Long-acting Β2-agonist Combination Research Articles

Long-acting muscarinic antagonist and long-acting β2-agonist combination for the treatment of maintenance therapy-naïve patients with chronic obstructive pulmonary disease: a narrative review.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Faster lung function impairment occurs earlier in the disease, particularly in mild-to-moderate COPD, highlighting the need for early and effective targeted interventions. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2024 report recommends initial pharmacologic treatment with a long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) combination in group B (0 or 1 moderate exacerbation not leading to hospitalization, modified Medical Research Council score of ⩾2, and COPD Assessment Test™ score of ⩾10) and E (⩾2 moderate exacerbations or ⩾1 exacerbation leading to hospitalization and blood eosinophil count <300 cells/µL) patients. In randomized controlled trials (RCTs), LAMA/LABA combination therapy improved lung function, St. George's Respiratory Questionnaire (SGRQ) total score, and Transitional Dyspnea Index (TDI) focal score and reduced the use of rescue medications, exacerbation risk, and risk of first clinically important deterioration (CID), compared with LAMA or LABA monotherapy. However, there is limited evidence regarding the efficacy and safety of LAMA/LABA combination therapy versus LAMA or LABA monotherapy in maintenance therapy-naïve patients. This review discusses the rationale for the early initiation of LAMA/LABA combination therapy in maintenance therapy-naïve patients with COPD. In post hoc analyses of pooled data from RCTs, compared with LAMA or LABA monotherapy, LAMA/LABA combination therapy improved lung function and quality of life and reduced COPD symptoms, risk of first moderate/severe exacerbation, risk of first CID, and use of rescue medication, with no new safety signals. In a real-world study, patients initiating LAMA/LABA had significantly reduced risk of COPD-related inpatient admissions and rate of on-treatment COPD-related inpatient admissions over 12 months than those initiating LAMA. Consequently, LAMA/LABA combination therapy could be considered the treatment of choice in maintenance therapy-naïve patients with COPD, as recommended by the GOLD 2024 report.

Factors Affecting the Success of Step-up Therapy in Patients With Moderate-Severe Asthma: A Real-Life Study.

Introduction: Clinical practice guidelines recommend regular adjustment of treatment to achieve control of asthma. A step-up approach based on the degree of disease control should be followed. Objective: To perform a real-life analysis of the factors that affect the success or failure of this therapeutic strategy and of the criteria applied by clinicians when applying a step-up approach in a representative sample of patients diagnosed with moderate-severe asthma. We performed a multicenter retrospective cohort study involving 226 Spanish specialist physicians (98 allergologists, 127 pulmonologists, and 1 family physician). We included 1254 patients (787 women) diagnosed with moderate-severe asthma who underwent step-up therapy during 2016. Step-up was successful in 44% of cases. The factors associated with success were presence of <2 comorbid conditions, lower grade of severity and therapy step before modification, absence of exacerbations during the previous year, fewer daytime/nighttime symptoms, and limitation in activities, as well as type of inhaled corticosteroid/ long-acting β₂-agonist combination after modification, lower body mass index, and higher fractional exhaled nitric oxide. An early increase in the maintenance dose once a lack of control was detected (≤3 months, >3 to ≤6 months, >6 to ≤12 months) was more likely to be successful. The factors that determine whether or not this therapeutic strategy manages to control asthma are time since onset of clinical impairment, previous grade of severity, number of comorbid conditions, previous exacerbations, and frequency of symptoms.

Comparative Safety and Effectiveness of Inhaled Corticosteroid and Long-Acting β2-Agonist Combinations in Patients With COPD

