HRQoL in moderate-to-very severe COPD., Methods: Patients received once-daily tiotropium 18 μg (n = 5244) or placebo (n = 4799) via HandiHaler ® (10 trials), or once-daily tiotropium 5 μg (n = 2622) or placebo (n = 2618) via Respimat ® inhaler (3 trials). St George's Respiratory Questionnaire (SGRQ) total scores were measured at baseline, and 6 months (13 trials) and 1 year (9 trials) from treatment start. Adjusted mean differences between treatments for change from baseline in total scores were calculated at each time-point for each trial. Responder and deteriorator rates (decrease or increase in score ≥4 units from baseline, respectively), net benefit (responder rate increase plus deteriorator rate decrease), and cumulative improvement and deterioration were determined., Results: Adjusted mean total score differences between treatments for change from baseline were significant (p < 0.05) in favor of tiotropium in 10/13 trials at 6 months and in 8/9 trials at 1 year. In all trials, estimated differences in responder rates between treatments favored tiotropium (significant [p < 0.05]: 5/13 trials at 6 months; 8/9 trials at 1 year). Net benefit favored tiotropium and cumulative improvement rates were consistently greater and deterioration rates consistently lower for tiotropium versus placebo., Conclusions: Tiotropium maintenance therapy significantly and consistently improved HRQoL in moderate-to-very severe COPD patients in a durable manner. These results may provide a benchmark for assessing benefits on HRQoL of other COPD treatments., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Current guidelines recommend inhaled pharmacologic therapy as the preferred route of administration for treating COPD. Bronchodilators (β 2 -agonists and antimuscarinics) are the mainstay of pharmacologic therapy in patients with COPD, with long-acting agents recommended for patients with moderate to severe symptoms or those who are at a higher risk for COPD exacerbations. Dry powder inhalers and pressurized metered dose inhalers are the most commonly used drug delivery devices, but they may be inadequate in various clinical scenarios (eg, the elderly, the cognitively impaired, and hospitalized patients). As more drugs become available in solution formulations, patients with COPD and their caregivers are becoming increasingly satisfied with nebulized drug delivery, which provides benefits similar to drugs delivered by handheld inhalers in both symptom relief and improved quality of life. This article reviews recent innovations in nebulized drug delivery and the important role of nebulized therapy in the treatment of COPD.

Background: Currently, the diagnosis of chronic obstructive pulmonary disease (COPD) requires a ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) of less than 0.70 as assessed by spirometry after bronchodilator use. However, many smokers who do not meet this definition have respiratory symptoms., Methods: We conducted an observational study involving 2736 current or former smokers and controls who had never smoked and measured their respiratory symptoms using the COPD Assessment Test (CAT; scores range from 0 to 40, with higher scores indicating greater severity of symptoms). We examined whether current or former smokers who had preserved pulmonary function as assessed by spirometry (FEV1:FVC ≥0.70 and an FVC above the lower limit of the normal range after bronchodilator use) and had symptoms (CAT score, ≥10) had a higher risk of respiratory exacerbations than current or former smokers with preserved pulmonary function who were asymptomatic (CAT score, <10) and whether those with symptoms had different findings from the asymptomatic group with respect to the 6-minute walk distance, lung function, or high-resolution computed tomographic (HRCT) scan of the chest., Results: Respiratory symptoms were present in 50% of current or former smokers with preserved pulmonary function. The mean (±SD) rate of respiratory exacerbations among symptomatic current or former smokers was significantly higher than the rates among asymptomatic current or former smokers and among controls who never smoked (0.27±0.67 vs. 0.08±0.31 and 0.03±0.21 events, respectively, per year; P<0.001 for both comparisons). Symptomatic current or former smokers, regardless of history of asthma, also had greater limitation of activity, slightly lower FEV1, FVC, and inspiratory capacity, and greater airway-wall thickening without emphysema according to HRCT than did asymptomatic current or former smokers. Among symptomatic current or former smokers, 42% used bronchodilators and 23% used inhaled glucocorticoids., Conclusions: Although they do not meet the current criteria for COPD, symptomatic current or former smokers with preserved pulmonary function have exacerbations, activity limitation, and evidence of airway disease. They currently use a range of respiratory medications without any evidence base. (Funded by the National Heart, Lung, and Blood Institute and the Foundation for the National Institutes of Health; SPIROMICS ClinicalTrials.gov number, NCT01969344.).

