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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)

Patients with COPD may require treatment with triple therapy of LABA/LAMA/ICS (Triple). Higher blood eosinophils are associated with an increased risk of acute exacerbations of COPD (AECOPD) and indicate greater probability of benefit from ICS and treatments targeting eosinophilic inflammation (EOS). The prevalence of patients with higher blood EOS levels still experiencing frequent or severe exacerbations in spite of Triple is unknown. Methods: This post-hoc analysis was conducted using the ACCESS study (GSK115058; NCT01516528), a prospective cohort of patients with COPD recruited from primary care across 6 European countries in 2011-12. Prevalence was evaluated based on the following baseline visit criteria: (a) treated with Triple; (b) EOS ≥ 150 cells/µL; (c) EOS≥300 cells/µL; (d) ≥ 2moderate/≥1hospitalized AECOPDs in the 12 months prior to baseline. Results: Of 2,887 evaluable participants: 7.2% were Triple users and had a history of frequent/hospitalized AECOPDs; 4.3% and 1.8% were Triple users with a history of frequent/hospitalized AECOPDs and with EOS ≥ 150 or ≥ 300 cells/µL, respectively (Table 1). Conclusions: In this primary care COPD cohort, we identified a small number of participants with frequent/hospitalized AECOPD whilst treated with Triple who also had higher EOS levels. These patients may benefit from medicines targeting eosinophil associated inflammation. GSK study RWD206; NCT01516528

Background: With new single inhaler triple therapies available for maintenance treatment of COPD, patients’ preferences need better understanding to inform prescribing. Objectives: Identify treatment preferences, priorities and goals and determine key COPD treatment attributes. Methods: Individuals ≥40 years, diagnosed with COPD (CAT/MMRC score ≥ 10/2) and receiving combination or monotherapy, participated in semi-structured telephone interviews or face-to-face focus groups (FG). These were recorded, transcribed verbatim and thematically analysed. Results: Ten interviews and one FG (n=4-6) were conducted in Germany, the UK and USA (N=46). Figure.1 shows inhaler attributes in order of importance. Interpretations of treatment effectiveness included symptom relief, speed of effect and reduction of exacerbations. Generally, patients wanted fewer inhalers to take and to take them less often. Satisfaction with current medication was reported but concerns were also voiced. Most reported a willingness to switch medication for better symptom control and simplified administration. Conclusions: COPD patients appear willing to change inhaler if offered an option with improved attributes. FG results corroborated interview findings, providing confidence that the attributes identified are appropriate for inclusion in a Discrete Choice Experiment, which will determine the relative importance of the identified attributes to patients when making treatment choices.

Background: COPD, cardiovascular disease and structural brain disease commonly coexist, but the relative contributions of COPD and cardiovascular disease to structural brain disease is unclear. Aim: The aim of this study was to determine the association between two different COPD phenotypes and structural brain disease. Methods: COPD patients were recruited from two populations. Group 1 were recruited from people attending for elective coronary angiography who had no exacerbations in the preceding year. Group 2 were recruited from people attending the respiratory outpatient department who had had at least 1 exacerbation in the preceding year. Participants underwent measurement of Framingham score (10-year risk of cardiovascular event), spirometry, arterial stiffness, skin capillary density, cardiac biomarkers, systemic inflammatory markers and structural brain MRI. Results: Group 1 had mild/moderate COPD with significantly higher cardiovascular risk whereas group 2 had moderate/severe COPD with lower cardiovascular risk (FEV1 % predicted 78±19 v 54±24 p Conclusion: Cardiovascular risk, rather than respiratory health, appears more strongly associated with white matter brain disease in these two groups of patients with COPD.

Background: Personalised therapy for COPD patients is debated. We investigated whether the rate of FEV1 decline differs between patients with and without ICS-containing medications, stratified by blood EOS level. Methods: The UK Clinical Practice Research Datalink (primary care records) and Hospital Episode Statistics (hospital records) were used to identify COPD patients with ≥2 FEV1 measurements ≥6 months apart. Follow-up started from first FEV1 until censoring at death, leaving database or first ICS-containing prescription (if not baseline ICS-containing user). The nearest blood EOS 2 years prior to the start of follow-up were used. Patients were classified at baseline as: high stratum EOS (≥150cell/µl) on ICS; high stratum EOS not on ICS; low stratum EOS ( Results: Median follow-up time was 4.2 years. *adjusted for: sex, age, smoking status, asthma, MI, stroke, HF, lung cancer, bronchiectasis, GORD, anxiety, depression, BMI, WBC count, neutrophil count, airflow obstruction (GOLD), AECOPD frequency, and MRC dyspnea. Conclusions: Regardless of blood EOS level, ICS-containing medication is associated with slower rates of FEV1 decline in COPD patients. Funding: GSK study 208602

