An Open, Multicentre Study of NASHA/Dx Gel (Zuidex TM ) for thetreatment of Stress Urinary Incontinence

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1 European Urology European Urology 48 (2005) Female UrologyöIncontinence An Open, Multicentre Study of NASHA/Dx Gel (Zuidex TM ) for thetreatment of Stress Urinary Incontinence Christopher R. Chapple a, *, François Haab b, Mauro Cervigni c, Christian Dannecker d, Aino Fianu-Jonasson e, Abdul H. Sultan f a Sheffield Teaching Hospitals NHS Trust, Urology Research, Royal Hallamshire Hospital, Glossop Road, Sheffield, South Yorkshire S10 2JF, UK b Tenon Hospital, Paris, France c San Carlo-Idi Hospital, Rome, Italy d University of Munich, Munich, Germany e Karolinska University Hospital, Huddinge, Sweden f Mayday University Hospital, Croydon, UK Accepted 10 May 2005 Available online 4 June 2005 Abstract Objective: The Zuidex TM system facilitates non-endoscopic urethral injection for stress urinary incontinence (SUI). It comprises four pre-filled syringes of non-animal stabilised hyaluronic acid/dextranomer (NASHA/Dx) gel and an Implacer TM device. This open, 12-month study was performed to evaluate the safety and efficacy of this system in women with SUI. Methods: Patients were aged 18 years with a history of SUI for 12 months (hypermobility and/or intrinsic sphincter deficiency), had failed prior non-invasive therapy and were invasive-therapy naïve. Up to two treatments with NASHA/Dx gel were permissible (re-treatment was offered at week 8). Positive response to treatment was defined as a reduction in provocation test leakage of 50% compared with baseline. Efficacy was also measured by 24-hour pad weight test leakage, and number of incontinence episodes/24 hours. Results: A total of 142 patients were enrolled, with a mean age of 55.7 years. The response rate was 78% at week 12, and 77% at month 12. Significant reductions in median provocation test leakage, 24-hour pad-weight test leakage and number of incontinence episodes/24 hours were observed at all time-points. At month 12, the median decreases from baseline in these three variables were 93%, 89% and 67%, respectively. Treatment-related adverse events were of a nature expected with urethral injection most were transient, and of mild or moderate intensity. Conclusions: Treatment with NASHA/Dx gel produced large, statistically significant reductions in urinary leakage sustained over 12 months and was well tolerated. These findings suggest that NASHA/Dx gel could be considered as an early intervention in treatment-naïve cases of SUI. # 2005 Elsevier B.V. All rights reserved. Keywords: Urinary incontinence; Stress; Female; Urethral injection; Non-animal stabilized hyaluronic acid; NASHA/Dx gel 1. Introduction Despite the availability of effective therapies for stress urinary incontinence (SUI), as many as 80% of women do not seek help for this distressing condition * Corresponding author. Tel ; Fax: address: c.r.chapple@sheffield.ac.uk (C.R. Chapple). [1,2]. The reasons for this may include embarrassment, perceptions of incontinence as a minor problem or part of the normal ageing process, concerns about the available treatment procedures and unwillingness to undergo an examination or surgery [1,3]. It has also been reported that the majority of SUI patients in the tertiary healthcare setting favour less invasive treatment such as a clinic procedure compared with more /$ see front matter # 2005 Elsevier B.V. All rights reserved. doi: /j.eururo

2 C.R. Chapple et al. / European Urology 48 (2005) invasive surgery, even if the probability of objective cure is reduced [4]. Thus, a general shift towards less invasive treatment would be desirable in the management of SUI. Urethral injection is a minimally invasive SUI therapy that potentially obviates the need for surgery. The procedure involves injection of an agent into the urethral submucosa to facilitate increased outlet resistance and reduced urinary leakage. The available clinical evidence indicates that this treatment may be similarly effective in patients with either urethral hypermobility or intrinsic sphincter deficiency as the dominant underlying pathophysiology [5]. Indeed, it has recently been recommended that conservative treatment including urethral injection may be initiated without the need for prior urodynamic investigation (i.e. without determining the pathophysiology) [6]. Zuidex TM implacement therapy (Q-Med AB, Uppsala, Sweden) comprises injection of non-animal stabilised hyaluronic acid/dextranomer (NASHA/Dx) gel via the Implacer TM device. NASHA/Dx gel is a biocompatible injectable agent, developed initially for the treatment of vesicoureteral reflux (VUR) in children [7]. It has a proven safety profile in this setting, with no emergent safety concerns over many years of clinical