David R. Staskin

Fourth international consultation on incontinence recommendations of the international scientific committee: Evaluation and treatment of urinary incontinence, pelvic organ prolapse, and fecal incontinence†‡§¶‖

P. Abrams , K.E. Andersson, L. Birder, L. Brubaker, L. Cardozo, C. Chapple, A. Cottenden, W. Davila, D. de Ridder, R. Dmochowski, M. Drake, C. DuBeau, C. Fry, P. Hanno, J. Hay Smith, S. Herschorn, G. Hosker, C. Kelleher, H. Koelbl, S. Khoury,* R. Madoff, I. Milsom, K. Moore, D. Newman, V. Nitti, C. Norton, I. Nygaard, C. Payne, A. Smith, D. Staskin, S. Tekgul, J. Thuroff, A. Tubaro, D. Vodusek, A. Wein, and J.J. Wyndaele and the Members of the Committees

Prospective Randomized Controlled Trial of Extended-Release Oxybutynin Chloride and Tolterodine Tartrate in the Treatment of Overactive Bladder: Results of the OBJECT Study

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

Pelvic floor electrical stimulation in the treatment of genuine stress incontinence: A multicenter, placebo-controlled trial

OBJECTIVE Our purpose was to determine the efficacy of transvaginal electrical stimulation in treating genuine stress incontinence. STUDY DESIGN This was a multicenter, prospective, randomized, double-blind, placebo-controlled 15-week trial comparing the use of an active pelvic floor stimulator with a sham device. Thirty-five women used an active unit and 17 control subjects used sham devices. Weekly and daily voiding diaries were recorded throughout the trial. Urodynamic testing, including pad test and subtracted cystometry, was done before and at the end of device use. Pelvic muscle strength was measured at baseline and at the end of the trial. Patients scored their symptoms on visual analog scales and completed quality-of-life questionnaires before and after therapy. RESULTS Significant improvements from baseline were found in patients using active devices but not in controls. Comparisons of changes from baseline between active-device and control patients showed that active-device patients had significantly greater improvement in weekly (p = 0.009) and daily (p = 0.04) leakage episodes, pad testing (p = 0.005), and vaginal muscle strength (p = 0.02) when compared with control subjects. Significantly greater improvement was also found for both visual analog scores of urinary incontinence (p = 0.007) and stress incontinence (p = 0.02), as well as for subjective reporting of frequency of urine loss (p = 0.002), and urine loss with sneezing, coughing, or laughing (p = 0.02), when compared with controls. Pad testing showed that stress incontinence was improved by at least 50% in 62% of patients using an active device compared with only 19% of patients using sham devices (p = 0.01). Voiding diaries showed at least 50% improvement in 48% of active-device patients compared with 13% of women using the sham device (p = 0.02). No irreversible adverse effects were noted in either group. CONCLUSIONS Transvaginal pelvic floor electrical stimulation was found to be a safe and effective therapy for genuine stress incontinence.

Update of AUA Guideline on the Surgical Management of Female Stress Urinary Incontinence

PURPOSE We updated the 1997 American Urological Association guideline on female stress incontinence. MATERIALS AND METHODS MEDLINE searches of English language publications from 1994 and new searches of the literature published between December 2002 and June 2005 were performed using identified MeSH terms. Articles were selected for the index patient defined as the otherwise healthy woman who elected to undergo surgery to correct stress urinary incontinence or the otherwise healthy woman with incontinence and prolapse who elected to undergo treatment for both conditions. RESULTS A total of 436 articles were identified as suitable for inclusion in the meta-analysis, and an additional 155 articles were suitable for complications data only due to insufficient followup of efficacy outcomes in the latter reports. Surgical efficacy was defined using outcomes pre-specified in the primary evidence articles. Urgency (resolution and de novo) was included as an efficacy outcome due to its significant impact on quality of life. The primary efficacy outcome was resolution of stress incontinence measured as completely dry (cured/dry) or improved (cured/improved). Complications were analyzed similarly to the efficacy outcomes. Subjective complications (pain, sexual dysfunction and voiding dysfunction) were also included as a separate category. CONCLUSIONS The surgical management of stress urinary incontinence with or without combined prolapse treatment continues to evolve. New technologies have emerged which have impacted surgical treatment algorithms. Cystoscopy has been added as a standard component of the procedure during surgical implantation of slings.