Rationale: In COPD, a higher level of blood eosinophils [EOS] may relate to an increased risk of exacerbations (AECOPD) [Vedel-Krogh, 2016] and is a promising biomarker of response to treatment with inhaled corticosteroids (ICS) [Pascoe, 2015]. We report the distribution of blood EOS levels in a primary care cohort of COPD patients. Methods: The ACCESS (Assessment of Comorbidities in COPD in European Symptomatic Subjects) was an observational study that prospectively recruited COPD patients across 5 European countries. There were minimal exclusion criteria, but patients with current asthma were excluded. White blood cell count (WBC), including EOS, was analyzed in local laboratories. Results: In a cohort of 2785 patients, mean blood EOS levels were 159 cells/µL or 2.2% of total WBC. Blood EOS ≥150 cells/µL or ≥2% were seen in 67% and 72% of patients respectively. Removing current users of ICS resulted in a minor difference in mean value (Non-users [N=1382] vs Users: 162 vs 157 cells/µL). No clinically important differences in EOS distribution were observed with any demographic or key clinical variables or exacerbations. Conclusions: In this post-hoc analysis, two thirds of COPD patients in primary care have blood EOS levels above the 150cells/µL level proposed as a threshold value to indicate potential benefit from ICS. Current use of ICS has minimal impact on EOS at a population level. Funding: GSK [115058; NCT01516528]

Background GOLD recommends the use of a LAMA or LABA in patients categorised as group A or B. In this post-hoc analysis, we sought to evaluate the effect of the LAMA/LABA GFF MDI, compared with its monocomponents and placebo (PBO) in COPD patients categorized as GOLD A or B. Methods Pooled analysis of two randomised, double-blind, PBO-controlled studies (PINNACLE-1 [NCT01854645] and -2 [NCT01854658]), in which patients received GFF MDI (14.4/9.6µg), GP MDI (14.4µg), FF MDI (9.6µg) or PBO MDI (all twice daily), or open-label tiotropium 18µg (once daily; PINNACLE-1 only), evaluated lung function over 24 weeks. Results ITT population included GOLD group A (n=227) and B patients (n=1360). Overall, GFF MDI increased the change from baseline in morning pre-dose trough FEV1 and peak change in FEV1 within 2h post-dose vs FF MDI, GP MDI and PBO in both GOLD A and GOLD B groups (Table). The effect of GFF MDI vs comparators was at least as large in GOLD group A patients as in GOLD group B. Conclusion In a post-hoc analysis, GFF MDI improved lung function vs GP MDI, FF MDI and PBO MDI in COPD patients categorised as GOLD A or B. Further evaluation of LAMA/LABAs in this patient population is warranted.

Introduction It is unknown if short-term worsening in COPD is a predictor of long-term poor outcome. We assessed whether worsening measured using a short-term composite measure (clinically important deterioration [CID]) would predict adverse outcomes in two large 3-year studies. Methods A CID was defined as any of: a decrease of ≥100mL in FEV1 or increase of ≥4 units in St George9s Respiratory Questionnaire (SGRQ) score from baseline or a moderate/severe exacerbation at ≤6 months (index date [ID]) in TORCH and ≤12-months ID in ECLIPSE. Association between presence (+) and absence (-) of CID status at ID and long-term deterioration in FEV1, health-status, future risk of exacerbations and all-cause mortality was assessed post hoc from ID until end of follow-up. Only subjects that did not withdraw before the ID were included in the analysis. Results In total, 2870 of 5292 (54%) and 1442 of 1973 (73%) patients with data post ID were CID+ in TORCH and ECLIPSE, respectively. In both studies, CID+ patients had a clinically significant deficit in FEV1 and health-status and higher exacerbation risk (p

Introduction Dual bronchodilators provide greater improvements in lung function vs monotherapy in patients with COPD. Here we investigated whether dual bronchodilation improved the St George9s Respiratory Questionnaire (SGRQ) domain scores vs monotherapy. Methods This was a post hoc pooled analysis of three 6-month, blinded, Phase III studies of umeclidinium/vilanterol (UMEC/VI, 62.5/25 mcg; ELLIPTA™) and tiotropium (TIO, 18 mcg; HandiHaler®) in patients with COPD. Outcomes included SGRQ total and domain scores (Activity, Symptoms and Impacts). Analyses were performed using a repeated measures model. Results Overall, 878 patients received UMEC/VI and 869 TIO. SGRQ score by domain and total SGRQ score at Days 28 and 168 are presented in the table. Conclusion While clinically significant improvements in health status were reported in both treatment arms, dual bronchodilation with UMEC/VI provided statistical improvements vs TIO monotherapy in total SGRQ score and in each of its domains at Day 28 and in the Symptoms domain at Day 168. Funded by GSK (ZEP117115 [NCT01777334], DB2113374 [NCT01316913], DB2113360 [NCT01316900]; 202066).

