Pharmacological strategies for self-management of asthma exacerbations.

Written action plans are effective within asthma self-management, but there are few guidelines about the specific medication adjustments which can be recommended for self-treatment of exacerbations. This review examines pharmacological strategies for self-management of asthma exacerbations in adults, including those for inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) users. Oral corticosteroids are well-established in clinical practice and clinical trials for the treatment of severe exacerbations, including during combination therapy. Evidence supports 7-10 days treatment, with no need to taper except to reduce side-effects. Doubling the dose of ICS is not effective. Several studies have shown benefit from high-dose ICS (2,400-4,000 microg beclomethasone equivalent) for 1-2 weeks. This may be achieved by adding a high-dose ICS inhaler to maintenance ICS or ICS/LABA therapy. There is inconclusive evidence about acutely increasing the dose of maintenance budesonide/formoterol for exacerbations, and no studies of this approach with fluticasone/salmeterol. For patients taking maintenance budesonide/formoterol, use of the same medication as-needed reduces exacerbations. Short-acting beta2-agonists are still effective in producing bronchodilation during combination therapy; however, a higher dose may be required. There is a need for further studies to clarify remaining issues about self-management of asthma exacerbations, particularly with regard to side-effects of treatment and patient acceptability.     

The future of the long-acting beta-adrenergic bronchodilators in the treatment of asthma.

The combination of long-acting beta-agonist (LABA) bronchodilators with inhaled corticosteroids (ICSs) has been shown to be an extremely effective treatment for asthma. Use of LABA as monotherapy for asthma is associated with increased adverse events including exacerbations and asthma deaths. However, intensive evaluation of the combined LABA-ICS therapy provided no signals of increased risk. LABA appears to potentiate the effects of ICS. This provides the opportunity for use a of lower ICS dose for asthma control with less risk of steroid side effects. The combination of formoterol and budesonide used as both maintenance and relief medications may offer superior asthma control with less medication use. The recent introduction of 24-hour LABA, which are in clinical trials, makes possible the concept of very effective once-daily combinations of LABA and ICS, which would be expected to increase patient adherence and improve asthma outcomes. The 24-hour LABA will likely be combined with a 24-hour anticholinergic to treat chronic obstructive pulmonary disease. Whether this dual combination with ICS will enhance our treatment of more severe asthma remains an exciting hypothesis to be tested.     

Asthma bronchiale – Aktuelle Diagnostik und Therapie

Bronchial asthma is a heterogeneous disease characterized by chronic airway inflammation. Different phenotypes can be distinguished based on the underlying type of inflammatory reaction (i.e. T_H2 vs. non-T_H2 cells), which is particularly important for patients with severe therapy refractive asthma, as new therapeutic strategies are directly targeted against T_H2-associated cytokines. Besides symptom control, successful asthma therapy also requires avoidance of exacerbations and fixed airflow limitation as well as the control of pharmacological side effects; therefore, early treatment with low-dose inhaled corticosteroid therapy (ICS) is required, if necessary in combination with a long-acting beta-2 agonist (LABA), preferably as fixed ICS/LABA combination. Before intensifying ICS therapy various factors, such as the inhalation technique have to be checked. Following increased dosage, controlled approaches to reduce ICS dosage again should not be forgotten in order to minimize drug side effects.     

Safety of regular use of long-acting beta agonists as monotherapy or added to inhaled corticosteroids in asthma. A systematic review

