The severity of airways obstruction as a determinant of treatment response in COPD

Peter MA Calverley¹, Romain A Pauwels^2*, Paul W Jones³, Julie A Anderson⁴, Jørgen Vestbo⁵

¹Clinical Research Centre, University Hospital Aintree, Liverpool, UK; ²Department of Pulmonary Disease, University Hospital, Ghent, Belgium; ³Department of Physiological Medicine, St George’s Hospital, London, UK; ⁴Biomedical Data Sciences, GlaxoSmithKline Research and Development, Greenford, UK; ⁵North West Lung Centre, Wythenshawe Hospital, Manchester, UK

*Sadly, Professor Pauwels died during the preparation of this manuscript.

Abstract: Guidelines recommend that patients with COPD are stratified arbitrarily by baseline severity (FEV₁) to decide when to initiate combination treatment with a long-acting β₂-agonist and an inhaled corticosteroid. Assessment of baseline FEV₁ as a continuous variable may provide a more reliable prediction of treatment effects. Patients from a 1-year, parallel-group, randomized controlled trial comparing 50 µg salmeterol (Sal), 500 µg fluticasone propionate (FP), the combination (Sal/FP) and placebo, (bid), were categorized post hoc into FEV₁ <50% and FEV₁ ≥50% predicted subgroups (n=949/513 respectively). Treatment effects on clinical outcomes – lung function, exacerbations, health status, diary card symptoms, and adverse events – were investigated. Treatment responses based on a pre-specified analysis explored treatment differences by severity as a continuous variable. Lung function improved with active treatment irrespective of FEV₁; Sal/FP had greatest effect. This improvement appeared additive in milder disease; synergistic in severe disease. Active therapy significantly reduced exacerbation rate in patients with FEV₁ <50% predicted, not in milder disease. Health status and breathlessness improved with Sal/FP irrespective of baseline FEV₁; adverse events were similar across subgroups. The spirometric response to Sal/FP varied with baseline FEV₁, and clinical benefits were not restricted to patients with severe disease. These data have implications for COPD management decisions, suggesting that arbitrary stratifications of baseline severity are not necessarily indicative of treatment efficacy and that the benefits of assessing baseline severity as a continuous variable should be assessed in future trials.

Keywords: chronic obstructive pulmonary disease, FEV₁, inhaled corticosteroid, long-acting β₂-agonist, subgroups