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.     

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.     

Triple Therapy for the Management of COPD: A Review

Triple therapy for COPD consists of a long-acting anti-cholinergic bronchodilator, a long-acting beta-agonist bronchodilator, and an inhaled corticosteroid. Guidelines from the Canadian Thoracic Society advocate triple therapy for some patients with moderate-to-severe COPD. The objective of this review was to evaluate the evidence based clinical efficacy of triple therapy compared to dual bronchodilator therapy (long-acting anti-cholinergic bronchodilator + beta-agonist bronchodilator) or long-acting anti-cholinergic bronchodilator monotherapy for managing COPD. A systematic literature search was conducted to identify relevant clinical evaluations of triple therapy in the management of moderate to severe COPD. Databases searched included: Medline; EMBASE; CINAHL and PubMed (non-Medline records only). Of 2,314 publications, 4 articles evaluated triple therapy for the management of COPD. Hospitalization rates for COPD exacerbations, reported in 2 trials, were significantly reduced with triple therapy compared to long-acting anti-cholinergic bronchodilator monotherapy, with reported relative risks of 0.53 (95% CI: 0.33, 0.86, p = 0.01) and 0.35 (95% CI: 0.16–0.78, p = 0.011). Exacerbation data is inconsistent between the two trials reporting this outcome. Lung function, dyspnea and quality of life data show statistical significant changes with triple therapy compared to long-acting anti-cholinergic bronchodilator monotherapy but the changes do not reach clinical importance. Triple therapy does decrease the number of hospitalizations for severe/acute COPD exacerbations compared with long-acting anti-cholinergic bronchodilator monotherapy. There is insufficient evidence to determine if triple therapy is superior to dual bronchodilator therapy.     

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.     

低剂量吸入糖皮质激素治疗轻度支气管哮喘回顾性分析

目前指南不再推荐β_2受体激动剂单独用于轻度持续性支气管哮喘(简称哮喘)的规律治疗,而最近临床研究支持吸入糖皮质激素(inhaled corticosteroids,ICS)对轻度持续性哮喘具有明显的益处.本文从轻度哮喘患者的气道炎症特点,ICS的使用策略及其联合用药方面,对近年有关ICS治疗轻度哮喘这一问题进行回顾性分析,为轻度哮喘的治疗提供参考意见.     

The effects of cigarette smoke on airway inflammation in asthma and COPD: therapeutic implications

Asthma and COPD are two chronic inflammatory disorders of the airway characterized by airflow limitation. While many similarities exist between these two diseases, they are pathologically distinct due to the involvement of different inflammatory cells; predominantly neutrophils, CD8 lymphocytes in COPD and eosinophils and CD4 lymphocytes in asthma. Cigarette smoking is associated with accelerated decline of lung function, increased mortality, and worsening of symptoms in both asthma and COPD. Furthermore, exposure to cigarette smoke can alter the inflammatory mechanisms in asthma to become similar to that seen in COPD with increasing CD8 cells and neutrophils and may therefore alter the response to therapy. Cigarette smoke exposure has been associated with a poor response to inhaled corticosteroids which are recommended as first line anti-inflammatory medications in asthma and as an add-on therapy in patients with severe COPD with history of exacerbations. While the main proposed mechanism for this altered response is the reduction of the histone deacetylase 2 (HDAC2) enzyme system, other possible mechanisms include the overexpression of GR-β, activation of p38 MAPK pathway and increased production of inflammatory cytokines such as IL-2, 4, 8, TNF-α and NF-K?. Few clinical trials suggest that leukotriene modifiers may be an alternative to corticosteroids in smokers with asthma but there are currently no drugs which effectively reduce the progression of inflammation in smokers with COPD. However, several HDAC2 enhancers including low dose theophylline and other potential anti-inflammatory therapies including PDE4 inhibitors and p38 MAPK inhibitors are being evaluated.     

