38th Annual Congress of the Italian Urodynamic Society (Continence, Neuro-Urology, Pelvic Floor) Centro Congressi San Raffaele, Milano, Italy 19–21 June 2014
Abstract 1 - LONG-TERM EFFICACY, SAFETY, AND QUALITY OF LIFE ANALYSIS OF REPEATED ONABOTULINUMTOXINA TREATMENT FOR PATIENTS WITH IDIOPATHIC OVERACTIVE BLADDER SYNDROME AND URINARY INCONTINENCE Stefano Salvatore(1), Christopher Chapple(2), David Sussman(3), Sidney Radomski(4), Peter Sand(5), Steven Guard(6), Jihao Zhou(7), Karl Dietrich Sievert(8), Victor Nitti(9) Irccs San Raffaele, Universita Vita-salute San Raffaele, Milano, Italia (1); Royal Hallamshire Hospital, Royal Hallamshire Hospital, Sheffield, Regno Unito (2); Nj School Of Osteopathic Medicine, Nj School Of Osteopathic Medicine, Newark, Nj, Stati Uniti D’ America (3); University Of Toronto, University Of Toronto, Toronto, Canada (4); University Of Chicago, University Of Chicago, Chicago, Il, Stati Uniti D’ America (5); Allergan, Ltd., Allergan Ltd., Marlow, Regno Unito (6); Allergan Inc, Allergan Inc, Bridgewater, Nj, Stati Uniti D’ America (7); University Of Tuebingen, University Of Tuebingen, Tuebingen, Germania (8); New York University, New York University, New York, Ny, Stati Uniti D’ America (9) INTRODUCTION AND AIM OF THE STUDY In patients with idiopathic overactive bladder syndrome and urinary incontinence who were inadequately managed by 1 anticholinergic, onabotulinumtoxinA has been shown to significantly improve urinary incontinence and quality of life in two large, placebo-controlled, multicenter, phase 3 trials. Less is known about the long-term efficacy, safety, and patientrelated quality of life outcomes of onabotulinumtoxinA for treatment of idiopathic overactive bladder. Herein we report the third, pre-specified interim analysis of a large, multicenter, extension study of the long-term efficacy, safety, and healthrelated quality of life outcomes of onabotulinumtoxinA for the treatment of patients with urinary incontinence due to idiopathic overactive bladder. MATERIALS AND METHODS On completion of the two pivotal, phase 3 studies, patients could enter a 3-year extension study to receive multiple treatments of onabotulinumtoxinA (ClinicalTrials.gov identifier NCT00915525). Retreatment criteria included patient request, 2 urgency urinary incontinence episodes within a 3-day period (as recorded in a patient bladder diary), post-void residual urine volume of 12 weeks since the previous treatment. At each treatment, patients received 20 intra-detrusor injections of onabotulinumtoxinA (total dose of 100 U), administered cystoscopically, avoiding the trigone. Data were integrated across the two phase 3 studies and the extension study. Patients receiving 1 onabotulinumtoxinA treatment in the evaluation period were analyzed by onabotulinumtoxinA treatment cycle (up to 5 cycles). The co-primary endpoints were the change from study baseline in the average frequency of daily urinary incontinence episodes and the proportion of patients with a positive treatment response (patient reporting condition as greatly improved or improved) on the Treatment Benefit Scale, both at week 12. Other variables assessed at week 12 included the changes from baseline in daily micturition episodes, daily urgency episodes, volume voided per micturition, Incontinence-Quality of Life total summary score, and the Role Limitations and Social Limitations domains of the King’s Health Questionnaire. Duration of effect, adverse events, and use of clean intermittent catheterization were also evaluated.
Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/nau.22620
2014 Wiley Periodicals, Inc.
RESULTS A total of 829, 603, 351, 216, and 137 patients received 1, 2, 3, 4, and 5 onabotulinumtoxinA 100 U treatments, respectively, at the time of this interim analysis. Of those patients, 544 patients were followed up for at least 2 years. As of June 2013, the median time of follow-up was 126 weeks (2.4 years). Discontinuations due to adverse events and lack of efficacy were low (4.5% and 4.9%, respectively). After repeat onabotulinumtoxinA treatment, daily urinary incontinence episodes were consistently reduced from a baseline mean value of 5.55; reductions at week 12 were 3.26, 3.70, 3.87, 3.20, and 3.22 in cycles 1 through 5, respectively. Continued reductions at week 12 compared with baseline values were also observed for other overactive bladder symptoms over repeated onabotulinumtoxinA treatment cycles: daily micturition episodes were reduced by 2.56, 2.91, 2.81, 2.37, and 2.55 in cycles 1 through 5, respectively, and urgency episodes showed reductions of 3.81, 4.08, 4.19, 3.66, and 3.77 in cycles 1 through 5, respectively. Mean increases from baseline in volume voided per micturition of 51.0, 55.9, 54.2, 48.4, and 48.0 mL were seen in cycles 1 through 5 at week 12 following onabotulinumtoxinA treatment. High proportions of patients treated with onabotulinumtoxinA reported positive responses on the Treatment Benefit Scale (74.0%, 80.9%, 80.4%, 79.4%, and 86.1% in cycles 1 through 5, respectively). Continued clinically meaningful improvements from baseline were observed for health-related quality of life measures with repeated onabotulinumtoxinA treatment. Thus, mean increases from baseline in the Incontinence-Quality of Life total summary score at week 12 were 26.0, 28.5, 26.6, 25.4, and 26.6 in cycles 1 through 5, respectively, which correspond to 2.5-fold change over the minimal important difference (þ10 points). Favorable changes in the Role Limitations and Social Limitations domains of the King’s Health Questionnaire were also observed at week 12 following repeated onabotulinumtoxinA treatments. Decreases from baseline in the Role Limitations domain exceeded the minimal important difference (5 points) by >5-fold, with changes of 28.5, 31.8, 28.7, 29.8, and 30.6 during the first 5 cycles. Social Limitations scores changed 18.4, 19.8, 17.2, 18.3, and 21.3 at cycles 1 through 5, respectively, which exceeded the minimal important difference by >3-fold at all cycles. The median duration of onabotulinumtoxinA effect, measured as the time to patient request for retreatment, was 24.0, 31.6, 27.9, 24.3, and 23.9 weeks at cycles 1 through 5, respectively. The most common adverse events in each treatment cycle were localized urological events (urinary tract infection, dysuria, urinary retention, and bacteriuria). No change in the profile of adverse events was observed over time. The rates of clean intermittent catheterization for any reason were low at 4.6%, 4.0%, 4.3%, 4.6%, and 2.9% at cycles 1 through 5, respectively. INTERPRETATION OF RESULTS Results from this third interim analysis of the 3-year extension study show that repeated onabotulinumtoxinA treatment resulted in sustained and clinically meaningful improvements in all overactive bladder symptoms, patient perception of improvement in their condition, and health-related quality of life. A consistent safety profile was observed, with no new safety signals, over this long-term study. CONCLUSIONS Long-term, repeated onabotulinumtoxinA 100 U treatment in patients with overactive bladder syndrome with urinary incontinence who were inadequately managed with 1 anticholinergic resulted in sustained improvements in over-
