Bronchodilators,receptors and cross-talk: Together is better?

The most widely used maintenance therapies in chronic obstructive pulmonary disease (COPD) are long-acting muscarinic antagonists (LAMAs), and a number of these drugs are now available in combination with long-acting β₂-agonists (LABAs). LAMAs inhibit the parasympathetic muscarinic pathway, while LABAs, as sympathomimetics, reduce airway smooth muscle (ASM) tone. As well as directly controlling the constriction and relaxation of ASM, muscarinic and adrenergic receptors are found on inflammatory cells, and drugs that target these receptors may also reduce inflammation in COPD. Evidence suggests that the muscarinic and adrenergic pathways cross-talk at the level of neuronal input to the ASM via second-messenger pathways within ASM cells. Although the cross-talk is not completely understood, pharmacologically targeting both pathways in COPD can maximize bronchodilation. Combining LAMAs and LABAs demonstrated improved efficacy compared with the individual therapies and so, for greater convenience, several fixed-dose combinations for once-daily use have been developed. These fixed-dose combinations demonstrate improvements in both lung-function and patient-reported outcomes compared with well-established monotherapies, with similar tolerability profiles to the individual agents.     

Reducing the Risk of Mortality in Chronic Obstructive Pulmonary Disease With Pharmacotherapy: A Narrative Review

In 2020, chronic obstructive pulmonary disease (COPD) was the fifth leading cause of death in the United States excluding COVID-19, and its mortality burden has been rising since the 1980s. Smoking cessation, long-term oxygen therapy, noninvasive ventilation, and lung volume reduction surgery have had a beneficial effect on mortality; however, until recently, the effects of pharmacologic therapies on all-cause mortality have been unclear. Inhaled pharmacologic treatments for patients with COPD include combinations of long-acting muscarinic receptor antagonists (LAMAs), long-acting-β_2-agonists (LABAs), and inhaled corticosteroids (ICS). The recent IMPACT and ETHOS clinical trials reported mortality benefits with ICS/LAMA/LABA triple therapy compared with LAMA/LABA dual therapy. In IMPACT, fluticasone furoate/umeclidinium/vilanterol therapy significantly reduced the risk of on-/off-treatment all-cause mortality vs umeclidinium/vilanterol (hazard ratio, 0.72; 95% CI, 0.53 to 0.99; P=.042). The ETHOS trial found a reduction in the risk of on-/off-treatment all-cause mortality in patients treated with budesonide/glycopyrrolate/formoterol vs glycopyrrolate/formoterol (hazard ratio, 0.51 [0.33 to 0.80]; nominal P=.0035). Both trials included populations of patients with symptomatic COPD at high risk of future exacerbations, and a post hoc analysis of the final retrieved vital status data suggested that the observed mortality benefits are conferred by the ICS component. In conclusion, triple therapy reduces the risk of mortality in patients with symptomatic COPD characterized by moderate or severe airflow obstruction and a recent history of moderate or severe exacerbations. This benefit is likely to be driven by reductions in exacerbations. Future research efforts should focus on improving the long-term prognosis of patients living with COPD.     

The use of long acting β₂-agonists, alone or in combination with inhaled corticosteroids, in chronic obstructive pulmonary disease (COPD): a risk-benefit analysis

