Current and Emerging Pharmacological Targets and Treatments of Urinary Incontinence and Related Disorders.

Overactive bladder syndrome with and without urinary incontinence and related conditions, signs, and disorders such as detrusor overactivity, neurogenic lower urinary tract dysfunction, underactive bladder, stress urinary incontinence, and nocturia are common in the general population and have a major impact on the quality of life of the affected patients and their partners. Based on the deliberations of the subcommittee on pharmacological treatments of the 7th International Consultation on Incontinence, we present a comprehensive review of established drug targets in the treatment of overactive bladder syndrome and the aforementioned related conditions and the approved drugs used in its treatment. Investigational drug targets and compounds are also reviewed. We conclude that, despite a range of available medical treatment options, a considerable medical need continues to exist. This is largely because the existing treatments are symptomatic and have limited efficacy and/or tolerability, which leads to poor long-term adherence. SIGNIFICANCE STATEMENT: Urinary incontinence and related disorders are prevalent in the general population. While many treatments have been approved, few patients stay on long-term treatment despite none of them being curative. This paper provides a comprehensive discussion of existing and emerging treatment options for various types of incontinence and related disorders.

Reduced versus standard intradetrusor OnabotulinumtoxinA injections for treatment of overactive bladder.

BACKGROUND: Intradetrusor onabotulinumtoxinA injection is an effective advanced treatment for overactive bladder. While the effective dosages have been well studied, very little data exist on treatment efficacy using differing injection techniques. The objective of this study was to determine whether the efficacy of a reduced injection technique of 5 injection sites was noninferior to the standard technique of 20 injection sites of intradetrusor onabotulinumtoxinA for treatment of overactive bladder. METHODS: In this randomized noninferiority trial, men and women seeking treatment of overactive bladder with intradetrusor onabotulinumtoxinA injections were randomized to receive 100 units administered via either a reduced injection technique of 5 injection sites or a standard injection technique of 20 injection sites. Subjects completed a series of standardized questionnaires at baseline and at 4-12 weeks postprocedure to determine symptom severity and treatment efficacy. The primary outcome was treatment efficacy as determined by Overactive Bladder Questionnaire-Short Form with a noninferiority margin of 15 points. Secondary outcomes were incidence of urinary tract infection and urinary retention requiring catheterization. RESULTS: Data from 77 subjects were available for analysis with 39 in the control arm (20 injections) and 38 in the study arm (5 injections). There was a significant improvement in both arms from baseline to follow-up in Overactive Bladder Questionnaire-Short Form and International Consultation on Incontinence Questionnaire scores (p < 0.001). Overall treatment success was 68% with no statistically significant difference between arms. A significant difference between arms was found on the Overactive Bladder Questionnaire-Short Form quality of life survey favoring the control arm (confidence interval [CI]: 0.36-20.5, p = 0.04). However, there were no significant differences between arms in the remaining validated questionnaires. The study arm did not demonstrate noninferiority to the control arm. Subjects in the study arm were significantly more likely to express a willingness to undergo the procedure again (odds ratio = 3.8, 95% CI: 1.42-10.67, p = 0.004). Adverse events did not differ between arms. CONCLUSIONS: A reduced injection technique for administration of intradetrusor onabotulinumtoxinA demonstrates similar efficacy to the standard injection technique but did not demonstrate noninferiority. Subjects preferred the reduced injection technique over the standard technique. A reduced injection technique is a safe and effective alternative to the standard technique.

One treatment with onabotulinumtoxinA relieves symptoms of overactive bladder in patients refractory to one or more oral medications.