active bladder symptoms and health-related quality of life, with no new safety signals. 2 - URGE AND STRESS URINARY INCONTINENCE FINDINGS AFTER DELIVERY: A PROSPECTIVE EVALUATION IN 709 WOMEN Filomena Sileo(1), Umberto Leone Roberti Maggiore(1), Alice Cola(1), Ilaria Baini(1), Fabio Del Deo(2), Gabriele Siesto(3), Massimo Candiani(1), Stefano Salvatore(1) Irccs San Raffaele, Universita Vita-salute San Raffaele, Milano, Italia (1); Dipartimento Della Donna, Del Bambino E Di Chirurgia Generale E Specialistica, Seconda Universita Degli Studi Di Napoli, Napoli, Italia (2); Irccs Humanitas, Istituto Clinico Humanitas, Rozzano, Italia(3) INTRODUCTION AND AIM OF THE STUDY Pregnancy and urinary symptoms have been correlated in many retrospective studies. However prospective data are still rare. The aim of our prospective longitudinal study was to evaluate the relationship among demographic characteristics, pregnancy-related factors, management of labour and mode of delivery and urinary symptoms before, during and after pregnancy and delivery. MATERIALS AND METHODS Cosecutive women referred to our Labour Ward were enrolled in this study, regardless their mode of delivery. Data collected in labour ward included: obstetric and medical history and, more in detail, data on management of labour and mode of delivery, lacerations,. During the hospitalization, women were asked, through an anonymous questionnaire, about their urinary, sexual and anal function before and during pregnancy. The main exclusion criterion was language barrier. After six months, women were asked the same questions by phone or through an anonymous online questionnaire. Continuous variables were compared with Mann-Whitney or Student’s ttest as appropriate. Proportions of categorical variables were analyzed for statistical significance by using the Fisher exact test. A P value < 0.05 was considered statistically significant. Data analysis was performed using IBM SPSS Statistics, version 21. RESULTS Seven hundreds and nine women were enrolled on admission in our Labour Ward between June 2012 and June 2013. Five hundreds (500/709, 71%) women answered the questions six months after delivery with a mean age of 34.2 years old (range, 20–49). Of the women interviewed, 287 (57,4%) were nulliparous, 166 (33,2%) had had at least one previous delivery (without previous Caesarean Section (CS)), 43 (8,6%) had had at least one CS (without previous delivery) and only 4 (0,8%) had had previously both. Mean BMI before pregnancy was 22.54 kg/m2 (range 13.97–44.53) while mean BMI at delivery was 27.08 kg/ m2 (range 18.08–48.89); 26/500 (5.2%) women were obese at the beginning of pregnancy, while the number raised to 104/ 500 (20.8%) at the end. Newborn mean weight was 3231.04 (rante 545–4830) with a number of 24/500 (4.8%) macrosome babies. In our population 332/500 (66.4%) women had a spontaneous vaginal delivery, 19/500 (3.8%) had a vaginal operative delivery and 149/500 (29.8%) had a Caesarean Section. In these preliminary data we decided to analyse urinary symptoms more in detail, i.e. urgency (U), urge incontinence (UI) and stress urinary incontinence (SUI) that are usually the most common disorders complained by women during pregnancy. Table I shows the distribution of U, UI and SUI before and during pregnancy, after delivery and the rate of de novo occurrence. Neurourology and Urodynamics DOI 10.1002/nau
Worsening during Pregnancy
De-novo in pregnancy
Worsening compared to 10/43 before pregnancy
De-novo post partum
Persistence from pregnancy
In the multivariate analysis considering each urinary PFD before pregnancy and age, parity, previous CS, BMI before pregnancy and hair type, BMI before pregnancy was significantly associated with UI (P ¼ 0.026, OR 1.087, CI 1.010, 1.170) and SUI (P ¼ 0.019, OR 1.082, CI 1.013, 1.155) before pregnancy. In the multivariate analysis considering each PFD worsening during pregnancy and age, hair type, parity, previous CS, obesity and gain of weight more than 20 kilos, SUI worsening during pregnancy resulted significantly associated with nulliparous (P ¼ 0.032, CI 0.215, 0.931). In the multivariate analysis considering each PFD after pregnancy and age, hair type, labour and being obese at the end of pregnancy, U de novo post partum was significantly associated with being obese at the end of the pregnancy (P ¼ 0.019, OR 0.519, CI 0.299, 0.900) while UI persistence resulted significantly associated with age (P ¼ 0.000, OR 1.119, CI 1.055, 1.187), labour (P ¼ 0.014, OR 0.387, CI 0.182, 0.824), hair type (P ¼ 0.027, OR 1.645, CI 1.059, 2.556) and being obese at the end of the pregnancy (P ¼ 0.002, OR 0.412, CI 0.233, 0.728); UI de novo post partum resulted significantly associated with age (P ¼ 0.000, OR 1,145, CI 1.062, 1.234) and being obese at the end of pregnancy (P ¼ 0.04, OR 0,366, CI 0.185, 0.726); also UI worsening post partum was significantly associated with age (P ¼ 0.009, OR 1.086, CI 1.021, 1.155) and being obese at the end of pregnancy (P ¼ 0.004, OR 0,413, CI 0.226, 0.756). In a univariate analysis, age was associated with SUI de novo post partum (P ¼ 0.002, OR 1.078, CI 1.028, 1.130) and SUI worsening post partum (P ¼ 0.003, OR 1.070, CI 1.023, 1.120) and also in a multivariate analysis age resulted associated to SUI persistence after pregnancy (P ¼ 0.018, OR 1.078, CI 1.012, 1.131). INTERPRETATION OF RESULTS The association between U and UI and BMI before pregnancy is well known in literature.Our results also demonstrate that BMI is already a relevant factor in a younger population such as fertile women and not only among old ladies. Regarding to urinary disorders during pregnancy and, in particular to U and UI which represents the most important symptoms of overactive bladder, it’s remarkable their high prevalence in our population, which can be explained not only by the age of the population itself (mean age is 34.2 y.o.) but probably also regarding to pregnancy and its changes to the urinary function and, especially, to the pelvic floor muscles and innervation. The importance of pregnancy itself on pelvic floor muscles and their role in preserving continence is, in fact, underlined also by the statistically significant association between SUI and nulliparous: the changes induced by pregnancy becomes relevant to a pelvic floor that has never experimented before a so dramatic change as first pregnancy. It’s not surprising that almost all the urinary PFD post partum (either persistent after pregnancy, de novo or worsen after
