The Airway Pathophysiology of COPD: Implications for Treatment

The pathophysiology of chronic obstructive pulmonary disease (COPD) is complex and can be attributed to multiple components: mucociliary dysfunction, airway inflammation and structural changes, all contributing to the development of airflow limitation, as well as an important systemic component. Current pharmacotherapies vary in their ability to address the underlying multi-component nature of COPD. Long-acting anticholinergics and long-acting β₂-agonists (LABAs) can both provide effective and convenient bronchodilation in moderate COPD (Stage II–GOLD) and are recommended as regular therapy in global treatment guidelines. However, there is evidence to suggest that LABAs can mediate additional benefits independent of their bronchodilatory effects and may help address the multi-component nature of COPD. Effects on mucociliary dysfunction and reduced bacterial-induced damage have been experimentally proven with LABAs, and anti-inflammatory activity and structural effects have also been suggested. The use of inhaled corticosteroids (ICSs) is now recommended for the treatment of COPD patients with frequent exacerbations. In addition, ICSs provide a range of anti-inflammatory effects in COPD and thus have effects that are complementary to those of LABAs. Recent data indicate that LABA/ICS combinations produce wide-ranging clinical benefits that are greater than with either agent alone. Other new strategies include selective phosphodiesterase 4 (PDE4) inhibitors, which in addition to anti-inflammatory activity, have been shown to provide bronchodilation in COPD. In summary, the potential to address the multicomponent nature of COPD with strategies such as LABA/ICS combination therapy, and the development of new treatments directed at novel targets means that the future for sufferers of COPD can be more optimistic.     

Defining the effects of an inhaled corticosteroid and long-acting beta-agonist on therapeutic targets.

The effects of inhaled corticosteroids (ICSs) and long-acting beta 2-agonists (LABAs) on therapeutic targets have significant clinical relevance regarding optimal management of asthma. Asthma pathophysiology involves two main components: smooth muscle dysfunction and airway inflammation. LABAs and ICSs provide complementary modes of action in that these agents modulate smooth muscle dysfunction/bronchoconstriction and airway inflammation, respectively. Despite the documented benefits of ICSs, they remain underutilized because of a variety of physician- and patient-associated reasons including safety concerns. Underlying these concerns are published reports that suggest systemic effects of high doses of ICSs: skin bruising, reduction of bone mineral density, cataracts, glaucoma, and impaired short-term growth in children. Simple strategies to reduce the potential adverse effects of inhaled steroids include using the lowest effective maintenance dose and optimizing steroid-sparing strategies, specifically combination therapy with a LABA, leukotriene modifier, or theophylline. LABA therapy, when added to ICS therapy, provides clinically significant steroid-sparing effects while at the same time reducing the rate at which asthma exacerbations occur. Available clinical evidence suggests that the combination of ICS plus LABA is the best available option for the management of moderate persistent asthma. Consequently, this combination is the preferred choice for treating moderate persistent asthma based on current National Asthma Education and Prevention Program guidelines for the diagnosis and treatment of asthma.     

Clinical safety of long-acting beta2-agonist and inhaled corticosteroid combination therapy in COPD

Long-acting beta2-agonist (LABA) and inhaled corticosteroid (ICS) combination therapy is recommended by international treatment guidelines for COPD. The current literature concerning the safety of LABAs and ICS, both as monotherapies and in combination, in patients with COPD is reviewed. Bronchodilators such as LABAs are key treatments for COPD due to their effects on bronchial smooth muscle and airflow limitation. LABAs are well-tolerated in patients with COPD, with a low incidence of reported adverse events (AEs). Most AEs associated with LABA use are due to systemic exposure and include muscle tremor and cardiac effects. Placebo-controlled studies in patients with COPD demonstrate that there is no increase in risk of cardiac AEs with LABA therapy. ICS therapy targets airway inflammation in COPD, and is associated with a reduction in the frequency of COPD exacerbations, and improvements in symptoms, lung function and health status. Localized effects such as oropharyngeal irritation are common with ICS, but are not considered to be serious. Potential ocular effects with ICS therapy in patients with COPD have been identified and require further investigation. Rare, but more serious AEs related to ICS use are the effects on bone and the suppression of endogenous cortisol production; however, the clinical relevance of these effects is unclear. Clinical data indicate that LABA/ICS combination therapy is more effective in COPD than either agent used alone and is not associated with any additional AEs.     

