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Inhaled corticosteroid (ICS)-containing therapies are the mainstay of pharmacological management of asthma. They can be administered alone or in combination with a long-acting bronchodilator, depending on asthma severity, and may also be supplemented with short-acting bronchodilators for as-needed rescue medication. Adherence to asthma therapies is generally poor and characterized by underuse of ICS therapies and over-reliance on short-acting bronchodilators, which leads to poor clinical outcomes. This article reviews efficacy versus systemic activity profiles for various dosing regimens of budesonide (BUD) and fluticasone propionate (FP). We performed a structured literature review of BUD and FP regular daily dosing, and BUD/formoterol (FOR) as-needed dosing, to explore the relationship between various dosing patterns of ICS regimens and the risk-benefit profile in terms of the extent of bronchoprotection and cortisol suppression. In addition, we explored how adherence could potentially affect the risk-benefit profile, in patients with mild, moderate, and moderate-to-severe asthma. With a specific focus on BUD or FP-containing treatments, we found that regular daily ICS and ICS/long-acting βInhaled corticosteroid (ICS)-containing therapies can be administered in a variety of ways depending on a patient’s asthma severity. Patients with mild asthma tend to experience symptom relief with as-needed or regular daily use of an ICS alone, whereas patients with more severe asthma may require regular daily use of an ICS plus a long-acting β

Nicola A Hanania,1 Scott Caveney,2 Tedi Soule,2 Lee Tombs,3 Sally Lettis,4 Courtney Crim,5,6 David M Mannino,7 Hitesh Patel,2 Isabelle H Boucot4 1Airways Clinical Research Center, Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA; 2US Medical Affairs, GlaxoSmithKline, Research Triangle Park, NC, USA; 3Precise Approach Ltd, Contingent Worker on Assignment at GlaxoSmithKline, Brentford, Middlesex, UK; 4Statistics, GlaxoSmithKline, Brentford, Middlesex, UK; 5R&D, GlaxoSmithKline, Research Triangle Park, NC, USA; 6Internal Medicine - Division of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 7Department of Preventive Medicine and Environmental Health, University of Kentucky, College of Public Health, Lexington, KY, USACorrespondence: Nicola A HananiaAirways Clinical Research Center, Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USAEmail hanania@bcm.eduIntroduction: Concerns have been raised about the practical use and clinical benefits of medications and inhalers in older patients with chronic obstructive pulmonary disease (COPD). Here, we report analyses according to age from five clinical trials evaluating medications administered using the ELLIPTA dry-powder inhaler (DPI).Methods: Efficacy and safety according to age groups (< 65 and ≥ 65 years) were assessed using data from five clinical trials in patients ≥ 40 years of age with symptomatic COPD. There was a mix of pre-specified and post hoc analyses of two 24-week trials with fluticasone furoate (FF)/vilanterol (VI) 100/25 μg; one 24-week trial with umeclidinium (UMEC) 62.5 μg; and two 12-week trials with UMEC 62.5 μg + FF/VI 100/25 μg. The primary endpoint was trough forced expiratory volume in 1 second (FEV1) obtained 23 and 24 hours after dosing on the last day of the study.Results: A total of 2876 patients < 65 years of age and 2148 patients ≥ 65 years of age were enrolled across all studies of whom 1333 and 1111 patients, respectively, received treatment at the doses presented. Statistically significant and clinically meaningful treatment differences in improvement from baseline in mean trough FEV1 were reported for active comparators versus placebo at study end for both < 65 and ≥ 65 years subgroups (FF/VI vs placebo: 143 mL and 111 mL; UMEC vs placebo: 110 mL and 123 mL; UMEC + FF/VI vs placebo + FF/VI: 136 mL and 105 mL; p< 0.001 for all comparisons). The incidence of adverse events reported for active treatments was similar between age groups.Conclusion: These data provide evidence to support the use of FF/VI, UMEC, or UMEC + FF/VI, all delivered via the ELLIPTA DPI, to treat older (≥ 65 years) and younger (< 65 years) patients with COPD.Keywords: COPD, elderly, ELLIPTA dry-powder inhaler, fluticasone furoate/vilanterol, multiple-inhaler triple therapy, umeclidinium

The COVID-19 pandemic has brought a renewed focus on appropriate management of chronic respiratory conditions with a heightened awareness of respiratory symptoms and the requirement for differential diagnosis between an asthma attack and COVID-19 infection. Despite early concerns in the pandemic, most studies suggest that well-managed asthma is not a risk factor for more severe COVID-related outcomes, and that asthma may even have a protective effect. Advice on the treatment of asthma and asthma attacks has remained unchanged. This article describes some challenges faced in primary care asthma management in adults and in teenagers, particularly their relevance during a pandemic, and provides practical advice on asthma attack recognition, classification, treatment and continuity of care. Acute attacks, characterised by increased symptoms and reduced lung function, are often referred to as exacerbations of asthma by doctors and nurses but are usually described by patients as asthma attacks. They carry a significant and underestimated morbidity and mortality burden. Many patients experiencing an asthma attack are assessed in primary care for treatment and continuing management. This may require remote assessment by telephone and home monitoring devices, where available, during a pandemic. Differentiation between an asthma attack and a COVID-19 infection requires a structured clinical assessment, taking account of previous medical and family history. Early separation into mild, moderate, severe or life-threatening attacks is helpful for continuing good management. Most attacks can be managed in primary care but when severe or unresponsive to initial treatment, the patient should be appropriately managed until transfer to an acute care facility can be arranged. Good quality care is important to prevent further attacks and must include a follow-up appointment in primary care, proactive regular dosing with daily controller therapy and an understanding of a patient's beliefs and perceptions about asthma to maximise future self-management.

