Incorporando nuevas evidencias sobre medicamentos inhalados en la EPOC. Asociación Latinoamericana de Tórax (ALAT) 2019

This document on COPD from the Latin American Chest Association (ALAT-2019) uses PICO methodology to analyze new evidence on inhaled medication and answer clinical questions. The following key points emerged from this analysis: 1) evidence is lacking on the comparison of short-acting vs. long-acting bronchodilators in patients with mild COPD; patients with moderate-to-severe COPD obtain greater benefit from long-acting bronchodilators; 2) the benefits of monotherapy with long-acting antimuscarinic agents (LAMA) and combined therapy with long-acting β₂-agonists and inhaled corticosteroids (LABA/ICS) are similar, although the latter is associated with a greater risk of pneumonia; 3) LABA/LAMA offer greater benefits in terms of lung function and risk of exacerbation than LABA/ICS (the latter involve an increased risk of pneumonia), 4) LAMA/LABA/ICS have greater therapeutic benefits than LABA/LAMA on the risk of moderate-severe exacerbations. With regard to the role of eosinophils in guiding the use of ICS, ICS withdrawal must be considered when the initial indication was wrong or no response is elicited, in patients with side effects such as pneumonia, and in patients with a low risk of exacerbation and an eosinophil blood count of <300 cells/μl. All this evidence, categorized according to the severity of the obstruction, symptoms, and risk of exacerbations, has been used to generate an algorithm for the use of inhaled medication in COPD.     

Guía de práctica clínica de la enfermedad pulmonar obstructiva crónica (EPOC) ALAT-2014: Preguntas y respuestas

ALAT-2014 COPD Clinical Practice Guidelines used clinical questions in PICO format to compile evidence related to risk factors, COPD screening, disease prognosis, treatment and exacerbations. Evidence reveals the existence of risk factors for COPD other than tobacco, as well as gender differences in disease presentation. It shows the benefit of screening in an at-risk population, and the predictive value use of multidimensional prognostic indexes. In stable COPD, similar benefits in dyspnea, pulmonary function and quality of life are achieved with LAMA or LABA long-acting bronchodilators, whereas LAMA is more effective in preventing exacerbations. Dual bronchodilator therapy has more benefits than monotherapy. LAMA and combination LABA/IC are similarly effective, but there is an increased risk of pneumonia with LABA/IC. Data on the efficacy and safety of triple therapy are scarce. Evidence supports influenza vaccination in all patients and anti-pneumococcal vaccination in patients < 65 years of age and/or with severe airflow limitation. Antibiotic prophylaxis may decrease exacerbation frequency in patients at risk. The use of systemic corticosteroids and antibiotics are justified in exacerbations requiring hospitalization and in some patients managed in an outpatient setting.     

Long-acting Muscarinic Antagonist Versus Inhaled Corticosteroid when Added to Long-acting β-agonist for COPD: A Meta-analysis

The purpose of this study was to systematically review the efficacy and safety of long-acting β-agonist/long-acting muscarinic antagonist (LABA/LAMA) and LABA/inhaled corticosteroid (ICS) combinations in patients with advanced chronic obstructive pulmonary disease (COPD). Randomized clinical trials of at least 12 weeks of duration comparing LABA/LAMA and LABA/ICS combinations were included. We chose forced expiratory volume in 1 second (FEV¹), St. George's Respiratory Questionnaire (SGRQ) score, Transitional Dyspnea Index (TDI), COPD Assessment Test (CAT) score, COPD exacerbations, mortality, and other safety parameters as outcome assessment criteria. We included six randomized controlled trials with a total of 4,319 patients. Most patients did not have a history of exacerbation. LABA/LAMA was associated with greater improvement in FEV¹ than LABA/ICS (mean difference (MD) 0.09L, 95%confidence interval (CI) 0.07 to 0.11L; high certainty). Two treatments appeared clinically equivalent in improving SGRQ (MD ?0.12, 95%CI ?1.16 to 0.92; high certainty), TDI (MD 0.15, 95%CI ?0.05 to 0.35; high certainty), and CAT scores (MD 0.28 95%CI ?0.29 to 0.85; moderate certainty). LABA/LAMA was associated with an absolute reduction of approximately 8% in the incidence of pneumonia compared with LABA/ICS (risk ratio 0.41, 95%CI 0.18 to 0.94; moderate certainty). There was no significant difference in safety and exacerbation outcomes. However, equivalence of two treatments could not be concluded due to imprecision especially for mortality, cardiac serious adverse events, and severe exacerbations. Our findings support the use of dual long-acting bronchodilators for patients with advanced COPD but without frequent exacerbations given the excess risk of pneumonia with LABA/ICS.     

