Prevalence and repair patterns of vesicovaginal fistula: a large retrospective population-based cohort analysis.

PURPOSE: Vesicovaginal fistulae (VVF) have a significant negative impact on quality of life, with failed surgical repair resulting in ongoing morbidity. Our aim was to characterize the rate of VVF repair and repair failures over time, and to identify predictors of repair failure. METHODS: We completed a population-based, retrospective cohort study of all women who underwent VVF repair in Ontario, Canada, aged 18 and older between 2005 and 2018. Risk factors for repair failure were identified using multivariable cox proportional hazard analysis; interrupted time series analysis was used to determine change in VVF repair rate over time. RESULTS: 814 patients underwent VVF repair. Of these, 117 required a second repair (14%). Mean age at surgery was 52 years (SD 15). Most patients had undergone prior gynecological surgery (68%), and 76% were due to iatrogenic injury. Most repairs were performed by urologists (60%). Predictors of VVF re-repair included iatrogenic injury etiology (HR 2.1, 95% CI 1.3-3.45, p = 0.009), and endoscopic repair (HR 6.1, 95% CI 3.1-11.1, p < 0.05,); protective factors included combined intra-abdominal/trans-vaginal repair (HR 0.51, 95% CI 0.3-0.8, p = 0.009), and surgeon years in practice (21 + years-HR 0.5, 95% CI 0.3-0.9, p = 0.005). Age adjusted annual rate of VVF repair (ranging from 0.8 to 1.58 per 100,000 women) and re-repair did not change over time. CONCLUSIONS: VVF repair and re-repair rates remained constant between 2005 and 2018. Iatrogenic injury and endoscopic repair predicted repair failure; combined intra-abdominal/trans-vaginal repair, and surgeon years in practice were protective. This suggests surgeon experience may protect against VVF repair failure.

Safety and efficacy of an α1 -blocker plus mirabegron compared with an α1 -blocker plus antimuscarinic in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia and overactive bladder: A systematic review and network meta-analysis.

AIM: Antimuscarinics and the ß3-adrenoreceptor agonist, mirabegron, are commonly used for treating patients with overactive bladder (OAB) and α1 -adrenoreceptor antagonists (α1 -blockers) are the main pharmacological agents used for treating lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). As these conditions commonly occur together, the aim of this systematic review was to identify publications that compared the use of an α1 -blocker plus mirabegron with an α1 -blocker plus antimuscarinic in men with LUTS secondary to BPH and OAB. A meta-analysis was subsequently conducted to explore the safety and efficacy of these combinations. METHODS: Included records had to be from a parallel-group, randomized clinical trial that was ≥8 weeks in duration. Participants were male with LUTS secondary to BPH and OAB. The indirect analyses that were identified compared an α1 -blocker plus OAB agent with an α1 -blocker plus placebo. The PubMed/Medical Literature Analysis and Retrieval System Online, the Excerpta Medica Database, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov registry were searched for relevant records up until March 5, 2020. Safety outcomes included incidences of overall treatment-emergent adverse events (TEAEs) and urinary retention, postvoid residual volume, and maximum urinary flow (Qmax ). Primary efficacy outcomes were micturitions/day, incontinence episodes/day, and urgency episodes/day, and secondary outcomes were Overactive Bladder Symptom Score and International Prostate Symptom Score. A Bayesian network meta-analysis approach was used for the meta-analysis. RESULTS: Out of a total of 1039 records identified, 24 were eligible for inclusion in the meta-analysis. There were no statistically significant differences between the α1 -blocker plus mirabegron and α1 -blocker plus antimuscarinic groups in terms of the comparisons identified for all the safety and efficacy analyses conducted. Numerically superior results were frequently observed for the α1 -blocker plus mirabegron group compared with the α1 -blocker plus antimuscarinic group for the safety parameters, including TEAEs, urinary retention, and Qmax . For some of the efficacy parameters, most notably micturitions/day, numerically superior results were noted for the α1 -blocker plus antimuscarinic group. Inconsistency in reporting and study variability were noted in the included records, which hindered data interpretation. CONCLUSION: This systematic review and meta-analysis showed that an α1 -blocker plus mirabegron and an α1 -blocker plus antimuscarinic have similar safety and efficacy profiles in male patients with LUTS secondary to BPH and OAB. Patients may, therefore, benefit from the use of either combination within the clinical setting.

