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COPD is a leading cause of death and disability. COPD therapy goals include reducing exacerbations and improving symptom control. Single-inhaler triple therapy (SITT) or multiple-inhaler triple therapy (MITT) is indicated for patients with frequent exacerbations despite bronchodilator therapy. No available evidence compares SITT vs MITT in Spain in terms of treatment persistence, exacerbations, and other outcomes. Do COPD patients in Spain initiating SITT vs MITT have improved persistence, exacerbations, and health care resource utilization? This real-world, observational, retrospective cohort study analyzed electronic health records in the Spanish National Healthcare System BIG-PAC database to identify COPD patients aged ≥ 40 years initiating SITT or MITT (using two or three inhalers) between June 1, 2018 and December 31, 2019. Comparative data on persistence (allowing up to 60 days without prescription refill), exacerbation rates, and health care resource utilization and costs during 12-month follow-up were analyzed. Multivariate adjusted analyses were performed. Eligible patients (N = 4,625) initiating SITT (n = 1,011) or MITT (n = 3,614) had a mean age of 70.9 years; most were male (73.9%) with mainly moderate (62.0%) or severe (26.5%) airflow limitation. Between-cohort baseline characteristics were similar. At 12-month follow-up, SITT patients had higher persistence (hazard ratio [HR] = 1.37; 95% CI = 1.22-1.53; P Patients initiating SITT had a clinically relevant improvement in persistence leading to reductions in mortality, incidence of exacerbations, and health care resource use with consequent mean cost savings.

Providers caring for patients with severe, therapy-resistant asthma have novel options for their treatment. Administration of additional inhaled corticosteroids at the time of increased symptoms, a strategy referred to as anti-inflammatory rescue or AIR, has been proved to be effective in reducing the frequency of exacerbations and improving asthma-related quality of life. Long-acting muscarinic antagonists can be used in combination with long-acting beta-agonist bronchodilators for additional bronchodilation. The care of the patient with severe asthma must also include a strategy to help avoid severe, life-threatening asthma attacks, with intense patient education and a recommended survival toolkit.

Peter Ascanius Jacobsen,1,2 Kristian Kragholm,2,3 Christian Torp-Pedersen,4 Ulla Møller Weinreich1,2 1Department of Respiratory Diseases, Aalborg University Hospital, Aalborg, Denmark; 2The Clinical Institute, Aalborg University, Aalborg, Denmark; 3Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark; 4Department of Clinical Research, Hillerød Hospital, Hillerød, DenmarkCorrespondence: Peter Ascanius Jacobsen, Department of Respiratory Diseases, Aalborg University Hospital, Mølleparkvej 4, Aalborg, DK-9100, Denmark, Tel +4597664800, Email Mail:peter.jacobsen@rn.dkIntroduction: Many chronic obstructive pulmonary disease (COPD) patients below retirement age are outside the workforce. The existing knowledge about association between acute exacerbation of COPD (AECOPD) and disability retirement is limited.Aim: The aim of this study is to explore disability retirement in COPD patients 3 years following first-ever AECOPD.Methods: This retrospective registry-based follow-up cohort study design is based on nationwide Danish registry data. Patients admitted to the hospital for the first time between 1999 and 2017 with AECOPD and age between 35 and 59 years, active in the workforce, were included in the study. Socio-demographics, comorbidities and inhaled medication use were explored. COPD patients’ hazard ratio of disability retirement during 3-year follow-up was calculated. Cox regression was used to examine the effects of covariates on disability retirement.Results: A total of 4032 patients were included in the study. During follow-up, 17.2% (692/4032) experienced disability retirement from the workforce. Factors associated with disability retirement were expressed as hazard ratio (95% confidence intervals): Higher age (ref. age 46– 50: Age 51– 55, 1.42, (1.12– 1.81); age 56– 59, 1.37 (1.08– 1.74)); living alone (1.34 (1.14– 1.56)); number of comorbidities for 1, 2, and 3 comorbidities (1.36 (1.14– 1.62), 1.57 (1.19– 2.07), 1.77 (1.20– 2.60)); emphysema (2.01 (1.44– 2.79)); depression (1.60 (1.12– 2.28)); cardiac comorbidity (1.38 (1.07– 1.78)); triple inhalation therapy (2.76 (2.20– 3.47)); ICS + LAMA or ICS + LABA treatment (1.82 (1.48– 2.23)); and ICS treatment (1.49 (1.17– 1.90)). Higher educational level was associated with a significantly reduced risk of disability retirement, medium, short higher and long higher educational level, relative to low education level (0.78 (0.67– 0.91), 0.63 (0.48– 0.83) and 0.27 (0.12– 0.60)).Conclusion: Patients vulnerable to disability retirement are patients with markers of severe COPD, comorbidities, and social vulnerability.Keywords: chronic obstructive pulmonary disease, return to work, early retirement, comorbidities