experience; [8] over 30,000 children have so far been treated with NASHA/Dx gel. The Implacer TM device was developed to facilitate standardised, guided urethral injection of NASHA/Dx gel without the need for endoscopy. This allows treatment to be administered in an office environment, increasing both convenience and patient acceptability. The first clinical study of NASHA/Dx gel via the Implacer TM for SUI showed that symptoms improved in the large majority of patients (76%), and that the treatment was well tolerated [9]. The present study was performed to investigate the clinical safety and efficacy of NASHA/Dx gel in a larger cohort of female patients with SUI. 2. Methods This open, non-comparative, multicentre study was performed in accordance with Good Clinical Practice and applicable regulatory requirements, as well as the principles of the International Conference on Harmonization (ICH). Signed informed consent was required from all patients Patient selection Women aged 18 years were eligible for the study if they had SUI confirmed by provocation test, and a history of the condition for 12 months. All patients had failed prior non-invasive treatment for SUI (e.g. pelvic floor exercises, biofeedback, electrical stimulation or drug therapy) and were invasive-therapy naïve. Exclusion criteria included poor bladder function (storage capacity <200 ml or post-void residual volume [PVRU] > 100 ml); detrusor overactivity or neurological conditions potentially responsible for the incontinence; cystocele, rectocele or prolapse grade III; previous surgery for SUI; on-going medication for SUI (except oestrogen therapy at a constant dose for 2 months); and pregnancy or lactation. Patients with VUR, genitourinary fistulae, interstitial cystitis or urinary tract infection (UTI) were also excluded. Urodynamic investigation was performed at baseline, though patients were not selected according to the pathophysiology of SUI (hypermobility or intrinsic sphincter deficiency) Treatment and follow-up Study treatment comprised the Zuidex TM system: ml injections of NASHA/Dx gel, delivered via the Implacer TM device. Local anaesthetic was administered before treatment (using either local anaesthetic gel or local infiltration); additional pain relief and sedatives were also permissible. The treatment procedure, described previously by van Kerrebroeck et al. [9] firstly required assembly of the Implacer TM device using four syringes, pre-filled with NASHA/Dx gel, with 50 mm 21 G needles attached. The device was inserted into the urethra, and the four needles released outwards to fixate the mid-urethra (the principle of this being that the urethral circumference was distended, thereby smoothing out the longitudinal folds). Sequentially, each needle was retracted 5 10 mm then advanced to penetrate the mucosa for delivery of the injection. The protocol stipulated administration of antibiotic prophylaxis after treatment, the dose and duration of medication being at the investigator s discretion. Follow-up visits were scheduled at weeks 4, 8 and 12, and months 6 and 12 after treatment. The visit at week 4 was for assessment of safety, with both safety and efficacy assessed at all other visits. At week 8, all women with persistent leakage and not improved to their satisfaction were offered a second treatment with NASHA/Dx gel Efficacy and safety assessments The primary efficacy assessment was provocation test urinary leakage. The bladder was filled with 300 ml saline, before the patient undertook the following exercise routine: stair-climbing (100 steps up and down), coughing strongly (10 times), running on the spot (1 minute), jumping on the spot with feet together (30 seconds), and jumping jacks (30 seconds). A positive response to treatment was defined as a reduction in provocation test leakage of 50% from baseline. Secondary efficacy assessments included 24-hour pad-weight testing, which was performed prior to all follow-up visits (preferably during the 24 hours immediately before the clinic visit). Patients were asked to complete a micturition diary for 6 days before every clinic visit, to record: number of incontinence episodes, number of micturition episodes, and (during 2 of the 6 days) volume voided/micturition. Patients also provided a global assessment of their incontinence problems at each visit, answering none, mild, moderate or severe to the question How would you describe your incontinence problems today? Quality of life (QoL) was measured using the King s Health Questionnaire (KHQ) [10]. The third section of the questionnaire was omitted as it is not applicable to SUI. For the remaining nine domains, scores in the range were recorded, with higher values indicating greater impairment. Adverse events (AEs) were graded as mild, moderate or severe. They were also classified as serious or non-serious, and judged to be related or unrelated to the study treatment. Urinalysis (dipstick