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

Background In patients with chronic obstructive pulmonary disease (COPD), the relationship between short-term bronchodilator reversibility and longer-term response to bronchodilators is unclear. Here, we investigated whether the efficacy of long-acting bronchodilators is associated with reversibility of airflow limitation in patients with COPD with a low exacerbation risk not receiving inhaled corticosteroids. Methods The double-blind, double-dummy EMAX trial randomised patients to umeclidinium/vilanterol 62.5/25 µg once daily, umeclidinium 62.5 µg once daily, or salmeterol 50 µg twice daily. Bronchodilator reversibility to salbutamol was measured once at screening and defined as an increase in forced expiratory volume in 1 s (FEV1) of ≥ 12% and ≥ 200 mL 10−30 min post salbutamol. Post hoc, fractional polynomial (FP) modelling was conducted using the degree of reversibility (mL) at screening as a continuous variable to investigate its relationship to mean change from baseline in trough FEV1 and self-administered computerised-Transition Dyspnoea Index (SAC-TDI) at Week 24, Evaluating Respiratory Symptoms-COPD (E-RS) at Weeks 21–24, and rescue medication use (puffs/day) over Weeks 1–24. Analyses were conducted across the full range of reversibility (−850–896 mL); however, results are presented for the range −100–400 mL because there were few participants with values outside this range. Results The mean (standard deviation) reversibility was 130 mL (156) and the median was 113 mL; 625/2425 (26%) patients were reversible. There was a trend towards greater improvements in trough FEV1, SAC-TDI, E-RS and rescue medication use with umeclidinium/vilanterol with higher reversibility. Improvements in trough FEV1 and reductions in rescue medication use were greater with umeclidinium/vilanterol compared with either monotherapy across the range of reversibility. Greater improvements in SAC-TDI and E-RS total scores were observed with umeclidinium/vilanterol versus monotherapy in the middle of the reversibility range. Conclusions FP analyses suggest that patients with higher levels of reversibility have greater improvements in lung function and symptoms in response to bronchodilators. Improvements in lung function and rescue medication use were greater with umeclidinium/vilanterol versus monotherapy across the full range of reversibility, suggesting that the dual bronchodilator umeclidinium/vilanterol may be an appropriate treatment for patients with symptomatic COPD, regardless of their level of reversibility.

Background: This analysis from the 6-month AUSTRI study (GSK115359, n=11,679) explored the rate and heterogeneity of severe exacerbations with fluticasone propionate (FP) alone compared with FP plus salmeterol (FSC) in patients aged ≥12 years with persistent asthma and a 1-year history of exacerbations. Methods: Primary cause of severe exacerbation was grouped as: environmental, allergic, infective and other. Patient characteristics according to exacerbation (yes/no), primary cause, and period before and after events (Day -14 to +14) vs a corresponding 29-day period in non-exacerbating patients, were analysed post-hoc. Results: 1077 (9.2%) patients reported ≥1 severe exacerbation during study. Exacerbation cause was recorded as environmental for 14.3% of exacerbations, allergic for 8.4%, and infective for 45.3%. Rate of asthma exacerbations was significantly reduced by 21.8% (Ratio: 0.782; 95% CI: 0.691-0.886) for FSC vs FP patients. In patients with exacerbation, mean rescue use (puffs/day) increased from 1.5 (Day -14) to 3.2 (Day 1) and back to 1.5 (Day +14), compared with mean 0.8 puffs/day in non-exacerbating patients (Fig. 1). Conclusions: In patients with a history of severe asthma exacerbations, regular twice-daily dosing with FSC was associated with a lower rate of asthma exacerbations compared with FP. Rescue medication use was higher pre- and post-exacerbation than the average for non-exacerbating patients. Funding: GSK (ID 213505)

Introduction Smoking may reduce the efficacy of inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD), but its impact on bronchodilator efficacy is unclear. This analysis of the EMAX trial explored efficacy and safety of dual- versus mono-bronchodilator therapy in current or former smokers with COPD. Methods The 24-week EMAX trial evaluated lung function, symptoms, health status, exacerbations, clinically important deterioration, and safety with umeclidinium/vilanterol, umeclidinium, and salmeterol in symptomatic patients at low exacerbation risk who were not receiving ICS. Current and former smoker subgroups were defined by smoking status at screening. Results The analysis included 1203 (50%) current smokers and 1221 (50%) former smokers. Both subgroups demonstrated greater improvements from baseline in trough FEV1 at week 24 (primary endpoint) with umeclidinium/vilanterol versus umeclidinium (least squares [LS] mean difference, mL [95% CI]; current: 84 [50, 117]; former: 49 [18, 80]) and salmeterol (current: 165 [132, 198]; former: 117 [86, 148]) and larger reductions in rescue medication inhalations/day over 24 weeks versus umeclidinium (LS mean difference [95% CI]; current: − 0.42 [− 0.63, − 0.20]; former: − 0.25 − 0.44, − 0.05]) and salmeterol (current: − 0.28 [− 0.49, − 0.06]; former: − 0.29 [− 0.49, − 0.09]). Umeclidinium/vilanterol increased the odds (odds ratio [95% CI]) of clinically significant improvement at week 24 in Transition Dyspnea Index versus umeclidinium (current: 1.54 [1.16, 2.06]; former: 1.32 [0.99, 1.75]) and salmeterol (current: 1.37 (1.03, 1.82]; former: 1.60 [1.20, 2.13]) and Evaluating Respiratory Symptoms–COPD versus umeclidinium (current: 1.54 [1.13, 2.09]; former: 1.50 [1.11, 2.04]) and salmeterol (current: 1.53 [1.13, 2.08]; former: 1.53 [1.12, 2.08]). All treatments were well tolerated in both subgroups. Conclusions In current and former smokers, umeclidinium/vilanterol provided greater improvements in lung function and symptoms versus umeclidinium and salmeterol, supporting consideration of dual-bronchodilator therapy in symptomatic patients with COPD regardless of their smoking status. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01855-y., Plain Language Summary Patients with chronic obstructive pulmonary disease (COPD) often require daily medication to control their COPD. Many patients with COPD are smokers, and smoking is one of the most common causes of COPD. This means that it is important to find out whether COPD medications are effective in both smokers and nonsmokers. We analyzed data from a clinical trial (EMAX) that investigated the use of a combination of two bronchodilators, which are inhaled medications that help to open the airways. We compared umeclidinium/vilanterol, a dual-bronchodilator combination, with a single bronchodilator (either umeclidinium or salmeterol) over 6 months. We found that both current and former smokers who were treated with umeclidinium/vilanterol had larger improvements in lung function than those receiving umeclidinium or salmeterol. Current or former smokers who were treated with umeclidinium/vilanterol used their reliever inhaler less than those treated with umeclidinium or salmeterol. Patients treated with umeclidinium/vilanterol were generally less likely to experience disease worsening compared with umeclidinium or salmeterol if they were former smokers, or compared with salmeterol if they were current smokers. Our findings suggest that umeclidinium/vilanterol may be more effective than a single bronchodilator for daily treatment of patients with COPD who are current or former smokers. Physicians should consider prescribing a combination of two bronchodilators to patients who have symptoms, whether or not they currently smoke, as well as encouraging smoking cessation for all patients. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01855-y.

