Real-World Adherence to and Persistence with Vibegron in Patients with Overactive Bladder: A Retrospective Claims Analysis.

INTRODUCTION: Vibegron is a ß3-adrenergic receptor agonist approved for overactive bladder (OAB). This analysis assessed real-world adherence and persistence with vibegron in patients with OAB, along with demographics and clinical characteristics associated with adherence and persistence. METHODS: This retrospective study used the Optum Research Database to identify patients treated with vibegron from April 2021 to August 2022 (identification period). Patients had ≥ 60 days of continuous pharmacy coverage in a commercial or Medicare Advantage plan following the index fill (follow-up). Adherence was assessed as proportion of days covered (PDC) from index to end of follow-up and was defined as PDC ≥ 80%. Persistence was measured as days to discontinuation of therapy (30-day gap) or end of follow-up. Data for adherence and persistence are presented descriptively. Characteristics associated with adherence and persistence were analyzed using multivariable models among patients with medical and pharmacy benefits during the 90 days before index (baseline). RESULTS: Overall, 9992 patients had a vibegron claim during the identification period; 9712 had ≥ 2 months of follow-up. Mean (SD) age was 74.2 (10.7) years; 68.2% were female. Mean (SD) PDC was 0.64 (0.34). Median (95% confidence interval) persistence was 142 (132-153) days. Of the 5073 patients who were ≥ 18 years old with continuous baseline pharmacy and medical benefits ≥ 90 days before index, 2497 (49.2%) were adherent. Patients were more likely to be adherent and persistent if they received a greater days' supply for the index fill and had baseline medication count ≥ 6. Patients were more likely to discontinue if their index copay was > $45. CONCLUSION: Nearly half of the patients initiating vibegron were adherent. Factors associated with adherence and persistence were more likely to be related to prescribing practices than patient characteristics. These results suggest it may be best to follow up with patients approximately 4 to 5 months after initiating treatment with vibegron.

Vibegron is a newer drug for treating overactive bladder. Vibegron was safe and worked well in clinical trials. However, there is no information on use of vibegron in a real-world population that is not a clinical trial. This study looked at how consistently and how long patients took vibegron after starting it. It also looked at what was common in patients who took vibegron consistently. To do this, the study used pharmacy prescription data from April 2021 to August 2022. It examined adherence to the study medication for each patient. Adherence is how many days patients had medication on hand compared to how long they were followed. The study also looked at persistence to the study medication. Persistence is how long a patient takes a medication before they stop taking it. Researchers then examined if there were reasons a patient may or may not take vibegron as prescribed. The study included prescription data for 9712 patients. The average age was 74 years and 68% of patients were female. Patients had their medication 64% of the time (adherence). On average, patients took their medication for 142 days before stopping (persistence). Patients had better adherence and persistence if they received a larger supply of medication at the pharmacy when first prescribed the medication and if they had more medications overall. Patients' age and gender did not affect adherence and persistence. Vibegron may be a good option for patients with overactive bladder. Follow-up with a provider may be considered 4 to 5 months after starting vibegron.

Effect of norepinephrine reuptake inhibitors combined antimuscarinic agents versus monotherapy for OSA: a systematic review and meta-analysis.

STUDY OBJECTIVES: Randomized controlled trials have shown that combining norepinephrine reuptake inhibitors and antimuscarinics can ameliorate the severity of obstructive sleep apnea (OSA). This article explores whether the effectiveness and safety of combining norepinephrine reuptake inhibitors with antimuscarinic agents surpass monotherapy for treating OSA. METHODS: We searched the randomized controlled trials (RCTs) with adult patients of OSA who received combination and monotherapy in eight databases from inception until April 5, 2023, next evaluated the included studies' quality, and conducted a meta-analysis and systematic review. The primary outcome was the apnea-hypopnea index (AHI). Secondary outcome measures included loop gain, hypoxic load, oxygen desaturation index, and Vpassive, among other indicators. We assessed the quality of the studies using Cochrane Methods criteria. RESULTS: Identifying four RCTs for systematic review and two for meta-analysis. The results of the meta-analysis showed that norepinephrine reuptake inhibitors combined with antimuscarinic agents in patients with OSA prolonged total sleep time by a mean of 28.20 min [95% CI (5.78, 50.61), P = 0.01], increased sleep efficiency by 4.73% [95%CI (0.50, 8.97), P = 0.03] compared with norepinephrine reuptake inhibitors alone. Other indices and adverse events were no statistical significance. The systematic reviews revealed that norepinephrine reuptake inhibitors combined with antimuscarinics may be superior to monotherapy in improving AHI and endotypic traits. CONCLUSIONS: This article demonstrated the potential advantages of combining norepinephrine reuptake inhibitors plus antimuscarinics for treating OSA, contrasting with the norepinephrine reuptake inhibitors alone, and revealed no statistically significant safety.

