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.     

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.     

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.     

Safety of long-acting beta-agonists in stable COPD: a systematic review

BACKGROUND: Some studies have suggested that use of long-acting beta(2)-agonists (LABAs) leads to an increased risk for adverse events in patients with stable COPD. The purpose of this review was to assess the safety, and secondarily the efficacy of LABAs. METHODS: The authors conducted a systematic review with metaanalysis of randomized clinical trials (> or = 1 month in duration) in the published literature that have compared LABAs with placebo or anticholinergics in stable poorly reversible and reversible COPD. RESULTS: MEDLINE, EMBASE, CINAHL, and the Cochrane Controlled Trials Register were searched to identify 27 studies. LABAs reduced severe exacerbations compared with placebo (relative risk [RR], 0.78; 95% confidence interval [CI], 0.67 to 0.91). There was no significant difference between LABA and placebo groups in terms of respiratory deaths (RR, 1.09; 95% CI, 0.45 to 2.64). Use of LABAs with inhaled corticosteroids reduced the risk of respiratory death compared with LABAs alone (RR, 0.35; 95% CI, 0.14 to 0.93). Patients receiving LABAs showed significant benefits in airflow limitation measures, health-related quality of life, and use of rescue medication. Finally, tiotropium decreased the incidence of severe COPD exacerbations compared with LABAs (RR, 0.52; 95% CI, 0.31 to 0.87). CONCLUSION: This review supports the beneficial effects of the use of LABAs in patients with stable moderate-to-severe COPD, and did not confirm previous data about an increased risk for respiratory deaths. Also, our analysis suggests the superiority of tiotropium over LABAs for the treatment of stable COPD patients.     

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.     

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 beta2-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.     

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.     

Uncontrolled asthma: a review of the prevalence, disease burden and options for treatment

An estimated 300 million people are affected by asthma worldwide and the burden is likely to rise substantially in the next few decades. Estimates of the prevalence of asthma range from 7% in France and Germany to 11% in the USA and 15-18% in the United Kingdom. Approximately 20% of these patients have severe asthma, of which 20% is inadequately controlled. Patients with inadequately controlled severe persistent asthma are at a particularly high risk of exacerbations, hospitalization and death, and often have severely impaired quality of life. Current management of asthma focuses on a stepwise approach tailored to disease severity. In addition to needing high-dose inhaled corticosteroids (ICS) and long-acting beta(2)-agonists (LABAs), patients with severe persistent asthma often require additional controller medications, such as anti-leukotrienes, oral LABAs, oral corticosteroids and/or anti-IgE therapy. There is currently little evidence on which to base treatment decisions in patients with inadequately controlled severe persistent asthma already treated with ICS and LABAs. The anti-IgE monoclonal antibody omalizumab is the most recent addition to the list of treatment options for these patients and has been shown to reduce exacerbations and emergency visits and improve lung function, symptom scores and quality of life in patients with difficult-to-treat asthma whose symptoms remain inadequately controlled despite receiving ICS and LABAs. Comparative trials are needed to determine the merits of different treatments and strategies for patients with inadequately controlled severe persistent asthma and to identify patients likely to benefit from new treatment options.     

Should Patients Switched from D to B in the GOLD 2017 Classification be Discontinued from Inhaled Corticosteroids?

Inhaled corticosteroids (ICSs) are the cornerstone of the treatment of asthma, but their role in COPD is limited. Several guidelines recommend their use in patients with severe airflow limitation, frequent exacerbations and asthma-COPD overlap (ACO), while the previous GOLD document recommended ICS for patients with high risk of exacerbations and a high level of symptoms (group D). Following the changes in the GOLD document 2017 update, in which impaired lung function is no longer considered as a determinant of exacerbation risk, a high number of COPD patients can now be labeled as group B (low risk of exacerbations and high level of symptoms) instead of D, and hence, no longer fulfill the indication for ICS. Since long-term therapy with ICS can entail secondary effects, the withdrawal of this treatment should be considered in this group of patients. In this article, we summarize the evidence for discontinuation of ICS in this subgroup of patients and provide suggestions for clinicians on the appropriate use on ICS in patients moving from D to B.     

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.     

The role of indacaterol for chronic obstructive pulmonary disease (COPD)

