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      Long-term safety and efficacy of formoterol fumarate inhalation solution in patients with moderate-to-severe COPD

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          Abstract

          Background

          Formoterol fumarate inhalation solution (FFIS; Perforomist ®) is a long-acting β 2-agonist (LABA) marketed in the US as a nebulized COPD maintenance treatment. Because long-term LABA use was associated with a potential increased risk of exacerbation or death in asthma patients, the US Food and Drug Administration (FDA) requested a postmarketing commitment study to evaluate long-term safety in COPD patients.

          Methods

          This was a multicenter, randomized, double-blind, placebo-controlled, noninferiority study. Patients (N=1,071; mean age, 62.6 years; 48.5% male; 89.7% white) with moderate-to-severe COPD on stable COPD therapy received FFIS (20 µg; n=541) or placebo (n=530) twice daily. The primary end point was the combined incidence of respiratory death, first COPD-related ER visit, or first COPD exacerbation-related hospitalization during 1 year post randomization. Noninferiority to placebo was concluded if the two-sided 90% CI of the HR of FFIS to placebo was <1.5. Secondary end points included spirometry.

          Results

          The planned 1-year treatment period was completed by 520 patients; 551 discontinued prematurely (FFIS: 45.7%; placebo: 57.4%). The median treatment duration was approximately 10 and 7 months for FFIS and placebo, respectively. Among 1,071 randomized patients, 121 had ≥1 primary event (FFIS: 11.8%; placebo: 10.8%). The estimated HR of a primary event with FFIS vs placebo was 0.965 (90% CI: 0.711, 1.308), demonstrating that FFIS was noninferior to placebo. No respiratory deaths were observed in the FFIS group. Adverse events were similar for FFIS vs placebo (patients with ≥1 treatment-emergent adverse events: 374 [69.1%] vs 369 [69.6%], respectively). Compared with placebo, FFIS demonstrated statistically greater improvements from baseline in trough FEV 1, FVC, percent predicted FEV 1, and patient-reported outcomes (Transition Dyspnea Index).

          Conclusions

          Nebulized FFIS was noninferior to placebo with respect to safety in patients with moderate-to-severe COPD. Additionally, fewer treatment withdrawals and larger lung function improvements were observed with FFIS compared with placebo when added to other maintenance COPD therapies.

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          Most cited references 15

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          The measurement of dyspnea. Contents, interobserver agreement, and physiologic correlates of two new clinical indexes.

          To improve the clinical measurement of dyspnea, we developed a baseline dyspnea index that rated the severity of dyspnea at a single state and a transition dyspnea index that denoted changes from that baseline. The scores in both indexes depend on ratings for three different categories: functional impairment; magnitude of task, and magnitude of effort. At the baseline state, dyspnea was rated in five grades from 0 (severe) to 4 (unimpaired) for each category. The ratings for each of the three categories were added to form a baseline focal score (range, 0 to 12). At the transition period, changes in dyspnea were rated by seven grades, ranging from -3 (major deterioration), to +3 (major improvement). The ratings for each of the three categories were added to form a transition focal score (range, -9 to +9). In 38 patients tested with respiratory disease, interobserver agreement was highly satisfactory for both indexes. The baseline focal score had the highest correlation (r = 0.60; P less than 0.001) with the 12-minute walking distance (12 MW), while significant, but lower, correlations existed for lung function. For the transition focal score, there was a significant correlation only with the 12 MW (r = 0.33; p = 0.04). These results indicate that dyspnea can receive a direct clinical rating that provides important information not disclosed by customary physiologic tests.
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            Chronic obstructive pulmonary disease as a risk factor for cardiovascular morbidity and mortality.

            Chronic obstructive pulmonary disease and other disorders, associated with reduced lung function, are strong risk factors for cardiovascular events, independent of smoking. Overall, when the lowest quintile of lung function, as measured by FEV1 is compared with the highest quintile, the risk of cardiovascular mortality increases by approximately 75% in both men and women. Having symptoms of chronic bronchitis alone increases the risk of coronary deaths by 50%. Reduced ratio of FEV1 to FVC by itself is a modest independent risk factor for coronary events, increasing the risk by 30%. However, if patients have ventricular arrhythmias, the risk of coronary events is increased twofold, suggesting that the cardiotoxic effects of obstructive airways disease are amplified in those who have underlying cardiac rhythm disturbances. In general, for every 10% decrease in FEV1, all-cause mortality increases by 14%, cardiovascular mortality increases by 28%, and nonfatal coronary event increases by almost 20%. These data indicate that chronic obstructive pulmonary disease is a powerful, independent risk factor for cardiovascular morbidity and mortality.
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              The FDA and safe use of long-acting beta-agonists in the treatment of asthma.

               B Chowdhury,  G. PAN (2010)
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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                1176-9106
                1178-2005
                2019
                27 December 2018
                : 14
                : 117-127
                Affiliations
                [1 ]Asthma Clinical Research Center, Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA
                [2 ]Pulmonary, Critical Care, and Sleep Medicine, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA
                [3 ]Global Medical Affairs, Mylan Inc., Canonsburg, PA, USA
                [4 ]Mylan Global Respiratory Group, Mylan Pharma UK Ltd., Sandwich, Kent, UK, dik.ng@ 123456mylan.co.uk
                Author notes
                Correspondence: Dik Ng, Mylan Pharma UK Ltd., Discovery Park, Sandwich, Kent CT13 9FF, UK, Tel +44 1304 62 6255, Email dik.ng@ 123456mylan.co.uk
                Article
                copd-14-117
                10.2147/COPD.S173595
                6311322
                © 2019 Hanania 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
                Original Research

                Respiratory medicine

                nebulization, copd, long-acting beta2-agonists, bronchodilators, safety

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