How can the findings of the EMAX trial on long-acting bronchodilation in chronic obstructive pulmonary disease be applied in the primary care setting?

This review addresses outstanding questions regarding initial pharmacological management of chronic obstructive pulmonary disease (COPD). Optimizing initial treatment improves clinical outcomes in symptomatic patients, including those with low exacerbation risk. Long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) dual therapy improves lung function versus LAMA or LABA monotherapy, although other treatment benefits have been less consistently observed. The benefits of dual bronchodilation in symptomatic patients with COPD at low exacerbation risk, and its duration of efficacy and cost effectiveness in this population, are not yet fully established. Questions remain on the impact of baseline symptom severity, prior treatment, degree of reversibility to bronchodilators, and smoking status on responses to dual bronchodilator treatment. Using evidence from EMAX (NCT03034915), a 6-month trial comparing the LAMA/LABA combination umeclidinium/vilanterol with umeclidinium and salmeterol monotherapy in symptomatic patients with COPD at low exacerbation risk who were inhaled corticosteroid-naïve, we describe how these findings can be applied in primary care.

Applying key learnings from the EMAX trial to clinical practice and future trial design in COPD.

Early MAXimisation of bronchodilation for improving COPD stability (EMAX) was a large, multicentre, multi-national, randomised, double-blind, 24-week trial. EMAX evaluated the efficacy and safety of dual bronchodilator therapy with umeclidinium bromide (UMEC)/vilanterol (VI) versus monotherapy with either UMEC or salmeterol (SAL) in symptomatic patients with chronic obstructive pulmonary disease (COPD) at low exacerbation risk who were not taking concomitant inhaled corticosteroid (ICS). EMAX generated evidence covering a wide range of patient-centred endpoints in COPD in addition to measures of lung function, clinical deterioration and safety. In addition, prospective and post hoc secondary analyses have generated clinically valuable information regarding the effects of baseline patient characteristics on treatment outcomes. Importantly, as concomitant ICS use was not permitted in this study, EMAX compared dual long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) therapy with LAMA or LABA monotherapy without potential confounding due to concurrent ICS use or withdrawal. EMAX demonstrated beneficial treatment effects of UMEC/VI over UMEC or SAL monotherapy as maintenance treatment across a range of different patient characteristics, with no forfeit in safety. Thus, the trial provided novel insights into the role of LAMA/LABA versus LABA and LAMA monotherapies as maintenance therapy for patients with symptomatic COPD at low risk of exacerbations. This article will explore the clinical implications of the main findings to date of the EMAX trial and consider the key learnings this trial offers for future trial design in COPD.

New Versus Old: The Impact of Changing Patterns of Inhaled Corticosteroid Prescribing and Dosing Regimens in Asthma Management.

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 ß2-agonist (LABA) dosing had a greater degree of bronchoprotection than as-needed BUD/FOR dosing or BUD/FOR maintenance and reliever therapy (MART) dosing, and still maintained low systemic activity. We also found that the benefits of regular daily ICS dosing regimens were diminished when adherence was low (50%); the shorter duration of bronchoprotection observed was similar to that seen with typical as-needed BUD/FOR usage. These findings have implications for aiding clinicians with selecting the most suitable treatment option for asthma management, and subsequent implications for the advice clinicians give their patients.

Inhaled 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 ß₂-agonist (LABA) to experience sufficient asthma control. However, failure to correctly adhere to ICS-containing therapies or an over-reliance on short-acting bronchodilators for symptom relief hinders optimal asthma management, thus negatively affecting overall patient health and wellbeing. Understanding how different dosing regimens affect the degree of bronchoprotection (efficacy) and cortisol suppression (systemic activity) of ICS treatments would benefit physicians by helping them to prescribe the most appropriate treatment for their patient's asthma. We performed a structured literature review of two ICS molecules­budesonide (BUD) (alone and combined with formoterol [FOR]) and fluticasone propionate (FP)­to explore the relationship between various ICS dosing regimens, and then used these findings to construct models for ICS risk­benefit profiles. Our models factored in different ICS dosing regimens­as-needed, regular daily dosing, and maintenance and reliever therapy (MART)­and various degrees of treatment adherence. We found that regular daily ICS and ICS/LABA dosing provided better bronchoprotection than as-needed BUD/FOR dosing or BUD/FOR MART dosing, but this benefit was diminished with low adherence. Regular daily dosing maintained low cortisol suppression, which indicated a fairly low risk of negative side effects. Our findings have subsequent implications for optimizing treatment in patients with asthma.