The differential risk of pneumonia among inhaled corticosteroid (ICS) use in patients with COPD requires more investigation, especially regarding beclomethasone-containing inhalers. The goal of this study was to compare the risk and benefit profile of different ICS/long-acting β2-agonist (LABA) combinations in patients with COPD. This retrospective cohort study was conducted by using national health insurance claims data from the years 2009 to 2015 in Taiwan and included patients with COPD with new ICS/LABA use. Propensity score matching and Cox regression models were used to estimate the hazard ratios of severe pneumonia and acute exacerbation for different ICS/LABA users. Both budesonide/formoterol (BUD/FOR) dry-powder inhalers and beclomethasone/formoterol (BEC/FOR) metered-dose inhalers, compared with fluticasone propionate/salmeterol (FLU/SAL) delivered via the same device type, were associated with a lower risk of severe pneumonia (BUD/FOR hazard ratio [HR], 0.83 [95%CI, 0.70-0.98]; BEC/FOR HR, 0.69 [95%CI, 0.58-0.81]) and severe acute exacerbation (BUD/FOR HR, 0.88 [95%CI, 0.78-0.99]; BEC/FOR HR, 0.82 [95%CI, 0.72-0.93]). After additionally adjusting for the average daily ICS dose, BUD/FOR dry-powder inhaler users continued to have a significantly decreased risk of severe pneumonia (18%), although BEC/FOR metered-dose inhaler users did not. The results were consistent in most of the prespecified subgroups and across all the sensitivity analyses. This study augments the existing evidence concerning the different safety and effectiveness outcomes of ICS/LABA combinations in patients with COPD, which may be considered when making clinical treatment decisions.

Effects of Direct Switching Dual Bronchodilators between Dry Powder and Soft Mist Inhalers in COPD Patients

Objective: Dual bronchodilation with long-acting muscarinic antagonist and long-acting β2-agonist combinations are available worldwide in COPD patients. However, the choice of agents remains under debate. We hypothesized that switching devices between dry powder and soft mist inhalers without a wash-out period to mimic clinical practice would improve clinical symptoms and lung function. The aim of this study was to examine the effects of switching between once-daily glycopyrronium/indacaterol (GLY/IND) or umeclidinium/vilanterol (UMEC/VI), dry powder inhalers, and tiotropium/olodaterol (TIO/OLO), a soft mist inhaler, in COPD patients. Methods: This was a prospective, open-label, 8-week, observational study with follow-up. Subjects included 57 COPD patients, who attended outpatient clinics at Shizuoka General Hospital for routine check-ups between February and December 2015, receiving GLY/IND (50/110 μg) or UMEC/VI (62.5/25 μg). After an 8-week run-in period, medications were switched to TIO/OLO (5/5 μg). Study outcomes included patient’s global rating (PGR), modified MRC (mMRC), COPD assessment test (CAT), and spirometric and forced oscillatory parameters after 8 weeks. PGR used in this study was a 7-point scale ranging from 1 to 7, with 4 in the middle. Patients who consented to switch from TIO/OLO to GLY/IND or UMEC/VI were followed-up thereafter. Results: In total, 53 patients completed the study (mean age, 75 years; 48 males and 5 females; GOLD 1/2/3/4 = 19/27/6/1; mMRC 0/1/2/3/4 = 14/22/12/4/1; UMEC/VI 26, GLY/IND 27). PGR, mMRC, and CAT improved in 20 (38%), 9 (17%), and 15 patients (28%), respectively. Respiratory system resistance at 5 Hz (R5), 20 Hz (R20), and the difference between R5 and R20 (R5 - R20) significantly improved. In a follow-up of 16 patients after switching from TIO/OLO to UMEC/VI (9) or GLY/IND (7), PGR, mMRC, and CAT improved in 5 (31%), 3 (12%), and 4 patients (25%), respectively, and R20 significantly improved (p = 0.011). Conclusions: Switching dual bronchodilators between dry powder and soft mist inhalers improves symptoms and airway narrowing in some COPD patients.

Cost Evaluation of Inhaler Therapies Used in Respiratory Diseases: 1998--2015 Period in Turkey

BackgroundWith the rise in life expectancy, the burden of chronic diseases, including obstructive pulmonary diseases, has increased throughout the world. ObjectivesTo evaluate the sales trends of inhaler pharmaceuticals. MethodsThe changes in box sales and sales amounts (in Turkish lira) of inhaler pharmaceuticals during the period 1998 to 2015 were examined and sales were projected for the next 3 years. Pharmaceuticals were classified according to form and pharmacological groups. ResultsThe sales of inhaler pharmaceuticals have increased rapidly since 2008. The fastest increase in consumption has occurred in short-acting β2 agonist preparations and nebulizer pharmaceuticals. Inhaled corticosteroid and long-acting β2 agonist combination sales have been the highest since 2002, when these products entered the Turkish market. ConclusionsThe inhaler pharmaceutical market has grown over the years, and this growth will continue in the future. The increased use of short-acting preparations, which should be used as symptom relievers, indicates that treatment management continues to be inadequate.

