Antimuscarinic Treatment Research Articles

Urethral Bulking Agents for the Treatment of Urinary Incontinence: Efficacy, Safety, and Impact on the Overactive Bladder Symptoms with an Underlying Detrusor Overactivity.

Background: Mixed urinary incontinence (MUI) has always represented a major therapeutic challenge and the management of this type of incontinence is often complicated by uncertain outcomes. Surgical options include interventions targeting both stress urinary incontinence (SUI) and urge urinary incontinence (UUI), although there are no international published guidelines that dictate whether it is better to start with surgical management to address the SUI or UUI component after the failure of conservative treatment. The aim of the present study is to evaluate the effectiveness of the Macroplastique (MPQ) procedure on overactive bladder (OAB) symptoms in women with MUI with a minimum follow-up of 1 year. Methods: A retrospective analysis of prospectively collected data was performed in two tertiary reference centers. We enrolled all women complaining of symptoms of SUI and OAB, dry or wet, with a urodynamically confirmed diagnosis of MUI [urodynamic stress incontinence (USI) with detrusor overactivity (DO)], who took a previous ineffective antimuscarinic treatment and underwent the MPQ procedure. We considered as objectively cured women who did not leak urine during the stress test and with a 1 h pad-test negative, while International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), ICIQ-OAB, Patient Global Impression of Improvement (PGI-I) scale, and a Visual Analogue Scale (VAS) were used to assess subjective outcomes. Results: A total of forty-six patients who met the inclusion criteria and who underwent the MPQ procedure were considered for the analysis. At the 1-year mark of follow-up, 72% of patients were objectively cured at stress test and 65% were objectively cured at pad-test, while 72% of women declared themselves subjectively cured. OAB symptoms significantly improved after MPQ and a complete resolution of OAB was recorded in 35% of patients. Conclusions: This study demonstrated that MPQ is a safe and effective option for the treatment of female MUI. Furthermore, MPQ significantly improves the symptoms of OAB and is able to completely cure this condition in a relevant percentage of women with MUI when pharmacological treatment fails.

Risk of antimuscarinic initiation with cholinesterase inhibitor use in Alzheimer's disease

BackgroundThe use of cholinesterase inhibitors (CHEIs) is commonly associated with urinary incontinence in patients with Alzheimer's disease (AD). This study evaluated the risk of antimuscarinic initiation drugs with the use of CHEIs in AD patients. MethodsThe study used a nested case-control study design involving 2013–2015 Medicare data of AD patients 65 years and older without antimuscarinic use in 2013. Cases were defined as those who initiated antimuscarinic treatment in 2014–2015. Controls with no antimuscarinic use were selected through incidence density sampling and matched to cases on age using a variable-ratio method. The CHEI utilization pattern was classified as current (event-30 days), recent (event-31 to event-90 days), and past (event-91 to event-180 days). Conditional logistic regression was used to assess the association between CHEI use and the risk of antimuscarinic initiation. ResultsThis study included 1,909 cases and 9,064 controls. The adjusted model found that overall CHEI (Adjusted Odds Ratio [aOR] = 1.90, 95 % Confidence Interval [CI]: 1.58–2.28) and current CHEI use (aOR = 1.62, 95 % CI: 1.18–2.21) were associated with an increase in the risk of antimuscarinic initiation compared to non-CHEI use. In addition, the current use of donepezil and rivastigmine significantly increased the risk of antimuscarinic initiation by 48 % (95 % CI: 1.03–2.12) and 171 % (95 % CI: 1.46–5.03), respectively. ConclusionThe study found an increased risk of antimuscarinic initiation with the current use of CHEIs, particularly with donepezil and rivastigmine. These findings underscore the need for careful medication management to minimize prescribing cascades and associated consequences in AD.

A Retrospective Database Analysis to Investigate Treatment Patterns and Health Care Resource Utilisation in Patients who CYCLe AntiMuscarinics in ENgland (CYCLAMEN)

