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Janelle Yorke,1,2 Naimat Khan,1,3 Adam Garrow,1 Sarah Tyson,1 Dave Singh,1,3 Jorgen Vestbo,1,4 Paul W Jones5 1Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; 2Christie Patient Centred Research, The Christie NHS Foundation Trust, Whittington, Manchester, UK; 3Medicines Evaluation Unit, Wythenshawe, Manchester, UK; 4Department of Respiratory Medicine, Wythenshawe Hospital, Manchester, UK; 5St George’s Hospital, University of London, London, UKCorrespondence: Janelle Yorke, Tel +44920 264411, Email janelle.yorke@nhs.netPurpose: The modified-Medical Research Council (mMRC) breathlessness scale consists of five grades that contain of a description of different activities. It has wide utility in the assessment of disability due to breathlessness but was originally developed before the advent of modern psychometric methodology and, for example contains more than one activity per grade. We conducted an evaluation of the mMRC structure.Patients and Methods: Cognitive debriefing was conducted with COPD patients to elicit their understanding of each mMRC activity. In a cross-sectional study, patients completed the mMRC scale (grades 0– 4) and an MRC-Expanded (MRC-Ex) version consisting of 10-items, each containing one mMRC activity. Each activity was then given a 4-point response scale (0 “not at all” to 4 “all of the time”) and all 10 items were given to 203 patients to complete Rasch analysis and assess the pattern of MRC item severity and its hierarchical structure.Results: Cognitive debriefing with 36 patients suggested ambiguity with the term “strenuous exercise” and perceived severity differences between mMRC activities. 203 patients completed the mMRC-Ex. Strenuous exercise was located third on the ascending severity scale. Rasch identified the mildest term was “walking up a slight hill” (logit − 2.76) and “too breathless to leave the house” was the most severe (logit 3.42).Conclusion: This analysis showed that items that were combined into a single mMRC grade may be widely separated in terms of perceived severity when assessed individually. This suggests that mMRC grades as a measure of individual disability related to breathlessness contain significant ambiguity due to the combination of activities of different degrees of perceived severity into a single grade.Keywords: psychometrics, Rasch analysis, patient reported outcomes, qualitative, scale development

Andras Bikov,1,2 Peter Lange,3,4 Julie A Anderson,5 Robert D Brook,6 Peter MA Calverley,7 Bartolome R Celli,8 Nicholas J Cowans,9 Courtney Crim,10 Ian J Dixon,9 Fernando J Martinez,11 David E Newby,12 Julie C Yates,10 Jørgen Vestbo1,2 1Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK; 2Division of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester, UK; 3Medical Department, Herlev and Gentofte Hospital, Herlev, Denmark; 4Section of Epidemiology, Department of Public Health, University of Copenhagen, Copenhagen, Denmark; 5Research & Development, GlaxoSmithKline, Middlesex, UK; 6University of Michigan Health System, Ann Arbor, MI, USA; 7University of Liverpool, Department of Medicine, Clinical Sciences Centre, University Hospital Aintree, Liverpool, UK; 8Pulmonary and Critical Care Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 9Statistics & Programming, Veramed Ltd., Twickenham, UK; 10Research & Development, GlaxoSmithKline, Research Triangle Park, NC, USA; 11Division of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, NY, USA; 12British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UKCorrespondence: Andras Bikov 2nd Floor ERC Building, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UKTel +36203141599Fax +441612915730Email andras.bikov@gmail.comPurpose: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide. Impaired lung function is associated with heightened risk for death, cardiovascular events, and COPD exacerbations. However, it is unclear if forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) differ in predictive value.Patients and Methods: Data from 16,485 participants in the Study to Understand Mortality and Morbidity (SUMMIT) in COPD were analyzed. Patients were grouped into quintiles for each lung function parameter (FEV1 %predicted, FVC %predicted, FEV1/FVC). The four highest quintiles (Q2–Q5) were compared to the lowest (Q1) to assess their relationship with all-cause mortality, cardiovascular events, and moderate-to-severe and severe exacerbations. Cox-regression was used, adjusted for age, sex, ethnicity, body-mass index, smoking status, previous exacerbations, cardiovascular disease, treatment, and modified Medical Research Council dyspnea score.Results: Compared to Q1 (< 53.5% FEV1 predicted), increasing FEV1 quintiles (Q2 53.5– 457.5% predicted, Q3 57.5– 461.6% predicted, Q4 61.6– 465.8% predicted, and Q5 ≥ 65.8%) were all associated with significantly decreased all-cause mortality (20% (4– 34%), 28% (13– 40%), 23% (7– 36%), and 30% (15– 42%) risk reduction, respectively). In contrast, a significant risk reduction (21% (4– 35%)) was seen only between Q1 and Q5 quintiles of FVC. Neither FEV1 nor FVC was associated with cardiovascular risk. Increased FEV1 and FEV1/FVC quintiles were also associated with the reduction of moderate-to-severe and severe exacerbations while, surprisingly, the highest FVC quintile was related to the heightened exacerbation risk (28% (8– 52%) risk increase).Conclusion: Our results suggest that FEV1 is a stronger predictor for all-cause mortality than FVC in moderate COPD patients with heightened cardiovascular risk and that subjects with moderate COPD have very different risks.Keywords: airflow limitation, cardiovascular risk, exacerbation, lung function, lung volumes, death rate