Fluticasone/salmeterol reduces remodelling and neutrophilic inflammation in severe equine asthma

Asthmatic airways are inflamed and undergo remodelling. Inhaled corticosteroids and long-acting β2-agonist combinations are more effective than inhaled corticosteroid monotherapy in controlling disease exacerbations, but their effect on airway remodelling and inflammation remains ill-defined. This study evaluates the contribution of inhaled fluticasone and salmeterol, alone or combined, to the reversal of bronchial remodelling and inflammation. Severely asthmatic horses (6 horses/group) were treated with fluticasone, salmeterol, fluticasone/salmeterol, or with antigen avoidance for 12 weeks. Lung function, central and peripheral airway remodelling, and bronchoalveolar inflammation were assessed. Fluticasone/salmeterol and fluticasone monotherapy decreased peripheral airway smooth muscle remodelling after 12 weeks (p = 0.007 and p = 0.02, respectively). On average, a 30% decrease was observed with both treatments. In central airways, fluticasone/salmeterol reversed extracellular matrix remodelling after 12 weeks, both within the lamina propria (decreased thickness, p = 0.005) and within the smooth muscle layer (p = 0.004). Only fluticasone/salmeterol decreased bronchoalveolar neutrophilia (p = 0.03) to the same extent as antigen avoidance already after 8 weeks. In conclusion, this study shows that fluticasone/salmeterol combination decreases extracellular matrix remodelling in central airways and intraluminal neutrophilia. Fluticasone/salmeterol and fluticasone monotherapy equally reverse peripheral airway smooth muscle remodelling.

UK-specific cost-effectiveness of tiotropium + olodaterol fixed-dose combination versus other LAMA + LABA combinations in patients with COPD.

ObjectiveThe aim of this study is to assess the cost-effectiveness of other long-acting muscarinic antagonist + long-acting β2 agonist combinations in comparison with Spiolto® Respimat® (tiotropium + olodaterol fixed-dose combination [FDC]) for maintenance treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease.MethodsA previously published individual-level Markov model was adapted for the perspective of the UK health care system, in line with recommendations from the National Institute for Health and Care Excellence. Individuals progressed through the model based on their forced expiratory volume in 1 second (FEV1) value at baseline and the post-improvement FEV1 value. Changes in FEV1 were taken from a mixed treatment comparison. Costs were obtained from a published cost-utility analysis of tiotropium in the treatment of chronic obstructive pulmonary disease in the UK. Uncertainty was assessed by deterministic and probabilistic sensitivity analysis.ResultsDuaklir® Genuair® (aclidinium bromide + formoterol fumarate FDC) and the free-dose combination of tiotropium + salmeterol were dominated by tiotropium + olodaterol FDC. The quality-adjusted life years and costs were identical for Ultibro® Breezhaler® (indacaterol + glycopyrronium FDC) and Anoro™ Ellipta® (umeclidinium + vilanterol FDC) compared with tiotropium + olodaterol FDC, resulting in identical incremental cost-effectiveness ratios.ConclusionThis analysis shows tiotropium + olodaterol FDC to be a cost-effective option for the maintenance treatment of adults with chronic obstructive pulmonary disease in the UK.

Outcome of Inhaler Withdrawal in Patients Receiving Triple Therapy for COPD.

