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David MG Halpin Department of Respiratory Medicine, University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UKCorrespondence: David MG Halpin, Email d.halpin@nhs.netAbstract: Real world data comprise information on health care that is derived from multiple sources outside typical clinical research settings. This review focuses on what real world evidence tells us about problems with the diagnosis of chronic obstructive pulmonary disease (COPD), problems with the initial and follow-up pharmacological and non-pharmacological management, problems with the management of exacerbations and problems with palliative care. Data from real world studies show errors in the management of COPD with delays to diagnosis, lack of confirmation of the diagnosis with spirometry, lack of holistic assessment, lack of attention to smoking cessation, variable adherence to management guidelines, delayed implementation of appropriate interventions, under-recognition of patients at higher risk of adverse outcomes, high hospitalisation rates for exacerbations and poor implementation of palliative care. Understanding that these problems exist and considering how and why they occur is fundamental to developing solutions to improve the diagnosis and management of patients with COPD.Keywords: COPD, real world studies, diagnosis, pharmacotherapy, exacerbations, palliative care

David MG Halpin,1 Robyn Kendall,2 Soham Shukla,3 Alan Martin,4 Dhvani Shah,5 Dawn Midwinter,6 Kai M Beeh,7 Janwillem WH Kocks,8– 11 Paul W Jones,12 Chris Compton,12 Nancy A Risebrough,13 Afisi S Ismaila3,14 1University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK; 2ICON Health Economics, ICON plc, Vancouver, BC, Canada; 3Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 4Value Evidence and Outcomes, GSK, Uxbridge, UK; 5ICON Health Economics, ICON plc, New York, NY, USA; 6Biostatistics, GSK, Brentford, UK; 7Insaf Respiratory Research Institute, Wiesbaden, Germany; 8General Practitioners Research Institute, Groningen, the Netherlands; 9Observational and Pragmatic Research Institute, Singapore; 10Groningen Research Institute Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 11Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 12Global Respiratory Franchise, GSK, Brentford, UK; 13ICON Health Economics, ICON plc, Toronto, ON, Canada; 14Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, CanadaCorrespondence: David MG Halpin, University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, EX1 2LU, UK, Tel +44 01392 201178, Email d.halpin@nhs.netPurpose: The 24-week INTREPID trial demonstrated the clinical benefits of once-daily single-inhaler triple therapy (SITT) with fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI) versus non-ELLIPTA multiple-inhaler triple therapy (MITT) in patients with symptomatic chronic obstructive pulmonary disease (COPD). This analysis assessed the cost-effectiveness of FF/UMEC/VI versus non-ELLIPTA MITT for the treatment of symptomatic COPD from a United Kingdom (UK) National Health Service (NHS) perspective.Patients and Methods: The analysis was conducted using the validated GALAXY COPD disease progression model. Baseline characteristics, treatment effect parameters (forced expiratory volume in 1 second and St. George’s Respiratory Questionnaire score [derived from exploratory COPD Assessment Test score mapping]), and discontinuation data from INTREPID were used to populate the model. UK healthcare resource and drug costs (2020 British pounds) were applied, and costs and outcomes were discounted at 3.5%. Analyses were conducted over a lifetime horizon from a UK NHS perspective. Model outputs included exacerbation rates, total costs, life years (LYs), quality-adjusted LYs (QALYs) and incremental cost-effectiveness ratio per QALY. Sensitivity analyses were conducted to assess the robustness of the results by varying parameter values and assumptions.Results: Over a lifetime horizon, FF/UMEC/VI provided an additional 0.174 (95% confidence interval [CI]: 0.024, 0.344) LYs (approximately 2 months), and 0.253 (95% CI: 0.167, 0.346) QALYs (approximately 3 months), at a cost saving of £ 1764 (95% CI: −£ 2600, −£ 678) per patient, compared with non-ELLIPTA MITT. FF/UMEC/VI remained the dominant treatment option, meaning greater benefits at lower costs, across all scenario and sensitivity analyses.Conclusion: Based on this analysis, in a UK setting, FF/UMEC/VI would improve health outcomes and reduce costs compared with non-ELLIPTA MITT for the treatment of patients with symptomatic COPD. SITT may help to reduce the clinical and economic burden of COPD and should be considered by physicians as a preferred treatment option.Keywords: chronic obstructive pulmonary disease, cost-effectiveness, health technology assessment, pragmatic, real-world, triple therapy

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

Nicola A Hanania,1 Jorge F Maspero,2 David MG Halpin,3 David J Jackson,4,5 Reynold A Panettieri,6 Mario Castro,7 Christian Domingo,8 Nadia Daizadeh,9 Rebecca Gall,10 Juby A Jacob-Nara,11 Benjamin Ortiz,10 Michel Djandji,9 Paul J Rowe,11 Yamo Deniz10 1Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA; 2Fundación CIDEA, Buenos Aires, Argentina; 3University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK; 4School of Immunology and Microbial Sciences, King’s College London, London, UK; 5Guy’s Severe Asthma Centre, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 6Child Health Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA; 7University of Kansas School of Medicine, Kansas City, KS, USA; 8Pulmonary Service, Corporació Sanitària Parc Taulí, Sabadell, Autonomous University of Barcelona, Barcelona, Spain; 9Sanofi, Cambridge, MA, USA; 10Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 11Sanofi, Bridgewater, NJ, USACorrespondence: Nicola A Hanania, Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA, Tel +1 713 798-2400, Email hanania@bcm.edu

David MG Halpin,1 Adrian Paul Rabe,2,3 Wei Jie Loke,4,5 Stacy Grieve,6 Patrick Daniele,6 Sanghee Hwang,6 Anna Forsythe6,7 1Respiratory Medicine, University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, Devon, UK; 2Primary Care and Public Health, Imperial College London, London, UK; 3Global Medical Affairs, AstraZeneca, Cambridge, UK; 4Lister Hospital, Stevenage, East and North Hertfordshire NHS Trust, Stevenage, UK; 5Ways Group, London, UK; 6North America Real World Advanced Analytics, Cytel, Inc., Waltham, MA, USA; 7Value and Access, Cytel, Inc., Waltham, MA, USACorrespondence: Anna Forsythe, Value and Access, Cytel, Inc., 1050 Winter Street, Suite 2700, Waltham, MA, 02451, USA, Tel +1-617-661-2011, Email Anna.Forsythe@cytel.comPurpose: There has been concern that asthma and chronic obstructive pulmonary disease [COPD] increase the risk of developing and exacerbating COVID-19. The effect of medications such as inhaled corticosteroids (ICS) and biologics on COVID-19 is unclear. This systematic literature review analyzed the published evidence on epidemiology and the burden of illness of asthma and COPD, and the use of baseline medicines among COVID-19 populations.Patients and Methods: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, Embase®, MEDLINE® and Cochrane were searched (January 2019–August 2021). The prevalence of asthma or COPD among COVID-19 populations was compared to the country-specific populations. Odds ratios (ORs) were estimated to compare healthcare resource utilization (HCRU) rates, and meta-analyses of outcomes were estimated from age-adjusted ORs (aORs) or hazard ratios (aHRs). Meta-analyses of COVID-19 outcomes were conducted using random effects models for binary outcomes.Results: Given the number and heterogeneity of studies, only 183 high-quality studies were analyzed, which reported hospitalization, intensive care unit (ICU) admissions, ventilation/intubation, or mortality. Asthma patients were not at increased risk for COVID-19–related hospitalization (OR = 1.05, 95% CI: 0.92 to 1.20), ICU admission (OR = 1.21, 95% CI: 0.99 to 1.1.48), ventilation/intubation (OR = 1.24, 95% CI: 0.95 to 1.62), or mortality (OR = 0.85, 95% CI: 0.75 to 0.96). Accounting for confounding variables, COPD patients were at higher risk of hospitalization (aOR = 1.45, 95% CI: 1.30 to 1.61), ICU admission (aOR = 1.28, 95% CI: 1.08 to 1.51), and mortality (aOR = 1.41, 95% CI: 1.37 to 1.65). Sixty-five studies reported outcomes associated with ICS or biologic use. There was limited evidence that ICS or biologics significantly impacted the risk of SARS-CoV-2 infection, HCRU, or mortality in asthma or COPD patients.Conclusion: In high-quality studies included, patients with asthma were not at significantly higher odds for adverse COVID-19–related outcomes, while patients with COPD were at higher odds. There was no clear evidence that baseline medication affected outcomes.Registration: PROSPERO (CRD42021233963).Keywords: healthcare resource utilization, mortality, SARS-COV-2, inhaled corticosteroids, biologics

