Long-acting bronchodilators in COPD: where are we now and where are we going?

Is it appropriate to treat all COPD patients with long-acting bronchodilators?

Both the TORCH (Toward a Revolution in COPD Health) [6] and UPLIFT (Understanding Potential Long-Term Impacts on Funtion with Tiotropium) [7] studies have documented that regular treatment with long-acting bronchodilators does not reduce the accelerated decline in lung function in some patients with COPD. This finding should not be considered unexpected as it is well known that COPD is not invariably progressive. Individual rates of decline in forced expiratory volume in 1 s (FEV₁) have been found to vary considerably across participants with COPD in both observational cohorts and intervention trials, ranging from decreases as rapid as 150–200 mL per year to increases of up to ∼150 mL per year [8]. A trial that disregards this fundamental aspect includes all COPD patients regardless of whether or not they are undergoing FEV₁ decline, but it is likely that bronchodilators are only effective in those who lose pulmonary function.

Data collected in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) observational study found that the rate of decline in FEV₁ over a 3-year period was highly variable, with an increase in the magnitude of the decline among current smokers, patients with bronchodilator reversibility, frequent exacerbators and patients with emphysema [9]. However, the mean rate of decline appeared to be inversely related to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage [9]. Intriguingly, both the TORCH [10] and UPLIFT [11] studies have suggested that long-acting bronchodilators reduce the rate of decline of post-bronchodilator FEV₁ in patients with GOLD stage II COPD. Since it is impossible to identify fast decliners, it seems appropriate to treat all COPD patients with bronchodilators, particularly those in the early stages of the disease, current smokers, those with emphysema or bronchodilator reversibility, and frequent exacerbators. It is noteworthy that a consensus initiative for optimising therapeutic appropriateness among Italian specialists concluded that regular therapy with long-acting bronchodilators should be started in obstructed patients in both the presence and absence of symptoms [12].

Is it better to start with a β₂-agonist or with an anti-muscarinic agent?

In almost all guidelines no distinction is made as to which class of bronchodilators should be considered first, but they only recommend the use of long-acting bronchodilator agents [3–5]. The National Institute for Health and Clinical Excellence (NICE), in its 2010 update of COPD treatment guidelines, reviewed all studies that compared long-acting β-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs), and concluded that there was no evidence to favour one treatment over another [4]. Whereas the GOLD guidelines [3] affirm that the choice depends on the availability of drugs and the patient’s response in terms of symptom relief and side-effects. However, data from efficacy trials suggest that twice-daily LABAs (salmeterol and formoterol) are preferable to short-acting anti-muscarinic agents (ipratropium) [13, 14], whereas once-daily tiotropium, a LAMA [15, 16], and indacaterol, an ultra-LABA [17], are superior to twice-daily LABAs.

Unfortunately, there is no head-to-head randomised controlled trial (RCT) that evaluates all the different monotherapies available, and it is unlikely that such a trial will ever be performed (given the increasing number of options available) [18]. In any case, it is likely that the lack of indication of the class of bronchodilators that must be used as first choice is due to the fact that the superiority of one class over another, which has been documented by some RCTs, can be correlated to a specific outcome or be obtained by a specific method of research. Thus, LABAs are more effective than LAMAs if we consider symptoms or health-related quality of life (HRQoL) as the primary outcome [19], although LAMAs also impact favourably on both outcomes [18]. By contrast, LAMAs appear to be more effective than LABAs if exacerbations are the expected primary outcome, and this is regardless of whether LABAs are administered on a twice-daily [16] or once-daily basis [20]. Therefore, the choice of bronchodilator to start treatment with in a patient with COPD mainly depends on the outcome of interest. In the symptomatic patient, there is no substantial difference between LABAs or LAMAs, whereas in frequent exacerbators, it seems preferable to use a LAMA.

Is it useful to use a bronchodilator with rapid onset of action?

It is not yet clear if the differences in bronchodilator onset of action (fast-onset action versus slow-onset action) have any clinical role in COPD. In COPD patients, symptoms vary over the day, with morning considered the time when symptoms are more severe [21]. It might be hypothesised that fast-acting agents could be more effective on these symptoms than those with a relatively slow onset of action by providing a rapid relief of symptoms after morning dosing [22]. In addition, adherence is lower for medications that do not have an immediate effect on symptoms [23]. Prompt symptom relief will give reassurance of effectiveness and could be a key factor in patient compliance. Obviously, among LABAs, agents with a rapid onset of action could be more effective on morning symptoms than those with a relatively slow onset of action. This means that in the symptomatic patient formoterol and indacaterol should be preferred to salmeterol, and glycopyrronium or aclidinium to tiotropium.

