Budesonide/formoterol for maintenance and reliever therapy in the management of moderate to severe asthma

The Global Initiative for Asthma (GINA) guidelines aim at improving asthma control and preventing future risk. For patients with moderate to severe asthma an inhaled corticosteroid (ICS) or an ICS/long‐acting β₂‐agonist (LABA) combination with a short‐acting β₂‐agonist (SABA) as reliever is recommended. Despite the availability of effective maintenance therapies, a large proportion of patients still fail to achieve guideline‐defined asthma control, and overuse of SABA reliever medication at the expense of ICS is commonly observed. New simplified treatment approaches may offer a solution and assist physicians to achieve overall asthma control. One such treatment approach, which is recommended in the GINA guidelines, is budesonide/formoterol for both maintenance and reliever therapy. This treatment strategy significantly reduces the rate of severe asthma exacerbations compared with ICS/LABA plus SABA and achieves equivalent daily symptom control compared with higher doses of ICS/LABA plus separate SABA for relief. These benefits are achieved at a lower overall steroid load, and budesonide/formoterol maintenance and reliever therapy is well tolerated in patients with moderate to severe asthma. This review discusses current asthma management in patients with moderate to severe disease and examines the evidence for alternative asthma management approaches.     

Acute asthma intervention: insights from the STAY study

In some patients, asthma control is improved by combining inhaled corticosteroids with long-acting beta(2)-agonists. However, fluctuating asthma control and exacerbations can still occur. The STAY study evaluated whether, in patients with moderate to severe asthma, replacing a short-acting beta(2)-agonist reliever with the combination of budesonide/formoterol as reliever would both provide rapid symptom relief and reduce asthma exacerbations. The study evaluated 2760 patients with asthma (4-80 years) randomized to budesonide 400 microg twice daily (bid) and terbutaline as reliever, budesonide/formoterol 100/6 microg bid and terbutaline as reliever, or budesonide/formoterol 100/6 microg bid both as maintenance and reliever. Children (age 4-11 years) used a once-daily maintenance dose. Budesonide/formoterol as maintenance and reliever significantly reduced severe exacerbation risk by 45% to 47% compared with the other 2 treatments and improved symptoms, awakenings, and lung function. The benefit was seen in patients of all ages. Subsequent studies have revealed that this beneficial effect of budesonide/formoterol as maintenance and reliever requires both components of the combination.     

Non-Corticosteroid Anti-Inflammatory Drugs in Asthma

Asthma is a chronic inflammatory disease of the airways. As airways inflammation plays a principal role in the pathogenesis of asthma, even in patients with mild disease, current recommendations give anti-inflammatory therapy a central position in the treatment of asthma. Although inhaled corticosteroids are the most widely used anti-inflammatory drugs in the management of patients with asthma, nonsteroidal anti-inflammatory agents may be used as a first step. Sodium cromoglycate (cromolyn sodium) and nedocromil are anti-inflammatory drugs which are effective in many patients with asthma of mild to moderate severity. Both drugs have been demonstrated to be well tolerated. Nedocromil is more potent than sodium cromoglycate, although the number of clinical studies that have compared these two drugs is small. Nedocromil may also be effective as a corticosteroid-sparing agent in the treatment of patients with asthma who require high dosages of inhaled corticosteroids. This may be important, as high dosages of inhaled corticosteroids may cause adverse effects. A novel approach to the treatment of asthma is represented by the leukotriene synthesis inhibitors and leukotriene receptor antagonists, new classes of anti-inflammatory drugs. Although the number of clinical studies with these agents is relatively small, they indicate effectiveness in the treatment of patients with mild to moderate asthma with no systemic adverse effects. Theophylline has only recently been reconsidered as a potential anti-inflammatory drug. Although serious toxicity may occur with this agent, theophylline is effective in reducing symptoms and improving lung function in patients with mild chronic asthma, even in those already treated with inhaled corticosteroids.     

