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Peter Alter,1 Kathrin Kahnert,2,3 Franziska C Trudzinski,4 Robert Bals,5 Henrik Watz,6 Tim Speicher,1 Sandra Söhler,1 Klaus F Rabe,7 Emiel FM Wouters,8,9 Claus F Vogelmeier,1 Rudolf A Jörres10 1Department of Medicine, Pulmonary, Critical Care and Sleep Medicine, Philipps University of Marburg (UMR), German Center for Lung Research (DZL), Marburg, Germany; 2Department of Internal Medicine V, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research (DZL), Munich, Germany; 3MediCenterGermering, Germering, Germany; 4Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Center for Lung Research (DZL), Heidelberg, Germany; 5Department of Internal Medicine V - Pulmonology, Allergology, Intensive Care Medicine, Saarland University Hospital, Homburg, Germany; 6Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 7LungenClinic Grosshansdorf and Department of Medicine, Christian-Albrechts University, Kiel, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 8Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht, Netherlands; 9Sigmund Freud Private University, Medical Faculty, Vienna, Austria; 10Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research (DZL), Munich, GermanyCorrespondence: Peter Alter, Department of Medicine, Pulmonary, Critical Care and Sleep Medicine, Philipps University of Marburg (UMR), German Center for Lung Research (DZL), Baldingerstrasse 1, Marburg, Germany, Tel +49 6421 5866140, Email Alter@uni-marburg.deBackground: The COPD Assessment Test (CAT) comprises eight questions. We evaluated the information that each of the questions and the total score contributed to outcomes and characteristics of chronic obstructive lung disease (COPD), including their dependence on smoking status.Methods: Patients with COPD of the COSYCONET cohort with Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 1– 4 and the former grade 0 were included. The evaluated outcomes included mortality, exacerbation risk, the comorbidities asthma, cardiac disease (coronary artery disease/heart failure), osteoporosis, and emphysema, for which a reduction in carbon monoxide transfer coefficient (KCO) < 55% predicted was considered as marker. Analyses were performed by Cox proportional hazard or logistic multiple regression analyses separately for smokers and nonsmokers.Results: In total, 2509 patients had complete data, among them 1884 nonsmokers (ex or never; 38.4% female; mean age±SD 66.1± 8.5 years) and 625 current smokers (45.1% female, 61.6± 7.9 years). The pattern of responses to the single questions of the CAT differed between outcome variables, as well as between smokers and nonsmokers, but in most cases the total score was superior to the single items. The CAT total score was associated with mortality (p< 0.05) only in nonsmokers, while for exacerbation frequency/severity, it was of about equal importance in smokers and nonsmokers. Regarding KCO, the total score was indicative (p< 0.05) only in nonsmokers. Particularly in smokers, single items could show opposite signs of their coefficients which therefore largely cancelled in the total score.Conclusion: Our results show in detail for which outcomes single items are informative in nonsmokers and current smokers with COPD, overall being more informative in nonsmokers. Only regarding exacerbation risk, the predictive value was similar in both groups. These results might be helpful to extract as much as possible information from a COPD questionnaire that is often part of routine assessment.Trial Registration: NCT01245933.Keywords: COPD, COPD assessment test CAT, clinical questionnaire, smoking status, mortality, exacerbation

Carolina Fischer,1,2 Maria Siakavara,1 Peter Alter,3 Claus Franz Vogelmeier,3 Tim Speicher,3 Hendrik Pott,4 Henrik Watz,5 Robert Bals,6,7 Franziska Trudzinski,8 Felix Herth,8 Joachim H Ficker,9 Manfred Wagner,9 Christoph Lange,10 Krista Stoycheva,10 Winfried Randerath,11 Jürgen Behr,12,13 Sebastian Fähndrich,14 Tobias Welte15 ,† Isabell Pink,15 Kathrin Kahnert,12,16 Werner Seeger,17 Stefan Kuhnert,17 Tobias Gessler,17 Nina Adaskina,18 Rudolf A Jörres1 1Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Bavaria, Germany; 2Department of Medicine I, Division of Respiratory Diseases, School of Medicine & Klinikum rechts der Isar, Technical University of Munich, Munich, Bavaria, Germany; 3Department of Medicine, Pulmonary, Critical Care and Sleep Medicine, Philipps University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Marburg, Hesse, Germany; 4Section of Airway Infections, Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Marburg, Hesse, Germany; 5Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Schlewig-Holstein, Germany; 6Department of Internal Medicine V, Pulmonology, Allergology, Critical Care Medicine, Saarland University Hospital, Homburg, Saarland, Germany; 7Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarland University Campus, Saarbrücken, Saarland, Germany; 8Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Member of the Center for Lung Research (DZL), Heidelberg, Baden-Wuerttemberg, Germany; 9Department of Respiratory Medicine, Allergology and Sleep Medicine, Klinikum Nuremberg, Nürnberg, Bavaria, Germany; 10Clinical Infectious Diseases, Research Center Borstel, Borstel, Germany; German Center for Infection Research (DZIF), Standort Hamburg-Lübeck-Borstel-Riems, Germany; Respiratory Medicine & International Health, University of Lübeck, Lübeck, Schleswig-Holstein, Germany; 11Krankenhaus Bethanien gGmbH, Klinik für Pneumologie und Allergologie, Zentrum für Schlaf- und Beatmungsmedizin, Solingen, North-Rhine Westphalia, Germany; 12Department of Medicine V, LMU University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research (DZL), Munich, Bavaria, Germany; 13Asklepios Fachkliniken München-Gauting, Gauting, Germany; 14Department of Pneumology, Faculty of Medicine, Medical Center, University of Freiburg, Baden-Wuerttemberg, Germany; 15Clinic for Pneumology, Hannover Medical School, Member of the German Center for Lung Research (DZL), Hannover, Lower Saxony, Germany; 16MediCenterGermering, Germering, Bavaria, Germany; 17University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, Hesse, Germany; 18CAPNETZ STIFTUNG, Hannover, Lower Saxony, Germany†Tobias We

Claus F Vogelmeier,1 Kai-Michael Beeh,2 Michael Schultze,3 Nils Kossack,4 Lena M Richter,4 Jing Claussen,5 Chris Compton,6 Stephen G Noorduyn,7,8 Afisi S Ismaila,8,9 Gema Requena10 1Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Centre Giessen and Marburg, Philipps-University Marburg, German Center for Lung Research (DZL), Marburg, Germany; 2Insaf Respiratory Research Institute, Wiesbaden, Germany; 3ZEG – Berlin Center for Epidemiology and Health Research GmbH, Berlin, Germany; 4WIG2 GmbH (Wissenschaftliches Institut für Gesundheitsökonomie und Gesundheitssystemforschung) - Scientific Institute for Health Economics and Health System Research, Leipzig, Germany; 5Global Medical Affairs, GSK, Munich, Germany; 6Global Medical, GSK, Brentford, UK; 7Value Evidence and Outcomes, R&D Global Medical, GSK, Mississauga, ON, Canada; 8Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada; 9Value Evidence and Outcomes, R&D Global Medical, GSK, Collegeville, PA, USA; 10Value Evidence and Outcomes, R&D Global Medical, GSK, Brentford, UKCorrespondence: Gema Requena, GSK, 980 Great West Road, Brentford, Middlesex, TW8 9GS, UK, Tel +44 20 80476893, Email gema.x.requena@gsk.comPurpose: Triple therapy (long-acting muscarinic antagonist/long-acting β2-agonist/inhaled corticosteroid) is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience recurrent exacerbations. Multiple-inhaler triple therapy (MITT) is associated with poor adherence and persistence. This study assessed comparative adherence and persistence to single-inhaler triple therapy (SITT) versus MITT among patients with COPD in a real-world setting in Germany.Patients and Methods: This retrospective analysis using the WIG2 benchmark database identified patients with COPD newly initiating triple therapy with MITT or SITT (fluticasone furoate/umeclidinium/vilanterol [FF/UMEC/VI] or formoterol/beclomethasone/glycopyrronium bromide [FOR/BDP/GLY]) November 2017–June 2019. Eligible patients were ≥ 35 years with 1 year’s continual insurance prior to triple therapy initiation and no previous record of triple therapy. Inverse probability of treatment weighting was used to balance baseline characteristics. Adherence was measured using proportion of days covered (PDC) at 6, 12, and 18 months post-treatment initiation; persistence (time until treatment discontinuation) was measured at 6, 12, and 18 months, with a gap of > 30 days used to define non-persistence.Results: Of 5710 patients included in the analysis (mean age 66 years), 71.4% initiated MITT and 28.6% initiated SITT (FF/UMEC/VI: 41.4%; FOR/BDP/GLY: 58.6%). Mean PDC was higher among SITT versus MITT users at all time points; at each time point, mean PDC was highest among FF/UMEC/VI users. During the first 6 months following treatment initiation, higher adherence was exhibited by FF/UMEC/VI (29%) and FOR/BDP/GLY (19%) users versus MITT users. Over the entire observation period, FF/UMEC/VI users had the highest proportion of persistent patients; at 18 months, 16.5% of FF/UMEC/VI users were persistent versus 2.3% of MITT users.Conclusion: Patients initiating SITT in Germany had significantly higher adherence and persistence compared with patients initiating MITT over 6 to 18 months following treatment initiation. Among SITT, FF/UMEC/VI users had the highest proportion of adherence and persistence.Keywords: comparative, multiple- or single-inhaler triple therapy, new-user, proportion of days covered, real-world analysis, treatment discontinuation

Mircea Gabriel Stoleriu,1,2,&ast; Michael Pienn,3,4,&ast; Rudolf A Joerres,5 Peter Alter,6 Tamas Fero,7 Martin Urschler,8 Gabor Kovacs,3,9 Horst Olschewski,3,9 Hans-Ulrich Kauczor,7,10 Mark Wielpütz,7,10 Bertram Jobst,7,10 Tobias Welte,11 Jürgen Behr,2,12 Franziska C Trudzinski,10,13 Robert Bals,14,15 Henrik Watz,16 Claus F Vogelmeier,6 Jürgen Biederer,10,17,18,&ast; Kathrin Kahnert2,12,19,&ast; On behalf of the COSYCONET Study Group1Division for Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich (LMU) and Asklepios Medical Center; Munich-Gauting, Gauting, 82131, Germany; 2Institute for Lung Health and Immunity and Comprehensive Pneumology Center with the CPC-M bioArchive; Helmholtz Center Munich; Member of the German Lung Research Center (DZL), Munich, 81377, Germany; 3Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; 4Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; 5Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Hospital of Ludwig-Maximilians-University Munich (LMU), Munich, 80336, Germany; 6Department of Medicine, Pulmonary and Critical Care Medicine, University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Marburg, 35033, Germany; 7Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany; 8Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria; 9University Clinic for Internal Medicine, Medical University of Graz, Division of Pulmonology, Graz, Austria; 10Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research DZL, Heidelberg, Germany; 11Department of Respiratory Medicine and Infectious Disease, Member of the German Center of Lung Research, Hannover School of Medicine, Hannover, Germany; 12Department of Medicine V, LMU University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany; 13Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Heidelberg, Germany; 14Department of Internal Medicine V-Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg, 66421, Germany; 15Helmholtz Institute for Pharmaceutical Research, Saarbrücken, 66123, Germany; 16Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Centre North, German Centre for Lung Research, Großhansdorf, Germany; 17Faculty of Medicine, Christian-Albrechts-Universität Zu Kiel, Kiel, Germany; 18University of Latvia, Faculty of Medicine, Riga, LV-1586, Latvia; 19MediCenterGermering, Germering, Germany&ast;These authors contributed equally to this workCorrespondence: Mircea Gabriel Stoleriu, Division of Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich (LMU) and Asklepios Lung Clinic Munich-Gauting, Marchioninistr. 15, 81377 Munich and Robert-Koch-Allee 2, Gauting, 82131, Germany, Tel +49 89 85791 4201, Email gabriel.stoleriu@helmholtz-munich.dePurpose: The aim of this study was to evaluate the association between computed tomography (CT) quantitative pulmonary vessel morphology and lung function, disease severity, and mortality risk in patients with chronic obstructive pulmonary disease (COPD).Patients and Methods: Participants of the prospective nationwide COSYCONET cohort study with paired inspiratory-expiratory CT were included. Fully automatic software, developed in-house, segmented arterial and venous pulmonary vessels and quantified volume and tortuosity on inspiratory and expiratory scans. The association between vessel volume normalised to lung volume and tortuosity versus lung function (forced expiratory volume in 1 sec [FEV1]), air trapping (residual volume to total lung capacity ratio [RV/TLC]), transfer factor for carbon monoxide (TLCO), disease severity in terms of Global Initiative for Chronic Obstructive Lung Disease (GOLD) group D, and mortality were analysed by linear, logistic or Cox proportional hazard regression.Results: Complete data were available from 138 patients (39% female, mean age 65 years). FEV1, RV/TLC and TLCO, all as % predicted, were significantly (p < 0.05 each) associated with expiratory vessel characteristics, predominantly venous volume and arterial tortuosity. Associations with inspiratory vessel characteristics were absent or negligible. The patterns were similar for relationships between GOLD D and mortality with vessel characteristics. Expiratory venous volume was an independent predictor of mortality, in addition to FEV1.Conclusion: By using automated software in patients with COPD, clinically relevant information on pulmonary vasculature can be extracted from expiratory CT scans (although not inspiratory scans); in particular, expiratory pulmonary venous volume predicted mortality.Trial Registration: NCT01245933.Keywords: COPD, computed tomography, pulmonary vasculature, vessel volume, vessel tortuosity, lung function