We describe the change in COPD outcomes over time in a cohort managed in primary care. Methods: The ACCESS (Assessment of Comorbidities in COPD in European Symptomatic Subjects; 115058 study; NCT01516528) was an observational study that prospectively recruited COPD patients across Europe. There were minimal exclusion criteria, but a significant smoking history was required. COPD outcomes collected over 24 months included COPD Assessment Test (CAT), COPD exacerbations, and airflow limitation. Change over time (from screening for FEV 1 [L]; from baseline for CAT) was described as a difference. A mixed linear model was used to explain the change in CAT score (annual) with baseline traits (country, age, gender, CVD comorbidity, smoking, exacerbations prior to study, CAT score) and exacerbations during the study period as covariates. Results: 2887 COPD patients (mean age: 66yrs; 30% females; mean of 59% FEV 1 % predicted, 0.61 exacerbations/person-year) had at screening FEV 1 mean of 1.68L [95% CI: 1.66;1.71]; Mean change in FEV 1 was 30.6mL (95%CI:12.8;48.4; N=2208) at 12M and -55.6mL [95%CI:-73.9;-37.3;N=1894] 12M to 24M . At baseline, mean CAT score was 15.0 [95%CI: 14.7;15.3]. Mean change in CAT score was mean of -0.04 score [95%CI: - -0.28, 0.21; N=2646] at 12M and 1.01 [95%CI: 0.74; 1.27; N=2342] at 24 M. Change in CAT score change was predicted both by FEV 1 and by CAT score at baseline and exacerbations during the study. Conclusions: In this large, well-defined, primary care cohort of COPD patients, a wide variation in disease progression was observed, with sustained worsening on average. CAT score change over two years was predicted by exacerbation frequency during the follow-up and disease severity traits. Funded by GSK.

Anxiety and depression are common comorbidities in patients with chronic obstructive pulmonary disease (COPD) and affect patients’ health status [1, 2]. Health status in COPD patients is frequently assessed by the St George’s Respiratory Questionnaire (SGRQ), which is a validated disease-specific questionnaire widely used in clinical trials [3], but complex and time-consuming to complete and score. Consequently, the COPD Assessment Test (CAT) has been developed [4]. This is a disease-specific health status questionnaire containing eight items with good sensitivity, reliability and responsiveness [4]. CAT scores are strongly positively correlated with SGRQ scores in patients with COPD [4]. Therefore, it is reasonable to hypothesise that those COPD patients with symptoms of anxiety and/or depression will report higher CAT scores (equalling worse health status) compared to those without symptoms. The latest version of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) document [5] recommends the CAT as a tool to assess the impact of COPD on the individual patient beyond airflow limitation. Although it was known that clinically relevant symptoms of anxiety and depression are more common in patients in GOLD stage IV compared to patients in GOLD stages I and II [1], the frequency distribution of patients with symptoms of anxiety and depression across the updated GOLD classification remains unknown. Recently, Sillen et al. [6] reported a prevalence of symptoms of anxiety and depression of 38% and 32%, respectively, in COPD patients with GOLD group D. We aimed to assess …

Objective: Estimate predictive validity for health status measure, the St. George9s Respiratory Questionnaire (SGRQ), among patients with COPD. Method: We used SGRQ data from the COPD Biomarker Qualification Consortium database of pooled individual patient data from medium term randomized clinical trials (N=12,043). Adjusted Hazard Ratios (HR) and 95% Confidence Intervals (95%CI) were used to estimate the association between quartiles of SGRQ at baseline, time to first event and time from first to second event for COPD exacerbations, hospital admissions for COPD, and all-cause death. Results: Risk of COPD outcomes increased with increasing quartiles of SGRQ score for all time to first event analyses; p for trend across quartiles

Background: Most patients with COPD referred for pulmonary rehabilitation (PR) have GOLD stage III/IV. To a lesser extent, patients with GOLD stage I or II are referred for PR. To date, it remains unknown whether and to what extent patients with GOLD stage I or II referred for PR differ from patients with GOLD stage I or II treated in primary or secondary care. Aim: To compare degree of dyspnea, health status, care dependency, functional status and mood status between GOLD I or II patients treated only by the general practitioner (GP, primary care), by GP in combination with chest physician (secondary care) or referred for PR (tertiary care). Methods: Demographics, mMRC, health status (CAT, CCQ, SGRQ-C), Care Dependency Scale (CDS), Timed-Up-and-Go (TUG) test and mood status (HADS) were assessed in 384 patients with COPD (n=93 from GP office; n=68 from outpatient consultation; n=223 from pre-PR assessment). Results: Tertiary GOLD I patients had worst mMRC and SGRQ-C total scores. Tertiary GOLD II patients had worst CCQ, SGRQ-C and HADS anxiety scores (p-value ≤0.05). No differences were observed in body composition or functional status (table 1). Conclusion: Although comparable airflow limitation, GOLD I or II patients can perceive high burden of COPD. These patients should be considered for PR, irrespective of mild to moderate degree of airflow limitation. Funded by Lung Foundation Netherlands (3.4.10.015) and GSK (SCO115406).

