Efficacy and Safety of Vibegron for Persistent Symptoms of Overactive Bladder in Men Being Pharmacologically Treated for Benign Prostatic Hyperplasia: Results From the Phase 3 Randomized Controlled COURAGE Trial.

PURPOSE: The efficacy and safety of vibegron, a ß3-adrenergic receptor agonist, was assessed among men with symptoms of overactive bladder (OAB) receiving pharmacologic treatment for benign prostatic hyperplasia (BPH) in a phase 3 randomized controlled trial. MATERIALS AND METHODS: Men ≥ 45 years with OAB symptoms and BPH, treated with α-blocker with/without 5α-reductase inhibitors, were randomized 1:1 to vibegron or placebo for 24 weeks. Coprimary end points were change from baseline at week 12 in mean daily micturitions and urgency episodes. Secondary end points were change from baseline at week 12 in mean nightly nocturia and daily urge urinary incontinence episodes, International Prostate Symptom Score‒storage score, and volume voided per micturition. Safety was evaluated via adverse events (AEs). RESULTS: Of 1105 participants randomized, 965 (87.3%) completed the trial. At week 12, vibegron was associated with significant reductions vs placebo in daily micturitions (least squares mean difference [95% CI], -0.74 [-1.02, -0.46]; P < .0001) and urgency episodes (-0.95 [-1.37, -0.54]; P < .0001). Vibegron was also associated with significant improvements vs placebo at week 12 in nocturia episodes (least squares mean difference, -0.22 [-0.36, -0.09]; P = .002), urge urinary incontinence episodes (-0.80 [-1.33, -0.27]; P = .003), International Prostate Symptom Score‒storage scores (-0.9 [-1.2, -0.6]; P < .0001), and volume voided (15.07 mL [9.13-21.02]; P < .0001). AE rates were similar in vibegron (45.0%) and placebo (39.0%) arms; AEs occurring in ≥ 2% of participants were hypertension (9.0% vs 8.3%), COVID-19 (4.0% vs 3.1%), UTI (2.5% vs 2.2%), and hematuria (2.0% vs 2.5%). CONCLUSIONS: In this trial, vibegron met all primary and secondary end points and was safe and well tolerated in men with OAB symptoms and pharmacologically treated BPH.

Comparative Efficacy and Side Effect Profiles of Interventions for Pediatric Saliva Control: A Cohort Study.

OBJECTIVE: To compare efficacy and side effect profile data on conservative, behavioral, pharmacological, and surgical treatments used for pediatric saliva control. STUDY DESIGN: A cohort study of children (n = 483) referred to a specialty Saliva Control service between May 2014 and November 2019 was performed, using quantitative data from pretreatment and post-treatment questionnaires (the Drooling Impact Scale [DIS], Drooling Rating Scale [DRS]) and recording of side effects. Overall, 483 children were included; treatment choices were based on published international guidelines. RESULTS: The greatest improvement was seen after intraglandular botulinum toxin A (BTX-A) injections (n = 207; 551 courses; mean DIS change, 34.7; 95% CI = 29.2-35.7) or duct transpositional surgery (n = 31; mean change in DIS, 29.0; 95% CI, 22.3-35.7). Oral anticholinergics were associated with good outcomes, with no significant statistical difference between glycopyrronium bromide (n = 150; mean DIS change, 21.5; 95% CI, 19.1-24.0) or trihexyphenidyl (n = 87; mean DIS change, 22.4; 95% CI, 18.9-25.8). Inhaled ipratropium bromide was not as efficacious (n = 80; mean DIS change, 11.1; 95% CI, 8.9-13.3). Oromotor programs were used in a selected group with reliable outcomes (n = 9; mean DIS change, 13.0). Side effects were consistent with previous studies. Overall, in cases of milder severity, enterally administered therapies provided a good first-line option. With more severe problems, BTX-A injections or saliva duct transpositional surgery were more effective and well tolerated. CONCLUSIONS: We describe a large, single-center pediatric saliva control cohort, providing direct comparison of the efficacy and side effect profiles for all available interventions and inform clinical practice for specialists when considering different options. BTX-A injections or saliva duct transpositional surgery seem to be more effective for saliva control that is more severe.

A Mediation Analysis Examining High Risk, Anticholinergic Medication Use, Delirium, and Dementia After Major Surgery.

