Long-acting Muscarinic Antagonist Combination Research Articles

Comparison of Clinical Outcomes Among Different Fixed-Dose Combinations of Long-Acting Muscarinic Antagonists and Long-Acting β2-Agonists in Patients With COPD

Researchers have yet to obtain conclusive evidence differentiating among fixed-dose combinations (FDCs) of long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs) for COPD in terms of real-world clinical outcomes. What are the differences between available LAMA/LABA FDCs in the risk of acute exacerbation (AE) and cardiovascular events? This retrospective cohort study based on a national insurance claims database included patients with COPD≥ 40 years of age who were newly prescribed glycopyrronium (GLY)/indacaterol (IND), umeclidinium (UMEC)/vilanterol (VI), or tiotropium (TIO)/olodaterol (OLO) FDC between January 1, 2015, and June 30, 2019. Propensity score matching and Cox regression models were used to compare outcomes of AE and cardiovascular events associated with LAMA/LABA FDC treatment. Among the 44,498 patients identified and included, 15,586 received GLY/IND, 20,460 received UMEC/VI, and 8,452 received TIO/OLO. Baseline characteristics were well balanced after 1:1 matching of UMEC/VI and GLY/IND, 2:1 matching of UMEC/VI and TIO/OLO, and 2:1 matching of GLY/IND and TIO/OLO. Risk of severe AE was lower among patients treated with UMEC/VI or GLY/IND than among those who received TIO/OLO (UMEC/VI vsTIO/OLO: 17.85 vs29.32 per 100 person-years; hazard ratio, 0.76; 95%CI, 0.68-0.84; GLY/IND vsTIO/OLO: 15.54 vs25.53 per 100 person-years; hazard ratio, 0.77; 95%CI, 0.67-0.88). In addition, GLY/IND users tended to have a lower risk of cardiovascular events than TIO/OLO users, but the difference dissipated when restricting follow up to a shorter duration. Our results revealed that the risk of severe AE was lower among patients with COPD receiving UMEC/VI or GLY/IND than among those receiving TIO/OLO, whereas the incidence of cardiovascular events was similar across groups but was slightly lower in GLY/IND users when compared with TIO/OLO users. Further research will be required to confirm these findings.

A randomized prospective study to compare the efficacy and safety of budesonide plus formoterol and tiotropium plus formoterol in patients having mild to moderate chronic obstructive pulmonary disease

Background: Chronic obstructive pulmonary disease (COPD) is a leading respiratory illness affecting the quality of lives around the world. The present study aims to compare the efficacy and safety of combination of inhaled corticosteroid (ICS) and long acting β2 agonist (LABA) with long acting β2 agonist and long acting muscarinic antagonist (LAMA) in treatment of mild to moderate COPD in a tertiary care hospital.Methods: Total 132 patients with COPD were recruited on the basis of inclusion and exclusion criteria for 8 weeks study from outpatient clinic. A complete pulmonary examination including spirometry examination was done to rule out severe and very severe forms of COPD. Spirometry was performed at the time of recruitment for evaluation of forced expiratory volume in one second (FEV1) and measurement of SpO2 at the time of recruitment at 2 weeks and 8 weeks. Appropriate statistical methods were used to compare the qualitative and quantitative primary and secondary efficacy end points, p value <0.05 was considered significant.Results: On analysis, there was a significant difference (p<0.05) was observed in FEV1 and SpO2 from baseline in ICS plus LABA group (n=66). A similarly significant difference (p<0.05) was observed in LABA and LAMA group (n=66). On comparison between ICS plus LABA and LABA plus LAMA no significant difference in FEV1 and SpO2 was observed between the two groups. More adverse drug reactions were observed in ICS plus LABA group than LAMA plus LABA group.Conclusions: Combination of ICS and LABA combination is as effective as combination of LABA and LAMA in patients having mild to moderate COPD. However, LABA and LAMA combination is preferable because it is associated with fewer side effects.

Comparisons of exacerbations and mortality among LAMA/LABA combinations in stable chronic obstructive pulmonary disease: systematic review and Bayesian network meta-analysis