Mucociliary dysfunction in COPD: effect of current pharmacotherapeutic options

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. COPD comprises multiple components which, as well as a systemic component, include pulmonary inflammation, airway remodelling and mucociliary dysfunction. The latter features contribute to the development of chronic, progressive airflow limitation. The mucociliary dysfunction component of COPD is due to mucus hypersecretion coupled with a decrease in mucus transport, and represents an important pathophysiological feature requiring appropriate treatment. Current international guidelines do not recommend the use of mucolytics in the treatment of stable COPD. In contrast, bronchodilators are central to symptomatic management of COPD, and include beta(2)-adrenoceptor agonists, anti-cholinergics and methylxanthines. Interestingly, long-acting beta(2)-agonists (LABAs), rather than short-acting beta(2)-agonists, have the potential to improve the mucociliary component of COPD, in addition to providing symptomatic treatment by their bronchodilator action. Combination therapy with a LABA and an inhaled corticosteroid has the potential to more fully address the multicomponent nature of COPD by providing important anti-inflammatory activity, which may indirectly further improve mucociliary clearance. Theoretically, anti-cholinergics are likely to have mixed effects on mucociliary function, but clinically these effects have been difficult to demonstrate. Finally, a number of novel targets for the treatment of airway mucociliary dysfunction have been identified, and targeting agents are currently in development.     

Long-acting beta-agonists in adult asthma: Evidence that these drugs are safe.

If asthma is not controlled with low-dose inhaled corticosteroids (ICS), by far the best next step is the addition of a long-acting, inhaled beta-agonist (LABA). Questions regarding the safety of this class of drug have been raised. However, careful examination of the reports which have caused concern in this regard does not reveal any evidence of an increased risk associated with the appropriate use (i.e. in combination with an inhaled ICS) of LABAs in asthma. There is much to suggest that the adverse outcomes associated with LABA monotherapy have been due to "masking of inflammation" rather than a toxic effect of the drugs. In some instances, this has likely allowed worsening asthma to be overlooked - with dire consequences. Studies in subjects receiving combination therapy with LABAs plus ICSs suggest that, if anything, there is an enhanced anti-inflammatory action with the LABA/ICS combination superior to that achieved with ICS alone at the same dose.     

Inhaled Corticosteroids for Chronic Obstructive Pulmonary Disease—The Shifting Treatment Paradigm

Chronic obstructive pulmonary disease (COPD) guidelines suggest using inhaled corticosteroids (ICS) in patients with severe airflow limitation or those at high risk of exacerbations. This recommendation is based on evidence demonstrating that ICS, especially when prescribed in fixed-dose combinations (FDC) with long-acting β2 agonists (LABA), improve quality of life (QoL), decrease exacerbations and hospitalisations, and have been associated with a trend towards a reduction in all-cause mortality. Audit shows that routine prescribing practice frequently uses inhaler therapies outside current guidelines recommendations; severe to very severe disease constitutes about 20% of all COPD patients, but up to 75% of COPD patients are prescribed an ICS, with significant numbers given ICS/LABA as first-line maintenance therapy. The role of ICS in the treatment paradigm for COPD is changing, driven by the growing evidence of increased risk of pneumonia, and the introduction of a new class of FDC; LABA and long-acting muscarinic antagonists (LAMA), which simplify dual bronchodilation and present a plausible alternative therapy. As the evidence base for dual therapy bronchodilation expands, it is likely that maximal bronchodilation will move up the treatment algorithm and ICS reserved for those with more severe disease who are not controlled on dual therapy. This change has already manifested in local COPD algorithms, such as those at Tayside, and represents a significant change in recommended prescribing practice. This review reassesses the role of ICS in the shifting treatment paradigm, in the context of alternative treatment options that provide maximal bronchodilation.     