BackgroundThe purpose of this study was to document outcomes following withdrawal of a single inhaler (step-down) in chronic obstructive pulmonary disease (COPD) patients on triple therapy (long-acting muscarinic antagonist and a combination of long-acting β2-agonists and inhaled corticosteroid), which a common treatment strategy in clinical practice.MethodsThrough a retrospective observational study, COPD patients receiving triple therapy over 2 years (triple group; n=109) were compared with those who had undergone triple therapy for at least 1 year and subsequently, over 9 months, initiated inhaler withdrawal (step-down group, n=39). The index time was defined as the time of withdrawal in the stepdown group and as 1 year after the start of triple therapy in the triple group.ResultsLung function at the index time was superior and the previous exacerbation frequency was lower in the stepdown group than in the triple group. Step-down resulted in aggravating disease symptoms, a reduced overall quality of life, decreasing exercise performance, and accelerated forced expiratory volume in 1 second (FEV1) decline (54.7±15.7 mL/yr vs. 10.7±7.1 mL/yr, p=0.007), but there was no observed increase in the frequency of exacerbations.ConclusionWithdrawal of a single inhaler during triple therapy in COPD patients should be conducted with caution as it may impair the exercise capacity and quality of life while accelerating FEV1 decline.

Use of asthma medication during pregnancy and risk of specific congenital anomalies: A European case-malformed control study

Pregnant women with asthma need to take medication during pregnancy. We sought to identify whether there is an increased risk of specific congenital anomalies after exposure to antiasthma medication in the first trimester of pregnancy. We performed a population-based case-malformed control study testing signals identified in a literature review. Odds ratios (ORs) of exposure to the main groups of asthma medication were calculated for each of the 10 signal anomalies compared with registrations with nonchromosomal, nonsignal anomalies as control registrations. In addition, exploratory analyses were done for each nonsignal anomaly. The data set included 76,249 registrations of congenital anomalies from 13 EUROmediCAT registries. Cleft palate (OR, 1.63; 95% CI, 1.05-2.52) and gastroschisis (OR, 1.89; 95% CI, 1.12-3.20) had significantly increased odds of exposure to first-trimester use of inhaled β2-agonists compared with nonchromosomal control registrations. Odds of exposure to salbutamol were similar. Nonsignificant ORs of exposure to inhaled β2-agonists were found for spina bifida, cleft lip, anal atresia, severe congenital heart defects in general, or tetralogy of Fallot. None of the 4 literature signals of exposure to inhaled steroids were confirmed (cleft palate, cleft lip, anal atresia, and hypospadias). Exploratory analyses found an association between renal dysplasia and exposure to the combination of long-acting β2-agonists and inhaled corticosteroids (OR, 3.95; 95% CI, 1.99-7.85). The study confirmed increased odds of first-trimester exposure to inhaled β2-agonists for cleft palate and gastroschisis and found a potential new signal for renal dysplasia associated with combined long-acting β2-agonists and inhaled corticosteroids. Use of inhaled corticosteroids during the first trimester of pregnancy seems to be safe in relation to the risk for a range of specific major congenital anomalies.

Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial

Roflumilast reduces exacerbations in patients with severe chronic obstructive pulmonary disease. Its effect in patients using fixed combinations of inhaled corticosteroids and longacting β2 agonists is unknown. We postulated that roflumilast would reduce exacerbations in patients with severe chronic obstructive pulmonary disease at risk for exacerbations, even in combination with inhaled corticosteroid and longacting β2 agonist treatment. For this 1-year double-blind, placebo-controlled, parallel group, multicentre, phase 3-4 trial, the Roflumilast and Exacerbations in patients receiving Appropriate Combination Therapy (REACT) study, we enrolled patients with severe chronic obstructive pulmonary disease from 203 centres (outpatient clinics, hospitals, specialised pulmonologists, and family doctors) in 21 countries. Eligible patients were 40 years of age or older with a smoking history of at least 20 pack-years and a diagnosis of chronic obstructive pulmonary disease with severe airflow limitation, symptoms of chronic bronchitis, and at least two exacerbations in the previous year. We used a computerised central randomisation system to randomly assign patients in a 1:1 ratio to the two treatment groups: roflumilast 500 μg or placebo given orally once daily together with a fixed inhaled corticosteroid and longacting β2 agonist combination. Background tiotropium treatment was allowed. All patients and investigators were masked to group assignment. The primary outcome was the rate of moderate to severe chronic obstructive pulmonary disease exacerbations per patient per year, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01329029. Between April 3, 2011, and May 27, 2014, we enrolled 1945 eligible participants and randomly assigned 973 to the roflumilast group and 972 to the placebo group. The rate of moderate-to-severe chronic obstructive pulmonary disease exacerbations was 13·2% lower in the roflumilast group than in the placebo group according to a Poisson regression analysis (roflumilast 0·805 vs placebo 0·927; rate ratio [RR] 0·868 [95% CI 0·753-1·002], p=0·0529), and 14·2% lower according to a predefined sensitivity analysis using negative binomial regression (0·823 vs 0·959; 0·858 [0·740-0·995], p=0·0424). Adverse events were reported by 648 (67%) of 968 patients receiving roflumilast and by 572 (59%) of 967 patients in the placebo group; adverse event-associated patient withdrawal from the study was also more common in the roflumilast group (104/968 [11%]) than in the placebo group (52/967 [5%]). The most frequently reported serious adverse events were chronic obstructive pulmonary disease exacerbations and pneumonia, and 17 (1·8%) deaths occurred in the roflumilast group compared with 18 (1·9%) in the placebo group. Our findings suggest that roflumilast reduces exacerbations and hospital admissions in patients with severe chronic obstructive pulmonary disease and chronic bronchitis who are at risk of frequent and severe exacerbations despite inhaled corticosteroid and longacting β2 agonist therapy, even in combination with tiotropium. Takeda.