BackgroundOnly few randomized controlled trials (RCTs) for head-to-head comparison have been conducted between various combinations of long-acting muscarinic antagonists (LAMAs) and long-acting beta-agonists (LABAs). Our study was conducted to compare acute exacerbation and all-cause mortality among different LAMA/LABA regimens using Bayesian network meta-analysis (NMA).MethodsWe searched Medline, EMBASE, and the Cochrane library (search date: July 1, 2019). We included parallel-group RCTs comparing LAMA/LABA combinations with other inhaled drugs in the stable COPD for ≥ 48 weeks. Two different network geometries were used. The geometry of network (A) had nodes of individual drugs or their combination, while that of network (B) combined all other treatments except LAMA/LABA into each drug class. This study was prospectively registered in PROSPERO; CRD42019126753.ResultsWe included 16 RCTs involving a total of 39,065 patients with stable COPD. Six combinations of LAMA/LABA were identified: tiotropium/salmeterol, glycopyrrolate/indacaterol, umeclidinium/vilanterol, tiotropium/olodaterol, aclidinium/formoterol, and glycopyrrolate/formoterol. We found that umeclidinium/vilanterol was associated with a lower risk of total exacerbations than other LAMA/LABAs in the NMA using network (A) (level of evidence: low or moderate). However, the significant differences were not present in the NMA of network (B). There were no significant differences among the LAMA/LABA combinations in terms of the number of moderate to severe exacerbations, all-cause mortality, major adverse cardiovascular events, or pneumonia.ConclusionsThe present NMA including all available RCTs provided that there is no strong evidence suggesting different benefits among LAMA/LABAs in patients with stable COPD who have been followed up for 48 weeks or more.Trial registration: This study was prospectively registered in PROSPERO; CRD42019126753.

Reducing and managing chronic obstructive pulmonary disease exacerbations with tiotropium + olodaterol

Objective The aim of this study was to review clinical evidence supporting the use of fixed-dose combination of tiotropium and olodaterol, a long-acting muscarinic antagonist (LAMA) and a long-acting β2-agonist (LABA), respectively, as the initial and follow-up treatment choice in patients with chronic obstructive pulmonary disease (COPD) as per Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2020 recommendations—the impact of this treatment strategy on the reduction in the risk of exacerbations—and the importance of early therapeutic interventions. Methods For this narrative review, the available literature was searched to identify studies including patients with COPD receiving tiotropium and olodaterol as either monotherapy or combination therapy and studies including patients with COPD receiving inhaled corticosteroids (ICS) in addition to long-acting bronchodilators. Relevant studies were included in the review. Results Patients with COPD are often prescribed ICS therapy, which, when used over a long term, can be associated with local and systemic adverse effects. The GOLD 2020 report recommends dual bronchodilator therapy as both an initial and follow-up treatment option. A LABA + LAMA combination is mechanistically synergistic, and cumulative evidence surrounding the efficacy and safety of fixed-dose combination of tiotropium and olodaterol supports therapeutic advantages over monotherapy in most patients with COPD. Conclusions The early stages of COPD may represent a “window of therapeutic opportunity” during which initiation of tiotropium and olodaterol dual bronchodilator therapy may improve lung function and quality of life and reduce exacerbations in patients with COPD.

Efficacy and Safety of Long-acting Beta-2 Agonist and Long-acting Muscarinic Antagonist Combinations in Patients with Chronic Obstructive Pulmonary Disease: Meta-analysis of Phase 3 Randomized Trials

Efficacy and Safety of Long-acting Beta-2 Agonist and Long-acting Muscarinic Antagonist Combinations in Patients with Chronic Obstructive Pulmonary Disease: Meta-analysis of Phase 3 Randomized Trials

A cross-sectional survey of current treatment and symptom burden of patients with COPD consulting for routine care according to GOLD 2014 classifications.

BackgroundAs part of the Respiratory Disease Specific Program (DSP) conducted to provide observations of clinical practice from a physician and matched patient viewpoint, this study aimed to establish how patients with COPD are treated according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification system and to quantify the symptom burden.MethodsData were obtained from the Respiratory DSP, a cross-sectional survey of patients with a diagnosis of COPD consulting for routine care in France, Germany, Italy, Spain, the UK, and the USA during the third quarter of 2013. Patients’ exacerbation risk and symptom data were used for classification into GOLD groups A−D based on GOLD 2014 criteria. Prescribing practices were stratified by physician type and time since patient diagnosis.ResultsA total of 903 physicians participated in the Respiratory DSP, with data from 1,641 patients included in this analysis. Most patients were classified into GOLD groups B (n=742; 45.2%) and D (n=704; 42.9%). Patients in groups A and D were most likely to be treated in line with GOLD recommendations (61.5% and 77.5%, respectively), compared with 40.1% for group B. Patients with a diagnosis within the past 12 months were more likely to be treated according to recommendations. Inhaled corticosteroids (ICSs) in combination with one or more long-acting bronchodilator were prescribed across all GOLD groups. Patterns of treatment were, in general, similar for patients treated by a primary care physician or a pulmonologist. COPD assessment test scores ≥10 indicating a high symptom burden were reported for >80% of patients.ConclusionThis analysis confirmed a high symptom burden among patients with COPD and indicates some misalignment of prescribing with GOLD recommendations, particularly regarding the role of ICS/long-acting β2-agonist (LABA) and ICS/LABA + long-acting muscarinic antagonist combinations across the different GOLD groups.