Indacaterol is the first long-acting β2-agonist (LABAs) approved for the treatment of chronic obstructive pulmonary disease (COPD) that allows for once-daily (OD) administration. It is rapidly acting, with an onset of action in 5 minutes, like salbutamol and formoterol but with a sustained bronchodilator effect, that last for 24 hours, like tiotropium. In long-term clinical studies (12 weeks to 1 year) in patients with moderate to severe COPD, OD indacaterol 150 or 300 μg improved lung function (primary endpoint) significantly more than placebo, and improvements were significantly greater than twice-daily formoterol 12 μg or salmeterol 50 μg, and noninferior to OD tiotropium bromide 18 μg. Indacaterol was well tolerated at all doses and with a good overall safety profile. Cost-utility analyses show that indacaterol 150 μg has lower total costs and better outcomes than tiotropium and salmeterol. These findings suggest that indacaterol can be considered a first choice drug in the treatment of the patient with mild/moderate stable COPD. However, in people with COPD who remain symptomatic on treatment with indacaterol, adding a long-acting muscarinic antagonist (LAMA) is the preferable option. In any case, it is advisable to combine indacaterol with a OD inhaled corticosteroid (ICS), such as mometasone furoate or ciclesonide, in patients with low FEV1, and, in those patients who have many symptoms and a high risk of exacerbations, to combine it with a LAMA and a OD ICS.KEY WORDS : Long-acting β2-agonists (LABAs), indacaterol, chronic obstructive pulmonary disease (COPD), combination therapy     

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.     

Inhaled corticosteroids and risk of tuberculosis—How bad is the risk?

Inhaled corticosteroids (ICS) have a central role in the management of obstructive airway diseases. Use of ICS in asthma and chronic obstructive pulmonary disease (COPD) is associated with a small but clear increase in incidence of pneumonia and tuberculosis. Since ICS use in obstructive airway diseases has beneficial effects with regard to symptoms, lung function, quality of life and exacerbations, denying the benefit of ICS solely based on this small elevated risk of pneumonias and tuberculosis is not justified. The present article attempts to elucidate mechanisms contributing to the increased risk, assesses the magnitude and risk factors of tuberculosis in patients using ICS and provides practical suggestions for practising clinicians.     

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.

     

Effectiveness of Treatment With Dual Bronchodilation (LABA/LAMA) Compared With Combination Therapy (LABA/ICS) for Patients With COPD: A Population-Based Study

BackgroundInitiation of treatment of COPD with a combination of a long-acting beta-agonist (LABA) and an inhaled corticosteroid (ICS) is frequent irrespective of the risk of exacerbations.MethodWe performed a retrospective, population-based, observational study aimed at comparing the effectiveness of a LABA/long-acting antimuscarinic agent (LAMA) and LABA/ICS in patients with COPD over a one-year follow-up. Data were obtained from an administrative healthcare claims database. The primary outcome was the risk of first exacerbation. A sensitivity analysis was conducted in a propensity-score matched population.ResultsThe population consisted of 14,046 COPD patients; 11,329 (80.6%) initiated LABA/ICS and 2717 (19.4%) LABA/LAMA. The matched population included 1650 patients in each arm. During follow-up, 69.6% patients in the LABA/ICS group and 64.4% in the LABA/LAMA group presented an exacerbation. The mean time to the first exacerbation was 6.03 months (95% confidence interval (CI): 5.94–6.12) for LABA/ICS and 6.4 months (95%CI: 6.21–6.59) for LABA/LAMA; p < 0.001. The time to scalation to triple therapy was also significantly prolonged in LABA/LAMA. Similar results were obtained in the matched population. LABA/LAMA was associated with a significantly lower risk of exacerbations and escalation to triple therapy compared to LABA/ICS, except in patients with frequent exacerbations and high blood eosinophils in which no differences were observed in the time to first exacerbation.ConclusionInitiation of treatment with LABA/LAMA was associated with a lower risk of exacerbation and escalation to triple therapy compared to LABA/ICS in the majority of patients with COPD in primary care.     

Tiotropium for the treatment of stable chronic obstructive pulmonary disease: a systematic review with meta-analysis

BACKGROUND: Current guidelines recommend the use of inhaled tiotropium in patients with stable chronic obstructive pulmonary disease (COPD). However, this statement is based on a relatively small number of randomized controlled trials (RCTs) and related systematic reviews. This review was undertaken to incorporate the more recent evidence available about the effectiveness of tiotropium bromide compared with placebo, iptratropium bromide or long-acting beta-agonists (LABAs), for the treatment of stable COPD patients. DATA SOURCE: Medline, EMBASE, CINAHL, and the Cochrane Controlled Trials Register (to February 2006) were searched to identify all published RCTs. We also searched bibliographies of relevant articles. RESULTS: Data from 13 RCT (6078 subjects, 80% male) showed that tiotropium reduced COPD-related exacerbations (OR=0.76; 95% CI: 0.68-0.87) and hospital admissions (OR=0.59; 95% CI: 0.47-0.73) compared with placebo. Also, tiotropium showed statistically significant improvement in lung function, including trough, average, and peak FEV(1) and FVC from baseline, compared with placebo and ipratropium. The administration of inhaled tiotropium lead to 30% reduction in COPD-related admissions (OR= 0.67; 95% CI: 0.46-0.98) compared with LABAs. Finally, increases in FEV(1) and FVC from baseline were significantly larger with tiotropium than with LABAs. CONCLUSIONS: This review clearly supports the beneficial effects of the use of tiotropium in stable moderate-to-severe COPD patients, and increases the evidence in favor of the superiority of tiotropium on LABAs.