Many men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) opt for self-management with non-prescription treatments. We wished to better characterize these men and understand their motivation and experience. We conducted an anonymous survey among 477 users of non-prescription treatments for LUTS. Participating men had a mean age (64.3 ± 7.8 years) and IPSS (17.7 ± 7.9 points) comparable to users of prescription medicines in non-interventional studies, indicating that they were not primarily motivated by mild symptom intensity. They had realistic expectations on efficacy and tolerability. While reasons for preference for a non-prescription treatment varied, 40.0

Mean voided volume (MVV) is a non-invasive indicator of urinary bladder capacity and frequently used as secondary or even primary endpoint in clinical studies of bladder function, particularly in the context of overactive bladder syndrome. We have analyzed previously reported results from two large, non-interventional studies (n = 1335 and 745 patients with overactive bladder syndrome treated with 30–45 mg propiverine ER) to address two questions: How does MVV relate to other typically used parameters of overactive bladder syndrome (primary aim)? Is MVV a normally distributed variable (secondary aim)? We found that distribution of MVV at baseline and after treatment exhibits a skewed distribution and deviates from a normal distribution, albeit not to a major extent. Basal MVV was weakly to moderately inversely correlated to numbers of urgency, incontinence and nocturia episodes (Spearman’s correlation coefficient 0.2224–0.2960) and somewhat stronger but still only moderately to micturition frequency (0.3296–0.3505). Associations of similar strength were found for absolute and % treatment-associated changes of MVV. MVV was not associated with age and only inconsistently with gender. We conclude that MVV should not be treated as a normally distributed variable and propose that at least partly different (patho)physiological factors may regulate MVV as compared to urgency, incontinence, frequency and nocturia. This should be considered in the choice of primary endpoint in clinical studies.

Unmet expectations are a major cause of perceived treatment failure and discontinuation of treatment. To enable evidence-based counselling of patients on realistic expectations, we determined the chance of patients with overactive bladder becoming free of a given symptom upon treatment with a muscarinic antagonist in a non-interventional setting. Two non-interventional studies included 1335 and 745 patients, respectively, who received 30 or 45 mg q.d. propiverine ER for 12 weeks. They were monitored for becoming free of urgency, urinary incontinence, frequency, or nocturia. Analyses were also performed in subgroups defined by basal symptom severity, age, and gender. Categorical data are shown as a percentage of the respective population. Continuous data are expressed as means or as median depending on whether the variability was considered to exhibit a normal distribution. The probability of becoming symptom-free was largest for incontinence and frequency (about 50%), but lesser for urgency (about 20%) and nocturia (about 10%). Greater basal severity of a symptom reduced the chance to become free of that symptom upon treatment, but the chance to become free of incontinence and frequency was still considerable. Age and gender had only minor if any effects on the chance of becoming symptom-free. These findings are in line with those of a limited number of randomized controlled trials. These data provide an evidence base for the counselling of patients with overactive bladder on realistic expectations of treatment outcomes. We propose that realistic expectations can lead to greater long-term adherence. Unmet expectations are a major reason why patients with overactive bladder syndrome discontinue treatment. To enable evidence-based counselling of patients on realistic expectations, we have determined the chance that patients with overactive bladder become free of urgency, incontinence, voiding frequency, and nocturia. Two non-interventional studies included 1335 and 745 patients, respectively, who received 30 or 45 mg q.d. propiverine ER for 12 weeks. Analyses were also performed in subgroups defined by basal symptom severity, age, and gender. The probability of becoming symptom-free was largest for incontinence and voiding frequency (about 50%), but lesser for urgency and nocturia (about 20%). Greater basal severity of a symptom reduced the chance to become free of that symptom upon treatment, but the chance to become free of incontinence and frequency was still considerable. Age and gender had only minor if any effects on the chance of becoming symptom-free. These data provide an evidence base for the counselling of patients with overactive bladder on realistic expectations of treatment outcomes. We propose that realistic expectations can lead to greater long-term adherence.