Inhaled combination therapy with long-acting beta 2-agonists and corticosteroids in stable COPD

Long-acting beta(2)-agonists (LABAs) have been shown to be effective first-line bronchodilators in the treatment of COPD patients, and inhaled corticosteroids (ICSs) have been shown to reduce the frequency and/or severity of exacerbations in COPD patients. The concomitant use of a LABA and an ICS can influence both airway obstruction (ie, smooth muscle contraction, increased cholinergic tone, and loss of elastic recoil), and airway inflammation (ie, increased numbers of neutrophils, macrophages, and CD8+ lymphocytes, elevated interleukin-8 and tumor necrosis factor-alpha levels, and protease/antiprotease imbalance). They are also able to reduce the total number of bacteria adhering to the respiratory mucosa in a concentration-dependent manner without altering the bacterial tropism for mucosa, and to preserve ciliated cells. Several clinical trials support the concept of inhaled combination therapy with LABAs and corticosteroids in stable COPD patients. This type of therapy not only improves airflow obstruction but also provides clinical benefits, as manifested by sustained reduction in overall symptoms, improvements in health-related quality of life, and reductions in exacerbations. All of these effects are very important because, despite recent advances in our understanding of COPD and its treatment, therapy remains suboptimal for a considerable number of patients.     

Effective management of COPD in primary care - the role of long-acting beta agonist/inhaled corticosteroid combination therapy.

Chronic obstructive pulmonary disease (COPD) is the internationally preferred term for chronic, progressive lung disorders which are characterised by airflow limitation that is not fully reversible. The symptoms of COPD - including breathlessness, cough, excessive sputum production and reduced muscle tone and muscle wasting - reflect the complex pathophysiology of the disease. In order to address these symptoms, treatment regimens should take into account the multiple components that contribute to COPD. Clinical evidence has emerged indicating that, especially in patients with severe COPD, long-acting beta(2)-agonists (LABAs) and inhaled corticosteroids (ICS) result in improvements in symptoms, reduce the frequency and severity of exacerbations, and improve health-related quality of life. This review evaluates the clinical evidence for the potential of LABA/ICS treatment to address the symptoms of COPD and whether combination therapy of this nature adds significant benefit to patients.     

Comparison and optimal use of fixed combinations in the management of COPD

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Indications for the use of long-acting β₂-agonists (LABAs) and inhaled corticosteroids (ICS) in patients with COPD are described in the various international guidelines, but no special recommendations are made concerning the use of combination inhalers containing a LABA as well as an ICS. To determine the place of combination inhalers in the treatment of COPD we reviewed recent literature concerning this subject. On molecular level ICS/LABA combination therapy has anti-inflammatory properties which cannot be attributed to ICS alone. All clinical studies indicate that the two available combinations (salmeterol/fluticasone and formoterol/budesonide) significantly reduce exacerbation rate of moderate/severe exacerbations when compared with placebo. Some studies also showed a significant reduction in exacerbation rate compared with LABA monotherapy, but not compared with ICS monotherapy. From the patient’s perspective, ICS/LABA combination inhalers are the first choice when both need to be prescribed, possibly improving patient compliance for ICS. Currently little evidence is available to predict if flexible treatment with LABA/ICS combination inhalers will improve disease control in COPD. Further studies are needed to elucidate the clinical benefit of combination inhalers versus the individual components in different inhalers, and to investigate the clinical benefit of flexible dosing of combination inhalers in patients with COPD.     

Long-acting beta2-agonists in asthma: an overview of Cochrane systematic reviews

According to major asthma management guidelines, long-acting beta2-agonists (LABAs) should be used only when asthma remains symptomatic in patients already receiving regular inhaled corticosteroids (ICSs). A large Cochrane systematic review provides evidence that LABAs are safe and beneficial in control of asthma; sub-group analyses indicating that this is true when ICSs are used and in their absence. Two other Cochrane systematic reviews have found that LABAs are more effective than regular short-acting beta2-agonists, and are as effective as theophylline with fewer side-effects. These reviews support guidelines in the use of LABA as additional therapy when asthma is inadequately controlled by ICS at moderate dose. However, guidelines may be too conservative, and more studies in stable mild asthma comparing their use and safety with placebo and ICS are required.     