Abstract pregnancy) are significantly associated with age; age has been always associated with the increase of urinary PFD prevalence among general population in other previous studies2 and this trend results confirmed also in our study. Another association well established in literature is the relationship between PFD and obesity: in our study it merges that being obese at the end of pregnancy is significantly associated with PFD; this probably means that the weight over pelvic floor muscles and their consequently stretching is an important risk factor for PFD if it exceeds physiological ranges. Probably, the stretching involves also other structure and, in particular, the pudendal nerve: its damage seems to be involved in almost all PFD, not only the urinary ones, thanks to its common innervation to the pelvic floor muscles, bladder and rectum. Even if it usually recovers 6 months after delivery, when the PFD is already referred before pregnancy, a summative damage of pudendal nerve can be involved in its persistency, such as in our association between UI persistence and labour. CONCLUSIONS Over the past decades, the very high prevalence of pelvic floor dysfunction among middle-aged women, i.e. pelvic organ prolapse and urinary and anal incontinence, has focused increasing attention on these disorders, leading to the study of likely risk factors for these conditions and, in particular, paying attention to pregnancy and mode of delivery. In fact, reduction in both perinatal and maternal mortality rates in recent decades underlines the need for a new attention on good quality of life during and after pregnancy; moreover there is the will to reduce social and medical costs associated to the development of urinary incontinence later in life. REFERENCES (1) Nygaard I, Barber MD, Burgio KL, Kenton K, Meikle S, Schaffer J, Spino C, Whitehead W, Wu J, Brody DJ. Prevalence of Symptomatic Pelvic Floor Disorders in US Women. JAMA. 2008; 300(11): 1311–1316; (2) Irwin, D. E., Milsom, I., Hunskaar, S. et al.: Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 2006, 50: 1306. 3 - MID-URETHRAL SLINGS FOR PERSISTENT OR RECURRENT FEMALE STRESS URINARY INCONTINENCE Elisabetta Costantini(1), Franca Natale(2), Giorgio Vittori(3), Manuel Di Biase(4), Francesca Quadrini(1), Amelia Pietropaolo(4), Eleonora Salvini(1), Herald Nikaij(4), Mauro Cervigni(5) Clinica Urologica Ed Andrologica, Ospedale Santa Maria Della Misericordia, Universita Degli Studi Di Perugia, Perugia, Italia (1); Uoc, Uoc Ginecologia Ospedale San Carlo-idi, Roma, Italia (2); Uoc, Uoc Ginecologia Ospedale San Carlo-idi, Roma, Italia (3); Clinica Urologica Ed Andrologica, Ospedale Santa Maria Della Misericordia, Universita Degli Studi Di Perugia, Perugia, Italia (4); Dipartimento Di Ostetricia E Ginecologia, Catholic University Of The Sacred Heart, Roma, Italia (5) INTRODUCTION AND AIM OF THE STUDY Patients with recurrent or persistent stress urinary incontinence (SUI) constitute a difficult therapeutic challenge. Previous operations might have left legacies such as scarring, adhesions and distorted anatomy, making repeat surgery arduous. Up to now, there is no consensus on the procedure of choice for treating persistent or recurrent SUI because of the relatively low number of patients included in the published studies and the variability of reported cure. The aim of this study was to determine the outcomes of Mid-urethral sling Neurourology and Urodynamics DOI 10.1002/nau
(MUS), retropubic or trans-obturator sling, after a failed primary surgery for SUI. MATERIALS AND METHODS This is a retrospective study performed in 2 high-volume urogynaecological centers. It included female patients with recurrent or persistent SUI (clinical and urodynamic diagnosis) treated with MUS, both retropubic (TVT) and trans-obturator (TOT). SUI was defined as persistent if it reappeared within 6 weeks from the anti-incontinence procedure and recurrent if it developed more than 6 weeks afterwards. The preoperative assessment included comprehensive medical history, lower urinary tract symptom evaluation, physical examination, a standardised Cough Stress Test (CST) with a bladder volume of 300ml, urinalysis, urine culture, uroflowmetry, post-void residual urine measurement and urodynamics. Incontinence was defined using the Ingelman-Sundberg scale (1). All definitions on the basis of the International Continence Society. Postoperative evaluations were performed at 3, 6, 12 months and then annually. We report data collected at the last follow-up. Subjective cure was defined as an affirmative response to the question of no more urinary leakage during physical activity, coughing or sneezing and reported no pads use in any situation. Subjective improvement was an affirmative answer to the question: ‘‘Are you satisfied with the results of the operation?’’ and at least 50% diminished need for pad use. Objective cure was defined as negative stress test at clinical evaluation and no longer needing pads. So the results were divided in dry (subjective and objective cured), improved (subjective improvement) and failed. For statistical analysis, we used the McNemar chi-square test to compare categorical variables between pre- and post-operative periods, the paired t-test for continuous parametric variables, and the Fisher exact test for continuous non-parametric variables. We considered P < 0.05 to be statistically significant. RESULTS We included in this study 48 women with recurrent or persistent SUI who had previously undergone different surgical procedures. Seventeen patients underwent TOT and 31 TVT. Table I shows type of surgery, and previous procedures N° SURGERY PTS
PREVIOUS SURGERY 7 CS 2 INJ 1 SLING
17 1 TOT 3 TVT 3 US 8 CS
5 IN 18 TOT
CS, Colposuspension; IN, Injectable; US: Uretrosuspension; SIS, Single Incision sling.
