Long-acting Muscarinic Antagonist Therapy Research Articles

Characterization of Obesity in Severe Asthma in the German Asthma Net

Asthma is increasingly recognized as heterogeneous, characterized by different endotypes, with obesity not only a distinct phenotype but a risk factor for severe asthma. We sought to understand the associations of obesity with relevant parameters of severe asthma, including asthma control, disease burden, and lung function. The German Asthma Net registry is a multicenter international real-life registry capturing long-term follow-up data. This analysis included 2213 patients (52 ± 16 years, 58% female, 29% with obesity [body mass index ≥30 kg/m2], 4.2 ± 4.3 exacerbations/year). The primary analysis assessed relationships between BMI and variables through univariate tests, followed by a multiple regression model. Secondary outcomes regarded clinically relevant variables in relation to weight groups. Patients with obesity were more frequently female, more likely to have depression and gastroesophageal reflux, and suffered from worse asthma control, lower quality of life, reduced static lung volumes, more pronounced hypoxemia, and higher blood neutrophil counts, all statistically significant. Blood eosinophils, exhaled nitric oxide, and total IgE were independent of obesity. In the multiple regression analysis, obesity was significantly associated with more frequent reflux and depression, reduced static lung function values, older age, poor asthma control, and long-acting muscarinic antagonist therapy, and inversely associated with bronchiectasis and nonsmoking status. In this large, well-characterized cohort, we identified the association of obesity with a significantly higher disease burden and a similar portfolio of inflammation type 2 markers in patients with and without obesity; therefore, patients with obesity seem similarly eligible for the treatment with biologics targeting these disease endotypes.

Clinical factors linked to the type of respiratory medication in COPD: results from the COSYCONET cohort.

The use of maintenance medication in patients with chronic obstructive pulmonary disease (COPD) in real life is known to deviate from recommendations in guidelines, which are largely based on randomized controlled trials and selected populations. We used the COSYCONET (COPD and Systemic Consequences - Comorbidities Network) cohort to analyze factors linked to the use of COPD drugs under non-interventional circumstances. COSYCONET is an ongoing, multi-center, non-interventional cohort of patients with COPD. Patients with COPD of Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 0-4 participating in visits 1-5 were included. Data covered the period from 2010 to 2018. Generalized linear models were used to examine the relation of COPD characteristics to different types of respiratory medication. A total of 1043 patients were included. The duration of observation was 4.5 years. Use of respiratory medication depended on GOLD grades 0-4 and groups A-D. Long-acting muscarinic antagonist therapy increased over time, and was associated with low carbon monoxide (CO) diffusing capacity, while inhaled corticosteroid (ICS) use decreased. Active smoking was associated with less maintenance therapy in general, and female sex with less ICS use. From the eight items of the COPD Assessment Test, only hill and stair climbing were consistently linked to treatment. Using data from a large, close to real-life observational cohort, we identified factors linked to the use of various types of respiratory COPD medication. Overall, use was consistent with GOLD recommendations. Beyond this, we identified other correlates of medication use that may help us to understand and improve therapy decisions in clinical practice. ClinicalTrials.gov NCT01245933.

Understanding the Updates in the Asthma Guidelines.

Asthma is a chronic inflammatory lung disease that affects millions of Americans, with variable symptoms of bronchospasm and obstruction among individuals over time. The National Heart, Lung, and Blood Institute (NHLBI) published the 2020 Focused Updates to the Asthma Management Guidelines based on the latest research since the 2007 Expert Panel Report-3 (EPR-3). The following article reviews the 21 new recommendations on the six core topics in asthma: use of intermittent inhaled corticosteroids, long-acting muscarinic antagonist therapy, use of the fractional exhaled nitric oxide test in asthma diagnosis and monitoring, indoor allergen mitigation, immunotherapy, and bronchial thermoplasty. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to rate recommendations as strong or conditional based on the evidence. The recommendations were based on systematic reviews of the literature and focused on patient-centered critical outcomes of asthma exacerbations, asthma control, and asthma-related quality of life. Understanding the recommendations with consideration of individual values through shared decision-making may improve asthma outcomes.