Pharmacologic rationale,efficacy and safety of the fixed-dose co-formulation of indacaterol and glycopyrronium

Chronic obstructive pulmonary disease (COPD) is a widespread respiratory disorder, usually characterized by progressive and poorly reversible airflow limitation. Inhaled long-acting bronchodilators, namely LABA (long-acting β₂-adrenergic agonists) and LAMA (long-acting muscarinic receptor antagonists) are the mainstay of COPD treatment. Because the symptoms of many patients with COPD do not satisfactorily improve by using a single, either LABA or LAMA bronchodilator, the synergism of action resulting from the combination of the different bronchodilating mechanisms activated by LABA and LAMA, respectively, can significantly contribute to a better disease control. Based on these clinical and pharmacological considerations, several LABA/LAMA fixed-dose combinations have been developed and experimentally evaluated. Within such a context, the drug co-formulation containing indacaterol and glycopyrronium is probably the LABA/LAMA association which has been most extensively studied during the last few years.     

LABA,LAMA und Kombinationen

Long-acting bronchodilators are the mainstay of pharmacological therapy in the treatment of chronic obstructive pulmonary disease (COPD). The aim of long-acting bronchodilator therapy is the improvement of symptoms and the prevention of exacerbations in patients with COPD. Both long-acting beta-2 agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are used for the treatment of COPD. The following LABAs are available: formoterol, salmeterol, indacaterol, olodaterol and vilanterol (in combination with the inhaled corticosteroid fluticasone fuorate). The LAMAs tiotropium, aclidinium, glycopyrronium are also available. The LAMA umeclidinium will probably be available in 2014. New LABA/LAMA fixed-dose combinations were recently evaluated in clinical studies and one combination (indacaterol/glycopyrronium) gained approval in 2013. The LABA/LAMA fixed-dose combinations vilanterol/umeclidinium, olodaterol/tiotropium and formoterol/aclidinium are filed for approval or are in the advanced stage of development. For a comprehensive evaluation of new LABA/LAMA fixed-dose combinations further investigations and publications of study results are needed.     

COPD: maximization of bronchodilation

The most recent guidelines define COPD in a multidimensional way, nevertheless the diagnosis is still linked to the limitation of airflow, usually measured by the reduction in the FEV₁/FVC ratio below 70%. However, the severity of obstruction is not directly correlated to symptoms or to invalidity determined by COPD. Thus, besides respiratory function, COPD should be evaluated based on symptoms, frequency and severity of exacerbations, patient’s functional status and health related quality of life (HRQoL). Therapy is mainly aimed at increasing exercise tolerance and reducing dyspnea, with improvement of daily activities and HRQoL. This can be accomplished by a drug-induced reduction of pulmonary hyperinflation and exacerbations frequency and severity. All guidelines recommend bronchodilators as baseline therapy for all stages of COPD, and long-acting inhaled bronchodilators, both beta-2 agonist (LABA) and antimuscarinic (LAMA) drugs, are the most effective in regular treatment in the clinically stable phase. The effectiveness of bronchodilators should be evaluated in terms of functional (relief of bronchial obstruction and pulmonary hyperinflation), symptomatic (exercise tolerance and HRQoL), and clinical improvement (reduction in number or severity of exacerbations), while the absence of a spirometric response is not a reason for interrupting treatment, if there is subjective improvement in symptoms. Because LABA and LAMA act via different mechanisms of action, when administered in combination they can exert additional effects, thus optimizing (i.e. maximizing) sustained bronchodilation in COPD patients with severe airflow limitation, who cannot benefit (or can get only partial benefit) by therapy with a single bronchodilator. Recently, a fixed combination of ultra LABA/LAMA (indacaterol/glycopyrronium) has shown that it is possible to get a stable and persistent bronchodilation, which can help in avoiding undesirable fluctuations of bronchial calibre.     

