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Ronald Chow,1 Olivia W So,1 James HB Im,2 Kenneth R Chapman,1 Ani Orchanian-Cheff,1 Andrea S Gershon,3 Robert Wu1 1University Health Network, University of Toronto, Toronto, ON, Canada; 2The Hospital for Sick Children, Toronto, ON, Canada; 3Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, CanadaCorrespondence: Ronald Chow, University Health Network, University of Toronto, Toronto, ON, Canada, Email ronald.chow@uhn.caIntroduction: Chronic obstructive pulmonary disease (COPD) is the third-leading cause of death globally and is responsible for over 3 million deaths annually. One of the factors contributing to the significant healthcare burden for these patients is readmission. The aim of this review is to describe significant predictors and prediction scores for all-cause and COPD-related readmission among patients with COPD.Methods: A search was conducted in Ovid MEDLINE, Ovid Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials, from database inception to June 7, 2022. Studies were included if they reported on patients at least 40 years old with COPD, readmission data within 1 year, and predictors of readmission. Study quality was assessed. Significant predictors of readmission and the degree of significance, as noted by the p-value, were extracted for each study. This review was registered on PROSPERO (CRD42022337035).Results: In total, 242 articles reporting on 16,471,096 patients were included. There was a low risk of bias across the literature. Of these, 153 studies were observational, reporting on predictors; 57 studies were observational studies reporting on interventions; and 32 were randomized controlled trials of interventions. Sixty-four significant predictors for all-cause readmission and 23 for COPD-related readmission were reported across the literature. Significant predictors included 1) pre-admission patient characteristics, such as male sex, prior hospitalization, poor performance status, number and type of comorbidities, and use of long-term oxygen; 2) hospitalization details, such as length of stay, use of corticosteroids, and use of ventilatory support; 3) results of investigations, including anemia, lower FEV1, and higher eosinophil count; and 4) discharge characteristics, including use of home oxygen and discharge to long-term care or a skilled nursing facility.Conclusion: The findings from this review may enable better predictive modeling and can be used by clinicians to better inform their clinical gestalt of readmission risk.Keywords: predictors, readmission, chronic obstructive pulmonary disease

Richard N van Zyl-Smit,1 Kenneth R Chapman,2 Huib AM Kerstjens,3 Christian Gessner,4 Hironori Sagara,5 Ana-Maria Tanase,6 Motoi Hosoe,6 Abhijit Pethe,7 David Lawrence,6 Hanns-Christian Tillmann,8 Peter D’Andrea7 1Division of Pulmonology and UCT Lung Institute, University of Cape Town, Cape Town, South Africa; 2Division of Respiratory Medicine, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; 3Department of Pulmonology, University of Groningen, University Medical Center Groningen, and Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands; 4Universitätsklinikum Leipzig, Germany POIS Leipzig GbR, Leipzig, Germany; 5Department of Medicine, Division of Respiratory Medicine and Allergology, Showa University School of Medicine, Tokyo, Japan; 6Novartis Pharma AG, Basel, Switzerland; 7Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 8Novartis Institutes for BioMedical Research, Translational Medicine, Basel, SwitzerlandCorrespondence: Ana-Maria Tanase, Novartis Pharma AG, Fabrikstrasse 4, Novartis Campus, Basel, Switzerland, Tel +41 79 899 98 22, Email ana-maria.tanase@novartis.comBackground: Once-daily, single-inhaler mometasone furoate/indacaterol acetate/glycopyrronium bromide (MF/IND/GLY, an ICS/LABA/LAMA) and MF/IND (an ICS/LABA) via Breezhaler® have been approved for the maintenance treatment of patients with asthma inadequately controlled with medium-or high-dose ICS or medium-or high-dose ICS/LABA treatment.Objective: Once-daily (o.d.) formulations of MF/IND/GLY and