Efficacy,Safety and Tolerability of Fesoterodine in Asian Patients with Overactive Bladder

Objectives: To assess the efficacy, safety, and tolerability of fesoterodine 4 and 8 mg once daily (QD) compared with placebo in Asian subjects with overactive bladder (OAB) after 12 weeks of treatment. Methods: This phase II, dose‐finding study consisted of a 2‐week placebo run‐in period followed by a 12‐week, randomized, double‐blind, placebo‐controlled, treatment period. Eligible subjects were aged ≥20 years with ≥8 micturitions per 24 h and ≥1 urgency urinary incontinence (UUI) episodes per 24 h reported in a 3‐day diary. The subjects were randomized to receive placebo, fesoterodine 4 mg, or fesoterodine 8 mg QD for 12 weeks. Results: Of 1232 subjects who entered the placebo run‐in period, 951 received double‐blind treatment. The mean number of UUI episodes per 24 h at baseline was 2.2 among the three treatment groups. The two fesoterodine groups showed statistically significant decreases from baseline in the mean number of UUI episodes per 24 h at week 12 (primary endpoint) compared with placebo. Most all‐causality adverse events (e.g. dry mouth and constipation) were mild or moderate. The percentage of subjects with severe adverse events was low and similar among the treatment groups (placebo, 1.3%; fesoterodine 4 mg, 1.9%; fesoterodine 8 mg, 1.0%). Conclusion: Fesoterodine 4 and 8 mg QD were significantly better than placebo in improving OAB symptoms. Overall, the two fesoterodine dosing regimens were well tolerated. These results suggest that fesoterodine 4 and 8 mg QD are effective and well‐tolerated treatments for OAB in Asian subjects.     

Efficacy and Safety of Propiverine and Solifenacin for the Treatment of Female Patients with Overactive Bladder: A Crossover Study

Objectives: To evaluate the clinical efficacy and tolerability of propiverine and solifenacin in female patients with overactive bladder (OAB). Methods: A prospective nonrandomized crossover study of propiverine 20 mg and solifenacin 5 mg was conducted. Female OAB patients were assigned alternately to treatment with propiverine for 8 weeks then solifenacin for 8 weeks (Group P‐S) or solifenacin for 8 weeks then propiverine for 8 weeks (Group S‐P). At baseline, 8th week and 16th week, symptoms were assessed using overactive bladder symptom score (OABSS). Results: A total of 121 patients were enrolled. Overall, 38 patients (31.4%) discontinued or dropped out and 83 patients were available for analysis (39 in Group P‐S and 44 in Group S‐P). In both groups, the total score and each score of OABSS were significantly improved after 8 weeks compared with baseline. In only Group P‐S (changing over from propiverine to solifenacin), urgency score in the 16th week was further improved significantly compared with the 8th week. The most bothersome symptom at baseline was urgency incontinence (50.6%), followed by urgency (37.3%). Even after symptom improvement, more than half of the patients were bothered by urgency or urgency incontinence. The incidence of adverse events of moderate and severe grade was higher during propiverine treatment than solifenacin (11.1% vs 2.9%, P = 0.039). Conclusion: Propiverine 20 mg and solifenacin 5 mg were effective for treating female OAB patients. Urgency was further improved after switching from propiverine to solifenacin, but not after switching from solifenacin to propiverine. Solifenacin was better tolerated than propiverine.     

Randomized,Single‐Blind,Parallel Study of the Effectiveness and Safety of Solifenacin versus Propiverine in the Treatment of Overactive Bladder