Leif Bjermer,1 Isabelle H Boucot,2 François Maltais,3 Edward M Kerwin,4 Ian P Naya,2 Lee Tombs,5 Paul W Jones,2 Chris Compton,2 David A Lipson,6,7 Claus F Vogelmeier8 1Respiratory Medicine and Allergology, Lund University, Lund, Sweden; 2Global Specialty & Primary Care, GSK, Brentford, Middlesex, UK; 3Centre de Pneumologie, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, Canada; 4Clinical Research Institute of Southern Oregon, Medford, OR, USA; 5Precise Approach Ltd, contingent worker on assignment at GSK, Stockley Park West, Uxbridge, Middlesex, UK; 6Respiratory Clinical Sciences, GSK, Collegeville, PA, USA; 7Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 8Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Member of the German Center for Lung Research (DZL), Marburg, GermanyCorrespondence: Leif BjermerRespiratory Medicine and Allergology, Skane University Hospital, 221 85 Lund, SwedenTel +46 46 17 23 25Email leif.bjermer@med.lu.seIntroduction: Limited prospective evidence is available to guide selection of first-line maintenance therapy in patients with COPD. This pre-specified analysis of the EMAX trial explored the efficacy and safety of dual- versus mono-bronchodilator therapy in maintenance-naïve and maintenance-treated patients.Methods: The 24-week EMAX trial evaluated lung function, symptoms (including rescue medication use), exacerbations, and safety with umeclidinium/vilanterol, umeclidinium, and salmeterol in symptomatic patients at low exacerbation risk who were not receiving inhaled corticosteroids. Maintenance-naïve and maintenance-treated subgroups were defined by maintenance bronchodilator use 30 days before screening.Results: The analysis included 749 (31%) maintenance-naïve and 1676 (69%) maintenance-treated patients. For both subgroups, improvements from baseline in trough FEV1 at Week 24 (primary endpoint) were greater with umeclidinium/vilanterol versus umeclidinium (mean difference [95% CI]; maintenance-naïve: 44 mL [1, 87]; maintenance-treated: 77 mL [50, 104]), and salmeterol (maintenance-naïve: 128 mL [85, 171]; maintenance-treated: 145 mL [118, 172]), and in rescue medication inhalations/day over 24 weeks versus umeclidinium (maintenance-naïve: − 0.44 [− 0.73, − 0.16]; maintenance-treated: − 0.28 [− 0.45, − 0.12]) and salmeterol (maintenance-naïve: − 0.37 [− 0.66, − 0.09]; maintenance-treated: − 0.25 [− 0.41, − 0.08]). In maintenance-naïve patients, umeclidinium/vilanterol numerically improved scores at Week 24 for Transition Dyspnea Index versus umeclidinium (0.37 [− 0.21, 0.96]) and versus salmeterol (0.47 [− 0.10, 1.05]) and Evaluating Respiratory Symptoms–COPD versus umeclidinium (− 0.26 [− 1.04, 0.53]) and versus salmeterol (− 0.58 [− 1.36, 0.20]), with similar improvements seen in maintenance-treated patients. All treatments were well tolerated across both subgroups.Conclusion: Similar to maintenance-treated patients, maintenance-naïve patients receiving umeclidinium/vilanterol showed greater improvements in lung function and symptoms compared with patients receiving umeclidinium or salmeterol. These findings provide support for the consideration of dual bronchodilator treatment in symptomatic maintenance-naïve patients with COPD.Keywords: COPD treatment, first-line therapy, maintenance-naïve, umeclidinium/vilanterol, umeclidinium, salmeterol

Background Symptomatic patients with chronic obstructive pulmonary disease (COPD) and low exacerbation risk still have disease instability, which can be improved with better bronchodilation. We evaluated two long-acting bronchodilators individually and in combination on reducing exacerbation risk and the potential impact of concurrent medication in these patients. Methods Integrated post hoc intent-to-treat (ITT) analysis of data from two large 24-week, randomized placebo (PBO)-controlled trials (NCT01313637, NCT01313650). Symptomatic patients with moderate-to-very-severe COPD with/without an exacerbation history were randomized (2:3:3:3) to once-daily: PBO, umeclidinium/vilanterol (UMEC/VI 62.5/25 μg [NCT01313650] or 125/25 μg [NCT01313637]), UMEC (62.5 [NCT01313650] or 125 μg [NCT01313637]) or VI (25 μg) via the ELLIPTA inhaler. Medication subgroups were segmented by treatment status at screening: a) maintenance-naïve or on maintenance medications, b) inhaled corticosteroid [ICS]-free or ICS-treated, c) low or high albuterol use based on median run-in use (

Background: SLS COPD was the first open-label randomised controlled trial demonstrating a reduction in moderate/severe COPD exacerbations with once-daily inhaled fluticasone furoate/vilanterol (FF/VI) in everyday clinical practice. Here we report FF/VI effectiveness and safety in predefined patient subgroups. Methods: Patients with COPD, exacerbation history, and receiving maintenance inhaler therapy, were randomised to initiate FF/VI 100/25 μg or continue usual care (UC) with 12 months’ follow-up. Annual rates of moderate/severe exacerbations (primary outcome), selected secondary outcomes, and incidence of pneumonia serious adverse events of special interest (SAESI) were compared between randomisation groups across various patient subgroups/baseline treatment strata. SAESI rates by actual treatment were also assessed. Results: Lower exacerbation rates were observed for FF/VI versus UC across all subgroups/strata, including ICS + LABA therapy subset (8.0% [0.1, 15.4]), except in patients without baseline airflow limitation (−0.5% [–29.8, 22.1]). Larger reductions compared to the overall analysis were observed for patients on ICS-containing regimens (excluding LAMA) before the study (15.6% [3.4, 26.3]), and with baseline CAT score

