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      New combinations in the treatment of COPD: rationale for aclidinium–formoterol

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          Abstract

          The current guidelines on chronic obstructive pulmonary disease (COPD) recommend the prominent use of bronchodilators, including long-acting β 2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs), while inhaled corticosteroids are recommended only in patients with severe disease or frequent exacerbations. LABA–LAMA combinations are indicated when single bronchodilators are insufficient to control COPD. A number of LABA–LAMA combinations are available, based on twice-daily or once-daily administration according to the 12- or 24-hour duration of action, respectively. The aclidinium–formoterol combination is based on the new LAMA aclidinium bromide, which has a high selectivity for M 3 muscarinic receptors and a fast onset of action, and the well-known LABA formoterol. Both drugs require twice-daily administration. The fixed-dose combination of aclidinium 400 μg/formoterol 12 μg has shown in randomized controlled trials fast and sustained bronchodilation that was greater than either monotherapy and provided clinically significant improvements in dyspnea and health status compared with placebo, also reducing the use of rescue medications. The overall incidence of adverse events was low and comparable to placebo. These data define the aclidinium–formoterol fixed-dose combination as a new treatment option for patients with COPD. The need for twice-daily administration could be an apparent disadvantage compared to the available once-daily LABA–LAMA combinations, but the immediately perceived benefit in reducing dyspnea due to the fast onset of action, as well as reported correct patient use and satisfaction with the Genuair inhaler might prove useful in favoring adherence.

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          Most cited references 35

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          Adherence to inhaled therapies, health outcomes and costs in patients with asthma and COPD.

          Suboptimal adherence to pharmacological treatment of asthma and chronic obstructive pulmonary disease (COPD) has adverse effects on disease control and treatment costs. The reasons behind non-adherence revolve around patient knowledge/education, inhaler device convenience and satisfaction, age, adverse effects and medication costs. Age is of particular concern given the increasing prevalence of asthma in the young and increased rates of non-adherence in adolescents compared with children and adults. The correlation between adherence to inhaled pharmacological therapies for asthma and COPD and clinical efficacy is positive, with improved symptom control and lung function shown in most studies of adults, adolescents and children. Satisfaction with inhaler devices is also positively correlated with improved adherence and clinical outcomes, and reduced costs. Reductions in healthcare utilisation are consistently observed with good adherence; however, costs associated with general healthcare and lost productivity tend to be offset only in more adherent patients with severe disease, versus those with milder forms of asthma or COPD. Non-adherence is associated with higher healthcare utilisation and costs, and reductions in health-related quality of life, and remains problematic on an individual, societal and economic level. Further development of measures to improve adherence is needed to fully address these issues. Copyright © 2013. Published by Elsevier Ltd.
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            Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study

            Background Aclidinium/formoterol is a twice-daily (BID) fixed-dose combination (FDC) in development for chronic obstructive pulmonary disease (COPD). The efficacy and safety of aclidinium/formoterol versus monotherapy and placebo in patients with COPD was assessed. Methods In this 24-week double-blind, parallel-group, active- and placebo-controlled, multicentre Phase III study, patients (≥40 years, post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity <70% and FEV1 ≥30% but <80% predicted normal) were randomised 2:2:2:2:1 to aclidinium/formoterol 400/12 μg (n = 385) or 400/6 μg (n = 381), aclidinium 400 μg (n = 385), formoterol 12 μg (n = 384) or placebo (n = 194) BID via Genuair®/Pressair®a. Results At Week 24, aclidinium/formoterol 400/12 μg and 400/6 μg lead to significant improvements from baseline in 1-hour post-dose FEV1 versus aclidinium (125 mL [95% CI: 90, 160; p < 0 · 001] and 69 mL [95% CI: 34, 105; p < 0.001], respectively) and trough FEV1 versus formoterol (85 mL [95% CI: 51, 119; p < 0.001] and 53 mL [95% CI: 19, 87; p < 0.01], respectively; co-primary endpoints). Additionally, aclidinium/formoterol 400/12 μg and 400/6 μg provided significant improvements in Transition Dyspnoea Index (TDI) focal score versus placebo (1.29 units [95% CI: 0.73, 1.86; p < 0.001] and 1.16 units [95% CI: 0.59, 1.73; p < 0.001], respectively; secondary endpoint). All treatments were well tolerated, with safety profiles of the FDCs similar to those of placebo and monotherapy. Conclusions Both aclidinium/formoterol BID doses significantly improved bronchodilation versus monotherapy, and dyspnoea versus placebo, with no increase in safety risk. Aclidinium/formoterol may be an effective treatment for patients with COPD. Trial registration ClinicalTrials.gov: NCT01462942. Electronic supplementary material The online version of this article (doi:10.1186/1471-2466-14-178) contains supplementary material, which is available to authorized users.
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              β2-agonist therapy in lung disease.

              β2-Agonists are effective bronchodilators due primarily to their ability to relax airway smooth muscle (ASM). They exert their effects via their binding to the active site of β2-adrenoceptors on ASM, which triggers a signaling cascade that results in a number of events, all of which contribute to relaxation of ASM. There are some differences between β2-agonists. Traditional inhaled short-acting β2-agonists albuterol, fenoterol, and terbutaline provide rapid as-needed symptom relief and short-term prophylactic protection against bronchoconstriction induced by exercise or other stimuli. The twice-daily β2-agonists formoterol and salmeterol represent important advances. Their effective bronchodilating properties and long-term improvement in lung function offer considerable clinical benefits to patients. More recently, a newer β2-agonist (indacaterol) with a longer pharmacodynamic half-life has been discovered, with the hopes of achieving once-daily dosing. In general, β2-agonists have an acceptable safety profile, although there is still controversy as to whether long-acting β2-agonists may increase the risk of asthma mortality. In any case, they can induce adverse effects, such as increased heart rate, palpitations, transient decrease in PaO2, and tremor. Desensitization of β2-adrenoceptors that occurs during the first few days of regular use of β2-agonist treatment may account for the commonly observed resolution of the majority of these adverse events after the first few doses. Nevertheless, it can also induce tolerance to bronchoprotective effects of β2-agonists and has the potential to reduce bronchodilator sensitivity to them. Some novel once-daily β2-agonists (olodaterol, vilanterol, abediterol) are under development, mainly in combination with an inhaled corticosteroid or a long-acting antimuscarinic agent.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2016
                15 February 2016
                : 12
                : 209-215
                Affiliations
                [1 ]Allergy/Pulmonary Rehabilitation, Istituti Clinici di Perfezionamento Hospital, Milan, Italy
                [2 ]Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy
                Author notes
                Correspondence: Cristoforo Incorvaia, Allergy/Pulmonary Rehabilitation, Istituti Clinici di Perfezionamento Hospital, 1 Via Bignami, Milan 20100, Italy, Tel +39 02 5799 3289, Fax +39 02 5799 3579, Email cristoforo.incorvaia@ 123456gmail.com
                Article
                tcrm-12-209
                10.2147/TCRM.S82034
                4760652
                26929634
                © 2016 Incorvaia et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Review

                Medicine

                inhalation device, safety, efficacy, combination, lama, laba, copd, bronchodilators

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