Initiation of treatment of COPD with a combination of a long-acting beta-agonist (LABA) and an inhaled corticosteroid (ICS) is frequent irrespective of the risk of exacerbations.We performed a retrospective, population-based, observational study aimed at comparing the effectiveness of a LABA/long-acting antimuscarinic agent (LAMA) and LABA/ICS in patients with COPD over a one-year follow-up. Data were obtained from an administrative healthcare claims database. The primary outcome was the risk of first exacerbation. A sensitivity analysis was conducted in a propensity-score matched population.The population consisted of 14,046 COPD patients; 11,329 (80.6%) initiated LABA/ICS and 2717 (19.4%) LABA/LAMA. The matched population included 1650 patients in each arm. During follow-up, 69.6% patients in the LABA/ICS group and 64.4% in the LABA/LAMA group presented an exacerbation. The mean time to the first exacerbation was 6.03 months (95% confidence interval (CI): 5.94-6.12) for LABA/ICS and 6.4 months (95%CI: 6.21-6.59) for LABA/LAMA; p0.001. The time to scalation to triple therapy was also significantly prolonged in LABA/LAMA. Similar results were obtained in the matched population. LABA/LAMA was associated with a significantly lower risk of exacerbations and escalation to triple therapy compared to LABA/ICS, except in patients with frequent exacerbations and high blood eosinophils in which no differences were observed in the time to first exacerbation.Initiation of treatment with LABA/LAMA was associated with a lower risk of exacerbation and escalation to triple therapy compared to LABA/ICS in the majority of patients with COPD in primary care.

Overactive bladder (OAB) and frailty are independently associated with patient burden. However, economic burden and treatment-taking behavior have not been well characterized among frail patients with OAB, which, given the varying safety and tolerability profiles of available treatments, is crucial.To assess costs, health care resource utilization, treatment-taking behavior (persistence and adherence) to OAB medication in older, frail OAB patients.This was a retrospective cohort study using international business machines MarketScan Medicare Supplemental claims data. Eligible frail patients (per Claims-based Frailty Index score) initiating mirabegron were 1:2 propensity score matched (based on age, sex, and other characteristics) with those initiating antimuscarinics and were followed up to 1 year. All-cause, per-person, per-month costs, health care encounters, persistence (median days to discontinuation assessed using Kaplan-Meier methods) and adherence (≥80% of proportion of days covered at Day 365) were compared.From 2527 patients with incident mirabegron (21%) or antimuscarinic (79%) dispensations, 516 incident mirabegron users (median age: 82 years, 64% female) were matched to 1032 incident antimuscarinic users (median age: 81 years, 62% female). Median cost was higher in mirabegron group ($1581 vs. $1197 per month); this was primarily driven by medication cost. There was no difference in medical encounters. Adherence (39.1% vs. 33.8%) and persistence (103 vs. 90 days) were higher in mirabegron users.Among frail older adults with OAB, mirabegron use was associated with higher costs and potential improvements in treatment-taking behaviors, particularly with respect to treatment adherence, versus those initiating antimuscarinics.

Patients with asthma who are suboptimally responsive to inhaled corticosteroids (ICS) and long-acting β

Triple therapy with an inhaled corticosteroid (ICS), a long-acting βWe used population health databases from Ontario, Canada to identify individuals aged 66 or older with COPD who started triple therapy between 2014 and 2017. Median time from diagnosis to triple therapy was estimated using the Kaplan-Meier method. We classified treatment pathways based on treatments received prior to triple therapy and evaluated whether pathways differed by exacerbation history, blood eosinophil counts or time period.Among 4108 COPD patients initiating triple therapy, only 41.2% had a COPD exacerbation in the year prior. The three most common pathways were triple therapy as initial treatment (32.5%), LAMA to triple therapy (29.8%), and ICS + LABA to triple therapy (15.4%). Median time from diagnosis to triple therapy was 362 days (95% confidence interval:331-393 days) overall, but 14 days (95% CI 12-17 days) in the triple therapy as initial treatment pathway. This pathway was least likely to contain patients with frequent or severe exacerbations (22.0% vs. 31.5%,Real-world prescription of triple therapy often does not follow COPD guidelines in terms of disease severity and prior treatments attempted.

Randomized controlled trials (RCTs) comparing triple therapies (inhaled corticosteroid [ICS], long-acting βThis NMA was conducted on the basis of a systematic literature review (SLR), which identified RCTs in adults aged at least 40 years with COPD. The RCTs compared different ICS/LABA/LAMA combinations or an ICS/LABA/LAMA combination with any dual therapy (ICS/LABA or LAMA/LABA). Outcomes of interest included forced expiratory volume in 1 s (FEVThe NMA was informed by five trials reporting FEVThe findings of this NMA suggest favorable efficacy with single-inhaler triple therapy comprising FF/UMEC/VI. Further analysis is required as additional evidence becomes available.

Current drug treatment of lower urinary tract disorders, for example, overactive bladder syndrome and lower urinary tract symptoms associated with benign prostatic hyperplasia, is moderately effective, has a low treatment persistence and some short- and long-term adverse events. Even if combination therapy with approved drugs may offer advantages in some patients, there is still a need for new agents.New bNew potential alternatives to currently used drugs/drug principles are emerging, but further clinical testing is required before they can be evaluated as therapeutic alternatives. It seems that for the near future individualized treatment with approved drugs and their combinations will be the prevailing therapeutic approach.