Patient characteristics are shown in Table II. Table II Pre-op characteristics of sample VARIABLE
58.83 + 10.45 (37-81)a
Body Mass Index
25.76 + 2.89 (21.45-36.51)a
39 pats (81.3%)c
data are given as mean SD (range); bdata are given as median (interquartile range); cdata are given as number of cases and percentage in parenthesis N (%). The median follow-up was 120 months (range 12–130). At the last follow-up the study showed an objective cure rate in 31 patients (64.5%). Basing on the pre-op grade of incontinence we had a cure rate of 80% in patients with pre-op grade I SUI, 58.3% in patients with pre-op garde II SUI and 68.4% in patients with pre-op grade III SUI. The groups are too small to compare statistically the three groups. The subjective cure rate was 77.1% (37 patients) and the subjective improvement was 10.4% (5 patients). Urodynamic data are reported in Table III. a
Table III Urodynamic data
(mean 151.1 + 64.5)
(mean 142.6 + 45.6)
(mean 353.8 + 69.5)
(mean 361.1 + 55.6)
6 patients (%)
9 patients (%)
(mean 18.7 + 11.6)
(mean 18.4 + 6.9)
(mean 21.5 + 8.3)
(mean 17.1 + 6.6)
*MacNemar test § t-test
In the TOT group the failure rate was 11.7% (2/17 patients) and in the TVT group it was 12.9% (4/31). This difference did not achieve the statistical significance. Beyond this, the TVT group showed ‘‘de novo’’ urge incontinence in 9.7% of cases and ‘‘de novo’’ urgency in 19.4% of patients; in the TOT group we observed ‘‘de novo’’ urge incontinence in 5.9% of cases and ‘‘de novo’’ urgency in 11.7% of patients. Comparing this data we did not find statistical significance. If we consider only the 22 patients in which a MUS was implanted after a failed MUS (group 1) we had a cure rate of 54.5% (12 patients) and an improvement of 22.7% (5 patients with grade 1 SUI) In the 26 women in which a MUS was implanted after a nonprosthetic anti-incontinence surgery (group 2) we had a cure rate of 80.8% (21 patients) and an improvement of 15.4% (4 patients - grade 1 in 3 and grade 2 in 1 patient). Comparing the results of group 1 with group 2 we found a statistical better outcome in group 2 (P ¼ 0.03) Neurourology and Urodynamics DOI 10.1002/nau
INTERPRETATION OF RESULTS There are a paucity of data on repeat sling after a failed primary SUI surgery and few studies have aimed to compare the retropubic and the trans-obturator approach in the treatment of recurrent or persistent SUI (2,3). Lee et al. (4) found a trend toward higher success for the retropubic approach, although the difference between the two groups was not statistically significanti. In our cohort we found a subjective cure rate of 77.1% and an objective cure rate of 64.5%; with no significant differences between the TVT and the TOT groups. The grade of SUI was not a risk factor of recurrence, while we obtained the better results when MUS were used after non prothesic antiincontinence surgery. CONCLUSIONS Our study demonstrates that MUS can be offered to patients with persistent or recurrent SUI. The cure rates and improvement rates of MUS are favourable, although lower than the cure rate for primary surgery. There is no consensus regarding the better approach to be used (retropubic or trans-obturator). We didn’t find statistical differences between TVT and TOT but the number of patients is low and for this reason prospective, randomized studies on this subject are needed. REFERENCES (1) Ingelman-Sundberg A. Urinary incontinence in woman, excluding fistulas. Acta Obstet Gynecol Scand 1952; 31: 266-291. (2) Anneleen Verbrugghe & Dirk De Ridder & Frank Van der Aa. A repeat mid-urethral sling as valuable treatment for persistent or recurrent stress urinary incontinence. Int Urogynecol J. 2012 Oct 24. [Epub ahead of print] (3) Ashish Pradhan & Preeti Jain & Pallavi M. Latthe. Effectiveness of midurethral slings in recurrent stress urinary incontinence: a systematic review and meta-analysis. Int Urogynecol J (2012) 23:831–841 4 - EFFICACY AND TOLERABILITY OF AGONIST-3 MIRABEGRON IN THE OVERACTIVE BLADDER IN WOMAN WITH OR WITHOUT PRIOR ANTIMUSCARINIC THERAPY Speranza Anna Iervolino(1), Mariateresa Pezzella(1), Antonio Grimaldi(1), Fabio Del Deo(1), Carolina Tammaro(1), Claudia Russo(1), Pasquale Gallo(2), Carlo Rappa(3), Nicola Colacurci(1), Marco Torella(1) Dipartimento Della Donna, Del Bambino E Di Chirurgia Generale E Specialistica, Seconda Universita Degli Studi Di Napoli, Napoli, Italia (1); Unita’ Operativa Ginecologia Ed Ostretricia, Ospedale Maggiore Di Crema, Crema, Italia (2); Ginecologia Ed Ostetricia, Ospedale Buon Consiglio Fate Bene Fratelli, Napoli, Italia (3) INTRODUCTION AND AIM OF THE STUDY Overactive bladder (OAB) is a common and chronic condition with a significant impact on quality of life, characterized by urinary urgency, frequency, or nocturia with or without urge urinary incontinence. The usual treatment approach is both behavioral and pharmacological. Behavioral interventions include lifestyle modifications, scheduling regimens, and pelvic foor muscle rehabilitations. Until now, pharmacotherapy has been based mainly on the use of antimuscarinics agents, the most important treatment option for the clinical management of symptoms of overactive bladder. If persistence with long-term medication in chronic diseases is typically low, for overactive bladder medication is lower than average. Thus, patient compliance may prove a challenge to the successful medical management of OAB, due to the often long-term nature of therapy and potential side effects of the agents used. High discontinuation rates have been observed in clinical trials of OAB drugs, due in part to adverse effects including but not
