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Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide.1,2 Patients with COPD often experience exacerbations which are defined as periods of acute worsening of respiratory symptoms necessitating additional treatment.3 Exacerbations contribute to the overall disease burden experienced by patients with COPD, with patients with frequent or prolonged exacerbations shown to have worse health status and faster disease progression compared with patients with infrequent exacerbations.4 Additionally, exacerbations are also associated with increased medical costs and health care resource utilization, with the highest clinical and financial burden associated with severe exacerbations requiring hospitalization.5-8 Finally, as well as recent prior COPD exacerbations being a risk factor for future exacerbations,3,9,10 studies have indicated that exacerbations are associated with an increased risk of all-cause mortality,10-13 and adverse cardiovascular (CV) events.14-16 The InforMing the Pathway of COPD Treatment (IMPACT) trial evaluated once-daily single-inhaler triple therapy with inhaled corticosteroid (ICS) /long-acting muscarinic receptor antagonist (LAMA) /long-acting beta2-agonist (LABA), fluticasone furoate/umeclidinium/vilanterol versus dual therapy with ICS/LABA, fluticasone furoate/vilanterol, or LAMA/LABA, umeclidinium/vilanterol, in patients with symptomatic COPD and a history of exacerbations.17 Treatment with fluticasone furoate/umeclidinium/vilanterol significantly reduced the annual rate of moderate/severe exacerbations versus fluticasone furoate/vilanterol and umeclidinium/vilanterol,17 in addition to a significant reduction in all-cause mortality with fluticasone furoate/umeclidinium/vilanterol compared with umeclidinium/vilanterol.18 Despite these observed benefits, previous studies have indicated that the use of ICSs may be associated with an increased risk of pneumonia in patients with COPD.17,19-21 Howev, Background: In the InforMing the Pathway of COPD Treatment (IMPACT) trial, single -inhaler fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) significantly reduced severe exacerbation rates and all -cause mortality (ACM) risk versus UMEC/VI among patients with chronic obstructive pulmonary disease (COPD). This post hoc analysis aimed to define the risk of ACM during and following a moderate/severe exacerbation, and further determine the benefit -risk profile of FF/UMEC/VI versus FF/VI and UMEC/VI using a cardiopulmonary composite adverse event (AE) endpoint. Methods: The 52 -week, double-blind IMPACT trial randomized patients with symptomatic COPD and & GE;1 exacerbation in the prior year 2:2:1 to once -daily FF/UMEC/VI 100/62.5/25mcg, FF/VI 100/25mcg, or UMEC/VI 62.5/25mcg. Post hoc endpoints included the risk of ACM during, 1-90 and 91-365 days post moderate or severe exacerbation and time -to -first cardiopulmonary composite event. Results: Of the 10,355 patients included, 5034 (49%) experienced moderate/severe exacerbations. Risk of ACM was significantly increased during a severe exacerbation event compared with baseline (hazard ratio [HR]: 41.22 [95% confidence interval (CI) 26.49-64.15]; p < 0.001) but not significantly different at 1-90 days post -severe exacerbation (HR: 2.13 [95% CI: 0.86-5.29]; p=0.102). Moderate exacerbations did not significantly increase the risk of ACM during or after an exacerbation. Cardiopulmonary composite events occurred in 647 (16%), 636 (15%), and 356 (17%) patients receiving FF/UMEC/VI, FF/VI, and UMEC/VI, respectively; FF/UMEC/VI significantly reduced cardiopulmonary composite event risk versus UMEC/VI by 16.5% (95% CI: 5.0-26.7; p=0.006). Conclusion: Results confirm a substantial mortality risk during severe exacerbations, and an underlying CV risk. FF/UMEC/VI significantly reduced the risk of a composite cardiopulmonary AE versus UMEC/VI.

