SELECTED POSTER PRESENTATIONS

SELECTED POSTER PRESENTATIONS The following summaries are based on posters presented at the American Urogynecological Society 2004 Scientific Meeting, held July 29-31, 2004, in San Diego, California. CENTRAL NERVOUS SYSTEM EFFECTS WITH TWO ANTICHOLINERGIC MEDICATIONS IN WOMEN WITH OVERACTIVE BLADDER Based on a poster presented by Sand PK,* Luber K, Dmochowski R *Northwestern University Medical School, Evanston, Illinois; Kaiser Permanente Southern California, San Diego, California; Vanderbilt University Medical Center, Nashville, Tennessee between treatment groups (Table). No significant differences were noted between treatment-naive patients and those with a history of treatment with anticholinergic agents. Older patients tended to report more CNS events, but the difference was not significantly different from younger patients or between treatment groups. The Overactive Bladder Performance of Extended- Release Agents (OPERA) trial compared long-acting formulations of the anticholinergic agents oxybutynin and tolterodine in women with symptomatic overactive bladder. Overall, the trial demonstrated similar reductions in urinary incontinence episodes in patients treated with either agent. However, significantly more patients treated with oxybutynin reported achieving total dryness, and they also had a significant reduction in micturition frequency, compared with tolterodine. In vitro studies suggest that anticholinergic medications might cross the blood-brain barrier, which would create a potential for central nervous system (CNS) side effects. The incidence of CNS events was not specifically evaluated in the OPERA trial. A retrospective analysis of data from the trial sought to determine the potential for CNS events with the extended-release formulations of oxybutynin and tolterodine. OPERA was a prospective, randomized, doubleblind, parallel group, multicenter, 12-week study. Participants were evaluated at weeks 2, 4, 8, and 12. The subanalysis describes the incidence of CNS events documented during the trial. The most common adverse event in OPERA was dry mouth, reported by 29.7% of oxybutynin patients and 22.3% of tolterodine patients. Overall, the incidence of CNS side effects was low and similar Table. CNS Events by Treatment Group CNS O T Event (n = 391) (n = 399) Dizziness 10 (2.6%) 7 (1.8%) Somnolence 3 (0.8%) 8 (2.0%) Insomnia 5 (1.3%) 0 Anxiety 3 (0.8%) 2 (0.5%) Tremor 1 (0.25 %) 1 (0.25% CNS = central nervous system; O = oxybutynin; T = tolterodine. Extended-release formulations of oxybutynin and tolterodine were associated with low rates of CNS events in the OPERA trial. No significant differences were noted between treatment-naive and treatmentexperienced patients. S860 Vol. 4 (10C) November 2004

URGENCY EPISODES WERE STATISTICALLY SIGNIFICANTLY REDUCED WITH SOLIFENACIN IN PATIENTS WITH OVERACTIVE BLADDER Based on a poster presented by Lucente V,* Swift S *Institute for Female Pelvic Medicine and Reconstructive Surgery, Allentown, Pennsylvania; Medical University of South Carolina, Charleston, South Carolina, for the Solifenacin Study Group Overactive bladder (OAB) affects 17% of women, 40% of whom do not seek medical attention. Almost 75% of affected women remain untreated. Solifenacin, a once-daily oral antimuscarinic agent under development for treatment of OAB, has demonstrated statistically significant reductions in OAB symptoms in multiple clinical trials. Patients treated with solifenacin have experienced reduced episodes of urgency, incontinence, and frequency, which have been associated with low rates of dry mouth, particularly at the 5-mg dose. An analysis of 4 pivotal clinical studies was undertaken to determine the change in the number of urgency episodes per 24 hours in patients treated with solifenacin. All 4 studies had a randomized, placebo-controlled design that permitted evaluation of the safety, efficacy, and tolerability of solifenacin. Symptomatic OAB patients who reported all micturitions per 24 hours and 1 or more incontinence or urgency episodes per 24 hours were enrolled in the studies. The patients were randomized to placebo or to solifenacin 5 mg once daily in 2 of the 4 studies, and the remaining 2 studies evaluated solifenacin 5 mg once daily and solifenacin 10 mg once daily versus placebo. The change in the number of urgency episodes per 24 hours was a secondary efficacy variable in all 4 studies. Efficacy was based on urgency data from micturition diaries completed during the 3 days prior to each monthly patient visit. Two principal analyses were conducted. One analysis focused on the mean and median reductions in the number of urgency episodes per 24 hours from each of the 4 studies. A pooled analysis of the studies employed analysis of covariance with baseline as a covariate to determine overall efficacy from the trials. The analysis included 1124 evaluable patients treated with placebo, 548 treated with solifenacin 5 mg once daily, and 1151 patients treated with solifenacin 10 mg once daily. At baseline, the mean number of urgency episodes was approximately 6 per 24-hour period. Changes from baseline to end of study averaged 2.9 episodes/24 hours with solifenacin 5 mg, 3.4 episodes/24 hours with solifenacin 10 mg, and 2.0 episodes/24 hours with placebo (P <.001 for both doses). Treatment effects (active vs placebo) were 1.4 and 1.48 episodes for the solifenacin 5-mg and solifenacin 10-mg treatment arms, respectively, and both differences were statistically significant (P <.001). Additionally, 62% of solifenacin 5-mg patients and 66% of solifenacin 10-mg patients reported that urgency episodes were reduced by at least 50% at study endpoint, compared with 44% of the placebo group. Subset analysis revealed that solifenacin was equally effective in reducing urgency episodes in women and men. Women treated with 5 mg solifenacin reported a reduction of 3.0 episodes of urgency from study baseline to endpoint. That difference, as well as the reduction achieved with 10 mg solifenacin, was statistically significant compared with placebo (P <.001). In an analysis involving more than 2800 symptomatic OAB patients, treatment with solifenacin was associated with statistically significant reductions in episodes of urgency. Solifenacin appears to be the first antimuscarinic agent to achieve statistically significant reductions in quantified episodes of urgency across multiple trials. This finding was confirmed when changes in urgency episodes were evaluated in the subgroup of women. NOCTURNAL POLYURIA IN WOMEN WITH NOCTURIA AND OVERACTIVE BLADDER SYMPTOMS Based on a poster presented by Drake NL, Flynn MK, Romero AA, Weidner AC, Amundsen CL Duke University Medical Center, Durham, North Carolina The prevalence of nocturnal polyuria increases with age in men complaining of nocturia and over- Advanced Studies in Medicine S861