Background Urgency-type urinary incontinence affects one in four older community-dwelling women and overlaps with other common aging-associated health syndromes such as cognitive impairment, physical mobility impairment, and depression. Observational studies have raised concern about potentially higher rates of delirium and dementia in older adults taking anticholinergic bladder medications, but few prospective data are available to evaluate the effects of these and other pharmacologic treatments for urgency incontinence on cognition and other multisystem functional domains important to older women. Methods The TRIUMPH study is a randomized, double-blinded, 3-arm, parallel-group trial comparing the multisystem effects of anticholinergic versus beta-3-adrenergic agonist bladder therapy and versus no active bladder anti-spasmodic pharmacotherapy in older women with urgency incontinence. Women aged 60 years and older (target N = 270) who have chronic urgency-predominant urinary incontinence and either normal or mildly impaired cognition at baseline are recruited from the community by investigators based in northern California, USA. Participants are randomized in equal ratios to take identically encapsulated oral anticholinergic bladder therapy (in the form of tolterodine 2 mg extended release [ER]), oral beta-3 adrenergic agonist bladder therapy (mirabegron 25 mg ER), or placebo daily for 24 weeks, with the option of participant-directed dose titration (to tolterodine 4 mg ER, mirabegron 50 mg ER, or matching placebo daily). Participants also receive patient-oriented information and instructions about practicing first-line behavioral management strategies for incontinence. The primary outcome is change in composite cognitive function over 24 weeks assessed by a comprehensive battery of cognitive tests, with a secondary exploration of the persistence of change at 36 weeks. Secondary outcomes include changes over 24 and 36 weeks in domain-specific cognitive function; frequency, severity, and impact of urgency-associated urinary symptoms; physical function and balance; sleep quality and daytime sleepiness; psychological function; and bowel function. Discussion The TRIUMPH trial addresses the need for rigorous evidence to guide counseling and decision-making for older women who are weighing the potential multisystem benefits and risks of pharmacologic treatments for urgency incontinence in order to preserve their day-to-day functioning, quality of life, and independence in older age. Trial registration ClinicalTrials.gov NCT05362292. Registered on May 5, 2022.

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.

Marcus Sim,1 Anthony Yii,1 Xiaomeng Xu,2 Priti Bahety,3 Chee Hong Loh,1 Aldo Amador Navarro Rojas,4 Dominique Milea,2 Augustine Tee1 1Department of Respiratory and Critical Care Medicine, Changi General Hospital, Singapore, Singapore; 2Value Evidence & Outcomes, Greater China and Intercontinental, GSK, Singapore, Singapore; 3Medical Affairs, GSK, Singapore, Singapore; 4Respiratory & Specialty Medical Lead, Greater China and Intercontinental, GSK, Singapore, SingaporeCorrespondence: Marcus Sim, Department of Respiratory and Critical Care Medicine, Changi General Hospital, 2 Simei Street 3, Singapore, 529889, Singapore, Tel +65 6788 8833, Email marcus.sim@mohh.com.sgIntroduction: There is limited real-world evidence regarding clinical practice for chronic obstructive pulmonary disease (COPD) in Singapore. We compared baseline clinical characteristics and evaluated outcomes in patients with COPD who initiated treatment with either a long-acting muscarinic antagonist (LAMA) or a LAMA and a long-acting β2-agonist (LAMA+LABA).Methods: This was a single-center observational study at Changi General Hospital, Singapore. Routine clinical data (hospital visits, case management, lung function, laboratory/imaging results, medication orders) were collected and compiled into a data warehouse. Eligible patients with COPD were ≥ 40 years old and newly prescribed LAMA or LAMA+LABA during the enrollment period. Patient characteristics in the baseline period (6 months) were compared between treatments. Clinical worsening was measured as a composite endpoint, defined as the first of a change in maintenance treatment class or a moderate-to-severe exacerbation during follow-up (12 months).Results: In total, 261 patients were included in the baseline period (LAMA: 73; LAMA+LABA: 188). In the baseline period, patients receiving LAMA+LABA versus LAMA had significantly lower body mass index, higher COPD Assessment Test score and worse lung function, and numerically higher exacerbation history. Prevalence of comorbidities was similar between treatment groups. In follow-up, high rates of clinical worsening were observed regardless of treatment regimen (LAMA: 38/73 [52%]; LAMA+LABA: 86/188 [46%]). Median time-to-clinical worsening was 340 days for the LAMA cohort and the raw median 154 days (interquartile range: 44– 225) for the LAMA+LABA cohort. Median medication dispensation rate (0.86; interquartile range: 0.56– 1.00) was similar between treatments.Conclusion: Patients initiating treatment with LAMA+LABA had more severe COPD than patients prescribed LAMA. The proportion of patients experiencing clinical worsening was similarly high in both cohorts, suggesting that early identification and treatment optimization are necessary.Keywords: COPD treatment, database analysis, dual bronchodilator, LABA, LAMA, inhaler prescription

Patient-reported outcomes such as the Patient Perception of Bladder Condition (PPBC) score are frequently used to characterize overactive bladder syndrome (OAB) patients and their treatment outcomes. However, little information is available on the relationship of such scores to OAB symptoms at the individual patient level.We have performed a post hoc analysis of two large noninterventional studies (n = 1345 and 745) in which patients received propiverine extended release (30 or 45 mg/day) for 12 weeks to determine the strength of nonparametric correlations between PPBC and OAB symptoms at baseline, after treatment and with treatment-associated changes thereof.PPBC was not correlated with age but with episode frequencies of urgency, incontinence, micturitions, and nocturia, but the strength of correlations was only moderate (Spearman rank correlation coefficient 0.2045-0.3553). Similarly moderate correlations were observed after treatment and when changes in PPBC were compared to those of OAB symptoms, although these correlations were somewhat stronger.PPBC is only moderately correlated to OAB symptoms indicating that it characterizes patients beyond what is captured by their symptoms.