BACKGROUND: The association between chronic obstructive pulmonary disease exacerbations and increased cardiovascular event risk has not been adequately studied in a heterogenous population with both low and high cardiovascular risk. METHODS AND RESULTS: This post hoc analysis of the IMPACT (Informing the Pathway of COPD Treatment) trial (N=10 355 symptomatic patients with chronic obstructive pulmonary disease at risk of exacerbations) evaluated time-dependent risk of cardiovascular adverse events of special interest (CVAESI) following exacerbations and impact of exacerbation history, cardiovascular risk factors, and study treatment on this association. Risk (time-to-first) of CVAESI or CVAESI resulting in hospitalization or death was assessed during and 1 to 30, 31 to 90, and 91 to 365 days after resolution of moderate or severe exacerbations. CVAESI risk was compared between the period before and during/after exacerbation. CVAESI risk increased significantly during a moderate (hazard ratio [HR], 2.63 [95% CI, 2.08– 3.32]) or severe (HR, 21.84 [95% CI, 17.71– 26.93]) exacerbation and remained elevated for 30 days following an exacerbation (moderate: HR, 1.63 [95% CI, 1.28– 2.08]; severe: HR, 1.75 [95% CI, 0.99– 3.11; nonsignificant]) and decreased over time, returning to baseline by 90 days. Risk of CVAESI resulting in hospitalization or death also increased during an exacerbation (moderate: HR, 2.46 [95% CI, 1.53– 3.97]; severe: HR, 41.29 [95% CI, 30.43– 56.03]) and decreased in a similar time-dependent pattern. Results were consistent regardless of exacerbation history, cardiovascular risk at screening, or study treatment. CONCLUSIONS: Overall risk of cardiovascular events was higher during and in the 30 days following chronic obstructive pulmonary disease exacerbations, even among those with low cardiovascular risk, highlighting the need for exacerbation prevention and vigilance for cardiovascular events following exacerbations. REGISTRATION: URL: https://clin

Reynold A Panettieri Jr,1 Carlos A Camargo Jr,2 Tariq Cheema,3 Sherif G El Bayadi,4 Stanley Fiel,5 Tania M Vila,6 Renu G Jain,6 Dawn Midwinter,7 Byron Thomashow,8 Andrea Ludwig-Sengpiel,9 David A Lipson10,11 1Child Health Institute of New Jersey, Rutgers University School of Medicine, New Brunswick, NJ, USA; 2Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 3Breathing Disorder Center, Allegheny Health Network, Pittsburgh, PA, USA; 4Department of Medicine, St. Joseph’s Health/SUNY Upstate, Syracuse, NY, USA; 5Atlantic Health Systems/Morristown Medical Center, Morristown, NJ, 07960, USA; 6GSK, Research Triangle Park, NC, USA; 7GSK, Brentford, UK; 8Department of Medicine, Columbia University Medical Center, New York, NY, USA; 9KLB Gesundheitsforschung Lübeck GmbH, Lübeck, Germany; 10Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 11GSK, Collegeville, PA, USACorrespondence: Reynold A Panettieri Jr, Rutgers University School of Medicine, 89 French Street, Suite 4210, New Brunswick, NJ, 08901, USA, Tel +1 732-235-6404, Email rp856@rbhs.rutgers.eduBackground: In the FULFIL trial, once-daily single-inhaler triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) resulted in reduced moderate/severe exacerbation rates and conferred significant improvements in lung function and health status in patients with chronic obstructive pulmonary disease (COPD) versus twice-daily budesonide/formoterol (BUD/FOR) dual therapy.Methods: FULFIL was a Phase III, randomized, double-blind, double-dummy, parallel-group study. Patients ≥ 40 years of age with symptomatic COPD were randomized 1:1 to FF/UMEC/VI 100/62.5/25 mcg or BUD/FOR 400/12 mcg. In this post hoc analysis, patients were categorized by exacerbation history in the year prior to study entry (≥ 1 moderate/severe exacerbation [recent exacerbation] versus no recent exacerbation). Endpoints included annual rate of on-tr