Peter Lange,1,2 David M Halpin,3 Denis E O’Donnell,4 William MacNee5 1Respiratory Section, Hvidovre Hospital, Copenhagen, Denmark; 2Department of Health, University of Copenhagen, Copenhagen, Denmark; 3Royal Devon and Exeter Hospital, Exeter, UK; 4Respiratory Investigation Unit, Queen’s University and Kingston General Hospital, Kingston, ON, Canada; 5MRC Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK Abstract: COPD is now widely recognized as a complex heterogeneous syndrome, having both pulmonary and extrapulmonary features. In clinical practice, the diagnosis of COPD is based on the presence of chronic airflow limitation, as assessed by post-bronchodilator spirometry. The severity of the airflow limitation, as measured by percent predicted FEV1, provides important information to the physician to enable optimization of management. However, in order to accurately assess the complexity of COPD, there need to be other measures made beyond FEV1. At present, there is a lack of reliable and simple blood biomarkers to confirm and further assess the diagnosis of COPD. However, it is possible to identify patients who display different phenotypic characteristics of COPD that relate to clinically relevant outcomes. Currently, validated phenotypes of COPD include alpha-1 antitrypsin deficiency, and “frequent exacerbators”. Recently, a definition and assessment of a new phenotype comprising patients with overlapping features of asthma and COPD has been suggested and is known as “asthma COPD overlap syndrome”. Several other phenotypes have been proposed, but require validation against clinical outcomes. Defining phenotypes requires the assessment of multiple factors indicating disease severity, its impact, and its activity. Recognition and validation of COPD phenotypes has an important role to play in the selection of evidence-based targeted therapy in the future management of COPD, but regardless of the diagnostic terms, patients with COPD should be assessed and treated according to their individual treatable characteristics. Keywords: COPD, asthma, ACOS, phenotype, diagnosis

Andrea Gabrio,1 Necdet B Gunsoy,2 Gianluca Baio,1 Alan Martin,3 Victoria F Paly,4 Nancy Risebrough,5 David MG Halpin,6 Dave Singh,7 Robert A Wise,8 MeiLan K Han,9 Fernando J Martinez,10 Gerard J Criner,11 Neil Martin,12 David A Lipson,13,14 Afisi S Ismaila15,16 1UCL Statistical Science, University College London, London, UK; 2Value Evidence & Outcomes, GlaxoSmithKline, Brentford, UK; 3Value Evidence and Outcomes, GlaxoSmithKline, Uxbridge, UK; 4Global HTA, Health Economics, Reimbursement & Outcomes, ICON Plc., Philadelphia, PA, USA; 5Global HTA, Health Economics, Reimbursement & Outcomes, ICON plc., Toronto, ON, Canada; 6University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK; 7The Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK; 8The Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 9University of Michigan, Pulmonary & Critical Care, Ann Arbor, MI, USA; 10Joan and Sandy Weill Department of Medicine, New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY, USA; 11Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA; 12Global Medical Affairs, GlaxoSmithKline, Uxbridge, UK; 13Development Clinical Sciences, GlaxoSmithKline, Collegeville, PA, USA; 14Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 15Value Evidence and Outcomes, GlaxoSmithKline, Collegeville, PA, USA; 16Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, CanadaCorrespondence: Afisi S Ismaila, Value Evidence and Outcomes, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA, 19426-0989, USA, Tel +19199320430; +19193158229, Email afisi.s.ismaila@gsk.comAbstract: Objectives: In the IMPACT trial (NCT02164513), triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) showed clinical benefit compared with dual therapy with either FF/VI or UMEC/VI in the treatment of chronic obstructive pulmonary disease (COPD). We used data from IMPACT to determine whether this translated into differences in COPD-related healthcare resource utilization (HRU) costs in a United Kingdom (UK) setting.Methods: In a within-trial analysis, individual patient data from the IMPACT intention-to-treat (ITT) population were analyzed to estimate rates of COPD-related HRU with FF/UMEC/VI, FF/VI, or UMEC/VI. A Bayesian approach was applied to address issues typically encountered with this kind of data, namely data missing due to early study withdrawal, subjects with zero reported HRU, and skewness. Rates of HRU were estimated under alternate assumptions of data being missing at random (MAR) or missing not at random (MNAR). UK-specific unit costs were then applied to estimated HRU rates to calculate treatment-specific costs.Results: Under each MNAR scenario, per patient per year (PPPY) rates of COPD-related HRU were lowest amongst those patients who received treatment with FF/UMEC/VI compared with those receiving either FF/VI or UMEC/VI. Although absolute HRU rates and costs were typically higher for all treatment groups under MNAR scenarios versus MAR, final economic conclusions were robust to patient withdrawals.Conclusions: PPPY rates were typically lower with FF/UMEC/VI versus FF/VI or UMEC/VI.Keywords: single-inhaler triple therapy, COPD, healthcare resource use, cost

Jill A Ohar,1 Gary T Ferguson,2 Donald A Mahler,3 M Bradley Drummond,4 Rajiv Dhand,5 Roy A Pleasants,4,6 Antonio Anzueto,7 David MG Halpin,8 David B Price,9,10 Gail S Drescher,11 Haley M Hoy,12 John Haughney,9 Michael W Hess,13 Omar S Usmani14 1Section of Pulmonary, Critical Care, Allergy, and Immunology, School of Medicine, Wake Forest University, Winston-Salem, NC, USA; 2Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 3Geisel School of Medicine at Dartmouth, Hanover, NH, USA; 4Division of Pulmonary Diseases and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 5Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN, USA; 6Department of Quality, University of Michigan, Ann Arbor, MI, USA; 7Pulmonology Section, University of Texas Health, and South Texas Veterans Health Care System, San Antonio, TX, USA; 8University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK; 9Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 10Observational and Pragmatic Research Institute, Singapore; 11Pulmonary Services Department, MedStar Washington Hospital Center, Washington, DC, USA; 12Transplant Center, Vanderbilt University Medical Center, Nashville, TN, USA; 13COPD Foundation, Kalamazoo, MI, USA; 14National Heart and Lung Institute, Imperial College London and Royal Brompton Hospital, London, UKCorrespondence: Jill A OharSection of Pulmonary, Critical Care, Allergy, and Immunology, School of Medicine, Wake Forest University, 1834 Wake Forest Road, Winston-Salem, NC 27109, USATel +1 336-716-8426Fax +1 336-716-7277Email johar@wakehealth.eduAbstract: Dry powder inhalers (DPIs) are breath actuated, and patients using DPIs need to generate an optimal inspiratory flow during the inhalation maneuver for effective drug delivery to the lungs. However, practical and standardized recommendations for measuring peak inspiratory flow (PIF)—a potential indicator for effective DPI use in chronic obstructive pulmonary disease (COPD)—are lacking. To evaluate recommended PIF assessment approaches, we reviewed the Instructions for Use of the In-Check™ DIAL and the prescribing information for eight DPIs approved for use in the treatment of COPD in the United States. To evaluate applied PIF assessment approaches, we conducted a PubMed search from inception to August 31, 2021, for reports of clinical and real-life studies where PIF was measured using the In-Check™ DIAL or through a DPI in patients with COPD. Evaluation of collective sources, including 47 applicable studies, showed that instructions related to the positioning of the patient with their DPI, instructions for exhalation before the inhalation maneuver, the inhalation maneuver itself, and post-inhalation breath-hold times varied, and in many instances, appeared vague and/or incomplete. We observed considerable variation in how PIF was measured in clinical and real-life studies, underscoring the need for a standardized method of PIF measurement. Standardization of technique will facilitate comparisons among studies. Based on these findings and our clinical and research experience, we propose specific recommendations for PIF measurement to standardize the process and better ensure accurate and reliable PIF values in clinical trials and in daily clinical practice.Keywords: chronic obstructive pulmonary disease, dry powder inhalers, peak inspiratory flow