MF/IND at different MF dose strengths have been compared with twice-daily (b.i.d.) fluticasone propionate/salmeterol xinafoate (FLU/SAL), and b.i.d. FLU/SAL+ o.d. tiotropium (TIO) in the PALLADIUM, IRIDIUM and ARGON studies.Methods: The similarity in study design and consistent outcomes in these studies prompted the pooling of data in this review to better characterise these novel once-daily controller formulations.Results: Pooled data from PALLADIUM and IRIDIUM studies showed comparable or greater efficacy with o.d. MF/IND formulations versus b.i.d. FLU/SAL. The o.d. MF/IND/GLY was superior to b.i.d. FLU/SAL in the IRIDIUM study, and similar to, if not more efficacious than b.i.d. FLU/SAL + o.d. TIO in the ARGON study.Conclusion: These formulations therefore provide novel once-daily treatment options for patients across asthma severity and flexibility for clinicians to step-up or step-down the treatment using the same device and formulations.Keywords: mometasone/indacaterol/glycopyrronium, mometasone/indacaterol, fluticasone/salmeterol, tiotropium, bronchodilator, lung function, asthma control, exacerbation

Xiaoshu Cao,1,2 Cristina de Oliveira Francisco,2 T Douglas Bradley,2– 4 Nasim Montazeri Ghahjaverestan,1,2 Susan M Tarlo,3,5,6 Matthew B Stanbrook,3,5 Kenneth R Chapman,3,5 Mark Inman,7 Azadeh Yadollahi1,2 1Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada; 2KITE, Toronto Rehabilitation Institute - University Health Network, Toronto, ON, Canada; 3Department of Medicine, University of Toronto, Toronto, ON, Canada; 4Department of Medicine, University Health Network Toronto General Hospital, Toronto, ON, Canada; 5Department of Medicine, University Health Network Toronto Western Hospital, Toronto, ON, Canada; 6Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada; 7Faculty of Medicine (Respirology), McMaster University, Hamilton, ON, CanadaCorrespondence: Azadeh Yadollahi, KITE, Toronto Rehabilitation Institute - University Health Network, Room 12-106, 550 University Avenue, Toronto, ON, M5G 2A2, Canada, Email azadeh.yadollahi@uhn.caRationale: Obstructive sleep apnea (OSA) is highly prevalent among patients with asthma, suggesting a pathophysiological link between the two, but a mechanism for this has not been identified.Hypothesis: Among patients with asthma, those with OSA will have greater overnight increases in thoracic fluid volume and small airways narrowing than those without OSA.Methods: We enrolled 19 participants with asthma: 9 with OSA (apnea-hypopnea index (AHI) ≥ 10) and 10 without OSA (AHI < 10). All participants underwent overnight polysomnography. Before and after sleep, thoracic fluid volume was measured by bioelectrical impedance and small airways narrowing was primarily assessed by respiratory system reactance at 5Hz using oscillometry.Results: Patients with asthma and OSA (OSA group) had a greater overnight increase in thoracic fluid volume by 120.5 mL than patients without OSA (non-OSA group) (164.4 ± 44.0 vs 43.9 ± 47.3 mL, p=0.006). Compared to the non-OSA group, the OSA group had greater overnight decrease in reactance at 5Hz (− 1.08 ± 0.75 vs 0.21 ± 0.27 cmH2O/L/s, p=0.02), and overnight increase in reactance area (14.81 ± 11.09 vs − 1.20 ± 2.46 cmH2O/L, p=0.04), frequency dependence of resistance (1.02 ± 0.68 vs 0.05 ± 0.18 cmH2O/L/s, p=0.04), and resonance frequency (2.80 ± 4.14 vs − 1.42 ± 2.13 cmH2O/L/s, p=0.04).Conclusion: Patients with asthma and co-existing OSA had greater overnight accumulation of fluid in the thorax in association with greater small airways narrowing than those without OSA. This suggests OSA could contribute to worsening of asthma at night by increasing fluid accumulation in the thorax.Keywords: asthma, obstructive sleep apnea, small airway narrowing, thoracic fluid volume