Lasse L Langholm,1,2 Sarah Rank Rønnow,1,3 Jannie MB Sand,1 Diana Julie Leeming,1 Ruth Tal-Singer,4 Bruce E Miller,4 Jørgen Vestbo,5 Morten A Karsdal,1 Tina Manon-Jensen1 1Nordic Bioscience A/S, Herlev, Denmark; 2University of Copenhagen, Faculty of Health and Medical Sciences, Department of Biomedical Sciences, Copenhagen, Denmark; 3University of Southern Denmark, The Faculty of Health Science, Odense, Denmark; 4Respiratory Medical Innovation, Value Evidence & Outcomes, GSK R&D, Collegeville, PA, USA; 5Division of Infection, Immunity and Respiratory Medicine, University of Manchester, and Manchester University NHS Foundation Trust, Manchester, UKCorrespondence: Lasse L LangholmNordic Bioscience A/S, Herlev Hovedgade 205-207, Herlev 2730, DenmarkTel +45 4452 5252Fax +45 4452 5251Email lla@nordicbio.comBackground: Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and lung tissue deterioration. Given the high vascularity of the lung, von Willebrand factor (VWF), a central component of wound healing initiation, has previously been assessed in COPD. VWF processing, which is crucial for regulating the primary response of wound healing, has not been assessed directly. Therefore, this study aimed to characterize wound healing initiation in COPD using dynamic VWF-processing biomarkers and to evaluate how these relate to disease severity and mortality.Methods: A cross-sectional analysis of plasma samples from the ECLIPSE study collected at year 1 from moderate to very severe COPD subjects (GOLD 2– 4, n=984) was performed. We applied competitive neo-epitope ELISAs specifically targeting the formation of and ADAMTS13-processed form of VWF, VWF-N and VWF-A, respectively.Results: VWF-A and VWF-N were significantly increased (VWF-N, p=0.01; VWF-A, p=0.0001) in plasma of symptomatic (mMRC score ≥ 2) compared to asymptomatic/mild symptomatic COPD subjects. Increased VWF-N and VWF-A levels were specifically associated with emphysema (VWF-N, p< 0.0001) or prior exacerbations (VWF-A, p=0.01). When dichotomized, high levels of both biomarkers were associated with increased risk of all-cause mortality (VWF-N, HR 3.5; VWF-A, HR 2.64).Conclusion: We demonstrate that changes in VWF processing were related to different pathophysiological aspects of COPD. VWF-N relates to the chronic condition of emphysema, while VWF-A was associated with the more acute events of exacerbations. This study indicates that VWF-A and VWF-N may be relevant markers for characterization of disease phenotype and are associated with mortality in COPD.Study Identifier: NCT00292552; GSK study code SCO104960.Keywords: von Willebrand factor processing, COPD, emphysema, exacerbations, increased mortality risk

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

Ejvind Frausing Hansen,1 Jens Dahlgaard Hove,1 Charlotte Sandau Bech,1 Jens-Ulrik Stæhr Jensen,2 Thomas Kallemose,3 Jørgen Vestbo4 1Medical Unit, Amager and Hvidovre Hospital, Copenhagen, Denmark; 2Medical Department, Herlev and Gentofte Hospital, Copenhagen, Denmark; 3Clinical Research Center, Amager and Hvidovre Hospital, Copenhagen, Denmark; 4School of Biological Sciences, University of Manchester and Manchester University NHS Foundation Trust, Manchester, UK Purpose: It is a challenge to control oxygen saturation (SpO2) in patients with exacerbations of COPD during admission. We tested a newly developed closed-loop system, O2matic®, and its ability to keep SpO2 within a specified interval compared with manual control by nursing staff. Patients and methods: We conducted a crossover trial with patients admitted with an exacerbation of COPD and hypoxemia (SpO2 ≤88% on room air). Patients were monitored with continuous measurement of SpO2. In random order, they had 4 hours with manually controlled oxygen and 4 hours with oxygen delivery controlled by O2matic. Primary outcome was time within a prespecified SpO2 target interval. Secondary outcomes were time with SpO2