Jean Bourbeau,1 Mona Bafadhel,2 Neil C Barnes,3,4 Chris Compton,3 Valentina Di Boscio,3 David A Lipson,5,6 Paul W Jones,3,7 Neil Martin,3,8 Gudrun Weiss,3 David MG Halpin9 1Respiratory Epidemiology and Clinical Research Unit, Department of Medicine, McGill University and Research Institute of the McGill University Health Centre, Montreal, QC, Canada; 2Nuffield Department of Medicine, University of Oxford, Oxford, Oxfordshire, UK; 3Respiratory Therapy Area, GlaxoSmithKline, Brentford, Middlesex, UK; 4William Harvey Institute, Bart’s and the London School of Medicine and Dentistry, London, UK; 5Clinical Sciences, GlaxoSmithKline, Collegeville, PA, USA; 6Pulmonary, Allergy and Critical Care Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 7Institute of Infection and Immunity, St George’s, University of London, London, UK; 8University of Leicester, Leicester, UK; 9University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UKCorrespondence: Jean BourbeauMcGill University Health Centre (MUHC), 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, CanadaTel +1 514 934-1934Fax +1 514 934-8577Email jean.bourbeau@mcgill.caAbstract: Chronic obstructive pulmonary disease (COPD) is associated with major healthcare and socioeconomic burdens. International consortia recommend a personalized approach to treatment and management that aims to reduce both symptom burden and the risk of exacerbations. Recent clinical trials have investigated single-inhaler triple therapy (SITT) with a long-acting muscarinic antagonist (LAMA), long-acting β2-agonist (LABA), and inhaled corticosteroid (ICS) for patients with symptomatic COPD. Here, we review evidence from randomized controlled trials showing the benefits of SITT and weigh these against the reported risk of pneumonia with ICS use. We highlight the challenges associated with cross-trial comparisons of benefit/risk, discuss blood eosinophils as a marker of ICS responsiveness, and summarize current treatment recommendations and the position of SITT in the management of COPD, including potential advantages in terms of improving patient adherence. Evidence from trials of SITT versus dual therapies in symptomatic patients with moderate to very severe airflow limitation and increased risk of exacerbations shows benefits in lung function and patient-reported outcomes. Moreover, the key benefits reported with SITT are significant reductions in exacerbations and hospitalizations, with data also suggesting reduced all-cause mortality. These benefits outweigh the ICS-class effect of higher incidence of study-reported pneumonia compared with LAMA/LABA. Important differences in trial design, baseline population characteristics, such as exacerbation history, and assessment of outcomes, have significant implications for interpreting data from cross-trial comparisons. Current understanding interprets the blood eosinophil count as a continuum that can help predict response to ICS and has utility alongside other clinical factors to aid treatment decision-making. We conclude that treatment decisions in COPD should be guided by an approach that considers benefit versus risk, with early optimization of treatment essential for maximizing long-term benefits and patient outcomes.Keywords: all-cause mortality, exacerbations, hospitalizations, ICS, LABA, LAMA

Simon Wan Yau Ming,1 John Haughney,2 Dermot Ryan,3 Iain Small,4 Federico Lavorini,5 Alberto Papi,6 Dave Singh,7 David MG Halpin,8 John R Hurst,9 Shishir Patel,10 Matthias Ochel,10 Janwillem Kocks,1,11,12 Victoria Carter,1 Antony Hardjojo,1 David B Price1,2 1Observational and Pragmatic Research Institute, Singapore, Singapore; 2Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 3Optimum Patient Care, Cambridge, UK; 4Peterhead Health Centre, Aberdeen, UK; 5Department of Experimental and Clinical Medicine, Careggi University Hospital, Florence, Italy; 6University of Ferrara, Ferrara, Italy; 7University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK; 8Royal Devon and Exeter Hospital, Exeter, UK; 9UCL Respiratory, University College London, London, UK; 10Chiesi Limited, Manchester, UK; 11General Practitioners Research Institute, Groningen, the Netherlands; 12University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, the NetherlandsCorrespondence: David B PriceCentre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD, UKTel +65 6802 9724Email dprice@opri.sgIntroduction: The Fostair® 100/6 (BDP/FF) pressurized metered-dose inhaler, delivering an extrafine formulation, is licensed for asthma and COPD in the UK. However, its real-life effectiveness for COPD has not been evaluated. This study compared the clinical effectiveness of BDP/FF against other licensed ICS/LABA combination inhalers: the Seretide® Accuhaler® (FP/SAL) and the Symbicort® Turbohaler® (BUD/FF).Methods: A matched historical cohort study was conducted using records of patients with diagnostic codes for COPD from the Optimum Patient Care Research Database (OPCRD). Patients who had received BDP/FF as their first ICS/LABA were matched 1:1 with patients who had received FP/SAL or BUD/FF, resulting in two matched comparisons. Additional analysis was conducted on patients who had never had diagnostic codes for asthma. Noninferiority in terms of the proportion of patients with moderate/severe COPD exacerbations on the different inhalers in the following year was assessed. Noninferiority was achieved if the upper CI limit were ≤ 1.2.Results: This study included 537 and 540 patient pairs in the BDP/FF vs FP/SAL cohort and the BDP/FF vs BUD/FF cohort, respectively. The proportion of patients with COPD exacerbations in the BDP/FF group was not significantly different from either the FP/SAL (68.7% vs 70.2%, AOR 0.89, 95% CI 0.67– 1.19) or BUD/FF group (68.5% vs 69.4%, AOR 0.79, 95% CI 0.58– 1.08). Noninferiority of BDP/FF in preventing COPD exacerbations was fulfilled in both comparisons. In patients without asthma, BDP/FF was also noninferior to BUD/FF (proportion with COPD exacerbations, 67.8% vs 64.7%, AOR 0.79, 95% CI 0.51– 1.1997). Additionally, a significantly lower proportion of patients prescribed BDP/FF had COPD exacerbations than FP/SAL (64.8% vs 73.7%, AOR 0.64 95% CI 0.43– 0.96).Conclusion: Initiating ICS/LABA treatment of COPD with extrafine-formulation BDP/FF was noninferior in preventing moderate/severe exacerbations compared to FP/SAL and BUD/FF.Keywords: metered-dose inhaler, dry-powder inhaler, chronic obstructive pulmonary disease, treatment efficacy, cost-effectiveness

Afisi S Ismaila,1,2 Nancy Risebrough,3 Melanie Schroeder,4 Dhvani Shah,5 Alan Martin,6 Emma C Goodall,7 Kerigo Ndirangu,5 Gerard Criner,8 Mark Dransfield,9 David MG Halpin,10 MeiLan K Han,11 David A Lomas12 1Value Evidence and Outcomes, GlaxoSmithKline plc, Collegeville, PA, USA; 2Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada; 3ICON Health Economics, ICON plc, Toronto, ON, Canada; 4Value Evidence and Outcomes, GlaxoSmithKline plc, Brentford, UK; 5ICON Health Economics, ICON plc, New York, NY, USA; 6Value Evidence and Outcomes, GlaxoSmithKline plc, Uxbridge, UK; 7Health Economics and Outcomes Research, GlaxoSmithKline plc, Mississauga, ON, Canada; 8Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA; 9Division of Pulmonary, Allergy, and Critical Care Medicine, Lung Health Center, University of Alabama at Birmingham, Birmingham, AL, USA; 10Department of Respiratory Medicine, Royal Devon and Exeter Hospital, Exeter, UK; 11University of Michigan, Pulmonary and Critical Care, Ann Arbor, MI, USA; 12UCL Respiratory, University College London, London, UKCorrespondence: Afisi S IsmailaValue Evidence and Outcomes, GlaxoSmithKline plc, 1250 South Collegeville Road, Collegeville, PA 19426-0989, USATel +1 919 315 8229Email afisi.s.ismaila@gsk.comBackground: We assessed the cost-effectiveness of single-inhaler fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) versus FF/VI or UMEC/VI from a Canadian public healthcare perspective, incorporating data from the IMPACT trial in chronic obstructive pulmonary disease (COPD) (NCT02164513).Methods: Baseline inputs and treatment effects from IMPACT were populated into the validated GALAXY-COPD disease progression model. Canadian unit costs and drug costs (Canadian dollars [C$], 2017) were applied to healthcare resource utilization and treatments. Future costs and health outcomes were discounted at 1.5% annually. Analyses were probabilistic, and outputs included exacerbation rates, costs, and life years (LYs) and quality-adjusted life years (QALYs) gained.Results: Compared with FF/VI and UMEC/VI over a lifetime horizon, the analyses predicted that treatment with FF/UMEC/VI resulted in fewer moderate and severe exacerbations, more LYs and more QALYs gained, with a small incremental cost. The base-case incremental cost-effectiveness ratio (ICER) per QALY gained was C$18,989 (95% confidence interval [CI]: C$14,665, C$25,753) versus FF/VI and C$13,776 (95% CI: C$9787, C$19,448) versus UMEC/VI. FF/UMEC/VI remained cost-effective versus both FF/VI and UMEC/VI in all sensitivity analyses, including in scenario analyses that considered different intervention and comparator discontinuation rates, and treatment effects for subsequent therapy.Conclusion: Treatment with FF/UMEC/VI was predicted to improve outcomes and be a cost-effective treatment option for patients with symptomatic COPD and a history of exacerbations compared with FF/VI or UMEC/VI, in Canada.Keywords: chronic obstructive pulmonary disease, cost-effectiveness, single-inhaler triple therapy, quality-adjusted life years, Canada