INTRODUCTION AND HYPOTHESIS: Patients with overactive bladder (OAB) often undergo prolonged treatment with one or more oral OAB medications. OnabotulinumtoxinA (onabotA), a type A botulinum toxin, may provide an appropriate alternative to oral treatments in patients intolerant of or refractory to one or more oral OAB medications. The GRACE study demonstrated real-world benefits of onabotA treatment for OAB in patients refractory to oral medications. This exploratory post hoc analysis of data from the GRACE study aims to determine if treatment history impacts benefit from treatment with onabotA. METHODS: This is a subanalysis of the GRACE study, a prospective observational study (NCT02161159) that enrolled patients with symptomatic OAB inadequately managed by at least one oral OAB medication. Patients had a treatment history of one or more anticholinergics (AC) and/or ß-3 adrenoreceptor agonists (ß-3) for relief of OAB; results were stratified according to treatment history. Patients in this analysis elected to discontinue oral medications upon treatment with onabotA. Safety was followed for 12 months in all patients that received at least 1 dose of onabotA; efficacy was determined over a 12-week period. RESULTS: Compared to baseline levels, significant reductions in urinary incontinence (UI), urgency, micturition, and nocturia were noted as early as 1 week and were sustained at 12 weeks, regardless of the type and number of oral medications taken before treatment with onabotA. At 12 weeks post-onabotA, the mean change from baseline UI episodes/day for those with a treatment history of only one AC was -2.4 (n = 43, p ≤ 0.001); more than one AC, -2.4 (n = 52, p ≤ 0.001); one ß-3, -3.3 (n = 12, p < 0.05); at least one AC and at least one ß-3, -3.2 (n = 56, p ≤ 0.001). Pad and liner use was significantly decreased at 12 weeks post-onabotA across all treatment history groups. Reductions in diaper pant use varied, with less of a reduction in patients with a treatment history of more than one AC compared to patients with a history of at least one AC and one ß-3 (p < 0.05) or those with a history of only one AC (p < 0.05). Overall, a total of 253/288 of patients (88%) reported improvements on the treatment benefit scale 12 weeks after treatment with onabotA, regardless of type and number of prior oral medications. In the population of patients that received at least one dose of onabotA (N = 504), 57 adverse events were reported in 38 patients (7.5%); 9 were serious (1.8%). Urinary retention was reported in 5 patients (1.0%); 1 was severe (0.2%). Symptomatic urinary tract infection was reported in 2 patients (0.4%). CONCLUSIONS: In this exploratory post hoc analysis of real-world data from the GRACE study, there were few significant differences in outcomes based on the type and number of prior oral medications. Thus, patients who are refractory to one or more oral OAB medications may benefit from earlier treatment with onabotA.

The impact of postinjection urinary tract infection on efficacy of intravesical onabotulinumtoxinA-A secondary analysis.

OBJECTIVES: To compare treatment response in women who did and did not develop a urinary tract infection (UTI) within 14 days after intravesical onabotulinumtoxinA injections for treatment of refractory urgency urinary incontinence (UUI). METHODS: This is a secondary analysis of women who received Onabotulinumtoxin A in the Refractory Overactive Bladder: Sacral Neuromodulation vs Botulinum Toxin Assessment (ROSETTA) Trial. Participants were grouped by presence or absence of UTI within 14 days of injection. UTI was defined as symptomatic with positive urine culture per the primary ROSETTA protocol. Our primary outcome was change from baseline in mean number of UUI episodes based on monthly 3-day bladder diaries averaged over 6 months. We performed t tests and chi-square/Fisher's exact for continuous and categorical variables. A p value of <0.05 was considered statistically significant. RESULTS: Of 187 participants in the onabotulinumtoxinA arm, 10 (5.3%) experienced UTI within 14 days of injection, and 177 (94.7%) did not. At baseline, groups did not differ in demographics, mean UUI episodes per day (no UTI [5.37 ± 2.65] vs. UTI [6.40 ± 3.02], p = 0.24), or other diary parameters. For our primary outcome, groups did not differ in the change in mean daily UUI episodes at 1 month (no UTI [-4.29 ± 2.75] vs. UTI [-3.74 ± 2.01]; mean difference [95% confidence interval, CI] -0.55 [-2.39 to 1.28], p: 0.55) or 6 months (no UTI [-3.63 ± 2.89] vs. UTI [-2.15 ± 3.18]; mean difference [95% CI] -1.48 [-3.44 to 0.48], p: 0.14). CONCLUSIONS: UTI within 14 days after intravesical injection of onabotulinumtoxinA for refractory UUI was not significantly associated with inferior treatment response at 1 or 6 months.

