Single-inhaler triple therapy utilizing the once-daily combination of fluticasone furoate, umeclidinium and vilanterol in the management of COPD: the current evidence base and future prospects

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Abstract

Maintenance pharmacological treatment for stable chronic obstructive pulmonary disease (COPD) is based on inhaled drugs, including long-acting muscarinic receptor antagonists (LAMA), long-acting β ₂-adrenoceptor agonists (LABA) and inhaled corticosteroids (ICS). Inhaled pharmacological treatment can improve patients’ daily symptoms and reduce decline of pulmonary function and acute exacerbation rate. Treatment with all three inhaled drug classes is reserved for selected, more severe, patients with COPD when symptoms are not sufficiently controlled by dual LABA/LAMA therapy and exacerbations are frequent. This review focuses on the role of single-inhaler triple therapy with once-daily fluticasone furoate/umeclidinium/vilanterol fixed-dose combination, which is in phase III clinical development for maintenance treatment of severe-to-very severe COPD. In this review, we summarize evidence providing the rationale for its use in COPD and discuss the gaps to be filled in this pharmacotherapeutic area.

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Most cited references 42

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Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease.

Peter Barnes (2013)

Reduced responsiveness to the anti-inflammatory effects of corticosteroids is a major barrier to effective management of asthma in smokers and patients with severe asthma and in the majority of patients with chronic obstructive pulmonary disease (COPD). The molecular mechanisms leading to steroid resistance are now better understood, and this has identified new targets for therapy. In patients with severe asthma, several molecular mechanisms have been identified that might account for reduced steroid responsiveness, including reduced nuclear translocation of glucocorticoid receptor (GR) α after binding corticosteroids. This might be due to modification of the GR by means of phosphorylation as a result of activation of several kinases (p38 mitogen-activated protein kinase α, p38 mitogen-activated protein kinase γ, and c-Jun N-terminal kinase 1), which in turn might be due to reduced activity and expression of phosphatases, such as mitogen-activated protein kinase phosphatase 1 and protein phosphatase A2. Other mechanisms proposed include increased expression of GRβ, which competes with and thus inhibits activated GRα; increased secretion of macrophage migration inhibitory factor; competition with the transcription factor activator protein 1; and reduced expression of histone deacetylase (HDAC) 2. HDAC2 appears to mediate the action of steroids to switch off activated inflammatory genes, but in patients with COPD, patients with severe asthma, and smokers with asthma, HDAC2 activity and expression are reduced by oxidative stress through activation of phosphoinositide 3-kinase δ. Strategies for managing steroid resistance include alternative anti-inflammatory drugs, but a novel approach is to reverse steroid resistance by increasing HDAC2 expression, which can be achieved with theophylline and phosphoinositide 3-kinase δ inhibitors. Long-acting β2-agonists can also increase steroid responsiveness by reversing GRα phosphorylation. Identifying the molecular mechanisms of steroid resistance in asthmatic patients and patients with COPD can thus lead to more effective anti-inflammatory treatments. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

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Prevalence of COPD in Spain: impact of undiagnosed COPD on quality of life and daily life activities.

M Miravitlles, J. Soriano, F. García-Río … (2009)

This study aimed to determine the prevalence of chronic obstructive pulmonary disease (COPD) in Spain and identify the level of undiagnosed disease and its impact on health-related quality of life (HRQL) and activities of daily living (ADL). A population-based sample of 4274 adults aged 40-80 years was surveyed. They were invited to answer a questionnaire and undergo prebrochodilator and postbronchodilator spirometry. COPD was defined as a postbronchodilator FEV(1)/FVC (forced expiratory volume in 1 s/forced vital capacity) ratio of <0.70. For 3802 participants with good-quality postbronchodilator spirometry, the overall prevalence of COPD was 10.2% (95% CI 9.2% to 11.1%) and was higher in men (15.1%) than in women (5.6%). The prevalence of COPD stage II or higher was 4.4% (95%CI; 3.8%-5.1%). The prevalence of COPD increased with age and with cigarette smoking and was higher in those with a low educational level. A previous diagnosis of COPD was reported by only 27% of those with COPD. Diagnosed patients had more severe disease, higher cumulative tobacco consumption and more severely impaired HRQL compared with undiagnosed subjects. However, even patients with undiagnosed COPD stage I+ already showed impairment in HRQL and in some aspects of ADL compared with participants without COPD. The prevalence of COPD in individuals between 40 and 80 years of age in Spain is 10.2% and increases with age, tobacco consumption and lower educational levels. The rate of diagnosised COPD is very high and undiagnosed individuals with COPD already have a significant impairment in HRQL and ADL.

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Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial.