Long-acting beta-agonists: anti-inflammatory properties and synergy with corticosteroids in asthma

PURPOSE OF REVIEW: Contemporary asthma management calls for combination inhaled corticosteroid (ICS) and long-acting beta-agonist (LABA) for patients with moderate to severe persistent asthma. This combination has consistently shown superior clinical efficacy compared with monotherapy with higher doses of ICS. It is unclear whether ICS and LABA act additively because of their complementary mechanisms of action, or whether they act synergistically based on possible favorable interactions between them. The purpose of this review is to summarize research findings on the anti-inflammatory activity of LABA published since October 2002 and to speculate on how these findings will affect future asthma management recommendations. RECENT FINDINGS: Combination ICS plus LABA consistently demonstrates superiority over ICS monotherapy in clinical outcomes such as pulmonary function, symptoms, and exacerbation rates, and is consistent with definitive data published before the review period. However, investigations into possible effects of LABA on inflammatory mediators are preliminary. Positive effects of LABA on some serum and bronchial inflammatory measures have been observed, but the clinical importance of these findings has not been established. SUMMARY: Current asthma treatment recommendations are based on clinical trials demonstrating improved clinical outcomes of combination ICS plus LABA over ICS alone. Whether LABA possesses clinically important benefits beyond bronchodilation remains to be established. Distinguishing anti-inflammatory activity of LABA will help define optimal long-term treatment regimens for asthma that not only improve pulmonary function, symptoms, and exacerbation rates but also protect against airway remodeling.     

Alternative mechanisms for long-acting beta(2)-adrenergic agonists in COPD.

beta(2)-Adrenergic agonists are commonly used as bronchodilators to treat patients with COPD. In addition to prolonged bronchodilation, long-acting beta(2)-agonists (LABAs) exert other effects that may be of clinical relevance. These include inhibition of airway smooth-muscle cell proliferation and inflammatory mediator release, as well as nonsmooth-muscle effects, such as stimulation of mucociliary transport, cytoprotection of the respiratory mucosa, and attenuation of neutrophil recruitment and activation. This review details the possible alternative mechanisms of action of the LABAs, salmeterol and formoterol, in COPD.     

Patterns of use of long‐acting bronchodilators in patients with COPD: A nationwide follow‐up study of new users in New Zealand

Background and objective

While several studies have found that prescribing practices do not conform to chronic obstructive pulmonary disease (COPD) treatment guidelines, none have examined longitudinal patterns of use of long‐acting beta₂‐agonist (LABA) and long‐acting muscarinic antagonist (LAMA) therapy across an entire country. We undertook a nationwide follow‐up study to describe treatment patterns in new users of long‐acting bronchodilators.

Methods

National health and pharmaceutical dispensing data were used to identify patients aged ≥45 years who initiated LABA and/or LAMA therapy for COPD between 1 February 2006 and 31 December 2013. Dispensings of LABAs, LAMAs and inhaled corticosteroids (ICSs) were aggregated into episodes of use of therapeutic regimens. Kaplan–Meier curves, sunburst plots and sequence index plots were generated to summarize, respectively, the duration of the first regimen, the sequences in which unique regimens were used and the patterns of use and non‐use during follow‐up.

Results

The study cohort included 83 435 patients with 290 400 person‐years of follow‐up. The most commonly initiated regimen was a LABA with an ICS. ICS use was inconsistent with international guidelines: over‐ and under‐treatment occurred in patients with infrequent and frequent exacerbations, respectively, and ICS monotherapy was common. The median duration of the first regimen was 46 days. Many patients used multiple regimens over time and periods of non‐use were common.

Conclusion

In this nationwide study, patterns of use of LABAs, LAMAs and ICSs were complex and often did not comply with treatment guidelines. Further work is required to address the discrepancy between guidelines and prescribing practices.