Comparative efficacy of fixed-dose combinations of long-acting muscarinic antagonists and long-acting β2-agonists: a systematic review and network meta-analysis

A number of long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) fixed-dose combinations (FDCs) for treatment of moderate-to-very severe chronic obstructive pulmonary disease (COPD) have recently become available, but none have been directly compared in head-to-head randomized controlled trials (RCTs). The purpose of this study was to assess the relative clinical benefit of all currently available LAMA/LABA FDCs using a Bayesian network meta-analysis (NMA). A systematic literature review identified RCTs investigating the efficacy, safety and quality of life associated with licensed LAMA/LABA FDCs for the treatment of moderate-to-very severe COPD. RCTs were screened for inclusion in the NMA using prespecified eligibility criteria. Data were extracted for outcomes of interest, including change in trough forced expiratory volume in 1 second (tFEV1) from baseline, St. George Respiratory Questionnaire (SGRQ) percentage of responders, Transition Dyspnea Index (TDI) percentage of responders, change in SGRQ score from baseline, change in TDI focal score from baseline, moderate-to-severe exacerbations, all-cause discontinuation, and discontinuation due to adverse events. Following screening, a total of 27 trials from 26 publications with 30,361 subjects were eligible for inclusion in the NMA. Nonsignificant results were seen in most analyses comparing efficacy, exacerbations and discontinuation rates of included LAMA/LABA FDCs (i.e. aclidinium/formoterol 400/12 µg, glycopyrronium/indacaterol 110/50 µg, tiotropium + olodaterol 5/5 µg, umeclidinium/vilanterol 62.5/25 µg). Meta-regression controlling for post-bronchodilator percentage of tFEV1 predicted at baseline as well as meta-regression adjusting for concomitant use of inhaled corticosteroids at baseline was performed to assess the magnitude of effect modification and produced similar results as observed in the base case analysis. All LAMA/LABA FDCs were found to have similar efficacy and safety. Definitive assessment of the relative efficacy of different treatments can only be performed through direct comparison in head-to-head RCTs. In the absence of such data, this indirect comparison may be of value in clinical and health economic decision-making.

Positioning new pharmacotherapies for COPD.

COPD imposes considerable worldwide burden in terms of morbidity and mortality. In recognition of this, there is now extensive focus on early diagnosis, secondary prevention, and optimizing medical management of the disease. While established guidelines recognize different grades of disease severity and offer a structured basis for disease management based on symptoms and risk, it is becoming increasingly evident that COPD is a condition characterized by many phenotypes and its control in a single patient may require clinicians to have access to a broader spectrum of pharmacotherapies. This review summarizes recent developments in COPD management and compares established pharmacotherapy with new and emerging pharmacotherapies including long-acting muscarinic antagonists, long-acting β-2 sympathomimetic agonists, and fixed-dose combinations of long-acting muscarinic antagonists and long-acting β-2 sympathomimetic agonists as well as inhaled cortiocosteroids, phosphodiesterase inhibitors, and targeted anti-inflammatory drugs. We also review the available oral medications and new agents with novel mechanisms of action in early stages of development. With several new pharmacological agents intended for the management of COPD, it is our goal to familiarize potential prescribers with evidence relating to the efficacy and safety of new medications and to suggest circumstances in which these therapies could be most useful.

Profile of a fixed-dose combination of tiotropium/olodaterol and its potential in the treatment of COPD.

Chronic obstructive pulmonary disease (COPD) is a progressive, debilitating disorder that results in frequent exacerbations and impacts quality of life. It represents a growing burden of health care cost, both from societal and economic perspectives. Short- and long-acting bronchodilators remain the mainstay of therapy in COPD patients. New fixed-dose combination inhalers with novel pharmacological combinations of long-acting β2-agonists and muscarinic antagonists and delivered once-daily through a variety of devices are currently being developed and licensed for the treatment of COPD. There is mounting research suggesting that combining a fixed dose of a β2-agonist and a muscarinic antagonist achieves better bronchodilation and clinical outcomes compared with either agent alone. These once-daily dosing inhalers are anticipated to impact favorably on patient preference and compliance. This review examines the fixed-dose combination of tiotropium bromide and olodaterol delivered by a Respimat® Soft Mist™ inhaler at doses of 2.5/5 μg and 5/5 μg in moderate-to-very-severe COPD, and its potential role in COPD compared with other long-acting β2-agonist with long-acting muscarinic antagonist combinations and delivery devices.