Background: Chronic obstructive pulmonary disease (COPD) clinical trials evaluating hard endpoints (mortality, hospitalized exacerbations) require a large number of subjects and prolonged observational periods. We hypothesized that a composite endpoint of respiratory outcomes (CERO) can help evaluate safety and benefit in COPD trials., Methods: Retrospective analysis of 5992 patients enrolled in the 4-year UPLIFT® trial, a randomized trial of tiotropium versus placebo in patients with moderate-to-severe COPD. Patients were permitted to continue using their usual COPD medications except for other anticholinergics. The CERO included deaths, respiratory failure, hospitalized exacerbations, and trial dropout due to COPD worsening. The incidence rates (IRs) per 100 patient-years and risk ratios (RRs and 95 % CI) were determined at years 1 to 4. The effect of treatments on CERO was similarly assessed. A power analysis helped calculate the sample size needed to achieve outcome differences between treatments., Results: The CERO IRs at years 1 to 4 for tiotropium versus placebo were 16, 13, 11, and 11, and 21, 16, 14, and 13, respectively. The RRs of CERO between tiotropium and placebo at the same time points were: RR-year 0.76 (0.67, 0.86), 0.80 (0.72, 0.88), 0.81 (0.74, 0.89), and 0.84 (0.77, 0.92). Using the IRs and RRs, the sample size (alpha = 0.05 two-sided, 90 % power) for studies of 1, 2, 3, and 4 years would be 1546, 1392, 1216, and 1504 per treatment group, respectively, with 575, 810, 930, 1383 required events, respectively, for hypothetical, event-driven studies., Conclusions: A composite endpoint incorporating relatively infrequent serious or significant COPD-related safety outcomes could be useful in clinical trials. In UPLIFT®, CERO events were significantly reduced in patients receiving tiotropium compared with placebo., Trial Registration: NCT00144339 .

Smoking cessation is the most effective strategy for slowing down the progression of chronic obstructive pulmonary disease (COPD) and reducing mortality in the approximately 50% of patients with diagnosed COPD who continue to smoke. While behavioral interventions (including simple advice) have modest efficacy in improving smoking quit rates, the combination of counseling and pharmacotherapy is more effective than either alone. When combined with even brief counseling, nicotine replacement therapy (NRT), bupropion SR, and varenicline have all been shown to be effective in promoting smoking cessation and sustained abstinence in smokers with COPD to a degree comparable to that observed in the general smoking population. However, the recidivism rate is high after initial quitting so that at the end of 1 year, approximately 80% or more of patients are still smoking. Thus, new approaches to smoking cessation are needed. One approach is to combine different pharmacotherapies, for example, nicotine patch plus rapidly acting NRT (e.g., gum or nasal spray) and/or bupropion or even varenicline plus either NRT or bupropion, in a stepwise approach over a varying duration depending on the severity of nicotine dependence and nicotine withdrawal symptoms during the quit attempt, as proposed in the American College of Chest Physicians Tobacco Dependence Took Kit. Electronic (e)-cigarettes, which deliver vaporized nicotine without most of the noxious components in the smoke from burning tobacco cigarettes, also has potential efficacy as a smoking cessation aid, but their efficacy and safety as either substitutes for regular cigarettes or smoking cessation aids require additional study. This task is complicated because e-cigarettes are currently unregulated and hundreds of different brands are currently available., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Tiotropium is an anticholinergic bronchodilator for symptom relief and reducing exacerbations with an established safety profile in patients with chronic obstructive pulmonary disease (COPD). Using data from the 4-year Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) study, we re-evaluated the safety of tiotropium HandiHaler® in patients who experienced recent myocardial infarction (MI), heart failure or unstable rhythm disorder during the study., Methods: A post-hoc analysis of all-cause mortality and serious cardiac adverse events (cardiac SAEs), including cardiac deaths and death unknown, was conducted in patients who had experienced cardiac arrhythmia, MI or cardiac failure during UPLIFT® and who completed the study. Descriptive analyses were performed., Results: Most patients experiencing cardiac events, for which they would have been excluded at baseline, remained in the trial. Kaplan-Meier analyses revealed a trend to later occurrence of cardiac SAEs with tiotropium HandiHaler® versus placebo. Patients who experienced a cardiac event and continued in UPLIFT® were not found to be at subsequently increased risk of all-cause mortality or cardiac SAEs with tiotropium treatment. Evaluation of deaths by major adverse cardiac events composite endpoints also showed that patients treated with tiotropium were not at increased risk of mortality or cardiac SAEs compared with placebo., Conclusions: Risk of cardiac events, mortality or SAEs was not increased by tiotropium in patients experiencing cardiac events for which they would have been excluded at study baseline. The findings support the cardiac safety of tiotropium HandiHaler® in patients with COPD.