Two doses of propiverine ER (30 and 45 mg/d) are available for the treatment of overactive bladder (OAB) syndrome. We have explored factors associated with the initial dosing choice (allocation bias), the decision to adapt dosing (escalation bias) and how dosing relative to other factors affects treatment outcomes. Data from two non-interventional studies of 1335 and 745 OAB patients, respectively, receiving treatment with propiverine, were analyzed post-hoc. Multivariate analysis was applied to identify factors associated with dosing decisions and treatment outcomes. Several parameters were associated with dose choice, escalation to higher dose or treatment outcomes, but only few exhibited a consistent association across both studies. These were younger age for initial dose choice and basal number of urgency and change in incontinence episodes for up-titration. Treatment outcome (difference between values at 12 weeks vs. baseline) for each OAB system was strongly driven by the respective baseline value, whereas no other parameter exhibited a consistent association. Patients starting on the 30 mg dose and escalating to 45 mg after 4 weeks had outcomes comparable with those staying on a starting dose of 30 or 45 mg. We conclude that dose escalation after 4 weeks brings OAB patients with an initially limited improvement to a level seen in initially good responders. Analysis of underlying factors yielded surprisingly little consistent insight.

339Background: Androgen deprivation therapy (ADT) with LHRH agonists leuprolide/goserelin compared to GnRH antagonists has been associated with higher risk for cardiovascular (CV) disease in patients with hormone-sensitive prostate carcinoma (hsPCa). Real life data from German PCa-patients with CV disease treated with ADT are lacking. Our study aimed to analyze occurrence of comorbidities with a focus on CV disease in hsPCa-patients treated with ADT. Methods: HsPCa-patients with initiation of ADT (1999–2014) and an ADT duration of a minimum of 12 months were included. Data were collected retrospectively from medical records and documented in a standardized electronic case report form by three German urological outpatient centers. Primary outcomes of interest were frequency of CV disease and hospitalization due to CV events. Descriptive statistics were performed. An ethics committee approval was obtained from Arztekammer Nordrhein. Results: Data from 753 patients were evaluated. The mean and median age of ...

287 Background: Preserving quality of life (QoL) is an important therapeutic aim in advanced prostate cancer (PCa). The effects of treatment on QoL were studied in a non-interventional study performed from 2010 until 2012 evaluating 1 year of treatment with a LHRH agonist, triptorelin pamoate 6-month depot (TP 6M). Methods: Data of 564 patients with advanced PCa treates in 129 German urology outpatient clinics were analysed. Data on QoL were collected by EORTC questionnaires (QLQ-C30 and -PR25) at baseline, 6 months and 12 months. The QLQ-C30 assesses functional QoL, global health and symptoms of disease, the QLQ-PR25 covers PCa specific symptoms and sexual activity. A clinically relevant improvement, i.e. increase of ≥10 points in the QLQ-C30 global health status/QoL scale, defined treatment responders. Response at month 6 compared to baseline was the primary study endpoint. Results: GlobalHealth Related (HR) QoL was similar over the 1 year follow-up period with a mean (± SD) score of 60.9 (±21.8) at baseline and 61.7 (±22.2) at 12 months. Within the first 6 months, 24.0% of patients were identified as responders (i.e. a clinically relevant improvement in this parameter of ≥10 points). The responder rate was maintained at 12 months of treatment (25.5%). This trend in QoL was also seen in the QLQ-C30 subscales, which were generally similar over the study period. QLQ-PR25 scores were also found to be similar over 1 year, although some deterioration was reported by sexually active patients, as expected. Subgroup analyses on response rates identified age, risk group, pretreatment for PCa and baseline QoL scores as predictors of change in QoL. Conclusions: Treatment with TP 6M over 12 months is associated with few changes in HRQoL and might lead in some patients to clinically meaningful improvements of HRQoL.