Darcy Marciniuk, Richard Hodder, Robert Cowie … (2007)

Treatment of moderate or severe chronic obstructive pulmonary disease (COPD) with combinations of inhaled corticosteroids, long-acting beta-agonists, and long-acting anticholinergic bronchodilators is common but unstudied. To determine whether combining tiotropium with salmeterol or fluticasone-salmeterol improves clinical outcomes in adults with moderate to severe COPD compared with tiotropium alone. Randomized, double-blind, placebo-controlled trial conducted from October 2003 to January 2006. 27 academic and community medical centers in Canada. 449 patients with moderate or severe COPD. 1 year of treatment with tiotropium plus placebo, tiotropium plus salmeterol, or tiotropium plus fluticasone-salmeterol. The primary end point was the proportion of patients who experienced an exacerbation of COPD that required treatment with systemic steroids or antibiotics. The proportion of patients in the tiotropium plus placebo group who experienced an exacerbation (62.8%) did not differ from that in the tiotropium plus salmeterol group (64.8%; difference, -2.0 percentage points [95% CI, -12.8 to 8.8 percentage points]) or in the tiotropium plus fluticasone-salmeterol group (60.0%; difference, 2.8 percentage points [CI, -8.2 to 13.8 percentage points]). In sensitivity analyses, the point estimates and 95% confidence bounds shifted in the direction favoring tiotropium plus salmeterol and tiotropium plus fluticasone-salmeterol. Tiotropium plus fluticasone-salmeterol improved lung function (P = 0.049) and disease-specific quality of life (P = 0.01) and reduced the number of hospitalizations for COPD exacerbation (incidence rate ratio, 0.53 [CI, 0.33 to 0.86]) and all-cause hospitalizations (incidence rate ratio, 0.67 [CI, 0.45 to 0.99]) compared with tiotropium plus placebo. In contrast, tiotropium plus salmeterol did not statistically improve lung function or hospitalization rates compared with tiotropium plus placebo. More than 40% of patients who received tiotropium plus placebo and tiotropium plus salmeterol discontinued therapy prematurely, and many crossed over to treatment with open-label inhaled steroids or long-acting beta-agonists. Addition of fluticasone-salmeterol to tiotropium therapy did not statistically influence rates of COPD exacerbation but did improve lung function, quality of life, and hospitalization rates in patients with moderate to severe COPD. International Standard Randomised Controlled Trial registration number: ISRCTN29870041.

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Author and article information

Contributors

Mario Malerba

Matteo Nardin

Giuseppe Santini

Nadia Mores

Alessandro Radaeli

Paolo Montuschi

Journal

Journal ID (nlm-ta): Ther Adv Respir Dis

Journal ID (iso-abbrev): Ther Adv Respir Dis

Journal ID (publisher-id): TAR

Journal ID (hwp): sptar

Title: Therapeutic Advances in Respiratory Disease

Publisher: SAGE Publications (Sage UK: London, England )

ISSN (Print): 1753-4658

ISSN (Electronic): 1753-4666

Publication date (Electronic): 14 March 2018

Publication date Collection: Jan-Dec 2018

Volume: 12

Electronic Location Identifier: 1753466618760779

Affiliations

[1-1753466618760779]Department of Translational Medicine-Respiratory Medicine, University of Piemonte Orientale, Novara/Vercelli, Italy

[2-1753466618760779]Department of Internal Medicine, University of Brescia, Brescia, Italy

[3-1753466618760779]Department of Pharmacology, Catholic University of the Sacred Heart, Agostino Gemelli University Hospital Foundation, Rome, Italy

[4-1753466618760779]Department of Pharmacology, Catholic University of the Sacred Heart, Agostino Gemelli University Hospital Foundation, Rome, Italy

[5-1753466618760779]Department of Emergency Medicine, ASST Spedali Civili di Brescia, Brescia, Italy

[6-1753466618760779]Department of Pharmacology, Faculty of Medicine, Catholic University of the Sacred Heart, Agostino Gemelli, University Hospital Foundation, Largo Francesco Vito, 1 – 00168, Rome, Italy

Author notes

[*] paolo.montuschi@ 123456unicatt.it

Article

Publisher ID: 10.1177_1753466618760779

DOI: 10.1177/1753466618760779

PMC ID: 5941662

PubMed ID: 29537340

SO-VID: c577a8ac-c097-4669-85ef-e9d30041b7a6

License:

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

History

Date received : 15 October 2017

Date accepted : 31 January 2018

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cover-date January-December 2018

Keywords: copd,fluticasone,pharmacotherapy,single-inhaler,triple therapy,umeclidinium,vilanterol

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Keywords: copd, fluticasone, pharmacotherapy, single-inhaler, triple therapy, umeclidinium, vilanterol

Single-inhaler triple therapy utilizing the once-daily combination of fluticasone furoate, umeclidinium and vilanterol in the management of COPD: the current evidence base and future prospects

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Most cited references 42

Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease.

Prevalence of COPD in Spain: impact of undiagnosed COPD on quality of life and daily life activities.

Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial.

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