Abstract limited to dry mouth, constipation, blurred vision, and headache. Solifenacin was consistently associated with the highest rate of persistence compared with the other antimuscarinics. The low rates of persistence with these agents highlight the need for new, effective and better-tolerated oral pharmacological agents. Mirabegron is a b3 adrenergic agonist developed for the treatment of OAB, with a mechanism of action different from that of antimuscarinic. Activation of the b3-AR by mirabegron stimulates the detrusor relaxation to promote urine storage leading to increased bladder capacity and increased duration between voids. Mirabegron has no effect on parasympathetic stimulation of detrusor contraction and bladder emptying so may reduce the risk of acute urinary retention compared with antimuscarinics. The aim of this study was to evaluate the efficacy and tolerability of mirabegron 50mg once daily in women with OAB, with or without previous antimuscarinic therapy. Primary endpoint: to evaluate mirabegron 50 mg/die to 12 weeks efficacy on the reduction of the mean number of micturitions/24 h and the mean number of urgency with or without urge incontinence episodes/24 h (urgency episodes significant are only those received with intensity grade 3 in the scale from 0 to 4 according to the Patient Perception of intensity of Urgency scale (PPIUS)) compared to treatment with solifenacin 5 mg/die and to previous treatment with solifenacin 5 mg/die. Secondary endpoint: assessing the tolerability of drug treatment by comparing the % of patients with adverse events and the mean value of the global satisfaction of the treatment by patients at 12 weeks of treatment in the different treatment groups. MATERIALS AND METHODS We conducted a multicenter study evaluating 150 patients with a diagnosis of OAB obtained by evaluating clinical and medical history, voiding diary and urodynamics, examined, in the period between the beginning of September 2013 and early October 2013, at Pelvic Floor Disorders’s clinic. By 150 women included in our study and, therefore, falling within the inclusion and exclusion’s criteria, 100 women who were diagnosed for the first time the OAB, and these women were divided into two treatment groups: GROUP A: 50 patients treated with mirabegron 50mg/die for 12 weeks; GROUP B: 50 patients treated with solifenacin 5mg/die for 12 weeks. The additional 50 women were patients already known to us and, therefore, with previous urodynamic diagnosis of OAB and reviewed at the control treatment; these women, while continuing antimuscarinic therapy with solifenacin 5 mg/day for more than three months expressed to stop teraphy, noting lack of improvement as well as the onset of troublesome side effects: GROUP C: 50 patients non-responder to solifenacin 5 mg/die treated with mirabegron 50 mg/die for 12 weeks. 22 women in the group C expressed a desire to discontinue solifenacin mainly due to insufficient efficacy; 24 women wanted to stop antimuscarinic especially bothersome side effects. Were predicted clinical controls at 4, 8 and 12 weeks. The patients completed a voiding diary for 3 days every 4 weeks. All patients were also instructed to conduct a proper water balance daily through the classical practices of bladder training. At 12 weeks, patients were subjected to a dichotomous comprehensive assessment (yes or no) of the most frequent side effects reported in the literature (dry mouth, constipation, blurred vision, urinary retention, cystitis, palpitations, hypertension), and also were asked to express an opinion on the therapy on the Neurourology and Urodynamics DOI 10.1002/nau
level of treatment satisfaction (efficacy and tolerability) through a number from 0 to 4 (0 disappointed, 1 slightly satisfied, 2 middle satisfied, 3 fairly satisfied, 4 highly satisfied). The data are presented as mean and standard deviation. The average values obtained were compared using the Student t test. RESULTS At 12 weeks, Mirabegron 50 mg/die proved comparable to solifenacin 5 mg/die in terms of therapeutic efficacy, both reducing the average of micturitions episodes/24 h (7.66 0.81 GROUP A vs. 7.73 0.93 in the group B, P < 0.05), both reducing the average of urgency with or without urge incontinence episodes/24 h (0.58 0.70 GROUP A vs. 0.66 0.57 GROUP B, P < 0.05). Just the same, Mirabegron 50mg/die proved equally effective in the group non-responders to prior therapy with solifenacin 5 mg/die. In fact, the average of micturitions episodes/24 h and the average of urgency with or without urge incontinence episodes/24 h in GROUP A and GROUP C were respectively 7.66 0.81 vs 7.94 0.86 and 0.58 0.33 vs 0.61 0.49, P < 0.05. 18% of woman (9 patients) in group C, at 12 weeks, reported improvement in symptoms such as to be dry. Mirabegron 50 mg/die at 12 weeks was more tolerated than solifenacin 5 mg/die; in effect, at the last control, the % of patients with at least one adverse reaction was 28% (14 women) in group A, 76% (38 women) in group B and 40% (20 women) in group C. The most commonly treatment-emergent adverse events was dry mouth. In particular, at 12 weeks, dry mouth occurred with a incidence of 2.2% in group A, 10.1% in group B and 2.6% in group C; The difference in the mean value of global satisfaction of the treatment between group A and group B, at 12 weeks, (2.98 0.75 group A vs 1.96 0.70 group B) was statistically significant (P < 0.001). Finally, the degree of satisfaction in group C (2.46 0.91) was comparable to group A (P < 0.001), so, under favorable profile of efficacy/tolerability, mirabegron can increase continuation of OAB’s therapy over time, also incorporating the patients who drop out of antimuscarinic therapy, mainly because of the high frequency of side effects. INTERPRETATION OF RESULTS At 12 weeks, the clinical efficacy of mirabegron 50mg/die was comparable to solifenacina 5mg/die; however the reduced adverse reactions and the highest level of satisfaction shows that mirabegron 50mg/die may increase the % of women with OAB who keeps long-term therapy, making minimal side effects and improving quality of life. CONCLUSIONS Mirabegron 50 mg is a new strategy for treating OAB, with a different mechanism of action than other oral drugs; despite the overlap in efficacy with solifenacin 5 mg, significant reduction of side effects makes the beta3-agonist potential first choice in treating OAB. Furthermore, thanks to the different mechanism of action, mirabegron can be effective even in women not responsive or women who can’t take antimuscarinic drugs. Are required, however, further studies with follow-up longer term to confirm this data. REFERENCES Christopher R. Chapple, Linda Cardozo, Victor W. Nitti, Emad Siddiqui, and Martin C. Michel Mirabegron in Overactive Bladder: A Review of Efficacy, Safety, and Tolerability Neurourology and Urodynamics 33:17–30 (2014) Khullar V, Cambronero J, Angulo JC, Wooning M, Blauwet MB, Dorrepaal C, Martin NE. Efficacy of mirabegron in patients with and without prior antimuscarinic therapy for overactive bladder: a post hoc analysis of a randomized EuropeanAustralian Phase 3 trial. BMC Urol. 2013 Sep 18;13:45. doi: 10.1186/1471-2490-13-45.
