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Claudio Micheletto,1 Fulvio Braido,2 Marco Contoli,3 Fabiano Di Marco,4 Pierachille Santus5 1Respiratory Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy; 2Department of Internal Medicine, Respiratory Diseases and Allergy Clinic, University of Genova, Azienda Policlinico IRCCS San Martino, Genoa, Italy; 3Department of Medical Sciences, University of Ferrara, Ferrara, Italy; 4Department of Health Sciences, Università degli Studi di Milano, Respiratory Unit, Papa Giovanni XXIII Hospital, Bergamo, Italy; 5Department of Health Sciences, Università degli Studi di Milano,Pulmonary Unit, Luigi Sacco University Hospital, ASST Fatebenefratelli, Milan, ItalyCorrespondence: Claudio MichelettoRespiratory Unit, Azienda Ospedaliera Universitaria Integrata, Piazzale Stefani 1, Verona 37122, ItalyTel +39 045 8122248Email claudio.micheletto@univr.itAbstract: While chronic obstructive pulmonary disease (COPD) continues to be a major cause of morbidity and mortality, pharmacological therapy has a definite benefit on symptoms as well as the frequency and severity of exacerbations, and general health. The most recent Global Initiative for Obstructive Lung Disease (GOLD) guidelines recommend triple therapy (long-acting beta2 agonists [LABA] + long-acting muscarinic antagonists [LAMA] + inhaled corticosteroids [ICS]) only for patients with exacerbations, elevated eosinophils, and without control using a LABA/LAMA or ICS/LABA combination. Long-term monotherapy with ICS is not currently recommended, but may be considered in association with LABAs in patients with a history of exacerbations and elevated eosinophils in spite of appropriate treatment with long-acting bronchodilators. However, long-term use of ICS in combination therapy has been associated with adverse effects, even if widely used in routine management for decades. The available evidence suggests that ICS can be rationally discontinued in patients with stable disease and is not likely to have unfavorable effects on lung function, overall health, or be associated with a greater risk of exacerbations. Indeed, it is widely accepted that ICS therapy should be limited to a small proportion of patients after careful assessment of the individual risk-benefit profile. Unfortunately, however, there are no international recommendations that provide specific guidance or a protocol for withdrawal of ICS. Herein, the available evidence on the use of ICS is reviewed and an easy to use tool is proposed that can provide clinicians with a simple management scheme to guide the most appropriate therapy for management of COPD and use of ICS. In management of COPD, a highly personalized approach is advocated so that the most appropriate therapy for each individual patient can be selected.Keywords: COPD, exacerbation, inhaled corticosteroids, LABA, LAMA, deprescribing

Paola Rogliani,1 Luigino Calzetta,1 Fulvio Braido,2 Mario Cazzola,1 Enrico Clini,3 Girolamo Pelaia,4 Andrea Rossi,5 Nicola Scichilone,6 Fabiano Di Marco7 1Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy; 2Department of Internal Medicine, IRCCS San Martino Genoa University Hospital, Genoa, Italy; 3Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy; 4Department of Medical and Surgical Sciences, Section of Respiratory Diseases, Magna Græcia University, Catanzaro, Italy; 5Pulmonary Unit, University of Verona, Verona, Italy; 6Department of Internal Medicine, University of Palermo, Palermo, Italy; 7Department of Health Sciences, Università degli Studi di Milano, Respiratory Unit, Papa Giovanni XXIII Hospital, Bergamo, Italy Objectives: The aim of this study was to assess the current evidence for long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) in the treatment of COPD.Materials and methods: A systematic literature search of randomized controlled trials published in English up to September 2017 of LABA/LAMA FDCs vs LABA or LAMA or LABA/inhaled corticosteroid (ICS) FDCs in COPD patients was performed using PubMed, Embase, Scopus, and Google Scholar. Outcomes including forced expiratory volume in 1 second (FEV1), Transition Dyspnea Index (TDI) scores, St George’s Respiratory Questionnaire (SGRQ) scores, exacerbations, exercise tolerance (endurance time [ET]), inspiratory capacity (IC), and rescue medication use were evaluated.Results: In total, 27 studies were included in the review. LABA/LAMA FDCs significantly improved lung function (FEV1) at 12 weeks compared with LABA or LAMA or LABA/ICS. These effects were maintained over time. Significant improvements with LABA/LAMA FDCs vs each evaluated comparator were also observed in TDI and SGRQ scores, even if significant differences between different LABA/LAMA FDCs were detected. Only the LABA/LAMA FDC indacaterol/glycopyrronium has shown superiority vs LAMA and LABA/ICS for reducing exacerbation rates, while olodaterol/tiotropium and indacaterol/glycopyrronium have been shown to improve ET and IC vs the active comparators. Rescue medication use was significantly reduced by LABA/LAMA FDCs vs the evaluated comparators. LABA/LAMA FDCs were safe, with no increase in the risk of adverse events with LABA/LAMA FDCs vs the monocomponents.Conclusion: Evidence supporting the efficacy of LABA/LAMA FDCs for COPD is heterogeneous, particularly for TDI and SGRQ scores, exacerbation rates, ET, and IC. So far, indacaterol/glycopyrronium is the LABA/LAMA FDC that has the strongest evidence for superiority vs LABA, LAMA, and LABA/ICS FDCs across the evaluated outcomes. LABA/LAMA FDCs were safe; however, more data should be collected in a real-world setting to confirm their safety. Keywords: LABA, LAMA, fixed-dose combination, COPD, systematic review