Robert A Wise,1 Kenneth R Chapman,2 Benjamin M Scirica,3,4 Sami Z Daoud,5 Dan Lythgoe,6 Esther Garcia-Gil7 1Medicine, Pulmonary and Critical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Department of Medicine, University of Toronto, Toronto, ON, Canada; 3Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA; 4Department of Medicine, Harvard Medical School, Boston, MA, USA; 5Late-Stage Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; 6Statistics, Phastar, Chiswick, London, UK; 7Respiratory & Immunology, BioPharmaceuticals Medical, AstraZeneca, Barcelona, SpainCorrespondence: Robert A WiseMedicine, Pulmonary and Critical Care, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD, 21224, USAEmail rwise@jhmi.eduPurpose: Chronic obstructive pulmonary disease (COPD) exacerbations are associated with increased risk of major adverse cardiovascular events (MACE) and mortality. Here, we investigate whether the safety and efficacy of aclidinium bromide differ due to exacerbation history in patients with COPD and increased cardiovascular risk.Patients and Methods: ASCENT-COPD was a Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study of patients with moderate-to-very severe COPD and increased cardiovascular risk. Patients were randomized 1:1 to receive aclidinium or placebo twice daily for up to 3 years. Outcomes included time to first MACE and all-cause mortality over 3 years, exacerbation rate during the first year on-treatment, and change in baseline pre-dose forced expiratory volume in 1 second (FEV1) over 3 years. This pre-specified subgroup analysis compared outcomes in patients receiving aclidinium vs placebo. The comparison of patients with vs without an exacerbation history was added following a protocol amendment to increase enrollment in the primary study.Results: Of 3589 patients, 2156 (60.1%) had ≥ 1 moderate or severe exacerbations in the prior year, compared with 1433 (39.9%) without prior exacerbations. Although patients with an exacerbation history had numerically higher rates of MACE and mortality regardless of treatment, aclidinium did not increase risk of MACE (≥ 1: hazard ratio [HR] 0.79, 95% confidence interval [CI]: 0.54– 1.16; none: HR 1.27, 95% CI: 0.65– 2.47; interaction P=0.233) or all-cause mortality (≥ 1: HR 1.08, 95% CI: 0.81– 1.43; none: HR 0.66, 95% CI: 0.36– 1.22; interaction P=0.154), regardless of exacerbation history. Aclidinium reduced the exacerbation rate vs placebo irrespective of exacerbation history (≥ 1: rate ratio [RR] 0.80, 95% CI: 0.68– 0.94; none: RR 0.69, 95% CI: 0.54– 0.89; interaction P=0.340) and improved FEV1 (interaction P=0.633).Conclusion: In patients with moderate-to-very severe COPD and increased cardiovascular risk, aclidinium did not increase risk of MACE or mortality and reduced exacerbation rate vs placebo, regardless of exacerbation history.Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01966107.Keywords: COPD, COPD exacerbation, aclidinium, MACE, mortality

Clarus Leung,1 Jean Bourbeau,2 Don D Sin,1 Shawn D Aaron,3 J Mark FitzGerald,4 François Maltais,5 Darcy D Marciniuk,6 Denis O’Donnell,7 Paul Hernandez,8 Kenneth R Chapman,9 Brandie Walker,10 Jeremy D Road,4 Liyun Zheng,1 Carl Zou,1 James C Hogg,1 Wan C Tan1 On behalf of the CanCOLD Collaborative Research Group1Centre for Heart Lung Innovation, St Pauls Hospital, The University of British Columbia, Vancouver, BC, Canada; 2Research Institute McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 3The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada; 4Department of Medicine, Vancouver General Hospital, University of British Columbia, Vancouver, Canada; 5Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Quebec City, Quebec, Canada; 6Respiratory Research Centre, University of Saskatchewan, Saskatoon, Canada; 7Department of Medicine, Queen’s University, Kingston, Canada; 8Department of Medicine, Dalhousie University, Halifax, Canada; 9Toronto General Hospital Research Institute, University of Toronto, Toronto, Canada; 10Department of Medicine, University of Calgary (BW), Alberta, CanadaCorrespondence: Wan C TanCentre for Heart Lung Innovation, St. Paul’s Hospital, University of British Columbia, Rm 166, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, CanadaTel +1-604-682-2344 ext 62749Fax +1-604-806-9274Email wan.tan@hli.ubc.caPurpose: To determine the spirometric-based prevalence of COPD across different regions in Canada and to evaluate the site