2020 NAEPP Guidelines Update and GINA 2021—Asthma Care Differences, Overlap, and Challenges

The 2020 National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group (NAEPP [2020 Focused Asthma Update]) guidelines and the Global Initiative for Asthma (GINA) 2021 strategy report are compared in this Rostrum article. The methodologies of each publication are described. Subsequently, 4 different selected pharmacological recommendations are compared in the 2 documents: step 1 for children 0 to 4 years of age with viral-induced wheezing, step 2 in ages 12 years and older with the intermittent use of inhaled corticosteroid, steps 3 and 4 with single-inhaler maintenance and reliever therapy with inhaled corticosteroids-formoterol (SMART), and steps 3, 4, and 5 with add-on long-acting muscarinic antagonist therapy. Nonpharmacological recommendations are also considered and contrasted, including for exhaled nitric oxide, environmental control, immunotherapy, and bronchial thermoplasty. Similarities and differences in these 2 documents are highlighted, and recommendations are made about harmonizing the approaches where possible.

Dual versus single long-acting bronchodilator use could raise acute coronary syndrome risk by over 50%: A population-based nested case-control study.

BackgroundCoronary heart disease occurs more frequently among patients with chronic obstructive pulmonary disease (COPD) compared to those without COPD. While some research suggests that long‐acting bronchodilators might confer an additional risk of acute coronary syndrome (ACS), information from real‐world clinical practice about the cardiovascular impact of using two versus one long‐acting bronchodilator for COPD is limited. We undertook a population‐based nested case–control study to estimate the risk of ACS in users of both a long‐acting muscarinic antagonist (LAMA) and a long‐acting beta2‐agonist (LABA) relative to users of a LAMA.MethodsThe study was based on the primary care PREDICT Cardiovascular Disease Cohort and linked data from regional laboratories and the New Zealand Ministry of Health's national data collections. The underlying cohort (n = 29,993) comprised patients aged 45–84 years, who initiated treatment with a LAMA and/or LABA for COPD between 1 February 2006 and 11 October 2016. 1490 ACS cases were matched to 13,550 controls by date of birth, sex, date of cohort entry (first long‐acting bronchodilator dispensing), and COPD severity.ResultsRelative to current use of LAMA therapy, current use of LAMA and LABA dual therapy was associated with a significantly higher risk of ACS (adjusted OR = 1.72; [95% CI: 1.28–2.31]).ConclusionDual long‐acting bronchodilator therapy, rather than LAMA mono‐therapy, could increase the risk of ACS by more than 50%. This has important implications for decisions about the potential benefit/harm ratio of COPD treatment intensification, given the modest benefits of dual therapy.

Prognostic and functional impact of perioperative LAMA/LABA inhaled therapy in patients with lung cancer and chronic obstructive pulmonary disease

BackgroundChronic obstructive pulmonary disease (COPD) is an important risk factor for postoperative complications and mortality. To determine the effects of perioperative combination therapy, using a long-acting muscarinic antagonist (LAMA) and a long-acting β2 agonist (LABA), on preoperative lung function, postoperative morbidity and mortality, and long-term outcome in COPD patients.MethodsBetween January 2005 and October 2019, 130 consecutive patients with newly diagnosed COPD underwent surgery for lung cancer. We conducted a retrospective review of their medical record to evaluate that LAMA/LABA might be an optimal regimen for patients with COPD undergoing surgery for lung cancer. All patients were received perioperative rehabilitation and divided into 3 groups according to the type of perioperative inhaled therapy and management: LAMA/LABA (n = 64), LAMA (n = 23) and rehabilitation only (no bronchodilator) (n = 43). We conducted a retrospective review of their medical records.ResultsPatients who received preoperative LAMA/LABA therapy showed significant improvement in lung function before surgery (p < 0.001 for both forced expiratory volume in 1 s (FEV1) and percentage of predicted forced expiratory volume in 1 s (FEV1%pred). Compared with patients who received preoperative LAMA therapy, patients with LAMA/LABA therapy had significantly improved lung function (ΔFEV1, LAMA/LABA 223.1 mL vs. LAMA 130.0 mL, ΔFEV1%pred, LAMA/LABA 10.8% vs. LAMA 6.8%; both p < 0.05). Postoperative complications were lower frequent in the LAMA/LABA group than in the LAMA group (p = 0.007). In patients with moderate to severe air flow limitation (n = 61), those who received LAMA/LABA therapy had significantly longer overall survival and disease-free survival compared with the LAMA (p = 0.049, p = 0.026) and rehabilitation-only groups (p = 0.001, p < 0.001). Perioperative LAMA/LABA therapy was also associated with lower recurrence rates (vs. LAMA p = 0.006, vs. rehabilitation-only p = 0.008).ConclusionsWe believe this treatment combination is optimal for patients with lung cancer and COPD.