David Price,1,2 William Henley,1,3 José Eduardo Delfini Cançado,4 Leonardo M Fabbri,5 Huib AM Kerstjens,6 Alberto Papi,7 Nicolas Roche,8 Elif &Scedil;en,9 Dave Singh,10 Claus F Vogelmeier,11 Elena Nudo,12 Victoria Carter,1 Derek Skinner,1 Rebecca Vella,1 Joan B Soriano,13 Maxim Kots,12 George Georges14 1Observational and Pragmatic Research Institute, Singapore; 2Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 3Health Statistics Group, Department of Health and Community Sciences, University of Exeter Medical School, Exeter, UK; 4Santa Casa de São Paulo Medical School, São Paulo, Brazil; 5Respiratory Medicine, Department of Translational Medicine and for Romagna, University of Ferrara, Ferrara, Italy; 6Department of Pulmonary Diseases, University of Groningen and University Medical Centre Groningen, and Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands; 7Respiratory Medicine, University of Ferrara, Ferrara, Italy; 8Department of Respiratory Medicine, APHP-Centre University of Paris, Cochin Hospital and Institute (UMR1016), Paris, France; 9Department of Pulmonary Medicine, Ankara University School of Medicine, Ankara, Turkey; 10Division of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK; 11Department of Internal Medicine, Pulmonary and Critical Care Medicine, University of Marburg, Member of the German Centre for Lung Research (DZL), Marburg, Germany; 12Global Medical Affairs, Chiesi Farmaceutici, S.p.A, Parma, Italy; 13Respiratory Department, Hospital Universitario de La Princesa and Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; 14Global Clinical Development, Chiesi Farmaceutici, S.p.A, Parma, ItalyCorrespondence: David Price, Observational and Pragmatic Research Institute, 22 Sin Ming Lane, &num;06-76, Midview City, 573969, Singapore, Tel +65 3105 1489, Email dprice@opri.sgBackground: Combined ICS and long-acting bronchodilators (LABD) more effectively reduce COPD exacerbations than LABD therapy alone. Corticosteroid-related adverse effects, including pneumonia, limit ICS use. Previous data suggest this risk is lower for extrafine beclometasone (ef-BDP). We compared pneumonia risk among new users of fixed dose ICS/LABD formulations containing ef-BDP, versus patients initiating LABD without any ICS.Methods: A propensity-matched historical cohort study design used data from OPCRD. COPD patients with ≥ 1 year of continuous data who initiated LABD or ICS/LABD formulations containing ef-BDP were matched. Primary outcome was time to pneumonia event, as treated, using either sensitive (physician diagnosed) or specific (physician diagnosed and x-ray or hospital admission confirmed) definitions, with non-inferiority boundary of 15%.Results: 23,898 COPD patients were matched, who were 68± 11 years, 54.3% male and 56% current-smokers, while 43% were former-smokers. Initiation of ef-BDP/LABD was not associated with an increased risk of pneumonia versus LABD, for either a sensitive 0.89 (0.78– 1.02), P = 0.08 or a specific 0.91 (0.78– 1.05), P = 0.18 definition of pneumonia. The probability of remaining pneumonia free 1-year after ef-BDP/LABD was 98.4%, which was comparable to LABD at 97.7%, and was sustained up to 6 years of observation; non-inferiority criterion was met for both definitions. Initiation of ef-BDP/LABD was also associated with a reduced risk of developing LRTIs in the propensity matched cohort.Conclusion: Risk of pneumonia when using ICS for the management of COPD reported in several randomised controlled trials may not be relevant with ef-BDP in a diverse real-world clinical population.Keywords: inhaled corticosteroids, pneumonia, COPD, extrafine beclometasone, long-acting bronchodilators

Peter Alter,1 Cosmina Stoleriu,2 Kathrin Kahnert,3,4 Markus Oliver Henke,5 Robert Bals,6 Franziska C Trudzinski,7 Henrik Watz,8 Tim Speicher,1 Sandra Söhler,1 Tobias Welte,9 Klaus F Rabe,10,11 Emiel FM Wouters,12,13 Claus F Vogelmeier,1 Rudolf A Jörres14 1Department of Medicine, Pulmonary, Critical Care and Sleep Medicine, Philipps University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Marburg, Germany; 2Asklepios Lungenklinik Gauting, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Gauting, Germany; 3Department of Medicine V, LMU University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany; 4MediCenterGermering, Germering, Germany; 5Klinik für Innere Medizin und Pneumologie, Krankenhaus Martha-Maria, Munich, Germany; 6Department of Internal Medicine V, Pulmonology, Allergology, Intensive Care Medicine, Saarland University Hospital, Homburg, Germany; 7Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Member of the Center for Lung Research (DZL), Heidelberg, Germany; 8Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 9Clinic for Pneumology, Hannover Medical School, Member of the German Center for Lung Research (DZL), Hannover, Germany; 10LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 11Department of Medicine, Christian-Albrechts-University, Kiel, Germany; 12Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht, Netherlands; 13Ludwig Boltzmann Institute for Lung Health, Vienna, Austria; 14Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, LMU University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, GermanyCorrespondence: Peter Alter, Department of Medicine, Pulmonary, Critical Care and Sleep Medicine, Philipps University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Baldingerstrasse 1, Marburg, 35033, Germany, Tel +49 6421 5866140, Email Alter@uni-marburg.deBackground: Many patients with chronic obstructive pulmonary disease (COPD) continue smoking. We used data from the “real-life” COSYCONET COPD cohort to evaluate whether these patients differed from patients with COPD who either had ceased smoking prior to inclusion or ceased during the follow-up time of the study.Methods: The analysis was based on data from visits 1– 5 (covering 4.5 years), including all patients with the diagnosis of COPD who were either ex-smokers or smokers and categorized as GOLD 1– 4 or the former GOLD 0 category. We compared the characteristics of smokers and ex-smokers at baseline (visit 1), as well as the course of lung function in the follow-up of permanent ex-smokers, permanent smokers and incident ex-smokers (smokers at visit 1 who ceased smoking before visit 5). We also identified baseline factors associated with subsequent smoking cessation.Results: Among 2500 patients who were ever-smokers, 660 were current smokers and 1840 ex-smokers at baseline. Smokers were younger than ex-smokers (mean 61.5 vs 66.0 y), had a longer duration of smoking but fewer pack-years, a lower frequency of asthma, higher forced expiratory volume in 1 sec (FEV1, 59.4 vs 55.2% predicted) and higher functional residual capacity (FRC, 147.7 vs 144.3% predicted). Similar results were obtained for the longitudinal subpopulation, comprising 713 permanent ex-smokers, 175 permanent smokers, and 55 incident ex-smokers. When analyzing the time course of lung function, higher FRC, lower FEV1 and the presence of asthma (p < 0.05 each) were associated with incident cessation prior to visit 5, while less airway obstruction was associated with smoking continuation.Conclusion: These findings, which were consistent in the cross-sectional and longitudinal analyses, suggest that lung hyperinflation was associated with being or becoming ex-smoker. Possibly, it is perceived by patients as one of the factors motivating their attempts to quit smoking, independent from airway obstruction.Keywords: COPD, smoking, smoking cessation, airway obstruction, lung hyperinflation

David MG Halpin,1 Kieran J Rothnie,2 Victoria Banks,3 Alexandrosz Czira,2 Chris Compton,4 Robert Wood,3 Theo Tritton,3 Olivia Massey,3 Rosie Wild,3 Neil Snowise,5 Kirill Nikitin,2 Raj Sharma,4 Afisi S Ismaila,6,7 Claus F Vogelmeier8 1University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK; 2Value Evidence and Outcomes, R&D Global Medical, GSK, Brentford, UK; 3Real-World Evidence, Adelphi Real World, Bollington, UK; 4Global Medical, GSK, London, UK; 5Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King’s College, London, UK; 6Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 7Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada; 8Department of Medicine, Pulmonary and Critical Care Medicine, University of Marburg, Member of the German Center for Lung Research (DZL), Marburg, GermanyCorrespondence: David MG Halpin, University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, EX1 2LU, UK, Tel +44 (0)1392 201178, Email d.halpin@nhs.netPurpose: Triple therapy comprising a long-acting muscarinic antagonist, long-acting β2-agonist and inhaled corticosteroid is recommended for patients with chronic obstructive pulmonary disease (COPD) who continue to experience frequent exacerbations or symptoms whilst receiving dual therapy. Adherence and persistence to multiple-inhaler triple therapy (MITT) is known to be poor. This study assessed comparative adherence to single-inhaler triple therapy (SITT) versus MITT in a real-world setting in England.Patients and Methods: This was a retrospective cohort study using linked primary care (Clinical Practice Research Datalink Aurum) and secondary care (Hospital Episode Statistics [HES] Admitted Patient Care) data to identify patients with COPD who were newly initiated on SITT or MITT between November 2017 and June 2019. Eligible patients were aged ≥ 35 years and had a forced expiratory volume in 1 second/forced vital capacity < 0.7, linkage to HES and continuous registration with a general practitioner for 12 months pre- and 6 months post-initiation. Inverse probability of treatment weighting was used to balance baseline characteristics between cohorts. Adherence was measured using the proportion of days covered by days’ supply of SITT or MITT prescriptions. Persistence was measured with a gap of > 30 days between the end of a prescription and the following refill used to determine non-persistence.Results: Overall, 4080 SITT and 6579 MITT users comprised the study cohort. After weighting, the baseline characteristics between the cohorts were comparable (absolute standardized mean difference < 10%). SITT users had significantly higher adherence than MITT users at 6, 12, and 18 months post-initiation (p< 0.001 for all comparisons). Median persistence was higher among SITT users than MITT users (5.09 months vs 0.99 months).Conclusion: Patients with COPD in England initiating SITT had significantly better adherence and persistence compared with MITT initiators. These improvements continued at least 18 months following treatment initiation.Keywords: COPD, Clinical Practice Research Datalink, Hospital Episode Statistics, MITT, proportion of days covered, SITT

Roland Buhl,1 Thomas Wilke,2 Nils Picker,3 Olaf Schmidt,4 Marlene Hechtner,5 Anke Kondla,5 Ulf Maywald,6 Claus F Vogelmeier7 1Pulmonary Department, Mainz University Hospital, Mainz, Germany; 2IPAM e.V, Wismar, Germany; 3Cytel Inc - Ingress-Health HWM GmbH, Wismar, Germany; 4Pulmonary Group Practice, Koblenz, Germany; 5Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; 6AOK PLUS, Dresden, Germany; 7Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Marburg, GermanyCorrespondence: Roland Buhl, Medizinische Klinik und Poliklinik - Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Langenbeckstraße 1, Mainz, 55131, Germany, Tel +49 6131 17 7271, Email roland.buhl@unimedizin-mainz.dePurpose: This study aimed to describe the real-world treatment of German incident COPD patients, compare that treatment with clinical guidelines, and provide insight into disease development after incident diagnosis. In addition, the economic burden of the disease by assessing COPD-related healthcare costs was described.Patients and Methods: Based on a German claims dataset, continuously insured individuals (04/2014-03/2019) aged 40 years or older with at least two incident pulmonologist’s diagnoses or one inpatient diagnosis of COPD (ICD-10-GM code J44.-; no respective diagnosis in a 12-month baseline period) were selected. Treatment patterns after incident diagnosis considering inhaled maintenance therapies identified by ATC codes (outpatient prescriptions) were analyzed. Prescription patterns were compared with recommendations of German COPD treatment guidelines. Severe exacerbations were assessed as hospitalizations with main diagnosis ICD-10-GM code J44.1. COPD-associated costs from the perspective of the health insurance fund AOK PLUS were calculated per patient-year (PY).Results: The sample comprised 17,464 incident COPD patients with a mean age of 71.5 years. 58.9% were male and the mean Charlson-Comorbidity-Index was 5.3. During follow-up (median: 2.0 years), 57.1% of the patients received at least one prescription of an inhaled maintenance therapy, whereas 42.9% did not. Among treated patients, 35.2% started their treatment with LABA/LAMA, 25.3% with LAMA monotherapy, 16.2% with LABA/ICS, and 7.8% with LABA/LAMA/ICS therapy. Within four weeks after initial diagnosis, ICS-containing therapies were prescribed in 14.1% of patients. Of all patients with a prescribed triple therapy, 68.9% had no corresponding exacerbation history documented. On average, 0.16 severe exacerbations and 0.19 COPD-related hospitalizations were observed per PY during available follow-up. Direct COPD-related costs were 3,693 €/PY, with COPD-related hospitalizations being responsible for about 79.2% of these costs.Conclusion: Long-acting bronchodilators are the mainstay of pharmacological treatment of incident COPD patients in Germany, in line with guideline recommendations. Yet, a considerable proportion of incident COPD patients did not receive any inhaled maintenance therapy.Keywords: COPD, real-world treatment, exacerbation frequency, healthcare costs