Real-world patterns and implications of short-acting β2-agonist use in patients with asthma in the United States

BackgroundShort-acting β₂-agonist (SABA) use is one measure reflecting asthma control.ObjectiveTo evaluate the associations between real-world SABA use and severe asthma exacerbations in the United States.MethodsPatients with asthma 12 years of age or older receiving SABA in the IBM MarketScan research databases of US administrative claims from September 30, 2014, to September 30, 2016, were evaluated. Patients with 12 months’ continuous eligibility before and after their first SABA claim (index SABA), an asthma diagnosis before through 60 days postindex, and either one additional SABA or at least 1 maintenance fill(s) were included. SABA claims postindex (including index fill) were grouped as follows: low: index only; medium: 2 to 3 canisters per year; and high: 4 or more canisters per year. Differences in SABA exposure with respect to disease severity groups and severe asthma exacerbations (hospitalizations, emergency visits, or outpatient systemic corticosteroids) were analyzed by analysis of variance and χ² (significance, P ≤ .05).ResultsA total of 135,540 patients were included: 62.8% women; mean (SD) age, 40.9 (18.3) years; SABA fills per 12-months postindex: 3.0 (2.7). Furthermore, 28% of patients filled 1 SABA, 47% 2 to 3, and 25% 4 or more canisters per year. Despite higher maintenance medication possession ratio with increasing SABA (low, 0.53 (0.37); medium, 0.59 (0.35); high, 0.66 (0.32)), annual exacerbation rate per person per year and percent of patients within each SABA group having at least 1 exacerbation rose as SABA fills increased (low, 1.00 (1.45), 45.8%; medium, 1.20 (1.62), 54.3%; high, 1.50 (1.94), 58.7%). Mean SABA fills differed between patients with 0 exacerbation, 2.8 (2.6); 1 exacerbation, 2.9 (2.5); and 2 or more exacerbations, 3.3 (2.9).ConclusionExacerbation risk increased with increasing SABA fills. Management strategies ensuring adequate anti-inflammatory therapy delivered to the airways when symptoms occur may be needed to mitigate asthma morbidity.     

Clinical implications of airway inflammation in mild intermittent asthma.

OBJECTIVE: To determine whether inhaled corticosteroids should be prescribed to patients with milder forms of asthma and whether markers of airway inflammation should be considered when making therapy decisions. DATA SOURCES: A PubMed search was performed of the English-language literature published in the preceding 10 years (January 1, 1993, through December 31, 2003) concerning epidemiology, pathophysiology, therapy, and prognosis of mild intermittent asthma, with asthma, mild, and intermittent as indexing terms. STUDY SELECTION: All relevant studies including author's expert opinions were selected. RESULTS: Several studies have addressed the question of a possible benefit of maintenance therapy (ie, inhaled steroids) in patients with mild intermittent asthma. Although a diminishing effect on airway inflammation has been widely demonstrated, even in patients with mild disease, the impact of inhaled steroids on the long-term prognosis is much less clear. For patients with mild disease who are long-term inhaled steroid users, alternative therapy strategies, including low-dose inhaled steroids and leukotriene receptor antagonists, have been advocated. CONCLUSIONS: Mild intermittent asthma is a disease characterized not only by infrequent symptoms and normal lung function but also by chronic airway inflammation, possibly resulting in irreversible airflow limitation if left unattended. Therefore, maintenance therapy, such as (low-dose) inhaled steroids or leukotriene receptor antagonists, should be considered in patients with mild disease. Future studies should give more insight into the impact of prolonged anti-inflammatory therapy on the long-term prognosis of mild intermittent asthma patients. Whether results from these studies will justify a more aggressive treatment for these patients remains to be answered.     