吸入性糖皮质激素增加哮喘患者肺炎风险

目的 探讨哮喘患者长期吸入激素(ICS)是否增加肺炎发生风险.方法 选择上海市杨浦区市东医院07年1月～ 07年12月哮喘患者共300例,其中使用ICS者156例(A组),未使用者144例(B组),并选择同期健康志愿者150例(C组).结果 随访6、12、18、24个月结束时,A组患者ICS使用总量分别为28.50 g、50.10 g、61.30 g、69.10 g,发生肺炎分别为10、23、37、53例次;B组发生肺炎分别为7、14、22、29例次;C组发生肺炎分别为9、16、26、33例次.B组和C组比较差异无统计学意义(P＞0.05).A组和B组、C组比较差异有统计学意义(P＜0.05).结论 长期使用ICS增加肺炎风险,随着剂量和时间增加,肺炎发病机会增高,但预后良好.     

Long-acting Beta-Agonists with and without Inhaled Corticosteroids and Catastrophic Asthma Events

Background

It is unclear whether long-acting β-agonists with concomitant inhaled corticosteroids increase asthma-related intubations and deaths. We pooled data on long-acting β-agonists with variable and concomitant inhaled corticosteroids to evaluate the risk for catastrophic asthma events.

Methods

We conducted searches of electronic databases, the US Food and Drug Administration website, clinical-trials registries, and selected references through December 2008. We analyzed randomized controlled trials in patients with asthma, which lasted at least 3 months, evaluated long-acting β-agonists compared with placebo or long-acting β-agonists with inhaled corticosteroids compared with corticosteroids alone, and included at least 1 catastrophic event, defined as asthma-related intubation or death.

Results

In pooled trial data that included 36,588 participants, long-acting β-agonists increased catastrophic events 2-fold (Peto odds ratio [OR] 2.10; 95% confidence interval [CI], 1.37-3.22). Statistically significant increases were seen for long-acting β-agonists with variable corticosteroids compared with placebo (OR 1.83; 95% CI, 1.14-2.95) and for concomitant treatment with corticosteroids compared with corticosteroids alone (OR 3.65; 95% CI, 1.39-9.55). Similar increases in risk were seen for variable and concomitant corticosteroid use, salmeterol and formoterol, and children and adults. When the analysis was restricted to trials with controlled corticosteroid use, given as part of the study intervention, concomitant treatment still increased catastrophic events compared with corticosteroids alone (OR 8.19; 95% CI, 1.10-61.18).

Conclusion

Long-acting β-agonists increase the risk for asthma-related intubations and deaths, even when used in a controlled fashion with concomitant inhaled corticosteroids.     

The CASE survey: Patient and physician perceptions regarding asthma medication use and associated oropharyngeal symptoms

BACKGROUND:

Oropharyngeal (OP) symptoms are common in asthma patients using inhaled corticosteroids (ICSs) alone and in combination with a long-acting beta₂-agonist (LABA). Patterns of medication use, level of asthma control and association with OP symptoms are not often reported in a nonstudy setting.

OBJECTIVES:

To determine the prevalence of OP symptoms among adult asthma patients using ICSs alone and an ICS plus a LABA; to investigate the relationships between medication use, asthma control and OP symptoms; and to assess family physicians’ (FPs’) perceptions of the prevalence and management of OP symptoms.

METHODS:

A random telephone survey of 1003 asthma patients and 250 FPs treating asthma patients was conducted from February to March 2005 across Canada.

RESULTS:

Twenty-four per cent of patients experienced OP symptoms; 67% of them spoke to their FPs about the OP symptoms. Thirty-one per cent of patients who experienced OP symptoms stopped or reduced their dose of medication. OP symptoms were reported by 25% of patients using ICSs and 22% using an ICS plus a LABA. The incidence of OP symptoms was not affected by the choice of inhalation device (metered-dose inhaler versus dry powder inhaler) or the use of a spacer. Fifty-eight per cent of patients had uncontrolled asthma; patients achieving a lower level of general education were more likely to have poor control. Patients with uncontrolled asthma were more likely than those with controlled asthma to report OP symptoms (28% versus 18%, respectively; P<0.05). Eighty-nine per cent of FPs had patients who had reported OP symptoms to them. FPs estimated that 15% of their patients experienced OP symptoms and that compliance to treatment worsened in approximately 20% of them.