Chronic obstructive pulmonary disease (COPD) is a slowly progressive, largely non-reversible pulmonary disease which is characterised by airflow limitation. It is one of the few diseases with an increasing mortality rate and by 2020 it is predicted to be the third leading cause of death. The mainstays of current treatment are long acting β? agonists (LABAs) coupled with an increasing reliance on inhaled corticosteroids (ICS). Two LABAs (salmeterol and formoterol) are currently licensed for COPD both as monotherapy and in combination with ICS (fluticasone propionate (FP) and budesonide respectively). A comprehensive review of the risk-benefit of these medicines in COPD is provided here which concludes that there is limited efficacy for LABAs in COPD either alone or in combination with ICS and no overall modification of the disease process. However, where directly compared, combination therapy usually provides an advantage over monotherapy. Importantly the apparent effectiveness of treatment may significantly depend upon the outcome measure chosen with some measures possibly underestimating the extent of benefit. ICS benefit may also be greater in those patients who respond to treatment. Set against this benefit are recent concerns that a number of issues related to the clinical trial design such as prior use of ICS and different withdrawal rates between groups may be significantly influencing results. Furthermore there is no evidence of a dose response relationship with regard to ICS dose. A key issue with combination therapy is the excess risk of pneumonia conferred by the use of an ICS in this patient population. This risk does not appear to be proportional to the ICS dose but may differ between FP and budesonide. We conclude that further studies are required to identify the optimal dose of ICS, in terms of both risk and benefit, and to confirm their benefit in steroid na?ve patients. Furthermore it will be important to determine whether the risk of pneumonia is apparent with both FP and budesonide and to identify factors which may predict steroid responsiveness in COPD.     

Risk of Severe Cardiovascular Events From Add-On Tiotropium in Chronic Obstructive Pulmonary Disease

Objective

To examine the risk of cardiovascular disease (CVD) from tiotropium added to inhaled long-acting β₂ agonists (LABAs) and inhaled corticosteroids (ICSs) in a nationwide population with chronic obstructive pulmonary disease (COPD).

Inhaled corticosteroids or long-acting β-agonists alone or in fixed-dose combinations in asthma treatment: A systematic review of fluticasone/budesonide and formoterol/salmeterol

Background: Inhaled corticosteroids (ICSs) and longacting inhaled β₂-agonists (LABAs) are recommended treatment options for asthma.Objective: This review compares the clinical effectiveness and tolerability of the ICSs fluticasone propionate and budesonide and the LABAs formoterol fumarate and salmeterol xinafoate administered alone or in combination.Methods: A systematic review of the clinical studies available on MEDLINE (database period, 1950-September 2009) was conducted to assess English-language randomized controlled trials in children and adults with asthma. Treatment outcomes included lung function, symptom-free days (SFDs), use of rescue/reliever medications, asthma exacerbations, and tolerability profile.Results: Use of fluticasone was associated with significantly greater improvement in lung function and better asthma symptom control than budesonide. Similarly, formoterol was associated with significantly greater improvement in lung function and better asthma symptom control (as measured by less rescue medication use and more SFDs) compared with salmeterol. Single inhaler combination regimens (budesonide/ formoterol and fluticasone/salmeterol) were frequently more effective in improving all treatment outcomes than either monotherapy alone. Across all comparisons, a review of studies in adults and children did not find statistically significant differences in outcomes between the ICS and LABA therapies considered in this research. In general, no differences in tolerability profiles were reported between the ICS and LABA options, although the risk for growth retardation was lower with fluticasone than budesonide and with budesonide/formoterol than with budesonide monotherapy.Conclusions: In this systematic review, fluticasone and formoterol appear to provide improved therapeutic benefits versus budesonide and salmeterol, respectively. Both fluticasone/salmeterol and budesonide/ formoterol combination therapies appeared to be associated with greater improvements in outcomes measures than the corresponding ICS and LABA monotherapies.     

Benefits and risks of adjunctive inhaled corticosteroids in chronic obstructive pulmonary disease: a meta-analysis