David MG Halpin,1 Robyn Kendall,2 Soham Shukla,3 Alan Martin,4 Dhvani Shah,5 Dawn Midwinter,6 Kai M Beeh,7 Janwillem WH Kocks,8– 11 Paul W Jones,12 Chris Compton,12 Nancy A Risebrough,13 Afisi S Ismaila3,14 1University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK; 2ICON Health Economics, ICON plc, Vancouver, BC, Canada; 3Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 4Value Evidence and Outcomes, GSK, Uxbridge, UK; 5ICON Health Economics, ICON plc, New York, NY, USA; 6Biostatistics, GSK, Brentford, UK; 7Insaf Respiratory Research Institute, Wiesbaden, Germany; 8General Practitioners Research Institute, Groningen, the Netherlands; 9Observational and Pragmatic Research Institute, Singapore; 10Groningen Research Institute Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 11Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 12Global Respiratory Franchise, GSK, Brentford, UK; 13ICON Health Economics, ICON plc, Toronto, ON, Canada; 14Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, CanadaCorrespondence: David MG Halpin, University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, EX1 2LU, UK, Tel +44 01392 201178, Email d.halpin@nhs.netPurpose: The 24-week INTREPID trial demonstrated the clinical benefits of once-daily single-inhaler triple therapy (SITT) with fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI) versus non-ELLIPTA multiple-inhaler triple therapy (MITT) in patients with symptomatic chronic obstructive pulmonary disease (COPD). This analysis assessed the cost-effectiveness of FF/UMEC/VI versus non-ELLIPTA MITT for the treatment of symptomatic COPD from a United Kingdom (UK) National Health Service (NHS) perspective.Patients and Methods: The analysis was conducted using the valid

Inhaled corticosteroids (ICS) have a class effect of increasing pneumonia risk in patients with COPD. However, pneumonia incidence varies widely across clinical trials of ICS use in COPD. This review clarifies methodological differences in defining and recording pneumonia events in these trials and discusses factors that could contribute to the varying pneumonia incidence. Literature searches and screening yielded 40 relevant references for inclusion. Methods used to capture pneumonia events in these studies included investigator-reported pneumonia adverse events, standardised list of signs or symptoms, radiographic confirmation of suspected cases and/or confirmation by an independent clinical end-point committee. In general, more stringent pneumonia diagnosis criteria led to lower reported pneumonia incidence rates. In addition, studies varied in design and population characteristics, including exacerbation history and lung function, factors that probably contribute to the varying pneumonia incidence. As such, cross-trial comparisons are problematic. A minimal set of standardised criteria for diagnosis and reporting of pneumonia should be used in COPD studies, as well as reporting of patients' pneumonia history at baseline, to allow comparison of pneumonia rates between trials. Currently, within-trial comparison of ICS-containing versus non-ICS-containing treatments is the appropriate method to assess the influence of ICS on pneumonia incidence.

Benjamin D Horne,1,2 Rehan Ali,3 Dawn Midwinter,3 Catherine Scott-Wilson,4 Courtney Crim,4 Bruce E Miller,5 David B Rubin4 1Intermountain Medical Center Heart Institute, Salt Lake City, UT, USA; 2Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, USA; 3GlaxoSmithKline Plc., Uxbridge, UK; 4GlaxoSmithKline Plc., Research Triangle Park, Raleigh, NC, USA; 5GlaxoSmithKline Plc., Collegeville, PA, USACorrespondence: Benjamin D HorneIntermountain Medical Center Heart Institute, 5121 S Cottonwood Street, Salt Lake City, UT 84107, USAEmail benjamin.horne@imail.orgIntroduction: The presence of cardiovascular (CV) risk factors and CV disease in patients with chronic obstructive pulmonary disease (COPD) leads to worse outcomes. A number of tools are currently available to stratify the risk of adverse outcomes in these patients with COPD. This post hoc analysis evaluated the Summit Lab Score for validation as a predictor of the first episode of moderate-to-severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and other outcomes, in patients with COPD and high arterial pulse wave velocity (aPWV).Methods: Data from a multicenter, randomized, placebo-controlled, double-blind study were retrospectively analyzed to evaluate treatment effects of once-daily fluticasone furoate/vilanterol 100/25 μg in patients with COPD and an elevated CV risk (aPWV≥ 11m/s) over 24 weeks. The previously derived Summit Lab Score and, secondarily, the Intermountain Risk Score (IMRS) were computed for each patient, with patients then stratified into tertiles for each score. Risk of moderate-to-severe AECOPD was analyzed across tertiles using Kaplan–Meier survival curve and Cox regression analyses.Results: In 430 patients with COPD, Kaplan–Meier probabilities of no moderate-to-severe AECOPD for Summit Lab Score tertiles 1, 2, and 3 were 92.3%, 95.5%, and 85.1%, respectively (P trend = 0.015), over 24 weeks.