Patient perceived improvement and medication resumption rates after intradetrusor onabotulinumtoxina for idiopathic urgency urinary incontinence.

INTRODUCTION AND HYPOTHESIS: Intradetrusor onabotulinumtoxinA (BTX-A) is a third-line therapy for overactive bladder (OAB), however several gaps exist in periprocedural care. Prior studies have demonstrated BTX-A efficacy at 2-3 weeks, but there are limited data documenting when patients should begin to note symptom improvement. The primary aim of this study was to evaluate patient-reported temporal improvement in symptoms, with secondary aim to evaluate medication resumption rates, following initial BTX-A injection. METHODS: A prospective, single-arm cohort study of patients with non-neurogenic urgency incontinence undergoing initial BTX-A injection was performed. Intradetrusor 100 units BTX-A was administered in standard 20-site template. Patients discontinued OAB medication(s) at BTX-A injection and completed a daily Patient Global Impression of Improvement (PGI-I) diary for 3 weeks. Data were collected at 1 month, including final satisfaction score, medication resumption rates, and adverse outcomes. RESULTS: Fifty-one patients were included, with 25 patients (49%) actively taking an OAB medication. Median time to first improvement was 3 days, at least "much better" (PGI-I <2) was 5 days, and maximal improvement was 7 days. Twenty of 25 patients (80%) opted to remain off OAB medications at 1 month based on symptomatic improvement following injection. Adverse outcomes included urinary tract infection in three patients (6%) and symptomatic incomplete emptying requiring temporary intermittent catheterization in two patients (4%). CONCLUSIONS: Median time to first and maximal improvement was 3 and 7 days, respectively, following initial 100 units BTX-A. Eighty percent of patients on medications opted to remain off at 1 month. These data may help further counsel patient expectations following initial BTX-A therapy.

Urinary tract infection following intradetrusor onabotulinumtoxina injection for non-neurogenic urgency incontinence: single- vs. multi-dose prophylactic antibiotic treatment regimens.

INTRODUCTION AND HYPOTHESIS: Urinary tract infection is one of the most common adverse events following onabotulinumtoxinA injection for urgency incontinence. Our hypothesis was that those undergoing injection for urgency incontinence who received more than one dose of prophylactic antibiotics have lower post-procedure urinary tract infection rates compared to those who receive a single dose. METHODS: We conducted a multi-center retrospective cohort study in females who underwent onabotulinumtoxinA injection for non-neurogenic urgency incontinence to evaluate the effect of single- vs. multi-dose prophylactic antibiotic regimens on the risk of post-procedure urinary tract infection. The primary outcome was the rate of urinary tract infection within 30 days of injection. Our sample size calculation required 136 subjects per group. RESULTS: Two hundred eighty-one patients were included from four centers. The single-dose cohort included 145 patients (51.6%), and the multi-dose cohort included 136 patients (48.4%). The mean age was 65 years, and patients were primarily Caucasian (81.4%). There was no difference in the rate of urinary tract infections diagnosed within 30 days of injection between the cohorts (single dose 13.8% vs. multi-dose 10.3%, p = 0.369). Those with a positive urine culture within 30 days of injection had a 15.2 times greater odds of having a post-procedure infection than those who did not (95% CI 3.19-72.53). There was no significant difference between the two cohorts in terms of adverse health events following injection. CONCLUSIONS: In females with non-neurogenic urgency incontinence undergoing onabotulinumtoxinA injection, multi-dose prophylactic antibiotic regimens were not associated with lower post-procedure urinary tract infection rates.

Is vitamin D replacement effective in the treatment of postpartum urinary incontinence?