Objectives: To compare the effectiveness and safety of solifenacin versus propiverine in the treatment of overactive bladder (OAB), in a single‐blind, randomized parallel study. Methods: Sixty‐six patients with OAB (14 men and 52 women) were randomly assigned to groups: solifenacin (5 mg/day) or propiverine (20 mg/day) and treated for 8 weeks. The primary outcome variable was mean change from baseline to end of treatment in urgency of the OAB symptom score (OABSS). Secondary outcomes were bladder diary variables: change over 24 h in the mean number of voids (daytime and nighttime), episodes of micturition urgency and incontinence, and mean volume voided. Patients also completed total OABSS and the King's Health questionnaires. Results: Group backgrounds were comparable except for the male to female proportion; 11:22 for solifenacin (n = 33) versus 3:30 for propiverine (n = 33). Adverse events were 6 of 29 (21%) for solifenacin versus 14 of 26 (54%) for propiverine (P = 0.017). Three patients were withdrawn for voiding difficulty (one in solifenacin and two in propiverine) and one patient for dry mouth (propiverine group). Change in OABSS urgency score was ?2.3 ± 1.4 for solifenacin (n = 28) versus ?1.3 ± 1.7 for propiverine (n = 23), (P = 0.0169). Total OABSS and other individual scores, and voiding diary parameters for both drugs showed improvements; however, between‐group difference was not established. Conclusion: Although both solifenacin 5 mg and propiverine 20 mg were effective in the treatment of OAB, solifenacin appeared to be more effective and tolerable.     

Potential Primary Endpoint for Exploratory Clinical Trial in Patients with Overactive Bladder: A Systematic Literature Review

Objectives

To identify a potential primary endpoint in an early‐phase exploratory trial among key overactive bladder (OAB) symptoms.

Methods

Placebo‐controlled double‐blinding trials in patients with OAB were extracted for systematic literature review. The correlation between key OAB symptoms recorded in bladder diaries and coefficient of variation (CV) in each study were assessed.

Results

Forty‐one controlled trials were extracted for the present review. Mean number of urgency episodes in 24 h was substantially associated with mean number of urgency incontinence episodes in 24 h, mean volume voided per micturition, and mean number of micturitions in 24 h (Spearman's r = 0.725, ?0.661, and 0.657, respectively). Mean number of micturitions in 24 h was also substantially associated with mean volume voided per micturition (Spearman's r = ?0.674). Mean number of incontinence episodes in 24 h was substantially associated with mean number of urgency incontinence episodes in 24 h and mean volume voided per micturition (Spearman's r = 0.840 and ?0.628, respectively). The median CV of mean volume voided per micturition in each trial was the smallest among all endpoints.

Conclusions

Our findings suggest that volume voided per micturition is a useful symptom for evaluating OAB candidate compounds in a small sample size and represents an effective primary endpoint, especially in exploratory clinical trials.     

Recent Advances in Intravesical Treatment of Overactive Bladder

The traditional medication for overactive bladder (OAB) is antimuscarinic agent, which targets muscarinic receptors. Recent investigations have revealed that muscarinic receptors are present in the urothelium and suburothelial sensory fibers, as well as in the detrusor. Urothelial dysfunction and abnormality of sensory receptor expression or transmitter release in suburothelial nerves could contribute to OAB refractory to antimuscarinics. Intravesical treatment to inhibit abnormal receptor expression or transmitter release in the sensory nerve terminals in the suburothelial space might provide beneficial therapeutic effects in the treatment of OAB. Intravesical resiniferatoxin (RTX) instillation and intravesical botulinum toxin A (BoNT‐A) injection are two promising treatment alternatives for refractory OAB. RTX at a high dose may cause undesired adverse events, such as hematuria, bladder pain or autonomic dysreflexia. RTX at a low concentration can decrease sensory urgency without influencing detrusor contractility; multiple instillations of low‐dose RTX may be required to achieve adequate desensitization of OAB. BoNT‐A, however, has a beneficial effect on detrusor contractility and causes large post‐void residual after injection in some patients. Therefore, careful dosage and injection site adjustment is mandatory to achieve satisfactory results using intravesical therapy.     