Symptoms, spirometry, exhaled nitric oxide, and asthma exacerbations in clinical practice

BACKGROUND: Patient symptoms, spirometry measurements, exacerbation rates, and exhaled nitric oxide (FE(NO)) levels have all been used to quantify asthma severity. OBJECTIVE: To determine the relationships among these disease surrogates in clinical practice. METHODS: Data were collected from 5 primary care asthma clinics on patient symptoms, reliever use, spirometry measurements, maintenance pharmacotherapy, disease severity (British Thoracic Society treatment step), and FE(NO) level. Exacerbation data (asthma-related unscheduled health care contact or rescue oral corticosteroid therapy) for the 12 months before and 3 months after the clinic visit were then obtained. RESULTS: A total of 267 adult asthmatic patients (mean [SEM] age, 51.6 [1.1] years; forced expiratory volume in 1 second, 86.3% [1.2%] of predicted) participated, and 157 exacerbations were captured. For the 12 months before the clinic visit, exacerbation rate was positively correlated with dose of inhaled corticosteroid (P < .001), treatment step (P < .001), reliever use (P = .002), and symptom score (P < .001) but was negatively correlated with FE(NO) level (P = .04); only symptom scores correlated with exacerbation rate in the 3 months after the visit. Levels of FE(NO) were significantly lower in frequently exacerbating patients receiving higher doses of maintenance inhaled corticosteroids compared with patients with mild disease who were corticosteroid naive (19.7 vs 40.4 ppb, P < .001). Measurement of FE(NO) was an insensitive method (sensitivity, 66.7%; specificity, 51.9% at a cutoff value of 20 ppb) for identifying patients who subsequently exacerbated. CONCLUSION: Levels of FE(NO) are paradoxically decreased in patients with more severe asthma and frequent exacerbations and may, therefore, be of limited utility in primary care.     

Assessment of asthma control and its impact on optimal treatment strategy

Achieving and maintaining optimal asthma control is a major asthma management goal advocated by the Global Initiative for Asthma (GINA). Recent evidence suggests that while asthma control is clearly achievable in most asthmatics, not all asthmatics attain optimal asthma control. The difficulty is compounded further because patients, physicians and regulatory bodies have different perceptions of what is meant by asthma control. The challenge therefore remains as to how best to assess asthma control and define management strategies to ensure that this control is achieved and maintained. Despite the availability of several patient-based tools for assessing asthma control, these are mostly employed in a research setting or in selected specialist clinics. A symptom-based treatment approach also may have its limitations because patients can be poor judges of disease symptoms and severity and under-estimation may lead to inadequate treatment of airway inflammation and airway hyperresponsiveness (AHR) when treatment is administered as on-demand reliever therapy, since the effect of treatment on these underlying features occurs over a longer time course. The clinical benefits of sustained maintenance treatment for at least 3 months has been documented in recent studies of salmeterol/fluticasone propionate combination, which have demonstrated correlations between reduction in airway inflammation/AHR and reduction in exacerbation rates. In view of the putative limitations of a purely symptom-based asthma management plan, we suggest that treatment should be focussed on management of all aspects of the disease rather than management of symptoms alone, with a practical approach being treatment for a minimum of 3 months with an optimal dose to ensure maximal effects are seen on asthma control, airway inflammation, lung function, and remodelling.     

