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Background: Overactive bladder (OAB) is characterized by urgency and frequency with (OAB wet) or without (OAB dry) urge urinary incontinence (UUI). In the phase 3 EMPOWUR trial, vibegron-a selective β 3 -adrenergic receptor agonist for the treatment of OAB-significantly improved daily number of urgency episodes and micturitions vs. placebo ( P  < 0.01). These post hoc analyses aimed to compare the efficacy of vibegron vs. placebo in OAB dry and wet populations., Methods: Patients were randomly assigned 5:5:4 to receive once-daily vibegron 75 mg, placebo, or tolterodine 4 mg extended release, respectively, for 12 weeks. Baseline criteria for OAB dry included an average of ≥8 micturitions, ≥3 urgency episodes, and <1 UUI episode per diary day and for OAB wet included an average of ≥8 micturitions and ≥1 UUI episode per diary day. Change from baseline in mean daily number of urgency episodes and micturitions was assessed in both populations., Results: Of the 1463 patients included in the full analysis set, 336 (23%) had OAB dry (vibegron, N  = 123; placebo, N  = 115; and tolterodine, N  = 98), and 1127 (77%) had OAB wet (vibegron, N  = 403; placebo, N  = 405; and tolterodine, N  = 319). Vibegron was associated with significant reductions (95% CIs of the least squares mean differences [LSMD] does not include 0) from baseline at week 12 vs. placebo in mean daily urgency episodes for the dry (LSMD [95% CI], ‒1.0 [‒2.0, ‒0.1]) and wet (‒0.6 [‒1.0, ‒0.1]) populations. Vibegron was associated with significant reductions from baseline at week 12 vs. placebo in mean daily micturitions for the dry (LSMD [95% CI], ‒0.8 [‒1.5, ‒ 0.1]) and wet (‒0.5 [‒0.8, ‒0.1]) populations. There were no significant differences in either outcome between tolterodine and placebo for either the dry or wet populations in this study., Conclusions: In this subgroup analysis from the EMPOWUR trial, vibegron was associated with significant reductions compared with placebo in urgency episodes and micturitions in both the OAB dry and wet populations, suggesting that vibegron is similarly efficacious for these endpoints in patients with and without UUI. This trial is registered with NCT03492281., Competing Interests: DS is an advisor for Astellas, Urovant Sciences, and UroCure; a meeting participant, lecturer, and investigator for Astellas and Urovant Sciences; and holds other interests in UroCure. JF is an investigator for Urovant Sciences, an investigator and speaker for Astellas Pharma and Pfizer Inc., and a speaker for Tolmar Inc. SV is a consultant and speaker for Urovant Sciences, a principal investigator for Clinical Research Consulting, and holds academic positions at Sacred Heart University and the University of Bridgeport. MK has received grant and/or research study funding from Allergan, Amphora, Astellas, Axonics, Boston Scientific, Coloplast, Cook Myosite, Dignify Therapeutics, EBT Medical, FemPulse, Ipsen, Taris, and Uro1 and is a consultant for Allergan, Astellas, Boston Scientific, Coloplast, Laborie, and Urovant Sciences. DKN is a consultant for Urovant Sciences. MR is a consultant and speaker for Urovant Sciences; a consultant and speaker for Astellas Pharma; and a consultant for Ferring. DDS, RJ, and PNM were employees of Urovant Sciences at the time the work was conducted., (Copyright © 2022 David Staskin et al.)

Introduction: Reductions in bothersome symptoms of overactive bladder (OAB) demonstrate improvement in clinical trials, but patient perception of meaningfulness of such improvement is lacking. In the 12-week phase 3 EMPOWUR trial, vibegron significantly reduced average daily number of micturitions, urgency episodes, and urge urinary incontinence (UUI) episodes vs placebo (P < 0.01 each). This analysis assessed meaningfulness of reductions in clinical endpoints observed in EMPOWUR using patient perception of improvement., Methods: An anchor-based approach using Patient Global Impression of Change (PGI-C) applied to phase 2 data allowed predefining phase 3 responder definitions. To confirm in phase 3, median change from baseline at week 12 in average daily number of micturitions, urgency episodes, and UUI episodes was generated for each PGI-C category and pooled across treatments. Based on predefined meaningful responder definitions, percentages of patients achieving ≥ 15% reduction in micturitions (post hoc), ≥ 50% reduction in urgency episodes (predefined), and ≥ 75% (predefined) and ≥ 90% (post hoc) reduction in UUI episodes were determined for patients receiving vibegron or placebo., Results: Across treatments, for micturitions, urgency episodes, and UUI episodes, median change from baseline to week 12 increased with greater subjective improvement based on PGI-C scores, and median reductions pooled across treatment groups were higher than the responder definitions that patients perceived as improved. Significantly more patients receiving vibegron vs placebo achieved ≥ 15% reduction in micturitions (56.3% vs 44.6%, respectively), ≥ 50% reduction in urgency episodes (39.5% vs 32.8%), ≥ 75% reduction in UUI episodes (49.3% vs 32.8%), and ≥ 90% reduction in UUI episodes (35.2% vs 23.5%) at week 12 (P < 0.05 each)., Conclusion: Significantly more patients treated with vibegron vs placebo in EMPOWUR achieved meaningful reductions in micturitions, urgency episodes, and UUI episodes that were associated with patient-perceived improvement. Results of these analyses support the meaningfulness of reductions in clinical endpoints observed in the 12-week EMPOWUR trial., Clinical Trials Registration: ClinicalTrials.gov identifier, NCT03492281., (© 2021. The Author(s).)

Combination treatment, i.e., the use of two or more drugs for the same condition, is frequent in medicine if monotherapy yields an insufficient therapeutic response. We review and challenge clinical study designs and formats of reporting outcomes for the evaluation of the benefit/risk ratio of combination treatment over monotherapy. We demonstrate that benefits of combination treatment at the group level overestimate the probability of benefit at the single patient level based on outcome simulations under almost any imaginable setting. Based on these findings, we propose that studies testing combination treatment should always report on percentages of responders to monotherapy and combination treatment. We provide equations that allow the calculation of the percentage of patients truly benefitting from combination (responders to both monotherapies) and that of patients exposed to risk of harm from adverse effects without a reasonable expectation of individual benefit. These considerations are explained based on real clinical data, mostly from the field of functional urology (male lower urinary tract symptoms).

Competing Interests: Conflict of interest statement: The author disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: D.S. is an advisor for Astellas, NewUro, Stimwave, UroCure, and Urovant Sciences; a meeting participant/lecturer and investigator for Astellas and Urovant Sciences; and holds other interests in UroCure.

Purpose: The long-term safety, tolerability and efficacy of vibegron in adults with overactive bladder were evaluated in the 40-week phase 3 EMPOWUR extension study., Materials and Methods: Patients who completed 12 weeks of once-daily vibegron 75 mg or tolterodine 4 mg extended release in EMPOWUR continued double-blind treatment; patients who completed 12 weeks of placebo were randomly assigned 1:1 to receive double-blind vibegron or tolterodine. The primary outcome was safety, measured by incidence of adverse events. Secondary outcomes included change from baseline at week 52 in average daily number of micturitions and urgency episodes (all patients), and urge and total urinary incontinence episodes (patients with overactive bladder wet) based on 7-day diary data., Results: Of 506 patients randomized 505 received ≥1 dose of medication, and 430 (85%) completed the study. A total of 12 patients (2.4%) discontinued owing to adverse events. The most common adverse events with vibegron/tolterodine (>5% in either group) were hypertension (8.8%/8.6%), urinary tract infection (6.6%/7.3%), headache (5.5%/3.9%), nasopharyngitis (4.8%/5.2%) and dry mouth (1.8%/5.2%). Improvements in efficacy end points were maintained for patients receiving vibegron for 52 weeks; least squares mean change from baseline to week 52 in micturitions was ‒2.4 for vibegron vs ‒2.0 for tolterodine; in urge urinary incontinence episodes ‒2.2 vs ‒1.7 (p <0.05); in urgency episodes ‒3.4 vs ‒3.2; and in total incontinence episodes ‒2.5 vs ‒1.9 (p <0.05). Among patients with overactive bladder wet 61.0% receiving vibegron experienced ≥75% reduction in urge urinary incontinence episodes after 52 weeks of treatment vs 54.4% with tolterodine, while 40.8% vs 34.2% experienced a 100% reduction., Conclusions: Vibegron demonstrated favorable long-term safety, tolerability and efficacy in patients with overactive bladder, consistent with results of the 12-week study.