active bladder (OAB) symptoms. Our objective was to determine the prevalence of nocturnal polyuria in a group of women complaining of nocturia and OAB symptoms. Additionally, we sought to determine whether the risk of nocturnal polyuria increases in women aged 60 years and older and to describe the impact of the symptoms on quality of life. Participants were women presenting to a urogynecology clinic with complaints of nocturia and OAB symptoms. Patients completed a 3-day voiding diary, the Nordic sleep questionnaire, the urinary distress inventory (UDI-6), and a nocturia distress visual log. The 24-hour urine production, nighttime urine production, and functional bladder capacity were determined from the bladder diary, and the nocturnal index was calculated by dividing nighttime urine production by functional bladder capacity. Nocturnal polyuria was defined as production of more than 33% of urine volume during an 8-hour sleep cycle. Patients were divided into 2 age groups: under age 60 years and 60+ years. Additionally, patients were subdivided into groups with and without nocturnal polyuria for further analysis. A total of 55 participants completed the study. Nine were younger than 60 years of age, and the remaining 46 were 60 years of age or older. None of the younger patients met the definition of nocturnal polyuria, whereas 31 of 46 older patients did demonstrate nocturnal polyuria (P Table. Nocturnal Polyuria by Age Age (yrs) <60 60+ P value (n = 9) (n = 46) Nocturnal polyuria 0 31 <.001 Median number of nighttime voids 3 3 24-hour urine output (median, ml) 1680 1755 Maximum bladder capacity (median, ml) 350 305 Nocturnal index 1.75 2.2 UDI-6 33.0 38.9 Nocturnal distress score 8 8 Insomnia score 11 11.5 Sleepiness score 7 8 UDI-6 = urinary distress inventory. <.001, Table). The age groups did not differ with respect to mean values for the UDI-6, nocturnal distress visual log, sleep, and insomnia scores. Moreover, when patients were divided according to whether they had nocturnal polyuria, scores between the groups did not differ for any of the outcomes measures assessed. The 24-hour urine output and maximum bladder capacity do not differ significantly by age in the diagnosis of nocturnal polyuria. In the community-dwelling population, women aged 60 years and older had an increased rate of nocturnal polyuria. The frequency/volume diary is a useful tool for the diagnosis of nocturnal polyuria. BOTULINUM A TOXIN (BOTOX) INJECTION FOR THE TREATMENT OF REFRACTORY OVERACTIVE BLADDER Based on a poster presented by Abdelmalak JB, Rackley RR, Vasavada SP, Ghoniem G, El-Azab AS, Moy L Cleveland Clinic Foundation, Cleveland, Ohio Botulinum A toxin (Botox) is a presynaptic inhibitor of acetylcholine release and an accepted treatment for skeletal muscle spasticity and focal smooth muscle contraction. Botox has also been injected into the detrusor muscle for treatment of urinary incontinence due to neurogenic detrusor overactivity. 1 The investigators report their results of a pilot study of Botox to treat patients with refractory overactive bladder (OAB). Eighteen patients with refractory OAB have been enrolled. The mean age of the patients is 57 years. Pretreatment evaluation consists of medical history, physical examination, urine and blood studies for infection, ultrasound of the upper urinary tract to rule out renal obstruction, and urodynamics and bladder ultrasound. The injection technique begins with the bladder filled with 100 ml of 2% lidocaine, which remains in the bladder for 20 minutes. Under cystoscopic visualization, the 300 U of Botox is injected into 30 sites in the detrusor muscle (10 U/0.1 ml/site). Patients have to complete a 3-day voiding diary, bladder perception (OABq) and quality of life questionnaires (Urinary Distress S862 Vol. 4 (10C) November 2004