ObjectiveTo assess the superiority of fesoterodine 8 mg vs 4 mg for improvement in urgency urinary incontinence (UUI) episodes and other diary variables, diary‐dry rate (proportion of patients with >0 UUI episodes on baseline diary and 0 UUI episodes on post‐baseline diary), and improvements in measures of symptom bother, health‐related quality of life (HRQL), and other patient‐reported outcomes (PROs).Patients and MethodsThis was a 12‐week, randomised, double‐blind, placebo‐controlled, multinational trial of men and women aged ≥18 years with overactive bladder (OAB) symptoms including UUI (ClinicalTrials.gov ID NCT01302067). Patients were randomised (2:2:1) to receive fesoterodine 8 mg, fesoterodine 4 mg, or placebo once daily; those randomised to fesoterodine 8 mg started with fesoterodine 4 mg once daily for 1 week, then 8 mg once daily for the remaining 11 weeks. Patients completed bladder diaries at baseline and weeks 4 and 12 and the Patient Perception of Bladder Condition (PPBC), Urgency Perception Scale (UPS), and Overactive Bladder Questionnaire (OAB‐q) at baseline and week 12. The primary endpoint was change from baseline to week 12 in UUI episodes per 24 h.ResultsAt week 12, patients receiving fesoterodine 8 mg (779 patients) had significantly greater reductions from baseline in UUI episodes, micturitions, and urgency episodes than patients receiving fesoterodine 4 mg (790) or placebo (386); diary‐dry rate was significantly higher in the fesoterodine 8‐mg group vs the fesoterodine 4‐mg and placebo groups (all P < 0.05). At week 12, patients receiving fesoterodine 8 mg also had significantly greater improvements in scores on the PPBC, UPS, and all OAB‐q scales and domains than patients receiving fesoterodine 4 mg or placebo (all P < 0.01). Patients receiving fesoterodine 4 mg had significantly greater improvements in UUI episodes, urgency episodes, and micturitions; significantly higher diary‐dry rates; and significantly greater improvement in PPBC scores and OAB‐q scores than patients receiving placebo (all P < 0.05). Dry mouth was the most commonly reported adverse event (AE) in the fesoterodine groups (placebo group, 3.4%; fesoterodine 4‐mg group, 12.9%; fesoterodine 8‐mg group, 26.1%); most cases were mild or moderate in all treatment groups. Rates of serious AEs and discontinuations due to AEs were low in all groups.ConclusionsIn a 12‐week, prospectively designed, superiority trial, fesoterodine 8 mg showed statistically significantly superior efficacy vs fesoterodine 4 mg and placebo, as measured by reductions in UUI episodes and other diary variables, diary‐dry dry rate, and improvements in measures of symptom bother, HRQL, and other PROs; clear evidence of dose‐dependent efficacy is unique to fesoterodine among antimuscarinics and other oral agents for the treatment of OAB. Fesoterodine 4 mg was significantly more effective than placebo on all outcomes except for improvements in UPS scores. These data support the benefit of having two doses of fesoterodine in clinical practice, with the recommended starting dose of 4 mg for all patients and the fesoterodine 8‐mg dose available for patients who require a higher dose to achieve optimal symptom relief.

Objective To assess the efficacy of fesoterodine 8 mg vs extended‐release ( ER ) tolterodine 4 mg for overactive bladder ( OAB ) symptoms in terms of patient‐reported outcomes in women and in men. Subjects and Methods Pooled data from two 12‐week, randomized, double‐blind, double‐dummy studies were analysed. Participants eligible for the studies were ≥18 years old, had self‐reported OAB symptoms for ≥3 months in 3‐day baseline diaries and had ≥8 micturitions and ≥1 urgency urinary incontinence ( UUI ) episode per 24 h. Individuals were randomized to fesoterodine (4 mg for 1 week then 8 mg for 11 weeks), ER tolterodine (4 mg), or placebo. Changes from baseline in 3‐day bladder diary variables and scores from the P atient P erception of B ladder C ondition ( PPBC ), U rgency P erception S cale ( UPS ), and O veractive B ladder Q uestionnaire ( OAB ‐q), were assessed, as was the ‘diary‐dry’ rate (the proportion of subjects with >0 UUI episodes according to baseline diary and no UUI episodes according to post‐baseline diary). The primary endpoint was the change from baseline to week 12 in UUI episodes. Results At week 12, women showed significantly greater improvement with fesoterodine 8 mg ( n = 1374) than with ER tolterodine 4 mg ( n = 1382) and placebo ( n = 679) in UUI episodes (primary endpoint), micturition frequency, urgency episodes, and all other diary endpoints (except nocturnal micturitions versus ER tolterodine), and also in scores on the PPBC , UPS , and all OAB ‐q scales and domains (all P < 0.005). Diary‐dry rates in women were significantly greater with fesoterodine (63%) than with tolterodine (57%; P = 0.002) or placebo (48%; P < 0.0001). In men, there were no significant differences in improvement in UUI episodes between any treatment groups at week 12. Improvements in men were significantly greater with fesoterodine 8 mg ( n = 265) than with ER tolterodine ( n = 275) for severe urgency and the OAB ‐q Symptom Bother domain and were also significantly greater with fesoterodine than with placebo ( n = 133) for micturition frequency, urgency episodes, severe urgency episodes, PPBC responses and scores on all OAB ‐q scales and domains at week 12 (all P < 0.04). The most frequently reported treatment‐emergent adverse events in both genders were dry mouth (women: fesoterodine, 29%; ER tolterodine, 15%; placebo, 6%; men: fesoterodine, 21%; ER tolterodine, 13%; placebo, 5%) and constipation (women: fesoterodine, 5%; ER tolterodine, 4%; placebo, 2%; men: fesoterodine, 5%; ER tolterodine, 3%; placebo, 1%). Urinary retention rates were low in women (fesoterodine, <1%; ER tolterodine, <1%; placebo, 0%) and men (fesoterodine, 2%; ER tolterodine <1%; placebo, 2%). Conclusion This analysis supports the superiority of fesoterodine 8 mg over ER tolterodine 4 mg on diary endpoints, including UUI , symptom bother and health‐related quality of life in women. In men, fesoterodine 8 mg was superior to ER tolterodine 4 mg for improving severe urgency and symptom bother.

