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Objectives: The recent publication of additional data retrieval for patients missing week 52 vital status in the original analyses of the ETHOS study provides the urgent need of updating previous network meta-analyses (NMA) to produce stronger evidence on mortality in patients receiving dual and triple FDCs according with the level of ICS dose., Methods: A NMA was performed to compare the effect of ICS/LABA/LAMA, ICS/LABA, and LABA/LAMA FDCs administered via the same inhaler device in COPD patients. The number need to treat (NNT) was also calculated., Results: When considering on-treatment all-cause of death (analyzed patients: 18,864), MD ICS/LABA/LAMA and MD ICS/LABA FDCs significantly reduced the risk of mortality vs. LABA/LAMA FDC (RR 0.59 95%CrI 0.35-0.97 and 0.61 95%CrI 0.38-0.99 respectively, P < 0.05); NNT ranged between 123 and 129. MD ICS/LABA/LAMA FDC also significantly reduced the risk of adjudicated cardiovascular mortality vs. LABA/LAMA FDC (RR 0.44 95%CI 0.19-0.97, P < 0.05). Low-dose (LD) ICS/LABA FDC did not significantly modulate mortality., Conclusion: MD ICS/LABA/LAMA and MD ICS/LABA FDCs were effective in reducing on-treatment all-cause of death, with MD ICS/LABA/LAMA FDC being effective also against adjudicated cardiovascular mortality. The protection against mortality was related with the level of ICS dose in the FDCs.

Introduction: Asthma symptoms can be relieved through a maintenance treatment combining long-acting β 2 -agonist and inhaled corticosteroids (LABA/ICS). However, for patients with inadequately controlled asthma, the LABA/ICS combination might not be sufficient, and clinical guidelines recommend the administration of inhaled long-acting muscarinic antagonists (LAMA) as an add-on therapy to better control asthma and improve lung function. For nearly two decades, the only LAMA to be approved on the market has been tiotropium., Areas Covered: We reviewed recent clinical studies evaluating the safety and efficacy of LABA/LAMA/ICS fixed dose combinations by searching the PubMed database. Molecular mechanisms and clinical data support the use of a once-daily, single-inhaler fixed dose combination of the LABA/LAMA/ICS indacaterol/glycopyrronium/mometasone (IND/GLY/MF), the first therapy combining three agents in a fixed dose approved in Europe for the treatment of uncontrolled asthma., Expert Opinion: IND/GLY/MF was superior to both IND/MF and salmeterol/fluticasone, a well-established LABA/ICS combination improving the lung function in uncontrolled asthma. Moreover, IND/GLY/MF, delivered through the Breezhaler inhaler in a single inhalation, is the first inhaled therapy prescribed alongside a digital companion, a sensor and the Propeller app, allowing for improved treatment adherence, reduced rescue inhaler usage and hospitalizations, increased patient satisfaction and asthma control.

Objectives: In some studies comparing triple with dual combination therapies in COPD there might be a possible effect of inhaler bias resulting from different inhaler devices being used in comparator arms. The aim of this study was a quantitative synthesis by considering the studies that directly compared triple ICS/LABA/LAMA vs. either dual LABA/LAMA or ICS/LABA therapies administered at fixed-dose combination (FDC) via the same inhaler device., Methods: A network meta-analysis was performed to assess the efficacy/safety impact of triple ICS/LABA/LAMA FDC compared with dual LABA/LAMA and ICS/LBA FDCs administered via the same inhaler device in COPD patients. The treatment ranking was reported via the surface under the cumulative ranking curve analysis (SUCRA)., Results: Data obtained from 21,909 COPD patients were extracted from the ETHOS, KRONOS, IMPACT, and TRILOGY studies, the only that fulfilled the strict inclusion criteria of this research. The weighted efficacy/safety profile resulting from SUCRA provided the following ranking in patients with low eosinophil count: ICS/LABA/LAMA>LABA/LAMA≫ICS/LABA; whereas in patients with high eosinophil count the ranking was as follows: ICS/LABA/LAMA>LABA/LAMA>ICS/LABA FDC., Conclusion: Triple ICS/LABA/LAMA FDC and dual LABA/LAMA or ICS/LABA FDCs are characterized by specific efficacy/safety profiles in agreement with the level of blood eosinophil count at baseline.