BackgroundPatients with overactive bladder may cycle through different antimuscarinic medications even though there is limited evidence to support this approach. ObjectiveTo describe treatment patterns and the associated health care resource utilisation (HCRU) according to antimuscarinic cycling groups. Design, setting, and participantsThe CYCLe AntiMuscarinics in ENgland (CYCLAMEN) study was a retrospective observational investigation that used primary care records from the Clinical Practice Research Datalink GOLD database linked to Hospital Episode Statistics secondary care data. Eligible patients (≥18 yr) were prescribed their first antimuscarinic between January 2014 and December 2017. Patients were categorised into groups prescribed one, two, or three or more (groups 1–3) consecutive unique antimuscarinics over 18 mo. Outcome measurements and statistical analysisThe HCRU rate and costs were calculated for the period of continuous antimuscarinic therapy (first antimuscarinic treatment episode) and the 18-mo follow-up period. Treatment sequence patterns were displayed using sunburst plots and Kaplan-Meier analysis was used to assess time on treatment. Results and limitationsOverall, 35 369 patients were included, of whom 31 760 (89.8%) received one antimuscarinic (group 1), 3182 (9.0%) received two (group 2), and 427 (1.2%) received three or more (group 3). The most common initial antimuscarinics were solifenacin (13 628 patients, 42.9%) in group 1, and oxybutynin in group 2 (1267 patients, 39.8%) and group 3 (200 patients, 46.8%). The median duration of the first antimuscarinic treatment episode was 57 d and <20% of patients were receiving any antimuscarinic after 18 mo. The number of primary care visits and mean costs increased across groups. The reasons for cycling could not be identified in this study. ConclusionsApproximately 10% of patients underwent sequential cycling with two or more antimuscarinics. Furthermore, as the majority discontinued treatment within 18 mo, there is a need to improve the management of these patients in the clinical care setting. Patient summaryWe investigated treatment patterns and health care use for patients with overactive bladder who were prescribed at least one antimuscarinic drug (AMD), which are drugs that reduce some of the impulses passing from the bladder to the brain. Around 10% of patients accessing primary health care in England received more than one sequential AMD. Most patients discontinued treatment, which may indicate inadequate management of their condition. Prescription of a higher number of AMDs was associated with higher health care costs.

The Impact of Muscarinic Antagonism on Psychosis-Relevant Behaviors and Striatal [11C] Raclopride Binding in Tau Mouse Models of Alzheimer's Disease.

Psychosis that occurs over the course of Alzheimer's disease (AD) is associated with increased caregiver burden and a more rapid cognitive and functional decline. To find new treatment targets, studies modeling psychotic conditions traditionally employ agents known to induce psychosis, utilizing outcomes with cross-species relevance, such as locomotive activity and sensorimotor gating, in rodents. In AD, increased burdens of tau pathology (a diagnostic hallmark of the disease) and treatment with anticholinergic medications have, separately, been reported to increase the risk of psychosis. Recent evidence suggests that muscarinic antagonists may increase extracellular tau. Preclinical studies in AD models have not previously utilized muscarinic cholinergic antagonists as psychotomimetic agents. In this report, we utilize a human-mutant-tau model (P301L/COMTKO) and an over-expressed non-mutant human tau model (htau) in order to compare the impact of antimuscarinic (scopolamine 10 mg/kg/day) treatment with dopaminergic (reboxetine 20 mg/kg/day) treatment, for 7 days, on locomotion and sensorimotor gating. Scopolamine increased spontaneous locomotion, while reboxetine reduced it; neither treatment impacted sensorimotor gating. In the P301L/COMTKO, scopolamine treatment was associated with decreased muscarinic M4 receptor expression, as quantified with RNA-seq, as well as increased dopamine receptor D2 signaling, as estimated with Micro-PET [11C] raclopride binding. Scopolamine also increased soluble tau in the striatum, an effect that partially mediated the observed increases in locomotion. Studies of muscarinic agonists in preclinical tau models are warranted to determine the impact of treatment-on both tau and behavior-that may have relevance to AD and other tauopathies.

A Comparative Study on the effectiveness and Tolerability of Mirabegron and Antimuscarinics in the treatment of Overactive bladder