Triple versus LAMA/LABA combination therapy for Japanese patients with COPD: A systematic review and meta-analysis

BackgroundIn symptomatic COPD patients with a history of exacerbations, additional treatment with inhaled corticosteroid (ICS) to long-acting muscarinic antagonist (LAMA) and long-acting beta-agonist (LABA) combination therapy is recommended based on the evidence of low incidence of exacerbations but with a caution for pneumonia. However, ethnic differences may affect the response to drugs. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of this treatment in the Japanese population (PROSPERO: CRD42020191978).MethodsWe searched relevant randomized control trials and analyzed the exacerbations, quality of life, lung function, and adverse events including pneumonia and mortality as the outcomes of interest.ResultsWe identified a total of three RCTs (N = 632). Treatment with ICS/LAMA/LABA triple therapy significantly decreased the exacerbations (rate ratio, 0.56; 95% CI, 0.38 to 0.85) and improved the trough FEV₁ (mean difference, 0.04; 95% CI, 0.01 to 0.07) compared to LAMA/LABA therapy. However, triple therapy showed a significantly higher incidence of pneumonia compared to LAMA/LABA (odds ratio, 3.38; 95% CI, 1.58 to 7.22). Concerning other adverse events including mortality, there were no significant difference between these therapies.ConclusionsIn the current meta-analysis of the Japanese population, we confirmed that triple therapy causes a higher incidence of pneumonia than LAMA/LABA treatment but is a more preferable treatment since it showed a lower incidence of exacerbations and higher trough FEV₁ in patients with symptomatic moderate to severe COPD. However, since the sample sizes were not statistically large enough, further trials involving Japanese patients are needed.     

Beyond lung function in COPD management: effectiveness of LABA/LAMA combination therapy on patient-centred outcomes

Bronchodilators are central to the management of chronic obstructive pulmonary disease (COPD). Clinical studies combining different classes of bronchodilators, in particular a long-acting muscarinic antagonist (LAMA) and a long-acting β2-agonist (LABA), have demonstrated greater improvements in lung function (forced expiratory volume in 1 second, FEV1) in patients with COPD than monotherapy. FEV1 has served as an important diagnostic measurement of COPD, and the majority of clinical studies of currently available pharmacotherapies grade effectiveness of treatment regimens based on improvements in FEV1. However, FEV1 alone may not adequately reflect the overall health status of the patient. Published evidence suggests that LABA/LAMA combination therapies demonstrate greater improvements in patient-centred outcomes such as dyspnoea, symptoms, rescue medication use, and quality of life than individual drugs used alone. Evaluating patient-centred outcomes associated with COPD is likely to play an important role in future research as a measure of overall treatment effectiveness. Raising awareness of the importance of outcomes beyond lung function alone, particularly in primary care where most patients initially present themselves for medical evaluation, should form a fundamental part of a more holistic approach to COPD management.     

Impact of Long-Acting Bronchodilators and Exposure to Inhaled Corticosteroids on Mortality in COPD: A Real-Life Retrospective Cohort Study

Introduction

We performed a real-life retrospective analysis to assess the impact of long-acting bronchodilator therapy and associated exposure to inhaled corticosteroids (ICS) on all-cause and cardiovascular mortality in patients with chronic obstructive pulmonary disease (COPD).

Methods

We used record linkage data from patients with a diagnosis of COPD in Tayside, Scotland, between 2001 and 2010. All-cause and cardiovascular mortality were assessed using Cox proportional hazard regression.

Results

A total of 4,133 patients were included, mean FEV₁ of 59.5 %, mean age of 68.9 years and mean follow-up of 4.6 years. There were 623 who were exposed to long-acting bronchodilators only and 3,510 to long-acting bronchodilators plus ICS. 1,372 patients (33 %) died during the study period. Compared with controls taking only long-acting bronchodilators either alone or in combination, all-cause mortality was reduced in patients taking long-acting muscarinic antagonist (LAMA) + ICS as dual therapy: adjusted hazard ratio 0.62 (95 % CI 0.45–0.85), but not by long-acting beta-agonist (LABA) + ICS: adjusted hazard ratio 1.02 (95 % CI 0.80–1.31). Cardiovascular mortality was not reduced by dual therapy with either LABA or LAMA and concomitant ICS exposure. All-cause and cardiovascular mortality were both reduced in patients taking triple therapy with LABA + LAMA + ICS: adjusted hazard ratio 0.51 (95 % CI 0.41–0.64) and 0.56 (95 % CI 0.35–0.90), respectively.

