Identification of responders to inhaled corticosteroids in a chronic obstructive pulmonary disease population using cluster analysis

David R Hinds, Rachael L DiSantostefano, Hoa V Le, Steven Pascoe, David R Hinds, Rachael L DiSantostefano, Hoa V Le, Steven Pascoe

Abstract

Objectives: To identify clusters of patients who may benefit from treatment with an inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) versus LABA alone, in terms of exacerbation reduction, and to validate previously identified clusters of patients with chronic obstructive pulmonary disease (COPD) (based on diuretic use and reversibility).

Design: Post hoc supervised cluster analysis using a modified recursive partitioning algorithm of two 1-year randomised, controlled trials of fluticasone furoate (FF)/vilanterol (VI) versus VI alone, with the primary end points of the annual rate of moderate-to-severe exacerbations.

Setting: Global.

Participants: 3255 patients with COPD (intent-to-treat populations) with a history of exacerbations in the past year.

Interventions: FF/VI 50/25 µg, 100/25 µg or 200/25 µg, or VI 25 µg; all one time per day.

Outcome measures: Mean annual COPD exacerbation rate to identify clusters of patients who benefit from adding an ICS (FF) to VI bronchodilator therapy.

Results: Three clusters were identified, including two groups that benefit from FF/VI versus VI: patients with blood eosinophils >2.4% (RR=0.68, 95% CI 0.58 to 0.79), or blood eosinophils ≤2.4% and smoking history ≤46 pack-years, experienced a reduced rate of exacerbations with FF/VI versus VI (RR=0.78, 95% CI 0.63 to 0.96), whereas those with blood eosinophils ≤2.4% and smoking history >46 pack-years were identified as non-responders (RR=1.22, 95% CI 0.94 to 1.58). Clusters of patients previously identified in the fluticasone propionate/salmeterol (SAL) versus SAL trials of similar design were not validated; all clusters of patients tended to benefit from FF/VI versus VI alone irrespective of diuretic use and reversibility.

Conclusions: In patients with COPD with a history of exacerbations, those with greater blood eosinophils or a lower smoking history may benefit more from ICS/LABA versus LABA alone as measured by a reduced rate of exacerbations. In terms of eosinophils, this finding is consistent with findings from other studies; however, the validity of the 2.4% cut-off and the impact of smoking history require further investigation.

Trial registration numbers: NCT01009463; NCT01017952; Post-results.

Keywords: Chronic obstructive pulmonary disease; Cluster analysis; Eosinophil; Inhaled corticosteroid; Long-acting β2-agonist.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Figures

Figure 1
Figure 1
Clusters maximising treatment differences in the FF/VI versus VI population (independent clustering solution, fully adjusted model). The model adjusted for investigator region, FEV1% predicted at randomisation, number of hospitalised exacerbations, number of steroid/antibiotic-treated exacerbations, COPD type—bronchitis, COPD type—emphysema, study ID, smoking status, ethnicity and reversibility subgroup. Numbers in parentheses are 95% CIs. COPD, chronic obstructive pulmonary disease; FEV1: forced expiratory volume in 1 s; FF, fluticasone furoate; RR, rate ratio; VI, vilanterol.
Figure 2
Figure 2
Treatment effect by blood eosinophil percentage. Each value represents the average treatment effect for each 20% of individuals ordered by eosinophil level, against the median of eosinophil within the group. The model adjusted for investigator region, study ID, forced expiratory volume in 1 s % predicted at randomisation and smoking status (model from the source clinical trials). p Value for linear trend of treatment effect: p=0.0081.
Figure 3
Figure 3
Validation test of clusters maximising treatment differences based on the SAL/fluticasone combination cluster analysis model (total fluticasone furoate/vilanterol trial population). The model adjusted for baseline forced expiratory volume in 1 s % predicted, reversibility status (yes/no for ≥12% improvement and ≥200 mL) and investigator region as a random effect. Numbers in parentheses are 95% CIs. RR, rate ratio.