Stress Incontinence Surgery Does Not Cause Pelvic Malignancy: A Population-Based Cohort Study.

PURPOSE: We sought to determine if stress urinary incontinence surgery (mesh or nonmesh) is associated with the development of pelvic malignancies later in life. MATERIALS AND METHODS: We performed a retrospective cohort study between January 1, 2002 and October 31, 2015 of all women in Ontario, Canada without a history of pelvic malignancy who underwent an index stress incontinence surgery. The primary outcome was a composite of any pelvic malignancy (including urological and gynecological cancers) following stress incontinence surgery. Secondarily, we considered each cancer individually. A survival analysis using a Cox proportional-hazards model with a 3-level categorical exposure (mesh surgery, nonmesh surgery, and control) was performed. Patients were followed until death, emigration or the study end (October 31, 2017). RESULTS: Of the women 74,968 underwent stress urinary incontinence surgery during the study period. There were 5,505,576 women in the control group. Over a median followup of 8.5 years (IQR, 5.5-11.9), 587 pelvic malignancies occurred in the surgery group. Women who underwent stress incontinence surgery had a reduced risk of pelvic malignancy independent of surgery type, compared to controls (Wald type 3 p <0.001; mesh HR, 0.68 [95% CI, 0.62-0.76]; p <0.0001; nonmesh HR, 0.37 [95% CI, 0.29-0.46]; p <0.0001). The individual pelvic cancers similarly demonstrated a reduced risk of malignancy following stress incontinence surgery. CONCLUSIONS: At a median followup of 8.5 years, women had no increased risk of pelvic malignancy following either mesh or nonmesh stress urinary incontinence surgery in a large population-based cohort.

What are the chances of improvement or cure from overactive bladder? A pooled responder analysis of efficacy and treatment emergent adverse events following treatment with fesoterodine.

AIM: This study describes patients with different degrees and combinations of symptom resolution in response to fesoterodine exposure to aid physicians in counselling patients with overactive bladder (OAB) on the likelihood of treatment success. METHODS: Data came from 12-week fixed-dose studies of fesoterodine. The proportions of patients experiencing symptom resolution and change in patient-reported outcome measures (PROM) at 4, 8, and 12 weeks were calculated. Treatment-emergent adverse events (TEAE) were reported according to response in urinary urgency episodes (UUE). The relationship between PROM and response was examined. RESULTS: Out of 6689 patients, 81.6% female, urgency urinary incontinence (UUI) episodes/24 h were more responsive to fesoterodine than UUE; with roughly 50% of patients reporting a 50% reduction and fewer than 10% reporting absence of UUE at 12 weeks compared to approximately 40%-50% reporting absence of UUI. TEAE was numerically lower in patients with greater response. There was a statistically significant relationship between improvement in urinary urgency and associated change in OAB-q symptom bother scores, r = 0.54, p < 0.001. At Week 4, 64.0%-76.7% of patients who had achieved a significant change in Patient Perception of Bladder Condition (PPBC) had a 50% reduction in UUI. At Week 12 this proportion was between 80% and 87.9%, with those being exposed to fesoterodine treatment reporting response in PPBC at numerically higher rates. CONCLUSION: These data provide clinicians with information from which they may usefully communicate the likelihood of symptom resolution in response to pharmacotherapy for OAB and answer a key clinical question posed by many care providers. Roughly ⅓ of fesoterodine treated patients reported a 50% reduction urgency and ¾ reported 50% resolution of incontinence at 12 weeks. Total resolution of all symptoms was seldom achieved.

Urinary retention after AdVance™ Sling: A multi-institutional retrospective study.