Is once- or twice-daily dosing preferable?

An important question that has been highlighted in recent years is whether it is preferable to administer a bronchodilator on a once- or twice-daily basis. Apparently, the duration of bronchodilation appears to determine the clinical efficacy of a bronchodilator at least in COPD. It has been suggested that, with an extended duration of bronchodilation, the net area under the time/airflow curve increases and persistent bronchorelaxant effects of once daily bronchodilators lead to increased morning FEV₁ following the last inhalation (“trough” FEV₁) [24]. This could result, on average, in less dyspnoea and facilitated lung emptying during tidal breathing at rest over 24 h [24]. Recently, however, a population pharmacodynamic model of the longitudinal FEV₁ response to an inhaled LAMA in COPD patients has suggested that with the same total daily dose of a new muscarinic receptor antagonist, aclidinium, a twice-daily regimen provides higher bronchodilation at trough than a once-daily regimen [25]. In any case, since there is a progressive attempt to shift attention towards controlling nocturnal symptoms and those present on awakening, which epidemiological studies indicate to be the most troublesome for COPD patients [21], the twice-daily dosing of bronchodilators should be considered a useful approach at least for the symptomatic treatment of COPD. Unfortunately, we cannot yet determine, even indirectly, whether twice-daily administration may be preferred to the once-daily dosing of bronchodilators, particularly when the drug is administered in the evening or early in the morning, due to a lack of evidence from appropriate large trials [26]. Nonetheless, a recent small short-term study (6 weeks of treatment) showed that aclidinium, a twice-daily LAMA, provided improvements in early-morning and night-time symptoms that were consistently numerically greater than those observed with tiotropium, which is a once-daily LAMA [27].

When can we add a second bronchodilator with a different mechanism of action?

Since there is no solid guidance on when to combine two bronchodilators with different mechanisms of action, an answer to this question, whether and when a second bronchodilator can be added (“dual” bronchodilator therapy) in patients with stable COPD, is imperative. Most specialists believe that patients not controlled by a single bronchodilator should be given two bronchodilators with different mechanisms of action [12]. Certainly this seems to be a good choice because using multiple drugs in combination may lower doses of individual agents, decrease adverse effects, simplify medication regimens, and improve compliance [2]. In effect, the revised 2014 GOLD recommendations indicate that the combined use of short-acting β-agonists or LABAs and LAMAs may be considered if symptoms are not improved with single agents [3]. Studies of LABA/LAMA combinations, to date, indicate that combining different classes of bronchodilator results in significantly greater improvements in lung function and other meaningful outcomes such as inspiratory capacity, dyspnoea, symptom scores, rescue medication use, and health status in comparison with individual drugs [28]. Nonetheless, according to the NICE guidelines [4], treatment with LAMAs plus LABAs is recommended in people with COPD who remain symptomatic on treatment with a LABA alone, whereas the LABA/LAMA combination is not recommended in those already taking a LAMA as sole maintenance therapy. However, this recommendation is certainly surpassed by recent evidence documenting that the regular addition of a LABA to a LAMA not only induces a larger bronchodilation than that obtained with only the LAMA [29], but also significantly improves many patient-reported outcomes [30].

When must we add an ICS?