David MG Halpin,1 Marc Miravitlles,2 Norbert Metzdorf,3 Bartolomé Celli4 1Department of Respiratory Medicine, Royal Devon and Exeter Hospital, Exeter, UK; 2Pneumology Department, Hospital Universitari Vall d’Hebron, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain; 3Respiratory Medicine, Boehringer Ingelheim Pharma GmBH & Co KG, Ingelheim am Rhein, Germany; 4Pulmonary Division, Brigham and Women’s Hospital, Boston, MA, USA Abstract: Severe exacerbations of COPD, ie, those leading to hospitalization, have profound clinical implications for patients and significant economic consequences for society. The prevalence and burden of severe COPD exacerbations remain high, despite recognition of the importance of exacerbation prevention and the availability of new treatment options. Severe COPD exacerbations are associated with high mortality, have negative impact on quality of life, are linked to cardiovascular complications, and are a significant burden on the health-care system. This review identified risk factors that contribute to the development of severe exacerbations, treatment options (bronchodilators, antibiotics, corticosteroids [CSs], oxygen therapy, and ventilator support) to manage severe exacerbations, and strategies to prevent readmission to hospital. Risk factors that are amenable to change have been highlighted. A number of bronchodilators have demonstrated successful reduction in risk of severe exacerbations, including long-acting muscarinic antagonist or long-acting β2-agonist mono- or combination therapies, in addition to vaccination, mucolytic and antibiotic therapy, and nonpharmacological interventions, such as pulmonary rehabilitation. Recognition of the importance of severe exacerbations is an essential step in improving outcomes for patients with COPD. Evidence-based approaches to prevent and manage severe exacerbations should be implemented as part of targeted strategies for disease management. Keywords: severe COPD exacerbations, hospitalization, prevention, treatment, bronchodilators, long-acting muscarinic antagonist

Chronic obstructive pulmonary disease (COPD) is a progressive condition characterized by airflow obstruction which ultimately kills many patients. It is common in both men and women and there is a 24-30% 5-year survival rate in the UK for those with severe disease. The annual death rate in the UK from COPD approaches that from lung cancer. Patients' symptoms can be improved by drug therapy, but stopping smoking is also an effective way of improving the outcome in patients at all stages of COPD. Predicting prognosis has been difficult in COPD due to the variable illness trajectory. However, assessment of severity of lung function impairment, frequency of exacerbations and requirement for long term oxygen therapy can help identify patients entering the final 12 months of life. Symptom burden and impact on activities of daily living for patients with COPD are comparable with that of cancer patients, and palliative care approaches are equally necessary, yet few publications exist to guide clinicians in this area. An evidence base exists for the management of dyspnoea with oxygen therapy and opioid drugs. There is less evidence for the effective treatment of depression and anxiety, fatigue and pain, and treatment is based on experience and considered best practice. This review discusses the problems that patients experience and offers practical guidance. The management of patients should be shared between primary and secondary care, with multidisciplinary teams being involved at an early stage. Patients and their families require honest and clear communication about the condition and what to expect in the future. The strict application of advance care planning and directives may not be feasible or appropriate, but there is evidence that attitudes towards resuscitation and artificial ventilation can be explored without distress. The requirement by patients and carers for surveillance and timely support is acknowledged, but how to provide such input is as yet unclear, with little evidence to support the widespread implementation of nurse-led management interventions. The hospice movement has become increasingly involved in the management of life-threatening, non-malignant disease and should be involved in the multidisciplinary care of patients dying from COPD. [ABSTRACT FROM AUTHOR]

Mike Thomas,1 David MG Halpin,2 Marc Miravitlles3 1Primary Care and Population Sciences, University of Southampton, Southampton, 2Department of Respiratory Medicine, Royal Devon and Exeter Hospital, Exeter, UK; 3Pneumology Department, Hospital Universitari Vall d’Hebron, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Barcelona, Spain Abstract: Inhaled bronchodilator medications are central to the management of COPD and are frequently given on a regular basis to prevent or reduce symptoms. While short-acting bronchodilators are a treatment option for people with relatively few COPD symptoms and at low risk of exacerbations, for the majority of patients with significant breathlessness at the time of diagnosis, long-acting bronchodilators may be required. Dual bronchodilation with a long-acting β2-agonist and long-acting muscarinic antagonist may be more effective treatment for some of these patients, with the aim of improving symptoms. This combination may also reduce the rate of exacerbations compared with a bronchodilator-inhaled corticosteroid combination in those with a history of exacerbations. However, there is currently a lack of guidance on clinical indicators suggesting which patients should step up from mono- to dual bronchodilation. In this article, we discuss a number of clinical indicators that could prompt a patient and physician to consider treatment escalation, while being mindful of the need to avoid unnecessary polypharmacy. These indicators include insufficient symptomatic response, a sustained increased requirement for rescue medication, suboptimal 24-hour symptom control, deteriorating symptoms, the occurrence of exacerbations, COPD-related hospitalization, and reductions in lung function. Future research is required to provide a better understanding of the optimal timing and benefits of treatment escalation and to identify the appropriate tools to inform this decision. Keywords: COPD, dual bronchodilation, monobronchodilation, ICS, triple therapy

Michael E Hyland,1 David MG Halpin,2 Sue Blake,3 Clare Seamark,3 Margaret Pinnuck,3 David Ward,3 Ben Whalley,1 Colin J Greaves,4 Adam L Hawkins,5 Dave Seamark3 1School of Psychology, University of Plymouth, Plymouth, 2Department of Respiratory Medicine, Royal Devon and Exeter Hospital, Exeter, 3Honiton Group Practice, Honiton, 4University of Exeter Medical School, Exeter, 5GSK House, Brentford, UK Background: A review of the effectiveness of relaxation techniques for chronic obstructive pulmonary disease patients has shown inconsistent results, but studies have varied in terms of technique and outcome measures. Aim: To determine patient preference for different relaxation techniques. Methods: Chronic obstructive pulmonary disease patients were presented with six techniques via a DVD and asked to rate the techniques in terms of effectiveness, rank in order of likely use, and comment. Results: Patients differed in the technique preferred and reason for that preference, but the most commonly preferred technique both for effectiveness and ease of use was “thinking of a nice place” followed by progressive relaxation and counting. Familiarity and ease of activity were commonly given reasons for preference. Conclusion: Rather than providing patients with a single technique that they might find difficult to implement, these results suggest that it would be better to give a choice. “Thinking of a nice place” is a popular but under-investigated technique. Keywords: COPD exacerbation, anxiety, relaxation techniques