Background: In COPD, eosinophilic airway inflammation is associated with disease severity, acute exacerbations and a positive response to systemic corticosteroids. Reliable biomarkers are needed for the detection of eosinophilic COPD. Aim: To investigate whether peripheral blood eosinophil (PBE) count can predict eosinophilic airway inflammation in stable COPD. We hypothesise that there is a positive association between PBE and sputum eosinophilia in COPD patients. Methods: Stable COPD patients (GOLD grade II-IV) with a history of acute exacerbation in the past year underwent spirometry, sputum induction and blood collection. Receiver operating characteristic (ROC) curve analysis was used to examine the predictive relationship between sputum eosinophilia (≥3%) and PBE. Results: 66 patients were recruited, 44 were males, with a mean(±SD) age of 70.51(±7.79) years and post bronchodilator FEV 1 % predicted of 57.04(±18.01)%. Almost half (48.5%) of the patients were 9frequent exacerbators9; 59% were in GOLD quadrant D. Sputum eosinophilia was present in 22 patients (33.3%). A significant correlation was found between sputum eosinophil percentage and PBE counts (r=0.495; p 9 /L). The best cut-off point for PBE count was 0.475×10 9 /L, with a sensitivity of 50%, specificity of 86.36%, and a positive likelihood ratio of 3.7. Conclusion: PBE count has a high specificity for sputum eosinophilia, allowing a positive diagnosis of eosinophilic COPD. This simple test could be used to target inflammation and inform treatment decisions in COPD.

Whilst cardiovascular comorbidity is prevalent in COPD and COPD exacerbations are associated with acute cardiac risk, it is unclear how a history of cardiovascular comorbidity affects exacerbation risk. The prospective, observational ACCESS study (Assessment of Comorbidities in COPD in European Symptomatic Subjects) from primary care In 6 European countries) was powered to compare the rate of exacerbations in COPD patients with or without cardiovascular disease (CVD) over 24 months. The definition of CVD has been previously reported (Vestbo J, et al. Eur Respir J 2013; 41:1017). At baseline, CVD patients were older and more likely to be ex-smokers, but had similar levels of COPD severity. Annualised rates of moderate/severe exacerbations and hospital admissions adjusted for important COPD indicators did not differ by CVD status. We conclude that there is no association between CVD and risk of COPD exacerbations. GSK-funded study HZC115058; NCT01516528.

Background: PT003 is a novel co-suspension MDI combination of two long-acting bronchodilators, the LAMA glycopyrronium (GP 14.4µg) and the LABA formoterol fumarate (FF 9.6µg). We investigated the efficacy and safety of PT003 vs individual components PT001 (GP MDI 14.4µg) and PT005 (FF MDI 9.6µg) in patients with moderate to very severe COPD in two Phase 3 studies (PINNACLE-1 and -2). Methods: In these two randomised, double-blind, placebo-controlled, parallel-group, multicentre studies patients received PT003, PT001, PT005 or placebo, all delivered via co-suspension technology MDI (7:6:6:3) twice-daily for 24 weeks; PINNACLE-1 included open-label tiotropium 18μg once-daily. Primary endpoints were change from baseline in morning trough FEV1 and computerised TDI focal score over 24 weeks. Results: For trough FEV1, PT003, PT001, and PT005 were superior to placebo and PT003 was superior to PT001 and PT005 (p

Background: Selection of treatment for a COPD exacerbation may vary according to physician habit and patient choice, but no studies have linked worsening of specific symptoms to the choice of treatment for the exacerbation. We used EXACT electronic diary data from a trial of extrafine formoterol/beclomethasone in COPD [Wedzicha Respir Med 2014;108:1153] to examine change in symptoms in patients receiving corticosteroids (CS) or antibiotics (AB) for an exacerbation. Methods: Data from both treatment arms were pooled. EXACT scores were aligned using the day the exacerbation was reported (Day 0). Changes in EXACT total and domain scores for breathlessness, chest symptoms and cough & sputum were calculated as the difference between peak (average of days 0-3) and baseline (average of days -21/-8). Change was compared (t-test) for any CS use (regardless of AB use) vs none and for any AB use (regardless of CS use) vs none. Results: Data from 449 events were available. The breathlessness score worsened significantly more in patients given CS (p=0.007), whereas cough & sputum worsened significantly more in patients given AB (p