Combination Treatment with Mirabegron and Solifenacin in Patients with Overactive Bladder: Efficacy and Safety Results from a Randomised, Double-blind, Dose-ranging, Phase 2 Study (Symphony)

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

Urinary Retention and Post-Void Residual Urine in Men: Separating Truth From Tradition

PURPOSE The definitions of acute and chronic urinary retention remain empirical and subject to wide interpretation. Standardized criteria have not been established and many questions remain unanswered. Moreover, the definition of significant post-void residual urine is unclear. We reviewed several aspects of urinary retention that require clarification with the objective of stimulating discussion among urologists to establish an accurate and coherent definition of urinary retention and significant post-void residual urine, and clarify risk factors. MATERIALS AND METHODS A MEDLINE search for articles written in English and published before April 2007 was done using a list of terms related to urinary retention. Articles not directly relevant to urinary retention or post-void residual urine were excluded. RESULTS The term urinary retention lacks precise clinical or urodynamic meaning. Use of this term to describe a symptom, a sign, and a condition further complicates the issue. Many factors can contribute to the development of retention, including bladder outlet obstruction, detrusor underactivity, and neurogenic bladder conditions. Community based studies and clinical trials in patients with benign prostatic enlargement and/or lower urinary tract symptoms yield different estimates of the incidence of retention and only provide information on the epidemiology of acute urinary retention. However, age, previous retention episodes, lower urinary tract symptoms, chronic inflammation, serum prostate specific antigen level, prostate size, and urodynamic variables appear to be predictors of acute urinary retention. Alpha-receptor antagonists and 5alpha-reductase inhibitors may be useful in preventing urinary retention episodes and progressive benign prostatic enlargement. Clinical trials on the short-term use of antimuscarinics have not provided evidence that these agents increase the risk of retention; data on longer term administration are needed. CONCLUSIONS Clinicians are adopting less invasive approaches (eg pharmacology or catheterization) to treating patients who present with the symptoms, sign, and condition of urinary retention. Faced with an abundance of new data on acute urinary retention, urologists need to reach a consensus about the risks of urinary retention; this may promote movement toward patient centered prevention strategies with tailored treatment options.

Efficacy and safety of oxybutynin chloride topical gel for overactive bladder: a randomized, double-blind, placebo controlled, multicenter study.

PURPOSE We assessed the efficacy and safety of oxybutynin chloride topical gel vs placebo in adults with overactive bladder. MATERIALS AND METHODS Men and women 18 years or older with urge predominant urinary incontinence were enrolled in randomized, parallel group, double-blind, placebo controlled Study OG05009 done at 76 clinics in the United States. Eligible patients were assigned to receive 1 gm oxybutynin chloride topical gel (10% weight per weight ethanol based formulation of oxybutynin) or matching placebo once daily for 12 weeks. Efficacy was assessed using data from 3-day urinary diaries and the primary outcome was the change from baseline in the number of urge incontinence episodes. Safety was monitored through adverse event reporting. Efficacy results in the oxybutynin chloride topical gel and placebo groups were compared by ANCOVA with last observations carried forward. RESULTS A total of 789 randomized patients, including 704 women (89.2%), with a mean age of 59 years were assigned to treatment with oxybutynin chloride topical gel (389) or placebo (400). The mean number of urge incontinence episodes decreased significantly more in patients treated with oxybutynin chloride topical gel than in those given placebo (-3.0 vs -2.5 per day, p <0.0001). Mean urinary frequency decreased (-2.7 per day, p = 0.0017) and voided volume increased (21.0 ml, p = 0.0018) significantly more in the oxybutynin chloride group than in the placebo group (-2.0 per day and 3.8 ml, respectively). Treatment related dry mouth was more frequent in the oxybutynin chloride group than in the placebo group (27 of 389 patients or 6.9% vs 11 of 400 or 2.8%). Application site reactions were infrequently observed in the oxybutynin chloride and placebo groups (21 of 389 patients or 5.4% and 4 of 400 or 1.0%, respectively). No serious treatment related adverse events occurred. CONCLUSIONS Oxybutynin chloride topical gel was efficacious in improving overactive bladder symptoms and was well tolerated in adult patients.

