Sender Herschorn

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

Efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: a randomised, double-blind, placebo-controlled trial.

BACKGROUND Neurogenic detrusor overactivity (NDO) frequently results in urinary incontinence (UI) which impairs quality of life (QOL) and puts the upper urinary tract at risk. OBJECTIVE To assess the effects of onabotulinumtoxinA (BOTOX(®), Allergan, Inc.) on UI, urodynamic variables, and QOL in incontinent patients with NDO. DESIGN, SETTING, AND PARTICIPANTS This multicentre, randomised, double-blind, placebo-controlled study enrolled patients with multiple sclerosis (MS; n=154) or spinal cord injury (SCI; n=121) with UI due to NDO (≥14 UI episodes per week). INTERVENTION Patients received 30 intradetrusor injections of onabotulinumtoxinA 200 U (n=92), 300 U (n=91), or placebo (n=92), avoiding the trigone. MEASUREMENTS Primary end point was change from baseline in UI episodes per week (week 6). Secondary end points included urodynamics (maximum cystometric capacity [MCC], maximum detrusor pressure during first involuntary detrusor contraction [P(detmaxIDC)]), and Incontinence Quality of Life (I-QOL) total score. Adverse events (AEs) were assessed. RESULTS AND LIMITATIONS At baseline, mean UI episodes per week (33.5) were similar across groups. At week 6, onabotulinumtoxinA 200 U and 300 U significantly reduced UI episodes per week (-21.8 and -19.4, respectively) compared with placebo (-13.2; p<0.01); onabotulinumtoxinA benefit was observed by the first posttreatment study visit at week 2. Improvements in MCC, P(detmaxIDC), and I-QOL at week 6 were significantly greater with both onabotulinumtoxinA doses than with placebo (p<0.001). Benefits were observed in both the MS and SCI populations. The median time to patient request for retreatment was the same for both onabotulinumtoxinA doses (42.1 wk) and greater than placebo (13.1 wk; p<0.001). Most frequent AEs were localised urologic events (urinary tract infections and urinary retention, which were dose related in patients not using clean intermittent catheterisation [CIC] at baseline). Significant increases in postvoid residual were observed in patients not using CIC prior to treatment, and 12%, 30%, and 42% of patients in the placebo, 200-U, and 300-U groups, respectively, initiated CIC posttreatment. CONCLUSIONS OnabotulinumtoxinA significantly reduced UI and improved urodynamics and QOL in MS and SCI patients with NDO. Both doses were well tolerated with no clinically relevant differences in efficacy or duration of effect between the two doses (http://www.clinicaltrials.gov; NCT00461292).

Results of a Randomized Phase III Trial of Mirabegron in Patients with Overactive Bladder

PURPOSE Many patients with overactive bladder discontinue pharmacotherapy due to suboptimal efficacy or side effects. Mirabegron, a β3-adrenoceptor agonist, may offer an effective and well tolerated alternative treatment for overactive bladder. MATERIALS AND METHODS A randomized, double-blind, placebo controlled trial was conducted in the United States and Canada. After a 2-week placebo run-in period, adults with overactive bladder symptoms for 3 or more months were randomized 1:1:1 to receive placebo, 50 or 100 mg mirabegron once daily for 12 weeks. Efficacy data were collected via patient completed diaries and quality of life assessments. Co-primary efficacy end points were changes from baseline to final visit in mean number of incontinence episodes per 24 hours and micturitions per 24 hours. Key secondary micturition and incontinence end points were also evaluated. Safety assessments included treatment emergent adverse events, laboratory assessments, vital signs, electrocardiograms and post-void residual volume. RESULTS Compared to placebo, 50 and 100 mg mirabegron groups demonstrated statistically significantly greater mean decreases (95% CI) from baseline for incontinence episodes (-1.13 [-1.35, -0.91], -1.47 [-1.69, -1.25] and -1.63 [-1.86, -1.40]) and micturitions (-1.05 [-1.31, -0.79], -1.66 [-1.92, -1.40] and -1.75 [-2.01, -1.48]) per 24 hours (p <0.05). Significant improvements in all key secondary end points were observed for both mirabegron doses vs placebo. The incidence of frequently reported treatment emergent adverse events (hypertension, urinary tract infection, headache, nasopharyngitis) was similar in the mirabegron and placebo groups. Dry mouth was reported for 1.5%, 0.5% and 2.1% of patients in the placebo, 50 and 100 mg mirabegron groups, respectively. CONCLUSIONS Once daily mirabegron in a 50 or 100 mg dose is an effective treatment for overactive bladder symptoms with a low occurrence of side effects.