CONCLUSIONS:

The prevalence of OP symptoms in asthma patients using ICSs and an ICS plus a LABA is significant. OP symptoms were found to be associated with a reduced patient education level, with a likelihood of reducing or stopping medication, and with a less well-controlled asthma patient. While FPs recognized that a significant proportion of their asthma patients experience OP symptoms and that OP symptoms may affect compliance, they underestimated the prevalence of this problem.     

支气管哮喘和慢性阻塞性肺疾病重叠的治疗策略

支气管哮喘（简称哮喘）和COPD两者的定义都表现为气流受限,但它们的危险因素及临床表现有所不同。然而,大量的临床观察发现哮喘患者表现出COPD表型,反过来,在COPD患者中也存在哮喘表型。流行病学资料表明老年慢性阻塞性气道疾病的患者中,一半或以上患者中存在哮喘和COPD重叠的现象,而这部分人被排除在目前各种临床药物试验之外。因此,对哮喘和COPD重替的研究有助于更好地解决哮喘COPD重叠患者的“特殊”临床特点,同时为COPD发病机制提供新的观点,亦为更好地预防、治疗及管理该重叠综合征作出最佳的选择。     

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.     

Japanese guidelines for adult asthma 2017

Adult bronchial asthma is characterized by chronic airway inflammation, and presents clinically with variable airway narrowing (wheezes and dyspnea) and cough. Long-standing asthma induces airway remodeling, leading to intractable asthma. The number of patients with asthma has increased; however, the number of patients who die of asthma has decreased (1.2 per 100,000 patients in 2015). The goal of asthma treatment is to enable patients with asthma to attain normal pulmonary function and lead a normal life, without any symptoms. A good relationship between physicians and patients is indispensable for appropriate treatment. Long-term management by therapeutic agents and elimination of the causes and risk factors of asthma are fundamental to its treatment. Four steps in pharmacotherapy differentiate between mild and intensive treatments; each step includes an appropriate daily dose of an inhaled corticosteroid, varying from low to high levels. Long-acting β₂-agonists, leukotriene receptor antagonists, sustained-release theophylline, and long-acting muscarinic antagonist are recommended as add-on drugs, while anti-immunoglobulin E antibody and oral steroids are considered for the most severe and persistent asthma related to allergic reactions. Bronchial thermoplasty has recently been developed for severe, persistent asthma, but its long-term efficacy is not known. Inhaled β₂-agonists, aminophylline, corticosteroids, adrenaline, oxygen therapy, and other approaches are used as needed during acute exacerbations, by choosing treatment steps for asthma in accordance with the severity of exacerbations. Allergic rhinitis, eosinophilic chronic rhinosinusitis, eosinophilic otitis, chronic obstructive pulmonary disease, aspirin-induced asthma, and pregnancy are also important issues that need to be considered in asthma therapy.     

Japanese guidelines for childhood asthma 2017

The Japanese Guideline for the Diagnosis and Treatment of Allergic Diseases 2017 (JAGL 2017) includes a minor revision of the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2012 (JPGL 2012) by the Japanese Society of Pediatric Allergy and Clinical Immunology. The section on child asthma in JAGL 2017 provides information on how to diagnose asthma between infancy and adolescence (0–15 years of age). It makes recommendations for best practices in the management of childhood asthma, including management of acute exacerbations and non-pharmacological and pharmacological management. This guideline will be of interest to non-specialist physicians involved in the care of children with asthma. JAGL differs from the Global Initiative for Asthma Guideline in that JAGL emphasizes diagnosis and early intervention of children with asthma at <2 years or 2–5 years of age. The first choice of treatment depends on the severity and frequency of symptoms. Pharmacological management, including step-up or step-down of drugs used for long-term management based on the status of asthma control levels, is easy to understand; thus, this guideline is suitable for the routine medical care of children with asthma. JAGL also recommends using a control test in children, so that the physician aims for complete control by avoiding exacerbating factors and appropriately using anti-inflammatory drugs (for example, inhaled corticosteroids and leukotriene receptor antagonists).