Rivastigmine for the management of anticholinergic delirium.

INTRODUCTION: Anticholinergic agents are commonly taken in overdose, often causing delirium. The spectrum of anticholinergic delirium ranges from mild agitation to severe behavioural disturbance. Physostigmine is an effective treatment for anticholinergic delirium, but its availability is limited. As rivastigmine is readily available, it has been used to manage anticholinergic delirium; however, there is limited research investigating its use. METHOD: This was a retrospective review of patients with anticholinergic delirium treated in two toxicology units with rivastigmine (oral capsule or transdermal patch) from January 2019 to June 2023. The primary outcome was the use of further parenteral treatment (sedation or physostigmine) for delirium post rivastigmine administration. RESULTS: Fifty patients were administered rivastigmine for the management of anticholinergic delirium. The median age was 36 years (interquartile range: 25-49 years) and 27 (54 per cent) were females. Features consistent with anticholinergic toxicity included tachycardia in 44 (88 per cent) and urinary retention requiring catheterisation in 40 (80 per cent). Forty-three patients (86 per cent) were treated with physostigmine before rivastigmine administration. Twenty-two were managed with transdermal rivastigmine (most commonly 9.5 mg/24 hour patch), and 28 with oral rivastigmine 6 mg. Further parenteral sedation and/or physostigmine treatment were required more often in patients given transdermal than oral rivastigmine [16/22 (73 per cent) versus 9/28 (32 per cent), P = 0.010)]. No patients had bradycardia or gastrointestinal symptoms following rivastigmine administration. One patient with a history of epilepsy had a seizure, 1.5 hours post physostigmine administration and 7 hours post transdermal rivastigmine. DISCUSSION: Rivastigmine has been increasingly used for the management of patients with anticholinergic delirium, due to the lack of availability of physostigmine. In this case series, rivastigmine transdermal patch appeared to be less effective than oral rivastigmine capsules, likely due to its slow onset of action and/or insufficient dose. CONCLUSION: Rivastigmine can be used to treat anticholinergic delirium. In our case series oral rivastigmine appeared more effective than transdermal rivastigmine.

What is the best first choice oral drug therapy for OAB?

AIMS: The management of overactive bladder (OAB) involves lifestyle changes and conservative measures in the first instance with the use of liquid/dietary advice, weight loss, and bladder training. Thereafter oral pharmacotherapy is instigated in symptomatic patients. Antimuscarinics and beta 3 agonists form the main classes of drug therapy in this field. Views on what is the best first line OAB treatment is changing based on recent evidence and adverse event profiles of these medications. METHODS: At the ICI-RS meeting 2023, Bristol, UK this topic was discussed and debated as a proposal. The following article summarizes the concepts presented that day as well as the interactive discussion that took place thereafter. RESULTS: OAB guidelines are moving in many circumstances to an either antimuscarinic or beta 3 agonist approach based on patient factors. Several studies have raised concerns on the long-term impact of antimuscarinics, in relation to cognition, dementia, cardiovascular events, and mortality all related to antimuscarinic load. Neither antimuscarinics nor beta 3 agonists have good persistence and adherence rates in the medium to long term. Several barriers also exist to prescribing including guidelines recommending utilizing drugs with the lowest acquisition cost and "step therapy." A newer approach to managing OAB is personalized therapy in view of the many possible etiological factors and phenotypes. These concepts are highlighted in this article. CONCLUSIONS: Current oral pharmacotherapy in managing OAB is limited by adverse events, adherence and persistence problems. Both antimuscarinics and beta 3 agonists are efficacious but most clinical trials demonstrate significant placebo effects in this field. Personalizing treatment to the individual seems a logical approach to OAB. There is a need for better treatments and further studies are required of existing treatments with high quality longer term outcomes.

Safety of Physostigmine for Pediatric Antimuscarinic Poisoning.