3 490 C.R. Chapple et al. / European Urology 48 (2005) assessment of protein, leucocytes, erythrocytes or nitrite) was performed at all follow-up visits, with urine culture if the urinalysis was abnormal. Post-void residual volume was measured by catheterisation or ultrasound, after treatment and at each follow-up visit. Immediately after treatment, patients were asked to rate the procedure as acceptable, unpleasant or very unpleasant Statistical analysis The primary efficacy analysis was the proportion of patients demonstrating a positive response to treatment at 12 months. Based on the highest possible variance and avoidance of the 95% confidence interval (CI) exceeding 10% of the reported value, the required sample size was 110 patients. To compensate for dropouts, approximately 150 patients should be recruited. The intention-to-treat (ITT) population, used for the primary analysis, was defined as all patients receiving study treatment. For inclusion in the per-protocol (PP) population, patients required no major protocol violations and complete provocation test results for baseline and month 12. Missing data for provocation test leakage (and for 24-hour padweight test and number of incontinence episodes/24 hours) were derived using multiple imputation (MI) methodology. The twosided 95% CI for the proportion of responders at each time-point was calculated using a normal approximation. Wilcoxon s signed rank test was used to calculate approximate p-values for the change from baseline at each time-point (significance level: 0.05). The proportion of patients reporting an improvement of at least one step from their baseline global assessment of incontinence problems was calculated for each time-point (last observation carried forward [LOCF] was used for missing values). Two-sided 95% CIs were calculated using a normal approximation. For KHQ results, missing data were imputed using LOCF; p-values for change from baseline were calculated using Wilcoxon s signed rank test (significance level: 0.05). 3. Results A total of 142 women were recruited into the study, all of whom were treated with NASHA/Dx gel and therefore included in the ITT population (their baseline characteristics are shown in Table 1). Thirty patients (21%) were taking oestrogen medication at baseline, and 126 patients (89%) received antibiotic prophylaxis after NASHA/Dx gel treatment. At week 8, 61 patients (43%) underwent a second treatment with NASHA/Dx gel. In total, 34 patients (24%) withdrew from the study prematurely the most common reason for this was lack of efficacy (59% of withdrawals). Ninety-two patients were included in the PP population. The proportion of procedures rated by the patients as acceptable was 85%, with 10% rated as unpleasant and 4% as very unpleasant. Furthermore, the vast majority of treatment procedures (92%) were performed without any technical difficulties Objective efficacy At month 12, 77% of patients demonstrated positive response (50% decrease in provocation test leakage; 95% CI: 69 85%, ITT population). At 8 weeks before re-treatment the corresponding proportion was 68% (95% CI: 60 76%). There was minimal decrease in the response rate between week 12 and month 12 (Fig. 1). A large and highly significant decrease in median provocation test leakage was observed, from 38.0 g at baseline to 2.2 g at 12 months (Table 2, ITT population). Similar decreases were also observed in 24-hour pad-weight test leakage and number of incontinence episodes/24 hours, with improvements sustained throughout the follow-up period. At month 12, the median decrease from baseline in provocation test leakage was 93%, while for 24-hour pad-weight test it was 89% and for the number of incontinence episodes/24 hours the reduction was 67%. The proportion of patients considered as essentially dry (24-hour padweight test leakage <8 g) was 60% at week 12 and 62% at month 12. For the PP population, the improvements appeared slightly greater than with the ITT population. At month Table 1 Demographic and SUI-related characteristics of the ITT population at baseline Demographic characteristics Age, years (mean [range]) 55.7 ( ) Body mass index, kg/m 2 (mean [range]) 25.7 ( ) Number of deliveries (mean [range]) 2.1 (0 5) Menopausal (n [%]) 88 (62.0%) SUI-related characteristics SUI symptoms for >5 years (n [%]) 71 (50.0%) Maximum cystometric 430 ( ) capacity, ml (mean [range]) Maximum urethral closure 51.2 ( ) pressure, cm H 2 O (mean [range]) Maximum urethral pressure, 58.8 ( ) cm H 2 O (mean [range]) Fig. 1. Proportion of patients demonstrating positive response to treatment: 50% reduction in provocation test leakage compared with baseline (ITT population).