Introduction : Treatment options for COPD have evolved rapidly in the last decade and inhaled bronchodilators have largely supplanted the use of oral bronchodilators because of their increased efficacy and excellent safety with topical delivery to the lung. Recently added to the therapeutic armamentarium are fixed-dose combinations (FDC) of two long acting bronchodilators. LAMAs (long acting muscarinic antagonists) and LABAs (long acting beta agonists) are the main classes available and use different pathways to effectively produce bronchial smooth muscle relaxation. Areas covered : The most recent inhaled FDC LAMA/LABA to come to market is Aclidinium Bromide and Formoterol Fumarate. We searched databases of PubMed, Cochrane Library, and manufacturers' websites and retrieved all the randomized-controlled trials (RCTs) conducted with these drugs up to September 2019. Expert opinion : It is likely that FDCs will become the core of our COPD pharmacotherapy for all but the mildest COPD patients. These individual drugs have excellent efficacy and safety records for the maintenance treatment of COPD. Studies have demonstrated that twice daily treatment with aclidinium/formoterol resulted in significant improvement in lung function and an improved exercise tolerance when compared to placebo. Adverse effects are within the range of what is seen with other LAMA/LABA combinations.

Introduction: COPD is highly prevalent in the US and globally, requiring new treatment strategies due to the high disease burden and increase in the aging population. Here, we profile the newly FDA-approved LONHALA MAGNAIR (glycopyrrolate [GLY]/eFlow® Closed System [CS]; 25 mcg twice daily), a nebulized long-acting muscarinic antagonist (LAMA) for the long-term maintenance treatment of COPD, including chronic bronchitis and/or emphysema. Areas covered: An overview of COPD and treatment landscape, focusing on GLY/eFlow CS, reviewing the published literature pertinent to the drug/device combination is reported. Expert commentary: GLY/eFlow CS consists of glycopyrrolate delivered via a novel electronic nebulizer and is the first nebulized LAMA to be approved by the FDA. GLY/eFlow CS has been studied in an extensive clinical development program, including phase II dose-ranging studies, two 12-week phase III studies demonstrating statistically significant and clinically important improvements in pulmonary function and patient-reported outcomes with a well-tolerated safety profile, and a 48-week phase III study highlighting the long-term safety of GLY/eFlow CS, along with long-term improvements in lung function and patient-reported outcomes. Additional studies are required to assess the impact of GLY/eFlow CS on COPD exacerbations, identify alternative uses of the eFlow CS nebulizer, and direct comparisons to other LAMAs.

Introduction: LABA+LAMA and LABA+ICS combinations are key pharmacological approaches to the treatment of COPD. However, both combination types can induce adverse events (AEs)., Areas Covered: Current literature on LABA+LAMA and LABA+ICS combinations has been reviewed with a specific focus on their safety profile in the treatment of COPD., Expert Opinion: Several meta-analyses have compared the pooled safety data from randomized clinical trials (RCTs) of LABA+LAMA combinations with LABA+ICS combinations. LABA+LAMA caused significantly less AEs and SAEs. However, this evidence in real life is less solid because of the lack of appropriate studies. A statistically significant reduction in the risk for pneumonia with LABA+LAMA compared with LABA+ICS has been repeatedly documented by various meta-analyses. The meta-analytic signal indicates that an equal number of patients would die or have cardiac SAEs on LABA+LAMA or LABA+ICS, and in an observational, real-life study the LABA+LAMA combination had similar or lower risk of these events in comparison to LABA+ICS. Nonetheless, since RCTs are conducted under widely varying conditions and, consequently, AE rates of a drug observed in a RCT cannot be directly compared with rates in the RCTs of another drug and may not reflect the rates observed in practice, we need more specific data.