Naimat Khan,1 Jørgen Vestbo,2 Adam Garrow,3 Pradeep Karur,4 Umme Kolsum,5 Sarah Tyson,6 Dave Singh,7 Janelle Yorke8 1The Medicines Evaluation Unit, Wythenshawe Hospital, Manchester, UK; 2University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK; 3Division of Population Health, University of Manchester, Manchester, UK; 4Medicines Evaluation Unit, Manchester, UK; 5University of Manchester, Manchester, UK; 6University of Manchester, School of Health Sciences, Manchester Academic Health Sciences Centre, Manchester, UK; 7University of Manchester, The Medicines Evaluation Unit, Manchester, UK; 8University of Manchester, School of Health Sciences, Manchester, UK Background: In COPD disturbed sleep is related to exacerbation frequency, poor quality of life, and early mortality. We developed the Manchester Respiratory-related Sleep Symptoms scale (MaRSS) to assess sleep-time symptoms in COPD. Methods: Focus groups including COPD and age-matched controls were used to develop an item-list, which was then administered to COPD patients and age-matched controls in a cross-sectional study. Hierarchical and Rasch analysis informed item selection and scale unidimensionality. Construct validity was examined using Pearson’s correlation with the Sleep Problems Index, St George’s Respiratory Questionnaire (SGRQ), and FACIT-Fatigue scale. MaRSS change scores from baseline (stable) to exacerbation were assessed in a separate substudy of COPD patients. Results: Thirty-six COPD patients and nine age-matched controls produced an initial 26-item list. The cross-sectional study involved 203 COPD patients (male: 63%, mean age 64.7 years) and 50 age-matched controls (male: 56%, mean age 65.8 years). Eighteen items were removed to develop an eight-item unidimensional scale covering breathlessness, chest tightness, cough, sputum production, lack of sleep, and medication use. MaRSS scores significantly correlated with sleep problems, SGRQ Total, and FACIT-Fatigue (r=0.58–0.62) and demonstrated a good fit to the Rasch model (chi-squared=29.2; P=0.04). In the substudy, MaRSS scores demonstrated a moderate effect size from baseline to exacerbation visit in 27 patients with 32 exacerbation episodes (Cohen’s d=0.6). Conclusion: The MaRSS is a reliable, valid, and clinically responsive measure of respiratory-related symptoms that disturb sleep. It is simple to use and score, making it suitable for research and clinical practice. Keywords: COPD, sleep, dyspnea, cough, sputum, outcome measure

Alicia Gayle,1 Scott Dickinson,2 Kevin Morris,1 Chris Poole,1 Alexander G Mathioudakis,3 Jørgen Vestbo3,4 1Market Access, Boehringer Ingelheim Ltd, Bracknell, UK; 2Medical and Scientific Affairs, Boehringer Ingelheim Ltd, Bracknell, UK; 3Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK; 4Manchester Academic Health Sciences Centre, Manchester University NHS Foundation Trust, Manchester, UK Purpose: The changes in grading of disease severity and treatment recommendations for patients with COPD in the 2017 GOLD strategy may present an opportunity for reducing treatment burden for the patients and costs to the health care system. The aim of this study was to assess the implications of the GOLD 2017 grading system in terms of change in distribution across GOLD groups A–D for existing patients in UK primary care and estimate the potential cost savings of implementing GOLD 2017 treatment recommendations in UK primary care.Patients and methods: Using electronic health record data from the Clinical Practice Research Datalink (CPRD), patients aged ≥35 years with spirometry-confirmed COPD, receiving care during 2016, were included. The cohort was graded according to the GOLD 2017 groups (A–D), and treatment costs were calculated, according to corresponding recommendations, to observe the difference in actual vs predicted costs.Results: When applying GOLD 2013 criteria, less than half of the cohort (46%) was assigned to GOLD A or B, as compared to 86% when applying the GOLD 2017 grading. The actual mean annual maintenance treatment cost was £542 per patient vs a predicted £389 for treatment according to the 2017 GOLD strategy.Conclusion: There is a potential to make significant cost savings by implementing the grading and treatment recommendations from the 2017 GOLD strategy. Keywords: COPD, GOLD, severity, economics