BackgroundSafety of long-acting beta agonists (LABA) has been questioned and recent evidence suggested a detrimental effect on asthma control as well as an increased risk of death.ObjectiveTo evaluate the safety of regular use of LABA compared with placebo or LABA added to inhaled corticosteroids (ICS) compared with ICS in persistent asthma.MethodsRandomized studies from MEDLINE, EMBASE, and Cochrane Controlled Trials Register were identified. Additionally, AstraZeneca, GlaxoSmithKline, Novartis and FDA clinical trials databases were searched. Primary outcomes were asthma exacerbations (AE) requiring systemic corticosteroids or hospitalization, life-threatening exacerbations and asthma-related deaths.ResultsWe identified 92 randomized clinical trials with 74,092 subjects. LABA (as monotherapy) reduced exacerbations requiring corticosteroids (Relative Risk [RR] = 0.80; 95% CI, 0.73–0.88), without detrimental effects on hospitalizations or life-threatening episodes. Contrarily, LABA showed a significant increase in asthma-related deaths (Relative Risk = 3.83; 95% CI, 1.21–12.14). Subgroup analysis suggests that children, patients receiving salmeterol, and a duration of treatment >12 weeks are associated with a higher risk of serious adverse effects; also there was a protective effect of concomitant use of ICS. On the other hand, combination of LABA/ICS reduced exacerbations (RR = 0.73; 95% CI, 0.67–0.79), and hospitalizations (RR = 0.58, 95% CI, 0.45–0.74). Combined therapy was also equivalent to ICS in terms of life-threatening episodes and asthma-related deaths. Again, children and use of salmeterol were associated with an increased risk of some severe outcomes as compared with adults and formoterol users, respectively.ConclusionsThis review reinforced the international recommendations in terms of the use of LABA remains the preferred add-on therapy to ICS for patients whose disease cannot adequately controlled with ICS, and that LABA cannot be prescribed as a monotherapy. Nevertheless, in spite of the protective effect of the ICS, children and salmeterol use still show an increased risk of non-fatal serious adverse events.     

Long-Acting Beta-Agonists and the Risk of Intensive Care Unit Admission in Children

Objective. A possible association between long-acting beta-agonists (LABA) and severe asthma exacerbations including death remains controversial. We examined whether LABA in the setting of combination therapy with inhaled corticosteroids (ICS) increase the risk of near-fatal asthma in children using a case–control study design. Methods. Medical records from admissions for asthma exacerbations in children 4–18 years of age during the 2005 calendar year at Children’s Hospital of Pittsburgh of UPMC were reviewed. Cases and controls were determined by pediatric intensive care unit (PICU) and floor admission, respectively. Exposure was defined by LABA use in combination with ICS versus ICS alone. Results. Records from 85 PICU and 96 pediatric floor admissions were reviewed. LABA use in combination with ICS did not increase the risk of PICU admission (odds ratio 1.07, 95% CI 0.46–2.52) compared to ICS only without LABA. After adjusting for demographics, asthma severity, history of PICU admissions, and concurrent infection, LABA/ICS use still did not increase the risk of PICU admission (adjusted odds ratio 0.84, 95% CI 0.26–2.76) compared to ICS alone. There were no deaths and five intubations within the study period. Conclusions. The combination of LABA and ICS did not appear to increase the risk of near-fatal asthma in children.     

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.     

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.     

Combination Inhalers Containing Inhaled Corticosteroids and Long-Acting β2-Agonists: Improved Clinical Efficacy and Dosing Options in Patients with Asthma

Combination therapy with inhaled corticosteroids (ICS) and long-acting β₂-agonists (LABA) is a recognized treatment for adults with moderate to severe asthma. The introduction of inhalers containing both an ICS and a LABA simplifies treatment and improves asthma control. This review discusses clinical evidence that budesonide/formoterol and salmeterol/fluticasone are effective and well tolerated in asthma treatment. Moreover, the rapid onset of effect and long duration of action of budesonide and formoterol make once-daily dosing, adjustable maintenance dosing, and the novel treatment strategy of using budesonide/formoterol for maintenance and as needed for symptom relief, valuable treatment options for patients with asthma.     

