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      Long-Term Triple Therapy De-escalation to Indacaterol/Glycopyrronium in Patients with Chronic Obstructive Pulmonary Disease (SUNSET): A Randomized, Double-Blind, Triple-Dummy Clinical Trial

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          Abstract

          There are no studies on withdrawal of inhaled corticosteroids in patients on long-term triple therapy in the absence of frequent exacerbations.

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          Susceptibility to exacerbation in chronic obstructive pulmonary disease.

          John R. Hurst, Jørgen Vestbo, Antonio Anzueto … (2010)
          Although we know that exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding of their frequency, determinants, and effects is incomplete. In a large observational cohort, we tested the hypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of disease severity. We analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Exacerbations were defined as events that led a care provider to prescribe antibiotics or corticosteroids (or both) or that led to hospitalization (severe exacerbations). Exacerbation frequency was observed over a period of 3 years. Exacerbations became more frequent (and more severe) as the severity of COPD increased; exacerbation rates in the first year of follow-up were 0.85 per person for patients with stage 2 COPD (with stage defined in accordance with Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages), 1.34 for patients with stage 3, and 2.00 for patients with stage 4. Overall, 22% of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations (two or more in the first year of follow-up). The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of the patient's recall of previous treated events. In addition to its association with more severe disease and prior exacerbations, the phenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated white-cell count. Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype. This has implications for the targeting of exacerbation-prevention strategies across the spectrum of disease severity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT00292552.)
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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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              Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial.

              P S Burge, P. Calverley, P W Jones … (2000)
              To determine the effect of long term inhaled corticosteroids on lung function, exacerbations, and health status in patients with moderate to severe chronic obstructive pulmonary disease. Double blind, placebo controlled study. Eighteen UK hospitals. 751 men and women aged between 40 and 75 years with mean forced expiratory volume in one second (FEV(1)) 50% of predicted normal. Inhaled fluticasone propionate 500 microgram twice daily from a metered dose inhaler or identical placebo. Efficacy measures: rate of decline in FEV(1) after the bronchodilator and in health status, frequency of exacerbations, respiratory withdrawals. Safety measures: morning serum cortisol concentration, incidence of adverse events. There was no significant difference in the annual rate of decline in FEV(1 )(P=0.16). Mean FEV(1) after bronchodilator remained significantly higher throughout the study with fluticasone propionate compared with placebo (P<0.001). Median exacerbation rate was reduced by 25% from 1.32 a year on placebo to 0.99 a year on with fluticasone propionate (P=0.026). Health status deteriorated by 3.2 units a year on placebo and 2.0 units a year on fluticasone propionate (P=0.0043). Withdrawals because of respiratory disease not related to malignancy were higher in the placebo group (25% v 19%, P=0.034). Fluticasone propionate 500 microgram twice daily did not affect the rate of decline in FEV(1) but did produce a small increase in FEV(1). Patients on fluticasone propionate had fewer exacerbations and a slower decline in health status. These improvements in clinical outcomes support the use of this treatment in patients with moderate to severe chronic obstructive pulmonary disease.
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                Author and article information

                Journal
                Title: American Journal of Respiratory and Critical Care Medicine
                Abbreviated Title: Am J Respir Crit Care Med
                Publisher: American Thoracic Society
                ISSN (Print): 1073-449X
                ISSN (Electronic): 1535-4970
                Publication date Created: August 2018
                Publication date (Print): August 2018
                Volume: 198
                Issue: 3
                Pages: 329-339
                Affiliations
                [1 ]Asthma and Airway Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
                [2 ]UCL Respiratory, University College London, London, United Kingdom
                [3 ]Department of Pulmonology, University of Medicine and Pharmacy, Timisoara, Romania
                [4 ]Novartis Pharma AG, Basel, Switzerland
                [5 ]Novartis Pharmaceuticals Corporation, East Hanover, New Jersey
                [6 ]Novartis Ireland Limited, Dublin, Ireland; and
                [7 ]Respiratory Clinical Science Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
                Article
                DOI: 10.1164/rccm.201803-0405OC
                PubMed ID: 29779416
                SO-VID: 9524ac71-ea34-44d7-b46c-1dd12612d1b0
                Copyright © © 2018
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