INTRODUCTION: Anticholinergic medications are known to cause adverse cognitive effects in community-dwelling older adults and medical inpatients, including dementia. The prevalence with which such medications are prescribed in older adults undergoing major surgery is not well described nor is their mediating relationship with delirium and dementia. We sought to determine the prevalence of high-risk medication use in major surgery patients and their relationship with the subsequent development of dementia. METHODS: This was a retrospective cohort study which used data between January 2013 and December 2019, in a large midwestern health system, including sixteen hospitals. All patients over age 50 undergoing surgery requiring an inpatient stay were included. The primary exposure was the number of doses of anticholinergic medications delivered during the hospital stay. The primary outcome was a new diagnosis of Alzheimer's disease and related dementias at 1-y postsurgery. Regression methods and a mediation analysis were used to explore relationships between anticholinergic medication usage, delirium, and dementia. RESULTS: There were 39,665 patients included, with a median age of 66. Most patients were exposed to anticholinergic medications (35,957/39,665; 91%), and 7588/39,665 (19.1%) patients received six or more doses during their hospital stay. Patients with at least six doses of these medications were more likely to be female, black, and with a lower American Society of Anesthesiologists class. Upon adjusted analysis, high doses of anticholinergic medications were associated with increased odds of dementia at 1 y relative to those with no exposure (odds ratio 2.7; 95% confidence interval 2.2-3.3). On mediation analysis, postoperative delirium mediated the effect of anticholinergic medications on dementia, explaining an estimated 57.6% of their association. CONCLUSIONS: High doses of anticholinergic medications are common in major surgery patients and, in part via a mediating relationship with postoperative delirium, are associated with the development of dementia 1 y following surgery. Strategies to decrease the use of these medications and encourage the use of alternatives may improve long-term cognitive recovery.

Fragility of overactive bladder medication clinical trials: A systematic review.

PURPOSE: Overactive bladder (OAB) syndrome significantly impairs quality of life, often necessitating pharmacological interventions with associated risks. The fragility of OAB trial outcomes, as measured by the fragility index (FI: smallest number of event changes to reverse statistical significance) and quotient (FQ: FI divided by total sample size expressed as a percentage), is critical yet unstudied. MATERIALS AND METHODS: We conducted a systematic search for randomized controlled trials on OAB medications published between January 2000 and August 2023. Inclusion criteria were trials with two parallel arms reporting binary outcomes related to OAB medications. We extracted trial details, outcomes, and statistical tests employed. We calculated FI and FQ, analyzing associations with trial characteristics through linear regression. RESULTS: We included 57 trials with a median sample size of 211 participants and a 12% median lost to follow-up. Most studies investigated anticholinergics (37/57, 65%). The median FI/FQ was 5/3.5%. Larger trials were less fragile (median FI 8; FQ 1.0%) compared to medium (FI: 4; FQ 2.5%) and small trials (FI: 4; FQ 8.3%). Double-blinded studies exhibited higher FQs (median 2.9%) than unblinded trials (6.7%). Primary and secondary outcomes had higher FIs (median 5 and 6, respectively) than adverse events (FI: 4). Each increase in 10 participants was associated with a +0.19 increase in FI (p < 0.001). CONCLUSIONS: A change in outcome for a median of five participants, or 3.5% of the total sample size, could reverse the direction of statistical significance in OAB trials. Studies with larger sample sizes and efficacy outcomes from blinded trials were less fragile.

Anticholinergic Burden in Patients Treated for Overactive Bladder: Second-Line Therapy with Tibial Nerve Stimulation as a Solution.

Overactive bladder (OAB) is a highly prevalent condition with significant associated comorbidities. Current management guidelines suggest the utilization of anticholinergic medication as a second line after nonpharmacological treatment. Tibial nerve stimulation (TNS), which has previously been thought to have been expensive and inaccessible, was relegated to a third-line therapy. However, given the recently discovered association between anticholinergic medication use and dementia as well as the recent FDA approval of transcutaneous tibial nerve stimulation (TTNS), there may be a need to revisit management guidelines. In this commentary, we identify the two types of TNS, percutaneous tibial nerve stimulation (PTNS) and TTNS and compare them with anticholinergics. By considering their respective efficacies, side-effects profiles, and associated costs, we make the case in this commentary for an update to guidelines that includes TNS as second-line OAB management ahead of anticholinergic medication.

Risk of falls or fall-related injuries associated with potentially inappropriate medication use among older adults with dementia.