INTRODUCTION AND HYPOTHESIS: The main objective of this study was to compare the effectiveness of pelvic floor muscle training, and vitamin D replacement in the treatment of urinary incontinence in the postpartum period of pregnant women with vitamin D deficiency. METHODS: The study was planned as an ancillary study of a study on the determination of the relationship between vitamin D deficiency and urinary incontinence in third-trimester pregnant women. Total 61 women who defined urinary incontinence at postpartum 8th week were included in the study. The participants were divided into two groups: the vitamin D replacement group and the pelvic floor muscle training (PFMT) group. Participants in both groups received appropriate treatment for 12 weeks. Initial evaluations of which Pelvic Organ Prolapse-Quantification stage, International Consultation on Incontinence Modular Questionnaire on Female Lower Urinary Tract Symptoms (ICIQ-FLUTS) query, and pelvic floor muscle strength were repeated after 12 weeks of treatment for each patient. RESULTS: In the vitamin D replacement group, there was a significant increase in Oxford scores measured after treatment compared with pre-treatment and a significant decrease in ICIQ-FLUTS scores. In the comparison of the groups, it was determined that the changes in the Oxford and ICIQ-FLUTS scores of the vitamin D group after treatment were significantly higher than those of the PFMT group. In this pilot study, it was determined that the effectiveness of vitamin D replacement in the treatment of pelvic floor dysfunction in pregnant women with hypovitaminosis D was significantly higher than PFMT. CONCLUSION: Vitamin D replacement may be useful in the treatment of urinary incontinence in pregnant women with hypovitaminosis D.

Urobiome changes differ based on OAB treatment in adult females.

INTRODUCTION AND HYPOTHESIS: Representatives of two classes of oral medication are often used to treat urgency urinary incontinence (UUI): solifenacin, an M3-receptor-selective antimuscarinic, and mirabegron, a beta-3 agonist. Two previous asynchronous drug-specific studies suggested different interactions between these medications and the urobiome despite identical methodologies, including recruitment, sample procurement, medication dose escalation strategy, determination of 12-week responders versus nonresponders, and data collection. This analysis compares data from these two studies using a uniform analytic approach. METHODS: Urine was collected aseptically via transurethral catheter from consenting participants for subsequent processing by the Expanded Quantitative Urine Culture (EQUC) protocol in two cohorts (n=50 and n=47) that were demographically similar. Species accumulation curves were generated to compare the total number of unique species detected. Indices that measure richness, evenness, and/or abundance were used to compare alpha (within sample) diversity. The Bray-Curtis Dissimilarity Index was used to determine between sample (beta) diversity. RESULTS: The majority of the 40 species detected in the pre-treatment urobiomes were detected in both cohorts. Both pre-treatment urobiomes were substantially similar in species richness, evenness, and diversity. Differences in pre-treatment urobiomes were associated with treatment response for solifenacin-treated participants only. In contrast, the pre-treatment urobiomes of mirabegron-treated participants were not associated with treatment response. Changes in the post-treatment urobiomes were detected in both cohorts with an increase in richness for both solifenacin (5-mg dose only) and mirabegron. CONCLUSIONS: Pre-treatment urobiome characteristics were associated with treatment response in participants treated with solifenacin, but not mirabegron. Differences exist in urobiome response after treatment with two medications that have known differences in mechanism of action.

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.

Effects of ospemifene on overactive bladder in postmenopausal women with vulvovaginal atrophy.

OBJECTIVE: Overactive bladder (OAB) is a complex and multifactorial syndrome associated with urinary frequency, urgency and incontinence. The menopause-associated hormonal changes play a role in the development of this condition. Vaginal estrogens are effective in improving OAB in postmenopausal women (PMW) with vulvovaginal atrophy (VVA). Ospemifene is a selective estrogen receptor modulator licensed for the treatment of VVA. This study aimed to evaluate the effects of ospemifene on OAB symptoms in PMW with VVA. METHODS: Forty PMW suffering from OAB and VVA received oral ospemifene (60 mg/day) for 12 weeks. All patients were assessed with a urodynamic study, a 3-day bladder diary and validated questionnaires (International Consultation on Incontinence Questionnaire - Urinary Incontinence Short Form [ICIQ-UI SF] and International Consultation on Incontinence Questionnaire - Overactive Bladder [ICIQ-OAB]) at enrollment and at the end of the study. RESULTS: Cytometric capacity, bladder compliance and verbal sensory threshold responses during bladder filling were improved after treatment. The voiding diary showed a significant reduction of daily voids, urge urinary incontinence episodes and nocturnal events. The median overall scores of the ICIQ-UI and ICIQ-OAB were also significantly improved. CONCLUSIONS: Our study suggest that treatment with ospemifene in PMW suffering from OAB is associated with a reduction of OAB symptoms due to a decreased bladder sensitivity and with an improvement in quality of life.