Primary Care Management of Asthma Exacerbations or Attacks: Impact of the COVID-19 Pandemic.

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.

Economic Evaluation of Umeclidinium/Vilanterol versus Umeclidinium or Salmeterol in Symptomatic Non-Exacerbating Patients with COPD from a UK Perspective Using the GALAXY Model.

INTRODUCTION: 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.

Efficacy of umeclidinium/vilanterol according to the degree of reversibility of airflow limitation at screening: a post hoc analysis of the EMAX trial.

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.

Future concepts in bronchodilation for COPD: dual- versus monotherapy.

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 ß2-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.

Efficacy and Safety of Umeclidinium/Vilanterol in Current and Former Smokers with COPD: A Prespecified Analysis of The EMAX Trial.

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.

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.

Effect of Age on Efficacy and Safety of Fluticasone Furoate/Vilanterol (FF/VI), Umeclidinium (UMEC), and UMEC + FF/VI in Patients with Chronic Obstructive Pulmonary Disease: Analyses of Five Randomized Clinical Trials.

Introduction: 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.

Dual Bronchodilator Therapy as First-Line Treatment in Maintenance-Naïve Patients with Symptomatic COPD: A Pre-Specified Analysis of the EMAX Trial.

Introduction: 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.

Treatment of COPD with Long-Acting Bronchodilators: Association Between Early and Longer-Term Clinically Important Improvement.

INTRODUCTION: 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.

The impact of fluticasone furoate/vilanterol on healthcare resource utilisation in the Salford Lung Study in chronic obstructive pulmonary disease.

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 < 0.001). LS mean annual rates of COPD-related PCCs were similar for FF/VI and UC (2.42 versus 2.46). All-cause PCC mean total cost/patient was £900 FF/VI versus £811 UC, but COPD-related PCC costs were similar (£116 versus £114). Direct COPD-related total medical costs/patient were significantly lower for FF/VI (LS geometric mean £806 versus £963 UC; p < 0.001). 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.

Impact of baseline COPD symptom severity on the benefit from dual versus mono-bronchodilators: an analysis of the EMAX randomised controlled trial.

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 [<20 (post hoc) and ⩾20 (pre-specified)]. Outcomes were also assessed using post hoc fractional polynomial modelling with continuous transformations of baseline CAT score covariates. RESULTS: Of the intent-to-treat population (n = 2425), 56% and 44% had baseline CAT scores of <20 and ⩾20, respectively. Umeclidinium/vilanterol demonstrated favourable improvements compared with umeclidinium and salmeterol for the majority of outcomes irrespective of the baseline CAT score, with the greatest improvements generally observed in patients with CAT scores <20. Fractional polynomial analyses revealed consistent improvements in lung function, symptoms and reduction in rescue medication use with umeclidinium/vilanterol versus umeclidinium and salmeterol across a range of CAT scores, with the largest benefits seen in patients with CAT scores of approximately 10-21. 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 <20, although benefits were seen up to scores of 30. This suggests that dual bronchodilation may be considered as initial therapy for patients across a broad range of symptom severities, not only those with severe symptoms (CAT ⩾20).Trial registration: NCT03034915, 2016-002513-22 (EudraCT number).The reviews of this paper are available via the supplemental material section.