Background: Quality of life (QOL) can be significantly impacted by symptoms of overactive bladder (OAB). Vibegron is a highly selective β 3 -adrenergic receptor agonist that showed efficacy in treatment of symptoms of OAB in the randomised, double-blind, placebo- and active-controlled phase 3 EMPOWUR trial. Here we report patient-reported QOL outcomes from the EMPOWUR trial., Methods: Patients were randomly assigned 5:5:4 to receive vibegron 75 mg, placebo or tolterodine 4 mg extended release, respectively, for 12 weeks. Patients completed the OAB questionnaire (OAB-q) at baseline and at week 12 and the patient global impression (PGI) scales for severity, control, frequency and leakage at baseline and at weeks 4, 8 and 12. Change from baseline at week 12 and responder rates (OAB-q: patients achieving a ≥10-point improvement; PGI: patients reporting best possible response) were assessed. Vibegron was compared with placebo, and no comparisons were made between vibegron and tolterodine., Results: Of the 1518 patients randomised, 1463 (placebo, n = 520; vibegron, n = 526; tolterodine, n = 417) had evaluable data for efficacy measures and were included in the analysis. Mean baseline OAB-q and PGI scores were comparable among treatment groups. At week 12, patients receiving vibegron had greater improvements from baseline in OAB-q subscores of coping, concern, sleep, health-related QOL total and symptom bother (P < .01 each) compared with patients receiving placebo; a greater proportion of patients receiving vibegron vs placebo were responders in the OAB-q coping (P < .05) and symptom bother scores (P < .0001). Compared with placebo, a greater proportion of patients who received vibegron achieved the best response on all PGI end-points at week 12 (P < .05 each) and were classified as responders (P < .05 each)., Conclusions: In the 12-week EMPOWUR trial, treatment with vibegron was associated with significantly greater and clinically meaningful improvement in OAB-q and PGI scores compared with placebo, consistent with improvements in OAB symptoms., Clinical Trial Registration: ClinicalTrials.gov identifier number NCT03492281., (© 2020 The Authors. International Journal of Clinical Practice published by John Wiley & Sons Ltd.)

Background: Overactive bladder (OAB) is common among older adults. The efficacy and safety of vibegron for the treatment of OAB were demonstrated in the international, phase III EMPOWUR trial. This subpopulation analysis from EMPOWUR assessed the efficacy and safety of vibegron in patients aged ≥ 65 and ≥ 75 years., Methods: In EMPOWUR, patients with OAB were randomly assigned 5:5:4 to receive once-daily vibegron 75 mg, placebo, or tolterodine 4 mg extended release, respectively, once daily for 12 weeks. Coprimary efficacy endpoints were change from baseline at week 12 in average daily number of micturitions and urge urinary incontinence (UUI) episodes; a key secondary efficacy endpoint was change from baseline at week 12 in average daily number of urgency episodes. Safety was assessed through adverse events (AEs). Efficacy analyses compared vibegron with placebo; no efficacy comparisons were made between vibegron and tolterodine., Results: Of the 1463 patients with evaluable efficacy data, 628 patients were aged ≥ 65 years, and 179 were aged ≥ 75 years. After 12 weeks, patients treated with once-daily vibegron 75 mg in both age subgroups showed significant improvements from baseline versus placebo in all three symptoms of OAB: daily micturitions (≥ 65 years, P < 0.0001; ≥75 years, P < 0.05), UUI episodes (≥ 65 years, P < 0.001; ≥ 75 years, P < 0.0001), and urgency episodes (≥ 65 years, P < 0.01; ≥ 75 years, P < 0.01). Significant reductions from baseline versus placebo in daily micturitions, UUI episodes, and urgency episodes were observed beginning at week 2 for patients aged ≥ 65 years treated with vibegron. In patients aged ≥ 65 years, 50.0% of those receiving vibegron versus 29.8% receiving placebo experienced a ≥ 75% reduction in UUI episodes at week 12 (P < 0.0001). Rates of cardiovascular-associated AEs were low for patients receiving vibegron (<2% of patients in either age subgroup) and similar to rates in patients receiving placebo. In patients aged ≥ 65 years, hypertension was reported by 1.2%, 3.1%, and 2.9% of patients receiving vibegron, placebo, and tolterodine, respectively; in patients aged ≥ 75 years, hypertension was reported by 1.3%, 3.3%, and 2.1%, respectively., Conclusions: In this subpopulation analysis of patients with OAB aged ≥ 65 and ≥ 75 years from the EMPOWUR study, once-daily vibegron 75 mg showed rapid onset and robust efficacy versus placebo and was generally safe and well tolerated, consistent with results from the overall population., Trial Registration: ClinicalTrials.gov identifier NCT03492281; registered April 10, 2018.

Background: In older patients with overactive bladder (OAB), mirabegron, a β 3 -adrenoreceptor agonist, represents an alternative treatment that may have a favorable risk-benefit profile., Objectives: Our objective was to further examine the safety and tolerability of mirabegron versus placebo treatment in patients aged ≥ 65 years with OAB-wet., Methods: We conducted a 12-week, double-blind, randomized, placebo-controlled phase IV study to compare mirabegron with placebo. Community-dwelling patients aged ≥ 65 years with OAB-wet (one or more incontinence episode and three or more urgency episodes, and an average of eight or more micturitions/24 h over a 3-day diary) were randomized to receive placebo or mirabegron 25 mg/day (optional dose escalation to 50 mg/day at week 4 or 8). Safety analyses were performed for adverse events (AEs) and vital signs on all randomized patients who received one or more dose of study drug., Results: Treatment-emergent AEs (TEAEs), the majority mild or moderate in severity, were reported in 39.4% of placebo patients and 44.2 and 49.8% of those who received mirabegron 25 mg or 50 mg, respectively. The most common TEAEs in mirabegron-treated patients were urinary tract infection, headache, and diarrhea. The incidence of TEAEs was slightly higher in mirabegron patients aged ≥ 75 years than in those aged < 75 years. There were no clinically meaningful differences in changes in vital signs from baseline to end of treatment for any treatment group, and no differences were observed between mirabegron and placebo treatment groups. TEAEs tended to occur early post exposure and were not dose related., Conclusions: Mirabegron treatment was well-tolerated in older adults with OAB-wet. Safety and tolerability were consistent with the known mirabegron safety profile., Trial Registration: This study is registered at ClinicalTrials.gov: NCT02216214.

Purpose: We assessed efficacy, safety and tolerability of vibegron, a novel, potent, highly selective β 3 -adrenoceptor agonist, administered 12 weeks at 75 mg once daily to patients with overactive bladder in an international phase III trial with placebo and active control., Materials and Methods: Adult patients with overactive bladder with 8.0 or more micturitions per day were randomized 5:5:4 to 75 mg vibegron, placebo or extended-release 4 mg extended-release tolterodine. Up to 25% of patients could have dry overactive bladder (less than 1.0 urge incontinence episode per day). Patients completed 7-day voiding diaries at baseline and weeks 2, 4, 8 and 12., Results: Of 1,518 randomized patients 90.4% completed the trial. At 12 weeks micturitions decreased by an adjusted mean of 1.8 episodes per day for vibegron vs 1.3 for placebo (p <0.001, co-primary end point) and 1.6 for tolterodine. Among incontinent patients urge incontinence episodes decreased by an adjusted mean 2.0 episodes per day for vibegron vs 1.4 for placebo (p <0.0001, co-primary end point) and 1.8 for tolterodine. Moreover, vibegron was statistically significantly superior to placebo for key secondary measures of number of urgency episodes, volume per micturition and proportion of incontinent patients with a 75% or greater reduction in urge incontinence episodes (all p <0.01). Among vibegron treated patients 1.7% discontinued treatment because of adverse events vs 1.1% for placebo and 3.3% for tolterodine. Incidence of hypertension was 1.7% for vibegron and for placebo., Conclusions: Once daily 75 mg vibegron provided statistically significant reductions in micturitions, urgency episodes and urge incontinence, and increased the volume per micturition. Treatment was well tolerated with a favorable safety profile.