Background: Despite antimuscarinic treatment options being available as the first line agents for overactive bladder (OAB), there is still a need for distinct treatment approaches to manage its suboptimal response and noncompliance. Mirabegron, a β3-adrenoceptor agonist, could be a better alternative to antimuscarinics in OAB treatment with a good effectiveness/tolerability balance. Aim: To compare the clinical profile of mirabegron and antimuscarinics in the treatment of overactive bladder. Method: A prospective, observational study was conducted in two groups of patients who received either mirabegron (n=120) or antimuscarinics (n=120) for the treatment of OAB. Effectiveness of the drugs were assessed at baseline, 4 and 8 weeks after the treatment using the Overactive Bladder Symptom Score (OABSS) and International Prostatic Symptom Score (IPSS) questionnaires. The safety assessment was done by measuring the post-void residual (PVR) urine volume and assessing the adverse drug reactions (ADR). The probability and severity of the ADRs were measured using Naranjo scale and Hartwig’s scale respectively. Also a subgroup analysis was carried out to compare the effectiveness of the two drugs in patients with OAB related to benign prostatic hyperplasia (BPH). Results: The overall effectiveness of antimuscarinics and mirabegron was found to be similar, but mirabegron showed better reduction in the daytime frequency (p=0.049). They also differ in safety profile with the overall incidence of adverse events being significantly higher in antimuscarinics group (15.83%) (19/120) than in the mirabegron group group (1.7%) (2/120) (p&lt;0.001). In the patients with OAB related to BPH also, there was a better reduction in the daytime frequency with mirabegron than with antimuscarinics, with overall effectiveness between groups being similar. In addition, mirabegron did not worsen the voiding symptoms and was found to be a better combination with alpha1 blockers than the antimuscarinics in patients with OAB related to BPH. No significant change was there in the PVR values within and between the groups. Conclusion: Mirabegron is a better alternative to antimuscarinics in the treatment of OAB with a distinct effectiveness/tolerability balance especially in patients with OAB related to BPH.

SC73 - Post holmium laser enucleation of prostate antimuscarinic treatment efficacy and tolerance. A high-volume center prospective study

SC73 - Post holmium laser enucleation of prostate antimuscarinic treatment efficacy and tolerance. A high-volume center prospective study

Aqua: A new questionnaire assessing anticholinergic side effects in neurogenic population (Aqua: Anticholinergic side effects questionnaire).

Validate a new questionnaire to assess the side effects secondary to anticholinergics in neurogenic population suffering from Adult neurogenic lower urinary tract dysfunction (ANLUTD). We conducted a prospective, monocentric study in a Neuro-urology Department of a University Hospital between February 2015 and April 2020. To allow a full psychometric validation of a questionnaire, the study protocol included 3 steps: qualitative interviews, feasibility study and validation study. The primary outcome was good psychometric properties defined with good internal consistency reliability (Cronbach's α>0.7) and good test-retest reliability (intraclass correlation coefficient (ICC)>0.7). we included 64 patients with ANLUTD secondary to neurogenic disorders. Feasibility study demonstrate very good acceptation and comprehension for 97% of patients. Validation study showed good internal consistency with Cronbach's α=0,69 and very good ICC=0,73. AQUA is composed with 8 items scoring 0 (no side effect) to 2 (major side effect) for a total score between 0 to 16. Time to fulfill is very quick. Mean score in our population was 4,1 (sd 2,9). AQUA is the first validated tool to assess side effects secondary to antimuscarinic treatment for neurogenic population suffering from ANLUTD. 2.

Risk of delirium associated with antimuscarinics in older adults: A case-time-control study.

BackgroundOlder adults are at an increased risk of delirium because of age, polypharmacy, multiple comorbidities and acute illness. Antimuscarinics are the backbone of the pharmacological management of overactive bladder. However, the safety profiles of antimuscarinics vary because of their dissimilarities to muscarinic receptor‐subtype affinities and are associated with differential central anticholinergic adverse effects.ObjectiveThis study aimed to examine delirium risk in new users of oxybutynin and solifenacin in older adults (≥ 65 years). In the secondary analyses, we examined the risk of delirium by type and dose of antimuscarinic.MethodWe applied a case‐time‐control design to investigate delirium risk in older adults who started taking oxybutynin and solifenacin. We used a nationwide inpatient hospital data (2005–2016), National Minimum Data Set, maintained by the Ministry of Health, New Zealand (NZ), to identify older adults with a new‐onset diagnosis of delirium. Eligible patients were older adults aged 65 at entry into the cohort on 1/1/2006. We used dispensing claims data to determine antimuscarinic treatment exposure. The antimuscarinic included in the study were new users of oxybutynin and solifenacin. These two antimuscarinics are subsidised by the Pharmaceutical Management Agency and are the most frequently used antimuscarinic in NZ. A conditional logistic regression model was used to compute matched odds ratios (MORs) and 95% confidence intervals (CIs). In the case‐time‐control design, we made separate analyses to evaluate the dose–response risk of delirium.ResultsWe identified 4818 individuals (mean age 82.14) from 2005 to 2015 with incident delirium and were exposed to at least one of the antimuscarinic of interest. The case‐time‐control matched odds ratio (MOR) for delirium with oxybutynin was (2.06, 95% confidence interval [CI] 1.07–3.96). Solifenacin was not associated with delirium (0.89 95%CI 0.64–1.23). In the sensitivity analyses, the case‐time‐control MOR for delirium using a shorter risk period (0–3 days) did not change the results. The dose–response risk of delirium was significant for oxybutynin (0.05, 95%CI 0.02–0.08) but not for solifenacin (−0.01, 95%CI −0.03 to 0.00). In addition, in the subgroup analyses, a statistically significant association of delirium was found for oxybutynin but not for solifenacin in the non‐dementia cohort (2.11,95% CI 1.08–4.13) and the dementia cohort (1.25, 95%CI 0.05–26.9).ConclusionThe study found that oxybutynin but not solifenacin is associated with a risk of new‐onset delirium in older adults. The higher blockade of M1 and M2 receptors by oxybutynin is likely to contribute to delirium than solifenacin, which is highly selective for the M3 receptor subtype. Therefore, the treatment choice with an M3 selective agent must be given due consideration, particularly in those with pre‐existing cognitive impairment.