Khaled Maman, Samuel Aballea, Jameel Nazir, Katia Desroziers, Mohamed-Elmoctar Neine, Emad Siddiqui, Isaac Odeyemi, Zalmai Hakimi Comparative Efficacy and Safety of Medical Treatments for the Management of Overactive Bladder: A Systematic Literature Review and Mixed Treatment Comparison http://dx.doi.org/10.1016/j.eururo.2013.11.010
5 - GROIN PAIN AFTER PROCEDURE OF TVT-O IN PATIENTS AFFECTED BY STRESS URINARY INCONTINENCE. IS IT A REAL PROBLEM? Paola Sorice(1), Andrea Braga(1), Giorgio Bogani(1), Simona Cantaluppi(1), Antonella Cromi(1), Fabio Ghezzi(1), Maurizio Serati(1) Universita Degli Studi Dell’insubria, Ospedale Filippo Del Ponte, Varese, Italia (1) INTRODUCTION AND AIM OF THE STUDY The Tension-free Vaginal Tape-Obturator (TVT-O) is the gold standard surgical procedure for stress urinary incontinence (SUI). Albeit TVT-O achieves the endpoints of safety, feasibility and effectiveness, one of the major concerns on its widespread diffusion is represented by postoperative groin pain . The primary aim of the present study was to assess the incidence and intensity of groin pain as well as its modification over the time in women undergoing TVT-O for pure SUI. Additionally we sought to identify the possible predictors of postoperative pain. MATERIALS AND METHODS This is a prospective single centre study, during period from Jenuary 2012 to December 2012. Data of consecutive patients with an urodynamic diagnosis of pure SUI were collected in an IRB approval database. TVT-O was performed according to the original technique described by de Leval . A single surgeon, with an extensive background in urogynecologic surgery, performed all the procedures. Groin pain intensity was assessed using visual analogue scale (VAS). Pain levels were recorded at 1th, 2th, 30th postoperative day and approximately 1 year (10 days) after the procedures. Each patient was asked to record the severity of pain expectancy on a 0 to 100-mm horizontal VAS, with 0 being no pain and 100 the worst pain imaginable. According to the results of Birth et al. , low, medium and high pain levels were defined by a score 33-mm, between 34- and 65-mm and 66-mm on 100-mm VAS. Exclusion criteria were: age 35, urodynamic diagnosis of overactive bladder, pelvic organ prolapse stage II according to the Pelvic Organ Prolapse Quantification scoring system, presence of reumatological disease and follow-up 0.2); while significant decreases in pain levels (P ¼ 0.02) and pain incidence (P ¼ 0.07) were recorded between postoperative day#2 and day#30. Additionally, both incidence (P ¼ 0.05) and intensity of pain (P ¼ 0.04) decreased from day#30 to 1 year of follow-up. None of the patients with pain required removing the sling. Considering preoperative variables (e.g., age, parity, BMI, menopausal status) no statistical independent predictors of high pain levels were observed (P > 0.05).
INTERPRETATION OF RESULTS Our results showed that groin pain is a considerable and worrying issue in the early post-operative period after TVT-O. Although the percentage of women with pain in early postoperative days is high, it decreases almost to disappear after 1 year. Additionally, albeit the high prevalence of pain only a minority of patients needed analgesic medications. Limitations of the present study include the relative small sample size of the population included. Additionally, a single skilled surgeon performed all the procedures, thus making our results not reliable in a setting without advanced urogynecological experience. However, the prospective study design and the long-term follow-up represent the main strengths of the present investigation. CONCLUSIONS Chronic groin pain after TVT-O insertion is a relatively uncommon occurrence requiring specialist treatment and intervention. Postoperative groin pain is an acceptable condition by the patients affected by SUI, if continence is achieved. Further studies evaluating how pain influences quality of life are needed to assess benefit of anti-incontinence procedure. REFERENCES 1. Tommaselli et all. Effects of a modified technique for TVT-O positioning on postoperative pain: single-blind randomized study. Int Urogynecol J (2012) 23:1293–1299 DOI 10.1007/ s00192-012-1758-3. 2. De Leval J (2003) Novel surgical technique for the treatment of female stress urinary incontinence: transobturator vaginal tape inside-out. Eur Urol 44:724–730 3. Bird SB, Dickson EW. Clinically significant changes in pain along the visual analog scale. Ann Emerg Med 2001;38:639-43
6 - BOTULINUM A TOXIN INTRAVESICAL INJECTIONS IMPROVES SEXUAL FUNCTION IN FEMALE PATIENTS AFFECTED BY NEUROGENIC DETRUSOR OVERACTIVITY Antonella Giannantoni(1), Marilena Gubbiotti(1), Raffaela Bruno(1), Jacopo A. Rossi De Vermandois(1), Herald Nikaj(1), Silvia Proietti(2) University Of Perugia, Ospedale S. Maria Della Misericordia, Dept. Of Urology And Andrology, Perugia, (1); Dep. Of Urology, Istituto Clinico Nhumanitas, Rozzano (mi), (2) INTRODUCTION AND AIM OF THE STUDY To date it is well know the role of onabotulinumtoxin-a (onabot/a) intravesical injection in significantly improving