heterogeneity of risk factors.Patients and Methods: In this cross-sectional, population-based study, random samples of non-institutionalized adults aged ≥ 40 years were generated by random digit dialling. Participants answered an interviewer-administered questionnaire and performed spirometry before and after bronchodilator administration. COPD was defined as post-bronchodilator FEV1/FVC < 0.70 (fixed ratio, FR) and as FEV1/FVC < 5th percentile (lower limits of normal, LLN). Separate logistic regression models were used to compute the risk (adjusted odds ratio, aOR) for COPD. I2 and Tau2 analyses were used to evaluate heterogeneity.Results: Out of 5176 (95%) participants, 4893 (47% male with mean age 56.6 years (95% confidence interval, 56.0– 57.2)) had spirometry that satisfied ATS criteria. The population prevalence of COPD was 16.2% (95% CI, 14.5– 17.8) by FR and 11.2% (95% CI, 9.7– 12.6) by LLN. Male predominance in prevalence was shown by FR but not by LLN criteria. Patient characteristics associated with an increased risk of COPD included: age (OR 1.56; 95% CI 1.33– 1.84); history of physician-diagnosed asthma (OR 3.30; 95% CI 2.42– 4.49); and childhood hospitalization for respiratory illness (OR 1.81; 95% CI 1.17– 2.80). In terms of smoking-related risk factors, current smoking status had the highest odds ratio (OR 3.49; 95% CI 2.55– 4.80). Variance in prevalence among sites was significantly reduced by adjusting for risk factors in Tau2 analyses. Higher odds of exposure for each risk factor was found in more severe COPD, suggesting that a higher risk could be linked to the development of severe disease.Conclusion: This study reports the population prevalence of COPD in nine urban cities which collectively represent the majority of the Canadian population and demonstrates that heterogeneity in prevalence among sites is substantially explained by variation in associated risk factors for COPD.Keywords: prevalence, heterogeneity, COPD

Alan Kaplan,1 Kenneth R Chapman,2 Syed M Anees,3 Irvin Mayers,4 Driss Rochdi,5 Michel Djandji,5 David Préfontaine,5 Andrew McIvor6 1Family Physician Airways Group of Canada, University of Toronto, Toronto, ON, Canada; 2Division of Respiratory Medicine, Department of Medicine, University of Toronto, Toronto, ON, Canada; 3Schulich School of Medicine & Dentistry – Western University, University of Windsor, ON, Canada; 4Division of Pulmonary Medicine, Department of Medicine, University of Alberta, Edmonton, AB, Canada; 5Novartis Pharmaceuticals Canada Inc., Montreal, QC, Canada; 6Department of Medicine, McMaster University, Firestone Institute for Respiratory Health, Hamilton, ON, Canada Purpose: In contrast to randomized controlled trials (RCTs), changes in maintenance pharmacotherapy in clinical practice occur without a washout period. The Prospective cohort study for the real-life effectiveness evaluation of glycOpyrronium With indacatERol combination in the management of COPD in Canada (POWER) study evaluated the real-life effectiveness of indacaterol/glycopyrronium (IND/GLY) following a direct switch from a long-acting muscarinic antagonist (LAMA, tiotropium) or long-acting β2-agonist (LABA)/inhaled corticosteroid (ICS) maintenance treatment (salmeterol/fluticasone [SFC]).Methods: POWER was a single-cohort, prospective, multicenter, interventional study in which patients with moderate-to-severe COPD, who remained symptomatic on their current treatment of once-daily (od) tiotropium 18 µg or twice-daily (bid) SFC (any dose), were switched to treatment with open-label IND/GLY 110/50 µg od for 16 weeks. Effectiveness end points were change from baseline in trough FEV1, transition dyspnea index (TDI) total scores, and COPD assessment test (CAT) scores at 16 weeks.Results: Trough FEV1 improved by 175 mL at Week 16 in patients who switched to IND/GLY. The change was 176 mL (95% CI: 135–217) when switched from tiotropium and 172 mL (95% CI: 85–258) when switched from SFC fixed-dose combination (FDC). At Week 16, significant improvements were observed in the mean TDI total scores (Δ=2.5) and CAT scores (Δ=-6.5) after the switch to IND/GLY treatment (both P