Inhaled triple therapy and airway hyperresponsiveness in persistent asthma

Adding a long-acting muscarinic antagonist (LAMA) is recommended in the guidelines for a patient with asthma not controlled on inhaled corticosteroid (ICS)/long-acting β-agonist (LABA). The change in forced expiratory volume in 1 second (FEV1) resulting from the addition of LAMA to ICS/LABA may be relatively small or less than the minimal clinically important difference, and as such, improved airway caliber is not the primary mechanism for a reduction in exacerbations with LAMA therapy. 1 Lipworth B.J. Emerging role of long acting muscarinic antagonists for asthma. Br J Clin Pharmacol. 2014; 77: 55-62 Crossref PubMed Scopus (33) Google Scholar Exacerbations are, in part, determined by the effects on airway hyperresponsiveness (AHR) in which a LAMA might be expected to confer additional airway smooth muscle–stabilizing effects when added to ICS/LABA. 2 Currie G.P. Jackson C.M. Ogston S.A. Lipworth B.J. Airway-stabilizing effect of long-acting beta2-agonists as add-on therapy to inhaled corticosteroids. Qjm. 2003; 96: 435-440 Crossref PubMed Scopus (23) Google Scholar Aside from effects on airway smooth muscle, there may be neuronal and paracrine actions of LAMAs that may reduce exacerbations. 1 Lipworth B.J. Emerging role of long acting muscarinic antagonists for asthma. Br J Clin Pharmacol. 2014; 77: 55-62 Crossref PubMed Scopus (33) Google Scholar Indirect challenge tests with agents such as mannitol are thought to be more physiological than direct agents such as histamine or methacholine in that they better reflect the underlying inflammation status as opposed to the function of airway smooth muscle alone. 3 Nair P. Martin J.G. Cockcroft D.C. et al. Airway hyperresponsiveness in asthma: measurement and clinical relevance. J Allergy Clin Immunol Pract. 2017; 5: 649-659.e2 Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar

Healthcare Resource Utilization, Exacerbations, and Readmissions Among Medicare Patients with Chronic Obstructive Pulmonary Disease After Long-Acting Muscarinic Antagonist Therapy Initiation with Soft Mist versus Dry Powder Inhalers.

BackgroundChronic obstructive pulmonary disease (COPD) is often managed with inhaled long-acting muscarinic antagonists (LAMAs), yet real-world data on healthcare resource utilization (HRU) by inhaler type are lacking. This study compared HRU after LAMA initiation with a soft mist inhaler (SMI) versus a dry powder inhaler (DPI).Patients and MethodsInclusion criteria were COPD diagnosis, age ≥40 years, LAMA initiation (index date = first LAMA SMI or DPI claim 9/1/14—6/30/18), and Medicare Advantage enrollment 1 year pre-index (baseline) to ≥30 days post-index (follow-up). Patients were followed to the earliest of discontinuation, switch, disenrollment, 1 year, or study end (7/31/18). Exclusion criteria were asthma, cystic fibrosis, or lung cancer diagnoses, unavailable demographics, multiple index LAMAs, or baseline LAMA use. Cohorts (SMI or DPI) were balanced on baseline characteristics using inverse probability of treatment weighting. Outcomes included per patient per month (PPPM) COPD-related HRU encounters, and exacerbations (defined as moderate [ambulatory visit with corticosteroid or antibiotic within ±7 days] or severe [emergency visit or inpatient admission]); and 30-day readmissions following COPD-related hospitalizations.ResultsAfter weighting, cohorts (SMI [n=5360] and DPI [n=22,880]) were similar in age (72 and 73 years, respectively), gender (both 52% female), and COPD severity score (31.3 and 31.5, respectively). Cohorts had similar counts of follow-up HRU encounters. However, the SMI cohort had fewer (mean ± standard deviation) COPD-related exacerbations (0.054±0.082 vs DPI cohort 0.059±0.088 PPPM, p<0.001) overall. Moreover, the SMI cohort had fewer severe exacerbations (0.030±0.058 vs DPI: 0.034±0.065 PPPM, p<0.001). Hospitalizations among SMI patients had a lower adjusted odds of readmission versus hospitalizations among DPI patients (odds ratio: 0.656, 95% confidence interval= 0.460, 0.937; p=0.020).ConclusionSMI initiators had significantly fewer COPD-related exacerbations than DPI initiators. In addition, lower odds of readmissions were observed following COPD-related hospitalizations among the SMI cohort, as compared with the DPI cohort.