AIMS: To identify risk factors for urinary retention following AdVance™ Sling placement using preoperative urodynamic studies to evaluate bladder contractility. METHODS: A multi-institutional retrospective review of patients who underwent an AdVance Sling for post-prostatectomy stress urinary incontinence from 2007 to 2019 was performed. Acute urinary retention (AUR) was defined as the complete inability to void or elevated post-void residual (PVR) leading to catheter placement or the initiation of intermittent catheterization at the first void trial postoperatively. Bladder contractility was evaluated based on preoperative urodynamics. RESULTS: Of the 391 patients in this study, 55 (14.1%) experienced AUR, and 6 patients (1.5%) had chronic urinary retention with a median follow-up of 18.1 months. In total, 303 patients (77.5%) underwent preoperative urodynamics, and there was no significant difference between average PdetQmax (26.4 vs. 27.4 cmH2 O), Qmax (16.6 vs. 16.2 ml/s), PVR (19.9 vs. 28.1 ml), bladder contractility index (108 vs. 103) for patients with or without AUR following AdVance Sling. Impaired bladder contractility preoperatively was not predictive of AUR. Time to postoperative urethral catheter removal was predictive of AUR (odds ratio, 0.83; 95% confidence interval, 0.73-0.94; p = .003). CONCLUSIONS: Chronic urinary retention after AdVance Sling placement is uncommon and acute retention is generally self-limiting. No demographic or urodynamic factors were predictive of AUR. Patients who developed AUR were more likely to have their void trials within 2 days following AdVance Sling placement versus longer initial catheterization periods, suggesting that a longer duration of postoperative catheterization may reduce the occurrence of AUR.

Is There an Association between Urinary Incontinence and Mortality? A Retrospective Cohort Study.

PURPOSE: Previous studies have shown an association between urinary incontinence and increased mortality independently of demographics and health status. However, they do not account for the effect of frailty as a state of vulnerability. We evaluated whether there is an association between urinary incontinence and mortality and, if so, whether adjustment for a frailty index would affect the association. MATERIALS AND METHODS: We performed a cross-sectional study in a nationally representative sample of 2,282 community dwelling individuals 50 years old or older who were surveyed between 2003 and 2006. The study primary outcome was overall survival as reported on December 31, 2011. We used design adjusted Cox proportional hazards regression models to estimate the hazard of mortality associated with urinary incontinence. We adjusted the models for demographics and a validated 45-item frailty index incorporating an accumulation of deficits in the domains of health and independence. RESULTS: Of the individuals 23% reported having urinary incontinence at least a few times per week. Stress urinary incontinence and urge urinary incontinence were associated with a 13.3% (95% CI 7.2-19.7) and 18.4% (95% CI 8.3-29.4) increase in the frailty index, respectively. Without controlling for frailty individuals with urinary incontinence were at higher risk for death (HR 1.39, 95% CI 1.13-1.72). When adjusted for the frailty index, the association between urinary incontinence and mortality was no longer significant (HR 1.10, 95% CI 0.89-1.36). CONCLUSIONS: The association between urinary incontinence and mortality can be understood based on increased frailty in incontinent individuals. Urinary incontinence itself is not independently associated with mortality. In clinical practice these findings underscore the importance of screening for frailty in addition to urinary incontinence.

Efficacy and Safety of Mirabegron versus Placebo Add-On Therapy in Men with Overactive Bladder Symptoms Receiving Tamsulosin for Underlying Benign Prostatic Hyperplasia: A Randomized, Phase 4 Study (PLUS).

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.

Effect of mirabegron on cognitive function in elderly patients with overactive bladder: MoCA results from a phase 4 randomized, placebo-controlled study (PILLAR).

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 ß3-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).

Surgical treatment of post-prostatectomy stress urinary incontinence in adult men: Report from the 6th International Consultation on Incontinence.

AIMS: To report the recommendations of the 6th International Consultation on Incontinence (ICI) on post-prostatectomy urinary incontinence. METHODS: The 6th ICI committee on surgical treatment of urinary incontinence in men assessed and reviewed the outcomes of surgical therapy and updated the prior recommendations published in 2013. Articles from peer-reviewed journals, abstracts from scientific meetings, and literature searches by hand and electronically formed the basis of this review. The resulting guidelines were presented at the 2016 ICI meeting in Tokyo, Japan. RESULTS: Voiding diary and pad tests are valuable for assessing quantity of leakage. Cystoscopy and/or urodynamics may be useful in guiding therapy depending on the type of incontinence and presumed etiology. Artificial Urinary Sphincter (AUS) is the preferred treatment for men with moderate to severe stress urinary incontinence (SUI) after RP. Male slings are an acceptable approach for men with mild to moderate SUI. Much discussion centers on the definition of moderate SUI. Injectable agents have a poor success rate in men with SUI. Options for recurrent SUI due to urethral atrophy after AUS implantation include changing the pressure balloon, downsizing the cuff and increasing the amount of fluid in the system. Infection and/or erosion demand surgical removal or revision of all or part of the prosthesis. CONCLUSIONS: Although there are several series reporting the outcomes of different surgical interventions for PPUI, there is still a need for prospective randomized clinical trials. Recommendations for future research include standardized workup and outcome measures, and complete reporting of adverse events at long-term.