Seminal papers in urology: anticholinergic therapy vs. onabotulinumtoxina for urgency urinary incontinence.

In this critical review, we explore the study design, strengths, and limitations of landmark trial "Anticholinergic therapy vs. onabotulinumtoxinA for urgency urinary incontinence". This trial was the first to directly compare two key treatment options for urge urinary incontinence - anticholinergic medication and intravesical botox, and still influences clinical guidelines a decade after publication. This non-inferiority, double-blinded, multi-centre randomised controlled trial administered Solifenacin or intra-detrusor botox to women, measuring outcomes six months post-treatment. Non-inferiority of the treatments was established, though Botox had a higher rate of retention and infection, with side effect profile rising as the key discriminator in selecting first-line therapy.

Effect of Nigella sativa L. seed oil on urinary incontinence and quality of life in menopausal women: A triple-blind randomized controlled trial.

Increased urinary incontinence is one of the most common changes during menopause. This study aimed to investigate the effect of Nigella sativa L. seed oil on urinary incontinence and quality of life (QoL) (primary outcomes) and sexual function (secondary outcome) in menopausal women. In this triple-blind randomized controlled trial, 60 women in Tabriz-Iran were equally allocated into two treatment and control groups using block randomization. The women applied 2-3 drops of Nigella sativa L. seed oil or placebo on their stomachs below the novel twice a day for 8 weeks. The data collection instruments were completed at baseline and just after the intervention. After intervention, the mean rank score of mixed urinary incontinence was significantly lower (p = .04) and the mean score of the incontinence-QoL was significantly higher (mean difference 12.63, 95% CI 2.33 to 22.93; p = .017) in the treatment group than the control group. However, there were no significant differences in stress incontinence, urge incontinence, sexual function, and menopause-specific QoL of women between the groups (p > .05). The results indicated the positive effect of the Nigella sativa L. seed oil on mixed incontinence and incontinence-QoL; nevertheless, to make a certain conclusion, further studies are required.

Efficacy of frankincense-based herbal product in urinary incontinence: A randomized, double-blind, placebo- and active-controlled clinical trial.

Urinary incontinence is a silent epidemic that has a serious impact on a person's quality of life (QOL). This study aimed to evaluate the efficacy of frankincense-based herbal product (FHP) in urinary incontinence compared with placebo and solifenacin. In this randomized, double-blind clinical trial, 120 postmenopausal women with mixed urinary incontinence were randomized to one of the three groups of FHP, placebo, and standard treatment (solifenacin). Frequency, amount of leakage, and score of urinary incontinence as well as the QOL were measured at the end of the second and fourth weeks and 2 weeks after the interruption of the treatment. The ICIQ-UI SF and I-QOL questionnaires were used for the measurements. Mean frequency of urinary incontinence and amount of leakage significantly decreased in the FHP and solifenacin groups in the fourth week compared to the placebo group. In addition, 2 weeks after treatment completion, the effects of the FHP were significant compared to the solifenacin group. Due to the effect of FHP on improving the QOL and also the prolonged effect of this drug, the use of FHP in urinary incontinence, as a complementary treatment could be suggested.

Heterogeneity of placebo effects on urinary incontinence in overactive bladder syndrome: A meta-analysis of Japanese placebo-controlled clinical trials.