BACKGROUND: Potentially inappropriate medications (PIMs) are prevalent in older adults with dementia and subsequent falls or fall-related injuries. The present study determined the risk of falls or fall-related injuries associated with PIM use in older adults with dementia. METHODS: The National Health Insurance Service-Elderly Cohort Database 2.0 (NHIS-ECDB 2.0) was used for this self-controlled case series (SCCS) study. This study included 1430 participants who went through exposure and non-exposure periods of PIM application among patients with dementia and experienced outcome events of falls or fall-related injuries between January 2016 and December 2019. The incidence of falls or fall-related injuries during the exposure and post-exposure periods was compared with that during the non-exposure period. Beers Criteria were used to define PIMs in patients with dementia. Negative binomial regression was conducted. The incidence rate ratio (IRR) was used to determine the risk of falls or fall-related injuries. RESULTS: During the exposure periods in which falls or fall-related injuries occurred, the mean number of PIMs among patients with dementia was 3.76 (SD = 2.99), and the most commonly used PIMs among patients with dementia were first-generation antihistamines (n = 283; 59.1%). Compared to the non-exposure period, the adjusted IRR during the exposure period was 1.57 (95% CI = 1.39-1.76). The risk of falls or fall-related injuries was increased when PIM use in patients with dementia was initiated (1-14 days: IRR = 2.76, 95% CI = 2.31-3.28; 15-28 days: IRR = 1.95, 95% CI = 1.48-2.56; ≥ 29 days: IRR = 1.17, 95% CI = 1.01-1.35). Especially, an increased risk of falls or fall-related injuries was associated with greater PIM use among patients with dementia. CONCLUSION: Among older adults with dementia, PIMs significantly increase the risk of falls and fall-related injuries. Therefore, strategies should be developed to manage PIM prescriptions in patients with dementia to prevent falls.

Topical Anticholinergics in the Management of Focal Hyperhidrosis in Adults and Children. A Narrative Review. / Anticolinérgicos tópicos en el manejo de la hiperhidrosis focal en adultos y niños. Una revisión narrativa.

Hyperhidrosis, or excessive sweating, is characterized by overactivity of the eccrine sweat glands, usually associated with dysfunction of the autonomic nervous system. Primary focal hyperhidrosis is the most common form and can affect the axillae, palms, soles, and/or face, often leading to significantly impaired quality of life and social functioning. Treatment is complex. Topical antiperspirants are normally recommended as the first-line treatment for mild hyperhidrosis. Multiple clinical trials and prospective studies support the efficacy and tolerability of oral and topical anticholinergics in the management of hyperhidrosis. Topical glycopyrronium, which has been investigated in at least 8 clinical trials enrolling more than 2000 patients, is probably the first-line pharmacological treatment for axillary hyperhidrosis in patients with moderate to severe disease poorly controlled with topical antiperspirants. Second-line treatments include botulinum toxin injections, microwave treatment, and oral anticholinergics. We review the use of topical anticholinergics in the management of focal hyperhidrosis in adults and children.

Characteristics of providers who prescribed only anticholinergic medications for overactive bladder in 2020.

BACKGROUND: Pharmacologic therapy for overactive bladder typically includes either an anticholinergic or a beta-3 agonist. Based on research that has demonstrated increased risks of cognitive impairment and dementia associated with anticholinergic use, current guidelines support the use of beta-3 agonists rather than anticholinergics in older patients. OBJECTIVE: This study aimed to describe the characteristics of providers prescribing only anticholinergics to treat overactive bladder in patients aged ≥65 years. STUDY DESIGN: The US Centers for Medicare and Medicaid Services publishes data on medications dispensed to Medicare beneficiaries. Data include the National Provider Identifier of the prescriber and the number of pills prescribed and dispensed for any given medication for beneficiaries aged ≥65 years. We obtained each provider's National Provider Identifier, gender, degree, and primary specialty. National Provider Identifiers were linked to an additional Medicare database that includes graduation year. We included providers who prescribed pharmacologic therapy for overactive bladder in 2020 for patients aged ≥65 years. We calculated the percentage of providers who prescribed only anticholinergics (and did not prescribe beta-3 agonists) for overactive bladder and stratified by provider characteristics. Data are reported as adjusted risk ratios. RESULTS: In 2020, 131,605 providers prescribed overactive bladder medications. Of those identified, 110,874 (84.2%) had complete demographic information available. Although only 7% of providers who prescribed medications for overactive bladder were urologists, prescriptions from urologists accounted for 29% of total prescriptions. Among providers prescribing medications for overactive bladder, 73% of female providers prescribed only anticholinergics, whereas 66% of male providers prescribed only anticholinergics (P<.001). The percentage of providers that prescribed only anticholinergics also varied by specialty (P<.001), with providers specialized in geriatric medicine being least likely to prescribe only anticholinergics (40%), followed by urologists (44%). Nurse practitioners (75%) and family medicine physicians (73%) were more likely to prescribe only anticholinergics. The percentage of providers who prescribed only anticholinergics was the highest for recent medical school graduates and decreased with time since graduation. Overall, 75% of providers within 10 years of graduation prescribed only anticholinergics, whereas only 64% of providers who were >40 years of age from graduation prescribed only anticholinergics (P<.001). CONCLUSION: This study identified considerable differences in prescribing practices based on provider characteristics. Female physicians, nurse practitioners, physicians trained in family medicine, and those who recently graduated from medical school were the most likely to prescribe only anticholinergic medications and not prescribe any beta-3 agonist for the treatment of overactive bladder. This study identified differences in prescribing practices based on provider demographics that may guide educational outreach programs.