Long-term treatment of older patients with overactive bladder using a combination of mirabegron and solifenacin: a prespecified analysis from the randomized, phase III SYNERGY II study.

AIMS: SYNERGY II was a 12-month phase III trial in patients with overactive bladder (OAB) symptoms that investigated the safety and efficacy of the combination of mirabegron and solifenacin in comparison with each monotherapy. This analysis evaluated the trial findings using four age subgroups (<65, ≥65, <75, and ≥75 years). METHODS: Eligible patients were ≥18 years with symptoms of "wet" OAB (urinary frequency and urgency with incontinence) for ≥3 months. Patients were randomized to receive once-daily solifenacin succinate and mirabegron (5 mg/50 mg; combination), solifenacin succinate, or mirabegron (4:1:1). Safety evaluations: treatment-emergent adverse events (TEAEs), vital signs, and electrocardiogram, post-void residual volume, and laboratory assessments. Primary efficacy variables: change from baseline to end of treatment in number of incontinence episodes/24 h and micturitions/24 h. RESULTS: Of 1794 patients (full analysis set), 614 (34.2%) and 168 (9.4%) were ≥65 and ≥75 years old, respectively. Overall, 856 (47.2%) patients experienced ≥1 TEAE. Higher TEAE incidences were typically observed for the combination versus both monotherapies (eg, constipation) and in the older versus younger age groups (eg, urinary tract infection). Increases in mean pulse rate from baseline of >1 bpm were noted in the combination and mirabegron younger age groups only. No clinically significant findings were observed in the other safety parameters. The efficacy variables improved with all treatments and the greatest improvements were typically observed with combination therapy. CONCLUSIONS: Mirabegron and solifenacin combination therapy was a well-tolerated and effective treatment for patients with OAB symptoms irrespective of their age.

The International Continence Society (ICS) report on the terminology for adult male lower urinary tract and pelvic floor symptoms and dysfunction.

INTRODUCTION: In the development of terminology of the lower urinary tract, due to its increasing complexity, the terminology for male lower urinary tract and pelvic floor symptoms and dysfunction needs to be updated using a male-specific approach and via a clinically-based consensus report. METHODS: This report combines the input of members of the Standardisation Committee of the International Continence Society (ICS) in a Working Group with recognized experts in the field, assisted by many external referees. Appropriate core clinical categories and a subclassification were developed to give a numeric coding to each definition. An extensive process of 22 rounds of internal and external review was developed to exhaustively examine each definition, with decision-making by collective opinion (consensus). RESULTS: A Terminology Report for male lower urinary tract and pelvic floor symptoms and dysfunction, encompassing around 390 separate definitions/descriptors, has been developed. It is clinically-based with the most common diagnoses defined. Clarity and user-friendliness have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in male lower urinary tract and pelvic floor dysfunction. Male-specific imaging (ultrasound, radiology, CT, and MRI) has been a major addition whilst appropriate figures have been included to supplement and help clarify the text. CONCLUSIONS: A consensus-based Terminology Report for male lower urinary tract and pelvic floor symptoms and dysfunction has been produced aimed at being a significant aid to clinical practice and a stimulus for research.

Placenta percreta into the urinary bladder: the importance of the urologist.

The incidence of placenta accreta spectrum is on the rise. The most serious entity within this spectrum is percreta: extension beyond the uterus. The bladder is most commonly involved in these cases and is especially relevant for the urologist. Important sequelae include hemorrhage, massive transfusion, maternal mortality and urinary tract injury. Approaching this disorder as well as associated urinary tract involvement in a standardized and multi-disciplinary fashion significantly improves outcomes and reduces morbidity. Herein, we present a case of complete placenta percreta involving the bladder that was successfully managed with minimal obstetrical and genitourinary morbidity.

The effect of selection and referral biases for the treatment of localised prostate cancer with surgery or radiation.