     

The scientific rationale for combining long-acting β2-agonists and muscarinic antagonists in COPD

Bronchodilators are the cornerstone of pharmacological management of COPD. For patients whose conditions are not sufficiently controlled by monotherapy, combining bronchodilators of different classes, in particular an inhaled muscarinic antagonist with an inhaled β₂-agonist, seems a convenient way of delivering treatment and obtaining superior results. When administered as combination therapy, short-acting bronchodilators provide superior bronchodilation compared with individual agents given alone. More recently, long-acting β₂-agonists (LABAs) and muscarinic antagonists (LAMAs) have been introduced, and current guidelines recommend regular use of these agents alone or as concurrent therapy in COPD to maximize bronchodilation. In particular, the combination of a LABA plus LAMA seems to play an important role. This article illustrates the scientific rationale for combining LABAs and LAMAs in COPD, reviews the clinical evidence to support these agents given in combination, and discusses their potential role in the management of patients with COPD.     

Triple Therapy in COPD: What We Know and What We Don't

Triple inhaled therapy for chronic obstructive pulmonary disease (COPD) consists of an inhaled corticosteroid (ICS), a long-acting β₂-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) taken in combination. Triple therapy is recommended by the Global initiative for Chronic Obstructive Lung Disease (GOLD) for patients who experience recurrent exacerbations despite treatment with either a dual bronchodilator (preferred initial therapy) or LABA/ICS combination (alternative initial therapy). Although there is evidence for the greater efficacy of triple therapy compared with LABA/ICS and LAMA monotherapy with regards to improved lung function, health status, and exacerbation rate, the efficacy of triple therapy when compared with dual bronchodilation (LABA/LAMA) is as yet unknown. As ICS use is associated with an increased risk of developing pneumonia, it is important to assess the risk/benefit ratio of triple therapy on an individual basis, and identify patients most likely to benefit. The role of elevated blood eosinophils as a biomarker for the identification of candidates for ICS treatment is currently debated, and further prospective evidence is required. This review assesses evidence for the efficacy and safety of triple therapy and postulates on the prospective evidence from ongoing studies. The potential for treating patients who experience further exacerbations on dual bronchodilation according to phenotype is also considered, as well as withdrawal of ICS from triple therapy in patients who are unlikely to benefit.     

Tiotropium and salmeterol/fluticasone combination do not cause oxygen desaturation in COPD

It has been documented that tiotropium is less likely to induce oxygen desaturation in stable COPD patients compared to long-acting beta2-agonists (LABAs) and combined administration of a LABA and an inhaled corticosteroid (ICS) reduces the potential for acute effects of LABA on blood-gas tensions. In this study, we have compared the acute effects of tiotropium 18 microg and salmeterol/fluticasone combination (SFC) 50/250 microg on arterial blood gases in 20 patients with stable COPD. Each subject was studied on 2 days, separated from one another by at least 4 days. Blood specimens were taken just before the inhalation and at 15, 30, 60, 180 and 360 min after inhalation of each treatment, and spirometry was performed at the same time points. As expected, both treatments significantly improved FEV1 (greatest changes were 0.20 L, 95% CI: 0.13-0.27 at 360 min after tiotropium; and 0.13 L, 95% CI: 0.06-0.19 at 180 min after SFC). The greatest mean changes from baseline in PaO2 were -1.7 (95% CI: -4.0 to 0.6)mmHg, p=0.134, after tiotropium; -0.8 (95% CI: -2.2 to 0.6)mmHg, after SFC. Both changes were observed after 15 min. Both drugs caused a small decrease in PaCO2 (greater changes: -1.9 (95% CI -3.2 to -0.6)mmHg, p=0.005 at 60 min after tiotropium; and -2.4 (95% CI: -3.5 to -1.3) mmHg, p=0.0002 at 180 min after SFC). These results indicate that both tiotropium and SFC are able to induce a significant long-last bronchodilation without affecting arterial blood gases. Moreover, they confirm that the impact of tiotropium on PaO2 is small and without clinical significance and the addition of a LABA to an ICS can reduce the potentially dangerous acute effect of the LABA on blood gases.     