Background: Alpha blockers are prescribed to manage lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Antimuscarinics are prescribed to treat overactive bladder (OAB).Objective: To investigate the safety of a combination of solifenacin (SOLI) and tamsulosin oral controlled absorption system (TOCAS) in men with LUTS and bladder outlet obstruction (BOO).Design, setting, and participants: Randomized, double-blind, parallel-group, placebo-controlled study in men aged >45 yr with LUTS and BOO for >= 3 mo, total International Prostate Symptom Score (IPSS) >= 8, BOO index >= 20, maximum urinary flow rate (Q(max)) <= 12 ml/s, and voided volume >= 120 ml.Interventions: Once-daily coadministration of TOCAS 0.4 mg plus SOLI 6 mg, TOCAS 0.4 mg plus SOLI 9 mg, or placebo for 12 wk.Outcome measurements and statistical analysis: Primary (safety) measurements: Q(max) and detrusor pressure at Q(max) (P(det)Q(max)). Other safety assessments included postvoid residual (PVR) volume. Secondary end points included bladder contractile index (BCI) score and percent bladder voiding efficiency (BVE). An analysis of covariance model compared each TOCAS plus SOLI combination with placebo.Results and limitations: Both active treatment groups were noninferior to placebo at end of treatment (EOT) for P(det)Q(max) and Q(max). Mean change from baseline PVR was significantly higher at all time points for TOCAS 0.4 mg plus SOLI 6 mg, and at weeks 2, 12, and EOT for TOCAS 0.4 mg plus SOLI 9 mg versus placebo. Both treatment groups were similar to placebo for BCI and BVE. Urinary retention was seen in only one patient receiving TOCAS 0.4 mg plus SOLI 6 mg. Limitations of the study were that prostate size and prostate-specific antigen level were not measured.Conclusions: TOCAS 0.4 mg plus SOLI 6 mg or 9 mg was noninferior to placebo at EOT for P(det)Q(max) and Q(max) in men with LUTS and BOO, and there was no clinical or statistical evidence of increased risk of urinary retention. (C) 2012 European Association of Urology. Published by Elsevier B. V. All rights reserved.

This study aimed to characterize the β-adrenoceptor (β-AR) subtype mediating relaxation of isolated human bladder strips and to explore relaxation by the novel β3-AR-selective agonist KUC-7322 for its relaxant effect on the human isolated detrusor and for its effect on the carbachol (CCh)-induced contractile response. In two parallel studies, relaxation of isolated human bladder strips was tested for the β-AR agonists isoproterenol, clenbuterol, BRL 37344, and KUC-7322. For the isoproterenol and KUC-7322 responses, antagonism by CGP 20712A, ICI 118551, and SR59230A was determined. The potency and efficacy of the reference agonists for detrusor relaxation was in line with their known β3-AR activity. KUC-7322 relative to isoproterenol was a full agonist with a pEC 50 of 5.95 ± 0.09 and 5.92 ± 0.11 in the two studies. SR59230A exhibited antagonism of the expected potency against isoproterenol (apparent p K B 7.2) but not against KUC-7322. Neither isoproterenol nor KUC-7322 nor forskolin significantly attenuated CCh-induced contraction. These results suggest that KUC-7322 displays full agonistic activity in relaxing the human detrusor without inhibiting the contraction induced by cholinergic stimulation. These characteristics, if proven in vivo, may be beneficial for the treatment of overactive bladder, as increased bladder capacity with a negligible effect on voiding contractions may be anticipated.