Purpose: PLUS investigated the efficacy and safety of mirabegron add-on therapy in men with overactive bladder symptoms receiving tamsulosin for underlying lower urinary tract symptoms attributable to benign prostatic hyperplasia., Materials and Methods: In this phase 4 study a 4-week 0.4 mg tamsulosin run-in period was followed by a 12-week, randomized, double-blind, treatment period in which patients initially received 25 mg mirabegron or placebo add-on therapy. At 4 weeks doses were titrated to 50 mg mirabegron or placebo equivalent. Efficacy end points were changes from baseline to end of treatment in mean number of micturitions per day (primary), mean volume voided per micturition, number of urgency episodes per day, total urgency and frequency score, and total International Prostate Symptom Score (secondary). Safety assessments included treatment emergent adverse events, and post-void residual volume, and maximum urinary flow measurements., Results: Of the 676 men most were 65 years old or older (380, 56.2%). Tamsulosin plus mirabegron was statistically superior to tamsulosin plus placebo in reducing the mean number of micturitions per day (-2.00 vs -1.62; adjusted difference -0.39; 95% CI -0.76, -0.02). Statistically superior results were noted for tamsulosin plus mirabegron in mean volume voided per micturition, urgency episodes per day, and total urgency and frequency score (not International Prostate Symptom Score). Higher overall treatment emergent adverse event rates were observed with tamsulosin plus placebo, although higher rates of drug related treatment emergent adverse events were noted with tamsulosin plus mirabegron. Urinary retention rates were higher in the tamsulosin plus mirabegron group. Post-void residual volume and maximum urinary flow results were not clinically meaningful., Conclusions: The results of PLUS underscore the utility of mirabegron add-on therapy to treat men with overactive bladder symptoms receiving tamsulosin for benign prostatic hyperplasia.

Background: Antimuscarinics are often used for treatment of overactive bladder (OAB), but exposure to medications such as antimuscarinics that have anticholinergic properties has been linked to adverse cognitive effects. A phase 4 placebo-controlled study (PILLAR; NCT02216214) described the efficacy and safety of mirabegron, a β 3 -adrenoreceptor agonist, for treatment of wet OAB in patients aged ≥65 years. This pre-planned analysis aimed to measure differences in cognitive function between mirabegron and placebo, using a rapid screening instrument for mild cognitive impairment: the Montreal Cognitive Assessment (MoCA)., Methods: Outpatients aged ≥65 years with wet OAB were randomized 1:1 to mirabegron or placebo, stratified by age (<75/≥75 years). There were no exclusion criteria regarding cognitive status. Patients randomized to mirabegron initially received 25 mg/day with an optional increase to 50 mg/day after week 4/8 based on patient/investigator discretion. The MoCA was administered at baseline and end of treatment (EoT, week 12). The study protocol was Independent Ethics Committee/Institutional Review Board-approved., Results: Of the 887 randomized patients who received ≥1 dose of study drug, 72.3% were female, 79.5% were white, and 28.1% were aged ≥75 years. All patients had ≥1 comorbidity and 94.3% were receiving ≥1 concomitant medication. One third of patients had a history of psychiatric disorders, the most common being depression (17.2%), insomnia (15.7%), and anxiety (11.4%). Baseline mean (standard error, SE) MoCA total scores were 26.9 (0.1) and 26.8 (0.1) in the mirabegron and placebo groups, respectively. Among patients with MoCA data available at baseline/EoT, 27.1% (115/425) and 25.8% (106/411) of mirabegron and placebo group patients, respectively, had impaired cognitive function at baseline (MoCA total score <26). There was no statistically significant change in adjusted mean (SE) MoCA total score from baseline to EoT in the mirabegron group (-0.2 [0.1]) or the placebo group (-0.1 [0.1])., Conclusions: Treatment with mirabegron for 12 weeks did not contribute to drug-related cognitive side effects in patients aged ≥65 years, as measured by the MoCA. Furthermore, the pattern of change in cognition over time in an older OAB trial population does not appear to differ from that of subjects receiving placebo., Trial Registration: NCT02216214 (prospectively registered August 13, 2014).

Background: The majority of patients with overactive bladder (OAB) are aged >65yr. There has been no prospectively designed study assessing treatment efficacy with the β3-adrenoreceptor agonist, mirabegron, specifically in this age group., Objective: A phase IV study comparing flexibly dosed mirabegron versus placebo in elderly patients with OAB and urgency incontinence., Design, Setting, and Participants: Community-dwelling patients aged ≥65yr with OAB for ≥3mo., Intervention: Following a 2-wk placebo run in, patients with one or more incontinence episodes, three or more urgency episodes, and an average of eight or more micturitions/24h were randomised 1:1 to double-blind 25mg/d mirabegron or matched placebo, for 12wk. After week 4 or 8, the dose could be increased to 50mg/d mirabegron/matched placebo based on patient and investigator discretion., Outcome Measurements and Statistical Analysis: Coprimary endpoints: change from baseline to end of treatment (EOT) in the mean numbers of micturitions/24h and incontinence episodes/24h. Secondary endpoints: change from baseline to EOT in the mean volume voided/micturition, mean number of urgency episodes/24h, and mean number of urgency incontinence episodes/24h. Analysis of covariance (ANCOVA) was used for the mean number of micturitions/24h, mean volume voided/micturition, and mean number of urgency episodes/24h. Stratified rank ANCOVA was used for the mean numbers of incontinence episodes/24h and urgency incontinence episodes/24h., Results and Limitations: Statistically significant improvements were observed for mirabegron versus placebo in change from baseline to EOT in the mean number of micturitions/24h, mean number of incontinence episodes/24h, mean volume voided/micturition, mean number of urgency episodes/24h, and mean number of urgency incontinence episodes/24h. Safety and tolerability were consistent with the known mirabegron safety profile., Conclusions: Mirabegron efficacy, safety, and tolerability over 12 wk were confirmed in patients aged ≥65yr with OAB and incontinence., Patient Summary: We examined the effect of mirabegron compared with placebo in people aged 65yr or older with overactive bladder and incontinence. Mirabegron improved the symptoms of overactive bladder compared with placebo. Side effects were similar to those already known for mirabegron., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Mirabegron, a β3-adrenoreceptor agonist, is an alternative drug to antimuscarinics for overactive bladder (OAB) symptoms., Objective: To summarise safety and efficacy reporting of mirabegron treatment for OAB symptoms., Design, Setting, and Participants: Pooled data analysed from 10 phase 2-4, double-blind, 12-wk mirabegron monotherapy studies in adults with OAB who had received one or more doses of study drug., Intervention: Mirabegron: 25 and 50mg; antimuscarinics: solifenacin (2.5, 5, and 10mg) and tolterodine extended release (4mg)., Outcome Measurements and Statistical Analysis: Baseline OAB-related characteristics, intrinsic and extrinsic factors, and analyses by age (<65 vs ≥65yr and <75 vs ≥75yr) and sex were assessed. Solifenacin 2.5 and 10mg groups were not included in the efficacy analyses (small patient numbers). Safety was evaluated using the proportion of treatment-emergent adverse events. Efficacy variables were derived from bladder diaries (baseline and week 12)., Results and Limitations: Baseline hypertension and diabetes were more frequent across treatment groups in the older versus younger age groups and in men versus women. Within sexes, frequencies were similar between treatment groups. Some differences were observed in baseline characteristics, including type of incontinence and medical history between sexes. No previously unreported safety concerns were identified. Improvements in efficacy (mean number of incontinence episodes/24h, micturitions/24h, urgency episodes/24h, volume voided/micturition, and nocturia episodes) versus placebo were observed in all treatment groups. Significant treatment-by-subgroup interactions included change from baseline in the mean number of incontinence episodes/24h by age (<65 vs ≥65yr), nocturia by age (<65 vs ≥65yr and <75 vs ≥75yr), and urgency episodes by previous OAB medication., Conclusions: Data from this integrated database of 10 mirabegron studies reaffirm the safety and efficacy profiles of mirabegron, solifenacin, and tolterodine in adults of different age groups and sexes., Patient Summary: Overactive bladder is a complex of symptoms including a compelling desire to pass urine that leads to increased frequency, which may lead to a degree of incontinence if you do not reach the toilet in time and may wake you from sleep. We pooled data from 10 different studies of mirabegron in patients with overactive bladder symptoms, and looked at the effect in the total number of patients who received the treatment, as well as in different age groups and between men and women. No new safety concerns were identified, and mirabegron improved the symptoms of overactive bladder., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Context: Oral pharmacotherapy consisting of antimuscarinics, β3-adrenoreceptor agonists, or combinations of these agents forms the mainstay of overactive bladder (OAB) management., Objective: To evaluate the efficacy and safety of combination therapy in patients with OAB., Evidence Acquisition: A literature search was conducted in June 2018 using Embase, MEDLINE, and Cochrane databases via Ovid and relevant congress abstracts. Studies reporting the efficacy/safety of two antimuscarinics or a β3-adrenoreceptor agonist plus an antimuscarinic were included., Evidence Synthesis: Publications reported on clinical efficacy, safety, and health-related quality of life (HRQoL) for mirabegron (M) plus solifenacin (S) from three 12-wk randomised controlled trials (RCTs)-SYMPHONY, SYNERGY, and BESIDE-and a 12-mo RCT, SYNERGY II. SYMPHONY reported statistically significant improvements in clinical symptoms and HRQoL with combination therapy versus solifenacin 5 mg (S5) and placebo. In SYNERGY, there were consistent improvements in urinary incontinence (UI) episodes/24 h and micturitions/24 h (coprimary endpoints), and in secondary efficacy parameters with mirabegron 25 mg (M25) + S5 and mirabegron 50 mg (M50) + S5 versus respective monotherapies. In patients with an inadequate response to S5 monotherapy (BESIDE), greater improvements in UI (primary endpoint) were noted for M50 + S5 versus S5 (p = 0.001). Combination therapy was noninferior to solifenacin 10 mg (S10) for reduction in UI and superior to S10 for improvement in micturition frequency (p < 0.001), and resulted in greater improvements from baseline in OAB-5 Dimension scores versus S5 and S10 (p < 0.01). In SYNERGY II, clinically meaningful and sustained improvements in clinical outcomes were observed for M50 + S5 versus M50 or S5. Combination therapy was well tolerated in all four trials. The incidence of adverse events (AEs) was similar across groups, and there were no notable differences in the incidence of specific AEs. Positive efficacy outcomes were observed in five studies of dual antimuscarinic therapy (trospium + solifenacin)., Conclusions: Mirabegron plus solifenacin provides effective, well-tolerated treatment for patients with OAB. Limited data for dual antimuscarinic therapy suggest a benefit in patients with moderate-to-severe symptoms., Patient Summary: Overactive bladder (OAB) is treated with medicines called antimuscarinics, such as solifenacin, propiverine, or trospium, or another β-adrenoreceptor agonist medicine called mirabegron, which works in a different way. We looked at published scientific studies of patients with OAB treated with mirabegron plus solifenacin together, or with two antimuscarinics. We found that mirabegron plus solifenacin can help reduce symptoms and improve quality of life. Patients tolerate this treatment well, with few patients experiencing side effects., (Copyright © 2019. Published by Elsevier B.V.)