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

Aim: The Salford Lung Study (SLS) in chronic obstructive pulmonary disease (COPD) was a randomised controlled trial evaluating the effectiveness and safety of initiating fluticasone furoate/vilanterol (FF/VI) 100/25 µg versus continuing usual care (UC) in patients with COPD and a history of exacerbations. Here, we investigate the impact of initiating FF/VI on healthcare resource utilisation (HRU) in SLS COPD. Methods: HRU and interventions were determined from patients’ electronic health records. Annual rates of on-treatment all-cause and COPD-related secondary care contacts (SCCs) and primary care contacts (PCCs) for FF/VI versus UC were analysed using a general linear model. Costs were derived from national data sources. Results: Least-squares (LS) mean annual rates of all-cause (9.81 versus 9.36) and COPD-related (1.57 versus 1.48) SCCs were similar for FF/VI and UC, as were rates of all-cause hospitalisations (0.87 versus 0.82). Mean duration of hospital stay/patient was 4.5 and 4.2 days, respectively. COPD-related SCC mean total cost/patient was £484 FF/VI and £475 UC. LS mean annual rates of all-cause PCCs were significantly higher for FF/VI (21.20 versus 18.88 UC; p Discussion: In patients with COPD and exacerbation history, FF/VI may represent a less costly alternative to current therapies. GlaxoSmithKline plc. study HZC115151; ClinicalTrials.gov NCT01551758. The reviews of this paper are available via the supplemental material section.

Background: CAT scores can be used to assess the effects of COPD on patient health status. Within a study cohort, higher CAT scores are associated with more frequent exacerbations (Kelly JF, et al. Respiration 2012;84:193–9) and predict exacerbations in patients at risk (Lee SD, et al. Respir Med 2014;108:600–8). Aim: To compare individual CAT item scores in cohorts with differing risk of exacerbation from two COPD trials. Methods: Data from the EMAX and IMPACT trials were used as baseline differences between these trials in total CAT score were small, but differences in exacerbation rates were large (Figure 1). The analysis was post hoc without statistical comparisons. Results: Compared with IMPACT, EMAX patients had less severe airflow limitation and a greater proportion were current smokers (Figure 1); however, individual CAT item scores were similar between the trials (Figure 2). Conclusion: Despite differences in exacerbation history of the two cohorts, mean individual CAT item scores were similar. Method: GSK (201749, NCT03034915; 116855, NCT02164513)

Background Short-acting β2-agonist (SABA) bronchodilators help alleviate symptoms in chronic obstructive pulmonary disease (COPD) and may be a useful marker of symptom severity. This analysis investigated whether SABA use impacts treatment differences between maintenance dual- and mono-bronchodilators in patients with COPD. Methods The Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids 1:1:1 to once-daily umeclidinium/vilanterol 62.5/25 μg, once-daily umeclidinium 62.5 μg or twice-daily salmeterol 50 μg for 24 weeks. Pre-specified subgroup analyses stratified patients by median baseline SABA use (low, 1), change in symptoms (Transition Dyspnoea Index [TDI], Evaluating Respiratory Symptoms-COPD [E-RS]), daily SABA use and exacerbation risk. A post hoc analysis used fractional polynomial modelling with continuous transformations of baseline SABA use covariates. Results At baseline, patients in the high SABA use subgroup (mean: 3.91 puffs/day, n = 1212) had more severe airflow limitation, were more symptomatic and had worse health status versus patients in the low SABA use subgroup (0.39 puffs/day, n = 1206). Patients treated with umeclidinium/vilanterol versus umeclidinium demonstrated statistically significant improvements in trough FEV1 at Week 24 in both SABA subgroups (59–74 mL; p p = 0.241]; low: 0.49 [p = 0.025]) and E-RS (high: 0.48 [p = 0.138]; low: 0.60 [p = 0.034]) scores. By contrast, significant reductions in mean SABA puffs/day with umeclidinium/vilanterol versus umeclidinium were observed only in high SABA users (high: − 0.56 [p p = 0.132]). Similar findings were observed when comparing umeclidinium/vilanterol and salmeterol. Fractional polynomial modelling showed baseline SABA use ≥4 puffs/day resulted in smaller incremental symptom improvements with umeclidinium/vilanterol versus umeclidinium compared with baseline SABA use Conclusions In high SABA users, there may be a smaller difference in treatment response between dual- and mono-bronchodilator therapy; the reasons for this require further investigation. SABA use may be a confounding factor in bronchodilator trials and in high SABA users; changes in SABA use may be considered a robust symptom outcome. Funding GlaxoSmithKline (study number 201749 [NCT03034915]).

Objective The aim of this pooled analysis was to assess the efficacy and safety of umeclidinium/vilanterol (UMEC/VI) 62.5/25 µg dual bronchodilation versus placebo in elderly symptomatic patients with chronic obstructive pulmonary disease (COPD). Methods We conducted a post hoc pooled analysis of data from 10 randomized controlled trials (RCTs). Change from baseline (CFB) in trough forced expiratory volume in 1 s (FEV1), proportion of FEV1 responders (≥ 100-mL increase from baseline), and safety were analyzed in patients aged