Effectiveness of drug treatment strategies to prevent asthma exacerbations and increase symptom-free days in asthmatic children: a network meta-analysis

Objective: To determine the effectiveness and safety of current maintenance therapies that include inhaled corticosteroids (ICS), long-acting β-agonists (LABA) and/or leukotriene receptor antagonists (LTRAs) in preventing exacerbations and improving symptoms in pediatric asthma. Methods: A systematic review with network meta-analysis was conducted after a comprehensive search for relevant studies in the PubMed, Cochrane Library, Embase and Clinical Trials databases, up to July 2014. Randomized clinical trials were selected comparing treatment strategies of the Global Initiative for Asthma guidelines. The full-text randomized clinical trials compared maintenance treatments for asthma in children (≤18 years) of ≥4 weeks duration, reporting exacerbations or symptom-free days. The primary and secondary effectiveness outcomes were the rates of moderate/severe exacerbations and symptom-free days from baseline, respectively. Withdrawal rates were taken as the safety outcome. Results: Included in the network meta-analysis was 35 trials, comprising 12?010 patients. For both primary and secondary outcomes, combined ICS and LABA was ranked first in effectiveness (OR 0.70, 95% CI: 0.52–0.97 and OR 1.23, 95% CI: 0.94–1.61, respectively, compared with low-dose ICS), but the result of secondary outcomes was statistically insignificant. Low-dose ICS, medium- or high-dose ICS and combined ICS and LTRA strategies were comparable in effectiveness. ICS monotherapies, and ICS?+?LABA and ICS?+?LTRA strategies were similarly safe. High-dose ICS had the highest rate of total withdrawals, but the difference was not significant. Conclusions: Combined ICS and LABA treatments were most effective in preventing exacerbations among pediatric asthma patients. Medium- or high-dose ICS, combined ICS and LTRAs, and low-dose ICS treatments seem to be equally effective.     

The importance of control in asthma management: do leukotriene receptor antagonists meet patient and physician needs?

Achieving control of asthma is a major goal of asthma management. Overreliance on high doses of a beta-agonist or a recent increase in beta-agonist requirement, increasing or wide variability in peak expiratory flow (PEF), and increased frequency of nocturnal symptoms are indicators of poor or declining asthma control, which should highlight the need to take action to avoid the risk of severe and potentially life-threatening asthma exacerbations. The prevention of exacerbations is important because these often require unscheduled physician visits and involve costly medical care. If control is not achieved, diagnosis, treatment, and compliance with therapy should be reviewed, stepping up to a more powerful treatment only if necessary to control symptoms. Many patients often receive inadequate treatment despite the best intentions of their physician. Incorrect inhaler technique and non-compliance with prescribed inhaled asthma therapy may contribute to treatment failure in 50% of patients and are recognized increasingly as reasons for poor response to treatment. Growing evidence indicates that leukotriene receptor antagonists (LTRAs) are useful as controller agents. As a simple tablet therapy, LTRAs should be considered as an alternative treatment option to inhaled corticosteroids in specific patient groups who are poorly compliant or reluctant to use inhaled corticosteroids. These agents reduce the risk of asthma exacerbations and are associated generally with improved compliance compared with inhaled corticosteroids or cromolyn sodium. Moreover, add-on therapy with LTRAs can provide additional benefits to patients whose asthma is not controlled adequately with existing doses of inhaled corticosteroids, and the complementary benefits obtained with these drugs facilitate the achievement of long-term control without the need for increasing the dose of corticosteroids.     

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.     

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.     

Cost‐effectiveness of budesonide/formoterol for maintenance and reliever asthma therapy in Denmark – Cost‐effectiveness analysis based on five randomised controlled trials