孟鲁司特钠对轻度持续哮喘患儿疗效和安全性的随机双盲安慰剂对照试验

目的研究孟鲁司特钠单用于治疗5~14岁轻度持续哮喘患儿的疗效和安全性。方法采用安慰剂随机双盲对照试验,对首诊诊断为轻度持续哮喘患儿,采用调查问卷方式采集患儿基线数据,经过2周安慰剂洗脱期,随机分为治疗组和对照组,分别睡前咀嚼口服孟鲁司特钠或安慰剂5 mg.d-1,疗程均为12周。在入组后4、8和12周记录哮喘日记卡内容：日间和夜间哮喘症状评分、β2受体激动剂使用频率、最大呼气峰流速（PEF）、因哮喘急性发作而需急诊或住院治疗的次数等;于治疗后12周检测肺功能指标：FEV 1%预计值、FEF 25%~75%。结果 2009年9月至2010年9月上海交通大学附属第一人民医院儿科哮喘专科门诊的轻度持续哮喘患儿安慰剂组纳入42例,孟鲁司特钠组纳入89例,至观察终点安慰剂组35例,孟鲁司特钠组77例进入分析。与安慰剂组相比,孟鲁司特钠组的PEF明显改善（P〈0.05）;每周日间和夜间哮喘症状平均评分、每月因哮喘发作而需急诊或住院就诊率和每周平均β2受体激动剂使用次数均下降,差异有显著统计学意义（P〈0.01）;治疗后12周孟鲁司特钠组FEV 1%、FEF 25%~75%较安慰剂组显著提高（P〈0.05）;研究期间两组患儿均未观察到不良反应事件。结论孟鲁司特钠单独用于轻度持续性哮喘患儿具有良好的疗效,不良反应少,患儿依从性高。     

How and by whom care is delivered influences anti-inflammatory use in asthma: Results of a national population survey

BACKGROUND: Studies examining the influence of provider behavior and patterns of care delivery on the use of anti-inflammatory asthma therapy have been limited to selected populations or have been unable to assess the appropriateness of therapy for individuals. We have previously reported the influence of sociodemographic variables and asthma severity on reported use of asthma medications in the United States. OBJECTIVE: We sought to examine the influence of patterns of care delivery and clinician behavioral factors on the use of anti-inflammatory medication by patients with asthma. METHODS: We performed a cross-sectional national random digit dial household telephone survey in 1998 of adult patients and parents of children with current asthma. Respondents were classified as having current asthma if they had a physician's diagnosis of asthma and were either taking medication for asthma or had asthma symptoms during the past year. RESULTS: One or more persons met the study criteria for current asthma in 3273 (7.8%) households in which a screening questionnaire was completed. Of the 2509 persons (721 children <16 years of age) with current asthma interviewed, 507 (20.1%) reported current use of anti-inflammatory medication. In a multiple logistic regression model controlling for asthma symptoms, reported anti-inflammatory use was significantly associated with patients reporting their physician having an excellent ability to explain asthma management (odds ratio [OR], 1.47; 95% CI, 1.09-1.98), scheduling regular visits to a physician for asthma (OR, 1.30; 95% CI, 1.02-1.64), having a written asthma action plan (OR, 1.63; 95% CI, 1.29-2.06), and being of white, non-Hispanic ethnicity (OR, 1.53; 95% CI, 1.19-1.98), along with markers of greater asthma morbidity, missing 6 or more days from work or school in the past year (OR, 1.29; 95% CI, 1.01-1.65), and hospitalization for asthma in the past year (OR, 1.74; 95% CI, 1.19-2.53). Anti-inflammatory use was less likely to be reported with younger age (OR, 0.82; 95% CI, 0.73-0.94), lower long-term asthma symptom burden (OR, 0.82; 95% CI, 0.71-0.94), use of 4 or fewer reliever inhaler canisters in the past year (OR, 0.50; 95% CI, 0.43-0.58), and smoking (OR, 0.50; 95% CI, 0.37-0.68). CONCLUSION: How asthma care is delivered influences the use of anti-inflammatory medication. Strategies to increase regular evaluation by a physician interested in asthma, particularly for minority patients, and to increase a physician's ability to communicate asthma management to patients might improve use of anti-inflammatory therapy among patients with asthma.     