Introduction Appropriate timing for dual bronchodilator therapy initiation in chronic obstructive pulmonary disease (COPD) management is uncertain. Combination therapy is recommended as step-up from monotherapy or first-line treatment in patients with persistent symptoms. In this setting, umeclidinium/vilanterol (UMEC/VI) demonstrated improved lung function and reduced rescue medication use over tiotropium/olodaterol (TIO/OLO). This subgroup analysis explored efficacy differences between these combinations in patients naïve to COPD maintenance therapy before study entry. Methods Post hoc analysis of an 8-week, randomized, open-label, assessor-blind, two-period crossover study (204990; NCT02799784) comparing UMEC/VI 62.5/25 mcg and TIO/OLO 5/5 mcg, focused on maintenance-naïve (MN) patients with moderate COPD and persistent symptoms (modified Medical Research Council dyspnea score ≥ 2). Change from baseline (CFB) in trough forced expiratory volume in 1 s (FEV1), percentage of FEV1 responders (CFB ≥ 100 ml), rescue medication use and safety were evaluated. Results The MN population comprised 63% of the intent-to-treat (ITT) population (148/236 patients) and had similar baseline demographics. At week 8, adjusted mean (standard error) improvements in trough FEV1 from baseline were clinically meaningful for both combinations (UMEC/VI: 167 [17] ml; TIO/OLO 110 [18] ml; adjusted mean difference [95% confidence interval (CI)]: 57 [23–92] ml; p = 0.001; %CFB: 11 vs. 8%). Proportion of FEV1 responders was greater with UMEC/VI versus TIO/OLO at week 8 (60 vs. 42%; odds ratio [95% CI] 1.90 [1.12–3.22]; p = 0.018). Reduction in rescue medication use was 0.20 (95% CI 0.07–0.34) puffs/day greater with UMEC/VI versus TIO/OLO over weeks 1–8 (p = 0.003). Adverse events incidence was similar (UMEC/VI: 24%; TIO/OLO: 29%). Conclusions These results highlight that the efficacy difference between UMEC/VI and TIO/OLO demonstrated in the ITT population is maintained in MN patients. Greater lung function improvements with UMEC/VI versus TIO/OLO were accompanied by symptom improvements, as reflected in a significantly lower need for supplemental rescue medication. Funding GSK. Trial registration NCT02799784

Background The COPD "frequent exacerbator" phenotype is usually defined by at least two treated exacerbations per year and is associated with a huge impact on patient health. However, existence of this phenotype and corresponding thresholds still need to be formally confirmed by statistical methods analyzing exacerbation profiles with no specific a priori hypothesis. The aim of this study was to confirm the existence of the frequent exacerbator phenotype with an innovative unbiased statistical analysis of prospectively recorded exacerbations. Methods Data from patients with COPD from the French cohort in Exacerbations of COPD Patients (EXACO) were analyzed using the KmL method designed to cluster longitudinal data and receiver operating characteristic (ROC) curve analysis to determine the best threshold to allocate patients to identified clusters. Univariate and multivariate analyses were performed to study characteristics associated with different clusters. Results Two clusters of patients were identified based on exacerbation frequency over time, with 2.89 exacerbations per year on average in the first cluster (n = 348) and 0.71 on average in the second cluster (n = 116). The best threshold to distinguish these clusters was two moderate to severe exacerbations per year. Frequent exacerbators had more airflow limitation, symptoms, and health-related quality of life impairment. A simple clinical score was derived to help identify patients at risk of exacerbations. Conclusions These analyses confirmed the existence and clinical relevance of a frequent exacerbator subgroup of patients with COPD and the currently used threshold to define this phenotype.

Most patients with COPD are recommended to initiate maintenance therapy with a single long-acting bronchodilator, such as a long-acting muscarinic antagonist or long-acting β2-agonist. However, many patients receiving mono-bronchodilation continue to experience high symptom burden, suggesting that patients are frequently not receiving optimal treatment. Treatment goals for COPD are often broad and not individually tailored, making initial treatment response assessments difficult. A personalised approach to initial maintenance therapy, based upon an individual's symptom burden and exacerbation risk, may be more appropriate.An alternative approach would be to maximise bronchodilation early in the disease course of all patients with COPD. Evidence suggests that dual bronchodilation has greater and consistent efficacy for lung function and symptoms than mono-bronchodilation, whilst potentially reducing the risk of exacerbations and disease deterioration, with a similar safety profile to mono-bronchodilators. Improvements in lung function and symptoms between dual- and mono-bronchodilation have also been demonstrated in maintenance-naïve patients, who are most likely to resemble those at first presentation in a clinical setting. Despite promising results, there are several evidence gaps that need to be addressed to allow decision makers to evaluate the merits of a widespread earlier introduction of dual bronchodilation.

Introduction Les bronchodilatateurs (BD) beta 2-agonistes de longue duree d’action (LABA) et/ou les anticholinergiques de longue duree d’action (LAMA) sont recommandes en traitement de 1re intention chez les patients atteints de BPCO. Leur association peut ameliorer les symptomes par rapport a la monotherapie. Cependant, les essais comparatifs n’ont pas exclu les patients sous corticoides inhales (CSI) ou deja traites par LAMA/LABA. L’etude Early MAXimisation of bronchodilation for improving COPD stability (EMAX) a compare umeclidinium/vilanterol (UMEC/VI), UMEC et salmeterol (SAL) chez des patients BPCO GOLD B symptomatiques ne recevant pas de CSI, ayant eu ≤ 1 exacerbation (E) moderee lors de la derniere annee et recevant ≤ 1 BD LA. Methodes Cette etude de 24 semaines en double aveugle, double placebo et a groupes paralleles a randomise les patients a UMEC/VI 62,5/25 μg 1/jour, UMEC 62,5 μg 1/jour ou SAL 50 μg 2/jour (ratio 1/1/1). Le critere d’evaluation principal etait le VEMS residuel a la semaine 24, comparant UMEC/VI a UMEC. Les criteres secondaires comprenaient la CI, la CVF, le TDI, le E-RS, le SGRQ, le CAT et le SGRSI. Le recours au salbutamol, le risque de 1re E moderee/severe et les effets indesirables (EI) ont ete notes. Des comparaisons entre UMEC/VI et les 2 monotherapies ont ete faites par la methode de la moyenne des moindres carres (MMC) en variation par rapport a la valeur initiale et en reponses cliniquement pertinentes. Resultats A l’inclusion, la population en ITT (N = 2425 [UMEC/VI 812 ; UMEC 804 ; SAL 809]) avait un VEMS post-BD moyen de 55 %, 50 % etaient des fumeurs actuels et 16 % ont eu 1 E moderee de BPCO au cours des 12 derniers mois. UMEC/VI a apporte des ameliorations plus grandes que UMEC (p Tableau 1 ). Conclusion UMEC/VI 1/jour apporte des ameliorations concordantes de la fonction pulmonaire et des symptomes, en particulier de la dyspnee par rapport a UMEC ou SAL chez les patients BPCO symptomatiques a faible risque d’E et sans CSI. Ces donnees soutiennent l’utilisation precoce de LAMA/LABA chez ces patients. Financement GSK, NCT03034915 .

