Bronchodilator effects of indacaterol and formoterol in patients with COPD

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Abstract

Background

Resting inspiratory capacity (IC) reflects static hyperinflation in chronic obstructive pulmonary disease (COPD). This study compared the effects of formoterol and indacaterol, a novel once-daily ultra-long-acting β2-agonist (or ultra-LABA), on resting IC and forced expiratory volume in 1 s (FEV1).

Methods

Thirty patients with COPD (mean FEV1/FVC 0.49, mean FEV1 56% predicted) each inhaled three treatments (two in randomized sequence followed by open-label formoterol) on separate study days: a single dose of indacaterol 300 μg, matching placebo, and two doses of formoterol 12 μg 12 h apart.

Results

Indacaterol and formoterol increased FEV1 and IC at all time points relative to placebo (p < 0.001). Peak effects on FEV1 were similar, while indacaterol had a greater effect on peak IC (31% vs 23% from pre-dose; p = 0.034). Indacaterol had a greater effect than formoterol on FEV1 at 8 h (1.47 vs 1.39 L; p = 0.014) and 24 h (1.44 vs 1.35 L; p = 0.003), and on IC from 4 to 24 h (differences of 0.13–0.19 L; p < 0.05). At 24 h, indacaterol and formoterol increased FEV1 by 17.7% and 7.5%, respectively, from pre-dose.

Conclusions

This study discriminated between the effects on IC and FEV1 of once daily indacaterol and twice daily formoterol. The greater effect of indacaterol on IC may translate into improved long-term clinical outcomes.

Introduction

Current guidelines emphasize that chronic obstructive pulmonary disease (COPD) is both preventable and treatable, while acknowledging that the condition is characterized by a progressive decline in lung function [1]. Bronchodilators are the cornerstone treatment for all COPD severity stages. In more pronounced stages of airflow obstruction, the regular use of one or more long-acting bronchodilators is recommended. These agents include the twice daily β2-agonists, formoterol and salmeterol, and the once-daily anticholinergic, tiotropium. Long-acting bronchodilators may improve exercise tolerance [2], [3], [4] as a result of bronchodilation and reduction of both static and dynamic hyperinflation.

The diagnosis and severity staging of COPD and measurement of response to therapy are based on objective measures of lung function, i.e. forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FVC). However, there is evidence that acute changes in resting FEV1 do not correlate with improvements in exertional dyspnoea and exercise capacity and vice versa [5], [6]. Other spirometric measures such as inspiratory capacity (IC) may correlate better with these measures of clinical response [5]. Resting IC represents the limit for inspiratory volume expansion following exhalation during tidal breathing, and therefore indirectly infers functional residual capacity, i.e. the degree of hyperinflation. Moreover, a decrease in IC during exercise indicates dynamic hyperinflation, assuming that total lung capacity remains constant. Finally, an increased resting IC is a better predictor of exercise tolerance in COPD than other lung function variables, e.g. FEV1 [5].

Indacaterol is a novel inhaled ultra-long-acting β2-agonist (ultra-LABA) being investigated for once daily use in subjects with COPD [7], [8]. Improved clinical benefits have been demonstrated with the long-acting anticholinergic tiotropium once-daily vs short-acting ipratropium four-times daily [9], and one of the proposed underlying mechanisms for this observation may be a prolonged effect of long-acting bronchodilators on lung emptying, by improving IC and reducing resting hyperinflation. The objective of the present exploratory study was to compare the response in FEV1 and IC between single doses of indacaterol and matched placebo, with the recommended daily dose of formoterol (12 μg twice daily) as an active control. Safety and tolerability were also assessed.

Section snippets

Patients (inclusion/exclusion criteria)

The study enrolled males and females aged 40–80 years, with a clinical diagnosis of COPD according to GOLD recommendations [10] and a smoking history of at least 10 pack-years. Spirometric criteria were a post-bronchodilator FEV1  40% predicted at screening and ≥1.0 L; FEV1 reversibility of ≥5% to salbutamol 400 μg (after an appropriate bronchodilator washout period: no use of short-acting bronchodilators for 6 h, no long-acting β2-agonists for 48 h, and no tiotropium for 72 h); and a

Patients

As planned, 30 subjects were randomized. Demographic and baseline characteristics are shown in Table 1. All subjects were Caucasian. No patient withdrew from the study.

Efficacy

Spirometry data were available for all 30 subjects on the formoterol treatment day, for all but one subject at the 23.5 and 24 h time points on the indacaterol day, and for all but one subject at 6 and 8 h and two subjects at 23.5 and 24 h on the placebo day, the reasons for missing measurements being administration of rescue

Discussion

The primary objective of this study was to compare and contrast indacaterol, placebo and formoterol in terms of their effects on two measures reflecting the airflow limitation of COPD, namely FEV1 and resting IC. Comparing peak effects, indacaterol and formoterol had similar effects on FEV1, whereas indacaterol had a significantly greater peak effect than formoterol on IC, although additional work is needed to determine clinical relevance. This pattern is reflected in the profile of relative

Acknowledgements

The authors thank patients and staff involved in this study, and the investigators at the other participating centres: Dr Rikke Riisbro, Cyncron (ex-Medicon Clinical Pharmacology) A/S, Copenhagen, Denmark, and Dr Pauline A. Palmer, Chiltern's Clinical Research Unit (CCRU), Slough, UK. The study was sponsored by Novartis Pharma AG. The authors were assisted in the preparation of the manuscript by Sarah Filcek (this support was funded by the study sponsor). The authors thank David Young of

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