Presentation of new GINA guidelines for paediatrics

The Global Initiative on Asthma (GINA) has provided guidelines for the management of children with asthma. For a step-wise approach to therapy, asthma is divided into four categories based on severity of symptoms: intermittent, mild persistent, moderate persistent, and severe persistent asthma. Long-term preventive therapy is distinguished from quick relief therapy in each group. Although these guidelines are clear and simple there have been few studies on asthma therapy for infants. Moreover, the existence of different wheezing phenotypes with varying pathogenic mechanisms hampers the interpretation of these studies. Transient wheezers have stopped wheezing by the age of 3 years and there is no relationship to atopy or a family history of asthma. In contrast, persistent wheezers continue to wheeze from the first year of life throughout school-age and have a high risk of atopy. Although they have normal lung function at birth, persistent wheezers develop significant decrements in lung function by the age of 6 years. Whether these impairments are amenable to prevention by early initiation of anti-inflammatory therapy remains to be seen. At present, there are no disease markers to identify the different wheezing phenotypes in infancy, although eosinophil counts and measurements of eosinophil cationic protein in serum may prove to be helpful in distinguishing these conditions.     

The effects of inhaled budesonide and formoterol in combination and alone when given directly after allergen challenge

BACKGROUND: The use of combination inhaled budesonide and formoterol as maintenance and reliever therapy significantly improves the risk and the time to exacerbations in asthma. OBJECTIVES: To explore the mechanisms underlying the effect of the reliever dose on exacerbations by examining the effect of combination therapy on the allergen challenge model when given after allergen exposure. METHODS: In a randomized, double-blind crossover study, single doses of budesonide/formoterol (400/12 mug), formoterol (12 mug), budesonide (400 mug), or placebo were administered during the acute bronchoconstriction response (early airway response) immediately after allergen inhalation in 15 patients with mild asthma. Allergen-induced late airway response (LAR), sputum inflammatory markers, airway hyperresponsiveness, and exhaled nitric oxide were measured. RESULTS: All active treatments significantly attenuated the LAR, with budesonide/formoterol significantly better than its monocomponents (maximum FEV(1) fall: placebo, [mean +/- SEM] 21.2% +/- 3.1%; budesonide/formoterol, 4.2% +/- 1.4%; formoterol, 7.5% +/- 1.7%; budesonide, 10.4% +/- 1.6%). Allergen-induced change in methacholine PC(20) was significantly attenuated by budesonide/formoterol, but not by its monocomponents. Sputum cell counts and exhaled nitric oxide increased significantly after all allergen challenges, with no significant attenuation by any of the treatments. Therapy with combination and formoterol alone, but not budesonide, significantly reduced the early airway response. CONCLUSION: A single dose of budesonide/formoterol was superior to its monocomponents in attenuating the allergen-induced LAR and airway hyperresponsiveness. These effects may represent the contribution of the reliever dose to the budesonide/formoterol maintenance and reliever regimen. CLINICAL IMPLICATIONS: The protective effect against allergic airway responses with a single reliever dose of budesonide/formoterol is predominantly related to greater functional antagonism of airway smooth muscles.     

What general practitioners and paediatricians think about their patients' asthma

The Asthma Insight and Reality in Europe (AIRE) study showed that the current management and treatment of asthma in Europe falls short of the goals set in the GINA guidelines. Patient care may be negatively influenced by the physicians' underestimation of their patients' disease state, and overestimation of their patients' knowledge of asthma management. We interviewed 118 paediatricians and 152 general practitioners (response rate 70 and 86%, respectively) in order to get an insight into the physicians view on his patients' asthma management. A questionnaire containing similar items to those used in the AIRE study was used. Dutch physicians believe that the asthma of the majority of their patients is well controlled and underestimate the prevalence of daytime symptoms. They believe that their patients are aware of the differences between reliever medication and maintenance medication and overestimate the number of patients in possession of a written action plan. Dutch paediatricians and general practitioners underestimate the severity of their patients' disease state and overestimate their patients' knowledge of disease management.     