The present study was primarily designed to explore various methodological aspects related to organ bath experiments evaluating human detrusor relaxation by the β-adrenoceptor agonist isoprenaline. Data are based upon a series of 30 consecutive patients, and this cohort was also used to explore possible effects of gender and age. KCl-induced contraction was related to strip length but not weight or cross-sectional area, indicating that the former is most suitable for data normalization. Storage of detrusor strips in cold buffer for up to 2 days did not affect contractile responses to KCl or efficacy of isoprenaline to cause relaxation but significantly affected the isoprenaline potency. No such alterations were observed with up to 1 day of cold storage. The type (KCl vs. passive tension) or strength of contractile stimulus had only minor effects on isoprenaline responses although these differences reached statistical significance in some cases. Similarly, gender and age had only minor if any effects on KCl-induced contraction or isoprenaline-induced relaxation, but the current data are too limited for robust conclusions. In summary we have evaluated experimental conditions for the testing of human detrusor strip contraction and relaxation which should be useful for future larger studies.

OBJECTIVE:To assess the onset of efficacy of fesoterodine 4 mg once daily on overactive bladder (OAB) symptoms after 1 week of treatment.PATIENTS AND METHODS:This was a prespecified analysis of data collected during the first week of a 12-week, open-label, single-arm, flexible-dose study of fesoterodine. Eligible subjects were adult men and women (aged ≥ 18 years) who reported urinary frequency (eight or more micturitions per 24 h) and urgency (three or more episodes per 24 h) in 5-day bladder diaries at baseline, and dissatisfaction with previous tolterodine or tolterodine extended-release treatment received within 2 years of screening. All subjects received fesoterodine 4 mg once daily during the first 4 weeks of treatment (with an optional dose increase to fesoterodine 8 mg after week 4). Early onset of efficacy of fesoterodine 4 mg was assessed based on changes from baseline to week 1 in variables recorded in 5-day bladder diaries, including total micturitions, urgency episodes, urgency urinary incontinence (UUI) episodes and nocturnal micturitions. Urgency and severe urgency episodes were defined as those rated ≥ 3 and ≥ 4, respectively, on the five-point Urinary Sensation Scale (USS) (1 = no urgency, 5 = UUI); frequency-urgency sum (a combined measure of micturition frequency and urgency) was defined as the sum of all USS ratings.RESULTS:All bladder diary variables, including total and nocturnal micturitions, UUI episodes, urgency episodes, severe urgency episodes and frequency-urgency sum per 24 h, were significantly improved (all P < 0.0001) after 1 week of treatment with fesoterodine 4 mg compared to baseline. The diary-dry rate at week 1 (i.e. subjects with at least one UUI episode at baseline who subsequently reported no UUI episodes on week 1 diary) was 38%.CONCLUSION:In this open-label study of subjects with OAB who had been previously treated and dissatisfied with tolterodine, fesoterodine 4 mg showed a rapid onset of efficacy at 1 week.

β(3)-Adrenoceptors have been demonstrated to mediate urinary bladder smooth muscle relaxation but proof of their expression at the protein level has been missing because of lack of suitable antibodies or radioligands. As among various available radioligands [(125)I]-iodocyanopindolol ([(125)I]-ICYP) exhibited the smallest problems in labeling cloned human β(3)-adrenoceptors in previous studies, we have explored its suitability to label β(3)-adrenoceptors in rat urinary bladder in saturation and competition radioligand binding experiments. Rat lung was used as an internal control and exhibited all characteristics expected from this tissue with regard to β1/β2-adrenoceptor labeling. Saturation and competition binding studies with [(125)I]-ICYP in rat bladder yielded saturable binding sites with an affinity compatible with β(3)-adrenoceptors. In competition experiments various agonists and antagonists largely exhibited a profile compatible with a population consisting largely of β(3)-adrenoceptors. However, the binding competition properties of ICI 118,551 and SR 59,230A were not easily explained by the idea of labeling a homogeneous β(3)-adrenoceptor population but interpretation of the data was limited by a high degree of non-specific binding in [(125)I]-ICYP concentrations required to label the receptors. We conclude that [(125)I]-ICYP can be used to label tissue β(3)-adrenoceptors but results obtained with this ligand have to be interpreted with caution.