Conclusion

In patients exposed to ICS, concomitant use of LAMA alone as dual therapy or in combination with LABA as triple therapy were associated with reductions in all-cause mortality, while concomitant use of LABA without LAMA conferred no reduction. Moreover, only triple therapy was found to confer benefits on cardiovascular mortality.     

Long‐acting beta2‐agonists versus long‐acting muscarinic antagonists in patients with stable COPD: A systematic review and meta‐analysis of randomized controlled trials

Several long‐acting bronchodilators have been developed and are widely used as first‐line treatment in patients with stable chronic obstructive pulmonary disease (COPD). However, the initial choice of therapy is still uncertain. The aim of this study was to examine the clinical efficacy and safety of long‐acting muscarinic antagonist (LAMA) and long‐acting beta2‐agonist (LABA) in patients with stable COPD. We searched several databases and manufacturers’ websites to identify relevant randomized clinical trials for meta‐analysis. Outcomes of interest were trough forced expiratory volume in 1 s (FEV₁), acute exacerbations, transitional dyspnoea index (TDI) score, St George's Respiratory Questionnaire (SGRQ) score and adverse events. Sixteen trials with a total of 22 872 patients were included in this study. Compared with LABA, LAMA were associated with a greater reduction in acute exacerbations (OR: 0.84, 95% CI: 0.74–0.94, P = 0.003) and fewer adverse events (OR: 0.92, 95% CI: 0.86–0.97, P = 0.005). There were no significant differences in trough FEV₁, TDI and SGRQ scores. In patients with stable COPD, LAMA were associated with a greater reduction in acute exacerbations and fewer adverse effects compared with LABA.     

Effectiveness of Treatment With Dual Bronchodilation (LABA/LAMA) Compared With Combination Therapy (LABA/ICS) for Patients With COPD: A Population-Based Study

BackgroundInitiation of treatment of COPD with a combination of a long-acting beta-agonist (LABA) and an inhaled corticosteroid (ICS) is frequent irrespective of the risk of exacerbations.MethodWe performed a retrospective, population-based, observational study aimed at comparing the effectiveness of a LABA/long-acting antimuscarinic agent (LAMA) and LABA/ICS in patients with COPD over a one-year follow-up. Data were obtained from an administrative healthcare claims database. The primary outcome was the risk of first exacerbation. A sensitivity analysis was conducted in a propensity-score matched population.ResultsThe population consisted of 14,046 COPD patients; 11,329 (80.6%) initiated LABA/ICS and 2717 (19.4%) LABA/LAMA. The matched population included 1650 patients in each arm. During follow-up, 69.6% patients in the LABA/ICS group and 64.4% in the LABA/LAMA group presented an exacerbation. The mean time to the first exacerbation was 6.03 months (95% confidence interval (CI): 5.94–6.12) for LABA/ICS and 6.4 months (95%CI: 6.21–6.59) for LABA/LAMA; p < 0.001. The time to scalation to triple therapy was also significantly prolonged in LABA/LAMA. Similar results were obtained in the matched population. LABA/LAMA was associated with a significantly lower risk of exacerbations and escalation to triple therapy compared to LABA/ICS, except in patients with frequent exacerbations and high blood eosinophils in which no differences were observed in the time to first exacerbation.ConclusionInitiation of treatment with LABA/LAMA was associated with a lower risk of exacerbation and escalation to triple therapy compared to LABA/ICS in the majority of patients with COPD in primary care.     

PDE4-inhibitors: a novel, targeted therapy for obstructive airways disease

Roflumilast is a selective once daily, oral phosphodiesterase-4 inhibitor that has recently been registered in all European Union countries as novel targeted therapy for COPD, while FDA approval for the USA market is expected in 2011. In several phase III trials in patients with moderate to (very) severe COPD and in patients with symptoms of chronic bronchitis and recurrent exacerbations, roflumilast showed sustained clinical efficacy by improving lung function and by reducing exacerbation rates. These beneficial effects have also been demonstrated when added to long-acting bronchodilators (both LABA and LAMA), underscoring the anti-inflammatory activity of roflumilast in COPD. Pooled data analysis showed overall mild to moderate, mostly self-limiting adverse events, mainly consisting of nausea, diarrhea and weight loss. In this review we discuss the results of the 4 registration studies showing promising effects of roflumilast in COPD and provide an overview of the topics that still need to be addressed.     