Comparison of Outcome Assessments in Patients with Overactive Bladder Receiving Anticholinergics

Objectives: Patient‐reported outcomes (PRO) reflect treatment benefits from the patient's perspective, and are a subjective method of evaluating the efficacy of overactive bladder (OAB) treatment. We examined the changes in voiding diaries and health‐related quality of life (HRQL) according to patient‐perceived treatment benefits in patients with OAB receiving propiverine. Methods: Thirty‐two patients (mean age ± S.D: 55.1 ± 14.1 years) with OAB were treated with 20 mg propiverine once daily for 12 weeks. The 3‐day voiding diary and the Korean version of the Overactive Bladder Questionnaire (OABq), which includes an eight‐item bothersome symptom scale, as well as 25 HRQL items, were assessed at baseline and at 12 weeks. Finally, patient perception of treatment benefit was evaluated as “no benefit,”“little benefit,” or “much benefit” after treatment. Results: According to patients' perceptions of treatment benefits, 16 (50%) patients perceived “much benefit” from their treatment (group A) and 16 (50%) patients perceived “little benefit” or “no benefit” from their treatment (group B). In both groups, there were significant improvements in the micturation parameters, OABq bothersome symptoms, and total HRQL score after 12 weeks of treatment (P < 0.05). Although there were no significant differences in the voiding diary parameters between the two groups, patients in group A showed significant improvement of the OABq bothersome symptom and total HRQL score compared to group B (P < 0.05). Conclusion: Anticholinergic treatment improves both OAB symptoms and HRQL, and patients' perceptions of treatment benefits correlate better with the OABq than with the voiding diary parameters.     

Tolterodine: A Safe and Effective Treatment for Older Patients with Overactive Bladder

OBJECTIVE: To investigate the clinical safety and efficacy of two dosages of tolterodine in older patients with symptoms attributable to overactive bladder. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group, multinational, phase III study. SETTING: Incontinence, older care, urological, and urogynecological clinics in the United Kingdom, France, and the Republic of Ireland. PARTICIPANTS: One hundred and seventy-seven older patients (age > or =65 years) with symptoms of urinary urgency, increased frequency of micturition (> or =8 micturitions/24 hours), and/or urge incontinence (> or =1 episode/24 hours). INTERVENTION: Tolterodine 1 mg or 2 mg twice daily (bid), or placebo, for 4 weeks. MEASUREMENTS: Safety and tolerability were evaluated through spontaneously reported adverse events, electrocardiogram, and blood pressure measurements. Efficacy was assessed using micturition diary variables: mean change from baseline in frequency of micturition and number of incontinence episodes/24 hours. RESULTS: The mean age of the patient population was 75 years. Overall, > or =87% of patients completed the study. Neither dosage of tolterodine was associated with serious drug-related adverse events during the study. No cardiac arrythmogenic events were noted. Dry mouth (mild to moderate intensity) was the most common adverse event in both the placebo and tolterodine treatment groups. Three percent of patients in the tolterodine 2 mg bid group discontinued treatment because of dry mouth, compared with 2% of placebo-treated patients. Compared with placebo, statistically significant decreases in micturition frequency were apparent in both tolterodine treatment groups. Furthermore, patients treated with tolterodine 2 mg bid had statistically significant decreases in urge incontinence episodes/24 hours and increases in volume voided per micturition compared with placebo. CONCLUSION: Tolterodine (taken for 4 weeks) is safe and shows efficacy, particularly at a dosage of 2 mg bid, in the treatment of older patients with urinary symptoms attributable to overactive bladder.     

Efficacy of Synthetic Suburethral Slings in Female Urinary Stress Incontinence with Overactive Bladder