OBJECTIVE:• To show the superior efficacy of fesoterodine over tolterodine extended release (ER) in a placebo-controlled overactive bladder (OAB) trial with predefined treatment comparisons for both diary measures and patient-reported outcomes.MATERIALS AND METHODS:• In this 12-week, double-blind, double-dummy trial, subjects reporting >1 urgency urinary incontinence (UUI) episode and ≥8 micturitions per 24 h at baseline were randomized to fesoterodine (4 mg for 1 week, 8 mg for 11 weeks), tolterodine ER 4 mg, or placebo. • Subjects completed 3-day bladder diaries, the Patient Perception of Bladder Condition (PPBC) and the Urgency Perception Scale (UPS) at baseline and weeks 1, 4 and 12 and the OAB Questionnaire at baseline and week 12.RESULTS:• A total of 2417 subjects were randomized. At week 12, fesoterodine 8 mg showed superiority over tolterodine ER 4 mg and placebo on UUI episodes (primary endpoint), micturitions, urgency and most other diary endpoints, and on the PPBC, UPS and all OAB Questionnaire scales and domains (all P < 0.05). • Superiority of fesoterodine 8 mg over tolterodine ER 4 mg was seen as early as week 4 (3 weeks after escalation to fesoterodine 8 mg). At week 1, fesoterodine 4 mg was superior to placebo on most diary variables, the PPBC and the UPS (all P < 0.05). Dry mouth and constipation rates were 28% and 4% with fesoterodine, 13% and 3% with tolterodine ER, and 5% and 2% with placebo. • Discontinuation rates as a result of adverse events were 5%, 3% and 2% for fesoterodine, tolterodine ER and placebo, respectively.CONCLUSIONS:• In this randomized study, which is the largest to compare antimuscarinic efficacy performed to date, fesoterodine 8 mg was superior to tolterodine ER 4 mg for UUI episodes, micturitions and urgency episodes, as well as for self-reported patient assessments of bladder-related problems, urgency, symptom bother and health-related quality of life. • The superiority of fesoterodine 8 mg over tolterodine ER 4 mg was observed as early as 3 weeks after escalation from fesoterodine 4 mg for most outcomes. These data may have important implications for the clinical management of OAB patients previously treated with tolterodine ER.

Nebivolol is a selective β1-adrenoceptor antagonist which, in addition, displays endothelium-dependent vasodilating properties in humans and other species. β3-Adrenoceptors have been proposed to be a molecular target of nebivolol-induced vasodilatation. Therefore, we have investigated possible β3-adrenoceptor agonism by nebivolol for relaxation of the human and rat urinary bladder (prototypical β3-adrenoceptor-mediated responses) as well as for cAMP accumulation in Chinese hamster ovary cells stably transfected with the human β-adrenoceptor subtypes. Nebivolol concentration-dependently relaxed both human and rat isolated urinary bladder strips but with low potency, similar to that reported for vasodilatation. However, nebivolol-induced bladder relaxation in either species was not inhibited by the β3-adrenoceptor antagonist SR 59,230A (10μM), although this compound inhibited the isoprenaline-induced relaxation with the expected potency. In radioligand binding studies nebivolol had lower affinity for human β3-adrenoceptors than the other two β-adrenoceptor subtypes, but this low affinity was in line with its potency to relax the bladder or isolated blood vessels. In functional studies nebivolol even in high concentrations did not stimulate cAMP formation via any of the three cloned human β-adrenoceptors or in rat bladder smooth muscle cells. Taken together these data demonstrate that nebivolol can relax not only vascular but also urinary bladder smooth muscle. However, they do not support the hypothesis that nebivolol is an agonist at cloned human β3-adrenoceptors or in rat or human urinary bladder.