Clinical data on the use of overactive bladder (OAB) medications are limited by the physician interpretation of adverse effects rather than those that are patient reported.The aim of the study was to evaluate the association between OAB medications and adverse drug events (ADEs) through the self-reporting U.S. Food and Drug Administration Adverse Event Report System database.The U.S. Food and Drug Administration Adverse Event Report System (FAERS) database was queried from 2004 to 2019. Adverse drug events were recategorized. Disproportionality analysis was used to detect the risk signals for each OAB medication and ADEs. χ 2 values were calculated to assess the association between ADEs and dosage.A total number of 14,102 reports were identified. The most frequently reported OAB medications were mirabegron (35%), transdermal oxybutynin (27%), and solifenacin (25%). Neuropsychiatric (NP) ADEs were highest with tolterodine and fesoterodine usage (16% and 15.6%, respectively) and transdermal oxybutynin had the lowest (6.5%). Increasing the dose of tolterodine or fesoterodine was not associated with increased NP ADEs. Oxybutynin had the highest risk of affect/mood disorder, agitation, and balance/movement disorder; however, it had the lowest risk of headache/migraine compared with all OAB medications. Mirabegron compared with all other OAB medications had the lowest risk of affect/mood disorder and agitation; however, it had the highest risk of headache and migraines.The FAERS database not only is a repository of ADEs but also may represent evolving prescribing habits for OAB medications. Transdermal oxybutynin had the lowest NP ADEs and may be appropriate for selected individuals.

Scopolamine has been used as a pharmacologic model for cognitive impairments in dementia and Alzheimer's disease. The validity of this model seems to be limited because findings in animals do not readily translate to novel treatments in humans. Biperiden is also a cholinergic deficit model for cognitive impairments but specifically blocks muscarinic M1 receptors. The effects of scopolamine and biperiden (and pirenzepine) are compared in animal studies and related to findings in humans. It is concluded that the effects on cognitive functions are different for scopolamine and biperiden, and they should be considered as different cognitive deficit models. Scopolamine may model more advanced stages of Alzheimer's disease whereas biperiden may model the early deficits in declarative memory in aging and mild cognitive impairment.

Bronchodilation is known to increase forced expiratory volume in 1 s (FEV1) and reduce hyperinflation in COPD. In a randomized controlled trial, we investigated whether combined inhaled long-acting β-agonist and muscarinic antagonist would alleviate maximal voluntary neuromuscular performance fatigue or enhance maximal muscle activation during cycling in patients with COPD. Despite increased FEV1, combination bronchodilator therapy did not reduce neuromuscular performance fatigue or enhance muscle activity or exercise tolerance in patients with mild-to-severe COPD.

Yanling Ding *, Lina Sun *, Ying Wang, Jing Zhang, Yahong Chen Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jing Zhang; Yahong Chen, Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, People’s Republic of China, Tel +86 13-8104-57631, Email jing_amy@126.com; chenyahong@vip.sina.comBackground: Several large randomized clinical trials (RCTs) have assessed the efficacy and safety of inhaled corticosteroid (ICS) combination regimens versus non-ICS therapy in patients with chronic obstructive pulmonary disease (COPD) at increased risk of exacerbation risk with mixed results.Methods: We performed a systematic literature review and meta-analysis of RCTs comparing the effect of ICS-containing combination therapy and non-ICS regimen in patients with COPD.Results: A total of 54 RCTs (N = 57,333) reported treatment effects on various outcomes and were eligible for inclusion. Overall, the number of patients experiencing moderate/severe exacerbations was significantly lower for ICS-containing combination therapy versus non-ICS therapy (RR: 0.86 [95% CI: 0.80– 0.93]). The annual rate of exacerbations was also significantly reduced by 22% (0.78 [0.72– 0.86]) with ICS-containing versus non-ICS therapy. The annual rate of exacerbations requiring hospitalisation was reduced by 31% versus non-ICS therapy (0.69 [0.54– 0.88]); similar reduction was observed for exacerbations requiring oral steroids (0.69 [0.66– 0.73]). Overall, the effect on trough FEV1 was comparable between ICS-containing and non-ICS therapies (follow-up: 6– 52 weeks); however, a significant improvement in lung function (trough FEV1) was observed for ICS/LABA versus LABA (MD: +0.04 L [0.03− 0.05]) and ICS/LABA/LAMA versus LAMA (MD: +0.09 L [0.05− 0.13]) regimens. In addition, a significant improvement in QoL was observed with ICS-containing versus non-ICS therapy (MD in SGRQ score: − 0.90 [− 1.50, − 0.31]).Conclusion: This meta-analysis demonstrated that a wide range of patients with COPD could benefit from dual and triple ICS-containing therapy.Keywords: meta-analysis, chronic obstructive pulmonary disease, inhaled corticosteroid, dual therapy, triple therapy, exacerbation

To assess real-world treatment profiles, including utilization rate, time to and reasons for discontinuation of combination pharmacotherapy with βWe retrospectively reviewed the records of OAB patients who received βOf the 2163 patients receiving βWhile underutilized among OAB patients refractory to monotherapy, combination pharmacotherapy showed a greater persistence rate than published mirabegron or antimuscarinic monotherapy when applied to patients with moderate to severe symptoms. Treatment-emergent voiding impairment is a concern associated with this mode of therapy. A small sample size at a single institution is the limitation of this study.