BACKGROUND: Several clinical trials have evaluated the benefits associated with adding an inhaled corticosteroid (ICS) to a long-acting bronchodilator in the treatment of severe or very severe (stage III or IV) chronic obstructive pulmonary disease (COPD). OBJECTIVE: We conducted a meta-analysis to elucidate the benefits and risks associated with adjunctive ICS treatment in patients with severe or very severe COPD. METHODS: A systematic literature search of MEDLINE, EMBASE, and the Cochrane Collaboration's Central Register of Controlled Clinical Trials (from initiation through April 2008) was conducted by 2 investigators working independently. A search strategy using key medical subject headings and text key words was performed using the Cochrane Collaboration's Highly Sensitive Search Strategy for MEDLINE and the McMaster University Health Information Research Unit EMBASE search strategy. To be included in this meta-analysis, studies had to be randomized controlled trials; compare the use of ICS in combination with long-acting beta-agonists (LABAs) or tiotropium with long-acting bronchodilator monotherapy; include only subjects with COPD and forced expiratory volume in 1 second (FEV(1)) <80% and an FEV(1)/forced vital capacity ratio <70%; follow up patients for a minimum of 24 weeks; and report data on either mortality or exacerbations. We evaluated 3 efficacy end points (exacerbations, mortality, and change in St. George's Respiratory Questionnaire [SGRQ] score), 2 tolerability end points (pneumonia and oral candidiasis), and study withdrawals. Rate ratios and relative risks (RRs) were calculated using a random effects model. Statistical heterogeneity was addressed using the Q statistic and I(2) value. The Egger weighted regression statistic and visual inspection of funnel plots were used to assess publication bias. RESULTS: A total of 9 studies met the inclusion criteria (N = 7,992 subjects). Seven trials provided exacerbation rates and 8 trials provided data on overall mortality. Change in SGRQ score from baseline was reported in 6 trials while pneumonia and oral candidiasis were reported in 5 and 6 studies, respectively. The incidence of patient withdrawal was reported in 8 studies. Exacerbations (rate ratio, 0.82; 95% CI, 0.72-0.92) and SGRQ score (weighted mean difference, -1.98 points; 95% CI, -2.56 to -1.40) were reduced with adjunctive ICS treatment but mortality was not affected (rate ratio, 0.86; 95% CI, 0.73-1.02). Both pneumonia (RR, 1.68; 95% CI, 1.28-2.21) and oral candidiasis (RR, 2.93; 95% CI, 1.94-4.42) were increased with adjuvant ICS treatment. Patient study withdrawal for any reason (RR, 0.83; 95% CI, 0.74- 0.93) was less likely with adjuvant ICS treatment. On visual inspection of the funnel plots, publication bias could not be ruled out for either efficacy or tolerability end point analysis. However, inspection of the Egger weighted regression statistic suggested the low likelihood of publication bias for all end points. CONCLUSIONS: Addition of an ICS to a LABA was associated with a reduced risk for exacerbations but an increased risk for pneumonia and oral candidiasis compared with long-acting bronchodilator monotherapy in this meta-analysis of 9 randomized controlled trials. While measured patient-perceived health and well-being increased to a statistically significant level, this did not translate into a clinically meaningful level for all patients with combination treatment. Lower risk of study withdrawal was observed in adjuvant ICS patients. The benefits and risks associated with adjunctive ICS treatment will need to be assessed when making decisions regarding its use.     

Medications for COPD: a review of effectiveness

Chronic obstructive pulmonary disease (COPD) is a common problem among patients presenting to primary care. This condition has multiple individual and combined treatment regimens. The goals of treatment are to improve quality of life, exercise tolerance, sleep quality, and survival; and to reduce dyspnea, nocturnal symptoms, exacerbations, use of rescue medications, and hospitalizations. All patients benefit from bronchodilator medications as needed. Long-acting inhaled anticholinergics are probably more beneficial than short-acting formulations. Use of inhaled corticosteroids might benefit patients with mild COPD who have an inflammatory component or significant reversibility on spirometry. Patients with moderate to severe disease benefit from the use of long-acting inhaled anticholinergics, inhaled corticosteroids, and possibly a long-acting beta2 agonist or mucolytics. For rescue therapy, short-acting beta2 agonists or combination anticholinergics with a short-acting beta2 agonist should be used. Inhaled corticosteroids should be considered before initiating a long-acting beta2 agonist. Caution should be used if a long-acting beta2 agonist is discontinued before initiation of an inhaled corticosteroid because this may precipitate exacerbations. Evidence to support the use of mucolytics, oral theophylline, and oral corticosteroids is limited. Patients with severe hypoxemia (i.e., arterial oxygen pressure less than 55 mm Hg or oxygen saturation less than 88 percent) should be given continuous oxygen.     