Objectives Many patients with chronic obstructive pulmonary disease (COPD) continue to smoke; however, the impact of smoking on bronchodilator responses is not well understood. This pre-specified analysis of the Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial compared umeclidinium/vilanterol (UMEC/VI) with UMEC and salmeterol (SAL) in current and former smokers. Methods This 24-week, double-blind, parallel-group trial randomised symptomatic patients at low exacerbation risk not receiving inhaled corticosteroids (ICS) to UMEC/VI 62.5/25 μg once-daily, UMEC 62.5 μg once-daily, or SAL 50 μg twice-daily. Outcomes included: lung function, patient-reported outcomes, moderate/severe exacerbation risk and clinically important deterioration (CID). Safety was also assessed. Results Overall, 1203 and 1221 patients were current and former smokers, with a mean (standard deviation [SD]) of 48.0 (25.5) and 48.8 (27.5) pack years, respectively. For current and former smokers respectively, mean (SD) age was 61.7 (7.7) and 67.5 (8.2) years, 47% and 35% were female, and 14% and 19% had experienced a moderate exacerbation in the prior year. At screening, mean (SD) post-bronchodilator forced expiratory volume in 1 second (FEV1) was 1647 (515) mL and 1545 (502) mL and mean (SD) COPD Assessment Test (CAT) score was 20.0 (6.2) and 18.3 (5.6). Change from baseline in trough FEV1 at Week 24 (primary endpoint) was statistically significantly greater with UMEC/VI versus UMEC and SAL for both current and former smokers (all p Conclusions Smoking status does not appear to have a major impact on the efficacy or safety of UMEC/VI. Funding GSK (201749; NCT03034915).

Background Prospective evidence is lacking regarding incremental benefits of long-acting dual- versus mono-bronchodilation in improving symptoms and preventing short-term disease worsening/treatment failure in low exacerbation risk patients with chronic obstructive pulmonary disease (COPD) not receiving inhaled corticosteroids. Methods The 24-week, double-blind, double-dummy, parallel-group Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised patients at low exacerbation risk not receiving inhaled corticosteroids, to umeclidinium/vilanterol 62.5/25 μg once-daily, umeclidinium 62.5 μg once-daily or salmeterol 50 μg twice-daily. The primary endpoint was trough forced expiratory volume in 1 s (FEV1) at Week 24. The study was also powered for the secondary endpoint of Transition Dyspnoea Index at Week 24. Other efficacy assessments included spirometry, symptoms, heath status and short-term disease worsening measured by the composite endpoint of clinically important deterioration using three definitions. Results Change from baseline in trough FEV1 at Week 24 was 66 mL (95% confidence interval [CI]: 43, 89) and 141 mL (95% CI: 118, 164) greater with umeclidinium/vilanterol versus umeclidinium and salmeterol, respectively (both p p = 0.018; vs salmeterol: 0.45 [95% CI: 0.15, 0.76], p = 0.004) and all other symptom measures at all time points. Regardless of the clinically important deterioration definition considered, umeclidinium/vilanterol significantly reduced the risk of a first clinically important deterioration compared with umeclidinium (by 16–25% [p p Conclusions Umeclidinium/vilanterol consistently provides early and sustained improvements in lung function and symptoms and reduces the risk of deterioration/treatment failure versus umeclidinium or salmeterol in symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids. These findings suggest a potential for early use of dual bronchodilators to help optimise therapy in this patient group.

Background: Symptom benefits of dual bronchodilation vs monotherapy in corticosteroid-free patients at low exacerbation risk have not been established using the Evaluating Respiratory Symptoms–COPD (E‑RS) scale. Aims: This pre-specified secondary analysis of the Early MAXimization of bronchodilation for improving COPD stability (EMAX) trial compared daily symptoms using E-RS in patients receiving umeclidinium/vilanterol (UMEC/VI), UMEC, or salmeterol (SAL). Methods: This double-blind, parallel-group trial randomised patients 1:1:1 to 24 weeks of UMEC/VI 62.5/25 μg once-daily, UMEC 62.5 μg once-daily or SAL 50 μg twice-daily. Change from baseline and proportion of responders over 24 weeks were analysed by 4-week periods for E-RS total score and Breathlessness, Cough & Sputum and Chest symptoms subscales. Results: At Weeks 21–24, mean symptom scores statistically significantly favoured UMEC/VI for 3 of 4 and all 4 symptom outcomes vs UMEC and SAL, respectively. Responder rates favoured UMEC/VI for all 4 outcomes vs UMEC and SAL (Figure). Treatment differences consistently favoured UMEC/VI vs UMEC and SAL from the first to last 4-week period. Differences between UMEC and SAL were not significant. Conclusion: UMEC/VI provided early and sustained improvement in a range of daily COPD symptoms vs UMEC or SAL in corticosteroid‑free low-risk symptomatic patients with COPD. Funding: GSK (201749; NCT03034915)

Background: The risk of short-term deterioration, assessed by the CID composite measure, is reduced with dual vs mono bronchodilators in inhaled corticosteroid (ICS)-free symptomatic patients with COPD. It is unclear if this protection alters with baseline severity of COPD. Aims: This pre-specified secondary analysis of the Early MAXimization of bronchodilation for improving COPD stability (EMAX) trial compared CID risk in the ITT population and in severity subgroups with a baseline GOLD spirometric grade 3 (FEV1 30–50% predicted) or COPD Assessment Test (CAT) score ≥20. Methods: This 24-week, double-blind, parallel-group trial randomised patients to umeclidinium/vilanterol (UMEC/VI) 62.5/25 µg QD, UMEC 62.5 µg QD, or salmeterol (SAL) 50 µg BID. Risk of a first CID was assessed using 3 definitions of CID (Figure). Results: In the ITT population and subgroups, CID risk was lower with UMEC/VI vs UMEC or SAL for all CID definitions, except in one instance (Figure). This protection was numerically higher in the GOLD 3 subgroup regardless of CID definition, but not in the CAT ≥20 subgroup. Conclusions: In symptomatic ICS-free patients at low exacerbation risk, UMEC/VI reduced CID risk vs UMEC and SAL. Compared with the ITT population, this protection was greater in patients with more severe airflow limitation but not with more symptoms. Funding: GSK (study 201749; NCT03034915)