Inhaled Corticosteroid Treatment in Chronic Obstructive Pulmonary Disease (COPD): Boon or Bane?

Inhaled corticosteroid (ICS)-based therapy is often used for patients with chronic obstructive pulmonary disease (COPD). However, this approach is under scrutiny because of ICS overuse in patients for whom it is not recommended and because of concerns about adverse events, particularly pneumonia, with long-term ICS use. Evidence suggests ICS may be beneficial in specific patients, namely, those with high blood eosinophil counts (eg, ≥300 cells/µL) or who are at a high risk of exacerbations. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2020 ABCD assessment tool, these patients belong in group D. For these patients, recommended initial treatment includes ICS in combination with long-acting β2-agonists (LABAs) when blood eosinophil counts are ≥300cells/µL or LABA + long-acting muscarinic antagonist (LAMA) when patients are highly symptomatic, that is, with greater dyspnea and/or exercise limitation. Follow-up treatments for patients with persistent dyspnea and/or exacerbations may include LABA + ICS, LABA + LAMA, or LABA + LAMA + ICS, with use of ICS being guided by blood eosinophil counts. In this review, differences in the inflammatory mechanism underlying COPD and asthma and the role of ICS treatment in COPD are summarized. Furthermore, findings from recent clinical trials where use of ICS-based dual or triple therapy in COPD was compared with LABA + LAMA therapy and trials in which ICS withdrawal was evaluated in patients with COPD are reviewed. Finally, a step-by-step guide for ICS withdrawal in patients who are unlikely to benefit from this treatment is proposed. A video of the author discussing the overall takeaway of the review article could be downloaded from the link provided: https://www.youtube.com/watch?v=Uq7Sr5jqPDI.

Tiotropium in children and adolescents with asthma

BackgroundAsthma is a major cause of morbidity in children, despite the availability of various treatments. In adults, tiotropium—a long-acting muscarinic antagonist—as add-on therapy to an inhaled corticosteroid with or without a long-acting β2-agonist provides clinical benefit with a safety profile similar to placebo. ObjectiveTo review published evidence on the efficacy and safety of tiotropium as add-on a long-acting muscarinic antagonist therapy in children and adolescents with asthma that is uncontrolled despite use of an inhaled corticosteroid with or without additional controller medication(s). MethodsWe searched PubMed from inception until June 12, 2018, for randomized controlled trials of children and adolescents aged 1 to 17 years treated with tiotropium and reporting a primary outcome of any pulmonary function test and a secondary outcome of adverse events. ResultsOverall, 7 randomized controlled trials of 1902 preschool children (aged 1-5 years; n = 102), school-age children (aged 6-11 years; n = 905), and adolescents (aged 12-17 years; n = 895) with moderate to severe asthma were included in the analysis. Once-daily tiotropium (5, 2.5, or 1.25 μg) improved lung function parameters, including peak and trough forced expiratory volume in 1 second, vs placebo. Commonly reported adverse events across treatment groups included asthma worsening or exacerbations, decreased peak expiratory flow rate, nasopharyngitis, viral respiratory tract infection, and respiratory tract infection. ConclusionOnce-daily tiotropium as add-on therapy is efficacious and safe in adolescents and children with moderate to severe asthma. These results support the expanded indication by regulatory authorities for add-on tiotropium in patients 6 years or older.

Combined aclidinium bromide and long-acting beta2-agonist for chronic obstructive pulmonary disease (COPD).

Combined aclidinium bromide and long-acting beta2-agonist for chronic obstructive pulmonary disease (COPD).

Long-acting muscarinic antagonist and long-acting β2-agonist therapy to optimize chronic obstructive pulmonary disease prior to lung cancer surgery.