Objectives: The aim of the present study was to investigate the efficacy of synthetic suburethral slings in female stress urinary incontinence (SUI) patients with overactive bladder (OAB). Methods: From May 2002 to April 2005, a total of 295 women with SUI underwent suburethral sling procedure. Of the 295 women, only those who were followed up for at least 12 months were included in the study, yielding 236 patients. The patients were divided into three groups: pure SUI; SUI with OAB dry; and SUI with OAB wet. Telephone questionnaires by were used to evaluate the postoperative improvement of SUI and storage symptoms. Results: There were significant differences in preoperative symptom score, quality of life (QoL) score, and preoperative voided volume among the three groups. There were no significant differences among the three groups in terms of the cure rate for the stress component (group 1, 88.6%; group 2, 86.2%; group 3, 86.7%; P = 0.943). Eighty percent of group 1 patients improved in frequency, but two patients (2.3%) complained of de novo urgency. In group 2, 81.5 and 82.7% improved in frequency and urgency, respectively, but one patient (1.7%) complained of de novo urge incontinence. In group 3, 76.9 and 84.4% improved in frequency and urge incontinence, respectively. Conclusion: Suburethral slings are simple, safe and highly effective in treating SUI with OAB.     

Efficacy of Propiverine in Improving Symptoms and Quality of Life in Female Patients with Wet Overactive Bladder

Objectives: The present prospective study was conducted to assess the effects of propiverine hydrochloride in improving symptoms and quality of life (QoL) in female patients with wet OAB. Methods: Propiverine was administered orally for 8 weeks to 58 female patients who had urgency incontinence. Prior to administration, and at 4 and 8 weeks after administration, symptoms and QoL of the patients were assessed using a micturition diary, the International Consultation on Incontinence Questionnaire‐Short Form (ICIQ‐SF), and the King's Health Questionnaire (KHQ). In addition, the relationships between changes in frequency of urinary incontinence or amount of urine leakage following treatment and changes in each domain of the KHQ were investigated by multiple regression analysis. Results: After administration of propiverine, the mean numbers of daily micturitions, incontinence episodes, and urgency episodes assessed on the basis of the micturition diary significantly improved in comparison to the baseline: from 11.7 to 9.6 for daily micturitions, from 2.8 to 1.1 for incontinence episodes, and from 5.9 to 2.3 for urgency episodes in 8 weeks. The mean of the ICIQ‐SF total scores significantly decreased, from 8.4 to 4.6 points at 4 weeks and to 3.6 points at 8 weeks. The mean scores for three individual items in the ICIQ‐SF, namely, frequency of incontinence episodes, amount of leakage, and impact on everyday life also significantly improved. The KHQ scores significantly improved at both 4 and 8 weeks post‐administration in all domains except personal relationships. In the multiple regression analysis, improvement in frequency of incontinence was significantly related to the domain of severity measure of the KHQ, while improvement in amount of leakage was significantly related to the domains of general health perception and social limitations. Conclusion: Propiverine hydrochloride contributed to improvements not only in symptoms but also in QoL in female patients with wet OAB.     

Clinical Impact of Solifenacin on Generic and Symptom‐Specific Quality of Life for Females with Overactive Bladder: Using the Overactive Bladder Symptom Score and Rand Medical Outcomes Study 36‐Item Health Survey

Objectives: We evaluated the effectiveness of antimuscarinic treatment on disease‐specific and generic quality of life (QoL) in females with clinically diagnosed overactive bladder (OAB) by prospectively analyzing improvements in the overactive bladder symptom score (OABSS) and the Rand Medical Outcomes Study 36‐Item Short Form Health Survey (SF‐36). Methods: We prospectively recruited newly diagnosed female patients with OAB. Pretreatment disease‐specific symptoms were documented, and generic QoL questionnaires were administered. All subjects received solifenacin 5 mg/day for >8 weeks. Symptoms and general health‐related QoL (HRQoL) were assessed using the OABSS and SF‐36, respectively. Other objective variables, such as maximum urinary flow rate and postvoid residual urine volume, were also evaluated. Results: Seventy‐eight subjects met all inclusion criteria and no exclusion criteria. After 8 weeks, the mean OABSS decreased by approximately 50% compared with baseline (from 9.1 ± 2.8 to 4.5 ± 3.6). All individual scores in OABSS improved after administration of solifenacin. Before treatment, the scores of the study subjects in all SF‐36 domains were significantly worse than the age‐ and gender‐adjusted Japanese national norms (P < 0.01), except the vitality (VT) scale. Intra‐group comparisons between age groups showed worse mental health (MH) scores in all age groups. In the OAB group, three mean SF‐36 scales (physical function [PF], VT, and MH) significantly improved after treatment. Conclusion: Treatment of OAB with solifenacin is associated with significant improvement in generic HRQoL and disease‐specific symptoms at 8 weeks after drug administration. Particularly for generic HRQoL as measured by the SF‐36, solifenacin treatment effectively improves three SF‐36 scores: PF, VT, and MH.     