Carolina Fischer,1 Rudolf A Jörres,1 Peter Alter,2 Franziska C Trudzinski,3 Önder Yildirim,4 Robert Bals,5 Claus F Vogelmeier,2 Diego Kauffmann-Guerrero,6 Jürgen Behr,6 Henrik Watz,7 Rolf Holle,8 Kathrin Kahnert6 And members of the COSYCONET study group1Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Munich, Germany; 2Department of Medicine, Pulmonary and Critical Care Medicine, University of Marburg (UMR), Germany, Marburg, Germany; 3Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany; 4Institute of Lung Biology and Disease (ILBD), Comprehensive Pneumology Center Munich (CPC-M), Munich, Germany; 5Department of Internal Medicine V - Pulmonology, Allergology, Intensive Care Medicine, Saarland University Hospital, Homburg, Germany; 6Department of Medicine V, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Munich, Germany; 7Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Grosshansdorf, Germany; 8Institute for Medical Informatics, Biometry and Epidemiology, University Hospital, LMU Munich, Munich, GermanyCorrespondence: Kathrin Kahnert, Department of Medicine V, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Ziemssenstraße 1, Munich, 80336, Germany, Email Kathrin.Kahnert@med.uni-muenchen.deIntroduction: In many chronic diseases, including COPD, the patients’ basic knowledge of the disorder has been shown to be relevant for the course of the disease. We studied which clinical and functional characteristics were related to this knowledge as well as the patients’ satisfaction with their knowledge about COPD.Methods: The study population comprised 645 patients of GOLD grades 1– 4 who participated in Visit 6 of the COSYCONET cohort (COPD and Systemic Consequences - Comorbidities Network). The assessments covered a broad panel of clinical and functional characteristics, including generic and disease-specific quality of life and the COPD Assessment Test (CAT). The study aim was addressed by two questions, referring to patients’ knowledge of the meaning of FEV1 and the overall satisfaction with their knowledge of COPD.Results: Knowledge of FEV1 was higher in patients of higher spirometric GOLD grades or exacerbation risk, in males, with higher educational level, and after participation in a prior educational training on COPD. Patients with more detailed knowledge showed a higher satisfaction with their knowledge. Satisfaction was associated with higher generic quality of life and a lower CAT score. Furthermore, satisfaction was higher in patients with a treatment plan but lower in patients with cardiac comorbidities. It appeared that females with basic education, high burden from COPD and low quality of life had the greatest knowledge deficits.Discussion: The results suggest room for education programs adapted to the educational level of the participants. They also emphasize the major role of a disease management plan for the patients.Keywords: chronic obstructive pulmonary disease, knowledge, education, satisfaction

Peter Alter,1 Kathrin Kahnert,2 Franziska C Trudzinski,3 Robert Bals,4 Henrik Watz,5 Tim Speicher,1 Sandra Söhler,1 Stefan Andreas,6 Tobias Welte,7 Klaus F Rabe,8 Emiel FM Wouters,9 Antonia Sassmann-Schweda,10 Hubert Wirtz,11 Joachim H Ficker,12,13 Claus F Vogelmeier,1 Rudolf A Jörres14 1Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Germany, Member of the German Center for Lung Research (DZL), Marburg, Germany; 2Department of Internal Medicine V, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany; 3Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; 4Department of Internal Medicine V - Pulmonology, Allergology, Intensive Care Medicine, Saarland University Hospital, Homburg, Germany; 5Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 6LungClinic Immenhausen and Department of Cardiology and Pneumology, University Medical Center Göttingen, Germany, Member of the German Center for Lung Research (DZL), Göttingen, Germany; 7Clinic for Pneumology, Hannover Medical School, Member of the German Center for Lung Research (DZL), Hannover, Germany; 8LungenClinic Grosshansdorf and Department of Medicine, Christian-Albrechts University, Kiel, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 9Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht, Netherlands and Ludwig Boltzmann Institute for Lung Health, Vienna, Austria; 10Center for Clinical Studies, Research Center Borstel, Borstel, Germany; 11Department of Internal Medicine I, Pneumology, University of Leipzig, Leipzig, Germany; 12Department of Respiratory Medicine, Allergology and Sleep Medicine, Klinikum Nuremberg, Nürnberg, Germany; 13Paracelsus Medical University Nuremberg, Nürnberg, Germany; 14Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, GermanyCorrespondence: Peter Alter, Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Baldingerstrasse 1, Marburg, Germany, Email Alter@uni-marburg.deBackground: Multimorbidity plays an important role in chronic obstructive pulmonary disease (COPD) but is also a feature of ageing. We estimated to what extent increases in the prevalence of multimorbidity over time are attributable to COPD progression compared to increasing patient age.Methods: Patients with COPD from the long-term COSYCONET (COPD and Systemic Consequences - Comorbidities Network) cohort with four follow-up visits were included in this analysis. At each visit, symptoms, exacerbation history, quality of life and lung function were assessed, along with the comorbidities heart failure (HF), coronary artery disease (CAD), peripheral arterial disease (PAD), hypertension, sleep apnea, diabetes mellitus, hyperlipidemia, hyperuricemia and osteoporosis. Using longitudinal logistic regression analysis, we determined what proportion of the increase in the prevalence of comorbidities could be attributed to patients’ age or to the progression of COPD over visits.Results: Of 2030 patients at baseline, 878 completed four follow-up visits (up to 4.5 years). CAD prevalence increased over time, with similar effects attributable to the 4.5-year follow-up, used as indicator of COPD progression, and to a 5-year increase in patients’ age. The prevalence of HF, diabetes, hyperlipidemia, hyperuricemia, osteoporosis and sleep apnea showed stronger contributions of COPD progression than of age; in contrast, age dominated for hypertension and PAD. There were different relationships to patients’ characteristics including BMI and sex. The results were not critically dependent on the duration of COPD prior to enrolment, or the inclusion of patients with all four follow-up visits vs those attending only at least one of them.Conclusion: Analyzing the increasing prevalence of multimorbidity in COPD over time, we separated age-independent contributions, probably reflecting intrinsic COPD-related disease progression, from age-dependent contributions. This distinction might be useful for the individual assessment of disease progression in COPD.Keywords: chronic obstructive pulmonary disease, comorbidities, multimorbidity, prognosis, disease progression

Peter Alter,1 Jan Orszag,2,3 Emiel FM Wouters,4,5 Claus F Vogelmeier,1 Rudolf A Jörres2 1Department of Medicine, Pulmonary and Critical Care Medicine, Philipps-University of Marburg (UMR), Germany, Member of the German Center for Lung Research (DZL), Marburg, Germany; 2Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany; 3Department of Anaesthesiology, University Hospital, LMU Munich, Munich, Germany; 4Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht, Netherlands; 5Ludwig Boltzmann Institute for Lung Health, Vienna, AustriaCorrespondence: Peter Alter, Department of Medicine, Pulmonary and Critical Care Medicine, Philipps-University of Marburg (UMR), Baldingerstrasse, Marburg, 35033, Germany, Email Alter@uni-marburg.deAbstract: Body plethysmography is a fundamental method for the assessment of static lung volumes. Although equipment is provided by several manufacturers, there are no established cross-vendor tools for quality control. In the process of quality control and analysis of data on hyperinflation from the large COPD cohort COSYCONET, hints appeared that plethysmographs of different vendors might yield different values for static lung volumes. Functional residual capacity (FRC) differed about 0.67 litres between plethysmographs of the manufacturer Vyaire and Ganshorn. Absolute differences of residual lung volume (RV) and total lung capacity (TLC) were similar. It appears undeniable that differences of this magnitude have an impact on clinical interpretation. Thus, device harmonization seems to be required.Keywords: lung function, body plethysmography, static lung volumes, functional residual capacity

David B Price,1,2 William Henley,1,3 José Eduardo Delfini Cançado,4 Leonardo M Fabbri,5 Huib AM Kerstjens,6 Alberto Papi,7 Nicolas Roche,8 Elif &Scedil;en,9 Dave Singh,10 Claus F Vogelmeier,11 Sara Barille,12 Elena Nudo,12 Victoria Carter,1 Derek Skinner,1 Rebecca Vella,1 George Georges13 1Observational and Pragmatic Research Institute, Singapore; 2Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 3Health Statistics Group, Institute of Health Research, University of Exeter Medical School, Exeter, UK; 4Santa Casa de São Paulo Medical School, São Paulo, Brazil; 5Respiratory Medicine, Department of Translational Medicine, University of Ferrara, Ferrara, Italy; 6Department of Pulmonary Diseases, University of Groningen and University Medical Centre Groningen, and Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, Netherlands; 7Respiratory Medicine, University of Ferrara, Ferrara, Italy; 8Department of Respiratory Medicine, APHP-Centre University of Paris, Cochin Institute, Paris, France; 9Department of Pulmonary Medicine, Ankara University School of Medicine, Ankara, Turkey; 10Division of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK; 11Department of Internal Medicine, Pulmonary and Critical Care Medicine, University of Marburg, Member of the German Centre for Lung Research (DZL), Marburg, Germany; 12Global Medical Affairs, Chiesi Farmaceutici, S.p.A., Parma, Italy; 13Global Clinical Development, Chiesi Farmaceutici, S.p.A., Parma, ItalyCorrespondence: David B Price, Observational and Pragmatic Research Institute, 22 Sin Ming Lane, #06-76, Midview City, 573969, Singapore, Email dprice@opri.sgBackground: Inhaled corticosteroids (ICS) afford therapeutic benefits in some COPD patients, but their widespread use is cautioned due to an increased risk of developing pneumonia. Subclass variations exist, and the risk profile differs for individual ICS. Formulation particle size has been identified as a potential effect modifier. The present study compared the risk of pneumonia among new COPD users of fixed-dose combination inhalers containing fine-particle fluticasone (fp-FDC-F) versus extrafine particle beclometasone (ef-FDC-BDP).Methods: A propensity matched historical cohort study was conducted using data from the Optimum Patient Care Research Database. COPD patients aged ≥ 40 years with ≥ 1 year of continuous medical data who initiated fp-FDC-F or ef-FDC-BDP were compared. The primary outcome was time to pneumonia event, as treated, using either sensitive (physician diagnosed) or specific (physician diagnosed and x-ray or hospital admission confirmed) definitions.Results: A total of 13,316 patients were matched. Initiation of fp-FDC-F (mean dosage furoate 99 μg; propionate 710 μg) was associated with an increased risk of pneumonia versus ef-FDC-BDP (mean beclometasone dose 395 μg), irrespective of definition (sensitive HR 1.38 95% CI 1.14– 1.68; specific HR 1.31 95% CI 1.05– 1.62).Conclusion: In the current investigation, we found that in comparison to extrafine beclomethasone, commencing a formulation containing fluticasone is associated with an increased risk of developing pneumonia. These observations support the idea that not all ICS are equal in their adverse effects and subclass variations exist and should be carefully considered in the treatment choice.Keywords: inhaled corticosteroids, pneumonia, COPD, extrafine beclomethasone, fluticasone