Resource use and healthcare costs in patients with overactive bladder who initiate treatment with mirabegron or antimuscarinic monotherapy in Catalonia: the MIRACAT study

Introduction and aimOveractive bladder (OAB) negatively impacts patient quality of life and may be associated with high resource use. Our aim was to describe the resource use, costs and persistence associated with mirabegron (MB) or antimuscarinic (AM) treatment in patients with OAB. Materials and methodsObservational retrospective study of medical records in adult patients initiating OAB treatment with MB or AM in Catalonia. Healthcare resource use (visits, hospital stays, tests, medication, absorbent pads) in the first year after treatment initiation was collected. Associated costs were estimated (є, reference year 2019), as well as treatment persistence. Treatment discontinuation was defined as the absence of prescription for at least 45 days or treatment change. ResultsThe mean cost per patient (SD) was є 1,640.20 (є 1,227.60) with MB and є 2,159.20 (є 2,264.40) with AM; the associated healthcare resource use cost was lower with MB compared to AM, except for OAB drug costs. Persistence after 12 months of treatment initiation was higher in MB (42.1%) compared to AM (33.0%), as was the median time until treatment discontinuation: 299 (95% CI: 270–328) vs 240 days (95% CI: 230–250). ConclusionsLower healthcare resource use was observed with MB compared to AM in the first year of index treatment, resulting in a lower mean direct cost per patient and year, despite its higher acquisition cost. Increased treatment persistence, as well as rational use of available treatments improves OAB management and, in return, patients’ quality of life.

Outcomes of a complementary and alternative medicine based on vitamins, herbal products, and amino acid as a first line treatment in idiopathic overactive bladder syndrome in men and women without bladder outlet obstruction.

To evaluate the efficacy and tolerability of a complementary and alternative medicine (CAM) called Kubiker (Naturmed, Montegranaro, FM, Italy), consisting of vitamins (C and D), herbal products (cucurbita maxima, capsicum annum, polygonum cuspidatum), and amino acid L-Glutamine, as first line treatment of (OAB). According to institutional protocols, data on patients addressing to a tertiary referral centre for OAB symptoms were recorded. OAB was evaluated through validated questionnaires including ICIQ-SF, USS, and OAB-q-SF. Patients with previous antimuscarinic or β3 agonist treatment, neurological disease or pathologies which may mimic OAB, including infections, were excluded. Only unobstructed patients were considered and were given CAM twice daily for 12 weeks. After treatment, symptoms were re-evaluated repeating previous questionnaires and PGI-I was given to evaluate perceived improvement. A total of 41 patients were evaluated and 35 respected inclusion criteria and were enrolled. All subjects had a full compliance and adherence with CAM medication intake. The median patient's age was 65 (56-73). Male were 8 (22.9%) while females were 27 (77.1%). Median baseline OAB-q SF and ICIQ-SF scores were 18 (15-25) and 9 (6-13), respectively. After treatment, 85.7% patients had a clinical benefit, with a significant reduction of OAB symptoms, also according to USS (p < 0.01). The median OAB-q SF and ICIQ-SF scores were 10 (7-15) and 6 (0-8) (p < 0.01). CAM was successful with an improvement in subjective patient's satisfaction, with a median PGI-I score of 2 (1-3). Patients (men and women) who still had UUI after 3 months CAM medication were eight (22.8%), and among them, those who did not refer any therapeutic benefit were five (14.3%). According to our study, CAM may be useful medication for a first line treatment of uncomplicated idiopathic OAB cases, providing a nonnegligible effects on symptoms. However, further studies are mandatory to draw definitive conclusions.

