Exacerbation heterogeneity in COPD: subgroup analyses from the FLAME study

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Exacerbation heterogeneity in COPD: subgroup analyses from the FLAME study

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Author(s): Claus F Vogelmeier ¹ , Kenneth R Chapman ² , Marc Miravitlles ³ , Nicolas Roche ⁴ , Jørgen Vestbo ⁵ , Chau Thach ⁶ , Donald Banerji ⁶ , Robert Fogel ⁶ , Francesco Patalano ⁷ , Petter Olsson ⁸ , Konstantinos Kostikas ⁷ , Jadwiga A Wedzicha ⁹

Publication date (Electronic): 10 April 2018

Journal: International Journal of Chronic Obstructive Pulmonary Disease

Publisher: Dove Medical Press

Keywords: indacaterol/glycopyrronium, salmeterol/fluticasone, LABA/LAMA, LABA/ICS

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Abstract

Background

The FLAME study compared once-daily indacaterol/glycopyrronium (IND/GLY) 110/50 μg with twice-daily salmeterol/fluticasone (SFC) 50/500 μg in symptomatic patients with moderate to very severe COPD and a history of exacerbations in the previous year.

Methods

This prespecified and post hoc subgroup analysis evaluated treatment efficacy on 1) moderate/severe exacerbations according to prior exacerbation history and treatment, and 2) types of exacerbations according to health care resource utilization (HCRU) during 1-year follow-up.

Results

IND/GLY reduced the rate of moderate/severe exacerbations versus SFC in patients with a history of 1 exacerbation (rate ratio [RR]: 0.83, 95% CI: 0.75–0.93), ≥2 exacerbations (RR: 0.85, 95% CI: 0.70–1.03) and ≥2 exacerbations or ≥1 hospitalization in the previous year (RR: 0.86, 95% CI: 0.74–1.00). Prolonged time-to-first exacerbation was observed in all the groups according to exacerbation history. Moderate/severe exacerbations decreased with IND/GLY versus SFC, independent of previous treatment. IND/GLY significantly reduced rates of moderate/severe exacerbations treated with antibiotics (RR: 0.79, 95% CI: 0.67–0.93) and systemic corticosteroids and antibiotics (RR: 0.80, 95% CI: 0.70–0.91); rates of exacerbations treated with systemic corticosteroids alone were comparable (RR: 0.99, 95% CI: 0.80–1.22).

Conclusion

Overall, IND/GLY demonstrated consistent beneficial effects versus SFC on moderate/severe exacerbations, independent of prior exacerbation history or treatment. The efficacy of IND/GLY on exacerbation prevention was superior to SFC for exacerbations treated with antibiotics with/without systemic corticosteroids and was similar for exacerbations treated with systemic corticosteroids alone.

Most cited references 16

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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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Global and regional estimates of COPD prevalence: Systematic review and meta–analysis

Davies Adeloye, Stephen Chua, Chinwei Lee … (2015)

Background The burden of chronic obstructive pulmonary disease (COPD) across many world regions is high. We aim to estimate COPD prevalence and number of disease cases for the years 1990 and 2010 across world regions based on the best available evidence in publicly accessible scientific databases. Methods We conducted a systematic search of Medline, EMBASE and Global Health for original, population–based studies providing spirometry–based prevalence rates of COPD across the world from January 1990 to December 2014. Random effects meta–analysis was conducted on extracted crude prevalence rates of COPD, with overall summaries of the meta–estimates (and confidence intervals) reported separately for World Health Organization (WHO) regions, the World Bank's income categories and settings (urban and rural). We developed a meta–regression epidemiological model that we used to estimate the prevalence of COPD in people aged 30 years or more. Findings Our search returned 37 472 publications. A total of 123 studies based on a spirometry–defined prevalence were retained for the review. From the meta–regression epidemiological model, we estimated about 227.3 million COPD cases in the year 1990 among people aged 30 years or more, corresponding to a global prevalence of 10.7% (95% confidence interval (CI) 7.3%–14.0%) in this age group. The number of COPD cases increased to 384 million in 2010, with a global prevalence of 11.7% (8.4%–15.0%). This increase of 68.9% was mainly driven by global demographic changes. Across WHO regions, the highest prevalence was estimated in the Americas (13.3% in 1990 and 15.2% in 2010), and the lowest in South East Asia (7.9% in 1990 and 9.7% in 2010). The percentage increase in COPD cases between 1990 and 2010 was the highest in the Eastern Mediterranean region (118.7%), followed by the African region (102.1%), while the European region recorded the lowest increase (22.5%). In 1990, we estimated about 120.9 million COPD cases among urban dwellers (prevalence of 13.2%) and 106.3 million cases among rural dwellers (prevalence of 8.8%). In 2010, there were more than 230 million COPD cases among urban dwellers (prevalence of 13.6%) and 153.7 million among rural dwellers (prevalence of 9.7%). The overall prevalence in men aged 30 years or more was 14.3% (95% CI 13.3%–15.3%) compared to 7.6% (95% CI 7.0%–8.2%) in women. Conclusions Our findings suggest a high and growing prevalence of COPD, both globally and regionally. There is a paucity of studies in Africa, South East Asia and the Eastern Mediterranean region. There is a need for governments, policy makers and international organizations to consider strengthening collaborations to address COPD globally.