Background: The PREFER study was an assessment of medication tolerability, treatment preference and symptom improvement during treatment with mirabegron (M) and tolterodine (T) extended release (ER) in patients with overactive bladder (OAB). In this analysis of PREFER, patient-reported outcomes (PROs) were assessed during treatment., Methods: PREFER was a two-period, 8-week crossover, double-blind, phase IV study (NCT02138747) of treatment-naïve adults with OAB ≥3 months randomized to 1 of 4 treatment sequences (M/T; T/M; M/M; T/T), separated by a 2-week washout. Tolterodine ER was dosed at 4 mg for 8 weeks and mirabegron was dosed at 25 mg for 4 weeks then increased to 50 mg for the next 4 weeks. At each visit, PROs related to treatment satisfaction, quality of life and symptom bother were assessed using the OAB Satisfaction (OAB-S; 3 independent scales/5 single-item overall assessments), OAB-q (total health-related QoL [HRQoL] and subscales [Sleep, Social, Coping, Concern] and Symptom Bother scale) and Patient Perception of Bladder Condition (PPBC) questionnaires. Responder rates were reported for OAB-q subscales based on a minimal important difference (MID; ≥ 10-point improvement) and OAB-S Medication Tolerability score ≥ 90., Results: In total, 358 randomized patients received ≥1 dose of double-blind study medication and completed ≥1 post-baseline value (OAB-S scale, OAB-q, PPBC): M/T (n = 154), T/M (n = 144), M/M (n = 30) or T/T (n = 30). At end of treatment (EoT), mirabegron and tolterodine ER were associated with similar mean improvements in 7 of the 8 OAB-S scores investigated, OAB-q scales and PPBC. A higher percentage of patients achieved clinically relevant improvements (MID) in OAB-q scales and OAB-S Medication Tolerability score during treatment with mirabegron than tolterodine ER., Conclusions: On average, patients with OAB experienced improvements in treatment satisfaction, HRQoL and symptom bother that were of a similar magnitude during treatment with mirabegron or tolterodine ER. However, during mirabegron treatment, patients were more likely to achieve clinically relevant improvements in tolerability and HRQoL (as measured by the MID for the OAB-q or an OAB-S Medication Tolerability score ≥ 90) than during tolterodine ER treatment., Trial Registration: NCT02138747 ; registered May 13, 2014.

Introduction and Hypothesis: The objective of this study was to assess the tolerability and treatment preference in patients with overactive bladder (OAB) treated with mirabegron or tolterodine., Methods: This was a two-period, 8-week crossover, double-blind, phase IV study (PREFER; NCT02138747) in treatment-naive adults with OAB for 3 months or longer randomized to one of four treatment sequences in a 5:5:1:1 ratio (mirabegron/tolterodine, tolterodine/mirabegron, mirabegron/mirabegron, or tolterodine/tolterodine), separated by a washout period of 2 weeks. The primary endpoint was drug tolerability using the Medication Tolerability scale of the OAB Treatment Satisfaction (OAB-S) questionnaire at end of treatment (EoT). Period-by-treatment interactions were analyzed to determine any effect of drug order. Patient preference, change from baseline in OAB symptoms, and treatment-emergent adverse events (TEAEs) were assessed., Results: A total of 358 randomized patients completed the OAB-S Medication Tolerability scale questionnaire at one or more visits after the baseline evaluation. The mean (95% CI) OAB-S Medication Tolerability scores were significantly higher (better tolerability) for mirabegron (86.29 [83.50, 89.08]) than for tolterodine (83.40 [80.59, 86.20]; p = 0.004). The period-by-treatment interaction was not significant (p = 0.955). Improvements in OAB-S Medication Tolerability scores at EoT were more evident in women, patients aged ≥65 years, and in patients without baseline incontinence, and were greater with mirabegron than with tolterodine extended release. There were no significant differences in patient preference or improvements in OAB symptoms. Significant differences in favor of mirabegron were observed for anticholinergic TEAEs (20.4% vs. 27.4%; p = 0.042) and specifically for gastrointestinal disorders (14.7% vs. 22.5%; p = 0.015)., Conclusions: Tolerability of mirabegron was significantly higher than that of tolterodine, and patient preference and improvements in OAB symptoms were comparable. Both treatments were well tolerated; however, anticholinergic side effects were higher with tolterodine.

Aims: To evaluate patient-reported outcomes (PROs) of combinations of solifenacin and mirabegron compared with solifenacin and mirabegron monotherapy and with placebo in patients with overactive bladder (OAB) from the SYNERGY trial., Methods: Following a 4-week placebo run-in, period patients (≥18 years) with OAB were randomized 2:2:1:1:1:1 to receive solifenacin 5 mg + mirabegron 25 mg (combination 5 + 25 mg), solifenacin 5 mg + mirabegron 50 mg, (combination 5 + 50 mg), solifenacin 5 mg, mirabegron 25 mg, mirabegron 50 mg or placebo for 12 weeks, followed by a 2-week washout period. At each visit, PROs related to quality of life, symptom bother, and treatment satisfaction were assessed, including OAB-q Symptom Bother score, health-related quality of life (HRQOL) Total score, treatment satisfaction-visual analogue scale (TS-VAS), and patient perception of bladder condition (PPBC) questionnaires., Results: Overall, 3527 patients were randomized into the study, with 3494 receiving double-blind treatment. At end of treatment (EoT), both combination groups showed greater improvements in OAB-q Symptom Bother score compared with the monotherapy groups (nominal P < 0.001). Statistically significant improvements in HRQOL Total scores were observed in the combination groups versus monotherapy groups (P ≤ 0.002). For both combination groups, the OAB-q Symptom Bother score responder rates at EoT were statistically significantly higher versus mirabegron monotherapy (P < 0.05). The mean adjusted changes from baseline to EoT for PPBC were greater in the combination groups compared with monotherapy groups., Conclusions: PROs showed that combination therapy provided clear improvements and an additive effect for many HRQOL parameters, including OAB-q Symptom Bother score, HRQOL Total score, and PPBC., (© 2017 Wiley Periodicals, Inc.)