INTRODUCTION: Physostigmine fell out of widespread use in the 1980s due to safety concerns; however, more recent research has demonstrated that its safety profile is better than previously thought. These studies have mainly included adults. We theorized that improved safety data may lead to more acceptance. Our objectives, therefore, were to characterize current frequency of use of physostigmine in pediatric patients as well as to study adverse effect rates in a national pediatric patient population. METHODS: The National Poison Data System was queried for cases of patients aged 0-18 years that involved single-substance exposures to antimuscarinic xenobiotics that were reported to a poison center between January 1, 2000, and December 31, 2020. Cases were stratified into groups by therapy received: benzodiazepines alone, benzodiazepines and physostigmine, physostigmine alone, or no physostigmine or benzodiazepines. Patient demographics, clinical effects, and medical outcomes were analyzed. RESULTS: A total of 694,132 cases were reviewed, and 150,075 were included for analysis. Nearly 5% (7562/150,075) of patients received specific pharmacological therapy with benzodiazepines, physostigmine, or both. A benzodiazepine as a single agent was the most frequently used pharmacologic therapy (92% of 7562). Among patients receiving any pharmacological therapy, only 8.3% (n = 627) of patients received physostigmine. Frequency of serious outcomes significantly increased across the study period among patients receiving benzodiazepines alone or with physostigmine. There was no increase in serious outcomes among patients receiving only physostigmine. CONCLUSIONS: Physostigmine frequency of use was low overall, but when used, was associated with less severe outcomes when compared to benzodiazepines.

A randomized controlled trial study on effectiveness between tadalafil versus combination mirabegron and solifenacin on treatment of ureteral stent-related symptoms.

Introduction: ureteral stents have common complications like ureteral stent-related symptoms (SRSs). This study investigated the effectiveness of tadalafil compared to mirabegron and solifenacin combination therapy in patients with ureteral SRSs after double-J (DJ) stent insertion. Methods: this double-blind, randomized clinical trial used consecutive random sampling in participants with SRSs after double-J stent insertion. The study was conducted at four different hospitals in Makassar, Indonesia, from July to December 2020. Ureteral stent-related morbidity indices which analyzed include urinary symptoms, pain, general health, quality of work, and sex scores. All of the indices were measured by ureteral symptom score questionnaire for the first, second, third, and fourth weeks after drug consumption, either tadalafil 10 mg/day (group A, n=25) and a combination of mirabegron 25 mg/day and solifenacin 5 mg/day (group B, n=28). Results: before the treatment procedure, the groups were comparable in age, gender, body mass index, DJ stent procedures, type, and indication. In general, the score in all parameters declined over the follow-up time for both groups. Group A had a lower urinary symptom score than group B at week III and week IV (all p-value < 0.001). In addition, group A had a lower pain score, general condition, work activity, and other complaints than group B at week II, week III, and week IV (all p-value <0.001). The sexual activity score is comparable between the group, except in week I. Conclusion: according to our results, we suggest tadalafil to minimize stent-related urinary symptoms and improve general health in patients with double J stent.

Bradyphrenia and Tachyphrenia in Idiopathic Parkinsonism Appear, in Part, Iatrogenic: An Observational Study with Systematic Review Background.

We question whether bradyphrenia, slowing of cognitive processing not explained by depression or a global cognitive assessment, is a nosological entity in idiopathic parkinsonism (IP). The time taken to break contact of an index finger with a touch-sensitive plate was measured, with and without a warning in the alerting signal as to which side the imperative would indicate, in 77 people diagnosed with IP and in 124 people without an IP diagnosis. The ability to utilise a warning, measured by the difference between loge-transformed reaction times (unwarned minus warned), was termed 'cognitive efficiency'. It was approximately normally distributed. A questionnaire on self- and partner perception of proband's bradyphrenia was applied. A multivariable model showed that those prescribed levodopa were less cognitively efficient (mean -5.2 (CI -9.5, -1.0)% per 300 mg/day, p = 0.02), but those prescribed the anti-muscarinic trihexyphenidyl were more efficient (14.7 (0.2, 31.3)% per 4 mg/day, p < 0.05) and those prescribed monoamine oxidase-B inhibitor (MAOBI) tended to be more efficient (8.3 (0.0, 17.4)%, p = 0.07). The variance in efficiency was greater within IP (F-test, p = 0.01 adjusted for any demographic covariates: coefficient of variation, with and without IP, 0.68 and 0.46, respectively), but not so after adjustment for anti-parkinsonian medication (p = 0.13: coefficient of variation 0.62). The within-participant follow-up time, a median of 4.8 (interquartile range 3.1, 5.5) years (101 participants), did not influence efficiency, irrespective of IP status. Perception of bradyphrenia did not usefully predict efficiency. We conclude that both bradyphrenia and 'tachyphrenia' in IP appear to have iatrogenic components, of clinically important size, related to the dose of antiparkinsonian medication. Levodopa is the most commonly prescribed first-line medication: co-prescribing a MAOBI may circumvent its associated bradyphrenia. The previously reported greater efficiency associated with (low-dose) anti-muscarinic was confirmed.