OBJECTIVES: The effect sizes, changes over time, and heterogeneity of placebo effects on frequency of urination for voiding disorders in Japanese clinical trials have been published. This study evaluated the characteristics of placebo effects on overall and urge incontinence in overactive bladder patients. METHODS: A meta-analysis of Japanese placebo-controlled clinical trials was conducted to determine placebo effects on the daily frequency of overall (n = 16) and urge (n = 11) incontinence and identify factors that should be considered in clinical trials. RESULTS: The between-study heterogeneity variance of placebo effects for overall and urge incontinence at 8 weeks was estimated as I2 = 70.3% and 64.2%, and the prediction interval for the ratio of means ranged from g = 0.31-0.91 and 0.32-0.81, respectively. Subgroup analysis using the random-effects model showed placebo effects in overall incontinence (p = 0.08) and urge incontinence (p < 0.0001). The ratio of means (95% confidence interval) of urge incontinence frequency from baseline to 4 (n = 10), 8 (n = 10), and 12 (n = 7) weeks were 0.65 (0.57, 0.74), 0.51 (0.42, 0.62), and 0.48 (0.36, 0.64), respectively, for the random-effects model. Regression analysis did not reveal any significant factors that influenced placebo effects. CONCLUSIONS: This meta-analysis confirmed the characterization of placebo effects on overall and urge incontinence, which demonstrates heterogeneity between trials. The impact of population, follow-up period, and endpoints on placebo effects should be considered when designing clinical trials for overactive bladder syndrome.

Intravesical Instillation of OnabotulinumtoxinA in the Treatment of Refractory Overactive Bladder in Participants with Urinary Incontinence.

PURPOSE: Intradetrusor injections of onabotulinumtoxinA are efficacious for the treatment of overactive bladder with urgency urinary incontinence in adults refractory to or intolerant of anticholinergics. Delivery of onabotulinumtoxinA via instillation would reduce the need for intradetrusor injections. The objective of this trial was to assess the efficacy and safety of intravesical instillation of an onabotulinumtoxinA + hydrogel admixture. MATERIALS AND METHODS: After review of a stage 1 safety phase by an independent committee, participants were recruited into stage 2 and randomized to either onabotulinumtoxinA 100, 300, 400, or 500 U, or placebo, all with hydrogel admixture. End points included change from baseline to week 12 in the number of urinary incontinence episodes (primary); micturition, urgency urinary, and nocturia episodes/day; volume voided per micturition; proportion of participants with a ≥50% decrease from baseline in urinary incontinence episodes/day; and Overactive Bladder Questionnaire total score. Adverse events were reported. RESULTS: Change from baseline to week 12 in number of urinary incontinence episodes was -2.72 with placebo and ranged from -0.89 to -1.85 in the onabotulinumtoxinA + hydrogel treatment groups. No difference from placebo was observed for any efficacy end point. The proportions of participants with treatment-emergent adverse events were similar among all groups, with asymptomatic bacteriuria the highest reported (6.7%-15.5%). There were no reports of urinary retention or elevated post-void residual volume. CONCLUSIONS: Intravesical instillation of an onabotulinumtoxinA + hydrogel admixture for the treatment of refractory overactive bladder was well tolerated, but it showed no improvement over placebo.

Predicting outcomes after intradetrusor onabotulinumtoxina for non-neurogenic urgency incontinence in women.

AIMS: Develop models to predict outcomes after intradetrusor injection of 100 or 200 units of onabotulinumtoxinA in women with non-neurogenic urgency urinary incontinence (UUI). METHODS: Models were developed using 307 women from two randomized trials assessing efficacy of onabotulinumtoxinA for non-neurogenic UUI. Cox, linear and logistic regression models were fit using: (1) time to recurrence over 12 months, (2) change from baseline daily UUI episodes (UUIE) at 6 months, and (3) need for self-catheterization over 6 months. Model discrimination of Cox and logistic regression models was calculated using c-index. Mean absolute error determined accuracy of the linear model. Calibration was demonstrated using calibration curves. All models were internally validated using bootstrapping. RESULTS: Median time to recurrence was 6 (interquartile range [IQR]: 2-12) months. Increasing age, 200 units of onabotulinumtoxinA, higher body mass index (BMI) and baseline UUIE were associated with decreased time to recurrence. The c-index was 0.63 (95% confidence interval [CI]: 0.59, 0.67). Median change in daily UUIE from baseline at 6 months was -3.5 (IQR: -5.0, -2.3). Increasing age, lower baseline UUIE, 200 units of onabotulinumtoxinA, higher BMI and IIQ-SF were associated with less improvement in UUIE. The mean absolute error predicting change in UUIE was accurate to 1.6 (95% CI: 1.5, 1.7) UUI episodes. The overall rate of self-catheterization was 17.6% (95% CI: 13.6%-22.4%). Lower BMI, 200 units of onabotulinumtoxinA, increased baseline postvoid residual and maximum capacity were associated with higher risk of self-catheterization. The c-index was 0.66 (95% CI: 0.61, 0.76). The three calculators are available at http://riskcalc.duke.edu. CONCLUSIONS: After external validation, these models will assist clinicians in providing more accurate estimates of expected treatment outcomes after onabotulinumtoxinA for non-neurogenic UUI in women.