David J Collier,1,2 Pascal Wielders,3 Job van der Palen,4,5 Logan Heyes,6 Dawn Midwinter,6 Kathryn Collison,7 Andy Preece,6 Neil Barnes,1,6 Raj Sharma6 1William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, UK; 2Wolfson Institute of Preventive Medicine, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, UK; 3Department of Pulmonary Diseases, Catharina Hospital, Eindhoven, Netherlands; 4Department of Pulmonology, Medisch Spectrum Twente, Enschede, Netherlands; 5Department of Research Methodology, Measurement, and Data Analysis, University of Twente, Enschede, Netherlands; 6Respiratory Therapy Area Unit, GlaxoSmithKline Plc., Stockley Park, Uxbridge, UK; 7Respiratory Medical Franchise, GlaxoSmithKline Plc., Research Triangle Park, Durham, NC, USACorrespondence: David J CollierWilliam Harvey Research Institute Clinical Research Centre, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UKTel +44 7961 383925 Fax +44 207 253 1901 Email d.j.collier@qmul.ac.ukIntroduction: Training in correct inhaler use, ideally in person or by video demonstration, can minimize errors but is rarely provided in clinics. This open-label, low-intervention study evaluated critical error rates with dry-powder inhalers (DPIs), before and after training, in patients with chronic obstructive pulmonary disease.Methods: Patients prescribed an inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) (ELLIPTA, Turbuhaler, or DISKUS), long-acting muscarinic antagonist (LAMA)/LABA (ELLIPTA or Breezhaler), or LAMA-only DPI (ELLIPTA, HandiHaler, or Breezhaler) were enrolled. Critical errors were assessed before training (Visit 1 [V1]; primary endpoint) and 6 weeks thereafter (Visit 2 [V2]; secondary endpoint). Logistic regression models were used to calculate odds

Neil Barnes,1,2 Takeo Ishii,3,4 Nobuyuki Hizawa,5 Dawn Midwinter,6 Mark James,3 Emma Hilton,1 Paul Jones1,71Respiratory Medicine Franchise, GlaxoSmithKline, Brentford, UK; 2William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, London, UK; 3Medical Affairs, GlaxoSmithKline K.K., Tokyo, Japan; 4Graduate School of Medicine, Nippon Medical School, Tokyo, Japan; 5Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan; 6Global Respiratory Department, GlaxoSmithKline, Stockley Park, UK; 7Institute of Infection and Immunity, St George’s University of London, London, UK Background: Blood eosinophil measurements may help to guide physicians on the use of inhaled corticosteroids (ICS) for patients with chronic obstructive pulmonary disease (COPD). Emerging data suggest that COPD patients with higher blood eosinophil counts may be at higher risk of exacerbations and more likely to benefit from combined ICS/long-acting beta2-agonist (LABA) treatment than therapy with a LABA alone. This analysis describes the distribution of blood eosinophil count at baseline in Japanese COPD patients in comparison with non-Japanese COPD patients.Methods: A post hoc analysis of eosinophil distribution by percentage and absolute cell count was performed across 12 Phase II–IV COPD clinical studies (seven Japanese studies [N=848 available absolute eosinophil counts] and five global studies [N=5,397 available eosinophil counts] that included 246 Japanese patients resident in Japan with available counts). Blood eosinophil distributions were assessed at baseline, before blinded treatment assignment.Findings: Among Japanese patients, the median (interquartile range) absolute eosinophil count was 170 cells/mm3 (100–280 cells/mm3). Overall, 612/1,094 Japanese patients (56%) had an absolute eosinophil count ≥150 cells/mm3 and 902/1,304 Japanese patients (69%) had a percentage eosinophil &