4 C.R. Chapple et al. / European Urology 48 (2005) Table 2 Urinary leakage before and after treatment with NASHA/Dx gel (ITT population). All values are median Provocation test leakage (g) 24-hour pad-test leakage (g) Baseline Week * 6.7 * 1.1 * Week * 3.2 * 0.7 * Month * 3.1 * 0.8 * Month * 2.6 * 0.9 y * p < vs. baseline. y p < vs. baseline. Number of incontinence episodes/24 hours 12, the positive response rate was 85%, while the decreases in provocation test leakage, 24-hour padweight test leakage and number of incontinence episodes/24 hours were 96%, 95% and 77%, respectively. Post-hoc analysis was performed to test whether baseline age (above or below 50 years), body mass index, maximum urethral closure pressure (MUCP), and menopausal status, were correlated with treatment response. None of these factors had a significant effect on the response rate. A further analysis showed that patients who underwent re-treatment at week 8 had a significantly higher median provocation test leakage at baseline than those treated only once (57.5 vs g, p = 0.022) Quality of life and subjective efficacy Statistically significant improvements were observed in 8/9 KHQ domains at month 6 and 6/9 domains at month 12 (Fig. 2). The most marked improvements were apparent in incontinence impact, physical limitations, social limitations and personal relationship. The only domain showing no significant decrease at either timepoint was general health perception. At baseline, patients global assessment of incontinence was moderate or severe in 88% of cases. At month 6, the proportion of patients reporting global assessment improved by at least one step compared to baseline was 67% (95% CI: 59 75%). The corresponding proportion at month 12 was 61% (95% CI: 53 69%). The proportion of patients reporting that their problems were mild or absent increased from 12% at baseline to 56% at month Safety and tolerability Of 263 reported AEs, 157 were considered to be related to the study treatment (the substance and/or injection procedure), affecting 81 patients (57%). Most treatment-related AEs (83%) were of mild or moderate intensity. The majority were also transient, the median duration being 7.0 days. They were also of a nature expected with injection therapy (Table 3), urinary retention being the most common. Injection site pseudocyst was reported in six patients all these cases resolved during the study (median duration: days). In three patients, the contents of the mass were drained through a cannula, and in another the mass was incised and drained. No surgical intervention was required for the remaining two patients, though one received short-term NSAID treatment. There were 19 treatment-related serious AEs 14 of these were urinary retention, where routine catheterisation required hospitalisation (hence the classification as serious). Another one was hospitalisation for administration of silicone injection therapy (Macroplastique 1 ) this was a protocol violation so the patient should have been withdrawn before hospitalisa- Table 3 Summary of the most frequently reported treatment-related adverse events (i.e. those with 5 occurrences) Adverse event No. of occurrences Fig. 2. Post-treatment improvements in quality of life, indicated by changes in King s Health Questionnaire domain scores. Urinary retention 29 (of which 14 were classified as serious) Urinary tract infection 17 Micturition urgency 17 Dysuria 11 Injection site reaction 11 Vaginal discomfort 10 Cystitis 8 Injection site pseudocyst 6 (of which 1 was classified as serious) Injection site pain 6 Injection site infection 3 (all of which were classified as serious) Fever 6 Micturition frequency 5 All were classified as non-serious, except where indicated.