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Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study.

Peter D’Andrea, Hungta Chen, C Vogelmeier … (2013)

QVA149 is an inhaled fixed-dose combination therapy under development for the treatment of chronic obstructive pulmonary disease (COPD). It combines indacaterol (a longacting β2-agonist) with glycopyrronium (a longacting muscarinic antagonist) as a dual bronchodilator. We aimed to compare the efficacy, safety, and tolerability of QVA149 versus salmeterol-fluticasone (SFC) over 26 weeks in patients with moderate-to-severe COPD. In this multicentre double-blind, double-dummy, parallel-group study, 523 patients (age 40 years or older, Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages II-III, without exacerbations in the previous year) were randomly assigned (1:1; via automated, interactive response technology and stratified for smoking status) to once-daily QVA149 110/50 μg or twice-daily SFC 50/500 μg for 26 weeks. Efficacy was assessed in the full analysis set (randomised patients who received at least one dose of study drug); safety was assessed in all patients who received at least one dose of study drug. The primary endpoint was to demonstrate the superiority of QVA149 compared with SFC for the standardised area under the curve from 0 to 12 h post dose for forced expiratory volume in 1 second (FEV1 AUC0-12h) after 26 weeks of treatment. This trial was registered at ClinicalTrial.gov, NCT01315249. Between March 25, 2011, and March 12, 2012, 259 patients were randomly assigned to receive QVA149 and 264 to receive SFC. At week 26, FEV1 AUC0-12h was significantly higher with QVA149 than with SFC (treatment difference 0·138 L; 95% CI 0·100-0·176; p<0·0001). Overall incidence of adverse events (including COPD exacerbations) was 55·4% (143 of 258) for the QVA149 group and 60·2% (159 of 264) for the SFC group. Incidence of serious adverse events was similar between treatment groups (QVA149, 13 of 258 [5·0%]; SFC 14 of 264 [5·3%]); COPD worsening was the most frequent serious adverse event (one of 13 [0·4%] and three of 14 [1·1%], respectively). Once-daily QVA149 provides significant, sustained, and clinically meaningful improvements in lung function versus twice-daily SFC, with significant symptomatic benefit. These results indicate the potential of dual bronchodilation as a treatment option for non-exacerbating symptomatic COPD patients. Novartis Pharma AG. Copyright © 2013 Elsevier Ltd. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Int J Chron Obstruct Pulmon Dis

Journal ID (iso-abbrev): Int J Chron Obstruct Pulmon Dis

Journal ID (publisher-id): International Journal of COPD

Title: International Journal of Chronic Obstructive Pulmonary Disease

Publisher: Dove Medical Press

ISSN (Print): 1176-9106

ISSN (Electronic): 1178-2005

Publication date Collection: 2018

Publication date (Electronic): 10 April 2018

Volume: 13

Pages: 1125-1134

Affiliations

[1 ]Member of the German Center for Lung Research (DZL), Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Marburg, Germany

[2 ]Asthma and Airway Centre, University Health Network and University of Toronto, Toronto, ON, Canada

[3 ]Pneumology Department, Hospital Universitari Vall d’Hebron, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain

[4 ]Service de Pneumologie AP-HP, Cochin Hospital, University Paris Descartes (EA2511), Paris, France

[5 ]Institute of Infection, Immunity and Respiratory Medicine, The University of Manchester and Manchester University NHS Foundation Trust, Manchester, UK

[6 ]Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

[7 ]Novartis Pharma AG, Basel, Switzerland

[8 ]Novartis Sverige AB, Täby, Sweden

[9 ]National Heart and Lung Institute, Imperial College London, London, UK

Author notes

Correspondence: Claus F Vogelmeier, Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Marburg 35043, Germany, Tel +49 6421 586 6451, Fax +49 6421 586 8987, Email claus.vogelmeier@ 123456med.uni-marburg.de

Article

Publisher ID: copd-13-1125

DOI: 10.2147/COPD.S160011

PMC ID: 5901128

SO-VID: ad7b93b2-d329-4886-83cb-f726ce17b02b

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Exacerbation heterogeneity in COPD: subgroup analyses from the FLAME study

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Abstract

Background

Methods

Results

Conclusion

Most cited references 16

Susceptibility to exacerbation in chronic obstructive pulmonary disease.

Global and regional estimates of COPD prevalence: Systematic review and meta–analysis

Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study.

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