Background: Combining the β3-adrenoceptor agonist mirabegron and the antimuscarinic (AM) agent solifenacin may improve efficacy in the treatment of overactive bladder (OAB) while reducing the AM side effects., Objective: The primary objective was to evaluate the efficacy of combinations of solifenacin/mirabegron compared with solifenacin 5mg monotherapy. The secondary objective was to explore the dose-response relationship and the safety/tolerability compared with placebo and monotherapy., Design, Setting, and Participants: A phase 2, factorial design, randomised, double-blind, parallel-group, placebo- and monotherapy-controlled trial, conducted at 141 sites in 20 European countries. Male and female patients were aged ≥18 yr with symptoms of OAB for ≥3 mo., Intervention: A total of 1306 patients (66.4% female) were randomised to 12 wk of treatment in 1 of 12 groups: 6 combination groups (solifenacin 2.5, 5, or 10 mg plus mirabegron 25 or 50 mg), 5 monotherapy groups (solifenacin 2.5, 5, or 10 mg, or mirabegron 25 or 50 mg), or placebo., Outcome Measurements and Statistical Analysis: Change from baseline to end of treatment in mean volume voided per micturition (MVV) (primary end point) and mean numbers of micturitions per 24 h, incontinence episodes per 24 h, and urgency episodes per 24 h were analysed using an analysis of covariance model. Safety assessments included treatment-emergent adverse events (TEAEs), blood pressure, pulse rate, postvoid residual (PVR) volume, and laboratory and electrocardiography (ECG) parameters., Results and Limitations: Compared with solifenacin 5 mg monotherapy, all combinations with solifenacin 5 or 10 mg significantly improved MVV, with adjusted differences ranging from 18.0 ml (95% confidence interval [CI], 5.4-30.0) to 26.3 ml (95% CI, 12.0-41.0). Three combination groups significantly reduced micturition frequency compared with solifenacin 5 mg, ranging from -0.80 (95% CI, -1.39 to -0.22) to -0.98 (95% CI, -1.68 to -0.27). Five of six combinations significantly reduced urgency episodes compared with solifenacin 5 mg, ranging from -0.98 (95% CI, -1.78, to -0.18) to -1.37 (95% CI, -2.03 to -0.70). No dose-related trends in TEAEs, blood pressure, pulse rate, PVR volume, or laboratory or ECG parameters were observed between combination and monotherapy groups, although the incidence of constipation was slightly increased with combination therapy., Conclusions: Combination therapy with solifenacin/mirabegron significantly improved MVV, micturition frequency, and urgency compared with solifenacin 5 mg monotherapy. All combinations were well tolerated, with no important additional safety findings compared with monotherapy or placebo., Patient Summary: To improve treatment of overactive bladder (OAB), mirabegron/solifenacin in combination was compared with each drug alone and placebo. Combination therapy improved OAB symptoms and had similar safety and acceptability., Trial Registration: Clinical trials.gov: NCT01340027., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction and Hypothesis: The Actionable Bladder Symptom Screening Tool (ABSST) was initially developed to identify patients with multiple sclerosis (MS) who could benefit from lower urinary tract assessment and treatment. Assessment of the measurement properties of the ABSST, including its ability to identify patients experiencing bladder symptoms related to overactive bladder (OAB), was undertaken in a general female population., Methods: One hundred women completed the ABSST, OAB Questionnaire Short Form (OAB-q SF), and a patient global impression of severity (PGI-S) scale. Half of the sample had urgency urinary incontinence (UUI), while the other half did not. Descriptive statistics, reliability, and validity were examined, as was sensitivity and specificity of the previous cut-off score established in MS., Results: Fifty-three women with UUI/OAB and 47 controls took part (71.0 % Caucasian). Patients with UUI/OAB were older (54.6 vs 40.4 years), had a higher body mass index (31.1 vs 26.4 kg/m(2)), and more comorbid conditions. The Cronbach's alpha reliability of ABSST was 0.90. High correlations with OAB-q SF Symptom Bother and Health Related Quality of Life (r = 0.83 and -0.81 respectively) supported concurrent validity. Using the PGI-S severity scores as a reference, the ABSST was able to distinguish patients with differing severity levels (known-group validity). Physician assessment of the need for further evaluation/treatment showed sensitivity (79 %) and specificity (98 %), supporting a cut-off score of ≥3., Conclusions: The previous MS ABSST scoring algorithm was validated in a non-neurogenic female population. ABSST is a reliable, valid, and sensitive tool for screening women with UUI/OAB.

The primary care provider is in an optimal position to identify and care for the patient affected by prostate-related lower urinary tract symptoms (BPH-LUTS). This assessment can be readily accomplished with a good history and only a few simple, in-office tests. In some instances, the primary care provider may believe that they do not have the experience, comfort level or time to perform an adequate evaluation of the problem. Therefore, in this article, we describe the function of the lower urinary tract, as well as the rationale behind the medical history, examination and tests needed in order to diagnose and treat, or refer, the patient presenting with BPH-LUTS. We will also update the literature-based STEP (simplified treatment of the enlarged prostate) approach, which was initially published in 2009, to include recently described therapeutic options.

Sling surgery has supplanted other anti-incontinence procedures as the treatment of choice for stress urinary incontinence. Iatrogenic obstruction after sling surgery is increasingly reported as the procedure becomes more and more popular. The rate of retention (defined as catheter-dependency for at least 28 days) has been estimated at 1-10%. Iatrogenic obstruction after sling surgery has a variable presentation and can include urinary urgency, urgency incontinence, hesitancy, straining to void, weak urinary stream, nocturia, incomplete emptying, frequency, dysuria or urinary tract infections. The evaluation and diagnosis rely upon a thorough patient history, physical examination, a urine flow test and postvoid residual volume. Cystoscopy and pressure-flow studies can also be considered. The single most important factor in the diagnosis of sling-related obstruction or voiding dysfunction is the temporal relationship between the sling procedure and onset of symptoms. Transient urinary retention can be managed with indwelling or intermittent catheter drainage. For those patients with moderate or symptomatic retention, surgical options for treatment include sling loosening, sling incision, sling excision, and urethrolysis.

Whilst symptoms of bladder outlet obstruction (BOO) and post micturition symptoms are more commonly reported in men a significant number of women may also complain of voiding dysfunction. However, despite the recent advances in the standardisation of terminology of lower urinary tract dysfunction there remains a lack of consensus regarding a precise diagnosis and definition of voiding abnormalities in women. In addition voiding symptoms may co-exist with storage symptoms as well as those associated with urinary incontinence. Consequently many patients present with a spectrum of different urinary symptoms, related to both storage and voiding, which may be multifactorial in origin or be related to one another. The purpose of this paper is to review the current literature in order to accurately define and classify female voiding dysfunction including causes and aetiology. In addition to reviewing the investigation and management of those women with voiding dysfunction recommendations are proposed for management in clinical practice as well as suggestions for future research., (Copyright © 2012 Wiley Periodicals, Inc.)

Aims: To characterize the response to fesoterodine treatment for overactive bladder (OAB) in subjects who did or did not choose to dose escalate in a flexible-dose study., Methods: Subjects were randomized to fesoterodine 4  mg or placebo. At week 2, subjects could remain on 4  mg (non-escalators) or choose to increase to 8  mg (escalators) for the remaining 10 weeks (sham escalation for placebo). Subjects completed 3-day bladder diaries at baseline, week 2 and week 12 noting micturitions, urgency episodes, and urgency urinary incontinence (UUI) episodes., Results: Sixty-three per cent of 438 subjects randomized to fesoterodine and 73% of 445 randomized to placebo dose escalated. At baseline, fesoterodine escalators had significantly more micturitions and urgency episodes than fesoterodine non-escalators (P < 0.001); at week 2, before dose escalation, diary-dry rate and improvement in micturitions and urgency episodes were significantly greater among fesoterodine non-escalators versus escalators (P < 0.001); and by week 12, after dose escalation, diary-dry rate and improvements in micturitions and UUI episodes were similar between fesoterodine non-escalators and escalators (P > 0.05). The placebo escalator group did not demonstrate a similar response over placebo non-escalators following the dose escalation decision point., Conclusion: A rapid and robust response to fesoterodine 4  mg was demonstrated in non-escalators. Subjects who chose to dose escalate to fesoterodine 8  mg at week 2 showed significant improvement by week 12 versus baseline and week 2 (prior to escalation), as well as versus placebo. Dose escalation to 8  mg fesoterodine provided subjects with efficacy and tolerability similar to those who were satisfied with the 4-mg dose., (Copyright © 2011 Wiley Periodicals, Inc.)

Aims: To report the conclusions of the Think Tank on mechanisms of incontinence and surgical cure in female and male SUI: surgical research initiatives during the ICI-RS meeting in 2010., Methods: The sub-group considered five areas for future research in stress urinary incontinence (SUI); (i) epidemiology and public health efforts in SUI, (ii) the basic sciences examining the physiology and pathophysiology of the continence mechanism, (iii) diagnostic techniques and clinical assessment of SUI, (iv) the future of treatment and surgical cure, and (v) the separate issue of male SUI., Results: Roadblocks to progress were identified for each of the five directions., Conclusions: Future research directions are suggested for each of these areas., (Copyright © 2011 Wiley-Liss, Inc.)