David MG Halpin,1 Ronald Dahl,2 Christoph Hallmann,3 Achim Mueller,3 Donald Tashkin4 1NHS SW, Royal Devon and Exeter Hospital, Exeter, Devon, England, UK; 2Allergy Centre, Odense University Hospital, Odense, Denmark; 3Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim am Rhein, Germany; 4Department of Medicine, David Geffen School of Medicine UCLA, Los Angeles, CA, USAIntroduction: Tiotropium is prescribed for the treatment of chronic obstructive pulmonary disease (COPD) and delivered via HandiHaler® (18 µg once daily) or Respimat® Soft Mist™ inhaler (5 µg once daily). The recent TIOtropium Safety and Performance In Respimat® (TIOSPIR™) study demonstrated that both exhibit similar safety profiles. This analysis provides an updated comprehensive safety evaluation of tiotropium® using data from placebo-controlled HandiHaler® and Respimat® trials.Methods: Pooled analysis of adverse event (AE) data from tiotropium HandiHaler® 18 µg and Respimat® 5 µg randomized, double-blind, parallel-group, placebo-controlled, clinical trials in patients with COPD (treatment duration ≥4 weeks). Incidence rates, rate ratios (RRs), and 95% confidence intervals (CIs) were determined for HandiHaler® and Respimat® trials, both together and separately.Results: In the 28 HandiHaler® and 7 Respimat® trials included in this analysis, 11,626 patients were treated with placebo and 12,929 with tiotropium, totaling 14,909 (12,469 with HandiHaler®; 2,440 with Respimat®) patient-years of tiotropium exposure. Mean age was 65 years, and mean prebronchodilator forced expiratory volume in 1 second (FEV1) was 1.16 L (41% predicted). The risk (RR [95% CI]) of AEs (0.90 [0.87, 0.93]) and of serious AEs (SAEs) (0.94 [0.89, 0.99]) was significantly lower in the tiotropium than in the placebo group (HandiHaler® and Respimat® pooled results), and there was a numerically lower risk of fatal AEs (FAEs) (0.90 [0.79, 1.01]). The risk of cardiac AEs (0.93 [0.85, 1.02]) was numerically lower in the tiotropium group. Incidences of typical anticholinergic AEs, but not SAEs, were higher with tiotropium. Analyzed separately by inhaler, the risks of AE and SAE in the tiotropium groups remained lower than in placebo and similarly for FAEs.Conclusion: This analysis indicates that tiotropium is associated with lower rates of AEs, SAEs, and similar rates of FAEs than placebo when delivered via HandiHaler® or Respimat® (overall and separately) in patients with COPD. Keywords: tiotropium, HandiHaler®, Respimat®

David MG Halpin,1 Marc Decramer,2 Bartolome Celli,3 Steven Kesten,4 Dacheng Liu,4 Donald P Tashkin51Royal Devon and Exeter Hospital, Devon, UK; 2Respiratory Division, Katholieke Universiteit Leuven, University Hospital, KU Leuven, Belgium; 3Pulmonary Division, Brigham and Women's Hospital, Boston, MA; 4Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT; 5Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USABackground: Exacerbations affect morbidity in chronic obstructive pulmonary disease (COPD). We sought to evaluate the association between exacerbation frequency and spirometric and health status changes over time using data from a large, long-term trial.Methods: This retrospective analysis of data from the 4-year UPLIFT® (Understanding Potential Long-term Impacts on Function with Tiotropium) trial compared tiotropium with placebo. Annualized rates of decline and estimated mean differences at each time point were analyzed using a mixed-effects model according to subgroups based on exacerbation frequency (events per patient-year: 0>0–1, >1–2, and>2). Spirometry and the St George's Respiratory Questionnaire (SGRQ) were performed at baseline and every 6 months (also at one month for spirometry).Results: In total, 5992 patients (mean age 65 years, 75% male) were randomized. Higher exacerbation frequency was associated with lower baseline postbronchodilator forced expiratory volume in one second (FEV1) (1.40, 1.36, 1.26, and 1.14 L) and worsening SGRQ scores (43.7, 44.1, 47.8, and 52.4 units). Corresponding rates of decline in postbronchodilator FEV1 (mL/year) were 40, 41, 43, and 48 (control), and 34, 38, 48, and 49 (tiotropium). Values for postbronchodilator forced vital capacity decline (mL/year) were 45, 56, 74, and 83 (control), and 43, 57, 83, and 95 (tiotropium). The rates of worsening in total SGRQ score (units/year) were 0.72, 1.16, 1.44, and 1.99 (control), and 0.38, 1.29, 1.68, and 2.86 (tiotropium). The proportion of patients who died (intention-to-treat analysis until four years [1440 days]) for the entire cohort increased with increasing frequency of hospitalized exacerbations.Conclusion: Increasing frequency of exacerbations worsens the rate of decline in lung function and health-related quality of life in patients with COPD. Increasing rates of hospitalized exacerbations are associated with increasing risk of death.Keywords: chronic obstructive pulmonary disease, exacerbations, forced expiratory volume in one second, health status, tiotropium

Chronic obstructive pulmonary disease (COPD) is the end result of a series of dynamic and cumulative gene-environment interactions over a lifetime. The evolving understanding of COPD biology provides novel opportunities for prevention, early diagnosis, and intervention. To advance these concepts, we propose therapeutic trials in two major groups of subjects: "young" individuals with COPD and those with pre-COPD. Given that lungs grow to about 20 years of age and begin to age at approximately 50 years, we consider "young" patients with COPD those patients in the age range of 20-50 years. Pre-COPD relates to individuals of any age who have respiratory symptoms with or without structural and/or functional abnormalities, in the absence of airflow limitation, and who may develop persistent airflow limitation over time. We exclude from the current discussion infants and adolescents because of their unique physiological context and COPD in older adults given their representation in prior randomized controlled trials (RCTs). We highlight the need of RCTs focused on COPD in young patients or pre-COPD to reduce disease progression, providing innovative approaches to identifying and engaging potential study subjects. We detail approaches to RCT design, including potential outcomes such as lung function, patient-reported outcomes, exacerbations, lung imaging, mortality, and composite endpoints. We critically review study design components such as statistical powering and analysis, duration of study treatment, and formats to trial structure, including platform, basket, and umbrella trials. We provide a call to action for treatment RCTs in 1 ) young adults with COPD and 2 ) those with pre-COPD at any age.

Purpose: Chronic obstructive pulmonary disease (COPD) and asthma are leading causes of morbidity and mortality. This narrative review provides an appraisal of the pharmacological and clinical characteristics of tiotropium in COPD and asthma, and examines how these compare with other long-acting bronchodilators. The evidence base is placed into context by relating it to factors affecting clinicians' choice of therapy., Main Findings: Desirable attributes of a long-acting muscarinic antagonist (LAMA) maintenance therapy include effective pharmacological bronchodilation, improved lung function, exacerbation efficacy, and positive effects on symptom control, exercise capacity and quality of life across a broad patient population. Tolerability and convenience of use are also important for patient well-being and treatment adherence. Tiotropium shows higher affinity for muscarinic receptors than ipratropium, and prolonged binding to the M 3 receptor compared with other LAMAs. In COPD, tiotropium has demonstrated improved lung function and exacerbation prevention compared with placebo or long-acting β 2 -agonists, similar exacerbation efficacy to other LAMAs, and enhanced symptom control and health status versus placebo. UniTinA-asthma ® showed the benefits of add-on tiotropium in patients with uncontrolled mild to moderate and severe asthma. Tiotropium is well tolerated, with an incidence of adverse events similar to placebo, except for known infrequent side effects of anticholinergics. Tiotropium HandiHaler ® and Respimat ® augment inhaler choice in COPD., Principal Conclusions: With over 10 years' prescribing history and 50 million patient-years of use, tiotropium has the benefit of a more extensive clinical evidence base than other long-acting bronchodilators, with demonstrated efficacy and safety in COPD and symptomatic asthma., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

This Executive Summary of the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 Report focuses primarily on the revised and novel parts of the document. The most significant changes include: (i) the assessment of chronic obstructive pulmonary disease has been refined to separate the spirometric assessment from symptom evaluation. ABCD groups are now proposed to be derived exclusively from patient symptoms and their history of exacerbations; (ii) for each of the groups A to D, escalation strategies for pharmacological treatments are proposed; (iii) the concept of de-escalation of therapy is introduced in the treatment assessment scheme; (iv)non-pharmacological therapies are comprehensively presented and (v) the importance of co-morbid conditions in managing COPD is reviewed., (© 2017 The American Thoracic Society. Published with permission from the American Thoracic Society.)