Vibegron shows high efficacy in pediatric patients with refractory daytime urinary incontinence.

PURPOSE: Sparse published reports exist nowadays on vibegron and pediatric overactive bladder, so its usefulness of this agent remains unclear. The purpose of this study was to clarify the effectiveness of vibegron for pediatric cases of daytime urinary incontinence (DUI), including refractory cases. METHODS: Participants comprised 57 patients treated with vibegron for DUI from March 2019 to April 2022. To investigate treatment outcomes and risk factors for pediatric patients with refractory DUI, the following factors were evaluated: age at initiatial administration; frequency of DUI; duration of vibegron treatment; presence of neurodevelopmental disorders (NDDs); presence of constipation; and anticholinergic medications before and after initiation of treatment. RESULTS: Patients included 38 boys and 19 girls with a median age at initial administration of 111 months (range: 64-202 months) and a median administration term of 6 months (range: 1-33 months). With treatment for 6 months, the response rate (complete response + partial response) was 68.3%. A total of 24 cases with NDD showed a 72.0% response rate at 6 months. As for the relationship between anticholinergic agents and vibegron, 15 cases were treated with vibegron as the first choice without anticholinergics (First-choice cases), and 33 cases were treated with vibegron alone after switching from anticholinergics (Switch cases). Vibegron was used in combination with anticholinergic agents in 9 cases (Add-on cases). Response rates at 6 months were 85.0% in First-choice cases, 66.3% in Switch cases, and 40.7% in Add-on cases. Univariate analyses failed to identify any significant risk factors for refractory cases. CONCLUSIONS: Vibegron was effective in pediatric cases of DUI, with efficacy demonstrated within a short time in many cases. Vibegron is expected to play a significant role in the treatment of DUI in pediatric cases.

Is anticholinergic and sedative drug burden associated with postdischarge institutionalization in community-dwelling older patients acutely admitted to hospital? A Norwegian registry-based study.

PURPOSE: Investigate the association between anticholinergic (AC) and sedative (SED) drug burden before hospitalization and postdischarge institutionalization (PDI) in community-dwelling older patients acutely admitted to hospital. METHODS: A cross-sectional study using data from the Norwegian Patient Registry and the Norwegian Prescription Database. We studied acutely hospitalized community-dwelling patients ≥70 years during 2013 (N = 86 509). Patients acutely admitted to geriatric wards underwent subgroup analyses (n = 1715). We calculated drug burden by the Drug Burden Index (DBI), use of AC/SED drugs, and the number of AC/SED drugs. Piecewise linearity of DBI versus PDI and a knot point (DBI = 2.45) was identified. Statistical analyses included an adjusted multivariable logistic regression model. RESULTS: In the total population, 45.4% were exposed to at least one AC/SED drug, compared to 52.5% in the geriatric subgroup. AC/SED drugs were significantly associated with PDI. The DBI with odds ratios (ORs) of 1.11 (95% CI 1.07-1.15) for DBI < 2.45 and 1.08 (95% CI 1.04-1.13) for DBI ≥ 2.45. The number of AC/SED drugs with OR of 1.07 (95% CI 1.05-1.09). The AC component of DBI with OR 1.23 and the number of AC drugs with OR 1.13. In the subgroup, ORs were closer to 1 for AC drugs. CONCLUSIONS: The use of AC/SED drugs was highly prevalent in older patients before acute hospital admissions, and significantly associated with PDI. The number, or just using AC/SED drugs, gave similar associations with PDI compared to applying the DBI. Using AC drugs showed higher sensitivity, indicating that to reduce the risk of PDI, a clinical approach could be to reduce the number of AC drugs.