References

    1. De Soyza A, Calverley PM. Large trials, new knowledge: the changing face of COPD management. Eur Respir J 2015;45:1692–703. 10.1183/09031936.00179714
    1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management and prevention of COPD: 2015 update to guidelines. (accessed 23 Mar 2015).
    1. Aaron SD. Management and prevention of exacerbations of COPD. BMJ 2014;349:g5237 10.1136/bmj.g5237
    1. Agarwal R, Aggarwal AN, Gupta D et al. . Inhaled corticosteroids vs placebo for preventing COPD exacerbations: a systematic review and metaregression of randomized controlled trials. Chest 2010;137:318–25. 10.1378/chest.09-1305
    1. Crim C, Calverley PM, Anderson JA et al. . Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J 2009;34:641–7. 10.1183/09031936.00193908
    1. Dransfield MT, Bourbeau J, Jones PW et al. . Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir Med 2013;1:210–23. 10.1016/S2213-2600(13)70040-7
    1. Ferguson GT, Anzueto A, Fei R et al. . Effect of fluticasone propionate/salmeterol (250/50 microg) or salmeterol (50 microg) on COPD exacerbations. Respir Med 2008;102:1099–108. 10.1016/j.rmed.2008.04.019
    1. Saha S, Brightling CE. Eosinophilic airway inflammation in COPD. Int J Chron Obstruct Pulmon Dis 2006;1:39–47.
    1. Sharafkhaneh A, Southard JG, Goldman M et al. . Effect of budesonide/formoterol pMDI on COPD exacerbations: a double-blind, randomized study. Respir Med 2012;106: 257–68. 10.1016/j.rmed.2011.07.020
    1. Szafranski WW, Cukier A, Ramirez A et al. . Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J 2003;21:74–81. 10.1183/09031936.03.00031402
    1. DeCoster DA, Jones M. Tailoring of corticosteroids in COPD management. Curr Respir Care Rep 2014;3:121–32. 10.1007/s13665-014-0084-2
    1. Weatherall M, Shirtcliffe P, Travers J et al. . Use of cluster analysis to define COPD phenotypes. Eur Respir J 2010;36:472–4. 10.1183/09031936.00035210
    1. DiSantostefano RL, Li H, Rubin DB et al. . Which patients with chronic obstructive pulmonary disease benefit from the addition of an inhaled corticosteroid to their bronchodilator? A cluster analysis. BMJ Open 2013;3:e001838 10.1136/bmjopen-2012-001838
    1. Breiman L. Classification and regression trees. New York, NY, USA: Chapman and Hall, 1983.
    1. Green RH, Pavord I. Stability of inflammatory phenotypes in asthma. Thorax 2012; 67:665–7. 10.1136/thoraxjnl-2012-201657
    1. Bafadhel M, McKenna S, Terry S et al. . Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial. Am J Respir Crit Care Med 2012;186:48–55. 10.1164/rccm.201108-1553OC
    1. Bathoorn E, Liesker JJ, Postma DS et al. . Anti-inflammatory effects of combined budesonide/formoterol in COPD exacerbations. COPD 2008;5:282–90. 10.1080/15412550802363360
    1. Brightling CE, Monteiro W, Ward R et al. . Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2000;356:1480–5. 10.1016/S0140-6736(00)02872-5
    1. Brightling CE, McKenna S, Hargadon B et al. . Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease. Thorax 2005;60: 193–8. 10.1136/thx.2004.032516
    1. Eltboli O, Brightling CE. Eosinophils as diagnostic tools in chronic lung disease. Expert Rev Respir Med 2013;7:33–42. 10.1586/ers.12.81
    1. Kitaguchi Y, Komatsu Y, Fujimoto K et al. . Sputum eosinophilia can predict responsiveness to inhaled corticosteroid treatment in patients with overlap syndrome of COPD and asthma. Int J Chron Obstruct Pulmon Dis 2012;7:283–9. 10.2147/COPD.S30651
    1. Leigh R, Pizzichini MM, Morris MM et al. . Stable COPD: predicting benefit from high-dose inhaled corticosteroid treatment. Eur Respir J 2006;27:964–71.
    1. Pascoe S, Locantore N, Dransfield MT et al. . Blood eosinophil counts, exacerbations and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials. Lancet Respir Med 2015;3:435–42. 10.1016/S2213-2600(15)00106-X
    1. Cowan DC, Taylor DR, Peterson LE et al. . Biomarker-based asthma phenotypes of corticosteroid response. J Allergy Clin Immunol 2015;135:877–83.e1. 10.1016/j.jaci.2014.10.026
    1. Fleming L, Wilson N, Regamey N et al. . Use of sputum eosinophil counts to guide management in children with severe asthma. Thorax 2012;67:193–8. 10.1136/thx.2010.156836
    1. Green RH, Brightling CE, McKenna S et al. . Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002;360:1715–21. 10.1016/S0140-6736(02)11679-5
    1. Eltboli O, Mistry V, Barker B et al. . Relationship between blood and bronchial submucosal eosinophilia and reticular basement membrane thickening in chronic obstructive pulmonary disease. Respirology 2015;20:667–70. 10.1111/resp.12475
    1. Hillas G, Loukides S, Kostikas K et al. . Biomarkers obtained by non-invasive methods in patients with COPD: where do we stand, what do we expect? Curr Med Chem 2009;16:2824–38. 10.2174/092986709788803178
    1. Gibson PG. Why inflammatory phenotyping is necessary for successful drug evaluation in asthma and COPD. Eur Respir J 2013;42:891–2. 10.1183/09031936.00038713
    1. Singh D, Kolsum U, Brightling CE et al. . Eosinophilic inflammation in COPD: prevalence and clinical characteristics. Eur Respir J 2014;44:1697–700. 10.1183/09031936.00162414

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