Soham Shukla,1 Dhvani Shah,2 Alan Martin,3 Nancy A Risebrough,4 Robyn Kendall,5 Claus F Vogelmeier,6 Isabelle Boucot,3 Lee Tombs,7 Leif Bjermer,8 Paul W Jones,3 Edward Kerwin,9 Chris Compton,3 François Maltais,10 David A Lipson,11,12 Afisi S Ismaila1,13 1Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 2ICON, New York, NY, USA; 3Value Evidence and Outcomes, GSK, Brentford, Middlesex, UK; 4Global Health Economics, and Outcomes Research and Epidemiology, ICON, Toronto, ON, Canada; 5Global Health Economics, and Outcomes Research and Epidemiology, ICON, Vancouver, BC, Canada; 6Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany; 7Precise Approach Ltd, Contingent Worker on Assignment at GSK, Brentford, Middlesex, UK; 8Respiratory Medicine and Allergology, Lund University, Lund, Sweden; 9Altitude Clinical Consulting and Clinical Research Institute of Southern Oregon, Medford, OR, USA; 10Centre de Pneumologie, Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Québec, QC, Canada; 11Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 12Respiratory Clinical Sciences, GSK, Collegeville, PA, USA; 13Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, CanadaCorrespondence: Afisi S IsmailaValue Evidence and Outcomes, GlaxoSmithKline 1250 South Collegeville Road, Collegeville, PA, 19426-0989, USATel +1 919 315 8229Email afisi.s.ismaila@gsk.comIntroduction: Dual bronchodilators are recommended as maintenance treatment for patients with symptomatic COPD in the UK; further evidence is needed to evaluate cost-effectiveness versus monotherapy. Cost-effectiveness of umeclidinium/vilanterol versus umeclidinium and salmeterol from a UK healthcare perspective in patients without exacerbations in the previous year was assessed using post hoc EMAX trial data.Methods: The validated GALAXY model was populated with baseline characteristics and treatment effects from the non-exacerbating subgroup of the symptomatic EMAX population (COPD assessment test score ≥ 10) and 2020 UK healthcare and drug costs. Outputs included estimated exacerbation rates, costs, life-years (LYs), and quality-adjusted LYs (QALYs); incremental cost-effectiveness ratio (ICER) was calculated as incremental cost/QALY gained. The base case (probabilistic model) used a 10-year time horizon, assumed no treatment discontinuation, and discounted future costs and QALYs by 3.5% annually. Sensitivity and scenario analyses assessed robustness of model results.Results: Umeclidinium/vilanterol treatment was dominant versus umeclidinium and salmeterol, providing an additional 0.090 LYs (95% range: 0.035, 0.158) and 0.055 QALYs (− 0.059, 0.168) with total cost savings of £ 690 (£ 231, £ 1306) versus umeclidinium, and 0.174 LYs (0.076, 0.286) and 0.204 QALYs (0.079, 0.326) with savings of £ 1336 (£ 1006, £ 2032) versus salmeterol. In scenario and sensitivity analyses, umeclidinium/vilanterol was dominant versus umeclidinium except over a 5-year time horizon (more QALYs at higher total cost; ICER=£ 4/QALY gained) and at the lowest estimate of the St George’s Respiratory Questionnaire treatment effect (fewer QALYs at lower total cost; ICER=£ 12,284/QALY gained); umeclidinium/vilanterol was consistently dominant versus salmeterol. At willingness-to-pay threshold of £ 20,000/QALY, probability that umeclidinium/vilanterol was cost-effective in this non-exacerbating subgroup was 95% versus umeclidinium and 100% versus salmeterol.Conclusion: Based on model predictions from a UK perspective, symptomatic patients with COPD and no exacerbations in the prior year receiving umeclidinium/vilanterol are expected to have better outcomes at lower costs versus umeclidinium and salmeterol.Keywords: COPD treatment, cost-effectiveness, umeclidinium, salmeterol, umeclidinium/vilanterol

Kathrin Kahnert,1 Rudolf A Jörres,2 Tanja Lucke,2 Franziska C Trudzinski,3 Pontus Mertsch,1 Christiane Bickert,1 Joachim H Ficker,4 Jürgen Behr,1 Robert Bals,5 Henrik Watz,6 Tobias Welte,7 Claus F Vogelmeier,8 Peter Alter8 On behalf of COSYCONET Study Group1Department of Medicine V, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany; 2Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany; 3Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; 4Department of Respiratory Medicine, Nürnberg General Hospital, Paracelsus Medical University, Nürnberg, Germany; 5Department of Internal Medicine V - Pulmonology, Allergology, Intensive Care Medicine, Saarland University Hospital, Homburg, Germany; 6Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 7Clinic for Pneumology, Hannover Medical School, Member of the German Center for Lung Research (DZL), Hannover, Germany; 8Department of Medicine, Pulmonary and Critical Care Medicine, University of Marburg (UMR), Germany, Member of the German Center for Lung Research (DZL), Marburg, GermanyCorrespondence: Kathrin KahnertDepartment of Medicine V, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, GermanyTel +49 89 4400 52590Fax +49 89 4400 54905Email kathrin.kahnert@med.uni-muenchen.deBackground: Patients with chronic obstructive pulmonary disease (COPD) often have osteoporosis and diabetes as comorbid conditions. Anti-diabetic medication, including metformin, has protective effects on osteoporosis in experimental studies. We therefore studied whether patients with COPD receiving anti-diabetic medication had a lower osteoporosis prevalence in a large COPD cohort, COSYCONET.Methods: Assessment of osteoporosis was based on patients’ reports of physician-based diagnoses and the presence of disease-specific medication. The predictive value of physical characteristics, lung function, comorbidities, cardiovascular medication, and the use of anti-inflammatory diabetes medication, including metformin, sulfonylureas, glinides or DPP4I, was evaluated using logistic regression analysis. ClinicalTrials.gov: NCT01245933.Results: In total, 2222 patients were eligible for analysis (863 [39%] female, mean age 65 y), 515 of whom had higher symptoms and exacerbations (Global Initiative for Chronic Obstructive Lung Disease group D). Osteoporosis was present in 15.8% of the overall cohort, and in 24.1% of GOLD D patients. Regression analyses identified the following as associated with osteoporosis (p < 0.05): female sex, higher age, lower body-mass index, asthma, higher air trapping, oral steroids, and cardiovascular medication. Although oral anti-diabetic medication was overall not associated with a lower prevalence of osteoporosis (p = 0.131), anti-inflammatory anti-diabetic medication (p = 0.009) and metformin-containing therapy (p = 0.039) were. This was driven by GOLD D patients.Conclusion: In a large COPD cohort, anti-inflammatory diabetes therapy, including metformin, was associated with a lower prevalence of osteoporosis, especially in patients with higher symptoms and exacerbations. These findings suggest a protective effect of common anti-diabetic medication on osteoporosis, possibly as a result of attenuated systemic inflammation.Keywords: chronic obstructive pulmonary disease, oral corticosteroids, inhaled corticosteroids, anti-inflammatory, metformin, diabetes

Alisa Stöber,1,2 Johanna I Lutter,1,3 Larissa Schwarzkopf,1,3,4 Florian Kirsch,1 Anja Schramm,5 Claus F Vogelmeier,6 Reiner Leidl1,7 1Institute of Health Economics and Health Care Management, Helmholtz Zentrum München, Neuherberg, Germany; 2Institute for Medical Information Processing, Biometry, and Epidemiology (IBE), Ludwig-Maximilians-University Munich (LMU), Munich, Germany; 3Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany; 4Institute fuer Therapieforschung (IFT), Working Group Therapy and Health Services Research, Munich, Germany; 5AOK Bayern, Service Center of Health Care Management, Regensburg, Germany; 6Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-University Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany; 7Munich Center of Health Sciences (MC-Health), Institute for Health Economics and Management, Ludwig-Maximilians-University Munich (LMU), Munich, GermanyCorrespondence: Alisa StöberInstitute of Health Economics and Health Care Management, Helmholtz Zentrum München, Neuherberg, 85764, GermanyTel +49 89 3187/43572Email alisa.stoeber@helmholtz-muenchen.dePurpose: Real-world evidence on the impact of forced expiratory volume in one second (FEV1) and exacerbations on health-related quality of life (HRQoL) in patients with chronic obstructive pulmonary disease (COPD) is sparse especially with regard to GOLD ABCD groups. This study investigates how changes in FEV1 and exacerbations affect generic and disease-specific HRQoL in COPD patients over one year.Methods: Using German claims data and survey data, we classified 3016 COPD patients and analyzed their health status by GOLD groups AB and CD. HRQoL was measured with the disease-specific COPD assessment test (CAT) and the visual analog scale (VAS) from the generic Euro-Qol 5D-5L. We applied change score models to assess associations between changes in FEV1 (≥ 100 mL decrease/no change/≥ 100 mL increase) or the development of severe exacerbations with change in HRQoL.Results: FEV1 decrease was associated with a significant but not minimal important difference (MID) deterioration in disease-specific HRQoL (mean change [95% CI]: CAT +0.74 [0.15 to 1.33]), while no significant change was observed in the generic VAS. Experiencing at least one severe exacerbation also had a significant impact on CAT deterioration (+1.58 [0.52 to 2.64]), but again not on VAS. Here, GOLD groups AB showed not only a statistically but also a clinically relevant MID deterioration in CAT (+2.1 [0.88 to 3.32]). These particular patient groups were further characterized by a higher probability of being male, having a higher mMRC and Charlson index, and a lower probability of having higher FEV1 or BMI values.Conclusion: FEV1 decline and the occurrence of ≥ 1 severe exacerbation are significantly associated with overall deterioration in disease-specific HRQoL. Preventing severe exacerbations particularly in patients without previous severe exacerbations (ABCD groups A and B) may help to stabilize the key patient-reported outcome HRQoL.Keywords: COPD, health-related quality of life, longitudinal study, real-world evidence, forced expiratory volume in 1 second, exacerbation

Claus F Vogelmeier,1 Joanna Diesing,2 Nils Kossack,2 Marc Pignot,3 Felix W Friedrich4 1Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Marburg, Hessen, Germany; 2WIG2 GmbH Scientific Institute for Health Economics and Health System Research, Leipzig, Sachsen, Germany; 3Kantar Health, Munich, Germany; 4AstraZeneca, Wedel, GermanyCorrespondence: Felix W FriedrichAstraZeneca GmbH, Tinsdaler Weg 183, Wedel, D-22880, GermanyTel +49 162 1398835Email felix.friedrich@astrazeneca.comBackground: Recent studies evaluating the predictive value of different variables on future exacerbations suggest exacerbation history as the strongest predictor. We examined the effect of exacerbation history on subsequent events in a large sample population with over 250,000 COPD patients using up to 8 years of longitudinal healthcare data from Germany.Methods: Patients 40 years or older with any COPD diagnosis in primary or secondary care were included from 2011 to 2017 (index period) from healthcare insurance claims (Germany; WIG2 research database), with 12 months before index date as baseline and at least 12-month follow-up. Exacerbations during baseline were defined as moderate (treatment with oral corticosteroids or antibiotics, J01AA, J01CA) or severe (emergency visit or hospitalization).Results: Patients without (category A), with one moderate (category B), or with either one severe or several baseline exacerbations (category C) experienced an average of 0.9 (CI 0.9– 0.9), 1.9 (CI 1.9– 1.9), and 6.3 (CI 6.1– 6.3) exacerbations during the first 3 years of follow-up, respectively. By 8 years, 87.0% (CI 86.6– 87.4), 70.5% (CI 69.9– 71.0) and 49.1% (CI 48.9– 49.3) of category C, B and A patients had experienced a subsequent exacerbation.Conclusion: Baseline exacerbations increased the likelihood of, and reduced time to subsequent exacerbations. Even patients without baseline exacerbations experienced exacerbations within three years, emphasizing the importance of adequate treatment in patients with less severe disease presentation as well.Keywords: chronic obstructive pulmonary disease, COPD, exacerbations, economic burden, healthcare resource utilization