Recent reports provide evidence-based guidelines for the withdrawal of inhaled corticosteroids (ICS) in COPD, but data on patients treated with ICS-based triple therapy are sparse and contradictory. We assessed the effect of ICS discontinuation on the incidence of severe exacerbation and pneumonia in a real-world population of patients with COPD who initiated triple therapy. We identified a cohort of patients with COPD treated with LAMA-LABA-ICS triple therapy during 2002-2018, age 50 or older, from the UK's CPRD database. Subjects who discontinued ICS were matched 1:1 on time-conditional propensity scores to those continuing ICS and followed for one year. Hazard ratios (HR) of severe exacerbation and pneumonia were estimated using Cox regression. The cohort included 42,667 patients who discontinued ICS matched to 42,667 who continued ICS treatment. The hazard ratio of a severe exacerbation with ICS discontinuation relative to ICS continuation was 0.86 (95% CI: 0.78-0.95), while for severe pneumonia it was 0.96 (95% CI: 0.88-1.05). The incidence of severe exacerbation after ICS discontinuation was numerically higher than after continuation among patients with two or more exacerbations in the prior year (HR 1.09; 95% CI: 0.94-1.26) and among those with FEV

David Mannino,1 James Siddall,2 Mark Small,2 Adam Haq,2 Marjorie Stiegler,3 Michael Bogart3 1Department of Medicine, University of Kentucky, Lexington, KY, USA; 2Respiratory DSP Franchise, Adelphi Real World, Bollington, UK; 3US Value Evidence and Outcomes, GlaxoSmithKline plc, Durham, NC, USACorrespondence: Michael Bogart, US Value Evidence and Outcomes, GlaxoSmithKline plc, 5 Moore Dr, Research Triangle Park, Durham, NC, USA, Tel +19198897413, Email michael.r.bogart@gsk.comPurpose: There is a high prevalence of chronic obstructive pulmonary disease (COPD) in the United States (US). Although guidelines are available for the treatment of COPD, evidence suggests that management of COPD in clinical practice is not always aligned with this guidance. This study aimed to further understand the current use of COPD maintenance medication in the US.Patients and Methods: This study was an analysis of data from the Adelphi Respiratory Disease Specific Programme (DSP™) 2019. Point-in-time data were collected from participating US physicians and their COPD patients. Physicians were either primary care physicians (PCPs) or pulmonologists, with a minimum workload of ≥ 3 COPD patients per month. Patients were aged ≥ 18 years with a physician-confirmed diagnosis of COPD.Results: In total, 171 physicians completed the survey (92 PCPs and 79 pulmonologists). Mean patient age was 66.4 years, 45% were female, with moderate COPD in 49.4% of patients and severe/very severe in 19.3%. Pulmonologists more frequently prescribed dual bronchodilation and triple therapy than PCPs, whereas inhaled corticosteroid/long-acting β2-agonist was more frequently prescribed by PCPs than pulmonologists. For both physician types, the most common reason for prescribing their patients’ current treatment was 24-hour symptom relief. The majority of PCPs (70.1%) and pulmonologists (71.9%) reported referring to COPD guidelines when making treatment decisions.Conclusion: Prescribing patterns for COPD patients were found to differ between PCPs and pulmonologists. Improved physician understanding of how to tailor treatment for each patient, based on current symptoms and exacerbation risk, could help optimize patient care in COPD.Keywords: COPD, inhaled corticosteroids, long-acting β2-agonist, long-acting muscarinic antagonist, maintenance therapy, survey

Objective: Long-acting muscarinic antagonists (LAMAs) have been used in the treatment of obstructive pulmonary diseases for years. Long-acting muscarinic antagonists were previously mainly used as bronchodilators in chronic obstructive pulmonary disease, but the use of LAMAs in the treatment of asthma has gained great interest. There is now ample evidence of the efficacy and safety of LAMAs as add-on therapy to inhaled corticosteroid (ICS) plus long-acting β 2-agonist (LABA) combinations in patients with moderate to severe uncontrolled asthma. Long-acting muscarinic antagonists have subsequently been included in asthma guidelines. This review summarizes the scientific evidence on the use of LAMAs in asthma and aims to provide a better understanding of the role of LAMAs in the asthma treatment care algorithm and the current gaps in our knowledge. Data sources: PubMed review using the following words: long-acting muscarinic antagonists, asthma, muscarinic receptors, tiotropium, glycopyrronium, umeclidinium. Study selections: This review focused on the key trials that led to the inclusion of LAMAs in asthma guidelines. In addition, we highlighted a number of studies with other study designs and populations. Results: We identified 6 major studies that led to inclusion in asthma guidelines and 3 studies with other study designs and populations. Conclusion: Long-acting muscarinic antagonists add-on therapy to ICS-LABA improves lung function, reduces exacerbations, and modestly improves asthma control in patients with moderate to severe asthma who are uncontrolled despite the use of ICS-LABA. Long-acting muscarinic antagonists are effective in all asthma phenotypes and endotypes.

Antipsychotic and sedative combinations are commonly used for treating agitation in the emergency department despite limited evidence regarding their comparative safety and efficacy.To compare the efficacy and safety of combination haloperidol, lorazepam, and diphenhydramine (B52) to combination haloperidol and lorazepam (52) in treating acute agitation.This multicenter, retrospective cohort study included adult patients ≥ 18 years of age who received either B52 or 52 at a Banner Health facility between August 2017 and September 2020. Patients were excluded if they had a pre-existing movement disorder or were withdrawing from alcohol. The primary outcome was administration of additional agitation medication(s) within 2 h of B52 or 52. Secondary outcomes included incidence of extrapyramidal symptoms, length of stay, and additional safety measures.There was no difference in administration frequency of additional agitation medication(s) (B52: n = 28 [14%] vs. 52: n = 40 [20%]; p = 0.11). Patients who received 52 were more likely to require an antimuscarinic medication within 2 days (15 vs. 6 patients, p = 0.04). Of the patients who received an antimuscarinic medication, none had documented extrapyramidal symptoms. The 52 group had shorter length of stay (13.8 vs. 17 h; p = 0.03), lower incidence of hypotension (7 vs. 32 patients; p0.001), and oxygen desaturation (0 vs. 6 patients; p = 0.01), and fewer physical restraints (53 vs. 86 patients; p = 0.001) compared with the B52 group.Both the B52 and 52 combinations infrequently required repeat agitation medication; however, the B52 combination resulted in more oxygen desaturation, hypotension, physical restraint use, and longer length of stay.