Pharmacotherapy for obstructive sleep apnea - A systematic review and meta-analysis of randomized controlled trials.

Continuous positive airway pressure is the first-line and gold-standard treatment for obstructive sleep apnea (OSA). Pharmacotherapy is not commonly used in treating OSA until recently. Combined noradrenergic and antimuscarinic agents have been clinically applied for OSA patients with variable results. This meta-analysis study aimed to investigate the efficacy of the combined regimen on OSA. A systematic literature search was performed up to November 2022 for the effects of the combined regimen on OSA. Eight randomized controlled trials were identified and systematically reviewed for meta-analysis. There were significant mean differences between OSA patients taking a combined regimen and placebo in apnea-hypopnea index (AHI) [mean difference (MD) -9.03 events/h, 95%CI (-16.22, -1.83 events/h; P = 0.01] and lowest oxygen saturation [MD 5.61%, 95% CI % (3.43, 7.80); P < 0.01]. Meta-regression showed that a higher proportion of male participants was associated with a greater reduction of AHI (p = 0.04). This study showed a positive but modest effect of pharmacotherapy in the reduction of OSA severity. The combination drugs are most applicable to male OSA patients based on their efficacy and pharmacological susceptibility. Pharmacotherapy may be applied as an alternative, adjunctive or synergistic treatment under careful consideration of its side effects.

The Role of Long-Acting Antimuscarinic Agents in the Treatment of Asthma.

The journey of using anticholinergics in the treatment of asthma started with anticholinergic-containing plants such as Datura stramonium and Atropa belladonna, followed by ipratropium bromide and continued with tiotropium, glycopyrronium, and umeclidinium. Although antimuscarinics were used in the maintenance treatment of asthma over a century ago, after a long time (since 2014), it has been recommended to be used as an add-on long-acting antimuscarinic agent (LAMA) therapy in the maintenance treatment of asthma. The airway tone controlled by the vagus nerve is increased in asthma. Allergens, toxins, or viruses cause airway inflammation and inflammation-related epithelial damage, increased sensory nerve stimulation, ganglionic and postganglionic acetylcholine (ACh) release by inflammatory mediators, intensification of ACh signaling at M1 and M3 muscarinic ACh receptors (mAChRs), and dysfunction of M2 mAChR. Optimal anticholinergic drug for asthma should effectively block M3 and M1 receptors, but have minimal effect on M2 receptors. Tiotropium, umeclidinium, and glycopyrronium are anticholinergic agents with this feature. Tiotropium has been used in a separate inhaler as an add-on treatment to inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA), and glycopyrronium and umeclidinium have been used in a single inhaler as a combination of ICS/LABA/LAMA in asthma in recent years. Guidelines recommend this regimen as an optimization step for patients with severe asthma before initiating any biologic or systemic corticosteroid therapy. In this review, the history of antimuscarinic agents, their effectiveness and safety in line with randomized controlled trials, and real-life studies in asthma treatment will be discussed according to the current data.

Pharmacological interventions for reducing catheter-related bladder discomfort in patients undergoing elective surgeries under general anaesthesia: A systematic review and meta-analysis.

Background and Aims: Catheter-related bladder discomfort (CRBD) is identified as a major concern after surgery as it can lead to increased morbidity and prolonged hospital stay. A suitable agent to prevent and treat postoperative CRBD is not yet established, and the literature is scarce in this regard. So, we aimed to find the efficacy of various drugs in preventing CRBD after elective surgery. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed for the study, and electronic databases like PubMed Central, Cochrane database and Embase were searched. The methodological quality of selected studies was assessed by the Cochrane Collaboration risk of bias tool. Review Manager 5.4.1 was used for statistical analysis. Results: The meta-analysis revealed that antimuscarinic agents were able to lower the incidence of CRBD significantly at 0 hour, 1 hour, 2 hours and 6 hours (P < 0.01) after the surgery. Tramadol was effective at 1 hour, 2 hours and 6 hours postoperatively (P < 0.01), whereas ketamine was effective at 2 and 6 hours (P < 0.01) postoperatively. Antiepileptic drugs (pregabalin and gabapentin) were able to lower the incidence of CRBD at 0 hour (P < 0.01), 1 hour (P < 0.05), 2 hours (P < 0.05) and 6 hours (P < 0.01) postoperatively while dexmedetomidine at 0 hour (P < 0.01) and 2 hours (P < 0.01) after the surgery. Injections paracetamol, amikacin and diphenhydramine were also shown to reduce the incidence of CRBD in separate randomised controlled trials. Conclusion: The current meta-analysis showed that antimuscarinic agents, tramadol, pregabalin, gabapentin, paracetamol and dexmedetomidine are effective in significantly reducing the incidence of postoperative CRBD.