Uso de recursos y costes sanitarios en pacientes con vejiga hiperactiva que inician tratamiento con mirabegrón o un antimuscarínico en monoterapia en Cataluña: estudio MIRACAT

Introduction and aimOveractive bladder (OAB) negatively impacts patient quality of life and may be associated with high resource use. Our aim was to describe the resource use, costs and persistence associated with mirabegron (MB) or antimuscarinic (AM) treatment in patients with OAB. Materials and methodsObservational retrospective study of medical records in adult patients initiating OAB treatment with MB or AM in Catalonia. Healthcare resource use (visits, hospital stays, tests, medication, absorbent pads) in the first year after treatment initiation was collected. Associated costs were estimated (€, reference year 2019), as well as treatment persistence. Treatment discontinuation was defined as the absence of prescription for at least 45 days or treatment change. ResultsThe mean cost per patient (SD) was € 1,640.20 (€ 1,227.60) with MB and € 2,159.20 (€ 2,264.40) with AM; the associated healthcare resource use cost was lower with MB compared to AM, except for OAB drug costs. Persistence after 12 months of treatment initiation was higher in MB (42.1%) compared to AM (33.0%), as was the median time until treatment discontinuation: 299 (95% CI: 270-328) vs 240 days (95% CI: 230-250). ConclusionsLower healthcare resource use was observed with MB compared to AM in the first year of index treatment, resulting in a lower mean direct cost per patient and year, despite its higher acquisition cost. Increased treatment persistence, as well as rational use of available treatments improves OAB management and, in return, patients’ quality of life.

Impact of Bladder Wall Thickness on the Outcomes of Antimuscarinic Treatment in Women with Overactive Bladder

Aim: This study aimed to evaluate the effect of bladder wall thickness (BWT) (using transabdominal ultrasound) on the outcomes of antimuscarinic treatment in women with overactive bladder. Methods: A total of 102 female patients with symptoms of OAB were recruited. All patients completed the Overactive Bladder version 8 (OAB-V8) (Arabic validation) and the International Consultation of Incontinence Questionnaire (ICIQ-SF). Patients completed the urodynamic study (UDS) including uroflowmetry and PVR and measures of BWT by transabdominal ultrasound. The patients were classified into 2 major groups: G1 (patients with BWT <5 mm) and G2 (patients with BWT ≥5 mm). The patients were re-evaluated after 3-month medication with solifenacin 10-mg oral tablet. Results: At baseline, the results of OAB-V8 and ICIQ-SF were significantly higher in G2 than G1 (p < 0.001). Regarding UDS, volume at 1st desire to void, volume at strong desire to void, and MBC were significantly higher in group 1 compared to group 2 (p = 0.001). Intravesical pressure at strong desire and patients’ number of DO were significantly increased in G2 (p < 0.05 and p = 0.001, respectively). After treatment, there was an improvement in both groups regarding OAB-V8, ICIQ-SF, bladder volume at 1st desire to void, bladder volume at strong desire to void, bladder volume at DO, MBC, intravesical pressure at strong desire, and the patients’ number with DO (decreased), and these improvements were statistically significant in group 1 compared to group 2 (p < 0.05). Conclusion: BWT showed a significant association with both OAB symptom scores and UDS parameters. The decrease in BWT is associated with a significantly higher response to solifenacin therapy regarding the UDS results.

Cardiovascular Risk in Users of Mirabegron Compared with Users of Antimuscarinic Treatments for Overactive Bladder: Findings from a Non-Interventional, Multinational, Cohort Study.

IntroductionDuring clinical trials, mirabegron, a β3-adrenoreceptor agonist, was associated with increased vital signs vs placebo in patients with overactive bladder.ObjectiveThe purpose of this study was to compare incidence rates of adverse cardiovascular (CV) outcomes following mirabegron or antimuscarinic use.MethodsWe conducted an observational post-marketing safety study utilising real-world data. The study population was identified within five sources: Danish and Swedish National Registers, Clinical Practice Research Datalink (UK), Optum (USA) and Humana (USA). Episodes of time when patients were new users of mirabegron or antimuscarinics (October 2012–December 2018) were sourced from prescriptions and matched on propensity scores. Occurrences of major adverse cardiovascular events (MACE), acute myocardial infarction (AMI), stroke, CV mortality and all-cause mortality were identified. Outcome incidence rates and hazard ratios from Cox models were estimated.ResultsOverall, 152,026 mirabegron and 152,026 antimuscarinic episodes were matched. The population consisted of 63.1% women and 72.6% were ≥ 65 years old. There were no appreciable differences in the incidence rates of MACE, AMI or stroke between users of mirabegron and antimuscarinics. Incidence rates of CV mortality (hazard ratio 0.83, 95% confidence interval 0.73–0.95) and all-cause mortality (hazard ratio 0.80, 95% confidence interval 0.76–0.84) were no higher with mirabegron vs antimuscarinics. Results restricted to episodes at high risk for CV events or stratified by age (< 65 years, ≥ 65 years) or prior overactive bladder medication use were consistent with overall findings.ConclusionsThis large, multinational study found no higher risk of MACE, AMI, stroke, CV mortality or all-cause mortality among users of mirabegron relative to users of antimuscarinics.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40264-021-01095-7.