Claus F Vogelmeier,1 Ian P Naya,2,3 François Maltais,4 Leif Bjermer,5 Edward M Kerwin,6 Lee Tombs,7 Paul W Jones,2 Chris Compton,2 David A Lipson,8,9 Isabelle H Boucot2,10 1Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany; 2Global Specialty & Primary Care, GSK, Brentford, Middlesex, UK; 3RAMAX Ltd, Bramhall, Cheshire, UK; 4Centre De Pneumologie, Institut Universitaire De Cardiologie Et De Pneumologie De Québec, Université Laval, Québec, Canada; 5Respiratory Medicine and Allergology, Lund University, Lund, Sweden; 6Altitude Clinical Consulting and Clinical Research Institute of Southern Oregon, Medford, OR, USA; 7Precise Approach Ltd, Contingent Worker on Assignment at GSK, Brentford, Middlesex, UK; 8Respiratory Clinical Sciences, GSK, Collegeville, PA, USA; 9Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 10Medical Emerging Markets, GSK, Brentford, Middlesex, UKCorrespondence: Claus F VogelmeierUniversity Medical Center Giessen and Marburg, Philipps-Universität Marburg, Member of the German Center for Lung Research (DZL), Baldingerstraße, Marburg, 35043, GermanyTel +49 6421/58-66451Email claus.vogelmeier@med.uni-marburg.deIntroduction: This post hoc analysis of the “Early MAXimization of bronchodilation for improving COPD stability” (EMAX) trial investigated whether patients achieving early clinically important improvement (CII) sustained longer-term improvements and lower risk of clinically important deterioration (CID).Methods: Patients were randomized to umeclidinium/vilanterol, umeclidinium, or salmeterol for 24 weeks. The patient-reported outcomes (PROs) Transition Dyspnea Index (TDI), Evaluating Respiratory Symptoms, St George’s Respiratory Questionnaire (SGRQ) and COPD Assessment Test (CAT) were assessed. CII, defined as attaining minimum clinically important differences (MCID) in ≥ 2 PROs, was assessed at Weeks 4, 12 and 24. CID was defined as a deterioration in CAT, SGRQ, TDI by the MCID and/or a moderate/severe exacerbation from Day 30.Results: Of 2425 patients, 50%, 53% and 51% achieved a CII at Weeks 4, 12 and 24, respectively. Patients with a CII at Week 4 versus those without had significantly greater odds of achieving a CII at Weeks 12 and 24 (odds ratio: 5.57 [95% CI: 4.66, 6.66]; 4.09 [95% CI: 3.44, 4.86]). The risk of a CID was higher in patients who did not achieve a CII at Week 4 compared with patients who did (hazard ratio [95% CI]: 2.09 [1.86, 2.34]). Patients treated with umeclidinium/vilanterol versus either monotherapy had significantly greater odds of achieving CII at Weeks 4, 12 and 24.Conclusion: Achieving a CII at Week 4 was associated with longer-term improvement in PROs and a reduced risk of deterioration. Further research is required to investigate the importance of an early response to treatment on the long-term disease course.Keywords: bronchodilator, clinically important improvement, clinically important deterioration, COPD symptoms, early improvement, patient-reported outcomes

Johanna I Lutter,1 Rudolf A Jörres,2 Franziska C Trudzinski,3 Peter Alter,4 Christina Kellerer,2,5 Henrik Watz,6 Tobias Welte,7 Robert Bals,8 Diego Kauffmann-Guerrero,9 Jürgen Behr,9 Rolf Holle,10 Claus F Vogelmeier,4 Kathrin Kahnert9 On behalf of the COSYCONET study group1Institute of Health Economics and Health Care Management, Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research, Munich, Germany; 2Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, LMU Hospital, Comprehensive Pneumology Center Munich (CPC-M), Munich, Germany; 3Department of Pneumology and Critical Care Medicine, Thoraxklinik University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; 4Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-University Marburg (UMR), Germany, Member of the German Center for Lung Research (DZL), Marburg, Germany; 5School of Medicine, Institute of General Practice and Health Services Research, Technical University of Munich (TUM), Munich, Germany; 6Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 7Department of Pneumology, Hannover Medical School, Hannover, Germany; 8Department of Internal Medicine V – Pulmonology, Allergology, Respiratory Intensive Care Medicine, Saarland University Hospital, Homburg, Germany; 9Department of Medicine V, University of Munich (LMU), Comprehensive Pneumology Center, Member of the German Center for Lung Research (DZL), Munich, Germany; 10Institute for Medical Informatics, Biometry and Epidemiology, LMU Hospital, Munich, GermanyCorrespondence: Kathrin KahnertDepartment of Internal Medicine V, University of Munich (LMU), LMU Hospital, Ziemssenstraße 1, Munich, 80336, GermanyEmail Kathrin.Kahnert@med.uni-muenchen.deBackground: In COPD patients of GOLD groups A and B, a high degree of treatment with inhaled corticosteroids (ICS) has been reported, which is regarded as overtreatment according to GOLD recommendations. We investigated which factors predict ICS use and which relationship it has to clinical and functional outcomes, or healthcare costs.Methods: We used pooled data from visits 1 and 3 of the COSYCONET cohort (n=2741, n=2053, interval 1.5 years) including patients categorized as GOLD grades 1– 4 and GOLD group A or B at both visits (n=1080). Comparisons were performed using ANOVA, and regression analyses using propensity matching and inverse probability weighting to adjust for differences between ICS groups. These were defined as having ICS at both visits (always) vs no ICS at both visits (never). Measures were divided into predictors of ICS treatment and outcomes.Results: Among 1080 patients, 608 patients were eligible for ICS groups (n=297 never, n=311 always). Prior to matching, patients with ICS showed significantly (p< 0.05 each) impaired lung function, symptoms and exacerbation history. After matching, the outcomes generic quality of life and CO diffusing capacity were increased in ICS patients (p< 0.05 each). Moreover, costs for respiratory medication, but not total health care costs, were significantly elevated in the ICS group by 780€ per year.Conclusion: ICS therapy in COPD GOLD A/B patients can have small positive and negative effects on clinical outcomes and health care costs, indicating that the clinical evaluation of ICS over-therapy in COPD requires a multi-dimensional approach.Keywords: COPD, inhaled corticosteroids, GOLD groups, overtreatment

Martina Veith,1 Julia Tüffers,1 Erika Peychev,1 Andreas Klemmer,1 Viktor Kotke,1 Sabina Janciauskiene,2 Susanne Wilhelm,1 Robert Bals,3 Andreas Rembert Koczulla,4 Claus Franz Vogelmeier,1 Timm Greulich1 1Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Member of the German Center for Lung Research, Marburg, Germany; 2Clinic for Pneumology, German Center for Lung Research (DZL), Medical University Hannover, Hannover, Germany; 3Department of Internal Medicine V, Pulmonology, Allergology, Respiratory and Intensive Care Medicine, Saarland Hospital, Homburg/Saar, Germany; 4Institute for Pulmonary Rehabilitation Research, Schoen Klinik Berchtesgadener Land, Teaching Hospital of Philipps-University of Marburg, Marburg, GermanyCorrespondence: Martina VeithDepartment of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Member of the German Center for Lung Research, Marburg, GermanyTel +4964215864723Fax +496421586370Email veithm@staff.uni-marburg.dePurpose: Alpha-1-antitrypsin deficiency (AATD) is a rare hereditary condition characterized by low circulating levels of alpha-1antitrypsin (AAT). While the association between AATD and COPD/emphysema is undisputed, the association between AATD and asthma or bronchiectasis is still a matter of debate.Aims and Objectives: Our study aimed to investigate the distribution of AAT genotypes between patients with COPD/emphysema, asthma and bronchiectasis. To back up the diagnostic labels, we described symptoms associated with the diagnosis.Methods: Between September 2003 and March 2020, 29,465 testing kits (AlphaKit®) were analyzed in the AAT laboratory, University of Marburg, Germany. The diagnosis of AATD has been made based on the measurements of AAT serum levels, followed by genotyping, phenotyping or whole gene sequencing depending on the availability and/or the need for more detailed interpretation of the results. The respiratory symptoms were recorded as well.Results: Regarding the distribution of the wild type allele M and the most frequent mutations S (E264V) and Z (E342K), no significant differences could be found between COPD/emphysema [Pi*MM (58.24%); Pi*SZ (2.49%); Pi*ZZ (9.12%)] and bronchiectasis [Pi*MM (59.30%) Pi*SZ (2.81%); Pi*ZZ (7.02%)]. When COPD/emphysema and bronchiectasis were recorded in the same patient, the rate of Pi* ZZ (14.78%) mutations was even higher. Asthma patients exhibited significantly less deficient genotypes [Pi*MM (54.81%); Pi*SZ (2%); Pi*ZZ (2.77%)] than two other groups. Associated respiratory symptoms confirmed the diagnosis.Conclusion: COPD/emphysema and bronchiectasis, but not asthma patients, exhibit higher frequency of AATD genotypes. Our data suggest that AATD testing should be offered to patients with COPD/emphysema and bronchiectasis.Keywords: SERPINA1, alpha-1-antitrypsin deficiency, bronchiectasis, asthma, diagnosis

Johanna I Lutter,1 Rudolf A Jörres,2 Tobias Welte,3 Henrik Watz,4 Benjamin Waschki,5 Peter Alter,6 Franziska C Trudzinski,7 Johan Ohlander,1,8 Jürgen Behr,9 Robert Bals,10 Michael Studnicka,11 Rolf Holle,12 Claus F Vogelmeier,6 Kathrin Kahnert9 1Institute of Health Economics and Health Care Management, Helmholtz Zentrum München GmbH - German Research Center for Environmental Health, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research, Munich, Germany; 2Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Comprehensive Pneumology Center Munich (CPC-M), Ludwig-Maximilians-Universität München, Munich 80336, Germany; 3Department of Pneumology, Hannover Medical School, Hannover 30625, Germany; 4Pulmonary Research Institute at Lungen Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf 22927, Germany; 5Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany; 6Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-University Marburg (UMR), Germany, Member of the German Center for Lung Research (DZL), Marburg 35043, Germany; 7Department of Diagnostic & Interventional Radiology, University Hospital of Heidelberg, Heidelberg, Germany; 8Institute for Risk Assessment Sciences, Utrecht University, Utrecht 3584 CM, Netherlands; 9Department of Internal Medicine V, University of Munich (LMU), Comprehensive Pneumology Center, Member of the German Center for Lung Research (DZL), Munich, 80336, Germany; 10Department of Internal Medicine V – Pulmonology, Allergology, Respiratory Intensive Care Medicine, Saarland University Hospital, Homburg 66424, Germany; 11Department of Pneumology, Paracelsus Medical University Salzburg, Universitätsklinikum Salzburg, Salzburg 5020, Austria; 12Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Ludwig-Maximilians-University Munich (LMU), Munich 81377, GermanyCorrespondence: Kathrin KahnertDepartment of Internal Medicine V, University of Munich (LMU), Comprehensive Pneumology Center, Member of the German Center for Lung Research (DZL), Ziemssenstr. 1, Munich 80336, GermanyEmail Kathrin.Kahnert@med.uni-muenchen.deBackground: Beyond smoking, several risk factors for the development of chronic obstructive pulmonary disease (COPD) have been described, among which socioeconomic status including education is of particular interest. We studied the contribution of education to lung function and symptoms relative to smoking in a group of never-smokers with COPD compared to a group of long-time ex-smokers with COPD.Methods: We used baseline data of the COSYCONET cohort, including patients of GOLD grades 1– 4 who were either never-smokers (n=150, age 68.5y, 53.3% female) or ex-smokers (≥ 10 packyears) for at least 10 years (n=616, 68.3y, 29.9% female). Socioeconomic status was analyzed using education level and mortality was assessed over a follow-up period of 4.5 years. Analyses were performed using ANOVA and regression models.Results: Spirometric lung function did not differ between groups, whereas CO diffusing capacity and indicators of lung hyperinflation/air-trapping showed better values in the never-smoker group. In both groups, spirometric lung function depended on the education level, with better values for higher education. Quality of life and 6-MWD were significantly different in never-smokers as well as patients with higher education. Asthma, alpha-1-antitrypsin deficiency, and bronchiectasis were more often reported in never-smokers, and asthma was more often reported in patients with higher education. Higher education was also associated with reduced mortality (hazard ratio 0.46; 95% CI 0.22– 0.98).Conclusion: Overall, in the COSYCONET COPD cohort, differences in functional status between never-smokers and long-time ex-smokers were not large. Compared to that, the dependence on education level was more prominent, with higher education associated with better outcomes, including mortality. These data indicate that non-smoking COPD patients’ socioeconomic factors are relevant and should be taken into account by clinicians.Keywords: COPD, never-smoker, education, socioeconomic status