Efficacy of combination therapy of mid-urethral sling and low-dose Abobotulinumtoxin-A injection in mixed urinary incontinence.

OBJECTIVES: To determine the outcome of combined transobturator tape sling (TOT) and low dose intradetrusor injection of Abobotulinumtoxin-A (Abobot-A, Dysport®) in women with mixed urinary incontinence (MUI). METHODS: This randomized, active comparator-controlled, parallel-group, two-part clinical trial was conducted on women who had positive Valsalva leak point pressure (VLPP) + detrusor overactivity (DO), cough-associated DO. In Part 1, 20 women with MUI who had a failure of medical and behavioral therapies to cure MUI, randomized in two groups receiving TOT surgery alone, or in combination with Dysport® injection (n = 10 in each group), and then Part 2 was initiated as a prospective open-label on 40 more patients. We performed cystoscopy and injected 300 U of Dysport®in 20-30 intradetrusor injection sites in each patient. RESULTS: The patient's symptoms in both groups decreased significantly after treatment. The symptoms were improved significantly in the combination therapy group according to the International Consultation on Incontinence Questionnaire-overactive bladder (ICIQ-OAB) questionnaire (p < .001), and International Consultation on Incontinence Questionnaire-urinary Incontinence-short form (ICIQ-UI-SF) (p = .041) in comparing with the TOT group. In Part 2, the mean score was 17.10 (4.75) for ICIQ-UI-SF and 9.22 (2.89) for ICIQ-OAB before the treatment. Twelve weeks after the intervention, the median (interquartile range: IQR) of ICIQ-OAB symptoms (2.0 [3.0]; p < .001) and ICIQ-UI-SF decreased, too (1. 0 [2.0]; p < .001). Considering improvement using Patient Global Impression of Improvement scale, 46 (92.0%) stated that they had significant subjective improvement of their symptoms. CONCLUSIONS: Combination therapy was accompanied with a promising effect in the patients with MUI according to the results of standardized questionnaires. However, further studies with controlled arms are recommended.

Changes in brain response to urgency before and after treatment of urgency urinary incontinence with onabotulinumtoxin A.

INTRODUCTION: To better understand the role of the brain in urgency urinary incontinence (UUI), we used onabotulinumtoxin A (BoNTA) as a probe to evaluate changes in the brain's response to urgency in successful and unsuccessful treatment. Because BoNTA acts peripherally, brain changes observed should represent a reaction to changes in bladder function caused by BoNTA, or changes in the brain's compensatory mechanisms, rather than a direct effect of BoNTA on the brain. METHODS: We recruited 20 women aged over 60 years with nonneurogenic UUI who were to undergo treatment with onabotulinum A toxin injected intravesically. We performed a baseline evaluation which included a 3-day bladder diary and functional magnetic resonance imaging with an urgency provocation task; we repeated this evaluation 6 weeks posttreatment. We performed an analysis of variance on a priori selected regions of interest and post hoc voxel-wise analysis on responders and nonresponders to treatment. RESULTS: We found a significant interaction in the right insula [F(1,18) = 5.5, p = 0.031]; activity was different during urgency provocation in responders and non-responders to therapy, before and after therapy. The supramarginal gyrus (SMG) and inferior frontal gyrus (IFG) also displayed significant interactions (p < 0.005). Activity in the periaqueductal gray and prefrontal cortex was correlated with number of leakage episodes (p < 0.05). CONCLUSION: The changes seen in the brain control mechanism after therapy likely reflect reduced bladder sensation caused by BoNTA's peripheral action. We ascribe the SMG and IFG changes to a coping mechanism for urgency which is reduced in those who respond well to treatment.