Background and Aims: Budesonide/formoterol maintenance and reliever therapy (Symbicort SMART®) is an effective asthma‐management regime where patients use budesonide/formoterol both as maintenance treatment and as additional doses as needed to improve overall asthma control by reducing symptoms and exacerbations. The aim of this study was to determine the cost‐effectiveness of the Symbicort SMART® regime in Denmark vs higher dose inhaled corticosteroid (ICS) plus reliever medication, similar dose inhaled corticosteroid/long‐acting β₂‐agonist (ICS/LABA) combination therapy plus reliever medication or higher dose of inhaled ICS/LABA combination therapy plus reliever medication. Methods: The cost‐effectiveness analyses were based on effectiveness and resource utilisation data, which were prospectively collected during the treatment period in five randomised clinical trials (duration: 24 weeks, 26 weeks or 1 year). Economic analyses were conducted from both a health care sector (direct costs) and a societal perspective [total costs, i.e direct costs + indirect costs (sick leave)]. The time horizon for the economic analyses was 1 year. The effectiveness measure used was the number of avoided severe exacerbations per patient per year. Results: Patients treated with budesonide/formoterol maintenance and reliever therapy showed statistically significant fewer severe exacerbations per patient compared with the alternative treatment regimes in all comparisons. Budesonide/formoterol maintenance and reliever therapy was a dominant treatment option when compared with higher dose ICS or higher dose ICS/LABA, i.e. it was more effective at a lower total cost. In two of the three comparisons with a similar ICS/LABA dose, Symbicort SMART® was dominant. Conclusion: Cost‐effectiveness analyses of budesonide/formoterol maintenance and reliever therapy show that the significant reduction in the number of severe exacerbations observed in all the included clinical studies is predominately obtained at lower costs compared with alternative treatment regimes. This indicates that budesonide/formoterol maintenance and reliever therapy is a cost‐effective treatment option in a Danish setting. Please cite this paper as: Wickstrøm J, Dam N, Malmberg I, Hansen BB and Lange P. Cost‐effectiveness of budesonide/formoterol for maintenance and reliever asthma therapy in Denmark – Cost‐effectiveness analysis based on five randomised controlled trials. The Clinical Respiratory Journal 2009; 3: 169–180.     

Combination Inhalers Containing Inhaled Corticosteroids and Long-Acting β2-Agonists: Improved Clinical Efficacy and Dosing Options in Patients with Asthma

Combination therapy with inhaled corticosteroids (ICS) and long-acting β₂-agonists (LABA) is a recognized treatment for adults with moderate to severe asthma. The introduction of inhalers containing both an ICS and a LABA simplifies treatment and improves asthma control. This review discusses clinical evidence that budesonide/formoterol and salmeterol/fluticasone are effective and well tolerated in asthma treatment. Moreover, the rapid onset of effect and long duration of action of budesonide and formoterol make once-daily dosing, adjustable maintenance dosing, and the novel treatment strategy of using budesonide/formoterol for maintenance and as needed for symptom relief, valuable treatment options for patients with asthma.     

The efficacy and safety of different long-acting β2-agonists combined with inhaled glucocorticoid regimens in patients with asthma: a network meta-analysis

Objective: To determine the efficacy and safety of current maintenance therapies consisting of different regimens of long-acting β2-agonists (LABA) with inhaled corticosteroids (ICS) in patients with asthma. Methods: A network meta-analysis (NMA) was conducted after a comprehensive search for relevant studies in the PubMed, Cochrane Library, and Embase databases up to January 1, 2017. Randomized clinical trials comparing LABA combined with ICS in patients with asthma were selected. Results: Seventeen trials were included in the analysis, comprising 10,961 patients and seven treatment regimens. Our NMA revealed that there were no statistically significant differences between agents regarding the frequency of moderate or severe exacerbations. For adverse effects, there were no significant differences between the included studies. Moreover, six of the results showed no statistically significant differences between agents regarding symptom-free days. The heterogeneity and inconsistency analysis of the outcomes showed that there were no differences between the regimens. Conclusions: Our findings have shown that there were no statistically significant differences between the different regimens of LABA?+?ICS regarding the frequency of moderate or severe exacerbations, adverse events, and symptom-free days.     

Pulmonale Erkrankungen im Alter

In asthma, inhaled corticosteroids (ICS) can be regarded as disease-modifying drugs. They represent the mainstay of pharmacotherapy of asthma. In elderly, ICS are currently underused. In chronic obstructive pulmonary disease (COPD), there is recent evidence to suggest that ICS may reduce the rate and severity of COPD exacerbations and may improve health-related quality of life. Particularly patients with moderate-to-severe COPD appear to benefit from ICS therapy. In both asthma and COPD, fixed combinations of ICS and long-acting beta 2-agonists may provide clinically meaningful benefits to patients and may represent a further therapeutic advantage.     

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.