Andreas Ronit,1 Thomas Kristensen,2 Yunus Çolak,3 Jørgen Tobias Kühl,4 Anna Kalhauge,2 Peter Lange,5,6 Børge G Nordestgaard,3,7 Jørgen Vestbo,8 Susanne D Nielsen,1 Klaus F Kofoed2,4 1Department of Infectious Diseases 8632, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; 2Department of Radiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; 3Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; 4Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; 5Department of Public Health, Section of Social Medicine, University of Copenhagen, Copenhagen, Denmark; 6Medical Unit, Respiratory Section, Hvidovre Hospital, Copenhagen University Hospital, Hvidovre, Denmark; 7Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 8Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK Objectives: Cardiovascular disease is often associated with COPD. Lung density quantification of images obtained from cardiac computed tomography (CT) scans would allow simultaneous evaluation of emphysema and coronary artery calcification score and provide further mechanistic insight into the relationship between these syndromes.Patients and methods: We assessed the agreement between lung density indices obtained by cardiac and full-lung CT scans. Paired cardiac and chest CT scans were assessed in 156 individuals with and without airflow limitation. Quantitative threshold indices of low attenuation area (LAA) and 15th percentile density index (PD15) were compared in terms of precision using Spearman’s correlation coefficient, accuracy using concordance correlation coefficient (CCC), and relative accuracy using P15 and P30. We also assessed the relationship between visually and quantitatively determined emphysema and used receiver operating characteristic curves to evaluate the ability of lung density indices to discriminate airflow limitation.Results: Correlation coefficients between lung density indices obtained from cardiac and chest CT scans were 0.49 for percent LAA (%LAA)-950 and 0.71 for PD15. Corresponding values for CCC, P15, and P30 were 0.33, 3.2, and 5.1, respectively, for %LAA-950, and 0.34, 17.3, and 37.8, respectively, for PD15. For both cardiac and chest CT scans, visually determined emphysema was associated with higher %LAA-950 and lower PD15, and the ability of %LAA-950 and PD15 to discriminate airflow limitation were comparable.Conclusion: Although chest CT imaging is preferable, cardiac CT imaging may also be used for lung emphysema quantification where association measures are of primary interest. Keywords: agreement, cardiac CT, chest CT, chronic obstructive pulmonary disease, emphysema, lung density

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

Dave Singh,1 Massimo Corradi,2 Monica Spinola,3 Alberto Papi,4 Omar S Usmani,5 Mario Scuri,3 Stefano Petruzzelli,3 Jørgen Vestbo1 1Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK; 2Department of Medicine and Surgery, University of Parma, Parma, Italy; 3Chiesi Farmaceutici SpA, Parma, Italy; 4Department of Medical Sciences, Research Centre on Asthma and COPD, University of Ferrara, Ferrara, Italy; 5National Heart and Lung Institute, Imperial College London, London, UK Abstract: The goals of COPD therapy are to prevent and control symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance. The triple combination therapy of inhaled corticosteroids (ICSs), long-acting beta2 agonists (LABAs), and long-acting muscarinic antagonists (LAMAs) has become an option for maintenance treatment of COPD and as a “step-up” therapy from single or double combination treatments. There is evidence that triple combination ICS/LABA/LAMA with different inhalers improves lung function, symptoms, and health status and reduces exacerbations. A new triple fixed-dose combination of extrafine beclomethasone dipropionate (100 µg/puff)/formoterol fumarate (6 µg/puff)/glycopyrronium bromide (12.5 µg/puff) has been developed as a hydrofluoroalkane pressurized metered dose inhaler. Two large pivotal studies showed that this extrafine fixed ICS/LABA/LAMA triple combination is superior to fixed ICS/LABA combined therapy and also superior to the LAMA tiotropium in terms of lung function and exacerbation prevention in COPD patients at risk of exacerbation. This review considers the new information provided by these clinical trials of extrafine triple therapy and the implications for the clinical management of COPD patients. Keywords: COPD, inhaled triple therapy, beclomethasone dipropionate, formoterol fumarate and glycopyrronium bromide