Marco Contoli,1 Paolo Solidoro,2 Fabiano Di Marco,3,4 Nicola Scichilone,5 Angelo Corsico,6 Fulvio Braido,7 Pierachille Santus4,8 1Research Centre on Asthma and COPD, Department of Medical Sciences, University of Ferrara, Ferrara, Italy; 2Cardiovascular and Thoracic Department, Città della Salute, Turin, Italy; 3Department of Health Sciences, University of Milan, Milan, Italy; 4Respiratory Unit, San Paolo Hospital, Milan, Italy; 5Department of Internal Medicine, Section of Pulmonology (DIBIMIS), University of Palermo, Palermo, Italy; 6Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 7Allergy and Respiratory Diseases Clinic, DIMI, University of Genoa, IRCS AOU San Martino-IST, Genoa, Italy; 8Pulmonary Rehabilitation Unit, Fondazione Salvatore Maugeri, Scientific Institute of Milan-IRCCS, Milan, Italy Abstract: The pathophysiology of chronic obstructive pulmonary disease (COPD) includes persistent airflow limitation, altered gas exchange, and enhanced chronic inflammatory response. According to disease severity in individual patients, exacerbations and comorbidities frequently occur. The overall nocturnal and daily symptoms have a strong impact on patient quality of life and clinical outcomes. Bronchodilators, by targeting two important aspects of COPD pathophysiology, ie, bronchoconstriction and lung hyperinflation, are the mainstay of therapy for COPD. Aclidinium bromide in particular is an anticholinergic molecule, approved for maintenance bronchodilator treatment of stable COPD, that combines high antimuscarinic activity with strong kinetic selectivity for the M3 receptor subtype. Moreover, the elevated plasma clearance of aclidinium has been related to low systemic bioavailability and low incidence of anticholinergic adverse events, whereas the reduced residence time at M2 receptors provides good cardiovascular safety. Altogether, these characteristics result in a high safety and tolerability profile. This review aims to reappraise the contribution of symptoms and of the level of quality of life determinants on COPD severity and to evaluate how therapeutic strategies with aclidinium may positively impact on these specific determinants of disease severity. Keywords: COPD, quality of life, daily symptoms, LAMA, aclidinium

Marco Contoli,1 Paolo Solidoro,2 Fabiano Di Marco,3,4 Nicola Scichilone,5 Angelo Corsico,6 Fulvio Braido,7 Pierachille Santus4,8 1Research Centre on Asthma and COPD, Department of Medical Sciences, University of Ferrara, Ferrara, Italy; 2Cardiovascular and Thoracic Department, Città della Salute, Turin, Italy; 3Department of Health Sciences, University of Milan, Milan, Italy; 4Respiratory Unit, San Paolo Hospital, Milan, Italy; 5Department of Internal Medicine, Section of Pulmonology (DIBIMIS), University of Palermo, Palermo, Italy; 6Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 7Allergy and Respiratory Diseases Clinic, DIMI, University of Genoa, IRCS AOU San Martino-IST, Genoa, Italy; 8Pulmonary Rehabilitation Unit, Fondazione Salvatore Maugeri, Scientific Institute of Milan-IRCCS, Milan, Italy Abstract: The pathophysiology of chronic obstructive pulmonary disease (COPD) includes persistent airflow limitation, altered gas exchange, and enhanced chronic inflammatory response. According to disease severity in individual patients, exacerbations and comorbidities frequently occur. The overall nocturnal and daily symptoms have a strong impact on patient quality of life and clinical outcomes. Bronchodilators, by targeting two important aspects of COPD pathophysiology, ie, bronchoconstriction and lung hyperinflation, are the mainstay of therapy for COPD. Aclidinium bromide in particular is an anticholinergic molecule, approved for maintenance bronchodilator treatment of stable COPD, that combines high antimuscarinic activity with strong kinetic selectivity for the M3 receptor subtype. Moreover, the elevated plasma clearance of aclidinium has been related to low systemic bioavailability and low incidence of anticholinergic adverse events, whereas the reduced residence time at M2 receptors provides good cardiovascular safety. Altogether, these characteristics result in a high safety and tolerability profile. This review aims to reappraise the contribution of symptoms and of the level of quality of life determinants on COPD severity and to evaluate how therapeutic strategies with aclidinium may positively impact on these specific determinants of disease severity. Keywords: COPD, quality of life, daily symptoms, LAMA, aclidinium