The role of long-acting muscarinic antagonist/long-acting β agonist fixed-dose combination treatment for chronic obstructive pulmonary disease in China: a narrative review

ObjectiveTo provide an overview of the existing international and Chinese evidence regarding dual bronchodilator inhalation therapy and to make recommendations for the further improvement of chronic obstructive pulmonary disease (COPD) management in clinical practice in China.BackgroundCOPD is a progressive lung disease that is characterized by persistent airflow limitation and is a major contributor to the disease burden in China. Symptoms in Chinese patients are relatively more severe. Currently, many Chinese COPD patients are undertreated. Dual bronchodilator therapy consisting of a long-acting muscarinic antagonist (LAMA) and a long-acting β agonist (LABA) is considered a good choice for COPD patients due to the increased bronchodilation without an increase in adverse events; these combinations can fill in the gap in currently available COPD treatments and provide new pharmacotherapy options for Chinese patients. LAMA/LABA fixed-dose combinations (FDCs) have become more important in clinical practice and guidelines in China regarding their therapeutic effects and safety.MethodsClinical trials on LAMA/LABA in COPD were retrieved in ClinicalTrials.gov, while important COPD guidelines published in English or Chinese were found in PubMed and Wanfang Database.ConclusionsWe recommend the adoption of a clinical pathway in China that includes an assessment and management algorithm that considers the clinical characteristics in China and classifies the phenotypic characteristics of COPD according to a suitable system. Based on the current information, we can conclude that LAMA/LABA FDCs are a suitable and economically viable choice to reduce symptoms and improve the quality of life (QoL) of patients.     

New Treatment Option for Chronic Obstructive Pulmonary Disease: Two Long-Acting Bronchodilators in a Single Metered-Dose Inhaler

Combination long-acting inhaled bronchodilators are central to the management of patients with moderate to very severe chronic obstructive pulmonary disease. Glycopyrrolate is a long-acting muscarinic antagonist (LAMA), and formoterol fumarate is a long-acting beta₂ agonist (LABA). In randomized controlled trials, this LAMA/LABA combination in a metered-dose inhaler was shown to be effective in improving pulmonary function and quality of life. Clinicians now have the availability of 3 delivery systems for LAMA/LABA therapy, including metered-dose inhaler, dry-powder inhaler, and Soft Mist inhaler. On the basis of numerous patient factors, such as cognitive ability, manual strength/dexterity, and peak inspiratory flow, clinicians may select the most appropriate inhalation device. For each inhalation device, persistent patient education is absolutely essential, including observation of patient use. International evidence-based guidelines stress the critical importance of ensuring correct use of inhalation devices.     

Inhaled Corticosteroids for Chronic Obstructive Pulmonary Disease—The Shifting Treatment Paradigm

Chronic obstructive pulmonary disease (COPD) guidelines suggest using inhaled corticosteroids (ICS) in patients with severe airflow limitation or those at high risk of exacerbations. This recommendation is based on evidence demonstrating that ICS, especially when prescribed in fixed-dose combinations (FDC) with long-acting β2 agonists (LABA), improve quality of life (QoL), decrease exacerbations and hospitalisations, and have been associated with a trend towards a reduction in all-cause mortality. Audit shows that routine prescribing practice frequently uses inhaler therapies outside current guidelines recommendations; severe to very severe disease constitutes about 20% of all COPD patients, but up to 75% of COPD patients are prescribed an ICS, with significant numbers given ICS/LABA as first-line maintenance therapy. The role of ICS in the treatment paradigm for COPD is changing, driven by the growing evidence of increased risk of pneumonia, and the introduction of a new class of FDC; LABA and long-acting muscarinic antagonists (LAMA), which simplify dual bronchodilation and present a plausible alternative therapy. As the evidence base for dual therapy bronchodilation expands, it is likely that maximal bronchodilation will move up the treatment algorithm and ICS reserved for those with more severe disease who are not controlled on dual therapy. This change has already manifested in local COPD algorithms, such as those at Tayside, and represents a significant change in recommended prescribing practice. This review reassesses the role of ICS in the shifting treatment paradigm, in the context of alternative treatment options that provide maximal bronchodilation.     