Jens Dollerup,1 Jørgen Vestbo,2 Tarita Murray-Thomas,3 Alan Kaplan,4 Richard J Martin,5 Emilio Pizzichini,6 Marcia M M Pizzichini,6 Anne Burden,7 Jessica Martin,7 David B Price7,8 1Dollerup Medical Consultancy, Kongens Lyngby, Denmark; 2Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, University of Manchester, Manchester, UK; 3Clinical Practice Research Datalink, Medicines and Healthcare products Regulatory Agency, London, UK; 4Family Physician Airways Group of Canada, Richmond Hill, ON, Canada; 5National Jewish Health, Denver, CO, USA; 6Federal University of Santa Catarina, Santa Catarina, Brazil; 7Observational and Pragmatic Research Institute Pte Ltd, Singapore; 8Centre for Academic Primary Care, University of Aberdeen, Aberdeen, UK Background: Previous research suggests exposure to nicotine replacement therapy (NRT) may be associated with an increased risk of cardiovascular disease (CVD).Methods: Using data from the United Kingdom’s Clinical Practice Research Datalink, this study aimed to evaluate CVD events and survival among individuals who attempted smoking cessation with the support of NRT compared with those aided by smoking cessation advice only. We studied CVD outcomes over 4 and 52 weeks in 50,214 smokers attempting to quit – 33,476 supported by smoking cessation advice and 16,738 with the support of NRT prescribed by their primary care physician. Patients were matched (2 smoking cessation advice patients:1 NRT patient) on demographic and clinical characteristics during a baseline year preceding their quit attempt. Cox proportional hazard regression, conditional negative binomial regression model, and conditional logistic regression were used to analyze data.Results: Mean (standard deviation) population age was 47 (11.2) years; 51% were females. Time to first diagnosis of ischemic heart disease (IHD) among NRT and smoking cessation advice patients was similar within the first 4 weeks, but shorter for NRT patients over 52 weeks (hazard ratio [HR]: 1.35, 95% confidence interval [CI]: 1.03–1.77). A similar trend was observed for cerebrovascular disease (HR: 1.54, 95% CI: 1.08–2.19). NRT patients with a prior diagnosis of IHD or cerebrovascular disease had a higher rate of primary or secondary care consultations for IHD or cerebrovascular disease by 52 weeks (rate ratio: 1.50, 95% CI: 1.14–1.99). Patients prescribed NRT had a shorter survival time over 52 weeks, compared with those receiving advice only (HR: 1.39, 95% CI: 1.09–1.76).Conclusion: Our findings suggest that treatment with NRT over 4 weeks does not appear to have an impact on cardiovascular risks. However, a longer follow-up period of 52 weeks resulted in an increase in cardiovascular events for patients prescribed NRT, compared with those receiving smoking cessation advice only.ENCePP registration ENCePP/SDPP/4238 Keywords: smokers, cardiovascular, risk, nicotine replacement therapy, smoking cessation advice

Adam P Garrow,1,2 Janelle Yorke,2 Naimat Khan,1 Jørgen Vestbo,3 Dave Singh,1 Sarah Tyson1 1University of Manchester Medicines Evaluation Unit, University Hospital of South Manchester Foundation Trust, 2School of Nursing, Midwifery and Social Work, University of Manchester, 3The University of Manchester Academic Health Science Centre, University Hospital South Manchester NHS Foundation Trust, Manchester, UK Background: Sleep problems are common in patients with chronic obstructive pulmonary disease (COPD), but the validity of patient-reported outcome measures (PROMs) that measure sleep dysfunction has not been evaluated. We have reviewed the literature to identify disease-specific and non-disease-specific sleep PROMs that have been validated for use in COPD patients. The review also examined the psychometric properties of identified sleep outcome measures and extracted point and variability estimates of sleep instruments used in COPD studies. Methods: The online EMBASE, MEDLINE, PsycINFO, and SCOPUS databases for all years to May 2014 were used to source articles for the review. The review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Criteria from the Medical Outcomes Trust Scientific Advisory Committee guidelines were used to evaluate the psychometric properties of all sleep PROMs identified. Results: One COPD-specific and six non-COPD-specific sleep outcome measures were identified and 44 papers met the review selection criteria. We only identified one instrument, the COPD and Asthma Sleep Impact Scale, which was developed specifically for use in COPD populations. Ninety percent of the identified studies used one of two non-disease-specific sleep scales, ie, the Pittsburgh Sleep Quality Index and/or the Epworth Sleep Scale, although neither has been tested for reliability or validity in people with COPD. Conclusion: The results highlight a need for existing non-disease-specific instruments to be validated in COPD populations and also a need for new disease-specific measures to assess the impact of sleep problems in COPD. Keywords: sleep, symptom assessment, chronic obstructive pulmonary disease, systematic review