The Novartis view on emerging drugs and novel targets for the treatment of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease characterized by airflow limitation and chronic inflammation in the lungs. The mainstay of drug therapy for COPD is represented by long-acting bronchodilators, an important aspect of Novartis' development program. Novel once-daily dosing bronchodilators, such as the long-acting muscarinic antagonist (LAMA) glycopyrronium and the LAMA/long-acting β₂-agonist (LABA) fixed-dose combination QVA149, have been shown to provide significant benefits to patients with COPD in terms of improvement in lung function, exercise tolerance, health-related quality of life, symptoms and reduction in the rate of exacerbations. Despite the benefits provided by these new treatment options, prevention of disease progression and control of exacerbations in certain patient phenotypes remain key challenges in the treatment of COPD. In order to address these needs and gain new insights into the complexity of COPD, Novartis is, in addition to bronchodilator-only therapies, developing LABA/inhaled corticosteroids (ICS) combinations to target inflammation, such as QMF149, as well as non-steroid based anti-inflammatory agents against key novel targets. These commitments are central to the Novartis' final goal of improving the standard of care in respiratory medicine and offering a better quality of life to patients with COPD.     

Incorporando nuevas evidencias sobre medicamentos inhalados en la EPOC. Asociación Latinoamericana de Tórax (ALAT) 2019

This document on COPD from the Latin American Chest Association (ALAT-2019) uses PICO methodology to analyze new evidence on inhaled medication and answer clinical questions. The following key points emerged from this analysis: 1) evidence is lacking on the comparison of short-acting vs. long-acting bronchodilators in patients with mild COPD; patients with moderate-to-severe COPD obtain greater benefit from long-acting bronchodilators; 2) the benefits of monotherapy with long-acting antimuscarinic agents (LAMA) and combined therapy with long-acting β₂-agonists and inhaled corticosteroids (LABA/ICS) are similar, although the latter is associated with a greater risk of pneumonia; 3) LABA/LAMA offer greater benefits in terms of lung function and risk of exacerbation than LABA/ICS (the latter involve an increased risk of pneumonia), 4) LAMA/LABA/ICS have greater therapeutic benefits than LABA/LAMA on the risk of moderate-severe exacerbations. With regard to the role of eosinophils in guiding the use of ICS, ICS withdrawal must be considered when the initial indication was wrong or no response is elicited, in patients with side effects such as pneumonia, and in patients with a low risk of exacerbation and an eosinophil blood count of <300 cells/μl. All this evidence, categorized according to the severity of the obstruction, symptoms, and risk of exacerbations, has been used to generate an algorithm for the use of inhaled medication in COPD.     

Switching from long‐acting beta‐agonist and inhaled corticosteroid to long‐acting beta‐agonist and long‐acting muscarinic antagonist for chronic obstructive pulmonary disease: a case report of inhaled corticosteroid withdrawal

Chronic obstructive pulmonary disease (COPD) is a medical condition characterised by persistent respiratory symptoms and airflow limitation. For the long‐term management of COPD, inhaled therapies are the main approach to maintenance treatment. In order to improve treatment efficacy and tolerability for patients with COPD, recent clinical trials have focused on the withdrawal of inhaled corticosteroids (ICSs), the use of which has been associated with adverse outcomes, including pneumonia. In this case report, a patient with Global Initiative for Chronic Obstructive Lung Disease grade 3 COPD was switched from a combined inhaled therapy of a long‐acting beta‐agonist (LABA) and ICS to a combination of a LABA and a long‐acting muscarinic antagonist (tiotropium/olodaterol) during hospitalisation for an acute exacerbation of COPD in April 2016. He was subsequently maintained in a stable condition, and was able to live and travel independently. This case report of successful ICS withdrawal suggests that, for moderate‐to‐severe COPD, if it is assessed individually, dual therapy of LABA and long‐acting muscarinic antagonist can be highly effective and well‐tolerated. Treatment compliance and lifestyle modifications have been shown to be critical in optimising treatment outcomes.