Effect of Indacaterol on Dynamic Lung Hyperinflation and Breathlessness in Hyperinflated Patients with COPD

Abstract

Indacaterol is a novel, inhaled once-daily ultra long-acting β2-agonist for the treatment of COPD. This randomised, double-blind, placebo-controlled, two-period crossover study evaluated the effect of two-week treatment with indacaterol 300 μg on peak and isotime exercise inspiratory capacity (IC) in patients with COPD. Patients (40-80 years) with post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 70%, percent predicted FEV1 ≥ 40% and ≤ 80%, smoking history ≥ 20 pack-years and functional residual capacity > 120% of predicted normal were randomised to receive indacaterol 300 μg or placebo once-daily via a single-dose dry powder inhaler. Following 14 days of treatment, IC at peak and isotime during constant-load (80% of maximum workload) cycle ergometry was analysed using linear mixed-effects models. Safety and tolerability were also monitored. Twenty-seven patients (67% male; mean age, 61.3 years) were randomised; 24 completed the study. On Day 14, indacaterol showed statistically significant improvements over placebo in peak (317 mL [95% CI: 118-517]; p < 0.01) and isotime IC (268 mL [95% CI: 104-432]; p < 0.01). Statistically significant improvements were observed with indacaterol versus placebo on Day 14 for the following secondary endpoints: resting IC, trough FEV1, dyspnoea (BDI/TDI and Borg CR10 scale at isotime) and exercise endurance time. Indacaterol was well tolerated, with no serious adverse events or deaths. In conclusion, indacaterol 300 μg administered once-daily showed a clinically relevant increase in IC after 14 days of treatment, reflecting a reduction in dynamic hyperinflation.

Use of exercise testing in the evaluation of interventional efficacy: an official ERS statement

“…Isotime dyspnoea, as measured by the CR-10 and VAS scales, is sufficiently sensitive to evaluate therapeutic interventions in COPD patients [45,62,99,101,118,120,127,129,131]. However, that improvements in patient-reported dyspnoea with bronchodilator therapy during CWRETs are variable is probably due to measurement variability in this outcome as well as the modest numbers of patients in several of these studies [156].…”

“…A decrease in isotime V′E may also be the consequence of reduced dead space volume to tidal volume ratio, because the metabolic and acid-base ventilatory demands of the task have been reduced or because the patient adopts a more efficient breathing pattern [45,101,114,115,118,127].…”

“…It has been shown that inspiratory capacity can be reliably determined at isotime and peak exercise in multicentre clinical trials [33,101,118,127].…”

“…Symptom ratings should precede inspiratory capacity manoeuvres by at least five breaths to avoid interference [147]. End-exercise dyspnoea is quite variable among subjects [110,152,157] and frequently patients rate it similarly after interventions [26,62,99,101,118,127,131]; reflecting that exercise tolerance may have increased, exercise is often terminated at a similar intensity of dyspnoea. Thus, a more robust approach for comparing the effect of interventions on dyspnoea during IETs or CWRETs is to compare dyspnoea at isotime, or standardised for V′O 2 [158] or V′E [158,159].…”

The clinical relevance of the emphysema-hyperinflated phenotype in COPD

“…Indacaterol, tiotropium, glycopyrronium bromide and aclidinium bromide also showed their ability to positively impact hyperinflation and improve exercise capacity [92,[125][126][127][128][129][130][131][132][133].…”