Background: Management guidelines of chronic obstructive pulmonary disease (COPD) are mainly based on results of randomised controlled trials (RCTs), but some authors have suggested limited representativeness of patients included in these trials. No previous studies have applied the full range of selection criteria to a broad COPD patient population in a real-life setting., Methods: We identified all RCTs of inhaled long-acting bronchodilator therapy, during 1999-2013, at ClinicalTrials.gov and translated trial selection criteria into definitions compatible with electronic medical records. Eligibility was calculated for each RCT by applying these criteria to a uniquely representative, well-characterised population of patients with COPD from the Optimum Patient Care Research Database (OPCRD)., Results: Median eligibility of 36 893 patients with COPD for participation in 31 RCTs was 23 % (interquartile range 12-38). Two studies of olodaterol showed the highest eligibility of 55 and 58 %. Conversely, the lowest eligibility was observed in two studies that required a history of exacerbations in the past year (3.5 and 3.9 %). For the patient subgroup with modified Medical Research Council score ≥2, the overall median eligibility was 27 %., Conclusions: By applying an extensive range of RCT selection criteria to a large, representative COPD patient population, this study highlights that the interpretation of results from RCTs must take into account that RCT participants are variably, but generally more representative of patients in the community than previously believed.

Background: A review of the effectiveness of relaxation techniques for chronic obstructive pulmonary disease patients has shown inconsistent results, but studies have varied in terms of technique and outcome measures., Aim: To determine patient preference for different relaxation techniques., Methods: Chronic obstructive pulmonary disease patients were presented with six techniques via a DVD and asked to rate the techniques in terms of effectiveness, rank in order of likely use, and comment., Results: Patients differed in the technique preferred and reason for that preference, but the most commonly preferred technique both for effectiveness and ease of use was "thinking of a nice place" followed by progressive relaxation and counting. Familiarity and ease of activity were commonly given reasons for preference., Conclusion: Rather than providing patients with a single technique that they might find difficult to implement, these results suggest that it would be better to give a choice. "Thinking of a nice place" is a popular but under-investigated technique.

Despite current therapeutic approaches asthma remains uncontrolled in a significant proportion of patients. Short-acting anticholinergic bronchodilators have a very long history of use in asthma, and recent data confirms the importance of acetylcholine as both a bronchoconstrictor and as a regulator of inflammation and remodeling in the lungs. Data from a comprehensive clinical trial programme, as well as use in primary care, show the efficacy and safety of tiotropium in adults with mild to moderate asthma when it is added to ICS and in severe asthma when it is added to high doses of ICS plus LABA, as well as in adolescents. Tiotropium is cost effective and its benefits are not restricted to particular phenotypes, making it a useful addition to the therapeutic options recommended by the Global Initiative for Asthma (GINA) for people with poorly controlled asthma at steps 4 & 5.

Background: Exacerbation frequency is related to disease progression, quality of life, and prognosis in COPD. Earlier diagnosis, along with interventions aimed at preventing exacerbations and delaying progression, may help reduce the global burden of disease. Long-acting inhaled bronchodilators are effective at maintaining symptom relief and are recommended as first-choice therapy for more symptomatic patients and those at risk of exacerbation., Methods: As prevention of exacerbations is a priority goal in COPD management and a number of different long-acting bronchodilators are available, we conducted a systematic review of exacerbation data from randomized controlled trials (published January 2000 to May 2014) comparing the effect of tiotropium versus placebo and/or other maintenance therapies., Results: Exacerbations were a primary endpoint in 12 publications (five studies: four comparing tiotropium with placebo; one with active comparator) and a secondary endpoint in 17 publications (seven studies: six comparing tiotropium with placebo; one with active comparator). Overall, tiotropium was associated with a longer time to first exacerbation event and fewer exacerbations (including severe exacerbations/hospitalizations) compared with placebo and long-acting β2-agonists. Tiotropium also showed similar efficacy to glycopyrronium and a fixed long-acting muscarinic antagonist/long-acting β2-agonist combination (glycopyrronium/indacaterol), although not all studies were powered to demonstrate differences in exacerbation outcomes. Exacerbation outcomes were comparable with both formulations of tiotropium (HandiHaler(®) 18 μg/Respimat(®) 5 μg)., Conclusions: The results of this comprehensive systematic review demonstrate tiotropium is beneficial in reducing exacerbation risk versus placebo or other maintenance treatments., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Tiotropium, a once-daily long-acting anticholinergic bronchodilator, has demonstrated efficacy in patients with asthma who were symptomatic despite treatment with medium- to high-dose inhaled corticosteroids (ICS)., Objective: The objective of this study was to evaluate the efficacy and safety of once-daily tiotropium Respimat (5 μg or 2.5 μg), compared with placebo Respimat, as add-on therapy to low- to medium-dose ICS for adults with symptomatic asthma., Methods: A phase III, double-blind, placebo-controlled trial was conducted (NCT01316380). Adults with symptomatic asthma receiving low- to medium-dose ICS (200-400 μg budesonide or equivalent dose) and a pre-bronchodilator forced expiratory volume in 1 second (FEV1) ≥60% and ≤90% of predicted normal were randomized to 12 weeks of treatment with once-daily tiotropium Respimat 5 μg or 2.5 μg, or placebo Respimat, as add-on therapy to ICS. The primary endpoint was peak FEV1(0-3h) response., Results: In total, 464 patients were randomized (61% female; mean age 43 years; mean baseline FEV1 78% of predicted normal). After 12 weeks, both tiotropium Respimat doses were superior to placebo (adjusted mean difference from placebo: 5 μg, 128 mL; 2.5 μg, 159 mL; both P < .001). Both doses of tiotropium Respimat were also superior to placebo with regard to the secondary endpoints of adjusted mean trough FEV1 and FEV1 area under the curve(0-3h) responses, and the other endpoints of morning and evening peak expiratory flow. Adverse events were comparable across the treatment groups., Conclusions: Once-daily tiotropium Respimat add-on therapy to low- to medium-dose ICS in adults with symptomatic asthma is an efficacious bronchodilator, and its safety and tolerability are comparable with those of placebo Respimat., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background : Most asthmatic women have normal pregnancies and complications are infrequent when their asthma is well-controlled. Symptom control and medical treatment are concerning to pregnant asthma suffers, as is the impact that their illness and treatment might have on their unborn baby. The aim was to investigate in a qualitative study the thoughts and feelings of women's experiences of asthma in pregnancy. Twenty-two women with asthma who had a pregnancy within two years were asked to participate. Seven women were interviewed when data saturation was achieved. Interviews were transcribed and analysed using the 'Framework' Method, independently analysed by two researchers and consensus reached concerning the construction of themes. The key themes that emerged were Asthma and pregnancy; Pregnancy and post-natal experiences; and Health professionals. These findings are globally interesting because of the prevalence of maternal asthma and they illustrate participants' experiences concerning their asthma care and their views on its improvement. Pregnant asthmatic women have concerns about their care and treatment which might be alleviated by outreach, joint working between respiratory doctors and nurse specialists, midwives and General Practice nurses. Targeted educational activities could form a part of this care delivery.