Adding Long-acting β-agonists to Inhaled Corticosteroids after Discharge from the Emergency Department for Acute Asthma: A Randomized Controlled Trial

Background: Relapses of asthma following emergency department discharge can be reduced with oral and inhaled corticosteroids (ICSs), but the benefits of long-acting β-agonists (LABAs) are unclear.
Objectives: To determine whether the addition of a LABA reduces relapses in patients with acute asthma.
Methods: This was a randomized, controlled, double-blind trial of 137 patients, aged 18–55 years, conducted in four Canadian EDs. Patients receiving high-dose ICSs or oral corticosteroids, and those who were medically unstable, were excluded. Patients were randomized to either fluticasone 1,000 μg/day with salmeterol 100 μg/day or fluticasone 1,000 μg/day alone. All patients were discharged on seven days of oral prednisone. The main outcome measure was relapse at 21 days.
Results: Both groups had similar baseline characteristics. After 21 days, seven of 69 patients (10.1%) treated with fluticasone/salmeterol and ten of 68 patients (14.7%) treated with fluticasone experienced a relapse (p = 0.42). Prior intubation, female gender, and prior use of ICSs were associated with relapse. There were no clinically or statistically significant differences in overall quality of life and individual domain scores. Fluticasone/salmeterol improved quality of life (p < 0.05) and relapses (24% to 13%; p = 0.35) in patients receiving ICSs at the time of emergency admission.
Conclusions: Outpatient treatment with a short course of systemic corticosteroids combined with ICSs is adequate for most patients with asthma discharged from the emergency department; those already receiving ICS agents may benefit from ICS/LABA combination therapy to improve quality of life. Larger studies are needed to confirm the role of inhaled LABAs in acute asthma.     

Managing Stable COPD in 2009: Incorporating Results from Recent Clinical Studies into a Goal-Directed Approach for Clinicians

Abstract

Chronic obstructive pulmonary disease (COPD) is prevalent in primary care practice and an important cause of functional decline, hospitalizations, and death. Recent clinical trials of COPD therapy demonstrate the ability of bronchodilators (especially long-acting β₂-agonists and anticholinergics), either alone or in combination with inhaled corticosteroids, to achieve the goals of managing stable disease. These management goals include: symptom relief, improvement in exercise tolerance and health status, prevention of exacerbations and progression of disease, and reduction in mortality. Recent studies of COPD treatment also provide important safety information to help clinicians address patient concerns about treatment risks. We reviewed recent clinical trials to develop concepts of care for the non-specialist clinician managing patients with stable COPD.     

Metatarsalgia

Abstract

Recognition of chronic obstructive pulmonary disease (COPD) is often missed or delayed in primary care. Once recognized, COPD is often undertreated or episodically treated, focusing on acute exacerbations without establishing maintenance treatment to control ongoing disease. Diagnostic and therapeutic pessimism result in missed opportunities to reduce exacerbations, maintain physical functioning, and reduce emergent health care requirements. Proactive diagnosis and evidence-based management can alleviate the impact of COPD on patients' lives. Smoking cessation has been proven to slow the rate of lung function decline. Maintenance pharmacotherapy and immunizations reduce exacerbations. Pulmonary rehabilitation improves respiratory symptoms and physical functioning and reduces rehospitalizations after exacerbations. Self-management education improves health-related quality of life and reduces inpatient and emergency care usage. Maintenance treatment with long-acting inhaled bronchodilators is appropriate beginning in moderate COPD to maintain airway patency and reduce exacerbations. Tiotropium is US Food and Drug Administration (FDA) approved to treat bronchospasm and reduce exacerbations in patients with COPD; salmeterol/fluticasone is FDA approved to treat airflow obstruction in COPD and reduce exacerbations in patients with a history of exacerbations. Other maintenance long-acting bronchodilators—salmeterol, formoterol, and budesonide/formoterol—are FDA approved to treat airway obstruction in COPD but lack an approved indication against exacerbations. FDA warnings on the use of long-acting beta-adrenergic agents (LABAs) in asthma specifically exempt COPD and do not apply to LABA/inhaled corticosteroid combinations used in COPD. The actual effectiveness achieved in practice with any COPD therapies depends on patients' inhaler technique, adherence, and persistence. Medication usage rates and inhaler proficiency may be improved by concordance, in which the health care provider and patient collaborate to make treatment plans sustainable in the patient's daily life. Practice redesign for whole-patient primary care provides additional tools for comprehensive COPD management. Innovations such as group visits and the patient-centered medical home provide newer ways to interact with COPD patients and their families. Patient-focused and evidence-based options enable primary care practices to manage COPD longitudinally and improve patient outcomes through the course of the disease.     