Table. Changes in [values] from Baseline to 6 Months 3-Month Follow-up 6-Month Follow-up Baseline Mean P value Mean P value Value Value % changes Value % changes F 10.7 8.8 17.7.01 10.3 3.7.06 L 4.2 2.5 40.4.01 2.5 40.4.46 U 6 4 33.3.08 4.2 30.23 BP 3.6 2.5 30.5.001 2.4 33.3.02 IIQ7 14.8 10.4 29.7.01 11 25.7.1 UDI6 10 8.1 19.23 8.7 13.2 F = frequency; L = leaks; U = urgency; BP = bladder perception; IIQ7 = Incontinence Impact Quesionnaire; UDI6 = Urinary Distress Inventory. Inventory-6 and Incontinence Impact Questionnaire- 7) before injection and at 3 and 6 months after injection. All patients tolerated the procedure very well. At a 3-month follow-up, there was improvement in most outcomes of 20% to 40%, which is statistically significant. At 6 months follow-up, the improvement was not as durable (Table). There were no short- or longterm complications except blood in urine after the injection, which is self-limited. Botox injected into the detrusor muscle is safe and effective for treatment of refractory OAB. The treatment is reversible, less invasive, and less expensive compared with other options. On the basis of the results of this pilot study, a multicenter, prospective study with long-term follow-up is warranted. REFERENCE 1. Reitz A, Stohrer M, Kramer G, et al. European experience of 200 cases treated with botulinum-a toxin injections into the detrusor muscle for urinary incontinence due to neurogenic detrusor overactivity. Eur Urol. 2004;45(4):510-515. DO CHRONIC CONDITIONS AND PSYCHOLOGICAL HEALTH PLAY A ROLE IN URINARY INCONTINENCE? Based on a poster presented by Romero AA, Jamison MG, Weidner AC, Amundsen CL Duke University Medical Center, Durham, North Carolina Urinary incontinence affects a substantial proportion of women across all age groups. Incontinence may be related to poor health and impairments in mental and physical functioning. Factors known to be associated with an increased prevalence of urinary incontinence include obesity, gynecologic operations, chronic respiratory illness, constipation, parity, and jobs involving heavy lifting. Studies evaluating individuals with urinary incontinence and associated functional loss have demonstrated that women with incontinence and functional loss secondary to incontinence are more likely to have more psychological distress. Resilience can be defined as the tendency to rebound, recoil or to spring back, the power of recovery. The benchmark of resilient behavior is the ability to maintain competent functioning despite interfering emotionality. The objective of this study was to compare physical and psychological health characteristics among 3 age groups of women with and without urinary incontinence and to evaluate the effects of incontinence on physical functioning. The Midlife Development in the United States Survey, a nationally representative random sample of 1735 women aged 25 to 75 years, was used. The survey evaluates more than 2000 variables. The Interactive Activity of Daily Living (iadl) assessed daily functioning such as limitations to climb stairs, bend or kneel, walk, or perform moderate activity. Combining questions on control over life, satisfaction with self, solution of life s problems, and contribution to others, a score measuring resilience, an overall measure of psychological health, was created. Women with and without urinary incontinence across 3 age groups (25 to 39 years, 40 to 59, and 60 to 75 years) were compared. The researchers further compared women without urinary incontinence or chronic conditions with women with urinary incontinence and individual chronic medical conditions. Advanced Studies in Medicine S863