Jaco Voorham,1,2 Simonetta Baldi,3 Luigi Santoro,4 Marjan Kerkhof,1,5 Marco Contoli,6 Leonardo M Fabbri,6 Huib AM Kerstjens,7 Jose Luis López-Campos,8 Nicolas Roche,9 Dave Singh,10 Claus F Vogelmeier,11 David B Price1,12 1Observational & Pragmatic Research Institute Pte Ltd, Singapore, Singapore; 2Data to Insights Research Solutions, Lisbon, Portugal; 3Department of Global Clinical Development, Chiesi SAS, Bois Colombes Cedex, France; 4Department of Global Clinical Development, Chiesi Farmaceutici S.p.A, Parma, Italy; 5Mescio Research, Blauwestad, The Netherlands; 6Section of Respiratory Medicine, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy; 7Department of Pulmonary Diseases, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands; 8Respiratory Diseases Unit, University Hospital Virgen Del Rocío, Seville, Spain; 9Service de Pneumologie, Hôpital Cochin, APHP, Centre-Université de Paris, Paris, France; 10University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK; 11Department of Internal Medicine, Pulmonary and Critical Care Medicine, University of Marburg, Member of the German Centre for Lung Research (DZL), Marburg, Germany; 12Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UKCorrespondence: David B PriceAcademic Primary Care, Division of Applied Health Sciences University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD 198785, UKTel +65 6962 3627Email dprice@opri.sgPurpose: This study aimed to evaluate the non-inferiority of initiating extrafine beclometasone dipropionate/formoterol fumarate (BDP/FF) versus double bronchodilation (long-acting beta-agonists [LABA]/long-acting muscarinic antagonists [LAMA]) among patients with a history of chronic obstructive pulmonary disease (COPD) exacerbations.Patients and Methods: A historical cohort study was conducted using data from the UK’s Optimum Patient Care Research Database. Patients with COPD ≥ 40 years at diagnosis were included if they initiated extrafine BDP/FF or any LABA/LAMA double therapy as a step-up from no maintenance therapy or monotherapy with inhaled corticosteroids (ICS), LAMA, or LABA and a history of ≥ 2 moderate/severe exacerbations in the previous two years. The primary outcome was exacerbation rate from therapy initiation until a relevant therapy change or end of follow-up. Secondary outcomes included rate of acute respiratory events, acute oral corticosteroids (OCS) courses, and antibiotic prescriptions with lower respiratory indication, modified Medical Research Council score (mMRC) ≥ 2, and time to first pneumonia diagnosis. The non-inferiority boundary was set at a relative difference of 15% on the ratio scale. Five potential treatment effect modifiers were investigated.Results: A total of 1735 patients initiated extrafine BDP/FF and 2450 patients initiated LABA/LAMA. The mean age was 70 years, 51% were male, 41% current smokers, and 85% had FEV1 < 80% predicted. Extrafine BDP/FF showed non-inferiority to LABA/LAMA for rate of exacerbations (incidence rate ratio [IRR] = 1.01 [95% CI 0.94– 1.09]), acute respiratory events (IRR = 0.98 [0.92– 1.04]), acute OCS courses (IRR = 1.01 [0.91– 1.11]), and antibiotic prescriptions (IRR = 0.99 [0.90– 1.09]), but not for mMRC (OR = 0.93 [0.69– 1.27]) or risk of pneumonia (HR = 0.50 [0.14– 1.73]). None of the a priori defined effect modifier candidates affected the comparative effectiveness.Conclusion: This study found that stepping up to extrafine BDP/FF from no maintenance or monotherapy was not inferior to stepping up to double bronchodilation therapy in patients with a history of exacerbations.Keywords: real-world, electronic health records, observational, comparative effectiveness, heterogeneity, chronic obstructive pulmonary disease

Roland Buhl,1 Michael Dreher,2 Stephanie Korn,1 Christian Taube,3 Christian Stock,4 Christoph M Zehendner,5 Anke Kondla,5 Claus F Vogelmeier6 1Pulmonary Department, Johannes Gutenberg University Mainz, Mainz, Germany; 2Clinic of Cardiology, Pneumology, Angiology and Internal Medicine Intensive Care, University Hospital RWTH Aachen, Aachen, Germany; 3Clinic for Pneumonology, University Medicine Essen – Ruhrlandklinik, Essen, Germany; 4Biostatistics + Data Sciences Corp, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany; 5HP Country Medical Affairs, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany; 6Department of Pneumology, University Hospital of Giessen and Marburg, Member of the German Center for Lung Research (DZL), Marburg, GermanyCorrespondence: Roland BuhlPulmonary Department, Johannes Gutenberg University Mainz, Langenbeckstraße 1, Mainz D-55131, GermanyTel +49 6131 17-7271Email roland.buhl@unimedizin-mainz.deBackground: The Global Initiative for Chronic Obstructive Lung Disease 2020 report recommends that patients with chronic obstructive pulmonary disease (COPD) suffering from persistent dyspnea, despite long-acting β2-agonist (LABA)/inhaled corticosteroid (ICS) maintenance therapy, are switched to either a long-acting muscarinic antagonist (LAMA)/LABA combination regimen or LAMA/LABA/ICS triple therapy. However, to date, no studies have investigated the direct switch from LABA/ICS to LAMA/LABA therapy—instead of switching to triple therapy—in a prospective, real-world, non-interventional setting.Methods: EVELUT® (NCT03954132) is an ongoing, prospective, open-label, multicenter, non-interventional study comparing the once-daily fixed-dose combination of tiotropium and olodaterol (tio/olo) versus any triple therapy (LAMA/LABA/ICS) in patients with COPD who are symptomatic despite LABA/ICS maintenance therapy. Patients with acute or frequent COPD exacerbations are excluded from the study. Participants will receive LABA/ICS maintenance treatment until Visit 1, followed by switching of treatment to tio/olo or LAMA/LABA/ICS. The primary endpoints are changes in modified Medical Research Council (mMRC) and COPD Assessment Test (CAT®) scores after approximately 12 weeks of treatment. Secondary endpoints are change in the patients’ general condition according to the Physician’s Global Evaluation score, the proportion of responders with a change in mMRC score of ≥ 1 and in CAT® score of ≥ 2, and patient satisfaction with the inhaler and therapy. The study is expected to enroll approximately 900 patients.Conclusion: EVELUT results are expected to add to the current real-world evidence informing therapeutic decisions for COPD in everyday clinical practice.Trial Registration: The European Union electronic Register of Post-authorisation Studies (EU PAS Register): EUPAS29784; the Federal Institute for Drugs and Medical Devices (BfArM): NIS Study No 7305; Clinicaltrials.gov: NCT03954132.Keywords: COPD, tiotropium/olodaterol, Spiolto® Respimat®, triple therapy, LAMA/LABA/ICS

Konstantinos Kostikas,1 Alexander J Mackay,2 Claus F Vogelmeier,3 Stefan-Marian Frent,4 Pritam Gupta,5 Donald Banerji,6 Francesco Patalano,7 Pascal J Pfister,7 Jadwiga A Wedzicha8 1Respiratory Medicine Department, University of Ioannina Medical School, Ioannina, Greece; 2National Heart and Lung Institute, Imperial College London, London, UK; 3Department of Medicine, Pulmonary and Critical Care Medicine, Philipps-Universität Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany; 4Department of Pulmonology, University of Medicine and Pharmacy Timisoara, Timisoara, Romania; 5Novartis Healthcare Pvt. Ltd., Hyderabad, India; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 7Novartis Pharma AG, Basel, Switzerland; 8Respiratory Clinical Science Section, National Heart and Lung Institute, Imperial College London, London, UKCorrespondence: Konstantinos KostikasRespiratory Medicine Department, University of Ioannina Medical School, Ioannina 45110, GreeceTel +30-6944780616Email ktkostikas@gmail.comBackground: Chronic obstructive pulmonary disease (COPD) exacerbations are difficult outcomes to measure in clinical trials. It would be valuable to be able to predict which patients are likely to benefit in terms of exacerbation prevention based on their early response in lung function and symptoms.Methods: This was a post-hoc analysis from the 52-week, randomized, double-blind, double-dummy, non-inferiority FLAME trial. Early clinically important improvement (ECII) was defined as achievement of minimal clinically important difference in trough forced expiratory volume in 1 second (FEV1; ≥ 100 mL increase) and one patient-reported outcome (PRO): either St. George’s Respiratory Questionnaire for COPD (≥ 4-unit reduction; D1), or COPD assessment test (≥ 2-point reduction; D2) at Week 4 or 12.Results: Approximately 18– 20% of patients achieved ECII at Week 4 or 12 post-randomization according to any of the two definitions. The rate of subsequent exacerbations was lower in patients who achieved ECII at Week 4 (D1: ratio of rates [95% CI], 0.85 [0.74 to 0.98]; D2, 0.88 [0.77 to 1.00]) or at Week 12 (D1, 0.85 [0.74 to 0.98]; D2, 0.86 [0.75 to 1.00]) versus patients not achieving ECII. Patients who achieved ECII experienced longer time-to-first exacerbation between Week 4 or 12 to end of study. More patients achieved ECII with indacaterol/glycopyrronium versus salmeterol/fluticasone according to both definitions at Week 4 (D1, odds ratio [95% CI], 1.69 [1.40 to 2.04]; D2, 1.61 [1.34 to 1.93]), and 12 (D1, 2.01 [1.66 to 2.44]; D2, 1.80 [1.48 to 2.18]).Conclusion: ECII is a novel composite endpoint, based on clinically relevant improvement in lung function and PROs in the early phase of treatment intervention that may predict subsequent exacerbation risk and may be used in clinical trials.Keywords: exacerbations, ECII, indacaterol/glycopyrronium, lung function, PROs

Martina Veith,1 Andreas Klemmer,1 Iker Anton,2 Rachid El Hamss,2 Noelia Rapun,2 Sabina Janciauskiene,3 Viktor Kotke,1 Christian Herr,4 Robert Bals,4 Claus Franz Vogelmeier,1 Timm Greulich1 1Department of Medicine, Pulmonary and Critical Care Medicine, Member of the German Center for Lung Research Marburg, University Medical Center Giessen And Marburg, Germany; 2Progenika Biopharma, S.A. A Grifols Company, Derio, Bizkaia, Spain; 3Department of Respiratory Medicine, Member of the German Center for Lung Research (DZL), Hannover Medical School, Biomedical Research in End Stage and Obstructive Lung Disease Hannover (BREATH), Hannover 30625, Germany; 4Department of Internal Medicine V, Pulmonology, Allergology, Respiratory and Intensive Care Medicine, Saarland Hospital, Homburg/Saar, GermanyCorrespondence: Martina VeithDepartment of Medicine, Pulmonary and Critical Care Medicine, Member of the German Center for Lung Research Marburg, University Medical Center Giessen and Marburg, Germany Tel +49 642 1586 4723Fax +49 642 158 6370Email veithm@staff.uni-marburg.dePurpose: Alpha-1-antitrypsin deficiency (AATD) is a rare hereditary condition resulting from the mutations in the SERPINA1 (serine protease inhibitor) gene and is characterized by low circulating levels of the alpha-1 antitrypsin (AAT) protein. The traditional algorithm for laboratory testing of AATD involves the analysis of AAT concentrations (nephelometry), phenotyping (isoelectric focusing, IEF), and genotyping (polymerase chain reaction, PCR); in selected cases, full sequencing of the SERPINA1 gene can be undertaken. New technologies arise that may make diagnosis easier and faster.Methods: We developed and evaluated a new diagnostic algorithm based on Luminex xMAP (multi-analyte profiling) technology using Progenika A1AT Genotyping Test. In an initial learning phase, 1979 samples from individuals suspected of having AATD were examined by both, a traditional and a “new” algorithm. In a second phase, 1133 samples were analyzed with the Luminex xMAP only.Results: By introducing a Luminex xMAP based algorithm, we were able to simultaneously identify 14 mutations in SERPINA1 gene (instead of two- S and Z-by using our old algorithm). Although the quantity of IEF assays remained unchanged, the nephelometric measurements and sequencing were reduced by 79% and 63.4%, respectively.Conclusion: The new method is convenient, fast and user-friendly. The application of the Luminex xMAP technology can simplify and shorten the diagnostic workup of patients with suspected AATD.Keywords: SERPINA1, diagnosis, Luminex xMAP technology, mutations