Preventing Clinically Important Deterioration of COPD with Addition of Umeclidinium to Inhaled Corticosteroid/Long-Acting β<Subscript>2</Subscript>-Agonist Therapy: An Integrated Post Hoc Analysis

Introduction

Assessing clinically important measures of disease progression is essential for evaluating therapeutic effects on disease stability in chronic obstructive pulmonary disease (COPD). This analysis assessed whether providing additional bronchodilation with the long-acting muscarinic antagonist umeclidinium (UMEC) to patients treated with inhaled corticosteroid (ICS)/long-acting β₂-agonist (LABA) therapy would improve disease stability compared with ICS/LABA therapy alone.

Methods

This integrated post hoc analysis of four 12-week, randomized, double-blind trials (NCT01772134, NCT01772147, NCT01957163, NCT02119286) compared UMEC 62.5 µg with placebo added to open-label ICS/LABA in symptomatic patients with COPD (modified Medical Research Council dyspnea scale score?≥?2). A clinically important deterioration (CID) was defined as: a decrease from baseline of?≥?100 mL in trough forced expiratory volume in 1 s (FEV₁), an increase from baseline of?≥?4 units in St George’s Respiratory Questionnaire (SGRQ) total score, or a moderate/severe exacerbation. Risk of a first CID was evaluated in the intent-to-treat (ITT) population and in patients stratified by Global initiative for chronic Obstructive Lung Disease (GOLD) classification, exacerbation history and type of ICS/LABA therapy. Adverse events (AEs) were also assessed.

Results

Overall, 1637 patients included in the ITT population received UMEC?+?ICS/LABA (n?=?819) or placebo?+?ICS/LABA (n?=?818). Additional bronchodilation with UMEC reduced the risk of a first CID by 45–58% in the ITT population and all subgroups analyzed compared with placebo (all p?<?0.001). Improvements were observed in reducing FEV₁ (69% risk reduction; p?<?0.001) and exacerbation (47% risk reduction; p?=?0.004) events in the ITT population. No significant reduction in risk of a SGRQ CID was observed. AE incidence was similar between treatment groups.

Conclusion

Symptomatic patients with COPD receiving ICS/LABA experience frequent deteriorations. Additional bronchodilation with UMEC significantly reduced the risk of CID and provided greater short-term stability versus continued ICS/LABA therapy in these patients.

Funding

GlaxoSmithKline (study number: 202067).

Plain Language Summary

Plain language summary available for this article.