Introduction : The aim was to investigate how the pattern of pharmacological treatment in Swedish patients with chronic obstructive pulmonary disease (COPD) has changed over a decade, and to identify factors associated with treatment. Methods : Data on patient characteristics and pharmacological treatment were collected using questionnaires from two separate cohorts of randomly selected primary and secondary care patients with a doctor's diagnosis of COPD in central Sweden, in 2005 ( n  = 1111) and 2014 ( n  = 1329). Cross-tabulations and chi-square tests were used to compare maintenance treatment in 2005 and 2014, and to investigate the distribution of treatment by the 2017 Global Initiative for Obstructive Lung Disease (GOLD) ABCD groups. Multinomial logistic regression was used to analyze associations with the major types of recommended treatments: bronchodilator therapy, combined long-acting beta-2-antagonists (LABA) + inhaled corticosteroids (ICS), and triple inhaled therapy. Results : The proportion of patients with no maintenance treatment, with only LABA + ICS, and with sole ICS statistically significantly decreased (36 vs. 31%, 16 vs. 12% and 5 vs. 2%, respectively), and the proportion with triple inhaled therapy statistically significantly increased (29 vs. 40%). In 2014, triple inhaled therapy was the most common treatment in all GOLD groups except group A. In 2014, previous frequent exacerbations [OR (95% CI) 2.34 (1.62 to 3.36)], worse COPD Assessment Test score [1.07 (1.05 to 1.09)], female sex [2.13 (1.56 to 2.91)], and access to a specific responsible doctor [1.95 (1.41 to 2.69)] were associated with triple inhaled therapy. Current smoking [0.40 (0.28 to 0.57)] and overweight [0.62 (0.41 to 0.93)] were inversely associated with triple inhaled therapy. Conclusions : Over the last decade, triple inhaled therapy has increased, and no maintenance treatment, ICS, or LABA + ICS has decreased. Triple inhaled therapy is the most common treatment and is associated with previous exacerbations, higher symptom level, female sex, and having a specific responsible doctor., Competing Interests: No potential conflict of interest was reported by the authors.

Introduction: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally and incidence rates are continuing to rise. Long-acting bronchodilators are the foundation on which current pharmacological approaches to COPD management are built, with long-acting muscarinic antagonists (LAMAs) and long-acting β 2 -agonists (LABAs) recommended across the spectrum of the disease continuum. Combining LAMAs and LABAs provides additional lung function improvements and relief of patient symptoms compared with either therapy alone. Several options for LAMA/LABA fixed-dose combinations (FDC) delivered via a single inhaler device are available; however, only recently has a LAMA/LABA FDC become available as a pressurized metered dose inhaler (MDI). Areas covered: This article describes the rationale for the development of the LAMA/LABA FDC of glycopyrrolate and formoterol fumarate, formulated by Co-Suspension™ Delivery Technology and delivered by MDI (GFF MDI). The clinical trial program of GFF MDI, including the pivotal Phase III studies (PINNACLE-1 and PINNACLE-2) that supported regulatory approval, are reviewed, providing insights into interpretation and future directions for research. Expert commentary: LAMA/LABA FDCs are already a crucial part of the COPD treatment paradigm, but additional data are needed in order to maximize their role as maintenance therapies in patients with COPD.

Introduction: Chronic obstructive pulmonary disease (COPD) is a respiratory problem with the highest prevalence and strongest socio-economic impact in the world and whose morbimortality keeps increasing. Treating this disease is a challenge in the field of pneumology since the market now offers a wide range of bronchodilators. Tiotropium bromide, a long-acting anticholinergic bronchodilator, is a drug used to deal with this pathology., Areas Covered: The UPLIFT study was a 4-year (2004-2008) clinical multi-center trial in which tiotropium bromide was compared with a placebo. We present a bibliographic resume covering the multiple sub-analyses published since the end of the clinical trial, between 2009-2015. These sub-analyses analyzed the results obtained in UPLIFT in parallel, provided additional data about safety profiles, exacerbations, hospitalization and mortality rates, and lung function, among others. Expert Commentary: Tiotropium bromide is a significant advance for the maintenance treatment of patients with COPD. The favorable results obtained leave the door open to the possibility of improving the natural history of COPD and confirmed tiotropium bromide as the gold standard drug as monotherapy for treatment of COPD.

Introduction: Chronic obstructive pulmonary disease (COPD) is a progressive disease with symptoms that can have a major impact on patients' physical health. The aim of this study was to evaluate quality of life (QoL), symptom severity and dyspnoea in COPD patients treated with aclidinium up to 24 weeks., Methods: In this prospective non-interventional multicentre study (198 centres in Sweden, Denmark, and Norway), COPD patients (age ≥40 years) who started treatment with aclidinium (initial therapy, change of treatment, or add-on therapy) could be included. Health-related QoL was obtained by COPD assessment test (CAT). Symptoms were evaluated on a 6-point Likert scale. The modified Medical Research Council (mMRC) Dyspnoea Scale was used as a simple grading system to assess the level of dyspnoea/shortness of breath from0 to 4. Patients on treatment with aclidinium who completed baseline and at least one follow-up visit (week 12 or 24) were included in the study population., Results: Overall, 1,093 patients were enrolled (mean 69 years, 54% females), one-third had ≥1 exacerbation the year prior to baseline. At enrolment, 48% were LAMA naïve. Mean (standard deviation, SD) CAT score decreased from 16.9 (7.7) at baseline to 14.3 (7.3) at week 24 (p<0.01) with a decrease in all individual CAT items (p<0.05). Mean difference in morning and night-time symptoms from baseline to week 24 was -0.60 (SD 2.51) and -0.44 (SD 2.48), respectively (both p<0.001). Mean (SD) mMRC Dyspnoea Scale changed from 1.6 (1.0) at baseline to 1.5 (1.0) at week 24 (p<0.001)., Conclusion: In this observational study of a Nordic real-life COPD population, treatment with aclidinium was associated with a clinically important improvement in QoL and morning and night-time symptoms, most pronounced in the LAMA naïve group. However, there is still room for improvement in the management of symptomatic COPD patients.