Bronchodilators are essential for the perioperative management of patients with chronic obstructive pulmonary disease (COPD) undergoing surgery for lung cancer. The objective of the present study was to examine whether the usage of a long-acting β2-agonist (LABA) with a long-acting muscarinic antagonist (LAMA) could optimize preoperative lung function and reduce the risk for postoperative pulmonary complications. Thirty-two consecutive patients with moderate-to-severe COPD who underwent a lobectomy for lung cancer and received preoperative LAMA (n=19) or LAMA/LABA (n=13) therapy between January 2005 and December 2015 were enrolled in this retrospective study. The improvement of preoperative pulmonary function and the postoperative morbidity were compared between the patients with preoperative LAMA, and LAMA/LABA therapy. Increases in the forced expiratory volume in one second (FEV1) were significantly larger in the LAMA/LABA group than in the LAMA group (0.26±0.05 l vs. 0.07±0.05 l; P=0.0145). More patients in the LAMA/LABA group than in the LAMA group showed a marked improvement of >10% in %FEV1 after bronchodilators (85 vs. 32%; P=0.0046). The incidence of postoperative pneumonia was significantly lower in the LAMA/LABA group than in the LAMA group (0 vs. 26%; P=0.044). In conclusion, the present study showed that preoperative LAMA/LABA therapy was associated with larger improvements in preoperative pulmonary function and less postoperative pneumonia than LAMA therapy. These results may lead to greater improvements in FEV1 and less postoperative pneumonia by encouraging preoperative LAMA/LABA therapy in this patient population.

Patterns of use of long-acting bronchodilators in patients with COPD: A nationwide follow-up study of new users in New Zealand.

While several studies have found that prescribing practices do not conform to chronic obstructive pulmonary disease (COPD) treatment guidelines, none have examined longitudinal patterns of use of long-acting beta2 -agonist (LABA) and long-acting muscarinic antagonist (LAMA) therapy across an entire country. We undertook a nationwide follow-up study to describe treatment patterns in new users of long-acting bronchodilators. National health and pharmaceutical dispensing data were used to identify patients aged ≥45 years who initiated LABA and/or LAMA therapy for COPD between 1 February 2006 and 31 December 2013. Dispensings of LABAs, LAMAs and inhaled corticosteroids (ICSs) were aggregated into episodes of use of therapeutic regimens. Kaplan-Meier curves, sunburst plots and sequence index plots were generated to summarize, respectively, the duration of the first regimen, the sequences in which unique regimens were used and the patterns of use and non-use during follow-up. The study cohort included 83 435 patients with 290 400 person-years of follow-up. The most commonly initiated regimen was a LABA with an ICS. ICS use was inconsistent with international guidelines: over- and under-treatment occurred in patients with infrequent and frequent exacerbations, respectively, and ICS monotherapy was common. The median duration of the first regimen was 46 days. Many patients used multiple regimens over time and periods of non-use were common. In this nationwide study, patterns of use of LABAs, LAMAs and ICSs were complex and often did not comply with treatment guidelines. Further work is required to address the discrepancy between guidelines and prescribing practices.

Cardiovascular Safety and Efficacy of Nebulized Glycopyrrolate/eFlow CS in Phase 3 Trials of Patients With Moderate to Very Severe COPD