Impact of microbiota and host immunologic response on the efficacy of anticholinergic treatment for urgency urinary incontinence.

INTRODUCTION AND HYPOTHESIS: Studies within the past decade have suggested associations among composition of the urinary microbiota, local immune responses, and urinary incontinence symptoms. To investigate these relationships, we evaluated the structure of the urinary microbiome, local inflammatory markers, and patient responses prior to and at 6-weeks after treatment with anticholinergic medication for urgency urinary incontinence (UUI). METHODS: Using a prospective pilot study, we enrolled women who presented with UUI symptoms and were prescribed treatment with anticholinergics. Catheterized urine samples were collected from participants at their baseline and 6-week follow-up visits for microbiological (standard and 16S rRNA gene phylotyping analyses) and cytokine analysis along with the UDI-6 questionnaire and 2-day bladder diary. RESULTS: Patients were Caucasian, post- menopausal, with a median age of 64 and median BMI of 30.1 kg/m2. Among the patients, 75% had UUI symptoms for less than 2 years, but with a frequency of at least a few times a week or every day. Most women were prescribed 10 mg oxybutynin ER daily at enrollment. Patients had varied urinary microbiota by culture and 16S phylotyping, with species of Lactobacillus being the most common, in six samples, in addition to taxa associated with Enterococcus, Staphylococcus, and mixed flora. Cytokine levels showed no differences before and after treatment with anticholinergics, nor correlation with urinary bacteria or microbiome composition. CONCLUSIONS: Our pilot study suggests factors in addition to the urinary microbiome and local immune responses may be involved in patients' response to anticholinergics for UUI.

Risk of overactive bladder after hysterectomy for uterine fibroids.

INTRODUCTION AND HYPOTHESIS: We evaluated the association between previous hysterectomy for uterine fibroids and the risk of developing overactive bladder (OAB). METHODS: We used national health insurance data. The hysterectomy group (aged 40 to 59) comprised patients who underwent hysterectomy for uterine leiomyoma or adenomyosis between 1 January 2011 and 31 December 2014, and the control group (aged 40 to 59) comprised patients who visited a medical facility for a checkup during the same time period. Propensity score matching (PSM, 1:1) was performed to balance confounders. OAB events were defined by drug prescriptions (beta 3 agonist or anticholinergics) for more than 1 month based on previous studies. RESULTS: After matching, 58,195 cases (hysterectomy group) and 58,195 controls (nonhysterectomy group) were enrolled. The mean follow-up period was 7.9 years in the nonhysterectomy group and 8.0 years in the hysterectomy group. There was no significant difference in the rate of OAB development between the groups (0.3% vs 0.3%; p=0.061). Additionally, compared with the nonhysterectomy group (hazard ratio: 1 (reference)), hysterectomy without adnexal surgery (hazard ratio: 1.169 [0.915-1.493]) and hysterectomy with adnexal surgery (hazard ratio: 1.342 [0.83-2.171]) did not significantly increase the risk of OAB after adjusting for confounders; this relationship remained nonsignificant after stratifying patients according to age group. CONCLUSIONS: Previous hysterectomy with or without adnexal surgery for the treatment of uterine fibroids did not increase the risk of developing OAB, defined as drug therapy lasting more than 1 month.

Extrapyramidal adverse events and anticholinergics use after the long-term treatment of patients with schizophrenia with the new long-acting antipsychotic Risperidone ISM®: results from matching-adjusted indirect comparisons versus once-monthly formulations of Paliperidone palmitate and Aripiprazole monohydrate in 52-week studies.