COPD and glycopyrronium responsiveness assessment: An appraisal.

Clinical Trial Registration: ECR/159/Inst/WB/2013/RR-20. Background: Glycopyrronium bromide (a long-acting antimuscarinic agent: LAMA) appears pharmacokinetically suitable for testing bronchodilator responsiveness as salbutamol (short-acting ß2-agonist: SABA). Exploring the feasibility, acceptability, degree of reversibility with glycopyrronium, and its comparison with that of salbutamol may be intriguing. Methods: New, consecutive, and willing outpatient attendees in the same season of the two consecutive years with chronic obstructive pulmonary disease (FEV1/FVC <0.07; FEV1 <80% of predicted) were subjected to serial responsiveness with inhalation of salbutamol first followed by 50 µg dry powder glycopyrronium [Salbutamol- Glycopyrronium] (phase-1) in the first year and glycopyrronium followed by salbutamol [Glycopyrronium- Salbutamol] (phase-2) in the following year. We looked for the acceptability, adverse reactions, and degree of changes in FEV1, FVC, FEV1/FVC, and FEF25-75 with comparison between the two groups. Results: The [Salbutamol- Glycopyrronium] group (n = 86) were similar in age, body mass index, and FEV1 to the [Glycopyrronium- Salbutamol] group (n = 88). Both the agents could make a significant (P <.0001) improvement in the parameters independently or as add-on when used serially in alternate orders. The intergroup difference at no stage was significant. The sensitive patients to salbutamol (n = 48), glycopyrronium (n = 44), and both (n = 12) have improvement of 165, 189, and 297 mL while a both-insensitive group (n = 70) had barely 44 mL of improvement. The protocol was universally accepted without any adverse events. Conclusion: Serial testing of salbutamol and glycopyrronium responsiveness in alternate orders provides an insight regarding the independent and the add-on effects of these two agents. About 40% of our chronic obstructive pulmonary disease patients had no clinically appreciable difference in FEV1 with the salbutamol + glycopyrronium combination inhalation.

Are antimuscarinic effects common in hydroxyzine overdose? A cohort analysis of antimuscarinic effects in hydroxyzine and diphenhydramine-poisoned patients.

INTRODUCTION: Exposures to hydroxyzine, a first-generation H1 antihistamine, have increased rapidly over the last two decades. Many assumptions about hydroxyzine poisoning are based on other antihistamines, like diphenhydramine. However, the receptor affinities of hydroxazine suggest that there should be fewer antimuscarinic findings than diphenhydramine. METHODS: This was a cohort study that compared hydroxyzine and diphenhydramine exposures reported to the National Poison Data System between January 1, 2000, and December 31, 2020, and the Toxicologic Investigators Consortium Core Registry between January 1, 2010, and December 31, 2020. The primary outcome was to assess for antimuscarinic findings in hydroxyzine-poisoned patients, using diphenhydramine-poisoned patients as a comparison group. The secondary outcomes were to assess for markers of overall toxicity. Inclusion criteria were single-substance exposures with known outcomes. Exclusion criteria for National Poison Data System exposures were chronic exposures, unintentional exposures, and patients younger than 12 years old. There were no exclusion criteria for exposures reported to the Toxicologic Investigators Consortium Core Registry. RESULTS: There were 17,265 hydroxyzine and 102,354 diphenhydramine exposures reported to the National Poison Data System and 134 hydroxyzine and 1,484 diphenhydramine exposures reported to the Toxicologic Investigators Consortium Core Registry that met inclusion criteria. In both datasets, hydroxyzine-poisoned patients had lower rates and relative risk of developing antimuscarinic findings or receiving physostigmine, with the exception of hyperthermia in the Toxicologic Investigators Consortium Core Registry dataset. Coma/central nervous system depression (major), respiratory depression, seizures, ventricular dysrhythmias, intubation, and benzodiazepine administration were less likely in hydroxyzine-poisoned patients, but central nervous system depression (mild) was more likely in exposures reported to the National Poison Data System. The mortality in hydroxyzine-poisoned patients was rare: 0.02% and 0.8% of exposures reported to the National Poison Data System and Toxicologic Investigators Consortium Core Registry, respectively. DISCUSSION: The clinical manifestations of hydroxyzine exposures are consistent with the pharmacology of hydroxazine. The clinical effects were consistent across two United States national datasets. Clinicians should not generalize the illness script of diphenhydramine exposures to hydroxyzine exposures. CONCLUSIONS: Hydroxyzine-poisoned patients were less likely to develop antimuscarinic findings than diphenhydramine-poisoned patients. Hydroxyzine-poisoned patients were more likely to have mild central nervous system depression than an antimuscarinic toxidrome.