Trospium 60 mg Once Daily (QD) for Overactive Bladder Syndrome: Results from a Placebo-Controlled Interventional Study

OBJECTIVES A once-daily (QD) formulation of trospium chloride has been developed for the management of overactive bladder syndrome (OAB). This randomized controlled trial evaluated the efficacy and tolerability of this new extended-release formulation, trospium chloride 60 mg QD. METHODS Adults with OAB with urinary urgency, frequency, and urgency urinary incontinence (UUI) were eligible for inclusion. Subjects received trospium 60 mg QD or placebo for 12 weeks. Change in the mean number of toilet voids per day and UUI episodes per day were the primary outcome variables. Changes in urgency severity were also assessed and adverse events (AEs) were recorded. RESULTS Overall, 564 subjects participated in the study (trospium QD 280; placebo 284). Trospium QD demonstrated significant improvement in both primary outcome variables. The mean number of toilet voids per day was reduced from approximately 13 at baseline to 10.3 for trospium QD versus 11.1 for placebo (P <0.001) at week 12, whereas the number of UUI episodes per day was reduced from approximately 4 at baseline to 1.7 at week 12 with trospium QD versus 2.4 for placebo (P <0.001). Trospium QD also reduced urgency severity (P <0.001) and increased voided volume (P <0.01) compared with placebo. Benefits over placebo were apparent within the first week of treatment. Trospium QD was well tolerated; the most frequent AEs being dry mouth (trospium QD 12.9%; placebo 4.6%) and constipation (7.5% versus 1.8%, respectively). Central nervous system side effects were rarely observed and were comparable between groups. CONCLUSIONS Trospium QD represents a convenient, effective, and well-tolerated treatment option for OAB.

Randomized, Double-blind, Placebo-controlled Trial of Flexible-dose Fesoterodine in Subjects With Overactive Bladder

OBJECTIVES To evaluate the efficacy and tolerability of flexible-dose fesoterodine vs placebo in subjects with overactive bladder (OAB). METHODS In a 12-week double-blind trial, subjects were randomized to fesoterodine 4 mg or placebo once daily, taken within 4 hours of bedtime. At week 2, subjects could increase the fesoterodine dose to 8 mg (sham escalation for placebo). Subjects completed 3-day bladder diaries, Patient Perception of Bladder Condition, and Urgency Perception Scale at baseline and weeks 2, 6, and 12 as well as OAB Questionnaire at baseline and week 12. RESULTS Of 883 subjects, 63% and 73% of the fesoterodine (n = 438) and placebo (n = 445) groups, respectively, opted for dose escalation. Week 12 improvements from baseline in total micturitions, urgency episodes, urgency urinary incontinence episodes, frequency-urgency sum, and all OAB Questionnaire scales and domains, but not nocturnal micturitions or nocturnal urgency episodes, were significantly greater with fesoterodine than placebo (all P <.05). Treatment differences in micturitions and frequency-urgency sum were significant by week 2 and in urgency urinary incontinence and urgency episodes by week 6. Significantly greater percentages of subjects taking fesoterodine had improved Patient Perception of Bladder Condition and Urgency Perception Scale scores at weeks 2, 6, and 12 (P <.05). Dry mouth (fesoterodine, 26%; placebo, 8%) and constipation (fesoterodine, 11%; placebo, 6%) were the most common adverse events. In both groups, 87% of the subjects completed the trial; 8% and 5% of the fesoterodine and placebo groups, respectively, discontinued because of an adverse event. CONCLUSIONS Flexible-dose fesoterodine was efficacious and generally well tolerated for treatment of OAB symptoms.

Trospium chloride has no effect on memory testing and is assay undetectable in the central nervous system of older patients with overactive bladder

Background:  Muscarinic receptors in the brain play an important role in cognitive function, especially memory, and there is growing awareness that specific antimuscarinic drugs for overactive bladder (OAB) may have adverse central nervous system (CNS) effects. Selection of an antimuscarinic OAB drug with reduced potential for CNS effects could be especially beneficial in the elderly people, in whom even the modest cognitive impairment may negatively affect independence.