Can Assessment of Disease Burden Prior to Changes in Initial COPD Maintenance Treatment Provide Insight into Remaining Unmet Needs? A Retrospective Database Study in UK Primary Care

This retrospective cohort study aimed to assess treatment patterns over 24 months amongst patients with chronic obstructive pulmonary disease (COPD), initiating a new COPD maintenance treatment, and to understand clinical indicators of treatment change. Patients included in the study initiated a long-acting β₂-agonist (LABA), a long-acting muscarinic antagonist (LAMA), or a combination of LABA and an inhaled corticosteroid (ICS/LABA) between January 1, 2009, and November 30, 2013, as recorded in the United Kingdom Clinical Practice Research Datalink (UK CPRD). Treatment modifications (switching or adding maintenance treatments) over 24 months were assessed, and patient characteristics, disease burden, medication and healthcare resource use during the 30 days before treatment modification were evaluated. The cohort comprised 17,258 patients [LABA (8%), LAMA (39%) and ICS/LABA (54%)] with similar age, body mass index and dyspnoea distribution. LABA users were more likely than LAMA users to add a maintenance therapy. Distinct patterns of treatment augmentations were noted, whereby LABA users typically received dual therapy before moving to triple therapy, while LAMA users moved to triple therapy by directly adding an ICS/LABA. Exacerbation events immediately prior to treatment change were not frequently recorded; however, the need for rescue short-acting medication and assessment of dyspnoea in the 30 days prior to the treatment change suggest that dyspnoea is a remaining unmet need driving therapy change.     

Triple Therapy in COPD: What We Know and What We Don't

Triple inhaled therapy for chronic obstructive pulmonary disease (COPD) consists of an inhaled corticosteroid (ICS), a long-acting β₂-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) taken in combination. Triple therapy is recommended by the Global initiative for Chronic Obstructive Lung Disease (GOLD) for patients who experience recurrent exacerbations despite treatment with either a dual bronchodilator (preferred initial therapy) or LABA/ICS combination (alternative initial therapy). Although there is evidence for the greater efficacy of triple therapy compared with LABA/ICS and LAMA monotherapy with regards to improved lung function, health status, and exacerbation rate, the efficacy of triple therapy when compared with dual bronchodilation (LABA/LAMA) is as yet unknown. As ICS use is associated with an increased risk of developing pneumonia, it is important to assess the risk/benefit ratio of triple therapy on an individual basis, and identify patients most likely to benefit. The role of elevated blood eosinophils as a biomarker for the identification of candidates for ICS treatment is currently debated, and further prospective evidence is required. This review assesses evidence for the efficacy and safety of triple therapy and postulates on the prospective evidence from ongoing studies. The potential for treating patients who experience further exacerbations on dual bronchodilation according to phenotype is also considered, as well as withdrawal of ICS from triple therapy in patients who are unlikely to benefit.     

Fixed‐dose combination of umeclidinium and vilanterol for patients with chronic obstructive pulmonary disease: A systematic review

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease that is predicted to be one of the leading causes of death worldwide. Pharmacologic treatment options of COPD are bronchodilators, using either long‐acting β2‐agonists (LABAs), or long‐acting muscarinic antagonists (LAMAs), or a combination of two. Anoro Ellipta (umeclidinium + vilanterol) dry powder inhaler, a fixed‐dose combination of LAMA and LABA, was Food and Drug Administration (FDA) approved in 2013 for COPD. The objective of this study is to evaluate the efficacy and safety of once daily umeclidinium/vilanterol (62.5 mcg/25 mcg) in COPD patients, focusing on pharmacodynamic and pharmacokinetic characteristics, efficacy and safety in clinical studies and cost. Literature search was done through PubMed (2004‐2017) using the terms umeclidinium, vilanterol, COPD, LABA and LAMA. Recent and significant clinical trials about the monocomponents and their combination were identified, in addition to reviews, guidelines for COPD, data from manufacturer and FDA product labels. The search was limited to English language studies on human subjects. Clinical data published on the combination of umeclidinium/vilanterol in patients with COPD have shown greater improvements in lung function compared to monotherapies. However, further studies comparing umeclidinium/vilanterol FDC (ANORO) to other LABA/LAMA combinations are needed.