Background: Fesoterodine is an antimuscarinic for the treatment of overactive bladder, a syndrome of urgency, with or without urgency urinary incontinence (UUI), usually with increased daytime frequency and nocturia. Our objective was to develop predictive models to describe the dose response of fesoterodine., Methods: Data from subjects enrolled in double-blind, placebo-controlled phase II and III trials were used for developing longitudinal dose-response models., Results: The models predicted that clinically significant and near-maximum treatment effects would be seen within 3 to 4 weeks after treatment initiation. For a typical patient with 11 micturitions per 24 hours at baseline, predicted change was -1.2, -1.7, and -2.2 micturitions for placebo and fesoterodine 4 mg and 8 mg, respectively. For a typical patient with 2 UUI episodes per 24 hours at baseline, predicted change was -1.05, -1.26, and -1.43 UUI episodes for placebo and fesoterodine 4 mg and 8 mg, respectively. Increase in mean voided volume was estimated at 9.7 mL for placebo, with an additional 14.2 mL and 28.4 mL for fesoterodine 4 mg and 8 mg, respectively., Conclusions: A consistent dose response for fesoterodine was demonstrated for bladder diary endpoints in subjects with overactive bladder, a result that supports the greater efficacy seen with fesoterodine 8 mg in post hoc analyses of clinical trial data. The dose-response models can be used to predict outcomes for doses not studied or for patient subgroups underrepresented in clinical trials., Trial Registration: The phase III trials used in this analysis have been registered at ClinicalTrials.gov (NCT00220363 and NCT00138723).

Oxybutynin, an antimuscarinic agent, is well established for the treatment of overactive bladder (OAB) and is the gold standard for the treatment of severe neurogenic bladder. Although oral oxybutynin is effective in relieving the urinary symptoms of OAB, medication adherence is low at least in part because of substantial anticholinergic adverse effects. The poor anticholinergic tolerability has been attributed to high circulating levels of N-desethyloxybutynin (DEO), a pharmacologically active product of presystemic metabolism of oral oxybutynin in the liver and gastrointestinal tract. Transdermal formulations of oxybutynin avoid first-pass metabolism and thereby produce lower DEO plasma concentrations. Oxybutynin chloride topical gel (OTG) (Gelnique(R), Watson Pharmaceuticals, Corona, CA, USA), a new gel-based transdermal formulation of oxybutynin, was approved by the U.S. Food and Drug Administration in January 2009. Results of a placebo-controlled U.S. phase III study demonstrated that OTG is efficacious in relieving symptoms of OAB and is associated with a low incidence of anticholinergic adverse events. Patients may find that OTG, with its excellent efficacy, convenient once-daily application and outstanding tolerability profile, is a valuable alternative to oral antimuscarinic agents for the treatment of OAB., (Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.)

The adoption of evidence-based medicine (EBM) recommendations in female pelvic surgical technique and surgical device intervention is contingent upon the availability of EBM and the willingness and ability of practitioners to accept and implement the recommendations. It can be assumed that there is virtually no disagreement among either the practitioners or the experts who practice the craft with regard to the benefits of applying scientific and clinical data that can be obtained from prior and ongoing experience to the selection of current treatments. However, there is significant controversy regarding the existence of adequate "evidence" and the mechanism for developing and applying the recommendations that can be distilled from the available data., ((c) 2010 Wiley-Liss, Inc.)

Objective: Fesoterodine is an antimuscarinic agent indicated for the treatment of overactive bladder (OAB) symptoms. The objective of this study was to evaluate the efficacy of fesoterodine versus placebo over selected intervals during a 24-hour period in subjects with OAB., Research Design and Methods: In a post hoc analysis, data were analyzed from two randomized, double-blind, placebo-controlled 12-week phase III trials in which subjects with a history of OAB symptoms for >or=6 months were treated with morning doses of fesoterodine 4 mg, fesoterodine 8 mg, or placebo., Clinical Trial Registration: These trials are registered at ClinicalTrials.gov (NCT00220363 and NCT00138723)., Main Outcome Measures: Changes were evaluated in number of micturitions, urgency episodes, urgency urinary incontinence (UUI) episodes, and mean voided volume (MVV) divided into three 8-hour intervals: 08:00-15:59 (daytime), 16:00-23:59 (evening), and 00:00-07:59 (nighttime). Comparisons with placebo were made using analysis of covariance (for least squares mean changes) and Wilcoxon rank sum test (for median percent changes); differences were considered significant at p < 0.05., Results: Data from 1674 subjects, 80% of whom were women, were included in the analysis. At the end of treatment, the least squares mean change from baseline for all efficacy endpoints was significantly greater with fesoterodine 4 mg and fesoterodine 8 mg compared with placebo during each 8-hour time interval (all p < 0.05). Median percent change in number of micturitions, urgency episodes, and UUI episodes also was significantly greater with both fesoterodine doses compared with placebo during all time intervals (all p < 0.05)., Conclusions: Fesoterodine 4 mg and 8 mg given once daily demonstrated efficacy over placebo for OAB symptoms during all three 8-hour intervals of a 24-hour period, thus providing clinical support for once-daily dosing. Limitations include that this was a post hoc analysis.

Purpose: An extended release formulation of trospium chloride was recently developed for the once daily treatment of overactive bladder. We investigated the safety, efficacy and tolerability of 60 mg trospium chloride once daily., Materials and Methods: Subjects with overactive bladder were randomized 1:1 to receive 60 mg trospium chloride once daily or placebo in this 12-week multicenter, parallel, double-blind, placebo controlled trial. Primary end points were calculated changes in diary recorded daily urinary frequency and daily urgency urinary incontinence episodes. Secondary end points were urgency severity, volume voided per void and the number of urgency voids per day. Safety was assessed by clinical examination, adverse event monitoring, clinical laboratory values and resting electrocardiograms., Results: Overall 601 subjects were prescribed trospium once daily (298) or placebo (303). Trospium once daily treatment resulted in significant improvements over placebo in all primary and key secondary efficacy outcomes at weeks 1 through 12. The most common adverse events were dry mouth (trospium 8.7% vs placebo 3%) and constipation (trospium 9.4% vs placebo 1.3%). Central nervous system adverse events were rare (headache with trospium 1.0% vs placebo 2.6%). No clinically meaningful changes in laboratory, physical examination or electrocardiogram parameters were noted., Conclusions: Trospium once daily provided significant improvements in overactive bladder symptoms (frequency, urgency urinary incontinence and urgency). Efficacy was similar to that seen previously with trospium chloride twice daily, while class effect anticholinergic adverse events occurred at comparatively low levels. Dry mouth was elicited at the lowest reported rate in the oral antimuscarinic drug class.

Purpose of Review: Mixed incontinence remains a problematic issue in clinical practice. Interventions designed to benefit one of the contributory symptoms often do no benefit the other constituent symptom. Recent evolution in the taxonomy of mixed incontinence as well as the increased reporting of standardized results has produced a better understanding of the response of this entity to clinical interventions., Recent Findings: Three main areas of development have occurred in the analysis of mixed incontinence. The advancements in definitional and taxonomic changes have clarified the concept and presentation of mixed incontinence. In light of these changes, results reported from pharmacologic or surgical interventions have improved. Several new studies have demonstrated the efficacy of these interventions in selected groups of patients using either pharmacologic or operative modalities., Summary: In well selected and symptomatically characterized patients, therapy directed at mixed incontinence can provide efficacious results. The implications of these positive outcomes suggest that therapy founded on appropriate symptomatic appraisal can produce generally salubrious outcomes. These outcomes must, however, be assessed with tools that allow adequate differentiation of symptomatic changes including methods that delineate not only cure but also symptom improvement.