Correlation between the NGF levels and questionnaire forms in patients receiving antimuscarinic treatment and those receiving onabotulinum toxin-A injection.

To compare nerve growth factor (NGF) levels in patients who received antimuscarinic, versus onabotulinum toxin-A (onaBoNT-A) injection, as well as to investigate whether there is a correlation between NGF levels, and 8-item overactive bladder questionnaire(OAB-V8), urogenital distress inventory (UDI)-6, and incontinence impact questionnaire (IIQ)-7 forms. Fourty adult patients with OAB were enrolled in this prospective study. An antimuscarinic was prescribed to 20 naive patients, and onaBoNT-A injection was administered to 20 patients, who were refractory to antimuscarinics. Urine samples were obtained before, and after 3rd and 6th months of treatment, and NGF levels were measured. Symptom scores of OAB-V8, UDI-6,and IIQ-7 were recorded. There was no significant difference between groups in terms of the initial OAB-V8, IIQ-7, and UDI-6 scores, whereas NGF values showed no significant difference over time in onaBoNT-A group (p=0.069, p=0.069). NGF levels were significantly lower in 3rd and 6th months, in patients receiving antimuscarinic (p=0.003, p=0.007); a strong correlation was found in 3rd month between the NGF levels, OAB-V8 scores (r=0.704, p=0.001), and IIQ-7 scores (r=0.676, p=0.001), and a moderate correlation between NGF levels, and UDI-6 scores (r=0.583, p=0.007). In the 6th months, a very strong correlation was found between NGF levels, and OAB-V8 scores (r=0.811, p=0.004), and a strong correlation was found between NGF levels, and IIQ-7 scores (r=0.671, p=0.001). In onaBoNT-A group, there was no significant correlation between NGF levels, and other variables. NGF level might be a good marker to evaluate effectiveness of treatment in patients receiving antimuscarinics, owing to correlation of urinary NGF levels with symptom scores. Lack of correlation in patients receiving onaBoNT-A injection could be a result of differences in the mechanism of action.

Antimuscarinic Cascade Across Individual Cholinesterase Inhibitors in Older Adults with Dementia.

Acetylcholinesterase inhibitors (AChEIs) have been associated with an increased risk of starting antimuscarinic treatment to treat overactive bladder (OAB)-an example of a prescribing cascade. Limited comparative data exist regarding the prescribing cascade of antimuscarinics across individual AChEIs in older adults with dementia. This study examined the association between individual AChEI use and antimuscarinic cascade in older adults with dementia. We conducted a new user retrospective cohort study from January 2005 to December 2018 using data from the TriNetX electronic medical record database, a federated electronic medical records network in the US. The cohort included patients 65 years or older with a diagnosis of dementia using AChEIs (donepezil, galantamine, or rivastigmine). Individual AChEIs were identified with index dates from 1 January 2006 to 31 June 2018, with a 1-year washout period. The study excluded patients with any antimuscarinic use and OAB diagnosis 1 year before the AChEI index date. The primary outcome of interest was the prescription of antimuscarinics within 6 months of the AChEI index date. A Cox proportional hazard model was used to assess the association between individual incident AChEI use and antimuscarinic prescribing cascade after controlling for several covariates. The study included 47,059 older adults with dementia who were incident users of AChEIs. Most of these patients were initiated with donepezil (83.1%), followed by rivastigmine (12.3%) and galantamine (4.6%). Overall, 8.16% of the study cohort had incident OAB diagnosis or antimuscarinic prescription. Antimuscarinics were initiated by 1725 (3.7%) older adults with dementia within 6 months of AChEI prescription, and cascade varied widely across individual agents-donepezil (3.9%), rivastigmine (2.6%), and galantamine (2.9%). Cox proportional hazard analyses revealed that donepezil users had an increased risk of receiving antimuscarinics (adjusted hazard ratio 1.55, 95% confidence interval 1.31-1.83) compared with rivastigmine. The findings were consistent in sensitivity analyses. This study found that donepezil use is more likely to lead to antimuscarinic cascade than rivastigmine. Future studies are needed to determine the potential consequences of this cascade in dementia.