SESSION TITLE: COPD 2 SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, November 1, 2017 at 01:30 PM - 02:30 PM PURPOSE: The GOLDEN Phase 3 studies in subjects with moderate-to-very-severe COPD assessed the efficacy and safety of a novel, nebulized glycopyrrolate (GLY) and were prospectively designed to include subjects with cardiovascular (CV) risk factors. METHODS: In two 12-week and one 48-week study, 2379 subjects were stratified by CV risk (high vs low) and randomized to placebo, GLY 25 or 50 mcg twice daily, or tiotropium (TIO; 18 mcg once daily). Safety, lung function, patient-reported outcomes and exacerbations were assessed by CV risk subgroup. RESULTS: Across studies, 1526 subjects were at high CV risk and 853 were at low CV risk. At week 12, the incidence of adverse events leading to discontinuation was similar in high and low CV risk subgroups and lower in GLY 25 and 50 mcg groups (high: 6.2% and 3.6%; low: 3.2% and 4.5%) than placebo (high: 9.0%; low: 9.9%). In the 48-week study, discontinuations were higher for GLY (high: 10.7%; low: 8.7%) vs TIO (3.7%; 1.2%, respectively), partly due to increased cough and COPD event rates. CV events of special interest were low in both CV risk subgroups, and generally similar between treatments at 12 weeks (high: placebo, 3.6%; GLY 25 mcg, 1.1%; GLY 50 mcg, 2.2%; low: 0.7%; 2.6%; 1.9%, respectively). Incidences at 48 weeks were similar in the high CV risk group and numerically higher for TIO than GLY in the low CV risk subgroup, particularly for arrhythmias (high: GLY, 5.0%; TIO, 5.1%; low: GLY, 2.3%; TIO, 4.1%). Major adverse cardiac events (MACE) occurred more frequently with placebo in the high CV risk subgroup at 12 weeks (incidence rate [IR] for high vs low: placebo, 25.1 vs 0; GLY 25 mcg, 0 vs 0; GLY 50 mcg, 24.3 vs 21.6). At 48 weeks, IR for MACE were higher for TIO than GLY (high vs low: GLY, 6.7 vs 6.0; TIO 24.3 vs 13.6). GLY led to statistically significant, clinically important improvements in trough forced expiratory volume in 1 second (FEV1) in high and low CV risk subgroups at week 12 vs placebo (25 mcg, 95 and 97 mL; 50 mcg, 99 and 113 mL, respectively, p<0.001). The overall change from baseline in trough FEV1 was similar across CV risk subgroups for GLY (100 and 94 mL) and TIO (84 and 107 mL) over 48 weeks’ treatment. At week 12, in both subgroups, GLY produced statistically significant improvements (p<0.05) vs placebo in St George’s Respiratory Questionnaire (SGRQ) and the proportion of GLY responders was consistently higher than placebo. Over 48 weeks, change from baseline in SGRQ was higher for GLY vs TIO in the high CV risk subgroup, as was the proportion of GLY SGRQ responders at 48 weeks (47% vs 39%). Change and response for the low risk group was numerically higher for TIO than GLY. Exacerbation rates were similar across all treatment groups and most exacerbations were moderate in severity in both subgroups after 12 and 48 weeks. CONCLUSIONS: Nebulized GLY had an acceptable safety/tolerability profile and improved lung function and patient-reported outcomes in subjects with COPD and CV risk factors for up to 48 weeks. CLINICAL IMPLICATIONS: Nebulized GLY is well tolerated and effective and provides a novel treatment option in patients who may require or benefit from nebulized long-acting muscarinic antagonist therapy. DISCLOSURE: Gary Ferguson: Grant monies (from industry related sources): Sunovion Pharmaceuticals Inc., Grant monies (from industry related sources): Boehringer Ingelheim, Other: Sunovion Pharmaceuticals Inc., Other: Boehringer Ingelheim Robert Tosiello: Employee: Sunovion Pharmaceuticals Inc. Thomas Goodin: Employee: Sunovion Pharmaceuticals Inc. Abstract describes analysis from Phase 3 trials of nebulized glycopyrrolate in COPD (not currently approved)

A retrospective study to assess clinical characteristics and time to initiation of open-triple therapy among patients with chronic obstructive pulmonary disease, newly established on long-acting mono- or combination therapy

IntroductionAn incremental approach using open-triple therapy may improve outcomes in patients with chronic obstructive pulmonary disease (COPD). However, there is little sufficient, real-world evidence available identifying time to open-triple initiation.MethodsThis retrospective study of patients with COPD, newly initiated on long-acting muscarinic antagonist (LAMA) monotherapy or inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) combination therapy, assessed baseline demographics, clinical characteristics, and exacerbations during 12 months prior to first LAMA or ICS/LABA use. Time to initiation of open-triple therapy was assessed for 12 months post-index date. Post hoc analyses were performed to assess the subsets of patients with pulmonary-function test (PFT) information and patients with and without comorbid asthma.ResultsDemographics and clinical characteristics were similar between cohorts in the pre-specified and post hoc analyses. In total, 283 (19.3%) and 160 (10.9%) patients had moderate and severe exacerbations at baseline, respectively, in the LAMA cohort, compared with 482 (21.3%) and 289 (12.8%) patients in the ICS/LABA cohort. Significantly more patients initiated open-triple therapy in the LAMA cohort compared with the ICS/LABA cohort (226 [15.4%] versus 174 [7.7%]; P<0.001); results were similar in the post hoc analyses. Mean (standard deviation) time to open-triple therapy was 79.8 (89.0) days in the LAMA cohort and 122.9 (105.4) days in the ICS/LABA cohort (P<0.001). This trend was also observed in the post hoc analyses, though the difference between cohorts was nonsignificant in the subset of patients with PFT information.DiscussionIn this population, patients with COPD are more likely to initiate open-triple therapy following LAMA therapy, compared with ICS/LABA therapy. Further research is required to identify factors associated with the need for treatment augmentation among patients with COPD.

Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial

Limited data are available for the efficacy of triple therapy with two long-acting bronchodilators and an inhaled corticosteroid in chronic obstructive pulmonary disease (COPD). We compared treatment with extrafine beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide (BDP/FF/GB; fixed triple) with tiotropium, and BDP/FF plus tiotropium (open triple). For this double-blind, parallel-group, randomised, controlled trial, eligible patients had COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) of less than 50%, at least one moderate-to-severe COPD exacerbation in the previous 12 months, and a COPD Assessment Test total score of at least 10. After a 2-week run-in period receiving one inhalation per day via single-dose dry-powder inhaler of open-label 18 μg tiotropium, patients were randomised (2:2:1) using a interactive response technology system to 52 weeks treatment with tiotropium, fixed triple, or open triple. Randomisation was stratified by country and severity of airflow limitation. The primary endpoint was moderate-to-severe COPD exacerbation rate. The key secondary endpoint was change from baseline in pre-dose FEV1 at week 52. The trial is registered with ClinicalTrials.gov, number NCT01911364. Between Jan 21, 2014, and March 18, 2016, 2691 patients received fixed triple (n=1078), tiotropium (n=1075), or open triple (n=538). Moderate-to-severe exacerbation rates were 0·46 (95% CI 0·41-0·51) for fixed triple, 0·57 (0·52-0·63) for tiotropium, and 0·45 (0·39-0·52) for open triple; fixed triple was superior to tiotropium (rate ratio 0·80 [95% CI 0·69-0·92]; p=0·0025). For week 52 pre-dose FEV1, fixed triple was superior to tiotropium (mean difference 0·061 L [0·037 to 0·086]; p<0·0001) and non-inferior to open triple (-0·003L [-0·033 to 0·027]; p=0·85). Adverse events were reported by 594 (55%) patients with fixed triple, 622 (58%) with tiotropium, and 309 (58%) with open triple. In our TRINITY study, treatment with extrafine fixed triple therapy had clinical benefits compared with tiotropium in patients with symptomatic COPD, FEV1 of less than 50%, and a history of exacerbations. Chiesi Farmaceutici SpA.

Is Combination Long-acting Beta-Agonist and Long-acting Muscarinic Antagonist Therapy the Future of COPD Therapy?

Is Combination Long-acting Beta-Agonist and Long-acting Muscarinic Antagonist Therapy the Future of COPD Therapy?

Efficacy of Tiotropium + Olodaterol in Patients with Chronic Obstructive Pulmonary Disease by Initial Disease Severity and Treatment Intensity: A Post Hoc Analysis.

