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Educational aims • To discuss fundamental questions relating to the use of bronchodilators that can lead to an optimisation of their utilisation. • To describe new bronchodilators that have recently been approved in some countries or are currently undergoing clinical development Image: Patrick J. Lynch, Wikimedia Commons Mario Cazzola1, 1Unit of Respiratory Clinical Mario Cazzola, Unita` di [email protected] 2 Pharmacology, Dept of System Farmacologia Clinica Clive Page Medicine, University of Rome Respiratoria, Dipartimento Tor Vergata, Rome, Italy di Medicina dei Sistemi, 2Sackler Institute of Pulmonary ` Pharmacology, Institute of Universita di Roma Tor Pharmaceutical Science, King’s Vergata, Via Montpellier 1, College London, London, UK 00133 Rome, Italy Long-acting bronchodilators in COPD: where are we now and where are we going? Statement of Interest Summary Mario Cazzola has received honoraria for Bronchodilators are central to the treatment of chronic obstructive pulmonary speaking and consulting disease (COPD) because they alleviate bronchial obstruction and airflow and/or financial support limitation, reduce hyperinflation, and improve emptying of the lung and exercise for attending meetings performance. For this reason, all guidelines highlight that inhaled bronchodilators from Abbott, Almirall, AstraZeneca, Boehringer are the mainstay of the current management of all stages of COPD. Ingelheim, Chiesi However, there are still fundamental questions regarding their use that require Farmaceutici, Dey, clarification to optimise utilisation of these drugs. It is crucial to address the GlaxoSmithKline, following questions. Is it appropriate to treat all COPD patients with long-acting Guidotti, Lallemand, bronchodilators? Is it better to start treatment with a b -agonist or with an anti- Malesci, Menarini 2 Farmaceutici, muscarinic agent in patients with stable mild/moderate COPD? Is it useful to use Mundipharma, Novartis, a bronchodilator with rapid onset of action? Is it preferable to administer a Pfizer, Sanovel, Sigma bronchodilator on a once- or twice-daily basis? Can a second bronchodilator Tau, Takeda and Valeas. be introduced for patients with stable COPD (‘‘dual’’ bronchodilator therapy), Clive Page has received and if so when? Are inhaled corticosteroids (ICSs) really useful in COPD patients speaker fees from without chronic bronchitis, since long-lasting bronchodilators may prevent Novartis and Almirall. He is a co-founder and exacerbations even in the absence of an ICS in frequent exacerbators? Finally, is has equity in Verona combined therapy really useful in non-frequent exacerbators? Pharma who are devel- Due to the the central role of bronchodilators in the treatment of COPD, there is oping RPL 554 as a novel still considerable interest in finding novel classes of bronchodilator drugs. bronchodilator. However, new classes of bronchodilators have proved difficult to develop because either new emerging targets are not really important and/or it is difficult to find substances capable of interacting with them. As a consequence, many research groups have sought to improve the existing classes of bronchodilators. Introduction limited reversibility of airflow obstruction ERS 2014 [1, 2]. The existing drug classes (b2-agonists Bronchodilators are central to the treatment and muscarinic receptor antagonists) work by of chronic obstructive pulmonary disease relaxing airway smooth muscle tone, leading HERMES syllabus link: (COPD), notwithstanding that there is often to reduced respiratory muscle activity and modules B.1.4 DOI: 10.1183/20734735.014813 Breathe | June 2014 | Volume 10 | No 2 111 Long-acting bronchodilators in COPD improvements in ventilatory mechanics, making decline in forced expiratory volume in 1 s it easier for patients to breathe. Bronchodilation (FEV1) have been found to vary considerably aims at alleviating bronchial obstruction and across participants with COPD in both obser- airflow limitation, reducing hyperinflation, and vational cohorts and intervention trials, ran- improving emptying of the lung and exercise ging from decreases as rapid as 150–200 mL performance [1, 2]. per year to increases of up to ,150 mL per The importance of bronchodilation year [8]. A trial that disregards this fun- explains why all guidelines highlight that damental aspect includes all COPD patients inhaled bronchodilators are the mainstay of regardless of whether or not they are under- the current management of COPD at all going FEV1 decline, but it is likely that stages of the disease [3–5]. However, the bronchodilators are only effective in those recent American College of Physicians who lose pulmonary function. (ACP)/American College of Chest Physicians Data collected in the ECLIPSE (Evaluation (ACCP)/American Thoracic Society (ATS)/ of COPD Longitudinally to Identify Predictive European Respiratory Society (ERS) guide- Surrogate Endpoints) observational study lines conclude that no sufficient evidence found that the rate of decline in FEV1 over a exists to support bronchodilator treatment in 3-year period was highly variable, with an asymptomatic COPD patients [5]. increase in the magnitude of the decline among current smokers, patients with bron- chodilator reversibility, frequent exacerbators Where are we now? and patients with emphysema [9]. However, the mean rate of decline appeared to be Although bronchodilators are important in inversely related to the Global Initiative for the management of patients with COPD, Chronic Obstructive Lung Disease (GOLD) there are still fundamental questions regarding stage [9]. Intriguingly, both the TORCH [10] their use that require clarification to optimise and UPLIFT [11] studies have suggested that utilisation of these drugs (table 1). long-acting bronchodilators reduce the rate of decline of post-bronchodilator FEV1 in patients Is it appropriate to treat all COPD with GOLD stage II COPD. Since it is im- patients with long-acting possible to identify fast decliners, it seems bronchodilators? appropriate to treat all COPD patients with bronchodilators, particularly those in the early Both the TORCH (Toward a Revolution in stages of the disease, current smokers, those COPD Health) [6] and UPLIFT (Understanding with emphysema or bronchodilator reversibil- Potential Long-Term Impacts on Funtion with ity, and frequent exacerbators. It is noteworthy Tiotropium) [7] studies have documented that that a consensus initiative for optimising thera- regular treatment with long-acting bronchodi- peutic appropriateness among Italian spe- lators does not reduce the accelerated decline cialists concluded that regular therapy with in lung function in some patients with COPD. long-acting bronchodilators should be started This finding should not be considered unex- in obstructed patients in both the presence and pected as it is well known that COPD is not absence of symptoms [12]. invariably progressive. Individual rates of Is it better to start with a b2-agonist or Table 1 General questions to be addressed with an anti-muscarinic agent? to optimise use of bronchodilators in COPD In almost all guidelines no distinction is N Is it appropriate to treat all COPD patients made as to which class of bronchodilators with long-acting bronchodilators? should be considered first, but they only N b Is it better to start with a 2-agonist or recommend the use of long-acting broncho- with an anti-muscarinic agent? dilator agents [3–5]. The National Institute for N Is it useful to use a bronchodilator with a Health and Clinical Excellence (NICE), in its rapid onset of action? 2010 update of COPD treatment guidelines, N Is once- or twice-daily dosing preferable? reviewed all studies that compared long-acting N When can we add a second bronchodilator b-agonists (LABAs) and long-acting muscari- with a different mechanism of action? nic antagonists (LAMAs), and concluded that N When must we add an ICS? there was no evidence to favour one treatment 112 Breathe | June 2014 | Volume 10 | No 2 Long-acting bronchodilators in COPD over another [4]. Whereas the GOLD guide- for medications that do not have an imme- lines [3] affirm that the choice depends on the diate effect on symptoms [23]. Prompt availability of drugs and the patient’s response symptom relief will give reassurance of in terms of symptom relief and side-effects. effectiveness and could be a key factor in However, data from efficacy trials suggest that patient compliance. Obviously, among twice-daily LABAs (salmeterol and formoterol) LABAs, agents with a rapid onset of action are preferable to short-acting anti-muscarinic could be more effective on morning symptoms agents (ipratropium) [13, 14], whereas once- than those with a relatively slow onset of daily tiotropium, a LAMA [15, 16], and indaca- action. This means that in the symptomatic terol, an ultra-LABA [17], are superior to patient formoterol and indacaterol should be twice-daily LABAs. preferred to salmeterol, and glycopyrronium or Unfortunately, there is no head-to-head aclidinium to tiotropium. randomised controlled trial (RCT) that evalu- ates all the different monotherapies available, Is once- or twice-daily dosing preferable? and it is unlikely that such a trial will ever be performed (given the increasing number of An important question that has been high- options available) [18]. In any case, it is likely lighted in recent years is whether it is that the lack of indication of the class of preferable to administer a bronchodilator on bronchodilators that must be used as

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