BACKGROUND: Consultation with radiation oncologists, in addition to urologists, is advocated for patients diagnosed with prostate cancer. Treatment patterns for patients receiving consultation from radiation oncologists in addition to urologists have not previously been described. METHODS: We conducted a matched cohort study of men with newly diagnosed non-metastatic prostate cancer in Ontario, Canada. Patients who underwent consultation with a radiation oncologist prior to treatment were matched 1:1 with patients managed by a urologist alone based on tumour and patient characteristics. We examined rates of active treatment (surgery or radiotherapy) within one year following diagnosis. RESULTS: Among 5708 matched pairs (11,416 patients), those who received radiation oncology consultation were more likely to undergo active treatments whether they had intermediate or high-risk disease (88.6% vs. 65.9%, p < 0.0001; adjusted odds ratio 4.0, 95% CI: 3.6-4.4) or low-risk disease (56.1% vs. 13.3%, p < 0.0001; adjusted odds ratio 8.4, 95% CI: 6.7-10.6). This effect persisted after considering age, comorbidity, tumour volume and year of diagnosis. CONCLUSIONS: Patients newly diagnosed with prostate cancer who receive radiation oncology consultation are associated with a higher rate of active treatment, compared to patients managed by urologists only. Selection and referral biases, and unmeasured confounding such as patient preference must be considered as important factors attributing this association.

Complications and Interventions in Patients with an Artificial Urinary Sphincter: Long-Term Results.

PURPOSE: The artificial urinary sphincter is a common treatment of male urinary incontinence. We sought to characterize long-term rates of artificial urinary sphincter revision/removal and reimplantation, and associated risk factors. MATERIALS AND METHODS: We performed a population based, retrospective study using the Ontario Health Insurance Plan database of all male patients who underwent artificial urinary sphincter implantation from 1994 to 2013. Hospital, diagnostic and billing codes were used to identify patients. The Kaplan-Meier method and multivariable Cox proportional hazards models were applied to examine the cumulative incidence of artificial urinary sphincter reimplantation and revision/removal, and identify risk factors, respectively. RESULTS: A total of 1,632 male patients underwent initial implantation of an artificial urinary sphincter. The 10-year revision/removal and reimplantation rates were 34% and 27%, respectively. There was no difference between high and low volume hospitals or between community and academic hospitals in terms of revision/removal. A high level of comorbidity was associated with an increasing risk of removal/revision. The reimplantation rate was significantly lower in patients who underwent insertion at hospitals with the highest volume of surgery (HR 0.55, 95% CI 0.37-0.82, p <0.01). A high level of comorbidity was not associated with an increasing risk of reimplantation. Preimplantation radiotherapy was not significantly associated with the risk of reimplantation (p = 0.17) or revision/removal (p = 0.95). Other factors were not significantly associated with reimplantation or revision/removal. CONCLUSIONS: Most men who undergo artificial urinary sphincter placement still have a device without repeat surgery 10 years following insertion. Radiotherapy does not increase the risk of repeat surgery. A high level of comorbidity was associated with an increasing risk of removal/revision.

Patient-reported outcomes from SYNERGY, a randomized, double-blind, multicenter study evaluating combinations of mirabegron and solifenacin compared with monotherapy and placebo in OAB patients.

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.

Patient-reported outcomes in patients with overactive bladder treated with mirabegron and tolterodine in a prospective, double-blind, randomized, two-period crossover, multicenter study (PREFER).

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.

A prospective, double-blind, randomized, two-period crossover, multicenter study to evaluate tolerability and patient preference between mirabegron and tolterodine in patients with overactive bladder (PREFER study).

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.

The Efficacy and Safety of OnabotulinumtoxinA or Solifenacin Compared with Placebo in Solifenacin Naïve Patients with Refractory Overactive Bladder: Results from a Multicenter, Randomized, Double-Blind Phase 3b Trial.

