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Management of severe COPD exacerbations: focus on beclomethasone dipropionate/formoterol/glycopyrronium bromide.

ABSTRACT: The major determinant of the decline in lung function, quality of life, and the increased mortality risk in patients with COPD is represented by severe acute exacerbations of the disease, that is, those requiring patients' hospitalization, constituting a substantial social and health care burden in terms of morbidity and medical resource utilization. Different long-term therapeutic strategies have been proposed so far in order to prevent and/or reduce the clinical and social impact of these events, the majority of which were extrapolated from trials initially focused on the effect of long-acting muscarinic antagonist and subsequently on the efficacy of long-acting ?2-agonists in combination or not with inhaled corticosteroids. The option to employ all three classes of molecules combined, despite the limited amount of evidence in our possession, represents a choice currently proposed by international guidelines; however, current recommendations are often based mainly on observational studies or on the results of secondary outcomes in randomized controlled trials. The present narrative review evaluates the available trials that investigated the efficacy of inhaled therapy to prevent COPD exacerbations and especially severe ones, with a particular focus on beclomethasone dipropionate/formoterol/glycopyrronium bromide fixed dose combination, which is the first treatment that comprises all the three drug classes, specifically tested for the prevention of moderate and severe COPD exacerbations.

SUBMITTER: Mantero M

PROVIDER: S-EPMC6072677 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Management of severe COPD exacerbations: focus on beclomethasone dipropionate/formoterol/glycopyrronium bromide.

Mantero Marco M Radovanovic Dejan D Santus Pierachille P Blasi Francesco F

International journal of chronic obstructive pulmonary disease 20180730

The major determinant of the decline in lung function, quality of life, and the increased mortality risk in patients with COPD is represented by severe acute exacerbations of the disease, that is, those requiring patients' hospitalization, constituting a substantial social and health care burden in terms of morbidity and medical resource utilization. Different long-term therapeutic strategies have been proposed so far in order to prevent and/or reduce the clinical and social impact of these even ...[more]

PMID: 30104872

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Project description:BackgroundGlycopyrronium bromide (NVA237) is an inhaled long-acting muscarinic antagonist in development for treatment of COPD. This study compared the efficacy and safety of once-daily (OD) and twice-daily (BID) glycopyrronium bromide regimens, using a novel model-based approach, in patients with moderate-to-severe COPD.MethodsDouble-blind, randomized, dose-finding trial with an eight-treatment, two-period, balanced incomplete block design. Patients (smoking history ≥10 pack-years, post-bronchodilator FEV1 ≥30% and <80% predicted, FEV1/FVC <0.7) were randomized to one of 16 independent sequences for 28 days. Primary endpoint: mean trough FEV1 at Day 28.Results385 patients (mean age 61.2 years; mean post-bronchodilator FEV1 53% predicted) were randomized; 88.6% completed. All OD and BID dosing regimens produced dose-dependent bronchodilation; at Day 28, increases in mean trough FEV1 versus placebo were statistically significant for all regimens, ranging from 51 mL (glycopyrronium bromide 12.5 μg OD) to 160 mL (glycopyrronium bromide 50 μg BID). Pharmacodynamic steady-state was reached by Day 7. There was a small separation (≤37 mL) between BID and OD dose-response curves for mean trough FEV1 at steady-state in favour of BID dosing. Over 24 hours, separation between OD and BID regimens was even smaller (FEV1 AUC0-24h maximum difference for equivalent daily dose regimens: 8 mL). Dose-response results for FEV1 at 12 hours, FEV1 AUC0-12h and FEV1 AUC0-4h at steady-state showed OD regimens provided greater improvement over placebo than BID regimens for total daily doses of 25 μg, 50 μg and 100 μg, while the reverse was true for OD versus BID regimens from 12-24 hours. The 12.5 μg BID dose produced a marginally higher improvement in trough FEV1 versus placebo than 50 μg OD, however, the response at 12 hours over placebo was suboptimal (74 mL). Glycopyrronium bromide was safe and well tolerated at all doses.ConclusionsGlycopyrronium bromide 50 μg OD provides significant bronchodilation over a 24 hour period, and in terms of FEV1 AUC0-24h is not significantly different than the same total daily dose administered BID. Importantly, OD dosing may confer better patient adherence. The results are consistent with previous glycopyrronium bromide studies and support once-daily dosing of glycopyrronium bromide 50 μg in patients with moderate-to-severe COPD.Trial registrationClinicalTrials.gov: NCT01119950.

Project description:Aclidinium-formoterol 400/12 µg is a long-acting muscarinic antagonist (LAMA) and a long-acting ?2-agonist in a fixed-dose combination used in the management of patients with COPD. This study aimed to assess the cost-effectiveness of aclidinium-formoterol 400/12 µg against the long-acting muscarinic antagonist aclidinium bromide 400 µg.A five-health-state Markov transition model with monthly cycles was developed using MS Excel to simulate patients with moderate-to-severe COPD and their initial lung-function improvement following treatment with aclidinium-formoterol 400/12 µg or aclidinium 400 µg. Health states were based on severity levels defined by Global Initiative for Chronic Obstructive Lung Disease 2010 criteria. The analysis was a head-to-head comparison without step-up therapy, from the NHS Scotland perspective, over a 5-year time horizon. Clinical data on initial lung-function improvement were provided by a pooled analysis of the ACLIFORM and AUGMENT trials. Management, event costs, and utilities were health state-specific. Costs and effects were discounted at an annual rate of 3.5%. The outcome of the analysis was expressed as cost (UK£) per quality-adjusted life-year (QALY) gained. The analysis included one way and probabilistic sensitivity analyses to investigate the impact of parameter uncertainty on model outputs.Aclidinium-formoterol 400/12 µg provided marginally higher costs (£41) and more QALYs (0.014), resulting in an incremental cost-effectiveness ratio of £2,976/QALY. Sensitivity analyses indicated that results were robust to key parameter variations, and the main drivers were: mean baseline forced expiratory volume in 1 second (FEV1), risk of exacerbation, FEV1 improvement from aclidinium-formoterol 400/12 µg, and lung-function decline. The probability of aclidinium-formoterol 400/12 µg being cost-effective (using a willingness-to-pay threshold of £20,000/QALY) versus aclidinium 400 µg was 79%.In Scotland, aclidinium-formoterol 400/12 µg can be considered a cost-effective treatment option compared to aclidinium 400 µg alone in patients with moderate-to-severe COPD.

Dataset Information

Management of severe COPD exacerbations: focus on beclomethasone dipropionate/formoterol/glycopyrronium bromide.

Publications

Management of severe COPD exacerbations: focus on beclomethasone dipropionate/formoterol/glycopyrronium bromide.

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