Ingrid L Titlestad,1 Annmarie T Lassen,2 Jørgen Vestbo1,3 1Department of Respiratory Medicine, 2Department of Emergency Medicine, Odense University Hospital, University of Southern Denmark, Odense, Denmark; 3Respiratory Research Group, Manchester Academic Health Sciences Centre, University Hospital South Manchester NHS Foundation Trust, University of Manchester, Manchester, UK Abstract: Implementation of noninvasive ventilation (NIV) as an add-on treatment has been routinely used in a non-intensive care setting since 2004 for patients with chronic obstructive pulmonary disease (COPD) and acute hypercapnic respiratory failure at a university hospital in Denmark. Although randomized controlled trials show lowered mortality rates in highly selected patients with acute exacerbation and respiratory failure, there are only few reports on long-term survival after receiving NIV. We present long-term all-cause mortality data from patients receiving NIV for the first time. Method: Data from medical records were retrospectively retrieved from all patients receiving NIV for the first time after being admitted acutely to an acute medical ward and further transfer to a respiratory ward with respiratory failure and a diagnosis of COPD in the period January 1, 2005 to December 31, 2007; patients were followed until January 2012. Demographic data collected included age, sex, diagnoses at discharge, and, when present, FEV1; a “not-to-intubate” order was also registered when listed. Results: In total, 253 patients (143 female, 110 male) received NIV for the first time. The median age was 72 years (range 46–91 years). The 30-day mortality rate was 29.3%. The 5-year survival rate was 23.7%. Women showed a trend towards better survival than men (25.7% vs 19.2%, P = 0.25), and the trend was even more pronounced for patients with COPD. Conclusion: The mortality rate of patients receiving NIV is high, as expected in a real-life setting, but with a 5-year survival rate of 23.7% with a trend towards more female than male long-term survivors. Keywords: COPD, acute respiratory failure, NIV, long-term survival

Jørgen VestboUniversity of Manchester, Manchester, UKI read with interest the paper entitled "Diagnosis of airway obstruction in the elderly: contribution of the SARA study" by Sorino et al in a recent issue of this journal.1 Being involved in the Global Initiative for Obstructive Lung Diseases (GOLD), it is nice to see the interest sparked by the GOLD strategy document. However, in the paper by Sorino et al, there are a few misunderstandings around GOLD and the fixed ratio (forced expiratory volume in 1 second/forced volume vital capacity < 0.70) that need clarification.View original paper by Sorino and colleagues.

Objectives: Chronic obstructive pulmonary disease (COPD) is underdiagnosed in the general population and possibly also in people living with HIV (PLWH). We evaluated the diagnostic performance of symptoms and risk factors for assessment of airflow limitation in PLWH and in uninfected controls. Methods: Spirometry was performed in the Copenhagen Comorbidity in HIV Infection (COCOMO) study and Copenhagen General Population Study (CGPS), and airflow limitation was defined by forced expiratory volume in 1 s/forced vital capacity < lower limit of normal. We calculated the sensitivity, specificity, predictive values and area under the curve (AUC) of symptoms and risk factors for assessment of airflow limitation in PLWH and uninfected controls. Results: A total of 1083 PLWH and 12 074 uninfected controls were included in the study. The sensitivity for sputum, chronic cough, breathlessness, wheezing, current and cumulative smoking and self‐reported COPD was higher, but the specificity lower, in PLWH than in uninfected controls. The negative and positive predictive values were largely similar between the groups. The AUCs were similar or slightly higher in PLWH and highest for > 20 pack‐years smoked [0.65; 95% confidence interval (CI) 0.58–0.72] and wheezing (0.64; 95% CI 0.57–0.71). A summed score for five variables was associated with slightly higher AUC in PLWH compared with uninfected controls [0.71 (95% CI 0.63–0.79) versus 0.65 (95% CI 0.63–0.68), respectively; P = 0.06]. Conclusions: Clinical variables were relatively poor discriminators of airflow limitation in PLWH and uninfected controls. Active COPD case finding by screening for symptoms and relevant exposures, as recommended in the general population, is likely to yield similar diagnostic power in PLWH. [ABSTRACT FROM AUTHOR]