Background: Patterns of health-care use and comorbidities present in patients in the period before diagnosis of chronic obstructive pulmonary disease (COPD) are unknown. We investigated these factors to inform future case-finding strategies., Methods: We did a retrospective analysis of a clinical cohort in the UK with data from Jan 1, 1990 to Dec 31, 2009 (General Practice Research Database and Optimum Patient Care Research Database). We assessed patients aged 40 years or older who had an electronically coded diagnosis of COPD in their primary care records and had a minimum of 3 years of continuous practice data for COPD (2 years before diagnosis up to a maximum of 20 years, and 1 year after diagnosis) and at least two prescriptions for COPD since diagnosis. We identified missed opportunites to diagnose COPD from routinely collected patient data by reviewing patterns of health-care use and comorbidities present before diagnosis. We assessed patterns of health-care use in terms of lower respiratory consultations (infective and non-infective), lower respiratory consultations with a course of antibiotics or oral steroids, and chest radiography. If these events did not lead to a diagnosis of COPD, they were deemed to be missed opportunities. This study is registered with ClinicalTrials.gov, number NCT01655667., Findings: We assessed data for 38,859 patients. Opportunities for diagnosis were missed in 32,900 (85%) of 38,859 patients in the 5 years immediately preceding diagnosis of COPD; in 12,856 (58%) of 22,286 in the 6-10 years before diagnosis, in 3943 (42%) of 9351 in the 11-15 years before diagnosis; and in 95 (8%) of 1167 in the 16-20 years before diagnosis. Between 1990 and 2009, we noted decreases in the age at diagnosis (0·05 years of age per year, 95% CI 0·03-0·07) and yearly frequency of lower respiratory prescribing consultations (rate ratio 0·982 opportunities per year, 95% CI 0·979-0·985). Prevalence of all comorbidities present at COPD diagnosis increased except for asthma and bronchiectasis, which decreased between 1990 and 2007, from 281 (33·4%) of 842 patients to 451 of 1465 (30·8%) for asthma, and from 53 of 842 (6·3%) to 53 of 1465 (3·6%) for bronchiectasis. In the 2 years before diagnosis, of 6897 patients who had had a chest radiography, only 2296 (33%) also had spirometry., Interpretation: Opportunities to diagnose COPD at an earlier stage are being missed, and could be improved by case-finding in patients with lower respiratory tract symptoms and concordant long-term comorbidities., Funding: UK Department of Health, Research in Real Life., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Being able to identify patients at risk of exacerbations is useful as it enables resources to be targeted at these patients., Aims: To test the theoretically-derived prediction that the frequency of non-asthma related visits to the general practitioner (GP) predicts exacerbations., Methods: Clinical and demographic data and both self-report and prescription-based adherence data were obtained from 166 patients diagnosed with asthma attending a GP clinic, all of whom were prescribed inhaled corticosteroids (ICS). Asthma exacerbations (treated by the GP or in hospital) and non-asthma visits and symptoms were assessed from notes for the subsequent 5 years., Results: Exacerbations correlated with non-asthma visits (0.35), severity as measured by BTS step (0.28), and with prescription-based adherence (0.28). Asthma severity correlated with non-asthma visits (0.35). Receiver operating curves showed that ≥2 non-asthma visits per year provided 79% sensitivity and 58% specificity for detecting ≥3 exacerbations over 5 years. Poor adherence predicted outcomes only for patients with high levels of non-asthma visits (≥3) and only for those reporting regular-but-less ICS use but not symptom-directed ICS use., Conclusions: Non-asthma visits are a good predictor of asthma exacerbations, particular in non-adherent patients. These results are consistent with a mechanism where exacerbations result from a combination of random oscillating specific and non-specific inflammatory processes. It is important to consider the total patient rather than just the lung when managing patients with asthma.

Introduction: Chronic obstructive pulmonary disease (COPD) exacerbations are associated with systemic consequences. Data from a 4-year trial (Understanding Potential Long-term Impacts on Function with Tiotropium [UPLIFT(®)], n = 5,992) were used to determine risk for nonlower respiratory serious adverse events (NRSAEs) following an exacerbation., Methods: Patients with ≥ 1 exacerbation were analyzed. NRSAE incidence rates (incidence rate [IR], per 100 patient-years) were calculated for the 30 and 180 days before and after the first exacerbation. NRSAEs were classified by diagnostic terms and organ classes. Maentel-Haenszel rate ratios (RR) (pre- and postexacerbation onset) along with 95% confidence intervals (CI) were computed., Results: A total of 3,960 patients had an exacerbation. The mean age was 65 years, forced expiratory volume in 1 s (FEV(1)) was 38% predicted, and 74% were men. For all NRSAEs, the IRs 30 days before and after an exacerbation were 20.2 and 65.2 with RR (95% CI) = 3.22 (2.40-4.33). The IRs for the 180-day periods were 13.2 and 31.0 with RR (95% CI) = 2.36 (1.93-2.87). The most common NRSAEs by organ class for both time periods were cardiac, respiratory system (other), and gastrointestinal. All NRSAEs as well as cardiac events were more common after the first exacerbation, irrespective of whether the patient had cardiac disease at baseline., Conclusions: The findings confirm that, after exacerbations, serious adverse events in other organ systems are more frequent, particularly those that are cardiac in nature.

Aims: This analysis was designed to provide a comparison between budesonide/formoterol and salmeterol/fluticasone for the relative incidence of pneumonia adverse events, pneumonia serious adverse events and pneumonia-related mortality in patients being treated for chronic obstructive pulmonary disease., Methods: An initial literature search revealed no suitable head-to-head trials between budesonide/formoterol and salmeterol/fluticasone and therefore a systematic review was conducted to find randomised controlled trials providing data for input into an adjusted indirect comparison of the two combination treatments using placebo as a common comparator. The Bucher adjusted indirect comparison method was used to calculate odds ratios and 95% confidence intervals., Results: Eight salmeterol/fluticasone trials and four budesonide/formoterol trials were identified as being relevant for the analyses. The proportion of patients experiencing a pneumonia adverse event was significantly lower with budesonide/formoterol than salmeterol/fluticasone (odds ratio, 0.47; 95% confidence interval, 0.28-0.80). The proportion of patients experiencing a pneumonia serious adverse event was also significantly lower with budesonide/formoterol than salmeterol/fluticasone (odds ratio, 0.41; 95% confidence interval, 0.19-0.86). However, there were too few events to draw any firm conclusions on pneumonia-related mortality., Conclusions: The results of the indirect comparison support the hypothesis that budesonide/formoterol is associated with fewer pneumonia events than salmeterol/fluticasone in chronic obstructive pulmonary disease. The limitations of the analysis are that the results from a single study, TORCH, have a large bearing on the overall findings of the analysis, and that there is heterogeneity in the length and the dosing of the included studies, although it does not appear that heterogeneity affected the reported results. Another important limitation is the lack of predefined diagnostic standards for pneumonia in these studies., (© 2011 Blackwell Publishing Ltd.)

Translating the growing evidence base on COPD management into practice can be challenging and understanding the strengths and weakness of published studies is crucial. Studies should conform to the standards of CONSORT statement; they should be sufficiently powered, participants should be randomised, there should be assignment concealment, and the outcome measures and analyses should be decided in advance. The interpretation of the results may be affected by age and severity inclusion criteria for the study and the exclusion of patients with co-morbid illnesses. Whether previous medication is continued or stopped can affect the interpretation of the results. Secondary analyses in sub-groups should be viewed with caution unless pre-specified and accommodated in the trial design and power calculations. Real world observational studies may be confounded by non-randomisation of participants but can sometimes yield valuable insights. The way in which the results are presented can influence their interpretation and their magnitude with respect to minimal important differences as well as statistical significance is important. Research help formulate management algorithms but often the questions they address are too specific to allow evidence-based sequencing of therapies.

Background: Recent clinical trials suggest that intermittent use of inhaled corticosteroids (ICS) is safe for mild persistent asthma. Intermittent ICS use is inconsistent with current guidelines but is a common form of non-compliance. The aim of this study was to investigate how asthma nurses advise patients to use ICS., Methods: Practice managers of 241 GP surgeries in the southwest of England were sent questionnaires to distribute to practice nurses., Results: Questionnaires were returned by 105 nurses (104 had asthma-specific training). There was a wide variation in attitudes to guideline-based care and advice given to patients. 97% indicated that they sometimes advised patients to decrease their ICS use, 85% sometimes advised patients to stop their ICS when their asthma was well controlled, and 70% reported sometimes advising intermittent use., Conclusion: Asthma nurse recommendations are often inconsistent with guidelines. There is considerable variation between different asthma nurses in the advice given to patients.

Chronic obstructive pulmonary disease (COPD) is a debilitating condition characterized by airflow limitation that is not fully reversible. It is a major cause of morbidity and mortality and represents substantial economic and social burden throughout the world. A range of interventions has been developed that decrease symptoms and address complications associated with COPD. However, to date few interventions have been unequivocally demonstrated to modify disease progression. Assessment of the potential for interventions to modify disease progression is complicated by the lack of a clear definition of disease modification and disagreement over appropriate markers by which modification should be evaluated. To clarify these issues, a working group of physicians and scientists from the USA, Canada and Europe was convened. The proposed working definition of disease modification resulting from the group discussions was "an improvement in, or stabilization of, structural or functional parameters as a result of reduction in the rate of progression of these parameters which occurs whilst an intervention is applied and may persist even if the intervention is withdrawn". According to this definition, pharmacologic interventions may be considered disease-modifying if they provide consistent and sustained improvements in structural and functional parameters. Smoking cessation and lung volume reduction surgery would both qualify as disease-modifying interventions.