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.

A Phase III, Randomized, Double-blind, Parallel-group, Placebo-controlled, Multicentre Study to Assess the Efficacy and Safety of the β3 Adrenoceptor Agonist, Mirabegron, in Patients With Symptoms of Overactive Bladder

OBJECTIVE To assess the efficacy and tolerability of mirabegron 25 mg and 50 mg once-daily vs placebo in patients with overactive bladder (OAB). MATERIALS AND METHODS Patients ≥18 years with OAB symptoms were recruited to a 2-week, single-blind, placebo run-in. Those with ≥8 micturitions per 24 hours and ≥3 urgency episodes were randomized 1:1:1 to once-daily mirabegron 25 mg or 50 mg, or placebo for 12 weeks. Primary endpoints were changes to final visit in mean number of incontinence episodes and micturitions per 24 hours. Key secondary endpoints were changes to final visit in mean volume voided or micturition, change to week 4 in mean number of incontinence episodes and micturitions per 24 hours, changes to final visit in mean level of urgency, number of urgency incontinence episodes, and urgency (grade 3 or 4) episodes per 24 hours. Patient-reported outcomes were assessed using the OAB-questionnaire, Patient Perception of Bladder Condition, and Treatment-Satisfaction-Visual Analog Scale. RESULTS Both mirabegron groups demonstrated statistically significant improvements in coprimary endpoints vs placebo. Mirabegron 50 mg demonstrated significantly greater improvements vs placebo in the following: change to final visit in mean volume voided per micturition and change to week 4 in mean number of incontinence episodes per 24 hours. Statistically significant improvements vs placebo were demonstrated by mirabegron 50 mg in all patient-reported outcome scales with no increase in the incidence of treatment-emergent adverse events vs placebo. CONCLUSION Mirabegron 25 mg and 50 mg were associated with significant improvements in efficacy measures of incontinence episodes and micturition frequency. Mirabegron was well tolerated vs placebo.

Tolterodine Treatment Improves Storage Symptoms Suggestive of Overactive Bladder in Men Treated With α-Blockers

BACKGROUND Some men receiving alpha-blocker therapy for lower urinary tract symptoms report persistent storage symptoms suggestive of overactive bladder (OAB). OBJECTIVE To evaluate the efficacy of tolterodine extended release (ER) in men on alpha-blocker therapy. DESIGN, SETTING, AND PARTICIPANTS This double-blind trial included men aged > or = 40 yr with frequency, urgency, and at least moderate problems reported on the Patient Perception of Bladder Condition (PPBC), despite being on a stable dose of alpha-blocker for > or = 1 mo. INTERVENTIONS Subjects were randomized to tolterodine ER 4 mg per day or placebo for 12 wk while continuing their prescribed alpha-blocker therapy. MEASUREMENTS At baseline and week 12, subjects completed the PPBC, International Prostate Symptom Score (IPSS), Overactive Bladder Questionnaire (OAB-q), and 5-d bladder diaries using the five-point Urinary Sensation Scale (USS). Frequency-urgency sum was defined as the sum of USS ratings for all micturitions. RESULTS AND LIMITATIONS PPBC improvement from baseline to week 12 was reported by 63.6% and 61.6% of subjects receiving tolterodine ER plus alpha-blocker and placebo plus alpha-blocker, respectively; this treatment difference, which was the primary end point, was not statistically significant (p>0.6699). At week 12, subjects receiving tolterodine ER plus alpha-blocker had significantly greater improvements versus placebo plus alpha-blocker in 24-h micturitions (-1.8 vs -1.2; p=0.0079) and daytime micturitions (-1.3 vs -0.8; p=0.0123); 24-h urgency episodes (-2.9 vs -1.8; p=0.0010), daytime urgency episodes (-2.2 vs -1.4; p=0.0017), and nocturnal urgency episodes (-0.5 vs -0.3; p=0.0378); frequency-urgency sum (-7.8 vs -5.1; p=0.0065); IPSS storage subscale (-2.6 vs -2.1; p=0.0370); and OAB-q symptom bother scale (-17.9 vs -14.4; p=0.0086) and coping domain (15.4 vs 12.4; p=0.0491). Acute urinary retention requiring catheterization occurred in < 1% of either group. There were no clinically meaningful changes in postvoid residual volume or maximum urinary flow rate. CONCLUSIONS Men with bothersome OAB symptoms despite continued alpha-blocker therapy showed significantly greater improvements in diary variables, IPSS Storage scores, and symptom bother when receiving additional tolterodine ER versus placebo plus alpha-blocker.