PURPOSE: In this double-blind, randomized study we compared the efficacy and safety of onabotulinumtoxinA or solifenacin vs placebo in patients with overactive bladder who had urinary incontinence and an inadequate response to or were intolerant of an anticholinergic. Post hoc analysis was done to compare the effects of onabotulinumtoxinA vs solifenacin. MATERIALS AND METHODS: Solifenacin naïve patients were randomized to onabotulinumtoxinA 100 U, solifenacin 5 mg, (which could escalate to 10 mg at week 6 according to predefined criteria) or placebo. Patients could request treatment 2 (open label onabotulinumtoxinA) after fulfilling prespecified criteria. End points included a change from baseline in the number of urinary incontinence episodes per day and the proportion of patients with a 100% reduction (dry) in the number of incontinence episodes per day as co-primaries, other urinary symptoms and quality of life, all at week 12, and adverse events. RESULTS: The change from baseline in incontinence episodes per day was significantly greater with onabotulinumtoxinA or solifenacin vs placebo (-3.19 or -2.56, respectively, vs -1.33, both p <0.001). The incontinence reduction was significantly greater for onabotulinumtoxinA vs solifenacin (p = 0.022). At week 12, 33.8% (vs placebo p <0.001), 24.5% (vs placebo p = 0.028) and 11.7% of patients receiving onabotulinumtoxinA, solifenacin and placebo, respectively, were dry. After treatment 2, which was open label onabotulinumtoxinA, 43.2%, 37.6% and 41.9% of patients in the onabotulinumtoxinA, solifenacin and placebo groups, respectively, were dry. Significant improvements in other urinary symptoms and quality of life were observed for both active treatments. Urinary tract infection in 25.5% of cases and urinary retention in 6.9% were more common with onabotulinumtoxinA. CONCLUSIONS: The efficacy of onabotulinumtoxinA and solifenacin was significantly higher than that of placebo. However, onabotulinumtoxinA showed significantly greater decreases in urinary incontinence than solifenacin with a third of patients achieving a 100% incontinence reduction. No unexpected safety signals were observed.

OnabotulinumtoxinA for the Treatment of Patients with Overactive Bladder and Urinary Incontinence: Results of a Phase 3, Randomized, Placebo Controlled Trial.

PURPOSE: Overactive bladder affects 12% to 17% of the general population and almost a third experience urinary incontinence, which may severely impact health related quality of life. Oral anticholinergics are the mainstay of pharmacological treatment but they are limited by inadequate efficacy or side effects, leading to a high discontinuation rate. We report the results of the first large (557 patients), phase 3, placebo controlled trial of onabotulinumtoxinA in patients with overactive bladder and urinary incontinence inadequately managed with anticholinergics. MATERIALS AND METHODS: Eligible patients with overactive bladder, 3 or more urgency urinary incontinence episodes in 3 days and 8 or more micturitions per day were randomized 1:1 to receive intradetrusor injection of onabotulinumtoxinA 100 U or placebo. Co-primary end points were the change from baseline in the number of urinary incontinence episodes per day and the proportion of patients with a positive response on the treatment benefit scale at posttreatment week 12. Secondary end points included other overactive bladder symptoms and health related quality of life. Adverse events were assessed. RESULTS: OnabotulinumtoxinA significantly decreased the daily frequency of urinary incontinence episodes vs placebo (-2.65 vs -0.87, p <0.001) and 22.9% vs 6.5% of patients became completely continent. A larger proportion of onabotulinumtoxinA than placebo treated patients reported a positive response on the treatment benefit scale (60.8% vs 29.2%, p <0.001). All other overactive bladder symptoms improved vs placebo (p ≤0.05). OnabotulinumtoxinA improved patient health related quality of life across multiple measures (p <0.001). Uncomplicated urinary tract infection was the most common adverse event. A 5.4% rate of urinary retention was observed. CONCLUSIONS: OnabotulinumtoxinA 100 U showed significant, clinically relevant improvement in all overactive bladder symptoms and health related quality of life in patients inadequately treated with anticholinergics and was well tolerated.

Efficacy and safety of combinations of mirabegron and solifenacin compared with monotherapy and placebo in patients with overactive bladder (SYNERGY study).