BACKGROUND: Risperidone ISM® is a newly developed long-acting injectable (LAI) treatment for schizophrenia in adults. In the absence of head-to-head comparisons with other similar antipsychotics, the objective of this study was to generate indirect evidence of some aspects of the safety and tolerability of Risperidone ISM compared to other LAI antipsychotics for treatment of patients with schizophrenia in the maintenance treatment setting. METHODS: A literature review was conducted systematically to identify maintenance treatment studies reporting safety and tolerability outcomes for LAI antipsychotic therapies. Following an assessment of between-trial heterogeneity, a matching-adjusted indirect comparison (MAIC) was performed to account for between-trial imbalances in patient characteristics and to generate comparative evidence for safety and tolerability endpoints. RESULTS: The analysis showed that incidence of extrapyramidal symptoms (EPS) was found to be numerically, but not statistically significantly, lower in patients receiving Risperidone ISM than in those receiving Paliperidone palmitate (PP) (OR [95% CI] 0.63 [0.29, 1.38], p = 0.253) and statistically significantly lower than with Aripiprazole monohydrate once-monthly (AOM) (OR [95% CI] 0.25 [0.12, 0.53], p < 0.001). Use of anticholinergic agents for the alleviation of EPS was also shown to be significantly lower in Risperidone ISM patients than in those receiving PP (OR [95% CI] 0.29 [0.10, 0.83], p = 0.021) or AOM (OR [95% CI] 0.01 [0.003, 0.06], p < 0.001), suggesting a superior tolerability profile for clinically relevant EPS. Results from the sensitivity analyses comparing stabilized and stable patients receiving Risperidone ISM to those receiving AOM yielded similarly favorable conclusions in line with the base case analyses. CONCLUSIONS: This MAIC is consistent with the safety and tolerability results obtained during the PRISMA-3 clinical trial in the long-term treatment of schizophrenia and suggests a favorable safety and tolerability profile in terms of EPS incidence and anticholinergic agent use, relative to other antipsychotic therapies used for treatment of patients with schizophrenia in the maintenance setting.

Persistent use of medical therapy after surgery for lower urinary tract symptoms: a retrospective database analysis.

PURPOSE: To determine how many men are able to remain off of medical therapy for lower urinary tract symptoms (LUTS) following surgery for benign prostatic obstruction (BPO). METHODS: The TriNetX Analytics Network was used to identify men who were taking medical therapy for BPO (at least one of: alpha-1 blockers, anticholinergics, B3 agonists, or 5-alpha-reductase inhibitors) and subsequently underwent surgery for BPO. They were then placed into one of six cohorts, classified based on the type of surgery they received: transurethral resection of the prostate (TURP), Laser vaporization of prostate (PVP), transurethral incision of the prostate (TUIP), prostatic urethral lift (PUL), water-vapor thermal therapy (WV), or Laser enucleation of the prostate (LEP). Our primary outcome was persistent use of medical therapy at 6-months-2-years postoperatively. Secondary outcome was surgical retreatment by 2 years postoperatively. Propensity-score matching (PSM) was used to control for various risk factors for lower urinary tract symptoms (LUTS). RESULTS: A total of 21,475 men were identified who were on medical therapy and subsequently underwent surgery, which included 12,294 TURP, 5290 PVP, 397 WV, 1308 PUL, 346 TUIP, and 1840 LEP. Medication use between 6 months and 2 years after surgery was 38% for LEP, 50% for WV, 61% for TURP, 63% for PUL, 65% for TUIP and 66% for PVP. All surgical modalities had higher odds of using medications when compared to LEP (p < 0.001). This remained significant after PSM for 9 potentially confounding variables. CONCLUSION: A large percentage of men continue medical therapy after surgery for BPO. Amongst multiple surgical modalities available, LEP appears to have the highest rates of medication discontinuation after surgery. In men who wish to avoid medications or who have cardiac risk factors, a discussion with their urologist to select the best option to minimize medical therapy should occur.

Higher anticholinergic burden from medications is associated with significant increase in markers of inflammation in the EPIC-Norfolk prospective population-based cohort study.

BACKGROUND: Higher medication anticholinergic burden is associated with increased risk of cardiovascular disease and cognitive decline. A mechanistic pathway has not been established. We aimed to determine whether inflammation may mediate these associations. METHODS: Participants were drawn from the European Prospective Investigation into Cancer, Norfolk cohort (40-79 years at baseline). Anticholinergic burden score (ACB) was calculated at first (1HC) (1993/97) and second (2HC) (1998/2000) health checks. Fibrinogen and C-reactive protein (CRP) were measured during 1HC and tumour necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) during 2HC. Cross-sectional associations between ACB and inflammatory markers were examined for both health checks. Prospective associations were also examined between 1HC ACB and 2HC inflammatory markers. Models were adjusted for age, sex, lifestyle factors, comorbidities and medications. RESULTS: In total, 17 678 and 22 051 participants were included in cross-sectional analyses for CRP, and fibrinogen, respectively. Furthermore, 5101 participants with data on TNF-α and IL-6 were included in the prospective analyses. Cross-sectionally, compared to ACB = 0, ACB ≥ 4 was associated with higher fibrinogen, beta (95% confidence interval) = 0.134 g/L (0.070, 0.199), CRP 1.175 mg/L (0.715, 1.634), IL-6 0.593 pg/mL (0.254, 0.932) and TNF-α 0.137 pg/mL (0.033, 0.241). In addition, a point increase in ACB was associated with higher levels of all markers. Prospectively, compared to ACB = 0, ACB ≥ 4 was associated with higher IL-6(pg/mL) of 0.019 (-0.323, 0.361) and TNF-α (pg/mL) of 0.202% (0.81, 0.323). A unit increase in ACB was associated with a significantly higher TNF-α and IL-6. CONCLUSION: Higher ACB was associated with higher inflammatory markers. Inflammation may mediate the relationship between anticholinergic medications and adverse outcomes.