The safety and efficacy of oxybutynin transdermal delivery system (oxybutynin-TDS) versus placebo in adults with urge and mixed urinary incontinence was investigated using combined results from double-blind stages of 2 phase 3 clinical trials. Study 1: placebo-controlled, parallel-group comparison of 3 oxybutynin-TDS doses in 12-week double-blind and open-label periods, followed by a 28-week open-label extension. Study 2 was a 12-week randomized, double-blind, placebo-controlled comparison of oxybutynin-TDS versus long-acting tolterodine and placebo, followed by a 52-week open-label extension. Efficacy analysis included 241 patients receiving oxybutynin-TDS, 244 receiving placebo. Most participants were Caucasian women (92%). Approximately 60% received prior anticholinergic therapy. Primary outcome was determined by changes from baseline to end of treatment in frequency of incontinence episodes, frequency of urination, and void volume. Oxybutynin-TDS was significantly more effective than placebo in reducing median daily incontinence episodes (-3.0 vs placebo -2.0; P=.00004) and daily urinary frequency (-2.0 vs -1.0; P=.0023), and in increasing void volume (25 mL vs 5.5 mL; P<.00001). Overall rates of anticholinergic adverse events (AEs) were 12.8% for oxybutynin-TDS and 11.0% for placebo (P=0.5421). The most common systemic anticholinergic AEs were dry mouth (7.0% for oxybutynin-TDS vs 5.3% for placebo) and constipation (2.1% vs 2.0%). Application site erythema occurred in 7.0% of participants who received oxybutynin-TDS (3.7% discontinuation rate); pruritus occurred in 16.1% (3.3% discontinuation rate). Transdermal oxybutynin was shown to be efficacious, with a proven safety profile. It may be utilized for patients with overactive bladder as a treatment option that could enhance compliance.

Purpose: To our knowledge there is no index in urology that yields a single, quantifiable and clinically interpretable measure of overactive bladder (OAB) symptoms, including urgency, 24-hour voiding frequency and urge urinary incontinence (UUI). Urgency is the most difficult of these symptoms to measure. The Indevus Urgency Severity Scale (Indevus Pharmaceuticals, Lexington, Massachusetts) was recently developed and validated to capture urgency severity per toilet void. The scale has been combined with 24-hour frequency and UUI episodes to create the OAB Symptom Composite Score (OAB-SCS). We present this composite score., Materials and Methods: Two multicenter trials were performed to determine the effects of trospium chloride given as 20 mg tablets vs placebo. A total of 1,157 patients, including 581 who received placebo and 576 who received trospium, were randomly assigned to treatment. Daily OAB-SCS totals were obtained for each patient for each day during the 7-day diary collection period for every visit., Results: The average baseline OAB-SCS value was 36. The mean change from baseline in the trospium and placebo groups was 5 and 1 OAB-SCS points in patients with mild OAB, 10 and 5 in patients with moderate OAB, and 13 and 9 in patients with severe OAB, respectively., Conclusions: The OAB-SCS discriminated between placebo and pharmacologically treated (trospium chloride) patients with OAB in this study. The OAB-SCS is an improvement over individual symptoms alone. It is easy to implement and interpret and it will prove to be a clinically relevant tool in clinical trials in which patient diary data are captured.

Lower urinary tract symptoms (LUTS) in men may arise from a variety of underlying causes, including benign prostatic hyperplasia. LUTS may have a significant component of storage symptoms (urgency, frequency, urge incontinence) at presentation; however, the absence of overactive bladder (OAB) symptoms does not necessarily imply pure outlet obstruction nor does their presence indicate the lack thereof. Symptomatic correlates to urodynamic findings are high when considering isolated OAB symptoms. However, mixed presentations or more overtly obstructive scenarios have less correlation with baseline symptom appraisal instruments. The ideal approach for diagnosis and management is predicated on a graded approach, with more invasive evaluation withheld for those men in whom presumptive therapy fails or who present with associated complex symptoms and in whom a higher level of intervention is being considered. The increasing incidence of LUTS with age implies a partial detrusor contribution, which must be considered in the overall management schema.

Urinary loss (flow) results from a relative lack of CM resistance with respect to the intravesical pressure. Surgical stabilization of the continence mechanism, at the level of the bladder neck or mid-urethra, compensates for the existing loss of urethral support and function by creating new zones for compression, absorption of transmitted pressure, and the preservation of sphincteric configuration. Our understanding of the pathophysiology of stress incontinence and the basis for surgical compensation continues to evolve. Mid-urethral complex support procedures have stimulated further investigation into the mechanics of continence.

Oxybutynin chloride (Ditropan, Alza) is widely regarded as the most efficient antimuscarinic agent for the treatment of bladder detrusor dysfunction resulting in urinary urgency, frequency and urge incontinence. Oxybutynin metabolism occurs primarily in the proximal gastrointestinal tract and the hepatic circulation and is mediated by the cytochrome P450 3A4 isozyme. The major degradation products are desethyloxybutynin, which possesses pharmacological activity, and phenylcyclohexylglycolic acid, which is metabolically inert. A major limitation to long-term compliance with immediate-release oxybutynin remains the necessity for twice- or thrice-daily dosing regimens to provide sustained pharmacological efficacy. Side effects induced by cytochrome P450 metabolism of oxybutynin into the primary metabolite desethyloxybutynin within the gut wall substantially affect the tolerability of the compound within the individual. The oral osmotic delivery system provides unique advantages for drug delivery and substantially alters the tolerability profile of the oxybutynin chloride compound. This extended-release formulation consists of a two component core encapsulated by a semi-permeable membrane. The osmotic gradient between the surrounding environment and the inner core of the delivery system remains constant and water absorption within the capsule is controlled by the semipermeable membrane causing a controlled release of drug, which is sustained over 24 h. Herein are reviewed the various pre- and post-approval trials which have documented the overall therapeutic index of the oral osmotic oxybutynin (Ortho-McNeil Pharmaceuticals). Subsequent post-market surveillance issues are reviewed as are new developments in oxybutynin delivery.

Objective: To compare the efficacy and tolerability of extended-release oxybutynin chloride and tolterodine tartrate at 12 weeks in participants with overactive bladder., Subjects and Methods: The OBJECT (Overactive Bladder: Judging Effective Control and Treatment) study was a prospective, randomized, double-blind, parallel-group study conducted between March and October 2000 at 37 US study sites. Participants who had between 7 and 50 episodes of urge incontinence per week and 10 or more voids in 24 hours received extended-release oxybutynin, 10 mg/d, or tolterodine, 2 mg twice daily. The outcome measures were the number of episodes of urge incontinence, total incontinence, and micturition frequency at 12 weeks adjusted for baseline., Results: A total of 315 women and 63 men were randomized and treated, and 332 participants (276 women, 56 men) completed the study. At the end of the study, extended-release oxybutynin was significantly more effective than tolterodine in each of the main outcome measures: weekly urge incontinence (P=.03), total incontinence (P=.02), and micturition frequency episodes (P=.02) adjusted for baseline. Both drugs improved symptoms of overactive bladder significantly from baseline to the end of the study as assessed by the 3 main outcome measures (P<.001). Dry mouth, the most common adverse event, was reported by 28.1% and 33.2% of participants taking extended-release oxybutynin and tolterodine, respectively (P=.32). Rates of central nervous system and other adverse events were low and similar in both groups., Conclusions: Extended-release oxybutynin was more effective than tolterodine as measured by end-of-study urge incontinence, total incontinence, and micturition frequency episodes. Both groups had similar rates of dry mouth and other adverse events.

The geriatric population presents a unique challenge to the health care provider. The incidence of common lower urinary tract disorders, such as benign prostatic hypertrophy (BPH), prostate cancer and incontinence increase dramatically with aging. In their more severe forms, these disorders may predispose to hydronephrosis and ultimately to renal deterioration. This review of lower urinary tract and ureterovesical junction (UVJ) physiology and pathophysiology, will focus on: (1) anatomic UVJ obstruction from prostate cancer, or severe bladder hypertrophy, (2) functional obstruction from compression or stretching of the UVJ during bladder distention from urinary retention, and (3) bladder decompensation in the female. We will present a diagnostic and treatment algorithm and discuss future trends in the geriatric population. Clearly, the geriatric health care provider always must consider the lower urinary tract when confronted with acute renal deterioration, because prompt diagnosis and treatment of significant, lower-urinary-tract disease can maximize recovery of renal function.

Objectives: To assess the long-term results of a transvaginal endoscopic Gore-Tex patch sling in women with genuine stress urinary incontinence due to urethral hypermobility and/or intrinsic sphincter deficiency, with or without coexistent urge incontinence., Methods: Between December 1989 and June 1994, we performed a Gore-Tex patch sling procedure in 141 consecutive women. All patients had documented stress urinary incontinence on preoperative videourodynamic testing. We conducted outcomes analysis using the information from postoperative office visits, detailed chart reviews, patient questionnaires, and telephone surveys., Results: A complete follow-up was available in 90 patients. The mean follow-up was 51 months (range 27 to 84). Their mean age was 54.2 years (range 32 to 86). Stress incontinence was completely cured in 80 (88.9%) of 90 patients. Pure stress incontinence persisted in 4 (4.4%) of 90 patients. Mixed incontinence occurred in 6 (6.7%) of 90 patients. Pure urge incontinence was experienced by 16 (17.8%) of 90 patients. Six patients required incision of the Gore-Tex patch for obstruction or retention; 3 remain continent. Five patients developed vaginal granulation tissue requiring Gore-Tex patch removal; 1 remains continent. There was no bladder or urethral erosion., Conclusions: The transvaginal Gore-Tex patch sling has provided durable efficacy with minimal morbidity for the treatment of stress urinary incontinence due to anatomic urethral hypermobility and/or intrinsic sphincter deficiency.