Table. Number of Chronic Conditions Age (yrs) UI No UI P value 25-39 3.3 2.3 <.01 40-59 4.3 2.6 <.01 60-75 5.2 2.0 <.01 UI = urinary incontinence. The prevalence of urinary incontinence was 15.1%, 36.3%, and 44% among the young, middle, and older groups, respectively. An evaluation of risk factors for urinary incontinence showed that obesity was the only factor that predicted increased risk across all age groups. Chronic lung disease, back conditions, chronic sleeping problems, hysterectomy, and parity of greater than 1 demonstrated inconsistent effects across age groups, but each factor had some effect on at least one age group. Across all age groups, women with incontinence had significantly more chronic conditions compared to women without (Table). A comparison of women with and without urinary incontinence revealed more health-related limitations on daily functioning in women with urinary incontinence. The iadl scores demonstrated significantly greater limitation among incontinent women across all age groups with respect to climbing stairs, bending, or kneeling. Comparison of resilience among women with and without incontinence showed significantly lower scores with respect to solution of life problems for all age groups of women with incontinence. Women with urinary incontinence have significantly more chronic conditions than women without urinary incontinence. Obesity is a risk factor for urinary incontinence across all age groups. Additional risk factors are hysterectomy, chronic sleeping problems, parity, and sciatica or backache. Women with incontinence demonstrated more health-related limitations on daily functioning and decreased resilience, especially in solving life problems. THE EFFECTS OF DARIFENACIN ON THE REDUCTION OF INCONTINENCE EPISODES IN PATIENTS WITH OVERACTIVE BLADDER Based on a presentation by Hill S Queen s Park Hospital, Blackburn, United Kingdom Overactive bladder (OAB) is a particularly prevalent condition among older populations. The unpredictability of urge incontinence can cause considerable distress that impairs quality of life. Darifenacin is a highly selective muscarinic M3 receptor antagonist developed for treatment of OAB. Because of the selectivity of the agent, the likelihood of tolerability and safety problems due to non-m3 blockade is reduced. A multicenter, double-blind, placebo-controlled trial evaluated darifenacin in patients with symptomatic OAB, with a particular emphasis on reducing episodes of incontinence. The trial involved adults with OAB symptoms for at least 6 months, including 5 or more urge incontinence episodes weekly, micturition frequency of 8 or more voids daily, and one or more urgency episodes daily. The patients were randomized to placebo or to one of 2 doses of darifenacin (7.5 mg or 15 mg, both once daily) and followed for 12 weeks. The primary endpoint was the change from baseline to 12 weeks in the number of weekly incontinence episodes. Efficacy was evaluated by means of a validated electronic diary. Tolerability and safety were evaluated by means of adverse event reports, laboratory assessment, vital signs, and withdrawal from the study. The trial involved 324 patients aged 21 to 88 years, 85% of whom were female and 27.2% of whom were 65 years of age or older. Median number of incontinence episodes weekly ranged between 13.7 and 17.3 in the 3 treatment groups. Overall, 293 (90.4%) patients completed the study. The principal reasons for discontinuation were adverse events and withdrawal of consent. Compared with placebo, both doses of darifenacin significantly reduced weekly episodes of incontinence. The 7.5-mg dose of darifenacin resulted in a median difference of 2.8 episodes versus placebo at 12 weeks (P =.007), and the difference was 4.3 episodes for the 15-mg dose (P <.001). Significant differences in favor of darifenacin were evident within 2 weeks after begin- S864 Vol. 4 (10C) November 2004

ning treatment. Significantly more darifenacin-treated patients achieved 50% or greater, 70% or greater, and 90% or greater reductions in incontinence episodes compared with placebo. The most common treatment-related adverse event was dry mouth, which occurred in 23.1% and 39.3% of patients treated with 7.5 mg and 15 mg of darifenacin, respectively. Constipation occurred in 15.7% of patients receiving 7.5 mg darifenacin and 25.2% of the 15-mg group. Few patients discontinued because of adverse events (0% with 7.5 mg darifenacin, 0.9% with 15 mg darifenacin). Treatment-related central nervous system adverse events occurred in 0.9% of the darifenacin 7.5-mg group and 3.7% of the 15-mg group. Treatmentrelated cardiovascular events occurred in 2.8% of the darifenacin 7.5-mg group and in 0.9% of patients receiving 15 mg. No serious adverse events or clinically relevant laboratory changes occurred during the trial. Darifenacin at once-daily doses of 7.5 mg and 15 mg significantly reduced the frequency of urge incontinence and allowed a substantial proportion of patients a level of continence approaching normal ( 90%). Darifenacin had a favorable tolerability and safety profile. The findings indicate that darifenacin represents a promising approach to the treatment of OAB. Advanced Studies in Medicine S865

NOTES S866 Vol. 4 (10C) November 2004