Overactive bladder medication prescription trends from 2014 to 2018.

PURPOSE: A growing literature points to an association between overactive bladder (OAB) medications and dementia. Given differences in side effects for extended-release (ER) and immediate-release (IR) anticholinergic formulations and beta-3 agonists, we examined prescription utilization patterns in a national dataset of older adults from 2014 to 2018. METHODS: We performed a retrospective study using the Medicare Part D Drug Spending Dashboard, a publicly available database that includes data from outpatient pharmacy claims from 2014 to 2018 in the United States. We identified total claims and total spending on common OAB medications, and further assessed trends by anticholinergic burden by medication, and immediate and ER formulations. RESULTS: There were 54.1 million claims for OAB medications, accounting for $10.1 billion (2018 United States dollars) in spending from 2014 to 2018. When considering beta-agonist, mirabegron accounted for 13.1% of total claims and 29.0% of total spending. Mirabegron accounted for a greater proportion of OAB medication claims and spending during the 5 years from 5.7% to 20.1% and 11.3% to 44%, respectively. IR anticholinergics accounted for fewer total claims over this period, from 58.5% to 42.6%. ER formulations increased in proportion of all OAB medication total claims from 35.8% to 37.5% from 2014 to 2016, and decreased to 37.3% by 2018. CONCLUSION: OAB medications and expenditures increased from 2014 to 2018. Mirabegron accounted for higher proportions and IR-formulations for decreased proportions of each from 2014 to 2018. The impact on clinical outcomes is a key area for future investigation considering our findings.

The risk of delirium and falls or fractures with the use of overactive bladder anticholinergic medications.

OBJECTIVE: To determine if OAB anticholinergics have an increased risk of delirium or falls/fractures relative to OAB beta-3 agonist medications. METHODS: This was a retrospective, cohort study using linked administrative data from the universal healthcare system of Ontario, Canada. Participants were all residents >66 years of age who newly initiated an OAB medication between January 2016 and March 2020. Coprimary outcomes were evidence of a hospital visit with delirium, or for a fall/fracture. We used matching weights to make the three exposure groups (beta-3 agonist, oxybutynin, or newer OAB anticholinergics) comparable across 82 baseline characteristics. We examined both the risk during the first 30 days (logistic regression) and the risk during continuous usage (proportional hazards). RESULTS: We identified 103 024 older adults who started OAB medications. With matching weights, all measured variables were similar. The 30-day incidence of delirium was 0.31%, and fall/fracture was 1.07%; there was no significantly increased risk of either delirium (oxybutynin users OR 1.28 [95% CI 0.84-1.96], newer OAB anticholinergic users OR 0.92 [95% CI 0.58-1.46]) or falls/fractures (oxybutynin users OR 1.19 [95% CI 0.95-1.49], newer OAB anticholinergic users OR 1.14 [95% CI 0.91-1.43]) compared to beta-3 agonist users. With continuous usage, there was an increased HR of delirium among users of newer anticholinergics (HR 1.13, 95% CI 1.02-1.26) and an increased HR for fall/fracture among oxybutynin users (HR 1.13, 95% CI 1.02-1.24). CONCLUSIONS: Compared to beta-3 agonists, the continuous use of oxybutynin is associated with a significantly increased risk of fall/fracture, and newer OAB anticholinergics are associated with a significantly increased risk of delirium.

Does gabapentin impact response to anticholinergics for overactive bladder?