Treatment Outcome of Overactive Bladder Patients Receiving Antimuscarinic Therapy for More than One Year

Objectives

Details on the therapeutic effects of long‐term antimuscarinic therapy have not been reported. Thus, the aim of this study is to evaluate the detailed long‐term therapeutic effect of antimuscarinic therapy.

Methods

All consecutive patients who visited the urologic outpatient clinics of a medical center for treatment of overactive bladder syndrome and received antimuscarinic therapy of 12 months or more were retrospectively reviewed. All medical records, including the Overactive Bladder Symptom score (OABSS), the modified Indevus Urgency Severity Scale and the International Prostate Symptoms score (IPSS) questionnaires, and uroflowmetry parameters were reviewed at each visit.

Results

A total of 140 patients had received 12 months or more of antimuscarinic therapy. Sustained therapeutic effects were observed by persistent decreases of IPSS‐storage score, IPSS‐total score and OABSS score. Moreover, the maximum flow rate did not change over time. A temporary increase in postvoid residual volume and decrease in voiding efficiency were found, but these parameters improved over long‐term visits. Side‐effects were observed in 81 patients (57.9%) and included dry mouth (n = 58, 41.4%), constipation (n = 48, 34.3%) and blurred vision (n = 4, 2.9%); all side‐effects were tolerable. Patients aged 75 years or more (n = 94) had a higher comorbidity rate (n = 46, 48.9%) before treatment but generally exhibited similar therapeutic effects as overall patients; elderly patients could also tolerate side‐effects.

Conclusion

Sustained therapeutic effects were observed in patients who received 12 months or more of antimuscarinic therapy, even in elderly patients. In addition, side‐effects in patients receiving long‐term therapy were also common but tolerable.     

Synergistic Effect by Co‐Administration of Tamsulosin and Solifenacin on Bladder Activity in Rats

Objectives: We examined the effects of alpha1‐adrenoceptor antagonist (tamsulosin hydrochloride) and antimuscarinic agent (solifenacin succinate) alone or in combination on the urinary adenosine triphosphate (ATP) level and cystometric parameters before and after bladder stimulation. Methods: Female rats were administered tamsulosin hydrochloride (0.5 or 3 µg/kg/h) and/or solifenacin succinate (20 or 100 µg/kg/h) via a subcutaneously implanted osmotic minipump. Rats receiving distilled water were used as control. After 2 weeks, continuous cystometry with physiological saline or 0.1% acetic acid solution was performed. Urinary ATP level was also measured before and after stimulation by 0.1% acetic acid solution. Results: During cystometry with bladder stimulation, the interval between voiding became shorter and the maximum voiding pressure (MVP) became higher in the control group. In the high‐dose tamsulosin and solifenacin groups, the inhibition of urinary frequency was observed. The MVP also became higher in the high‐dose tamsulosin group, but such a change was not seen in the high‐dose solifenacin group. In case of low‐dose administration, either agent alone did not inhibit the increase of urinary frequency and MVP due to bladder stimulation. However, co‐administration of these ineffective low doses of tamsulosin and solifenacin resulted in the inhibition of urinary frequency. The high‐dose or low‐dose solifenacin group and the co‐administration group showed similar inhibition of the increase of urinary ATP after bladder stimulation. Conclusion: Tamsulosin may have a different effect on the bladder and/or the neuronal pathways that is unrelated to ATP, so the combination of tamsulosin and solifenacin may synergistically inhibit urinary frequency after bladder stimulation.