The effects of long-acting β2-agonists plus inhaled corticosteroids for early reversibility in patients with airway obstruction.

Salbutamol, as a short-acting β2-agonist, was popularly used in the past for detection of reversibility in patients with airway obstruction when it was the only drug available in the treatment of airway obstruction. Today, the combination of long-acting β2-agonists (LABA) and inhaled glucocorticoids are the first choice of therapy, with or without the presence of reversibility, in patients with airway obstruction. We aimed to compare the efficacy of salbutamol and long acting β2-agonists plus inhaled glucocorticoids for early reversibility test in patients with airway obstruction. Symptomatic patients (cough, dyspnea, and/or wheezing) with airway obstruction according to pulmonary function testing (FEV1/FVC value less than 70% of expected) who had never used bronchodilators before or had not received short- or long-acting inhaled bronchodilator therapy within the most recent 12 hours were evaluated. Reversibility measurements were made by administering the combination of long-acting β2-agonists (LABA) and inhaled glucocorticoids after 15 minutes. A total of 90 patients were evaluated. The mean age of patients was 57.3±17.7 (range, 8-88) years and the male-to-female ratio was 69/21. The baseline pulmonary function test results were mean FVC; 2,747±1,181 mL and 74.7%±21.4%, mean FEV1; 1,716±825 mL and 57.5%±19.0%, mean FEV1/FVC; 61.4%±7.4%. The bronchodilator drugs given before reversibility testing were as salmeterol/fluticasone (FTC/SAL), formoterol/budesonide (BUD/FOR), beclomethasone dipropionate/formoterol (BDP/FOR) and salbutamol (SLB) in 24, 22, 24 and 20 patients, respectively. The reversibility was positive in 33 (36.7%) patients. The absolute change and percentage of change in mean FEV1 were 206±252 mL, 13.2%±16.6% for FTC/SAL group, 273±201 mL, 14%±8% for BUD/FOR group, 240±151 mL, 18.7%±15.9% for BUD/FOR groupand 171±116 mL, 13.3%±11.8% for SLB group. There was no statistically significant for reversibilty results between LABAs/inhaledsteroids and SLB group. And the patients with positivere versibility test were significantly higher in both of BUD/FOR and BDP/FOR groups than SLB group. We think that performance of an early reversibility test using the combination of a LABA and an inhaled corticosteroid for treatment would enhance both the education of the patient in using the device and the reliability of the drug. And, we suggest that: "you should make the reversibility test with Long-Acting β2-Agonists plus Inhaled Corticosteroids which used in treatment of obstructive lung diseases".