5 492 C.R. Chapple et al. / European Urology 48 (2005) tion. There were only two withdrawals from the study attributable to AEs. At every time-point, over 95% of urinalysis tests showed no clinically relevant abnormalities. Similarly, the overall proportion of samples with no sign of UTI was at least 97% at all time-points. The median PVRU was 10 ml at baseline, decreasing to 5 ml at months 6 and 12. The number of micturitions/24 hours changed little during the study, the median values being 7.2 at baseline, and 6.8 at months 6 and 12. The median volume voided/micturition was 234 ml at baseline, 225 ml at month 6 and 206 ml at month Discussion This study has demonstrated that the majority of patients with SUI respond positively to treatment with NASHA/Dx gel. The proportion of patients reporting 50% reduction in provocation test leakage was close to 80% by week 12, with little change between this timepoint and month 12. Strikingly, the median decreases from baseline in both provocation test leakage and 24- hour pad-weight test leakage were around 90% at month 12. Treatment was well tolerated, with an AE profile as expected with any urethral injection procedure. These results are similar to those reported in the previous study of NASHA/Dx gel via the Implacer TM [9]. That study involved patients selected according to similar criteria, and the proportional reductions in leakage were similar to those reported here. Patients in the present study were not selected according to presumed pathophysiology (hypermobility and/or intrinsic sphincter deficiency). The lack of an effect of baseline MUCP on treatment response would appear to support the notion that urethral injection of NASHA/Dx gel may be effective regardless of the pathophysiology of leakage. There was also no apparent effect of patient age, menopausal status or body mass index on treatment outcome, though patients with greater leakage at baseline were more likely to need re-treatment. Overall, the vast majority of patients with SUI may be considered as eligible for treatment with NASHA/Dx gel. The lack of any significant deterioration in urinary leakage during the first 12 months after treatment in the present study implies that patients initially responding to treatment with NASHA/Dx gel may continue to benefit for an extended period of time. Indeed, 24- month results from the previous study of Zuidex TM show no significant differences between months 3, 12 and 24 in median provocation test leakage, [11] and an earlier study of NASHA/Dx gel indicated responses lasting at least 6 7 years in the majority of patients [12]. Further long-term data with NASHA/Dx gel are awaited with interest. The most common AE in this study was urinary retention, which may indicate either reflex inhibition due to transient local swelling or, simply, functionally occlusive coaptation of the urethra. In the latter case, the properties of NASHA/Dx gel are favourable. After injection, the hyaluronic acid component of the gel is metabolised relatively quickly, reducing the implant volume and facilitating early resolution of urinary retention. The volume is then stabilised by in-growth of endogenous connective tissue, maintaining long-term efficacy [7]. In a study of NASHA/Dx gel in children with VUR, the implant volume decreased by 18% within 2 weeks, but only by 1% between 2 weeks and 3 months.[13] While there was a small number of treatment-related serious AEs in the present study, most of these were urinary retention and all resolved during the study (median duration: 3 days). There were only two withdrawals from the study due to AEs. NASHA/Dx gel had no adverse effects on bladder function and the number of post-treatment UTIs was favourably low. While there were six reports of treatment-related pseudocyst, this represented a small proportion of patients, and all resolved during the study. Pseudocysts have been reported in association with other injectable agents (collagen, PTFE and carbon-coated zirconium beads) [14 16] and there are no direct long-term sequelae after their resolution. If drainage of the pseudocyst does not occur spontaneously, surgical intervention may be required. Often, the requirement for such intervention coincides with treatment failure and the need for other surgical treatment of SUI. It is increasingly recognised that subjective improvement after treatment is at least as important as objectively reduced leakage. The present study indicated significant improvements in all but one KHQ domain (general health perception), while two domains (personal relationship and sleep/energy) showed significant improvement at month 6 but not at month 12. In this regard, it must be borne in mind that the median score for personal relationship was zero at both time-points, while sleep is not usually affected by SUI. A previous investigation of QoL following NASHA/Dx gel treatment indicated a similar degree of improvement in KHQ domains [17]. This study also found that the QoL improvements were correlated with objective leakage reduction. It has been observed that the subjective benefits of treatment for stress urinary incontinence are not necessarily correlated with objective reductions in leakage [18,19]. Therefore, the fact that NASHA/Dx gel provides both subjective and objective benefit is significant.