IntroductionThe once-daily long-acting muscarinic antagonist (LAMA) tiotropium and once-daily long-acting β2-agonist (LABA) olodaterol have been studied as a once-daily fixed-dose combination (FDC) in patients with chronic obstructive pulmonary disease (COPD). Two large, 52-week, double-blind, parallel-group studies in patients with moderate–very severe COPD demonstrated that tiotropium + olodaterol significantly improved lung function and symptoms versus the monocomponents. This post hoc analysis determined effects on lung function by prior LAMA or LABA maintenance treatment and initial disease severity.Methods5162 patients were randomized and treated with olodaterol 5 µg, tiotropium 2.5 µg, tiotropium 5 µg, tiotropium + olodaterol 2.5/5 µg, or tiotropium + olodaterol 5/5 µg (all once daily via Respimat® inhaler). Primary efficacy (lung-function) end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0–3) and trough FEV1 responses (i.e., change from baseline). Pooled data are presented for the following subgroups: prior maintenance treatment with LAMA or LABA, Global initiative for chronic Obstructive Lung Disease (GOLD) 2 (predicted FEV1 50% to <80%) and 3 (30% to <50%)/4 (<30%), sex, age, and prior use of inhaled corticosteroids.ResultsTiotropium + olodaterol FDC improved lung function over the monocomponents in patients with GOLD 2 and 3–4 disease, irrespective of prior LAMA or LABA maintenance therapy; most comparisons between FDCs and their respective monocomponents were statistically significant (P < 0.05). FEV1 AUC0–3 and trough FEV1 responses for the individual treatments were generally greater in patients with less severe COPD at baseline.ConclusionsTiotropium + olodaterol 5/5 µg significantly improved FEV1 AUC0–3 and trough FEV1 in all GOLD severity groups compared to olodaterol 5 µg and tiotropium 5 µg alone, irrespective of whether patients had received prior LAMA or LABA maintenance treatment. Improvements from baseline in lung function were generally greater in patients with less severe disease.FundingBoehringer Ingelheim.Trial registration: ClinicalTrials.gov numbers, NCT01431274 and NCT01431287.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-015-0218-0) contains supplementary material, which is available to authorized users.

Long-acting muscarinic antagonist use in adults with asthma: real-life prescribing and outcomes of add-on therapy with tiotropium bromide.

BackgroundRandomized controlled trials indicate that addition of a long-acting muscarinic antagonist (LAMA) such as tiotropium may improve asthma control and reduce exacerbation risk in patients with poorly controlled asthma, but broader clinical studies are needed to investigate the effectiveness of LAMA in real-life asthma care.MethodsMedical records of adults with asthma (aged ≥18 years) prescribed tiotropium were obtained from the UK Optimum Patient Care Research Database for the period 2001–2013. Patients diagnosed with chronic obstructive pulmonary disease were excluded, but no other clinical exclusions were applied. Two primary outcomes were compared in the year before (baseline) and the year after (outcome) addition of tiotropium: exacerbations (asthma-related hospital emergency department attendance or inpatient admission, or acute oral corticosteroid course) and acute respiratory events (exacerbation or antibiotic prescription with lower respiratory consultation). Secondary outcomes included lung function test results and short-acting β2 agonist usage. The Wilcoxon signed-rank test was used for variables measured on the interval scale, the marginal homogeneity test for categorized variables, and the paired t-test for lung function indices.ResultsOf the 2,042 study patients, 83% were prescribed an inhaled corticosteroid and 68% a long-acting β2 agonist during the baseline year; 67% were prescribed both. Comparing baseline and outcome years, the percentage of patients having at least one exacerbation decreased from 37% to 27% (P<0.001) and the percentage having at least one acute respiratory event decreased from 58% to 47% (P<0.001). There were no significant changes in lung function, and usage of short-acting β2 agonists (in salbutamol/albuterol equivalents) increased from a median (interquartile range) of 274 (110, 548) to 329 (110, 603) μg/day (P=0.01).ConclusionIn this real-life asthma population, addition of LAMA therapy was associated with significant decreases in the incidence of exacerbations and antibiotic prescriptions for lower respiratory tract infections in the following year.

Brève. Mesure du NO expiré chez le jeune enfant : facteur prédictif de survenue d’un asthme ?

The 2020 National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group (NAEPP [2020 Focused Asthma Update]) guidelines and the Global Initiative for Asthma (GINA) 2021 strategy report are compared in this Rostrum article. The methodologies of each publication are described. Subsequently, 4 different selected pharmacological recommendations are compared in the 2 documents: step 1 for children 0 to 4 years of age with viral-induced wheezing, step 2 in ages 12 years and older with the intermittent use of inhaled corticosteroid, steps 3 and 4 with single-inhaler maintenance and reliever therapy with inhaled corticosteroids–formoterol (SMART), and steps 3, 4, and 5 with add-on long-acting muscarinic antagonist therapy. Nonpharmacological recommendations are also considered and contrasted, including for exhaled nitric oxide, environmental control, immunotherapy, and bronchial thermoplasty. Similarities and differences in these 2 documents are highlighted, and recommendations are made about harmonizing the approaches where possible.