Abstract urinary symptoms, urodynamic dysfunction and Quality of Life in patients affected by neurogenic detrusor overactivity (NDO), but we do not know whether the neurotoxin is also able to improve the sexual life of these patients. The aim of the present study was to investigate the effects of onabot/a intravesically injected on urinary symptoms and sexual function in female patients affected by ND. MATERIALS AND METHODS Eighteen female patients affected by NDO and urge urinary incontinence, 15 with Multiple Sclerosis and 3 with Parkinson’s disease, were prospectively included in the study. Mean age SD was 51.33 15.4 yrs and mean disease duration was 11.22 7.7 yrs. After a baseline examination including a 3-days voiding diary, urodynamics and the standardized ‘‘Female Index of Sexual Function’’ (FSFI) questionnaire, patients underwent intravesical injection of onabot/a, 100 U diluted in 10 ml of normal saline, under cystoscopic guidance, avoiding the trigone. The 3-days voiding diary, urodynamics and the FSFI questionnaire were repeated after three months from treatment. The obtained results were compared to those detected at baseline examination. Statistical analysis was performed by means of Wilcoxon’s test. RESULTS Three months after treatment a significant increase in mean daytime urinary frequency (from 10.34 4.4 at baseline to 6.7 2.9, P < 0.01), in mean night-time urinary frequency (from 3.8 2.9 at baseline to 1.2 2.1, P < 0.05) and in mean urinary incontinence episodes/day (from 4.6 3.9. at baseline to 1.6 1.9, P < 0.01) were observed. 15 patients were completely continent. Urodynamic parameters also significantly improved and mean FSFI score significantly changed: from 50.83 33.48 at baseline to 59.44 32.15 (P ¼ 0.023) at 3 mos follow-up. Particularly, questions 2, 3, 4, 5, related to sexual interest and desire, and questions 10, 11 and 12, related to lubrication and orgasm, appeared significantly improved. (Table) ITEMS
BASELINE (mean ± SD)
3 MOS F-UP (mean ± SD)
INTERPRETATION OF RESULTS It is well known that urinary symptoms greatly affect the quality of life of patients affected by neurogenic bladder. These symptoms strongly limit daily life activities and particularly the presence of urinary incontinence, can affect the sexual life of these patients. Our results show that the improvement in urinary symptoms and the disappearance of UUI in female patients with neurogenic disease, as obtained by onabot/a intravesical injections, are able to significantly change some aspects of their sexual activity. Particularly important is the improvement in sexual interest and desire we obtained in these patients, which could be explained by a possible amelioration of the psychological status, related to the disappearance of incontinence. As a consequence, other aspects of sexual activity can be positively influenced, as lubrication and orgasm. CONCLUSIONS Urge urinary incontinence, particularly in patients with neurogenic diseases, inflicts a substantial personal burden on many aspects of patients’ lives, including coping strategies and satisfaction with sexual life. This result, which has never shown before, add another important contribution for the activity of the neurotoxin in the treatment of patients with neurogenic voiding and sexual dysfunction. REFERENCES - Lombardi G, Del Popolo G, Macchiarella A, Mencarini M, Celso M. Sexual rehabilitation in women with spinal cord injury: a critical review of the literature. Spinal Cord. 2010 Dec;48:842-9. - Mangera A, Apostolidis A, Andersson KE, Dasgupta P, Giannantoni A, Roehrborn C, Novara G, Chapple C. An Updated Systematic Review and Statistical Comparison of Standardised Mean Outcomes for the Use of Botulinum Toxin in the Management of Lower Urinary Tract Disorders. Eur Urol. 2013 Nov 1.
7 - DESMOPRESSIN IN THE TREATMENT OF NOCTURIA IN PATIENTS AFFECTED BY NEUROGENIC BLADDER
Antonella Giannantoni(1), Marilena Gubbiotti(1), Raffaela Bruno(1), Jacopo A. Rossi De Vermandois(1), Herald Nikaj(1), Silvia Proietti(2) University Of Perugia, Ospedale S. Maria Della Misericordia, Dept. Of Urology And Andrology, Perugia, (1); Dept. Of Urology, Istituto Clinico Humanitas, Rozzano (mi), (2) INTRODUCTION AND AIM OF THE STUDY The efficacy and safety of desmopressin in the treatment of adults with nocturia have been assessed in several randomized trials, but few information exist on its application in patients affected by Parkinson’s disease (PD) or Multiple Sclerosis (MS). The aim of the present study was to investigate the efficacy and safety of desmopressin administration in PD and MS patients affected by nocturia, in a medium term follow up. MATERIALS AND METHODS 32 patients with PD and 11 with MS were included in this prospective open label study. Inclusion criteria were nocturia defined as an average of 2 voids per night and nocturia index scores >1, with a serum sodium >135 mmol/l. Exclusion criteria were urinary retention, post-void residual volume higher than 150 ml or clinically relevant, treatment with drugs known or suspected to interact with desmopressin, uncontrolled hypertension or clinically relevant cardiac failure. Study design and treatment. After a baseline evaluation including a 7-day voiding diary, serum chemistry and the Nocturia Quality of Life questionnaire (N-QoL), patients under-
Neurourology and Urodynamics DOI 10.1002/nau
went treatment with desmopressin 60 mg sublingually administered at bedtime for 7 days. Patients with 50% or greater reduction in nocturnal voids at day 7 continued to assume the same drug dosage for 24 weeks. Patients who did not report such a response to treatment, after the 1 week changed to desmopressin 120 mg for the whole observation time. Voiding diary, serum chemistry and N-QoL questionnaire were repeated after 1, 12 and 24 weeks of treatment. Primary end point was the proportion of patients with a 50% or greater reduction in the mean number of nocturnal voids after treatment compared with baseline. Secondary end points were changes in nocturnal urinary volume, duration of the sleep period until the first nocturnal void, change in quality of life, safety of treatment with desmopressin. RESULTS At week 1 a significant reduction (>50%) in the mean number of nocturnal voids, mean nocturnal urinary volume, mean duration of the sleep period until the first nocturnal void and a significant increase in mean N-QoL total score were observed in 19 patients (44.1%), who continued to assume desmopressin 60 mg for 24 weeks. 13 patients (30.2%) discontinued treatment due mainly to nausea and diarrhea. Eleven patients changed to desmopressin 120 mg; nine of them reached the 24 wks follow up and 2 of them stopped assuming the drug due to a serum sodium < 135 mmol/l. Overall, at 24 weeks follow-up, 28 patients (65.12%) reported significant effects in all the considered parameters. (Table I) Endpoints