Introduction: Measuring symptom improvement over time can inform the appropriate timing of follow-up assessments to monitor response to COPD treatment. Aims: This post-hoc analysis of the Early MAXimization of bronchodilation for improving COPD stability (EMAX) trial compared early symptom improvement in response to umeclidinium/vilanterol (UMEC/VI), UMEC, or salmeterol (SAL) in inhaled corticosteroid-free symptomatic patients with COPD at low exacerbation risk. Methods: This 24-week double-blind, parallel-group trial randomised patients 1:1:1 to UMEC/VI 62.5/25 μg once-daily, UMEC 62.5 μg once-daily, or SAL 50 μg twice-daily. Symptom improvements were evaluated at the population level by least squares mean change from baseline in Evaluation of Respiratory Symptoms (E-RS) score and percentage of rescue-free days weekly from Week 1 to 8 (post hoc) and at Weeks 21–24. Results: Adjusted mean weekly E-RS total score and rescue medication use improved rapidly and consistently from Week 1 to 8 with all treatments (Figure). Statistically significant treatment differences favouring UMEC/VI were maintained throughout treatment, with similar between-treatment differences at Weeks 4, 8 and 21–24. Conclusion: The added symptomatic benefits of UMEC/VI versus UMEC or SAL were apparent at Week 1, fully established by Week 4, and sustained over 24 weeks. Funding: GSK (201749; NCT03034915)

Background Elderly patients with chronic obstructive pulmonary disease (COPD) and those with more severe airway limitation are perceived to experience reduced efficacy from inhaled bronchodilators, especially those administered in a dry powder inhaler. This study compared the efficacy and safety of a long-acting muscarinic antagonist/long-acting β2-agonist dry powder combination in elderly patients with COPD and patients with moderate-to-very severe airflow limitation. Methods This post hoc pooled analysis of seven randomized studies of ≥12 weeks’ duration investigated the efficacy and safety of umeclidinium/vilanterol (UMEC/VI) 62.5/25 μg versus tiotropium (TIO) 18 μg or fluticasone propionate/salmeterol (FP/SAL) 250/50 μg. Change from baseline in trough forced expiratory volume in 1 s (FEV1), a common efficacy measure in all trials, proportion of FEV1 responders (≥100 mL increase from baseline) and safety outcomes were analyzed at Day 28, 56, and 84 in patients classified by age ( Results The pooled intent-to-treat population comprised 3821 patients (≥65 years: 44–45%; ≥75 years: 9–10%; GOLD stage 3/4: 50–55%); 2246, 874, and 701 patients received UMEC/VI, TIO, or FP/SAL, respectively. Significant improvements in trough FEV1 at Day 84 were observed with UMEC/VI versus TIO or FP/SAL irrespective of age (all p ≤ 0.029) or GOLD stage (all p Conclusion UMEC/VI consistently demonstrated improved lung function versus TIO and FP/SAL across age and airflow limitation severity subgroups, with no safety concerns, indicating that UMEC/VI provides no loss in efficacy or additional safety concerns for both elderly patients with COPD and patients with severe/very severe airway limitation.

Introduction Long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) combination therapy is more effective than monotherapies for improving lung function, breathlessness and health status, in patients with moderate-to-severe COPD (Oba et al. Thorax 2016:71;15–25). Current Global initiative for chronic Obstructive Lung Disease (GOLD) strategy highlights that first-line maintenance therapy in symptomatic GOLD B patients is LAMA or LABA monotherapy (GOLD 2018 report). The Early MAXimal bronchodilation for improving COPD stability (EMAX) trial aims to compare the efficacy and safety of UMEC/VI (LAMA/LABA), UMEC (LAMA) and salmeterol (SAL [LABA]) in symptomatic, steroid-free GOLD B patients with COPD (study 201749; NCT03034915) to inform the positioning of dual versus monotherapy within treatment guidelines for GOLD B patients. Methods EMAX is a 24 week, multicentre, double-blind, double-dummy, parallel-group study. Patients (n=2,431) were randomised 1:1:1 to UMEC/VI 62.5/25 mcg, UMEC 62.5 mcg or SAL 50 mcg (figure 1). Patients were required to be aged ≥40 years, current/former smokers (≥10 pack-years), with a forced expiratory volume in 1 s (FEV1)/forced vital capacity ratio Conclusions EMAX is the largest study to date investigating the efficacy of LAMA/LABA versus monotherapy in inhaled corticosteroid-naive symptomatic GOLD B patients, and the first prospective study to explore the impact of these regimens in maintenance-naive patients (a pre-specified subgroup) and assess COPD stability using the CID. The study has completed; upon completion of data analysis, the results should help clarify when, and in which population, LAMA/LABA should be initiated as first-choice maintenance therapy. Funding GSK (study 201749). Please refer to page A268 for declarations of interest related to this abstract.

Rationale: Symptom relief is a key treatment goal in patients with chronic obstructive pulmonary disease (COPD). However, there are limited data available on the response to bronchodilator therapy in patients at low risk of exacerbations with different levels of symptom severity. This study compared treatment responses in patients with a range of symptom severities as indicated by baseline COPD assessment test (CAT) scores. Methods: The 24-week EMAX trial evaluated the benefits of umeclidinium/vilanterol versus umeclidinium or salmeterol in symptomatic patients at low exacerbation risk who were not receiving inhaled corticosteroids. This analysis assessed lung function, symptoms, health status, and short-term deterioration outcomes in subgroups defined by a baseline CAT score [Results: Of the intent-to-treat population ( n = 2425), 56% and 44% had baseline CAT scores of Conclusions: Patients with symptomatic COPD benefit similarly from dual bronchodilator treatment with umeclidinium/vilanterol. Fractional polynomial analyses demonstrated the greatest treatment differences favouring dual therapy in patients with a CAT score