Non-inferior and more feasible transcutaneous tibial nerve stimulation in treating overactive bladder: A systematic review and meta-analysis.

OBJECTIVES: Overactive bladder (OAB) is identified as a urinary urgency accompanied by frequency and nocturia with or without urgency urinary incontinence in the nonexistence of a urinary tract infection or other evident pathologies. This systematic review and meta-analysis aimed to evaluate the efficacy of the transcutaneous tibial nerve stimulation (TTNS) versus percutaneous tibial nerve stimulation (PTNS) or anticholinergic drugs in reducing symptoms and improving the quality of life for OAB patients. METHODS: We performed a systematic search in Medline, Embase, and CENTRAL, in which we included randomized controlled trials that compared TTNS with anticholinergic drugs or PTNS in treating idiopathic OAB. We evaluated the following outcomes: 3-day voiding diary (voiding frequency/day, daytime micturition frequency/day, nighttime micturition frequency/day, number of urgency episodes/day, number of incontinence episodes/day, and mean voiding volume), symptom bother, health related quality of life (HRQoL), and adverse events. We used 95% as a confidence interval (CI) and p < 0.05. Standardized mean difference (SMD) was used for continuous outcomes, and the risk ratio (RR) was used for dichotomous outcomes. RESULTS: There was no significant difference comparing TTNS with anticholinergic drugs or PTNS regarding voiding frequency/day (SMD = -0.01, 95% CI -0.33 to 0.32), nighttime micturition frequency/day (SMD = -0.28, 95% CI -0.94 to 0.37), number of urgency episodes/day (SMD = -0.05, 95% CI -0.36 to 0.26), number of incontinence episodes/day (SMD = -0.04, 95% CI -0.32 to 0.25), symptom bother (SMD = -0.19, 95% CI -0.55 to 0.16), HRQoL (SMD = 0.27, 95% CI -0.32 to 0.85), and adverse events (RR = 0.07, 95% CI 0.01 to 0.54). CONCLUSION: The current meta-analysis reveals that there is no statistically significant difference between TTNS versus PTNS or anticholinergic drugs for the nonsurgical management of OAB patients.

Efficacy of mirabegron, a ß3 -adrenoreceptor agonist, in Japanese women with overactive bladder and either urgency urinary incontinence or mixed urinary incontinence: Post-hoc analysis of pooled data from two randomized, placebo-controlled, double-blind studies.

OBJECTIVE: To confirm if mirabegron 50 mg shows efficacy in women with overactive bladder and either urgency urinary incontinence or mixed urinary incontinence versus placebo. METHODS: Post-hoc analyses were carried out using pooled data from a Japanese phase IIb and a phase III study. The primary efficacy end-point was baseline to end-of-treatment change in the mean number of micturitions/24 h. The secondary end-points were changes in the mean voided volume/micturition, mean number of urgency and incontinence episodes/24 h, and mean number of nocturia episodes/night. Other end-points were quality of life and incontinence normalization rates. RESULTS: Women with urgency urinary incontinence (placebo n = 204, mirabegron n = 214) and mixed urinary incontinence (placebo n = 122, mirabegron n = 139) were included. Change in mean micturitions/24 h at end-of-treatment for mirabegron was statistically significant versus placebo in both populations; the effect size increased over time. For all secondary end-points, median changes for mirabegron were statistically significant versus placebo at end-of-treatment, except for nocturia for the urgency urinary incontinence population and urgency for the mixed urinary incontinence population. Mirabegron showed larger improvements versus placebo in all quality-of-life domains, except for general health perception in the urgency urinary incontinence population. Incontinence normalization rates for mirabegron were 47.2% and 49.6% in the urgency urinary incontinence and mixed urinary incontinence populations, respectively, versus 42.6% and 39.3% for placebo. CONCLUSIONS: Mirabegron 50 mg significantly improved key overactive bladder symptoms versus placebo in women with urgency urinary incontinence, and it also improved most overactive bladder symptoms, including micturition frequency, in patients with mixed urinary incontinence. These findings support the benefits of using mirabegron in the female overactive bladder wet population.