Introduction: Currently the treatment of chronic obstructive pulmonary disease (COPD) has limited effectiveness and there is a need to develop new drugs. International guidelines recommend the use of long-acting bronchodilators (β2 agonists and anti-cholinergics/muscarinics), inhaled steroids and associations between these drugs in the maintenance treatment of moderate-to-severe COPD., Area Covered: Vilanterol trifenate is a new once-daily highly selective β2-agonist available in USA and Europe in association with umeclidinium bromide (a long-acting anti-muscarnic agent) and fluticasone furoate (an inhaled corticosteroid) for the once-daily maintenance treatment of COPD. Vilanterol combined in fixed-dose treatments has been tested in numerous clinical trials involving thousands of patients. Expert commentary: These new once-daily formulations have the potential to improve compliance to long-term inhaled therapy. This paper will review the clinical and experimental data regarding vilanterol use in the regular treatment of COPD as well as provide a critical discussion of possible future treatment settings.

Bronchodilators are mainstay for the symptomatic treatment of chronic obstructive pulmonary disease (COPD) and the introduction of long-acting bronchodilators has led to an improvement in the maintenance treatment of this disease. Various clinical trials have evaluated the effects of fixed dose long-acting β2-agonists (LABA)/long-acting anti-muscarinics (LAMA) combinations and documented greater improvements in spirometry but such improvements do not always translate to greater improvements in symptom scores or reduction in the rates of exacerbation compared with a single component drug. An analysis of whether this significantly greater change in spirometry with combination therapy is additive or synergistic was undertaken and is the subject of this review. Bronchodilators are not disease modifiers and whilst glucocorticosteroids have been shown to reduce rates of exacerbation in moderate to severe COPD, the increase risk of pneumonia and bone fractures is a motivation enough to warrant developing novel anti-inflammatory and disease-modifying drugs and with the expectation of positive outcomes.

Umeclidinium is a novel inhaled long-acting muscarinic receptor antagonist (LAMA) approved for treatment of chronic obstructive pulmonary disease (COPD). It provides a bronchodilation of at least 24 h, is well tolerated and has a safe profile. In this article, we describe its pharmacokinetic and pharmacodynamic characteristics. Moreover, we present a meta-analysis of randomized clinical trials carried out in COPD patients, in which the change of forced expiratory volume in 1 s (FEV1) induced by umeclidinium has been compared with that elicited by placebo or the active compound tiotropium. The data generated by the pivotal trials indicate that umeclidinium bromide delivered once-daily via the Ellipta™ inhaler is an effective and well-tolerated treatment for COPD. Therefore, it could to be used as an alternative to LAMAs already in the market, although substantial information is still lacking. It is likely that in the future, umeclidinium will be used frequently, mainly in combination with vilanterol, which is a new once-daily long-acting β2-agonist (LABA).

Introduction: Umeclidinium (UMEC) is a long-acting inhaled antagonist of muscarinic cholinergic receptors. The FDA approved UMEC for maintenance treatment of chronic obstructive pulmonary disease (COPD) in 2013 and it became available for commercial use as a single agent in 2014. After tiotropium, this is the only other once daily LAMA available for COPD patients., Areas Covered: In this article, we have comprehensively reviewed the pharmacokinetic properties and analyzed the currently available randomized controlled trials on the efficacy and safety profile of UMEC. We have discussed the current clinical application of UMEC and its future implication., Expert Opinion: UMEC is the newer long-acting antimuscarinic agent (LAMA) that has demonstrated significant improvement in lung function and improved the quality of life in moderate-to-severe COPD patients. It is suitable for once daily dosing, has low anticholinergic side effects and is well tolerated. Overall, it is a safe, effective and convenient LAMA for maintenance therapy in COPD patients.