     

Asthma treatment in a population-based cohort: putting step-up and step-down treatment changes in context

OBJECTIVE: To assess the frequency and types of visits related to modifications in the intensity of asthma medications. PATIENTS AND METHODS: We retrospectively reviewed the medical records of adults (aged 18-40 years) and children (aged 6-17 years) living in Olmsted County, Minnesota, to evaluate changes in asthma medications by dose and drug class and site and type of visit (routine vs unscheduled) at the time of changes. All records from all visits were reviewed for each patient to identify asthma-related visits at all sites of care from January 1, 2002, through December 31, 2003. RESULTS: The study consisted of 397 adults and children. In 255 patients, 597 asthma medication changes occurred. Step-up changes usually occurred because of an exacerbation or loss of control of asthma and adhered to the medication hierarchy in the national asthma guidelines. Twenty step-up changes involved skipping inhaled corticosteroid (ICS) monotherapy and moving directly to combined ICSs plus a long-acting beta-agonist (LABA). Lack of documentation of asthma symptom frequency or interference with activities made it impossible to determine whether these 'skips' were appropriate. Only 78 physician-directed step-down changes were documented, usually to a lower dose of combined ICSs and LABAs or a move from combined ICSs and LABAs to anti-inflammatory monotherapy. Patients initiated additional step-down changes between encounters. Step-down changes occurred at routine or follow-up asthma visits, but the limited number of such visits provided few opportunities for step-down care. CONCLUSION: The continuing episodic-style treatment of asthma aimed at exacerbation management facilitates step-up changes in asthma therapy. The dearth of asthma evaluation visits limited opportunities to step down use of asthma medications and to provide long-term asthma management.     

Optimizing maintenance therapy for chronic obstructive pulmonary disease: strategies for improving patient-centered outcomes

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with substantial morbidity and mortality. Published practice guidelines and treatment algorithms for COPD are designed to increase awareness of the problem and improve patient care; however, <40% of subjects diagnosed with COPD are receiving appropriate maintenance therapy. OBJECTIVE: This paper reviews the use of maintenance therapy in COPD and examines the optimal timing for initiating such therapy based on the available literature. METHODS: Relevant publications were identified through a search of MEDLINE (1995-May 2007) using the terms COPD, guidelines, treatment, maintenance therapy, bronchodilator, ipratropium, tiotropium, beta-agonist, salmeterol, and inhaled corticosteroid. English-language publications discussing pharmacologic maintenance therapy for COPD, including practice statements/guidelines, randomized controlled clinical trials, systematic reviews, and meta-analyses, with a focus on agents currently approved for use in the United States, were selected for inclusion. RESULTS: Although guidelines and algorithms agree on the importance of regularly scheduled maintenance therapy to reduce symptoms of COPD, minimize activity limitations, and improve health status, the timing of the initiation of such therapy is debatable. In most instances, maintenance medications, which include long-acting beta(2)-agonists, long-acting anticholinergics, and combination products, are prescribed late in the disease process and mainly for patients with severe disease. However, there is increasing evidence that the use of maintenance therapy early in the disease process may be associated with improvements in such outcomes as lung function, symptoms, exercise tolerance, exacerbations of COPD, and quality of life. CONCLUSION: The high burden associated with COPD highlights the need to initiate maintenance therapy before a substantial decline in lung function has occurred.     

Asthma management and prevention: current perspectives

The continuing evolution of asthma treatment and prevention are reflected in updated guidelines from the National Asthma Education and Prevention Program and Global Initiative for Asthma as well as other recent publications. The 2007 Expert Panel Report 3 guidelines designate severity and control, mediated by considerations of current impairment and future risk, as the primary concepts in assessing and monitoring asthma. Severity should ideally be determined at the time of diagnosis, after which control becomes the central focus of asthma management. In the area of treatment, inhaled corticosteroids (ICSs) remain first-line therapy for longterm asthma management in children and adults. For patients whose severity of asthma requires more than low-dose ICSs, or whose asthma cannot be well controlled on monotherapy with low-dose ICSs, evidence supports the efficacy of combination therapy consisting of an ICS plus an inhaled long-acting beta2-agonist (LABA) or an increase to medium-dose ICSs. For children >5 years of age and adults not controlled on low-dose ICSs, the combination of a low-dose ICS plus an inhaled LABA is equivalent in terms of outcomes to the use of medium-dose ICS. For children <5 years of age not controlled on low-dose ICSs, increasing the dose of ICSs is preferred to the addition of a LABA to low-dose ICS therapy as no studies using combination therapy have been conducted for patients in this age group. With regard to asthma prevention, approaches to primary prevention (to avoid allergen sensitization) and secondary prevention (to avoid disease progression) are still very much in the developmental stage, while tertiary prevention (to avoid asthmatic stimuli) has been more successful particularly in pediatric patients. Written action plans as part of self-management processes appear to improve physician-patient communication and disease status tracking. Other considerations in successful asthma management include patient education and monitoring of adherence to treatment regimens.     