OBJECTIVE: To evaluate the potential of solifenacin 5 mg combined with mirabegron 25 or 50 mg to deliver superior efficacy compared with monotherapy, with acceptable tolerability, in the general overactive bladder (OAB) population with urinary incontinence (UI). PATIENTS AND METHODS: After a 4-week placebo run-in, patients aged ≥18 years with wet OAB (urgency, urinary frequency and UI) for ≥3 months who recorded on average ≥8 micturitions/24 h, ≥1 urgency episode/24 h, and ≥3 UI episodes over the 7-day micturition diary, were eligible for randomisation to double-blind treatment [2:2:1:1:1:1 ratio, solifenacin 5 mg + mirabegron 25 mg (combined S5 + M25 group); solifenacin 5 mg + mirabegron 50 mg (combined S5 + M50 group); solifenacin 5 mg; mirabegron 25 mg; mirabegron 50 mg; or placebo for 12 weeks], and 2-weeks' single-blind, placebo run-out. Co-primary efficacy variables were change from baseline to end of treatment (EoT) in the mean number of UI episodes/24 h and micturitions/24 h, assessed using a 7-day electronic micturition diary. Secondary efficacy variables included change from baseline to EoT in the mean volume voided/micturition, change from baseline at weeks 4, 8, 12 and EoT in mean number of UI episodes/24 h, micturitions/24 h, urgency episodes/24 h, urgency UI (UUI) episodes/24 h and nocturia episodes/24 h; the percentage of patients (responders) achieving zero UI episodes/24 h at EoT in the last 7 days prior to each visit, micturition frequency normalisation (<8 episodes/24 h) at weeks 4, 8, 12 and EoT; and the number of UUI episodes and nocturia episodes in the 7-day diary. Safety assessments included incidence and frequency of treatment-emergent adverse events (TEAEs), post-void residual (PVR) urine volume, and changes from baseline in laboratory parameters. RESULTS: Whilst the combined S5 + M50 group was superior to solifenacin 5 mg for UI, with a mean (standard error) adjusted difference of -0.20 (0.12) UI episodes/24 h (95% confidence interval -0.44, 0.04, P = 0.033), there was no statistical superiority vs mirabegron 50 mg [-0.23 (0.12) UI episodes/24 h; P = 0.052]. In secondary analyses, all active treatment groups had greater improvements in UI episodes/24 h vs placebo, with effect sizes for the combined therapy groups (combined S5 + M25 group: -0.70 episodes/24 h; combined S5 + M50 group: -0.65 episodes/24 h) that were substantially higher than those obtained with monotherapy (range -0.37 episodes/24 h for mirabegron 25 mg to -0.45 episodes/24 h for solifenacin 5 mg). For micturitions/24 h, adjusted change from baseline to EoT was greater in the combined therapy groups vs monotherapies (combined S5 + M50 group, nominal P values 0.006 and <0.001 vs solifenacin 5 mg and mirabegron 50 mg, respectively; combined S5 + M25 group, nominal P values 0.040 and 0.001 vs solifenacin 5 mg and mirabegron 25 mg, respectively). All active treatment groups had greater improvements in the mean numbers of micturitions/24 h vs placebo, with effect sizes for the combined therapy groups (combined S5 + M25 group: -0.85 micturitions/24 h; combined S5 + M50 group: -0.95 micturitions/24 h) higher than with mirabegron monotherapy (25 mg: -0.36; 50 mg: -0.39 micturitions/24 h) and solifenacin 5 mg (-0.56 micturitions/24 h). The combined S5 + M50 group was statistically significantly superior to both monotherapies at EoT for UUI episodes, urgency episodes and nocturia, with effect sizes that appeared to be additive. The combined S5 + M25 group was statistically significantly superior to mirabegron 25 mg for the same variables, except for nocturia. In responder analyses at the EoT, odds ratios in favour of both combined therapies vs monotherapies were shown for the proportion of patients with zero UI episodes and those achieving micturition frequency normalisation. There was a slightly increased frequency of TEAEs in the combined therapy groups vs monotherapies and placebo. Most of the TEAEs were mild or moderate in severity. Events indicative of urinary retention were reported slightly more frequently in the combined therapy groups vs monotherapy and placebo. PVR volume was slightly increased in the combined therapy groups vs solifenacin 5 mg, mirabegron monotherapy, and placebo groups. There were slightly higher frequencies of dry mouth, constipation, and dyspepsia in the combined therapy groups vs monotherapies. There were no concerns regarding electrocardiograms and laboratory data. CONCLUSION: In the largest OAB study to date, combined therapy with solifenacin 5 mg + mirabegron 25 mg and solifenacin 5 mg + mirabegron 50 mg provided consistent improvements in efficacy compared with the respective monotherapies across most of the outcome parameters, with effect sizes generally consistent with an additive effect. Although the combined S5 + M50 group did not achieve a statistically significant effect vs mirabegron 50 mg in the primary analysis of one of the co-primary endpoints (change from baseline in mean number of UI episodes/24 h), it approached statistical significance (P = 0.052), and the nominal P values for the other co-primary endpoint (micturitions/24 h) were <0.05. Most effects of combined therapy vs monotherapy were observable by week 4. The clinical relevance of the improvements seen with combined therapy for several objective OAB outcome measures was also supported by the improvements of combined therapy vs monotherapy in the responder analyses.