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

Kenneth R Chapman,1 Joanna Chorostowska-Wynimko,2 A Rembert Koczulla,3 Ilaria Ferrarotti,4 Noel G McElvaney5 1Department of Medicine, University of Toronto, Toronto, ON, Canada; 2Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland; 3Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-University, Marburg, Germany; 4Center for Diagnosis of Inherited Alpha-1 Antitrypsin Deficiency, Department of Internal Medicine and Therapeutics, Pneumology Unit, University of Pavia, Pavia, Italy; 5Department of Medicine, Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland Abstract: Alpha 1 antitrypsin deficiency is a hereditary condition characterized by low alpha 1 proteinase inhibitor (also known as alpha 1 antitrypsin [AAT]) serum levels. Reduced levels of AAT allow abnormal degradation of lung tissue, which may ultimately lead to the development of early-onset emphysema. Intravenous infusion of AAT is the only therapeutic option that can be used to maintain levels above the protective threshold. Based on its biochemical efficacy, AAT replacement therapy was approved by the US Food and Drug administration in 1987. However, there remained considerable interest in selecting appropriate outcome measures that could confirm clinical efficacy in a randomized controlled trial setting. Using computed tomography as the primary measure of decline in lung density, the capacity for intravenously administered AAT replacement therapy to slow and modify the course of disease progression was demonstrated for the first time in the Randomized, Placebo-controlled Trial of Augmentation Therapy in Alpha-1 Proteinase Inhibitor Deficiency (RAPID) trial. Following these results, an expert review forum was held at the European Respiratory Society to discuss the findings of the RAPID trial program and how they may change the landscape of alpha 1 antitrypsin emphysema treatment. This review summarizes the results of the RAPID program and the implications for clinical considerations with respect to diagnosis, treatment and management of emphysema due to alpha 1 antitrypsin deficiency. Keywords: alpha 1 antitrypsin deficiency, computed tomography, emphysema, efficacy

Marc Miravitlles,1 Kenneth R Chapman,2 Ferran Chuecos,3 Anna Ribera,4 Esther Garcia Gil3 1Department of Pneumology, Vall d’Hebron University Hospital, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain; 2Asthma & Airway Centre, University Health Network, Toronto Western Hospital and University of Toronto, Toronto, ON, Canada; 3Global Medicines Development, AstraZeneca PLC, Barcelona, Spain; 4Global Medical Affairs, AstraZeneca PLC, Barcelona, Spain Background: Patients with chronic obstructive pulmonary disease (COPD) experience respiratory symptoms, which impair quality of life. This pooled analysis of two Phase III studies assessed the impact of aclidinium/formoterol on patients with COPD categorized by symptom status.Methods: Data were pooled from two 24-week, randomized, placebo-controlled studies of twice-daily aclidinium/formoterol 400/12 µg in moderate-to-severe COPD (ACLIFORM [NCT01462942] and AUGMENT [NCT01437397]). These post hoc analyses evaluated the efficacy of aclidinium/formoterol versus placebo or monotherapies in patients defined as less/more symptomatic by a) Evaluating Respiratory Symptoms (E-RS™) score ≥10/

Anthony D D’Urzo,1 Edward M Kerwin,2 Kenneth R Chapman,3 Marc Decramer,4 Robert DiGiovanni,5 Peter D’Andrea,6 Huilin Hu,6 Pankaj Goyal,5 Pablo Altman6 1Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada; 2Clinical Research Institute of Southern Oregon, PC, Medford, USA; 3Asthma and Airway Centre, University Health Network, Toronto Western Hospital, Toronto, ON, Canada; 4Respiratory Division, University of Leuven, Leuven, Belgium; 5Novartis Pharma AG, Basel, Switzerland; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA Background: Chronic use of inhaled anticholinergics by patients with chronic obstructive pulmonary disease (COPD) has raised long-term safety concerns, particularly cardiovascular. Glycopyrronium