Norbert Königsdorfer,1 Rudolf A Jörres,1 Sandra Söhler,2 Tobias Welte,3 Jürgen Behr,4 Joachim H Ficker,5 Robert Bals,6 Henrik Watz,7 Johanna I Lutter,8 Tanja Lucke,1 Frank Biertz,9 Peter Alter,10 Claus F Vogelmeier,10 Kathrin Kahnert4 1Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Comprehensive Pneumology Center Munich (CPC-M), Ludwig-Maximilians-Universität München, Munich 80336, Germany; 2ASCONET Study Coordination Office, University of Marburg, Marburg 35043, Germany; 3Department of Pneumology, Hannover Medical School, Hannover 30625, Germany; 4Department of Internal Medicine V, University of Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, Munich 80336, Germany; 5Department of Respiratory Medicine, Allergology and Sleep Medicine, General Hospital Nuernberg, Paracelsus Medical University, Nuernberg, Germany; 6Department of Internal Medicine V, Pneumology, Allergology, Respiratory Intensive Care Medicine, Saarland University Hospital, Homburg 66424, Germany; 7Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North, Member of the German Center for Lung Research, Grosshansdorf 22927, Germany; 8Institute of Health Economics and Health Care Management, Helmholtz Zentrum München GmbH – German Research Center for Environmental Health, Comprehensive Pneumology Center Munich (CPC-M), Munich 85764, Germany; 9Institute for Biostatistics, Hannover Medical School, Hannover 30625, Germany; 10Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-University Marburg, Marburg 35043, GermanyCorrespondence: Kathrin KahnertDepartment of Internal Medicine V, University of Munich, Comprehensive Pneumology Center, Member of the German Center for Lung Research, Ziemssenstr. 1, Munich 80336, GermanyTel +49 89 4400 2590Email Kathrin.Kahnert@med.uni-muenchen.deBackground: Adherence to COPD medication is often considered to be lower than in other chronic diseases. In view of the frequent comorbidities of COPD, the economic impact of nonadherence and the potential for adverse effects, a direct comparison between the adherence to respiratory and nonrespiratory medication in the same patients seems of particular interest.Objectives: We aimed to investigate the intake of respiratory and nonrespiratory medication in the same patients with COPD and frequent comorbidities.Method: Within the COPD cohort COSYCONET, we contacted 1042 patients, mailing them a list with all medication regarding all their diseases, asking for regular, irregular and non-intake.Results: Valid responses were obtained in 707 patients covering a wide spectrum of drugs. Intake of LABA, LAMA or ICS was regular in 91.9% of patients, even higher for cardiovascular and antidiabetes medication but lower for hyperlipidemia and depression/anxiety medication. Regular intake of respiratory medication did not depend on GOLD groups A-D or grades 1–4, was highest in patients with concomitant cardiovascular disorders and was lowest for concomitant asthma. It was slightly larger for LAMA and LABA administered via combined compared to single inhalers, and lower when similar compounds were prescribed twice. Most differences did not reach statistical significance owing to the overall high adherence.Conclusion: Our results indicate a high adherence to respiratory medication in participants of a COPD cohort, especially in those with cardiovascular comorbidities. Compared to the lower adherence reported in the literature for COPD patients, our observations still suggest some room for improvement, possibly through disease management programs.Keywords: COPD, treatment adherence, respiratory medication, nonrespiratory medication

Peter Alter,1 Barbara A Mayerhofer,2 Kathrin Kahnert,3 Henrik Watz,4 Benjamin Waschki,5,6 Stefan Andreas,7,8 Frank Biertz,9 Robert Bals,10 Claus F Vogelmeier,1 Rudolf A Jörres2 1Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Marburg, Germany; 2Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the Center for Lung Research (DZL), Munich, Germany; 3Department of Internal Medicine V, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany; 4Pulmonary Research Institute at Lungen Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 5Department of Pneumology, LungenClinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 6Department of General and Interventional Cardiology, University Heart Center, Hamburg, Germany; 7Department of Cardiology and Pneumology, University Medical Center, Goettingen, Germany; 8Lung Clinic, Immenhausen, Germany; 9Institute for Biostatistics, Center for Biometry, Medical Informatics and Medical Technology, Hannover Medical School, Hannover, Germany; 10Department of Internal Medicine V - Pulmonology, Allergology, Intensive Care Medicine, Saarland University Hospital, Homburg, GermanyCorrespondence: Peter AlterDepartment of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Baldingerstrasse 1, Marburg 35033, GermanyTel +49 6 421 586 6140Email Alter@uni-marburg.de&#x00A0Rudolf A JörresInstitute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the Center for Lung Research (DZL), Ziemssenstrasse 1, Munich 80336, GermanyTel +49 8 944 005 2466Email Rudolf.Joerres@med.uni-muenchen.de &#x00A0Background: A substantial prevalence of cardiovascular disease is known for COPD, but detection of its presence, relationship to functional findings and contribution to symptoms remains challenging. The present analysis focusses on the cardiovascular contribution to COPD symptoms and their relationship to the patients’ diagnostic status, medication and echocardiographic findings.Methods: Patients from the COPD cohort COSYCONET with data on lung function, including FEV1, residual volume/total lung capacity (RV/TLC) ratio, diffusing capacity TLCO, and echocardiographic data on left ventricular ejection fraction (LVEF) and end-diastolic diameter (LVEDD), medical history, medication, modified British Medical Research Council dyspnea scale (mMRC) and Saint Georges Respiratory Questionnaire (SGRQ) were analyzed.Results: A total of 1591 patients (GOLD 0–4: n=230/126/614/498/123) fulfilled the inclusion criteria. Ischemic heart disease, myocardial infarction or heart failure were reported in 289 patients (18.2%); 860 patients (54%) received at least one cardiovascular medication, with more than one in many patients. LVEF56 mm was found in 204 patients (12.8%), of whom 74 (36.3%) had neither a cardiovascular history nor medication. Among 948 patients (59.6%) without isolated hypertension, there were 21/55 (38.2%) patients with LVEF56 mm, who lacked both a cardiac diagnosis and medication. LVEDD and LVEF were linked to medical history; LVEDD was dependent on RV/TLC and LVEF on FEV1. Exertional COPD symptoms were best described by mMRC and the SGRQ activity score. Beyond lung function, an independent link from LVEDD on symptoms was revealed.Conclusion: A remarkable proportion of patients with suspicious echocardiographic findings were undiagnosed and untreated, implying an increased risk for an unfavorable prognosis. Cardiac size and function were dependent on lung function and only partially linked to cardiovascular history. Although the contribution of LV size to COPD symptoms was small compared to lung function, it was detectable irrespective of all other influencing factors. However, only the mMRC and SGRQ activity component were found to be suitable for this purpose.Keywords: COPD, heart failure, echocardiography, medication, dyspnea, symptoms

Frits ME Franssen1,2, Peter Alter,3 Nadav Bar,4 Birke J Benedikter5,6, Stella Iurato,7 Dieter Maier,8 Michael Maxheim,3 Fabienne K Roessler,4 Martijn A Spruit,1–2,9 Claus F Vogelmeier,3 Emiel FM Wouters1,2, Bernd Schmeck3,5 On behalf of the SysMed-COPD consortium 1Department of Research and Education, CIRO, Horn, The Netherlands; 2Department of Respiratory Medicine, Maastricht University Medical Centre, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands; 3Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Marburg, Germany; 4Department of Chemical Engineering, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; 5Institute for Lung Research, Universities of Giessen and Marburg Lung Centre, Philipps-University Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany; 6Department of Medical Microbiology, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands; 7Viscovery Software GmbH, Vienna, Austria; 8Biomax Informatics AG, Planegg, Germany; 9REVAL - Rehabilitation Research Center, BIOMED - Biomedical Research Institute, Faculty of Rehabilitation Sciences, Hasselt University, Diepenbeek, BelgiumAbstract: Chronic airflow limitation is the common denominator of patients with chronic obstructive pulmonary disease (COPD). However, it is not possible to predict morbidity and mortality of individual patients based on the degree of lung function impairment, nor does the degree of airflow limitation allow guidance regarding therapies. Over the last decades, understanding of the factors contributing to the heterogeneity of disease trajectories, clinical presentation, and response to existing therapies has greatly advanced. Indeed, diagnostic assessment and treatment algorithms for COPD have become more personalized. In addition to the pulmonary abnormalities and inhaler therapies, extra-pulmonary features and comorbidities have been studied and are considered essential components of comprehensive disease management, including lifestyle interventions. Despite these advances, predicting and/or modifying the course of the disease remains currently impossible, and selection of patients with a beneficial response to specific interventions is unsatisfactory. Consequently, non-response to pharmacologic and non-pharmacologic treatments is common, and many patients have refractory symptoms. Thus, there is an ongoing urgency for a more targeted and holistic management of the disease, incorporating the basic principles of P4 medicine (predictive, preventive, personalized, and participatory). This review describes the current status and unmet needs regarding personalized medicine for patients with COPD. Also, it proposes a systems medicine approach, integrating genetic, environmental, (micro)biological, and clinical factors in experimental and computational models in order to decipher the multilevel complexity of COPD. Ultimately, the acquired insights will enable the development of clinical decision support systems and advance personalized medicine for patients with COPD.Keywords: chronic obstructive pulmonary disease, personalized medicine, systems medicine, review

Jørgen Vestbo,1 Claus F Vogelmeier,2 Mark Small,3 James Siddall,3 Robert Fogel,4 Konstantinos Kostikas4,51Division of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester, UK; 2Department for Pulmonary Medicine, Philipps-University of Marburg, Marburg, Germany; 3Respiratory Research, Adelphi Real World, Bollington, UK; 4Global Medical Affairs, Novartis Pharma AG, Basel, Switzerland; 5Respiratory Medicine Department, University of Ionnina Medical School, Ionnina, GreeceBackground: Blood eosinophils may predict response to inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) where ICS is recommended in patients at high risk of exacerbations. The proportion of patients who may benefit the most from ICS-based therapy was quantified in a real-world population.Materials and methods: European data from the Adelphi Real World Respiratory Disease Specific Programme™ 2017 survey were collected from consecutive COPD patients by participating physicians. Overall, 1,528 patients were assessable for Global Initiative for COPD (GOLD) 2017 status and were included in the analysis.Results: More GOLD D patients had elevated eosinophil counts compared with GOLD B. The proportions of GOLD D patients with a history of ≥2 exacerbations and eosinophil counts of ≥150, ≥300, and ≥400 cells/μL were 81.2%, 39.4%, and 24.6%, respectively. In total, 10.6% of the patients had ≥300 eosinophils/μL and a history of ≥2 exacerbations. ICS-based therapy was received by 41.5% of GOLD B and 68.0% of GOLD D patients.Conclusion: There was no apparent relation between ICS use and eosinophil blood count. There are differences in the distributions of patients with frequent exacerbations and/or high blood eosinophil counts and the use of ICS in COPD. These data may provide information for the implementation of future treatment recommendations.Keywords: COPD, exacerbations, inhaled corticosteroids, eosinophils, observational study

Timm Greulich,1 Sina Mager,1 Tanja Lucke,2 Andreas Rembert Koczulla,1 Robert Bals,3 Sebastian Fähndrich,3 Rudolf A Jörres,2 Peter Alter,1 Anne Kirsten,4 Claus Franz Vogelmeier,1 Henrik Watz4 1Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Centre Giessen and Marburg, Philipps-University, Member of the German Centre for Lung Research (DZL), Marburg, Germany; 2Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine Ludwig-Maximilians-Universität München, Munich, Germany; 3Department of Internal Medicine V, Pulmonology, Allergology, Respiratory and Intensive Care Medicine, Saarland Hospital, Homburg/Saar, Germany; 4Pulmonary Research Institute at Lungen Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Centre for Lung Research (DZL), Grosshansdorf, GermanyIt has been increasingly recognized that the numbers of blood eosinophils (eos) might be an important biomarker in patients with COPD to identify patients at risk for exacerbations and for treatment to inhaled corticosteroid (ICS) treatment or anti-interleukin-5 therapy.1–3 However, data about the stability of blood eos counts over time are rare. We used data from the multicenter COSYCONET study to analyze the variability of eos by strata over a period of 18 months.4

Roland Buhl,1 Carl-Peter Criée,2 Peter Kardos,3 Claus F Vogelmeier,4 Konstantinos Kostikas,5 Nadine S Lossi,6 Heinrich Worth7 1Pulmonary Department, Mainz University Hospital, Mainz, 2Department of Sleep and Respiratory Medicine, Evangelical Hospital Goettingen-Weende, Bovenden, 3Group Practice and Centre for Allergy, Respiratory and Sleep Medicine, Red Cross Maingau Hospital, Frankfurt am Main, 4Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-University Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany; 5WorldWide Medical Affairs Respiratory, Novartis Pharma AG, Basel, Switzerland; 6Clinical Research, Respiratory, Novartis Pharma GmbH, Nürnberg, 7Facharztforum Fürth, Fürth, Germany Background: No observational studies have evaluated the “real-world” effectiveness of dual bronchodilation comprising a long-acting β2-agonist plus a long-acting muscarinic antagonist vs that of triple therapy (long-acting β2-agonist plus long-acting muscarinic antagonist plus inhaled corticosteroid) in COPD.Materials and methods: DACCORD is a non-interventional, observational clinical study that recruited patients following COPD maintenance therapy initiation or change in maintenance therapy between or within therapeutic class. Given the non-interventional nature of the study, the decision to initiate or change medication had to be made by the patients’ physicians prior to inclusion in DACCORD. We used a matched-pairs analysis to compare disease progression in two patient groups: those receiving dual bronchodilation vs those receiving triple therapy (each group n=1,046).Results: In two subgroups of patients matched according to a broad range of demographic and disease characteristics, over 1 year, fewer patients receiving dual bronchodilation exacerbated than those receiving triple therapy (15.5% vs 26.6%; P