The combination of the noradrenergic agent atomoxetine plus the antimuscarinic oxybutynin has recently been shown to improve upper airway physiology and reduce obstructive sleep apnea (OSA) severity. However, the effects of different antimuscarinics when combined with atomoxetine is limited. This study aimed to determine the effects of atomoxetine combined with two different antimuscarinics with varying M-subtype receptor selectivity on OSA severity and upper airway physiology. Ten people with predominantly severe OSA completed a double-blind, randomized, placebo-controlled, cross-over trial. Participants completed three overnight in-laboratory sleep studies after either 80 mg atomoxetine + 5 mg solifenacin succinate (ato-sol) or 80 mg atomoxetine + 2 mg biperiden hydrochloride (ato-bip) or placebo. OSA severity, ventilatory stability (loop gain), respiratory-arousal threshold (via epiglottic manometry), next-day subjective sleepiness [Karolinska Sleepiness Scale (KSS)], and alertness were compared between conditions. Neither drug combination altered the apnea/hypopnea index versus placebo (

Objective To evaluate the long-term safety and efficacy of indacaterol/glycopyrronium (IND/GLY) in patients with COPD in a real-world setting in Japan. Methods This 52-week, multicentre, post-marketing surveillance conducted in Japan between December 2013 and August 2019 included patients using IND/GLY for the first time to relieve airway obstructive disorder-related symptoms. Safety outcomes included the incidence of adverse events (AEs), serious AEs (SAEs), adverse drug reactions (ADRs), and serious ADRs during the 52-week period. The incidence of priority variables, including cardiovascular/cerebrovascular (CCV) AEs, β-adrenergic-related or anticholinergic AEs and cough, was also assessed. Safety outcomes were also evaluated in elderly patients. Efficacy outcomes included a physician's global assessment, COPD assessment test (CAT) and lung function test. Results Of the 1,167 patients registered, 1,108 were included in the safety and efficacy analysis. In the safety analysis population, the incidence of AEs was 13.54%, that of SAEs was 4.69%, that of ADR was 3.61%, and that of serious ADRs was 0.36% over 52 weeks. CCV AEs, β-adrenergic-related and anticholinergic AEs and cough were reported as 2.62%, 1.99% and 0.63%, respectively. The physician's global assessment showed that the overall response rate at the last assessment was 74.19%. The mean (95% confidence interval) CAT scores decreased from the start of treatment to Week 52 with IND/GLY (-6.9 [-7.8 to -6.1]). The lung function (FEV1 and FVC) improved over time from the start of IND/GLY to Week 52. Conclusion IND/GLY demonstrated a good long-term safety profile in a real-world setting in Japanese patients with COPD, with beneficial effects in terms of the lung function and symptoms in clinical use.

Purpose To evaluate the potential of a Cox marginal structural model (MSM) to estimate the time-varying causal inference of a known clinical trial association where the effectiveness of inhaled corticosteroid- (ICS-) versus non-ICS-containing treatments has been compared in patients with chronic obstructive pulmonary disease (COPD). Methods This retrospective study from 2006 to 2016 used linked data from Clinical Practice Research Datalink-GOLD, Hospital Episode Statistics and Office for National Statistics mortality. A Cox MSM, incorporating a new-user design, was deemed capable of replicating a clinical trial-like pathway. Repeated outcomes for exacerbation events and stabilised weights were used to include time-varying and fixed covariate exposures. Results Of 45,958 patients, 55% were male; 52% had moderate COPD. ICS-treated patients had a higher incidence of comorbid asthma than non-ICS-treated patients. Adjusted hazard risk ratios for any exacerbation event: ICS/long-acting β2-agonist (LABA) versus long-acting muscarinic antagonist (LAMA), 1.07 (95% confidence interval 1.04-1.10); ICS/LABA versus LABA/LAMA, 1.05 (1.00-1.10); ICS/LABA/LAMA versus LAMA, 1.04 (1.01-1.06); ICS/LABA/LAMA versus LABA/LAMA 1.02 (0.97-1.07). Conclusions The Cox MSM was not able to fully demonstrate results consistent with the previously established benefits of ICS-containing treatments seen in clinical trials. Future studies should continue to investigate causal inference methods and their capability to estimate the long-term outcomes of treatment in COPD.