is a once-daily anticholinergic with greater receptor selectivity than previously available agents. Methods: We assessed the safety of inhaled glycopyrronium using data pooled from two analysis sets, involving six clinical studies and over 4,000 patients with COPD who received one of the following treatments: glycopyrronium 50 µg, placebo (both delivered via the Breezhaler® device), or tiotropium 18 µg (delivered via the HandiHaler® device). Data were pooled from studies that varied in their duration and severity of COPD of the patients (ie, ≤12 weeks duration with patients having moderate or severe COPD; and >1 year duration with patients having severe and very severe COPD). Safety comparisons were made for glycopyrronium vs tiotropium or placebo. Poisson regression was used to assess the relative risk for either active drug or placebo (and between drugs where placebo was not available) for assessing the incidence of safety events. During post-marketing surveillance (PMS), safety was assessed by obtaining reports from various sources, and disproportionality scores were computed using EMPIRICA™. In particular, the cardiac safety of glycopyrronium during the post-marketing phase was evaluated.Results: The overall incidence of adverse events and deaths was similar across groups, while the incidence of serious adverse events was numerically higher in placebo. Furthermore, glycopyrronium did not result in an increased risk of cerebro-cardiovascular events vs placebo. There were no new safety reports during the PMS phase that suggested an increased risk compared to results from the clinical studies. Moreover, the cardiac safety of glycopyrronium during the PMS phase was also consistent with the clinical data.Conclusion: The overall safety profile of glycopyrronium was similar to its comparators indicating no increase in the overall risk for any of the investigated safety end points. Keywords: COPD, drug safety, glycopyrronium, post-marketing surveillance

Marcos Ribeiro, Kenneth R ChapmanAsthma and Airway Centre, University Health Network, Toronto Western Hospital, University of Toronto, Toronto, ON, CanadaAbstract: Long-acting bronchodilators have been shown to improve multiple clinical outcomes in chronic obstructive pulmonary disease (COPD) including lung function, symptoms, dyspnea, quality of life, and exacerbations. Indacaterol is a novel, inhaled, long-acting β2-agonist providing 24-hour bronchodilation with once-daily dosing. It is currently approved for the maintenance treatment of COPD to be administered as 150 or 300 µg once-daily doses as licensed in many countries and 75 µg as licensed in the US by means of a single-dose dry powder inhaler. The data from clinical development support a favorable safety and tolerability profile within the β2-agonist drug class, with no relevant issues identified. Current evidence indicates that indacaterol is suitable for use as first-line monotherapy in COPD patients with moderate disease (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage II) and beyond that do not require an inhaled corticosteroid (ICS) as per GOLD guidelines, or in combination with an ICS in severe or very severe patients with repeated exacerbations. Data from trials with the novel once-daily β2-agonist, indacaterol, indicate superior bronchodilation and clinical efficacy over twice-daily long-acting β2-agonists and at least equipotent bronchodilation as once-daily tiotropium. Bronchodilators are central in the symptomatic management of COPD. It is likely that once-daily dosing of a bronchodilator would be a significant convenience and probably a compliance-enhancing advantage, leading to improved overall clinical outcomes in patients with COPD.Keywords: indacaterol, onset of action, chronic obstructive pulmonary disease, bronchodilators, once-daily, long-acting β2-agonists