Purpose: We identify a provocative maneuver to enhance the sensitivity of cystometry in detecting detrusor instability when urge incontinence is suspected based on clinical history., Materials and Methods: A total of 134 consecutive women with clinical urge incontinence underwent carbon dioxide cystometry between August 1995 and October 1996. The bladder was filled to maximal capacity with the patient supine. Six provocative maneuvers were performed consecutively to evoke detrusor instability, including lying supine, rising to a seated position, walking toward the bathroom, handwashing, coughing and sitting on the toilet with instructions not to void. Subjects were divided into 2 groups depending on the order of maneuvers. Sitting on the toilet was the last maneuver for group 1 (80 patients) and was in the middle of the sequence for group 2 (54)., Results: Sitting on the toilet evoked detrusor instability in 37.5% of group 1 and 53.8% of group 2. This maneuver with instructions not to void was the most provocative stimulus in eliciting detrusor instability with a detection rate of 68.4% for all subjects., Conclusions: Sitting on the toilet with the bladder at maximal capacity is the most provocative maneuver for detecting detrusor instability. The incidence of suspected detrusor instability is enhanced by using this test during routine cystometry.

Despite the prevalence of urinary incontinence, most affected women don't seek help, primarily because of embarrassment or because they are not aware that effective treatment is available. Failure to store urine may be caused by an abnormality in any component of the lower urinary tract. Common abnormalities are poor bladder compliance and bladder outlet failure. Patients who experience failure to empty can present with recurrent urinary tract infections, retention or incontinence. Using a symptom-based classification of incontinence, this would be referred to as overflow incontinence. Other possible categories of urinary incontinence are failure to store and empty and functional incontinence. A combination of a failure to store and empty is difficult to diagnose and treat clinically. Treatments are directed at the particular cause of incontinence and can include medical or surgical therapies.

Objectives: To determine the efficacy of daily or every-other-day electrical stimulation in treating detrusor instability (urge) or urge plus genuine stress (mixed) urinary incontinence in women., Methods: A multicenter, prospective, nonrandomized study enrolled subjects with urge and mixed urinary incontinence assigned to daily or every-other-day treatments (15 minutes twice daily) using pelvic floor stimulation. Outcome measures assessed were (1) leakage episodes, nocturnal episodes, voiding frequency, total voids, and pad count, and (2) patient subjective assessment and quality of life., Results: Seventy-two subjects were enrolled. Sixty-eight subjects completed the 20-week protocol: 33 treated daily and 35 treated every other day. The entire study group (n = 68) experienced a significant decrease in total leaks (P < 0.001), nocturnal episodes (P = 0.001), pad count (P = 0.002), and total voids (P = 0.003) and on visual analog scales. Sixty-nine percent (n = 46) of subjects with urge or mixed incontinence were cured or improved by at least 50%, with 28% (n = 19) being cured. There were no significant differences between daily and every-other-day users. Nonresponse was correlated with number of previous therapies (P < 0.001) and number of vaginal deliveries (P = 0.007). Overall, subjects were 93% compliant with device use, and 72% (n = 47) were satisfied with the therapy., Conclusions: Twenty weeks of pelvic floor electrical stimulation therapy is effective in treating urge and mixed urinary incontinence, regardless of daily or every-other-day treatments.

Purpose: We investigated patient satisfaction with a reusable undergarment for urinary incontinence., Subjects and Setting: One hundred seventy-five participants with reported urinary incontinence from two urology-based clinics at large teaching hospitals and one prostate cancer support group participated in the study., Methodology: Each participant was given a minimum of one reusable undergarment for urinary incontinence. Participants used the undergarment for an average of 10 days (range 1 to 60 days). During the trial period, subjects alternated the reusable undergarment with their previous urine-containment devices, usually disposable pads, while the undergarment was being washed. Patient satisfaction was evaluated with a questionnaire., Primary Outcome Measures: Patient satisfaction with the reusable undergarment was measured for six categories: (1) physical comfort, (2) ability to keep skin dry, (3) ability to prevent wet spots, (4) discretion, (5) odor control, and (6) confidence when wearing the garment versus previously used containment devices., Results: Of the 175 subjects, 126 (33% female and 67% male) completed and returned the 7-page questionnaire. All respondents reported at least one urinary incontinent episode while wearing the reusable undergarment. Occurrence and degree of leakage by self-report varied from light leakage (33%) to moderate leakage (48%) and heavy leakage (17%). Patient satisfaction was measured as follows: (1) 83% rated the overall comfort of the undergarment as very good or excellent; (2) 52% said they felt very dry or dry when wearing the product after an incontinent episodes; (3) 75% rated the ability to prevent wet spots on outer clothing as adequate or excellent; (4) 75% rated the discretion of this product as excellent; (5) 80% rated the ability to control odor as adequate or excellent; and (6) 67% felt more confidence with this reusable undergarment than with other products with which they were familiar., Conclusion: The reusable garment provided effective containment from urine loss among this group of incontinent women and men.

In this era of rapid, scientific medical advances, we still live with the myth that urinary incontinence should be accepted as a normal part of aging. Urinary incontinence, however, should not be considered a disease but rather a symptom or sign of an underlying problem. Patients with urinary incontinence now have many places to turn for advice and medical treatment. In addition to urologists, gynecologists, and geriatricians, nurses are actively involved in the evaluation and management of patients with urinary incontinence. The purpose of this article is to outline a systematic nursing approach to the evaluation, diagnosis, and treatment of patients with urinary incontinence in an office setting.

The first hydraulic artificial urinary sphincter came into clinical use in 1972. The original prototype has undergone many modifications resulting from advances in mechanical design, applications of new technology, and clinical experience. This evolutionary process has culminated in the AS800, the most frequently used hydraulic artificial urinary sphincter in the U.S. today. Although the AS800 device most closely approximates the biological urinary sphincter, clinical demands for an ever more ideal urinary sphincter require the ongoing improvement of this device.

Pelvic floor muscle exercises are recommended as an initial treatment to women with stress urinary incontinence. This treatment is often unsuccessful because of patient noncompliance. A post-test, experimental control group design was used to examine Pender's (1992) concept of an external cue to action, an audiocassette tape, to enhance patient compliance to pelvic floor exercises. Eighty-six women with urodynamically evaluated stress urinary incontinence participated through a Pelvic Floor Exercise Unit at a large teaching hospital. Patients received biofeedback training and written information to reinforce pelvic floor muscle exercises during a 45-min appointment with a nurse. Patients were instructed to perform the exercises for 10 min twice daily. Forty-three women randomly assigned to an experimental group received an audiocassette tape. Four to 6 weeks later all patients completed a researcher-developed questionnaire that was validity and reliability tested assessing pelvic floor exercise compliance. The 43 patients (100%) who received the audiocassette tape reported compliance with "routine" exercises. Twenty-two of 34 patients (65%) who did not receive the tape were compliant (P = 0.0003). Thirty-four of 41 patients (83%) who received the tape reported exercise compliance twice a day, while 4 of 34 patients (12%) in the control group were similarly compliant (P = 0.0000). The findings suggest adding an audiocassette tape to a pelvic floor exercise program enhances patient compliance for incontinent women compared to verbal and written instruction combined with biofeedback.

We constructed a pubovaginal sling using the Gore-tex Soft Tissue Patch and 2-0 polytetrafluoroethylene (PTFE) suspension suture and placed it in 122 consecutive incontinent women with urethral hypermobility and/or intrinsic sphincter deficiency. We performed a retrospective outcome analysis using a questionnaire-based telephone survey. The mean follow-up period was 24.4 months. Stress incontinence was cured in 88% of patients (equally effective in type II and type III incontinence), de novo postoperative urinary frequency occurred in 32% of cases, and preoperative urinary frequency resolved postoperatively in 51% of patients. Significant urinary obstruction occurred in 5% of patients. Vaginal granulation tissue with exposed sling occurred in 4% of patients. There was no urethral or bladder erosion. The treatment of female stress incontinence with a PTFE sling is effective and durable with minimal complications. Furthermore, this technique addresses many of the presumed technical shortcomings of endoscopic needle suspensions.