Peter Alter,1 Klaus F Rabe,2,3 Holger Schulz,4 Claus F Vogelmeier,1 Rudolf A Jörres5 1Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany; 2LungenClinic Grosshansdorf, Member of the German Center for Lung Research (DZL), Airway Research Center North (ARCN), Grosshansdorf, Germany; 3Christian-Albrechts University, Airway Research Center North (ARCN), Kiel, Germany; 4Helmholtz-Zentrum München, Institute of Epidemiology, German Research Center for Environmental Health, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany; 5Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany Introduction: For interpretation of body plethysmographic static hyperinflation, reference values are of crucial importance. Earliest reference values have been published by the European Coal and Steel Community (ECSC) and are based on sex, body height and age as predictors. As obesity can lead to a reduction of functional residual capacity (FRC) in lung-healthy subjects, more recent approaches included body weight or body surface area. This raises the question whether these models are appropriate in patients with COPD-induced hyperinflation. Method: Several FRC prediction models and their relation to body weight were analyzed in 1513 patients with stable COPD (mean [SD] age: 64.5 [8.2] years; GOLD grades 1–4: 219/722/484/88), a subset of the multicenter COPD and Systemic Consequences – Comorbidities Network cohort. Results: Absolute values of FRC were inversely related to body mass index (p

Peter Kardos,1 Ingo Mokros,2 Rüdiger Sauer,3,4 Claus F Vogelmeier5,6 1Group Practice and Centre for Allergy, Respiratory, and Sleep Medicine, at Maingau Red Cross Hospital, Frankfurt am Main, Germany; 2AstraZeneca GmbH, Unternehmensbereich Medizin, Wedel, Germany; 3Group Practice with Respiratory, Allergy and Sleep Unite, Lung Center, Ulm, Germany; 4Health Center Clinic Blaubeuren, Blaubeuren, Germany; 5Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-University Marburg, Marburg, Germany; 6German Center for Lung Research (DZL), Giessen, Germany Purpose: DINO and DACOTA were prospective, noninterventional studies assessing the health status and quality of life of patients with COPD newly treated with roflumilast 500 µg once-daily add-on therapy.Patients and methods: Patients were evaluated over 6 months. Clinical COPD questionnaire (CCQ) and COPD assessment test (CAT) scores were recorded at baseline and after 3 and 6 months. In DACOTA, post-bronchodilator FEV1 was recorded at each time point.Results: Of 5,462 and 3,645 patients recruited into DINO and DACOTA, respectively, 3,274 patients in DINO and 916 patients in DACOTA completed the 6-month visit. Almost all patients had severe or very severe airway obstruction; mean baseline CCQ total score was 3.9 in DINO and 3.7 in DACOTA. Overall, 33.8% of patients in DACOTA and 30.6% in DINO discontinued treatment prematurely. Significant and clinically relevant improvements in CCQ total scores were observed in both studies (mean change from baseline of 1.36 in DINO and 0.91 in DACOTA at Month 6 [all P

Claus F Vogelmeier,1 Kenneth R Chapman,2 Marc Miravitlles,3 Nicolas Roche,4 Jørgen Vestbo,5 Chau Thach,6 Donald Banerji,6 Robert Fogel,6 Francesco Patalano,7 Petter Olsson,8 Konstantinos Kostikas,7 Jadwiga A Wedzicha9 1Member of the German Center for Lung Research (DZL), Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Marburg, Germany; 2Asthma and Airway Centre, University Health Network and University of Toronto, Toronto, ON, Canada; 3Pneumology Department, Hospital Universitari Vall d’Hebron, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain; 4Service de Pneumologie AP-HP, Cochin Hospital, University Paris Descartes (EA2511), Paris, France; 5Institute of Infection, Immunity and Respiratory Medicine, The University of Manchester and Manchester University NHS Foundation Trust, Manchester, UK; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 7Novartis Pharma AG, Basel, Switzerland; 8Novartis Sverige AB, Täby, Sweden; 9National Heart and Lung Institute, Imperial College London, London, UK Background: The FLAME study compared once-daily indacaterol/glycopyrronium (IND/GLY) 110/50 µg with twice-daily salmeterol/fluticasone (SFC) 50/500 µg in symptomatic patients with moderate to very severe COPD and a history of exacerbations in the previous year. Methods: This prespecified and post hoc subgroup analysis evaluated treatment efficacy on 1) moderate/severe exacerbations according to prior exacerbation history and treatment, and 2) types of exacerbations according to health care resource utilization (HCRU) during 1-year follow-up. Results: IND/GLY reduced the rate of moderate/severe exacerbations versus SFC in patients with a history of 1 exacerbation (rate ratio [RR]: 0.83, 95% CI: 0.75–0.93), ≥2 exacerbations (RR: 0.85, 95% CI: 0.70–1.03) and ≥2 exacerbations or ≥1 hospitalization in the previous year (RR: 0.86, 95% CI: 0.74–1.00). Prolonged time-to-first exacerbation was observed in all the groups according to exacerbation history. Moderate/severe exacerbations decreased with IND/GLY versus SFC, independent of previous treatment. IND/GLY significantly reduced rates of moderate/severe exacerbations treated with antibiotics (RR: 0.79, 95% CI: 0.67–0.93) and systemic corticosteroids and antibiotics (RR: 0.80, 95% CI: 0.70–0.91); rates of exacerbations treated with systemic corticosteroids alone were comparable (RR: 0.99, 95% CI: 0.80–1.22). Conclusion: Overall, IND/GLY demonstrated consistent beneficial effects versus SFC on moderate/severe exacerbations, independent of prior exacerbation history or treatment. The efficacy of IND/GLY on exacerbation prevention was superior to SFC for exacerbations treated with antibiotics with/without systemic corticosteroids and was similar for exacerbations treated with systemic corticosteroids alone. Keywords: indacaterol/glycopyrronium, salmeterol/fluticasone, LABA/LAMA, LABA/ICS

Timm Greulich,1 Konstantinos Kostikas,2 Mina Gaga,3 Maryam Aalamian-Mattheis,2 Nadine S Lossi,4 Francesco Patalano,2 Xavier Nunez,5 Veronica A Pagano,5 Robert Fogel,6 Claus F Vogelmeier,1,* Andreas Clemens2,7,* 1University Medical Center Giessen and Marburg, German Center for Lung Research (DZL), Marburg, Germany; 2Novartis Pharma AG, Basel, Switzerland; 37th Respiratory Medicine Department, Athens Chest Hospital Sotiria, Athens, Greece; 4Novartis Pharma GmbH, Nürnberg, Germany; 5TFS Develop, Barcelona, Spain; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 7Heart Center Freiburg University, Cardiology and Angiology I, Faculty of Medicine, Freiburg, Germany *These authors contributed equally to this work Purpose: COPD is a progressive disease characterized by exacerbations and a decline in health status and lung function. Clinically important deterioration (CID) is a composite endpoint used to evaluate treatment efficacy. This analysis evaluated the impact of a direct switch to once-daily indacaterol/glycopyrronium 110/50 µg (IND/GLY) from previous monotherapy with a long-acting β2-agonist (LABA) or long-acting muscarinic antagonist (LAMA) or with an LABA and an inhaled corticosteroid (LABA + ICS) on reducing CID. Methods: CRYSTAL was a 12-week, prospective, multicenter, randomized, open-label study conducted in clinical practice settings. Three definitions of CID (D1–D3) were used, including: 1) ≥100 mL decrease in trough forced expiratory volume in 1 second (FEV1), 2) ≥1 point decrease in transition dyspnea index (TDI) and/or ≥0.4 points increase in clinical COPD questionnaire score (CCQ), or 3) an acute moderate/severe exacerbation (AECOPD). In D1 and D2, either TDI or CCQ was evaluated along with FEV1 and AECOPD, whereas in D3, all 4 parameters were included. ClinicalTrials.gov number: NCT01985334. Results: Of the 2,159 patients analyzed, 1,622 switched to IND/GLY and 537 continued their baseline treatments. The percentage of patients with a CID was significantly lower after a direct switch to IND/GLY versus LABA or LAMA using all 3 CID definitions (D1: odds ratio [OR] 0.41 [95% CI: 0.30–0.55]; D2: OR 0.41 [95% CI: 0.31–0.55]; D3: OR 0.39 [95% CI: 0.29–0.52]). Compared with LABA + ICS, IND/GLY also reduced the risk of CID (D1: OR 0.76 [95% CI: 0.56–1.02]; D2: OR 0.75 [95% CI: 0.56–1.00]; D3: OR 0.67 [95% CI: 0.51–0.89]). Conclusion: In this analysis, IND/GLY reduced the risk of a CID in moderate COPD patients after direct switch from LABA + ICS or LABA or LAMA in real-life clinical practice. Keywords: clinically important deterioration/CID, direct-switch, pragmatic, open-label, clinical COPD questionnaire/CCQ, transition dyspnea index/TDI

Margarethe E Wacker,1 Katharina Kitzing,1,2 Rudolf A Jörres,3 Reiner Leidl,1,4 Holger Schulz,5 Stefan Karrasch,3,5 Annika Karch,6 Armin Koch,6 Claus F Vogelmeier,7 Rolf Holle1 On behalf of the COSYCONET Study Group 1Institute of Health Economics and Health Care Management, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research, Neuherberg, 2Institute for Medical Information Processing, Biometrics and Epidemiology (IBE), LMU Munich, 3Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, 4Institute of Health Economics and Health Care Management, Munich Center of Health Sciences, Ludwig-Maximilians-Universität München, Munich, 5Institute of Epidemiology I, Helmholtz Zentrum Mu¨nchen GmbH, German Research Center for Environmental Health, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research, Neuherberg, 6Institute for Biostatistics, Hannover Medical School, Hannover, 7Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-University Marburg, Member of the German Center for Lung Research, Marburg, Germany Background: Although patients with COPD often have various comorbidities and symptoms, limited data are available on the contribution of these aspects to health care costs. This study analyzes the association of frequent comorbidities and common symptoms with the annual direct and indirect costs of patients with COPD. Methods: Self-reported information on 33 potential comorbidities and symptoms (dyspnea, cough, and sputum) of 2,139 participants from the baseline examination of the German COPD cohort COSYCONET was used. Direct and indirect costs were calculated based on self-reported health care utilization, work absence, and retirement. The association of comorbidities, symptoms, and COPD stage with annual direct/indirect costs was assessed by generalized linear regression models. Additional models analyzed possible interactions between COPD stage, the number of comorbidities, and dyspnea. Results: Unadjusted mean annual direct costs were €7,263 per patient. Other than COPD stage, a high level of dyspnea showed the strongest driving effect on direct costs (+33%). Among the comorbidities, osteoporosis (+38%), psychiatric disorders (+36%), heart disease (+25%), cancer (+24%), and sleep apnea (+21%) were associated with the largest increase in direct costs (p

Antonio R Anzueto,1,2 Claus F Vogelmeier,3 Konstantinos Kostikas,4 Karen Mezzi,4 Sebastian Fucile,5 Giovanni Bader,4 Steven Shen,5 Donald Banerji,5 Robert Fogel5 1University of Texas Health Science Center, 2South Texas Veterans Healthcare System, University of Texas, San Antonio, TX, United States; 3Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Marburg, Germany; 4Novartis Pharma AG, Basel, Switzerland; 5Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States Background: Endpoints that evaluate deterioration rather than improvement of disease may have clinical utility in COPD. In this analysis, we compared the effects of different maintenance treatments on the prevention of clinically important deterioration (CID) in moderate-to-severe COPD patients.Methods: Data were analyzed from three 26-week studies comparing indacaterol/glycopyrronium (IND/GLY) with tiotropium (TIO) or salmeterol/fluticasone (SFC). Two definitions of CID were used; each was a composite of three outcome measures typically associated with COPD. Definition 1 (D1) comprised a ≥100 mL decrease in forced expiratory volume in 1 second (FEV1), a ≥4-unit increase in St George’s Respiratory Questionnaire, and a moderate-to-severe COPD exacerbation. In Definition 2 (D2), a ≥1-unit decrease in transition dyspnea index replaced FEV1.Results: Using D1, IND/GLY significantly reduced the risk of first or sustained CID versus either TIO (hazard ratio 0.72 [0.61, 0.86], P=0.0003 and 0.73 [0.61, 0.89], P=0.001) or SFC (0.67 [0.57, 0.80] and 0.63 [0.52, 0.77], both P