Kenneth R Chapman1, Charles M Fogarty2, Clare Peckitt3, Cheryl Lassen3, Dalal Jadayel3, Juergen Dederichs4, Mukul Dalvi4, Benjamin Kramer5On behalf of the INDEED (indacaterol: handling and preference evaluation of the Breezhaler device in COPD) study investigators1University of Toronto, Toronto, Canada; 2Spartanburg Medical Research, Spartanburg, SC, United States; 3Novartis Horsham Research Centre, Horsham, West Sussex, UK; 4Novartis Pharma AG, Basel, Switzerland; 5Novartis Pharmaceuticals, East Hanover, NJ, USAAbstract: For optimal efficacy, an inhaler should deliver doses consistently and be easy for patients to use with minimal instruction. The delivery characteristics, patients’ correct use, and preference of two single-dose dry powder inhalers (Breezhaler and HandiHaler) were evaluated in two complementary studies. The first study examined aerodynamic particle size distribution, using inhalation profiles of seven patients with moderate to very severe chronic obstructive pulmonary disease (COPD). The second was an open-label, two-period, 7-day crossover study, evaluating use of the inhalers with placebo capsules by 82 patients with mild to severe COPD. Patients’ correct use of the inhalers was assessed after reading written instructions on Day 1, and after training and 7 days of daily use. Patients’ preference was assessed after completion of both study periods. Patient inhalation profiles showed average peak inspiratory flows of 72 L/minute through Breezhaler and 36 L/minute through HandiHaler. For Breezhaler and HandiHaler, fine particle fractions were 27% and 10%, respectively. In the second study, correct use of Breezhaler and HandiHaler was achieved by >77% of patients for any step after 7 days; 61% of patients showed an overall preference for Breezhaler and 31% for HandiHaler (P = 0.01). Breezhaler is a low-resistance inhaler suitable for use by patients with a range of disease severities. Most patients used both inhalers correctly after 7 days, but more patients showed an overall preference for the Breezhaler compared with the HandiHaler. These are important factors for optimum dose delivery and successful COPD management.Keywords: Breezhaler, HandiHaler, COPD, use, preference, dose delivery

Background: Indacaterol is an inhaled, long-acting β(2)-agonist providing 24-h bronchodilation with once-daily dosing in patients with COPD.Methods: Subjects with moderate to severe COPD who completed a 26-week, randomized, double-blind study were eligible for enrollment in an extension, during which treatment with double-blind indacaterol, 150 or 300 μg once daily, or placebo was continued for a further 26 weeks. The primary objective was to evaluate the long-term safety of indacaterol. Efficacy end points included trough (24 h postdose) FEV(1) at 52 weeks, exacerbations, and health status (St. George Respiratory Questionnaire [SGRQ]).Results: Four hundred fifteen subjects participated in the extension. Adverse events, mostly mild or moderate, occurred in 76%, 77%, and 68% of subjects receiving indacaterol, 150 μg; indacaterol, 300 μg; and placebo, respectively. Serious adverse events occurred in 10.4%, 12.3%, and 10.5%, respectively. Indacaterol had no clinically significant effects on ECG findings (corrected QT interval) or on serum potassium or plasma glucose levels. Indacaterol increased trough FEV(1) relative to placebo throughout the study (difference of ≥ 170 mL at week 52). No tolerance to its bronchodilator effect was detected. Indacaterol treatment was accompanied by significant reductions in COPD exacerbations (rate ratios compared with placebo, 0.62-0.64; P < .05) and as-needed albuterol use (1.2-1.4 puffs/d decrease, P < .001 compared with placebo). Health status improved with indacaterol treatment, with decreases from baseline in mean total SGRQ score generally > 4 units.Conclusions: During 1 year of treatment, indacaterol was well tolerated and provided significant and well-maintained bronchodilation that was accompanied by improved clinical outcomes.Trial Registry: ClinicalTrials.gov; No.: NCT00677807; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Symptomatic disease due to nontuberculous mycobacteria (NTM) is known to occur commonly in the presence of structural lung disease, but is not described in association with asthma. