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Kris Vanhaecht,1,2 Cathy Lodewijckx,1 Walter Sermeus,1 Marc Decramer,3,4 Svin Deneckere,1,5 Fabrizio Leigheb,6 Paulo Boto,7 Seval Kul,8 Deborah Seys,1 Massimiliano Panella1,6 1Department of Public Health and Primary Care, Leuven Institute for Healthcare Policy, KU Leuven – University of Leuven, 2Department of Quality Management, University Hospitals Leuven, 3Department of Clinical and Experimental Medicine, KU Leuven – University of Leuven, 4University Hospitals Leuven, Leuven, 5Medical Department, Delta Hospitals Roeselare, Roeselare, Belgium; 6Department of Translational Medicine, University of Eastern Piedmont, Vercelli, Italy; 7Department of Health Services Policy and Management, Centro de Investigação em Saúde Pública, Escola Nacional de Saúde Pública, Universidade Nova de Lisboa, Lisbon, Portugal; 8Department of Biostatistics, School of Medicine, University of Gaziantep, Gaziantep, Turkey Purpose: Current in-hospital management of exacerbations of COPD is suboptimal, and patient outcomes are poor. The primary aim of this study was to evaluate whether implementation of a care pathway (CP) for COPD improves the 6 months readmission rate. Secondary outcomes were the 30 days readmission rate, mortality, length of stay and adherence to guidelines. Patients and methods: An international cluster randomized controlled trial was performed in Belgium, Italy and Portugal. General hospitals were randomly assigned to an intervention group where a CP was implemented or a control group where usual care was provided. The targeted population included patients with COPD exacerbation. Results: Twenty-two hospitals were included, whereof 11 hospitals (n=174 patients) were randomized to the intervention group and 11 hospitals (n=168 patients) to the control group. The CP had no impact on the 6 months readmission rate. However, the 30 days readmission rate was significantly lower in the intervention group (9.7%; 15/155) compared to the control group (15.3%; 22/144) (odds ratio =0.427; 95% confidence interval 0.222–0.822; P=0.040). Performance on process indicators was significantly higher in the intervention group for 2 of 24 main indicators (8.3%). Conclusion: The implementation of this in-hospital CP for COPD exacerbation has no impact on the 6 months readmission rate, but it significantly reduces the 30 days readmission rate. Keywords: COPD, care pathway, readmission, quality improvement, cluster randomized controlled trial

Carlos A Camillo,1,2 Daniel Langer,1,2 Christian R Osadnik,1,3–5 Lisa Pancini,2 Heleen Demeyer,1,2 Chris Burtin,1,6 Rik Gosselink,1,2 Marc Decramer,2 Wim Janssens,2 Thierry Troosters1,2 1KU Leuven, Department of Rehabilitation Sciences, Leuven, Belgium; 2University Hospital Leuven, Respiratory Division and Rehabilitation, Leuven, Belgium; 3Monash University, Department of Physiotherapy, Melbourne, VIC, Australia; 4Institute for Breathing and Sleep, Melbourne, VIC, Australia; 5Monash Health, Monash Lung and Sleep, Melbourne, VIC, Australia; 6Hasselt University, Rehabilitation Research Centre, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Diepenbeek, Belgium Abstract: The impact of rehabilitation-induced changes in 6-minute walk distance (6MWD) on the survival of patients with chronic obstructive pulmonary disease (COPD) has not been fully elucidated. This study sought to determine the association of baseline 6MWD and its changes after pulmonary rehabilitation (PR) with 5-year survival in patients with COPD. Patients who were referred to a 12-week outpatient PR program were followed up for 5 years postcompletion, and survival status was verified. Survival was analyzed according to four groups based upon initial 6MWD (6MWDi) and its changes (Δ6MWD) after PR (Group 1: 6MWDi ≥350 m and Δ6MWD ≥30 m; Group 2: 6MWDi ≥350 m and Δ6MWD 30 m after PR are associated with worse 5-year survival in patients with COPD. Keywords: pulmonary disease, chronic obstructive, exercise training, mortality, 6-minute walk test, minimally important difference

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

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