Early and sustained symptom improvement with umeclidinium/vilanterol versus monotherapy in COPD: a post hoc analysis of the EMAX randomised controlled trial.

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.

Efficacy of umeclidinium/vilanterol versus umeclidinium and salmeterol monotherapies in symptomatic patients with COPD not receiving inhaled corticosteroids: the EMAX randomised trial.

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 < 0.001). Umeclidinium/vilanterol demonstrated consistent improvements in Transition Dyspnoea Index versus both monotherapies at Week 24 (vs umeclidinium: 0.37 [95% CI: 0.06, 0.68], 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 < 0.01]) and salmeterol (by 26-41% [p < 0.001]). Safety profiles were similar between treatments. 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.

Efficacy and safety of the dual bronchodilator combination umeclidinium/vilanterol in COPD by age and airflow limitation severity: A pooled post hoc analysis of seven clinical trials.

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 ß2-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 (<65, ≥65, and ≥75 years of age) and severity of baseline airflow limitation (Global initiative for chronic Obstructive Lung Disease [GOLD] stage 2 [moderate] and stage 3/4 [severe/very severe]). A 24-week analysis was also conducted for the UMEC/VI versus TIO comparison. 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 < 0.001). The proportion of FEV1 responders at Day 84 was significantly greater with UMEC/VI versus TIO or FP/SAL across all age groups (all p ≤ 0.016) and GOLD stages (all p < 0.001). Safety profiles were similar between treatment groups. 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.

Impact of prior and concurrent medication on exacerbation risk with long-acting bronchodilators in chronic obstructive pulmonary disease: a post hoc analysis.

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 (< 3.6 or ≥ 3.6 puffs/day). Time to first moderate/severe exacerbation (Cox proportional hazard model) and change from baseline in trough forced expiratory volume in 1 s (FEV1; mixed model repeated measures) were analyzed. Safety was also assessed. RESULTS: Of 3021 patients (ITT population; UMEC/VI: n = 816; UMEC: n = 825; VI: n = 825; PBO: n = 555), 36% had a recent exacerbation history, 33% were maintenance-naïve, 51% were ICS-free. Mean baseline albuterol use was 5.1 puffs/day. In the ITT population, UMEC/VI, UMEC, and VI reduced the risk of a first exacerbation versus PBO by 58, 44, and 39%, respectively (all p < 0.05). UMEC/VI provided significant risk reductions versus PBO in all subgroups. VI had no benefit versus PBO in maintenance-naïve, ICS-free, and low rescue use patients and was significantly less effective than UMEC/VI in these subgroups. UMEC had no significant benefit versus PBO in maintenance-naïve and ICS-free patients. All bronchodilators improved FEV1 versus PBO, and UMEC/VI significantly improved FEV1 versus both monotherapies across all populations studied (p < 0.05). All bronchodilators were similarly well tolerated. CONCLUSIONS: Results suggest that UMEC/VI reduces exacerbation risk versus PBO more consistently across medication subgroups than UMEC or VI, particularly in patients with no/low concurrent medication use. Confirmed prospectively, these findings may support first-line use of dual bronchodilation therapy in symptomatic low-risk patients.

Benefit and safety of fluticasone furoate/vilanterol in the Salford Lung Study in chronic obstructive pulmonary disease (SLS COPD) according to baseline patient characteristics and treatment subgroups.

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 <10 (25.3% [-0.4, 44.4]). Pneumonia SAESI rates were similar for FF/VI versus UC across all subgroups/strata, except the LABA, LAMA or LABA + LAMA stratum (incidence ratio 2.8 [0.9, 8.5]). SAESI rates were not increased for FF/VI versus other ICS + LABA. CONCLUSIONS: Initiating FF/VI versus continuing UC reduced exacerbation rates without increased pneumonia SAESI risk compared to other ICS-containing regimens and in various patient subgroups, consistent with primary study findings. FF/VI may be a therapeutic option for a broad population of COPD patients, including those with more severe disease.