Revefenacin is the first once-daily long-acting muscarinic antagonist (LAMA) for nebulization use in maintenance therapy for patients with chronic obstructive pulmonary disease (COPD).To investigate the safety and tolerability profile of revefenacin at the approved dose (175 μg), compared with placebo and a lower dose (88 μg), for the treatment of COPD.Available randomized controlled trials (RCTs), both published and unpublished, were identified via databases. Risk differences (RDs) and risk ratios (RRs), with their corresponding 95% confidence intervals (CIs) were calculated as effect sizes.One unpublished RCT and four articles containing 5 RCTs were included. Combined results showed that there were no significant differences between COPD patients receiving 175 μg revefenacin and those receiving a placebo, concerning the risk of discontinuation due to adverse events (AEs), any all-grade AE, or any serious AE. 175 μg revefenacin also did not significantly increase the risk of antimuscarinic-related AEs, cardiovascular AEs, or 12 commonly reported AEs. Plus, a lower dose of 88 μg was shown to share a comparable safety profile with the 175 μg revefenacin. A non-significant trend towards a decrease in risks of AEs for 175 μg revefenacin was observed. The most frequently reported AE for each group was COPD worsening/exacerbation.Revefenacin at the approved dose is generally well-tolerated and safe with minimal AEs, which supports its use as a once-daily nebulized LAMA for the treatment of moderate to severe stable COPD. Additional studies are needed to complete the safety and tolerability profile.

RATIONALE: Whether biomarkers can be used to predict response to inhaled corticosteroids (ICS) or long-acting muscarinic antagonists (LAMA) in mild persistent asthma is unclear. OBJECTIVES: In a prespecified exploratory analysis of a randomized clinical trial of 295 participants 12 years of age or older with uncontrolled mild persistent asthma, we sought to identify biomarkers of treatment response after 12 weeks of ICS (mometasone, 200 μg or 220 μg twice/d), LAMA (tiotropium, 5 μg/d), or placebo in adults (⩾18 yr) and adolescents (12–17 yr) separately. METHODS: The primary outcome was a composite outcome of asthma control (treatment failure, asthma control days, and forced expiratory volume in 1 second [FEV(1)]). Analyses examined type 2 inflammatory biomarkers and physiologic biomarkers. We assessed the area under the receiver operating characteristic curve (AUC) for response to ICS and LAMA (each versus placebo). An AUC of 0.5 suggests no discrimination, 0.7–0.8 is considered acceptable, more than 0.8–0.9 is considered excellent, and more than 0.9 is considered outstanding. RESULTS: In 237 adults, sputum and blood eosinophil levels and fractional exhaled nitric oxide (Fe(NO)) each predicted ICS response (AUCs: 0.61 [95% confidence interval (CI), 0.53–0.69], 0.64 [95% CI, 0.56–0.72], and 0.62 [95% CI, 0.54–0.70], respectively; all P

Antimuscarinic medications are often discontinued, and there is a paucity of data regarding patient experience of medications within this class.The objective of this study is to qualitatively explore patient experience of antimuscarinic medications used for overactive bladder using reviews on Drugs.com.We examined reviews prior to February 2, 2020 (available since 2008) for oral antimuscarinic medications. User content was reviewed qualitatively via inductive content analysis. Investigators coded third-party impressions, categorizing each review as positive, mostly positive, mostly negative, or negative. The prevalence of side effects, themes, and impressions are described, with comparisons by drug using χ2, Mann-Whitney U, and Kruskal-Wallis tests, as appropriate. Correlation between ordinal and categorical variables was performed using Tau and Spearman correlation coefficients, respectively.We analyzed 469 user reviews. 68.2% reported symptom improvement. The most common side effects were dry mouth (29%) and fatigue (10.7%). Fewer neurologic side effects were reported in the solifenacin (13.9%) and trospium (none) groups (P = 0.009). Tolterodine and trospium immediate release had lower rates of ears, nose, and throat side effects (22.5% and 26.2%, respectively, P = 0.001.) Analysis of themes suggested 2 domains driving overall satisfaction: improvement and side effects. Improvement was associated with a positive satisfaction score (ρ = 0.64, P0.001) and gestalt impression (ρ = 0.74, P0.001). The factors that most negatively affected these measures were persistent symptoms followed by gastrointestinal side effects (P0.001).Our data suggest important differences within this class of medication both in terms of side effects and patient satisfaction. Furthermore, symptom improvement is the leading factor for patient satisfaction, whereas gastrointestinal side effects are associated with dissatisfaction.

The aim of this study was to evaluate the pharmacokinetics, safety, and tolerability of aclidinium bromide/formoterol fumarate in patients from China with moderate-to-severe chronic obstructive pulmonary disease (COPD).In this open-label, repeat-dose, 5-day pharmacokinetic study (NCT03276078) of inhaled aclidinium bromide/formoterol fumarate 400/12 µg twice daily, plasma concentrations of aclidinium, formoterol, and two aclidinium metabolites (LAS34823, LAS34850) were assessed (days 1 and 5). Adverse event (AE) data were collected.Twenty patients (15 [75%] males) with a mean age of 59.2 years were included. Median (range) time to maximum concentration on days 1 and 5 was 0.08 (0.08-0.50) and 0.08 (0.08-0.50) h, respectively, for aclidinium; and 1.00 (0.08-3.00) and 0.08 (0.08-1.50) h, respectively, for formoterol. Mean elimination half-life and accumulation ratio for area under the concentration-time curve during a dosage interval (AUCAclidinium/formoterol 400/12 µg twice daily was well-tolerated in patients from China with moderate-to-severe COPD. Safety findings were consistent with the known safety profile.ClinicalTrials.gov, NCT03276078.