Background: In chronic obstructive pulmonary disease (COPD), both the time needed for patients to gain symptom improvement with long-acting bronchodilator therapy and whether an early response is predictive of a sustained response is unknown. This study aimed to investigate how quickly meaningful symptom responses are seen in patients with COPD with bronchodilator therapy and whether these responses are sustained. Methods: Early MAXimisation of bronchodilation for improving COPD stability (EMAX) was a 24-week, double-blind, double-dummy, parallel-group trial that randomised patients to umeclidinium/vilanterol (UMEC/VI), umeclidinium or salmeterol. Daily Evaluating Respiratory Symptoms in COPD (E-RS:COPD) score and rescue salbutamol use were captured via an electronic diary and analysed initially in 4-weekly periods. Post hoc analyses assessed change from baseline in daily E-RS:COPD score and rescue medication use weekly (Weeks 1–8), and association between E-RS:COPD responder status at Weeks 1–4 and later time points. Results: In the intent-to-treat population ( n = 2425), reductions from baseline in E-RS:COPD scores and rescue medication use were apparent from Day 2 with all treatments. Treatment differences for UMEC/VI versus either monotherapy plateaued by Week 4–8 and were sustained at Weeks 21–24; improvements were consistently greater with UMEC/VI. For all treatments, most patients (60–85%) retained their Weeks 1–4 E-RS:COPD responder/non-responder status at Weeks 21−24. Among patients receiving UMEC/VI who were E-RS:COPD responders at Weeks 1–4, 70% were responders at Weeks 21–24. Conclusion: Patients with symptomatic COPD had greater potential for early symptom improvements with UMEC/VI versus either monotherapy. This benefit was generally maintained for 24 weeks. Early monitoring of treatment response can provide clinicians with an early indication of a patient’s likely longer-term response to prescribed bronchodilator treatment and will facilitate appropriate early adjustments in care. Clinical Trial Registration: NCT03034915, 2016-002513-22 (EudraCT Number). The reviews of this paper are available via the supplemental material section.

Rationale: Current GOLD strategy document positions both combination regimens of inhaled corticosteroid plus a long-acting β2-agonist [i.e. ICS/LABA] and long-acting muscarinic antagonist plus LABA [i.e. LAMA/LABA] for symptomatic patients with recurrent exacerbations. Methods: The InforMing the PAthway of COPD Treatment (IMPACT) study was a phase III, double-blind, parallel-group, multicenter study that compared the efficacy and safety of single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol 100/62.5/25µg (FF/UMEC/VI), FF/VI 100/25µg or UMEC/VI 62.5/25µg, all using the ELLIPTA® inhaler in symptomatic patients with COPD and exacerbation history, randomised 2:2:1, respectively to 52 weeks of treatment. The primary efficacy results on the annual rate of moderate or severe exacerbations are presented separately. Additional endpoints included change from baseline [CFB] in forced expiratory volume in 1s (trough FEV1), St George’s Respiratory Questionnaire (SGRQ) for FF/VI compared with UMEC/VI. Results: Of the 10 355 patients enrolled, 4134 received FF/VI and 2070 received UMEC/VI. At Week 52, there was a statistically significant improvement in trough FEV1 with UMEC/VI vs FF/VI (mean CFB 40mL and –3mL, treatment difference 43mL [95% CI: 28, 58mL]; p Conclusions: UMEC/VI improved lung function compared with the once daily ICS/LABA FF/VI in patients with symptomatic COPD and at risk of exacerbations whereas the SGRQ Total score was similar. These results may help to inform treatment choices for this patient population.

Rationale: Current GOLD strategy document positions both combination regimens of inhaled corticosteroid plus a long-acting β2-agonist [ICS/LABA] and LABA plus long-acting muscarinic antagonist [LAMA/LABA] for symptomatic patients with recurrent exacerbations (GOLD D) but only LAMA/LABA for persistently symptomatic patients with ≤ 1 non-hospitalized exacerbations (GOLD B). A recent study suggests superiority of LABA/LAMA over ICS/LABA (NEJM 2016;374:23) Methods: The InforMing the PAthway of COPD Treatment (IMPACT) study evaluated the annual rate of moderate/severe exacerbations on fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25μg vs. UMEC/VI (LAMA/LABA) 62.5/25μg and FF/VI (ICS/LABA) 100/25μg over 52-weeks in symptomatic patients with ≥1 exacerbation. This analysis compared annual rate and time to first (TTF) exacerbation between UMEC/VI and FF/VI in the intention-to-treat (ITT) population and within subgroups (some analyses were post-hoc). Findings: In the ITT analysis, FF/VI reduced exacerbation rate vs. UMEC/VI (p Conclusion: In IMPACT, exacerbation rate reduction favoured FF/VI vs. UMEC/VI in the ITT, GOLD D and baseline triple therapy-treated patients. In baseline LAMA-treated patients, and consistent with FLAME findings, there was a trend favouring UMEC/VI but low statistical power limited confirmation. Funding: GSK (NCT02164513)

Guidelines for chronic obstructive pulmonary disease (COPD) management are based largely on results from double-blind randomised controlled trials (RCTs) of efficacy. These trials have high internal validity and test whether a drug is efficacious, but they are conducted in highly selected populations that may differ significantly from patients with COPD seen in routine practice.We compared the baseline characteristics, healthcare use and outcomes between the Salford Lung Study (SLS), an open-label effectiveness RCT, with six recent large-scale efficacy RCTs. We also calculated the proportion of SLS patients who would have been eligible for inclusion in an efficacy RCT by applying the inclusion criteria used in efficacy trials of combination treatments.SLS patients were older, included more females and more current smokers, had more comorbidities (including asthma), and had more often experienced exacerbations prior to inclusion. In the SLS, rates of moderate or severe exacerbations, incidence of overall serious adverse events (SAEs), and SAEs of pneumonia were more frequent. A maximum of 30% of patients enrolled in the SLS would have been eligible for a phase IIIa regulatory exacerbation study.Patients in large COPD efficacy RCTs have limited representativeness compared with an effectiveness trial. This should be considered when interpreting efficacy RCT outcomes and their inclusion into guidelines.