Study design of a phase 4, real-world study (COMPOSUR) to evaluate vibegron in patients with overactive bladder.

BACKGROUND: Overactive bladder (OAB) is defined as urinary urgency accompanied by frequency and nocturia, with or without urge urinary incontinence (UUI). Vibegron, a selective ß3-adrenergic receptor agonist approved in the US in December 2020, demonstrated efficacy in reducing symptoms of OAB and was safe and well tolerated in the 12-week EMPOWUR trial and its 40-week, double-blind extension trial. The goal of the COMPOSUR study is to evaluate vibegron in a real-world setting to assess patient treatment satisfaction, tolerability, safety, duration of treatment, and persistence. METHODS: This is a 12-month, prospective, observational, real-world study, with an optional 12-month extension to 24 months, in the US assessing adults ≥ 18 years old starting a new course of vibegron. Patients must be previously diagnosed with OAB with or without UUI, symptomatic for ≥ 3 months before enrollment, and receive prior treatment with an anticholinergic, with mirabegron, or with a combination of an anticholinergic and mirabegron. Enrollment is performed by the investigator following exclusion and inclusion criteria guided by US product labeling, reinforcing a real-world approach. Patients complete the OAB Satisfaction with Treatment Questionnaire (OAB-SAT-q) monthly and the OAB Questionnaire short form (OAB-q-SF) and Work Productivity and Activity Impairment Questionnaire (WPAI:US) at baseline and monthly for 12 months. Patients are followed up via phone call, in-person visits, or telehealth (ie, virtual) visits. The primary endpoint is patient treatment satisfaction as determined by the OAB-SAT-q satisfaction domain score. Secondary endpoints include percent positive responses to individual OAB-SAT-q questions, additional OAB-SAT-q domain scores, and safety. Exploratory endpoints include adherence and persistence. DISCUSSION: OAB leads to a significant decrease in quality of life, as well as impairment of work activities and productivity. Persistence with OAB treatments can be challenging, often due to lack of efficacy and adverse effects. COMPOSUR is the first study to provide long-term, prospective, pragmatic treatment data for vibegron in the US and the resultant effect on quality of life among patients with OAB in a real-world clinical setting. Trial registration ClinicalTrials.gov identifier: NCT05067478; registered: October 5, 2021.

TReating Incontinence for Underlying Mental and Physical Health (TRIUMPH): a study protocol for a multicenter, double-blinded, randomized, 3-arm trial to evaluate the multisystem effects of pharmacologic treatment strategies for urgency-predominant urinary incontinence in ambulatory older women.

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.

The association between anticholinergic burden and mobility: a systematic review and meta-analyses.

BACKGROUND: As people age, they accumulate several health conditions, requiring the use of multiple medications (polypharmacy) to treat them. One of the challenges with polypharmacy is the associated increase in anticholinergic exposure to older adults. In addition, several studies suggest an association between anticholinergic burden and declining physical function in older adults. OBJECTIVE/PURPOSE: This systematic review aimed to synthesise data from published studies regarding the association between anticholinergic burden and mobility. The studies were critically appraised for the strength of their evidence. METHODS: A systematic literature search was conducted across five electronic databases, EMBASE, CINAHL, PSYCHINFO, Cochrane CENTRAL and MEDLINE, from inception to December 2021, to identify studies on the association of anticholinergic burden with mobility. The search was performed following a strategy that converted concepts in the PECO elements into search terms, focusing on terms most likely to be found in the title and abstracts of the studies. For observational studies, the risk of bias was assessed using the Newcastle Ottawa Scale, and the Cochrane risk of bias tool was used for randomised trials. The GRADE criteria was used to rate confidence in evidence and conclusions. For the meta-analyses, we explored the heterogeneity using the Q test and I2 test and the publication bias using the funnel plot and Egger's regression test. The meta-analyses were performed using Jeffreys's Amazing Statistics Program (JASP). RESULTS: Sixteen studies satisfied the inclusion criteria from an initial 496 studies. Fifteen studies identified a significant negative association of anticholinergic burden with mobility measures. One study did not find an association between anticholinergic intervention and mobility measures. Five studies included in the meta-analyses showed that anticholinergic burden significantly decreased walking speed (0.079 m/s ± 0.035 MD ± SE,95% CI: 0.010 to 0.149, p = 0.026), whilst a meta-analysis of four studies showed that anticholinergic burden significantly decreased physical function as measured by three variations of the Instrumental Activities of Daily Living (IADL) instrument 0.27 ± 0.12 (SMD ± SE,95% CI: 0.03 to 0.52), p = 0.027. The results of both meta-analyses had an I2 statistic of 99% for study heterogeneity. Egger's test did not reveal publication bias. CONCLUSION: There is consensus in published literature suggesting a clear association between anticholinergic burden and mobility. Consideration of cognitive anticholinergic effects may be important in interpreting results regarding the association of anticholinergic burden and mobility as anticholinergic drugs may affect mobility through cognitive effects.