Surgical treatment of stress incontinence in men.

The committee was charged with the responsibility of reviewing and evaluating all published data relating to surgical treatment of male urinary incontinence since the previous consultation in 2004.

Mirabegron for the treatment of overactive bladder: a prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double-blind, placebo-controlled, phase III studies.

To examine pooled efficacy data from three, large phase III studies comparing mirabegron (50 and 100 mg) with placebo, and pooled safety data including additional mirabegron 25 mg and tolterodine extended release (ER) 4 mg results.

Prevalence, Severity, and Symptom Bother of Lower Urinary Tract Symptoms among Men in the EPIC Study: Impact of Overactive Bladder

BACKGROUND Lower urinary tract symptoms (LUTS) are prevalent among men. OBJECTIVE To describe the prevalence, severity, and symptom bother of LUTS in all men and men with overactive bladder (OAB) symptoms in the EPIC study. DESIGN, SETTING, AND PARTICIPANTS A secondary analysis of data from EPIC, a multinational population-based survey of 19,165 adults, was performed. Current International Continence Society definitions were used for individual LUTS and OAB; OAB cases were defined as men reporting urgency. MEASUREMENTS Participants were asked about the presence of individual LUTS and associated symptom bother. LUTS severity was measured using the International Prostate Symptom Score (IPSS). RESULTS AND LIMITATIONS There was substantial overlap of storage, voiding, and postmicturition symptoms among all men (n=7210) and in men with OAB symptoms (n=502); men with OAB symptoms were more likely to experience multiple LUTS subtypes. Among both populations, nocturia was the most commonly reported symptom, except for urgency (the hallmark symptom) among men with OAB symptoms; terminal dribble and sensation of incomplete emptying were the most common voiding and postmicturition symptoms. The prevalence of all LUTS increased with age among the general population; only storage LUTS increased with age among men with OAB symptoms. Number of LUTS and mean IPSS increased with age in both populations but were higher among men with OAB symptoms at all ages; the proportion reporting moderate-severe LUTS was higher than the general population (30% vs 6%). The proportion of men with OAB symptoms reporting symptom bother increased with urgency severity and severity and number of LUTS. LUTS severity may have been underestimated by the IPSS, which does not assess incontinence. CONCLUSIONS Men with LUTS commonly experience coexisting storage, voiding, and postmicturition symptoms, emphasizing the need for comprehensive urologic assessments. Men with OAB symptoms reported more LUTS and greater severity than the general population. Symptom bother was related to number of LUTS and urgency severity.

Early experience with intraurethral collagen injections for urinary incontinence

We report on 41 patients (10 men and 31 women) who underwent collagen injections for urethral incompetence. Mean followup was 6 months (range 3 to 11 months) in men cured or improved, 8.4 months (range 3 to 15 months) in women who were cured and 4.5 months (range 2 to 10 months) in women who were improved. In women the procedure was usually performed through a periurethral approach while they were under local anesthesia and in men it was performed transurethrally while under either general or local anesthesia. Of the 31 women 28 (90.3%) were cured (15) or improved (13). Mean maximum Valsalva pressure increased from 31 cm. water before injection to 85 cm. water at 6 months after injection in women who were cured or improved. The mean amount of collagen used in the female group was 12.7 cc (range 2.5 to 47.5) and the mean number of treatments was 2 (range 1 to 7). Of the men 7 (70%) had successful results (2 cured and 5 improved). In contrast to the women, they required a mean of 51.8 cc (range 7.5 to 82.5) of collagen and a mean of 6 treatments (range 3 to 12). Of 5 patients with bladder instability 4 did not improve. One patient suffered acute bacterial prostatitis and 2 patients had post-injection urinary retention. All women with little or no bladder neck hypermobility (types 1 and 3) were either cured or improved. We conclude that intraurethral collagen injection is safe and simple to perform. The results achieved in women are acceptable. In men, while collagen does provide improvement, the cost-to-benefit ratio and effectiveness are less than those in women. Instability may obviate a good outcome.