Bronchodilator effects of indacaterol and formoterol in patients with COPD
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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New developments in inhaler devices within pharmaceutical companies: A systematic review of the impact on clinical outcomes and patient preferences
2015, Respiratory MedicineCitation Excerpt :Therefore, the formoterol treatment arm was not selected and discontinued in the long-term study. One dose of indacaterol 300 μg (administered via the single-dose dry powder inhaler) resulted in similar peak effects on FEV1 as two doses of formoterol 12 μg (inhaled 12 h apart via Aerolizer® inhaler) [37]. Indacaterol had a greater effect on peak inspiratory capacity (p = 0.034); cough occurred more frequently following indacaterol administered using the Breezhaler® device.
Comparison of airway dimensions with once daily tiotropium plus indacaterol versus twice daily Advair<sup>®</sup> in chronic obstructive pulmonary disease
2015, Pulmonary Pharmacology and TherapeuticsAssessment of acute bronchodilator effects from specific airway resistance changes in stable COPD patients
2014, Respiratory Physiology and NeurobiologyCitation Excerpt :Indacaterol caused acute bronchodilation, reduced lung hyperinflation, and alleviated dyspnea perception at rest (Table 2). The changes in static and dynamic lung volumes were consistent with those observed with indacaterol in previous studies (Rennard et al., 2008; Beier et al., 2009; Rossi et al., 2012), as well as with salbutamol in very large samples of COPD patients (Newton et al., 2002; Deesomchok et al., 2010). In fact, both the severity of the disease evaluated by MRC score or GOLD stage, and lung function parameters at baseline were similar among these studies.
Société de Pneumologie de Langue Française. Guidelines for clinical practice. Management of COPD. Update 2012: Pulmonary function tests
2014, Revue des Maladies RespiratoiresTherapeutic potential for novel ultra long-acting β <inf>2</inf>- agonists in the management of COPD: Biological and pharmacological aspects
2012, Drug Discovery TodayCitation Excerpt :Indacaterol, the first ultra-LABA approved in the EU for the maintenance bronchodilatory treatment of COPD in adults, shows a rapid and 24-hour bronchodilatory action that enables for once-daily administration. Phase II studies provide data that indacaterol has a good cardiovascular safety profile and no antagonism with rescue medications [42–46]. The doses approved for registration were 150 and 300 μg once-daily [39]; moreover in the same study the efficacy of indacaterol at different doses (150–300 and 600 μg) at 24 hours were as good as formoterol 12 μg twice-daily.
Acute effects of indacaterol on lung hyperinflation in moderate COPD: A comparison with tiotropium
2012, Respiratory MedicineCitation Excerpt :Indeed, a reduction of pulmonary hyperinflation, as reflected by an increase in inspiratory capacity (IC), has been shown to occur in moderate-to-severe COPD patients treated with either salmeterol19 or tiotropium,20,21 and this was consistently associated with a reduction in dyspnea and an increase in exercise tolerance. In a recent study, Beier and colleagues22 found that high-dose indacaterol (300 μg) caused a significantly larger increase in IC than the recommended dose of formoterol. The present study was designed to investigate whether the lower available dose of indacaterol (150 μg) can also reduce pulmonary hyperinflation in comparison with either placebo or the recommended dose of tiotropium (18 μg), the other available once-daily bronchodilator, in patients with moderate COPD.