Persistence with mirabegron or antimuscarinic treatment for overactive bladder syndrome: Findings from the PERSPECTIVE registry study.

ObjectivesThis analysis from the PERSPECTIVE (a Prospective, Non‐interventional Registry Study of Patients Initiating a Course of Drug Therapy for Overactive Bladder) study evaluated treatment persistence with mirabegron or antimuscarinics over a 12‐month period.MethodsParticipants were adults diagnosed with overactive bladder (OAB) by their health care provider (HCP), who were initiating mirabegron or antimuscarinic treatment. The HCP made all treatment decisions, and patients were followed for 12 months with no mandatory scheduled visits. Information requests were sent to patients at baseline and months 1, 3, 6, and 12. Patients were nonpersistent if they switched, discontinued, or added OAB medications/therapies to their initial treatment. Reasons for discontinuation and switching patterns were investigated.ResultsOverall, 1514 patients were included (613 mirabegron and 901 antimuscarinic initiators). Persistence rates decreased steadily over time in both groups. A low proportion of patients added or switched medication at each time point. Unadjusted Kaplan‐Meier analysis showed similar persistence rates for both groups. When the data were adjusted for patient characteristics (age, sex, and OAB treatment status), mirabegron initiators had higher persistence rates. No significant differences were noted in unadjusted median time to end of persistence. However, end of treatment persistence by any cause was longer with mirabegron (median: 9.5 vs 6.7 months for antimuscarinics). HCPs stated that the most common reasons for nonpersistence were no symptomatic improvement and side effect aversion.ConclusionsTreatment persistence was longer for mirabegron compared with antimuscarinic initiators after controlling for patient characteristics. End of treatment persistence by any cause was also longer with mirabegron.

Efficacy of atropine and scopolamine on airway contractions following exposure to the nerve agent VX

Nerve agents are highly toxic organophosphorus compounds that inhibit acetylcholinesterase resulting in rapid accumulation of the neurotransmitter acetylcholine (ACh) causing a cholinergic syndrome including respiratory failure. In the present study, respiratory responses and antimuscarinic treatment efficacy was evaluated ex vivo using rat precision-cut lung slices (PCLS) exposed to the nerve agent VX. The respiratory effects were evaluated either by adding exogenous ACh directly to the culture medium or by applying electric-field stimulation (EFS) to the PCLS to achieve a release of endogenous ACh from neurons in the lung tissue.The airway contraction induced by both methods was enhanced by VX and resulted in lingering airway recovery, in particular when airways were exposed to a high VX-dose. Both contractions induced by EFS and exogenously added ACh were significantly reduced by administration of the antimuscarinic drugs atropine or scopolamine. Two additions of atropine or scopolamine after maximal ACh-induced airway response was demonstrated effective to reverse the contraction. By adding consecutive doubled doses of antimuscarinics, high efficiency to reduce the cholinergic airway response was observed. However, the airways were not completely recovered by atropine or scopolamine, indicating that non-muscarinic mechanisms were involved in the smooth muscle contractions.In conclusion, it was demonstrated that antimuscarinic treatment reversed airway contraction induced by VX but supplemental pharmacological interventions are needed to fully recover the airways. Further studies should therefore clarify the mechanisms of physiological responses in lung tissue following nerve agent exposures to improve the medical management of poisoned individuals.

A study of cancer occurrence in users of mirabegron and antimuscarinic treatments for overactive bladder