Long-acting β2 agonists and corticosteroids restore the reduction of histone deacetylase activity and inhibit H2O2-induced mediator release from alveolar macrophages

BackgroundTreatment of COPD with a combination of long-acting β2 agonists and corticosteroids is currently used worldwide. The mechanisms of the anti-inflammatory effects and their associations with histone deacetylase (HDAC) activity remain unclear. MethodsHuman alveolar macrophages were isolated and stimulated with H2O2 in the presence of varying concentrations of long-acting β2 agonists and corticosteroids. Supernatants were collected for IL-8 and MMP-9 measurements. Cell lysates were analyzed for HDAC (mainly HDAC1/HDAC2) activity. Quantitative real-time PCR was performed to determine the levels of IL-8 and MMP-9 mRNA. ResultsBoth long-acting β2 agonists, salmeterol and formoterol, and corticosteroids, fluticasone and budesonide, showed anti-inflammatory effects to a certain extent on H2O2-induced IL-8 and MMP-9 release in alveolar macrophages. Combinations of long-acting β2 agonists and corticosteroids exerted greater effects to suppress mediator release, and both transcription and translation of IL-8 and MMP-9 were inhibited. It seemed that the levels of IL-8 and MMP-9 after H2O2 stimulation were inversely associated with the activity of HDAC. H2O2 stimulation resulted in a significant decrease in HDAC activity and was associated with an increase in mediator release. In contrast, treatment with long-acting β2 agonists, corticosteroids or theophylline restored the H2O2-induced decrease in HDAC activity and inhibited mediator release. ConclusionCombinations of long-acting β2 agonists and corticosteroids exerted greater effects on the suppression of mediator release in relation to the enhancement of HDAC activity. This supports at least in part the likely contribution of anti-inflammatory effects of long-acting β2 agonists and corticosteroids to the clinical benefits seen in COPD patients.

Controversies regarding long-acting β2-agonists

This review examines the literature regarding the efficacy and safety of long-acting β2-agonists as add-on therapy to inhaled corticosteroids. The Global Initiative for Asthma (GINA) 2009 guidelines and the National Heart, Lung, and Blood Institute (NHLBI) 2007 asthma guidelines recommend adding long-acting β2-agonists to patients inadequately controlled on inhaled corticosteroids. These recommendations must be balanced against published data which demonstrate a signal of increased morbidity and mortality with use of long-acting β2-agonists. These conflicting data raise the question of whether or not there may be genotypic or phenotypic discriminators leading to disparate responses to long-acting β2-agonists. The combination of long-acting β2-agonists and inhaled corticosteroids demonstrates improvement in asthma control and exacerbation rates; however, long-acting β2-agonists are not recommended for use as monotherapy or without optimization of inhaled corticosteroid dose. Although the majority of asthmatic patients appear to benefit from the addition of long-acting β2-agonists, there are concerns that a small proportion of patients, including steroid-naïve patients and African Americans, may not obtain such benefits. Thus far, studies have not clearly demonstrated genotypic or phenotypic differences explaining the variability in response.

Quality of Life Is Improved in Persistent Asthma Subjects Treated With Mometasone Furoate/Formoterol: A New Inhaled Corticosteroid/Long-Acting Beta2-Agonist Combination

PURPOSE: To assess disease-specific quality-of-life in subjects with persistent asthma treated with mometasone furoate/formoterol (MF/F), a newly developed inhaled corticosteroid (ICS)/long-acting β2-agonist combination, administered via a pressurized metered-dose inhaler.

Triple inhaled therapy in stable chronic obstructive pulmonary disease: the earlier, the better?

Inhaled long-acting bronchodilators (of β2-agonist or muscarinic antagonist type) or corticosteroids are used in stable chronic obstructive pulmonary disease (COPD) treatment in a step-up approach according to disease severity. Consequently, in more severe disease triple therapy with two bronchodilators and an inhaled corticosteroid can often be encountered in clinical practice, but its short- and long-term effects on disease outcomes are not very well known. The results of a study evaluating the short-term effects of budesonide/formoterol (inhaled corticosteroid/inhaled long-acting β2-agonist combination) and tiotropium (inhaled long-acting muscarinic antagonist) against tiotropium alone are analysed and discussed. On a short-term basis, triple therapy improves lung function, health status and disease morbidity irrespective of disease severity. Long-term benefits of triple inhaled therapy including the effects of its precocious use in less severe COPD subjects should be evaluated.