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine whether asthma control in Canada had improved since the last major survey in 1999 by exploring how well patients' asthma was controlled, how much they knew about asthma control, and how they used health care resources.DESIGN: National telephone survey of patients between April and August 2004.SETTING: Canada.PARTICIPANTS: Eight hundred ninety-three adults 18 to 54 years old diagnosed with asthma more than 6 months before the survey.MAIN OUTCOME MEASURES: Patients' control of their asthma, patients' knowledge about asthma, the frequency and duration of periods of worsening asthma, and patients' use of health care resources to manage those periods.RESULTS: In total, 26 210 households listed in a consumer database were contacted. Excluding ineligible households and households with a language barrier, a member of 13% of the households completed the 35-minute survey. Based on definitions in Canadian guidelines, 53% of patients had symptomatic uncontrolled asthma. In the previous year, almost all asthma patients had experienced worsening of symptoms that lasted on average 13.6 days for patients with uncontrolled asthma and 8.0 days for patients with controlled asthma (P < .02). Markedly more patients with uncontrolled asthma used health care resources for episodes of asthma than patients with controlled asthma did (72% vs 15% for urgent office visits, P < .01; 32% vs 3% for emergency department visits, P < .01; and 7% vs 0% for hospitalizations, P < .01) in the year before the survey. Patients were confused about the differences between reliever and controller medications. One third of patients claimed that no one had taught them about asthma medications, and one quarter said they had received no training on how to recognize the early signs of asthma worsening.CONCLUSION: Asthma control and management remained suboptimal in Canada and relatively unchanged since the previous major survey in 1999. [ABSTRACT FROM AUTHOR]

To determine the effects of concurrent beta 1-adrenoceptor blocker or calcium channel antagonist administration on the haemodynamic sequelae of an inhaled beta 2-selective adrenoceptor agonist bronchodilator, we examined echocardiographically the effects of fenoterol (400 micrograms) by metered dose inhaler following oral pre-treatment with (a) placebo, (b) atenolol or (c) diltiazem. Following placebo, fenoterol produced significant decreases in diastolic blood pressure (14% +/- 6%), total peripheral vascular resistance (TPR) (31% +/- 9%) and end-systolic stress (ESS) (15% +/- 21%). Cardiac output rose significantly (42% +/- 23%) as did heart rate (25% +/- 13%). After atenolol, responses to fenoterol were significantly blunted. Post- fenoterol heart rate, systolic blood pressure, % fractional shortening, stroke volume, ejection fraction, cardiac output and pressure/volume ratio increased significantly less after atenolol pre-treatment as compared to placebo pretreatment. TPR decreased significantly less. After diltiazem pre-treatment, the response to inhaled fenoterol was not different from that following placebo pre-treatment. We conclude that atenolol blunts the haemodynamic changes induced by fenoterol inhalation whereas diltiazem has little effect. [ABSTRACT FROM AUTHOR]

Long-acting beta-agonists are a pillar of therapy for many patients with asthma because they are the preferred add-on therapy to inhaled corticosteroids. However, a recent meta-analysis documented a substantial increase in severe exacerbations requiring hospital admission and life-threatening asthma exacerbations in patients treated with long-acting beta-agonists. A careful evaluation of this meta-analysis raises several concerns about its applicability to current practice. Pivotal trials evaluating the benefit of adding long-acting beta-agonists to inhaled corticosteroids were not included. The authors of the current paper call for physicians to continue their usual practice of using long-acting beta-agonists as adjunctive therapy, as well as for an independent meta-analysis of individual patients using inhaled corticosteroids and long-acting beta-agonists concomitantly. [ABSTRACT FROM AUTHOR]