Objectives Successful treatment of delirium depends on the detection of the reversible contributors. Drugs with delirogenic properties are the most prevalent reversible cause of delirium. Methods This observational study is based on data from Arzneimittelsicherheit in der Psychiatrie, a multicenter drug surveillance program in German-speaking countries recording severe adverse drug reactions (ADRs) in psychiatric inpatients. The present study analyzes drug-induced delirium (DID) during treatment with antidepressants and antipsychotics. Results A total of 436 565 psychiatric inpatients were treated with antidepressants and/or antipsychotics during the observation period from 1993 to 2016 in the participating 110 hospitals. Overall, 254 cases (0.06% of all patients treated with antidepressants and/or antipsychotics) of DID were detected. Implicated either in combination or alone (multiple drugs were implicated in 70.1% of DID), clomipramine (0.24%), amitriptyline (0.21%), and clozapine (0.18%) showed the highest incidence rates of DID. When implicated alone (98 cases overall), clozapine (0.11%) followed by amitriptyline (0.05%) were most likely causally associated with the occurrence of DID. Drugs with strong antimuscarinic properties generally exhibited higher risk of DID. Conclusions With an incidence rate of

Background The aim of the study is to determine that Glycopirrolate is safe and effective in decreasing drooling in children with medical complexity under 3 years of age. Medical treatment is based on anticholinergic drugs as transdermal scopolamine, benzotropine and GLY. GLY (Glycopyrronium bromide) is a synthetic quaternary ammonium anticholinergic agent with poor blood–brain barrier penetration and consequently has limited central effects. Actually, the oral GLY formulation was approved by the United States Food and Drug Administration (FDA) to treat drooling in children aged 3–16 years. Five studies reported on GLY use for the treatment of drooling in children with cerebral palsy and other conditions with neurological impairment; four are prospective studies while one a retrospective review. Methods this is a case report of eighteen children (sex ratio 11/8, median age 17 months, range 2–36 months) under three years of age, followed by a multidisciplinary team at the Bambino Gesù Children Hospital. The median follow-up was of 31.5 months (range 1–69 months). Response to treatment was assessed according to the Drooling Impact Scale administered at time 0 and after 1 month. All patients have an important neurological impairment: nine patients have a cerebral palsy (Gross Motor Function Classification System class V) and nine a genetic/malformative syndrome. Twelve patients have a tracheostomy and two need mechanical ventilation. Gastrostomy is present in 16 out of 18 patients. All patients received Glycopirrolate. The median starting daily dose was 0.065 mg/kg/die (range 0.02–0.21 mg/kg/die) three times a day. The drooling impact scale was administered at time O and after 1 month. Results Four out 18 patients stopped treatment for adverse event, lack of efficacy or parental decision. The mean Drooling Impact Scale at time 0 was 89 (range 81–100) and after 1 month 61(range 43–78); the difference was statistically significant (P Conclusions This is the first study to determine the safety and effectiveness of Glycopyrrolate in decreasing drooling in a specific subset of patients. No major side effects were observed. Further comparative studies are needed to confirm our results.

Four long-acting muscarinic antagonists (LAMAs), tiotropium, glycopyrronium, aclidinium, and umeclidinium, are currently available for the treatment of stable chronic obstructive pulmonary disease (COPD). However, no integrated analysis has sought to determine the effectiveness of these LAMAs. Thus, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of LAMA versus placebo in patients with stable COPD.A literature search of relevant randomized control trials that administered LAMA to stable COPD patients was conducted, and the exacerbations, quality of life (QoL), dyspnea score, lung function, and adverse event of patients were evaluated.A total of 33 studies were included in this meta-analysis. LAMA significantly decreased the frequency of exacerbations compared to the placebo (OR 0.75; 95% CI 0.66 to 0.85; P 0.001). The mean changes in the St George's Respiratory Questionnaire score (mean difference, -3.61; 95% CI, -4.27 to -2.95; P 0.00001), transitional dyspnea index score (mean difference 1.00; 95% CI 0.83 to 1.17; P 0.00001), and trough FEVLAMA is superior to placebo due to lower frequency of exacerbations and adverse events, as well as higher trough FEV

Mario Cazzola,1 Paola Rogliani,1 Rossella Laitano,1 Luigino Calzetta,2 Maria Gabriella Matera3 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy; 2Unit of Respiratory Diseases and Lung Function, Department of Medicine and Surgery, University of Parma, Parma, Italy; 3Unit of Pharmacology, Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, ItalyCorrespondence: Mario Cazzola Email mario.cazzola@uniroma2.itAbstract: Although pharmacological treatment of COPD is codified in different guidelines and strategy documents, there is abundant evidence of discrepancy between what they suggest and what health professionals prescribe, especially in low-risk groups where there is widespread overprescription of triple therapy. It is therefore necessary to clarify when the use of triple therapy is indicated in COPD patients and when it is preferable to maintain treatment with dual bronchodilation. In this article, we discuss our views based on our experience and what is reported in the literature and try to give answers to these two questions. The evidence generated by pivotal RCTs supports the use of triple therapy in patients who present for the first time and have severe airway obstruction, are symptomatic, have had frequent moderate or severe exacerbations in the previous year, and have peripheral eosinophilia. However, it is difficult to determine whether step-up is useful in all other cases because the available data are quite conflicting. It is likely that the inconsistency in the information generated by the various available studies may explain the prescribing behaviour of many physicians who do not adhere to recommendations of guidelines and strategies. However, it is necessary to establish whether and when the addition of an ICS to the LAMA/LABA combination is effective, to determine whether triple therapy can induce an additional clinical benefit over dual bronchodilation, irrespective of a preventive effect on COPD exacerbations, to establish its value, and to examine whether cost differences can support the use of triple therapy over combined LAMA/LABA therapy in real life.Keywords: dual bronchodilation, triple therapy, ICSs, LABs, LAMAs