Objective This post-authorization safety study (EU PAS Register Number: EUPAS16088) was designed to compare the incidence of cancer outcomes in patients treated with mirabegron versus antimuscarinic medications. Methods Cohorts of mirabegron initiators during 2012–2018 were propensity-score matched to antimuscarinic medication initiators within real-world data sources (Danish National Registers, Swedish National Registers, Clinical Practice Research Datalink [UK], Optum [US], and Humana [US]). Incident cancer cases were identified during follow-up from direct linkage to cancer registers or validated through medical record review or through physician questionnaires. Comparisons of sex-specific composite cancer outcomes (cancer of the lung/bronchus, colon/rectum, melanoma of skin, urinary bladder, non-Hodgkin lymphoma, kidney/renal pelvis, pancreas, prostate in men and breast and uterus in women) were made overall and for person-time in the first year and after the first year following start of treatment, for all ages and for the subgroup ≥65 years. Results Among the 80,637 mirabegron initiators matched to 169,885 antimuscarinic medication initiators, 68% were at least 65 years of age and 66% were women. Over 5000 incident cancer cases were observed overall. Incidence rates were higher for men than women for composite and individual cancer outcomes. The pooled fixed effects hazard ratios for composite cancer outcomes (all ages) were 1.05 (95% confidence interval [CI]: 0.98–1.14) for women and 1.06 (95% CI: 0.98–1.14) for men. Results were similar in persons ≥65 years. Conclusions The results suggest no association between mirabegron use and risk of cancer, compared with antimuscarinic medications, in either men or women. Registration: EU PAS Register Number: EUPAS16088

Abstract 13154: Cardiovascular Risk in Users of Mirabegron Relative to Users of Antimuscarinic Treatments for Overactive Bladder: Findings From a Non-interventional, Real-world Data Safety Study

Introduction: During clinical trials, mirabegron, a β3-adrenoreceptor agonist, was associated with increased heart rate and systolic/diastolic blood pressure vs placebo in patients with overactive bladder (OAB). We studied the association between mirabegron and cardiovascular (CV) outcomes in an observational post-marketing safety study using real-world data. Methods: The study population was identified within five data sources: Danish and Swedish National Registers, Clinical Practice Research Datalink (UK), Optum (US), and Humana (US). Episodes of time when patients were new users of mirabegron or antimuscarinic medications (AMs) from 2012 to 2018 were sourced from prescription/dispensing information and matched on propensity scores. Major adverse CV events (MACE), acute myocardial infarction (AMI), stroke, and CV and all-cause mortality were identified from register linkage or validated through medical record review or physician questionnaires. Incidence rates of these outcomes during person-time of current use were estimated along with hazard ratios (HRs) from Cox models. Results: In total, 152,026 mirabegron episodes were matched to an equal number of AM episodes. The study population was 63.2% female and 72.6% were ≥65 years old. Baseline CV risk factors were similar between matched groups. There were no appreciable differences in the incidence rates of MACE, AMI, and stroke among current users of mirabegron relative to AMs (Table). The incidence rates of CV mortality (HR: 0.83, 95% confidence interval [CI]: 0.73, 0.95) and all-cause mortality (HR: 0.80, CI: 0.76, 0.84) were no higher with mirabegron vs AMs. Results restricted to episodes at high risk for CV events or stratified by age (&lt;65, ≥65 years) or prior OAB medication use were consistent with overall findings. Conclusions: This large, multinational study found no higher risk of MACE, AMI, stroke, or CV or all-cause mortality among current users of mirabegron relative to users of AMs.

Neurobiological mechanisms associated with antipsychotic drug-induced dystonia.

Dystonia is by far the most intrusive and invalidating extrapyramidal side effect of potent classical antipsychotic drugs. Antipsychotic drug-induced dystonia is classified in both acute and tardive forms. The incidence of drug-induced dystonia is associated with the affinity to inhibitory dopamine D2 receptors. Particularly acute dystonia can be treated with anticholinergic drugs, but the tardive form may also respond to such antimuscarinic treatment, which contrasts their effects in tardive dyskinesia. Combining knowledge of the pathophysiology of primary focal dystonia with the anatomical and pharmacological organization of the extrapyramidal system may shed some light on the mechanism of antipsychotic drug-induced dystonia. A suitable hypothesis is derived from the understanding that focal dystonia may be due to a faulty processing of somatosensory input, so leading to inappropriate execution of well-trained motor programmes. Neuroplastic alterations of the sensitivity of extrapyramidal medium-sized spiny projection neurons to stimulation, which are induced by the training of specific complex movements, lead to the sophisticated execution of these motor plans. The sudden and non-selective disinhibition of indirect pathway medium-sized spiny projection neurons by blocking dopamine D2 receptors may distort this process. Shutting down the widespread influence of tonically active giant cholinergic interneurons on all medium-sized spiny projection neurons by blocking muscarinic receptors may result in a reduction of the influence of extrapyramidal cortical-striatal-thalamic-cortical regulation. Furthermore, striatal cholinergic interneurons have an important role to play in integrating cerebellar input with the output of cerebral cortex, and are also targeted by dopaminergic nigrostriatal fibres affecting dopamine D2 receptors.