Background: Hospital admissions for exacerbations of chronic obstructive pulmonary disease (COPD) impact considerably on disease evolution and healthcare provision. Building on previous studies, this study postulated that COPD patients could be stratified by risk of admission to determine which groups provide the greatest burden on resources, and how interventions should be targeted to prevent admissions., Methods: COPD admissions during 1997-2003 in three Strategic Health Authorities in England were analysed (n=80,291). Patients admitted during winter (1 November-31 March) were stratified into three groups according to the number of admissions during the previous year: 0 (NIL), 1-2 (MOD) or >or=3 (FRQ). Winter weeks were classified as "average", "above average", "high", or "very high" risk, compared with the long-term mean., Results: The risk of admission during winter for FRQ and MOD patients was 40% and 12% respectively. NIL patients contributed to 70% of winter admissions, and 90% of the variation between "average" and "very high" weeks, versus 9% and 1% for MOD and FRQ., Conclusions: Patients with no previous admissions have lower individual risk, but contribute to a high overall utilisation of health care resources and should be targeted to prevent admissions. Focusing upon high-risk patients (frequent attenders or more severe) may only reduce a small proportion of admissions, and therefore clinicians should ensure that all COPD patients receive appropriate therapy to reduce risk of exacerbations.

Background: Identifying chronic obstructive pulmonary disease (COPD) patients at increased risk of mortality is an important component of effective disease management., Methods: A pooled analysis of patients with severe COPD, from two well-controlled 1-year studies, was conducted using Cox regression and spline analysis to evaluate predictability of baseline demographic data and in-study variables for mortality risk, and to evaluate the effect of treatment allocation to budesonide and formoterol, versus their respective control groups, on these outcomes., Results: In the pooled analysis, a Cox regression model reported a higher baseline St George's Respiratory Questionnaire (SGRQ) total score as a significant predictor of mortality (hazard ratio 1.037 [95% confidence interval 1.021-1.054]; p<0.0001). The 36-item short-form health survey (SF-36) mental and physical component scores were also predictive of an increased mortality risk (p<0.05). Age, forced expiratory volume in 1 s (FEV(1)), body mass index and smoking status were not significant predictors. Spline analysis of baseline variables revealed a linear association between SGRQ total score and mortality risk over 1 year (logarithmic scale). Other baseline variables, including FEV(1), showed different bimodal patterns in the spline analysis. There was no difference in mortality in the formoterol versus the non-formoterol treatment group while budesonide-containing treatment was associated with reduced 1-year, all-cause, in-study mortality compared with non-budesonide therapy., Conclusion: Health status measured by SGRQ and SF-36 may be important for predicting COPD patients at increased mortality risk, with SGRQ total score emerging as the strongest predictor compared with other baseline covariates.

Objective: This systematic review examines the published evidence on the pharmacoecomonics of Symbicort. Symbicort is a combination inhaler used in asthma and chronic obstructive pulmonary disease (COPD) that contains budesonide and formoterol. In asthma, Symbicort can be used as fixed or adjustable dose maintenance therapy as well as for both maintenance and reliever therapy (SMART)., Method: A literature search of PubMed was carried out to find all publications on the pharmacoeconomics of Symbicort. Additional studies were searched for in the reference lists of the papers retrieved and by searching tables of contents of relevant journals. A total of 13 studies on Symbicort in asthma and 2 studies on Symbicort in COPD were found., Results: Total costs were lower with Symbicort than with separate inhalers containing budesonide and formoterol. Adjustable dosing maintained control of asthma using less medication and was associated with lower treatment costs than fixed dosing with Symbicort or the combination of fluticasone/salmeterol. SMART improves asthma control, reduces exacerbations and reduces direct and indirect costs compared to fixed maintenance therapy with either Symbicort or fluticasone/salmeterol. In COPD, Symbicort offers clinical advantages over therapy with the monocomponents and these are achieved at little or no extra cost.

Phosphodiesterases (PDEs) are important enzymes that hydrolyze the cyclic nucleotides adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) to their inactive 5' monophosphates. They are highly conserved across species and as well as their role in signal termination, they also have a vital role in intra-cellular localization of cyclic nucleotide signaling and integration of the cyclic nucleotide pathways with other signaling pathways. Because of their pivotal role in intracellular signaling, they are now of considerable interest as therapeutic targets in a wide variety diseases, including COPD where PDE inhibitors may have bronchodilator, anti-inflammatory and pulmonary vasodilator actions. This review examines the diversity and cellular localization of the isoforms of PDE, the known and speculative relevance of this to the treatment of COPD, and the range of PDE inhibitors in development together with a discussion of their possible role in treating COPD.

In order to assess the confidence of healthcare professionals in diagnosing and managing COPD telephone interviews were conducted with 60 practice nurses and 46 general practitioners (GPs) in 2001 and 61 nurses and 39 GPs in 2005. The nurses all ran respiratory clinics. 80% of GPs were confident about diagnosing COPD and this had increased from 52% in 2001. Fifty five percent of nurses were confident and there was no change from 2001. In 2005, 79% of GPs and 70% of nurses were confident about differentiating asthma and COPD. Smoking history, breathlessness, age of onset, lack of response to asthma therapy and cough were reported as features differentiating COPD from asthma. Most respondents stated that spirometry is essential to diagnose COPD and in 2005 nearly all practices had access to a spirometry service. GPs were more confident about interpreting spirometry results in 2005 than nurses and their confidence had increased significantly from 2001. In 2005, nearly all respondents had heard of pulmonary rehabilitation, and significantly more had a programme in their area in 2005 than 2001 (69% vs. 49% p=0.05). Fifty four percent of GPs were confident about which patients to refer for long term oxygen therapy in 2005 but nurses were less confident. There had not been any significant change between 2001 and 2005. In 2005 only 35% of respondents had access to a pulse oximeter. When presented with case scenarios, GPs self-reported confidence was not reflected in their diagnoses or investigation and management strategies and they seem to favour cardiac over respiratory diagnoses.

Chronic obstructive pulmonary disease (COPD) is associated with important extrapulmonary, or systemic, effects. There is systemic as well as pulmonary inflammation in COPD and this, together with systemic oxidative stress, contributes to their development. Skeletal muscle dysfunction contributes to exercise limitation. There is a loss of muscle mass and a reduction in the proportion of type 1 fibers. Sedentarism, hypoxia, corticosteroid therapy, nutritional depletion and systemic inflammation may contribute to its development. Weight loss is another important effect. It is associated with a worse prognosis, which changes with therapy and may be due to reductions in calorie intake, changes in intermediate metabolism and effects of systemic inflammation. Cardiovascular disease is a frequent cause of death in COPD and coronary artery disease, left ventricular failure and arrhythmias are systemic effects of COPD, as well as comorbidities sharing a common etiology. Exacerbations of COPD may increase the risk of coronary events by increasing the level of systemic inflammation. Osteoporosis is more common in COPD (even after adjusting for corticosteroid usage) and may be due to a combination of inactivity and the effects of systemic inflammation. COPD is also associated with systemic endothelial dysfunction and CNS abnormalities (including depression), which may also be due to the effects of systemic inflammation. These systemic effects respond to COPD treatments, including pulmonary rehabilitation, nutritional supplementation and inhaled corticosteroids, as well as specific drugs, such as bisphosphonates or diuretics. There is growing evidence that novel approaches, such as the use of statins, may also be of value.

Chronic obstructive pulmonary disease (COPD) is a multicomponent disease with inflammation at its core, and a major cause of morbidity and mortality. It represents a substantial economic and social burden throughout the world. Currently, COPD is the fifth leading cause of death worldwide, and despite advances in management, mortality is expected to increase in the coming decades, in marked contrast to other chronic diseases, such as heart disease and stroke, where there have been considerable decreases in mortality. On a patient level, the burden of COPD to patients and their families and carers is high, both in terms of health-related quality of life and health status. Health care providers and patients often underestimate the substantial morbidity associated with COPD; the condition is also frequently underdiagnosed and undertreated, which further compromises morbidity. Reducing the burden of COPD requires better evaluation and diagnosis, as well as improved management of chronic symptoms. As exacerbations and hospitalizations represent an important driver of the cost and morbidity of COPD, high priority should be given to interventions aimed at delaying the progression of disease, preventing exacerbations, and reducing the risk of comorbidities to alleviate the clinical and economic burden of disease.