INTRODUCTION AND HYPOTHESIS: It is unknown whether gabapentin modulates the therapeutic effect of anticholinergics (AC) in patients with overactive bladder. We hypothesized that pre-existing gabapentin use would improve response rates in these patients. METHODS: Female patients treated with AC between 2010-2018 were identified. Data were collected on gabapentin use, indication, dose and duration of use as well as demographic and clinical characteristics. Patients were stratified by those that only took AC and those that took both AC and gabapentin ("combination therapy"). Response was determined through chart review. Descriptive statistics were expressed as medians and interquartile ranges (IQR). Pairwise analysis was performed using Wilcoxon rank-sum. Multivariable logistic regression was used to identify independent variables predicting response. A subgroup analysis was performed in patients with chronic pain disorders. RESULTS: Seven hundred fifty-six subjects met all criteria; 16.5% (n = 125) were on combination therapy. Those taking gabapentin were more likely to have chronic (49.6% vs. 22.5%, p < 0.001) or neuropathic pain (25.6% vs. 9.4%, p < 0.001) and to use narcotics (41.6% vs. 15.5%, p < 0.001). Patients taking combination therapy were not more likely to improve compared to patients taking AC alone (41.6% vs. 47.7%, p = 0.211), which persisted after adjusting for confounders (aOR = 1.02, 95% CI: 0.63-1.65). In the 182 patients with chronic pain, those receiving combination therapy were more likely to respond than those taking AC alone (35.2% vs. 21.9%, p = 0.0015), although this did not persist after adjusting for confounders (aOR = 1.15, 95% CI: 0.70-1.90). CONCLUSIONS: Pre-existing gabapentin use does not seem to influence response to AC in patients with overactive bladder.

Anticholinergics and serious adverse events in pediatric procedural sedation: A report of the pediatric sedation research consortiums.

BACKGROUND: Pediatric sedation is a clinical activity with potential for serious but rare airway adverse events, particularly laryngospasm. Anticholinergic drugs, atropine and glycopyrrolate, are frequently used with the intention to improve sedation safety by virtue of their antisialagogue effects. AIMS: The objective of this study is to describe the current practice of anticholinergic use in pediatric sedation and to compare the frequency of serious sedation-related adverse events in patients who received anticholinergics to those who did not. METHODS: We examined prospectively collected data from the Pediatric Sedation Research Consortium database. Patient characteristics, procedure type, sedation provider, sedatives, location of sedation, anticholinergic administered, adverse events, and airway interventions were reported. Propensity score matching and multivariable logistic regression were used to test whether any association exists between anticholinergic use and serious sedation-related adverse events. RESULTS: Anticholinergics were administered in 7.1% (n = 18 707) of all cases (n = 263 883) reported between November 2011 and October 2017. When anticholinergics were used, atropine was used in 22% (n = 4111) and glycopyrrolate in 78.1% (n = 14 601) of sedations. Use of anticholinergics was more common in patients with well-described risk factors for airway adverse events: active/history of upper respiratory infection, history of reactive airway disease/asthma, and exposure to smoke. However, infants and ASA 3 patients were not associated with higher rate of anticholinergic use. Anticholinergic use was independently associated with an increase in the odds of serious adverse events, OR 1.8 (95% CI 1.6-2.1), especially airway adverse events. CONCLUSIONS: In this large Pediatric Sedation Research Consortium study, we found the use of anticholinergic adjuvants independently associated with greater odds of serious adverse events, especially airway adverse events, after adjusting for well-known sedation risk factors using propensity score matching and multivariate analysis.

A study to translate and validate the Thai version of the Victoria Respiratory Congestion Scale.

PURPOSE: Few clinical tools are available to objectively evaluate death rattles in palliative care. The Victoria Respiratory Congestion Scale (VRCS) was adapted from the Back's scale, which has been widely utilized in research and clinical practice. The VRCS will be translated into Thai and research will be conducted to determine its validity and reliability in assessing death rattles in palliative care. METHODS: Two qualified language specialists converted the original tool into Thai and then back to English. Between September 2021 and January 2022, a cross-sectional study was undertaken at a palliative care unit at Ramathibodi Hospital to determine the Thai VRCS's validity and reliability. Two evaluators independently assessed the volume of secretion noises using the Thai VRCS. The criterion-related validity of VRCS was determined by calculating the correlation between the sound level obtained with a standard sound meter and the VRSC scores using Spearman's correlation coefficient method. To assess inter-rater reliability and agreement measurement on ratings, we utilized a two-way random-effects model with Cohen's weighted kappa agreement. RESULTS: Forty patients enrolled in this study with a mean age of 75.3 years. Fifty-five percent had a cancer diagnosis. Spearman's rho correlation coefficient was found to be 0.8822, p < 0.05, indicating a highly significant link. The interrater reliability analysis revealed that the interrater agreement was 95% and the Cohen's weighted kappa agreement was 0.92, indicating near-perfect agreement. CONCLUSIONS: Thai VRCS demonstrated excellent criteria-related validity and interrater reliability. Using the Thai VRCS to assess adult palliative care patients' death rattles was recommended.