Nocturnal voids Baseline
24 weeks (60 μg)
I grade, patients with urinary flow 100 ml. Median age for male patients was 67.3 (range 34– 84) and 51.5 (range 29–71) for female patients. 16 patients Neurourology and Urodynamics DOI 10.1002/nau
(50%) had an overactive bladder with urinary incontinence (wet OAB), while the remainder 16 had dry OAB. Each patient performed at least two consecutive urodynamic evaluation including the cystometry and pressure / flow study with a 6 Fr double lumen catheter and endorectal catheter for abdominal pressure misuration. The median filling speed with peristaltic pump was 30 ml / min. Men have performed the examination in orthostatic position, while female patients in sitting position. Cystometric capacity, bladder compliance, overactive detrusorial contraction, both phasic and terminal, presence of obstruction calculated with BOOI, bladder contractility (BCI) and finally the difference between isometric detrusorial pressure (pdetiso) and detrusorial pressure at maximum flow (pdet Qmax) using the ‘‘stop-test’’ during the micturiction phase, were the considered parameters. As control cases we used the urodynamic results considering the same parameters in a consecutive women’s series, median age 63,5 years (range: 52–78), with clinical symptoms of urinary stress incontinence. Levofloxacin 500 mg p.o. was given one hour before urodynamic evaluation to all patients. RESULTS Detrusorial unhinibited contractions (overactive contractions) were present in 21 patients (65,6%), phasic overactivity in 4 patients (12,5%), terminal overactivity in 8 (25%), and both phasic and terminal overactivity in 9 (28,1%). Incontinence associated with detrusor overactivity has been detected in 13 patients amoung 16 reporting it in clinical history. The compliance was normal in 22 patients (68,7%), reduced in 10 patients (31,2%). All patients with reduced compliance showed DO. The mean cystometric capacity amounted to 245 ml, (range: 118–431, SD: 89,2). The mean detrusor pressure at maximum flow (pdetQmax) was 36 cmH2O (range 5–110, SD: 22). The mean isometric detrusor pressure (pdetiso) was 70 cmH2O (range 18–172, SD: 36,2). The mean difference (delta) between pdet iso and pdetQmax was 34 cmH2O (range: 7–112, SD: 26). After pressure flow study the mean BOOI was 11.5. 4 patients were obstructed, 7 equivocal and 21 unobstructed. The median BCI was 98.4. 18 patients resulted with hypocontractility. All patients had a positive delta (pdet iso – pdet Qmax) after stop test.In the control cases, only one patient (10%), had phasic overactivity. Compliance was normal in 100% of patients. The mean cystometric capacity was 286,5, (range: 121–476 SD 110,7). The mean detrusor pressure at maximum flow was 12,5 cmH2O (range: 4–23; SD: 6). The mean of isometric detrusor pressure after stop test was 6.4 cmH2O (range: 0–19; SD: 5,5). The mean difference (delta) between the previous was equal to 6 cmH2O (range: 17 – 2); SD: 4,3). Obstruction (BOO) has not been shown in any case. Table I shows the different pressure value between the two groups, during pressure/flow study. No patient had major complications and no patient required hospitalization.
INTERPRETATION OF RESULTS Our prospective study evaluated the relation between OAB and DO in a consecutive series of patients. Our results showed a
Abstract percentage of DO moderately higher than reported in literature but confirmed that not all the patients with OAB have a DO during fillin cystometric evaluation. Pressure-flow study that normally is used for determination of the obstruction and grade of obstruction (BOOI) and for the determination of the contractility (BCI) may be also used to emphasize a latent DO. By utilizing the stop test, during voiding phase, we releaved that all patients with OAB, had a pdet iso greater than pdetQmax. Maybe this condition is determinated by an alterated spinal reflex of pudendal nerve, that through the external urethral sphincter does not have a potential modulative effect on bladder function in OAB patients. There is no a unique urodynamic pattern of the patients with OAB: normal or reduced compliance, no DO, phasic DO, terminal DO, phasic and terminal DO, bladder outlet obstruction, no obstruction, normal contractility, hypocontractility. Pdet isometric,after Stop Test, is always higher than Pdet Qmax in the group of patients with clinical OAB but there is a wide difference in the value of the ‘‘delta’’. Urodynamic investigation for every patients with OAB may perhaps allow to personalize the treatment of this disease and choose which treatment (anticholinergic, beta sympatichomimetic, PFME) is the best as first approach.
Neurourology and Urodynamics DOI 10.1002/nau
CONCLUSIONS Urodynamic evaluation in OAB may allow to differentiate different pictures synonymous of different patients which are clinically included into the common nosologic entity of overactive bladder syndrome. A pdet isometric higher than pdet Qmax, after stop test, is a urodynamic sign always present in OAB but the delta is very variable. Urodynamic evaluation is a well tolerated procedure with no major complications. All patients, after detailed explanation, agreed to do it. Not only physicians but the patients too, have a better knowledge of the pathophysiology of their symptoms and we suppose that also the compliance to the treatment, both rehabilitation and pharmacotherapy is higher. There is no reason to not perform urodynamic evaluation in OAB patients. REFERENCES 1. Hashim H, Abrams P.: Is the bladder a reliable witness for predicting detrusor overactivity? J Urol 2006;175:191-4;discussion 194-5. 2. Chapple C.: Overactive bladder and Underactive bladder: A Symptom Syndrome or Urodynamic Diagnosis? Editorial. Neurourology and Urodynamics 2013; 32: 305-307.