The last big question that still awaits a definitive answer is whether and when to add an inhaled corticosteroid (ICS) (“combined” therapy). This is a crucial question because ICSs are still overprescribed, by both general practitioners [31] and pulmonologists [32], and there is now growing concern that this drug class may increase the risk of pneumonia in some patients with COPD. Moreover, although monotherapy with ICSs is not approved for the treatment of COPD, even specialists in respiratory medicine sometimes prescribe ICS monotherapy to COPD patients [32]. The magnitude of the drawbacks of ICSs in COPD when compared with the benefits [33] explain why all national and international COPD guidelines recommend ICSs only for patients with severe impairment and high risk of exacerbations. NICE guidelines encourage the use of ICS with bronchodilators if patients have moderate or severe COPD and are still symptomatic, or are experiencing two or more exacerbations requiring treatment per year [4]. The GOLD strategy recommends ICSs in combination with LABAs or, alternatively, with LAMAs for those patients who have few symptoms but are at a high risk of exacerbations (group C patients) and also for those patients who have many symptoms and a high risk of exacerbations (group D patients) [3]. The very recent Spanish COPD guidelines [34], which recognise the clinical heterogeneity of COPD and suggest a specific therapeutic approach directed by the so-called clinical phenotypes of the disease, recommend that ICSs can be used in the mixed COPD phenotype characterised by airflow obstruction that is not completely reversible and accompanied by symptoms or signs of an increased reversibility of the obstruction. Moreover, ICSs may be tried in patients at severity level II (moderate COPD) who persist with exacerbations despite treatment with one or two long-acting bronchodilators. In patients at severity level III (severe COPD) who do not present a level of control of symptoms or exacerbations with two drugs (two long-acting bronchodilators or one long-acting bronchodilator plus an ICS), triple therapy (LAMA+LABA+ICS) can be used.

ICSs are more effective in frequent exacerbators with chronic bronchitis predominance and in those with overlap between COPD and asthma [35]. Therefore, there is room for the use of ICSs in COPD, or at least in some subtypes of COPD [36]. The right question now becomes not whether they should not be used at all, unless patients have concomitant asthma [37], but, instead, which patients with COPD can benefit from therapy with ICSs. Consequently, we must decide if ICSs are really useful in COPD patients without chronic bronchitis, whether long-lasting bronchodilators may prevent exacerbations even in the absence of an ICS in frequent exacerbators and the utility of combined therapy in nonfrequent exacerbators [38]. Moreover, it is essential to establish whether LAMA/LABA combination therapy is preferred over LAMA plus LABA/ICS, and whether addition of an ICS to the LAMA/LABA combination provides additional clinical value because data are still too scarce and studies too short to generate a strong recommendation. The answer to these questions would allow us to optimise the use of ICSs in COPD [33].

New examples of existing bronchodilator classes

Novel classes of bronchodilators

Novel classes of bronchodilators have proved difficult to develop, but there is still a continued interest in generating new bronchodilators that act via emerging targets, particularly given the concerns over the long-term safety of β₂-agonists [69]. Progress to date has been limited, this is likely to be because these new targets are not really important and/or it is difficult to find substances capable of interacting with them.

Potassium channel openers, vasoactive intestinal peptide analogs, rho kinase inhibitors, brain natriuretic peptide and analogs, nitric oxide donors, E-prostanoid receptor 4 agonists, and bitter taste receptor agonists are considered potential new classes of bronchodilators (table 3) [1]. They influence alternative targets that seem important for inducing bronchodilation. Unfortunately, the development of many of them is delayed or blocked because of limited efficacy and/or safety problems [1].

An alternative approach is to develop molecules designed to have two distinct primary pharmacological actions based on distinct pharmacophores, i.e. bifunctional drugs, which might be able to deliver complementary pharmacological activities for the treatment of patients with asthma or COPD. Currently, the first bifunctional bronchodilator/anti-inflammatory drugs (phosphodiesterase (PDE)3/PDE4 inhibitors) are in clinical development [1].

There is documentation that the PDE3 isoenzyme predominates in airway smooth muscle and inhibition of this enzyme, rather than PDE4, leads to airway smooth muscle relaxation, whereas the PDE4 isoenzyme is the predominant isoenzyme in the majority of inflammatory cells, including neutrophils [70]. Consequently, dual PDE3/PDE4 inhibitors can combine bronchodilation with anti-inflammatory activity, representing a potential new class of drugs for the treatment of patients with asthma or COPD [70]. Recently, a dual PDE3/PDE4 inhibitor RPL554 has been developed. It produces a rapid, significant and sustained bronchodilator effect in patients with mild-to-moderate COPD and also in patients with asthma when administered by the inhaled route and appears to be at least as effective as salbutamol as a bronchodilator [71]. At the same dose that elicits bronchodilation, RPL554 also exhibits highly significant anti-inflammatory effects in humans, as it is able to reduce the ability of lipopolysaccharide to induce recruitment of inflammatory cells into the airways, particularly the absolute numbers of neutrophils, eosinophils, lymphocytes and macrophages [71].