Indacaterol,a novel inhaled,once-daily,long-acting beta<Subscript>2</Subscript>-agonist for the treatment of obstructive airways diseases

Indacaterol is a novel once-daily, long-acting beta₂-agonist developed for the treatment of chronic obstructive pulmonary disease (COPD) and asthma. The present review summarizes the preclinical and clinical data of indacaterol, including recent data from phase II and III trials. These clinical studies suggest that indacaterol produces rapid and sustained bronchodilation in patients with COPD, and asthma of different severities. Until now, clinical studies of up to 1-year’s duration have been at least partially published, which have confirmed the suitability of indacaterol for once-daily dosing, along with a favorable overall safety and tolerability profile in the long-term treatment of COPD. Data on relevant outcomes in asthma are more limited, especially with regard to chronic treatment. Therefore, it appears that indacaterol monotherapy will have its therapeutic potential primarily in COPD, where anti-inflammatory treatment is not fully established and issues about a potential risk of long-acting beta₂-agonist use causing increased mortality have not been raised. As data from more advanced clinical trials have been published, a more complete picture of the full therapeutic potential of indacaterol in COPD has emerged, including patient-reported outcomes (eg, symptoms and quality of life) or additional pivotal outcomes (eg, exacerbation rates, disease progression, exercise capacity, and the development of hyperinflation). Finally, the pharmacological profile of indacaterol makes it an attractive partnering agent for future fixedcombination therapies in both asthma and COPD, eg, with once-daily inhaled corticosteroids or long-acting antimuscarinergic bronchodilators. The outlook and potential of indacaterol are further discussed. An erratum to this article can be found online at . An erratum to this article can be found at     

Effect of long-acting beta-agonists on the frequency of COPD exacerbations: a meta-analysis

What is Known and Objective: Inhaled long‐acting beta‐agonists have been licensed for the treatment of chronic obstructive pulmonary disease (COPD) since the late 1990s, and they improve lung function and symptoms of dyspnoea. However, the evidence that long‐acting beta‐agonists alone can reduce the rate of COPD exacerbations is not conclusive. This meta‐analysis was performed to evaluate their effect on the frequency of exacerbations. Methods: MEDLINE, EMBASE, CINAHL and the Cochrane trials database were searched for the review. Randomized controlled trials of greater than or equal to 24 weeks’ treatment duration comparing long‐acting beta‐agonists (LABAs) with placebo were reviewed. Studies were pooled to yield odds ratios (ORs) with 95% confidence intervals (CIs). Results and Discussion: Seventeen randomized controlled trials (11871 randomized subjects) met the inclusion criteria and were selected for analysis. Salmeterol, formoterol and indacaterol significantly reduced COPD exacerbations compared with placebo. Salmeterol significantly reduced COPD exacerbations with both study arms exposed or not exposed to inhaled corticosteroids (ICS). The summary ORs were 0·79 (95% CI: 0·67–0·92; P < 0·01) and 0·80 (95% CI: 0·65–0·99; P = 0·04), respectively. However, when both arms were not exposed to ICS, there was no significant reduction in exacerbations with formoterol compared with placebo. The 'summary OR was 0·93 (95% CI: 0·75–1·15; P = 0·50). What is New and Conclusion: Long‐acting beta‐agonists reduce the frequency of COPD exacerbations. Salmeterol, formoterol and indacaterol significantly reduced COPD exacerbations compared with placebo. Salmeterol but not formoterol decreased exacerbations significantly in the absence of ICS.