Patient Perception of Bladder Condition after Treatment with Solifenacin and Tolterodine in Overactive Bladder Patients.

BACKGROUND: Solefinacin and Tolterodine are new generation antimuscarinics claimed to have bladder specific action and less adverse effect like dry mouth. The objective of the study was to compare the improvement in urinary symptoms among patients using solefinacin and tolterodine with overactive bladder symptoms. METHODS: A hospital based cross-sectional comparative study was done for one year duration. All patients with overactive bladder symptoms were included and in every alternate patient's solefinacin and tolterodine were given after taking note of baseline OAB symptoms, PPBC score and UPS score. Participants were followed up after one month and noted improvement in endpoint OAB symptoms. Comparison of baseline to end-point symptoms changes among each group of participants were analyzed for statistical significance. RESULTS: Among 101 participants included in the study, 49 participants were in solefinacin group and 52 participants were in tolterodine group. The end-point comparison of urgency symptoms were improved by 20.1±6.76 (mean ± SD) units in solefinacin group and by 17.0 ± 9.18 units in tolterodine group. Urgency perception score improved to 2.1±0.66 for patients under solefinacin and 2±0.73 for tolterodine. Patient perception of bladder condition (PPBC) showed improvement in solefinacin group by 3.2±1.26 units and in tolteradine by 2.8±1.54 units (p = 0.165). Comparing the patient's perception of treatment outcome, massive improvement was reported by 81.6% of those receiving Solefinacinand 65.4% receiving tolterodine, though not statistically significant ( p = 0.131). CONCLUSIONS: Solefinacin and Tolterodine showed improvement in urinary symptoms, UPS and PPBC. Both showed comparable efficacy without significant superiority over one another.

Effect of oxybutynin and reboxetine on obstructive sleep apnea: a randomized, placebo-controlled, double-blind, crossover trial.

STUDY OBJECTIVES: Although recent investigations combining noradrenergic and antimuscarinic drugs have shown promising short-term results to treat obstructive sleep apnea (OSA), the mid-term effect and optimal dosage remain uncertain. The present study aimed to evaluate the effect of 1 week of 5 mg oxybutynin and 6 mg reboxetine (oxy-reb) on OSA versus placebo. METHODS: We performed a randomized, placebo-controlled, double-blind, crossover trial comparing the effect of 1 week of oxy-reb versus 1 week of placebo on OSA severity. At-home polysomnography was performed at baseline and after each week of intervention. RESULTS: Fifteen participants (male 66.7%) aged 59 [44-62] years (median [interquartile range]) with a mean body mass index of 33.1 ± 6.6 kg/m2 were included. No significant difference in apnea-hypopnea index (AHI) was observed between conditions (estimated marginal means [95% confidence interval] at baseline: 39.7 [28.5-55.3]; oxy-reb: 34.5 [22.7-52.3]; placebo: 37.9 [27.1-52.9]; p = 0.652), but oxy-reb improved average oxygen desaturation (p = 0.016) and hypoxic burden (p = 0.011) and lowered sleep efficiency (p = 0.019) and rapid eye movement sleep (p = 0.002). Moreover, participants reported reduced sleep quality during the week of oxy-reb compared to the week of placebo (4.7 [3.5; 5.9] vs. 6.5 [5.5; 7.5] on a 0-10 visual analogic scale, respectively; p = 0.001). No significant differences in sleepiness, vigilance, and fatigue were observed. No serious adverse events occurred. CONCLUSIONS: Administration of oxybutynin 5 mg and reboxetine 6 mg did not improve OSA severity assessed by AHI, but did alter sleep architecture and sleep quality. Reduced average oxygen desaturation and hypoxic burden were also observed. CLINICAL TRIAL: ClinicalTrials.gov, https://clinicaltrials.gov, NCT04394143.