Job van der Palen,1,2 Wendy Moeskops-van Beurden,1 Carolyn M Dawson,3 Wai-Yee James,3 Andrew Preece,4 Dawn Midwinter,4 Neil Barnes,5 Raj Sharma6 1Department of Pulmonology, Medisch Spectrum Twente, Enschede, the Netherlands; 2Department of Research Methodology, Measurement, and Data Analysis, University of Twente, Enschede, the Netherlands; 3William Harvey Heart Centre, St Bartholomew Hospital, London, UK; 4Respiratory Therapy Area Unit, GlaxoSmithKline, Stockley Park, UK; 5Medical Department, GlaxoSmithKline, Brentford, UK; 6Respiratory Medical Franchise, GlaxoSmithKline, Brentford, UK Background: Administering maintenance COPD therapy with a combination of multiple inhalers may increase inhaler errors. This study evaluated the potential benefits of using a single Ellipta dry powder inhaler (DPI) compared with two combinations of DPIs commonly used to deliver triple maintenance therapy.Methods: Patients receiving inhaled COPD medication were enrolled in this multicenter, randomized, open-label, placebo-device, crossover study with a 2×2 complete block design (NCT0298218), which comprised two substudies: Ellipta vs Diskus + HandiHaler (substudy 1) or Turbuhaler + HandiHaler (substudy 2). Patients demonstrated inhaler use after reading the relevant patient information leaflet (PIL). A trained investigator assessed user errors (critical errors [errors likely to result in no or significantly reduced medication being inhaled] and overall errors). The primary endpoint was the proportion of patients making ≥1 critical error after reading the PIL. The secondary endpoints included error rates during ≤2 reassessments following investigator instruction (if required), instruction time, and patient preference.Results: After reading the PIL, significantly fewer patients made critical errors with Ellipta compared with Diskus + HandiHaler (9% [7/80] vs 75% [60/80], respectively; P<0.001) or Turbuhaler&

Surya P Bhatt,1 Mark T Dransfield,1 John R Cockcroft,2 Jie Wang-Jairaj,3 Dawn A Midwinter,3 David B Rubin,4 Catherine A Scott-Wilson,4 Courtney Crim4 1Division of Pulmonary, Allergy and Critical Care Medicine and UAB Lung Health Center, University of Alabama at Birmingham, Birmingham, AL, USA; 2Department of Cardiology, Wales Heart Research Institute, Cardiff, 3GSK, Stockley Park, Uxbridge, UK; 4GSK, Research Triangle Park, NC, USA Introduction: Chronic obstructive pulmonary disease (COPD) is associated with increased cardiovascular morbidity and mortality. Elevated arterial stiffness, measured by aortic pulse wave velocity (aPWV), is a cardiovascular risk surrogate and is potentially modifiable by inhaled corticosteroid/long-acting beta2-agonist combinations in patients with COPD.Materials and methods: The effects of once-daily inhaled fluticasone furoate/vilanterol (FF/VI) 100/25 µg, VI 25 µg, versus placebo on arterial stiffness in patients with COPD and baseline aPWV ≥11.0 m/s were investigated in a 24-week, multicenter, double-blind, randomized, stratified (by COPD exacerbation history), parallel-group, placebo-controlled trial. Eligible patients were ≥40 years old, with ≥10 pack-year smoking history, forced expiratory volume in 1 s (FEV1)/forced vital capacity ≤0.70, and post-bronchodilator FEV1 ≤70% of predicted. Patients with a major cardiovascular event in the previous 6 months/current severe heart failure/uncontrolled hypertension were excluded. Primary endpoint is change from baseline in aPWV after 24 weeks of treatment. Safety analyses included adverse events (AEs).Results: The intent-to-treat population included 430 patients: FF/VI (n=135), VI (n=154), and placebo (n=141). Patients were predominantly male (79%) and Asian or White (each 48%), with a mean age of 68.5 years (standard deviation [SD] =7.9), percentage predicted post-bronchodilator FEV1 50.1% (SD =13.3), and aPWV 13.26 m/s (SD =2.22) at s