Severe asthma: advances in current management and future therapy

Effective treatment of severe asthma is a major unmet need because patients' symptoms are not controlled on maximum treatment with inhaled therapy. Asthma symptoms can be poorly controlled because of poor adherence to controller therapy, and this might be addressed by using combination inhalers that contain a corticosteroid and long-acting β(2)-agonist as reliever therapy in addition to maintenance treatment. New bronchodilators with a longer duration of action are in development, and recent studies have demonstrated the benefit of a long-acting anticholinergic bronchodilator in addition to β(2)-agonists in patients with severe asthma. Anti-IgE therapy is beneficial in selected patients with severe asthma. Several new blockers of specific mediators, including prostaglandin D(2), IL-5, IL-9, and IL-13, are also in clinical trials and might benefit patients with subtypes of severe asthma. Several broad-spectrum anti-inflammatory therapies that target neutrophilic inflammation are in clinical development for the treatment of severe asthma, but adverse effects after oral administration might necessitate inhaled delivery. Macrolides might benefit some patients with infection by atypical bacteria, but recent results are not encouraging, although there could be an effect in patients with predominant neutrophilic asthma. Corticosteroid resistance is a major problem in patients with severe asthma, and several molecular mechanisms have been described that might lead to novel therapeutic approaches, including drugs that could reverse this resistance, such as theophylline and nortriptyline. In selected patients with severe asthma, bronchial thermoplasty might be beneficial, but thus far, clinical studies have not been encouraging. Finally, several subtypes of severe asthma are now recognized, and in the future, it will be necessary to find biomarkers that predict responses to specific forms of therapy.     

Improving asthma outcomes in large populations

This article summarizes our experience using administrative, survey, and telephone information to define asthma severity, impairment, risk, and quality of care in our large Kaiser Permanente population. Our data suggest that the 2-year Healthcare Effectiveness Data and Information Set definition of persistent asthma is a good surrogate for survey-defined persistent asthma, and thus it would be reasonable to direct asthma population management and quality-of-care assessments at patients with Healthcare Effectiveness Data and Information Set-defined persistent asthma for 2 years in a row. For population management, the numbers of short-acting β-agonist (SABA) canisters dispensed and validated tools on mail or telephone surveys have been used to assess asthma impairment. Algorithms based on pharmacy data (SABA canister and oral corticosteroid dispensings and prior emergency hospital care) have been used to assess the risk domain of asthma control. The asthma medication ratio (controllers divided by controllers plus SABAs) has been shown to be related to improved outcomes and is recommended as an asthma quality-of-care marker. It is hoped that outreach to patients and providers based on these indicators will improve asthma outcomes in patients cared for in individual practices, as well as in large health plans.     

Childhood asthma: a rational approach to treatment

Asthma is a common, but frequently underdiagnosed and undertreated, condition in childhood. In most children, the diagnosis of asthma can be made on the basis of history, physical examination, and simple investigations. Successful management of asthma is contingent upon both patient and parents having a clear understanding of the condition, the goals, and specific details of treatment. The majority of children with asthma can be managed by avoidance of provoking factors, and suppression of symptoms with drug therapy. Drug therapy should follow a logical scheme such that a child with mild, infrequent asthma attacks would receive intermittent bronchodilator therapy, whereas a child with severe chronic asthma would ultimately be treated with maintenance steroids. Response to therapy should be assessed by serial measurement of pulmonary function. Certain features peculiar to infantile asthma demand a modified approach to the management of asthma in this age group.     

Understanding mild persistent asthma in children: the next frontier

Limitations in asthma prevalence studies and difficulties in diagnosing pediatric asthma lead to uncertainty over the full extent of mild persistent asthma in children and adolescents. Although recent surveys have reported that the majority of pediatric patients with asthma in the United States and Europe have symptoms consistent with mild disease, these surveys have limitations in design. Thus, the true prevalence of mild asthma remains unknown. It is unclear whether children with mild persistent asthma progress to more severe asthma, but the risk of severe asthma exacerbations seems to be unrelated to the symptom severity. Clinical studies restricted to pediatric patients with mild asthma are limited, but available data do suggest substantial morbidity of mild persistent asthma in this population and support inhaled corticosteroid intervention. There is a need for further investigation into the true prevalence of mild persistent asthma in children and adolescents, and optimal treatment.