Shortages of agents used to treat antimuscarinic delirium.

INTRODUCTION: Antimuscarinic delirium (AD), a potentially life-threatening condition frequently encountered by emergency physicians, results from poisoning with antimuscarinic agents. Treatment with physostigmine and benzodiazepines is the mainstay of pharmacotherapy, and use of dexmedetomidine and non-physostigmine centrally-acting acetylcholinesterase inhibitors (cAChEi) such as rivastigmine has also been described. Unfortunately, these medications are subject to drug shortages which negatively impact the ability to provide appropriate pharmacologic treatment of patients with AD. METHODS: Drug shortage data were retrieved from the University of Utah Drug Information Service (UUDIS) database from January 2001 through December 2021. Shortages of first-line agents used to treat AD (physostigmine and parenteral benzodiazepines) and second-line agents (dexmedetomidine and non-physostigmine cAChEi) were examined. Drug class, formulation, route of administration, reason for shortage, shortage duration, generic status, and whether the drug was a single-source product (made by only one manufacturer) were extracted. Shortage overlap and median shortage durations were calculated. RESULTS: Twenty-six shortages impacting drugs used to treat AD were reported to UUDIS from January 1, 2001 to December 31, 2021. Median shortage duration for all medication classes was 6.0 months. Four shortages were unresolved at the end of the study period. The single medication most often on shortage was dexmedetomidine, however benzodiazepines were the most common medication class on shortage. Twenty-five shortages involved parenteral formulations, and one shortage involved the transdermal patch formulation of rivastigmine. The majority (88.5%) of shortages involved generic medications, and 50% of products on shortage were single-source. The most common reported reason for shortage was a manufacturing issue (27%). Shortages were often prolonged and, in 92% of cases, overlapped temporally with other shortages. Shortage frequency and duration increased during the second half of the study period. CONCLUSION: Shortages of agents used in the treatment of AD were common during the study period and affected all agent classes. Shortages were often prolonged and multiple shortages were ongoing at study period end. Multiple concurrent shortages involving different agents occurred, which could hamper substitution as a means of mitigating shortage. Healthcare stakeholders must develop innovative patient- and institution-specific solutions in times of shortage and work to build resilience into the medical product supply chain to minimize future shortages of drugs used for treatment of AD.

Treatment of Ureteral Stent-Related Symptoms.

BACKGROUND: The aim of the study was to assess the effectiveness of the main classes of drugs used at reducing morbidity related to ureteric stents. SUMMARY: After establishing a priori protocol, a systematic electronic literature search was conducted in July 2019. The randomized clinical trials (RCTs) selection proceeded in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and was registered (PROSPERO ID 178130). The risk of bias and the quality assessment of the included RCTs were performed. Ureteral Stent Symptom Questionnaire (USSQ), International Prostate Symptom Score (IPSS), and quality of life (QoL) were pooled for meta-analysis. Mean difference and risk difference were calculated as appropriate for each outcome to determine the cumulative effect size. Fourteen RCTs were included in the analysis accounting for 2,842 patients. Alpha antagonist, antimuscarinic, and phosphodiesterase (PDE) inhibitors significatively reduced all indexes of the USSQ, the IPSS and QoL scores relative to placebo. Conversely, combination therapy (alpha antagonist plus antimuscarinic) showed in all indexes of the USSQ, IPSS, and QoL over alpha antagonist or antimuscarinic alone. On comparison with alpha blockers, PDE inhibitors were found to be equally effective for urinary symptoms, general health, and body pain parameters, but sexual health parameters improved significantly with PDE inhibitors. Finally, antimuscarinic resulted in higher decrease in all indexes of the USSQ, the IPSS, and QoL relative to alpha antagonist. KEY MESSAGE: Relative to placebo, alpha antagonist alone, antimuscarinics alone, and PDE inhibitors alone have beneficial effect in reducing stent-related symptoms. Furthermore, there are significant advantages of combination therapy compared with monotherapy. Finally, PDE inhibitors are comparable to alpha antagonist, and antimuscarinic seems to be more effective than alpha antagonist alone.