6 C.R. Chapple et al. / European Urology 48 (2005) While there has been no direct comparison of NASHA/Dx gel with another injectable agent, the efficacy of NASHA/Dx gel appears similar to that of other injectable agents [20]. Clearly, future head-tohead studies would be valuable. However, the inherent properties of NASHA/Dx gel distinguish it from other available injectable agents. It is fully biocompatible, there is no risk of allergenicity or immunogenicity, and both constituents are biodegradable, eliminating the potential for permanent accumulation in the body [21,22]. Furthermore, NASHA/Dx gel can be administered without the need for endoscopic guidance. This reduces the level of equipment and facilities required for treatment, potentially increasing cost-effectiveness as well as convenience. Given patients preference for minimally invasive therapy, [4] and the high proportion of patients in the present study rating the injection procedure as acceptable (approximately 85%), the availability of NASHA/Dx gel may encourage an increased proportion of women with SUI to seek medical assistance. Presently, the majority of women who do not respond adequately to non-invasive treatment such as pelvic floor exercises are offered surgery. However, the present study indicates that NASHA/Dx gel is a well tolerated and effective treatment that is in line with general patient preference for intervention for SUI. Therefore, this treatment appears to be a feasible alternative to the surgical options in the large number of patients requiring active treatment. In all cases, the treatment decision should be taken on the basis of informed discussion between the physician and patient. Based on the current literature, it remains debatable as to whether formal urodynamic assessment is predictive of outcome, and it can be argued that this testing is less necessary with urethral injection than with more invasive surgical procedures. 5. Conclusions Injection of NASHA/Dx gel into the mid-urethra via the Implacer TM device was well tolerated and produced large, significant reductions in the symptoms of SUI. These objective benefits were accompanied by subjective improvements in patients global assessment of incontinence problems and clinically meaningful improvements in QoL. All these benefits were sustained over 12 months, with little or no deterioration between week 12 and month 12. These results suggest that treatment with NASHA/Dx gel may be considered as a potential alternative to surgery following failure of non-invasive therapy. References [1] Andersson G, Johansson JE, Garpenholt O, Nilsson K. 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BJU Int 2005;95: [7] Stenberg A, Lackgren G. A new bioimplant for the endoscopic treatment of vesicoureteral reflux: experimental and short-term clinical results. J Urol 1995;154: [8] Lackgren G, Wahlin N, Skoldenberg E, Stenberg A. Long-term followup of children treated with dextranomer/hyaluronic acid copolymer for vesicoureteral reflux. J Urol 2001;166: [9] van Kerrebroeck P, ter Meulen F, Larsson G, Farrelly E, Edwall L, Fianu-Jonasson A. Efficacy and safety of a novel system (NASHA/Dx copolymer using the Implacer device) for treatment of stress urinary incontinence. Urology 2004;64: [10] Kelleher CJ, Cardozo LD, Khullar V, Salvatore S. A new questionnaire to assess the quality of life of urinary incontinent women. Br J Obstet Gynaecol 1997;104: [11] van Kerrebroeck P, Larsson G, Fianu-Jonasson A. The Zuidex system for the treatment of stress urinary incontinence: 24-month follow-up. Joint Meeting of the International Continence Society and UroGynecological Association, Paris, France, August 2004:Abstract 667. [12] Stenberg AM, Larsson G, Johnson P. Urethral injection for stress urinary incontinence: long-term results with dextranomer/hyaluronic acid copolymer. Int Urogynecol J Pelvic Floor Dysfunct 2003;14:335 8, discussion 338. [13] Kirsch AJ, Perez-Brayfield MR, Scherz HC. Minimally invasive treatment of vesicoureteral reflux with endoscopic injection of dextranomer/hyaluronic acid copolymer: the Children s Hospitals of Atlanta experience. J Urol 2003;170: [14] Hartanto VH, Lightner DJ, Nitti VW. Endoscopic evacuation of Durasphere. Urology 2003;62: [15] McKinney CD, Gaffey MJ, Gillenwater JY. Bladder outlet obstruction after multiple periurethral polytetrafluoroethylene injections. J Urol 1995;153: [16] Sweat SD, Lightner DJ. Complications of sterile abscess formation and pulmonary embolism following periurethral bulking agents. J Urol 1999;161:93 6. 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7 494 C.R. Chapple et al. / European Urology 48 (2005) using a copolymer system: impact on quality of life. BJU Int 2004; 94: [18] Rodriguez LV, Raz S. Prospective analysis of patients treated with a distal urethral polypropylene sling for symptoms of stress urinary incontinence: surgical outcome and satisfaction determined by patient driven questionnaires. J Urol 2003;170: [19] Elkadry EA, Kenton KS, FitzGerald MP, Shott S, Brubaker L. Patientselected goals: a new perspective on surgical outcome. Am J Obstet Gynecol 2003;189: [20] Lightner DJ. Review of the available urethral bulking agents. Curr Opin Urol 2002;12: [21] Stenberg A, Larsson E, Lindholm A, Ronneus B, Lackgren G. Injectable dextranomer-based implant: histopathology, volume changes and DNA-analysis. Scand J Urol Nephrol 1999;33: [22] Stenberg AM, Larsson G, Johnson P, Heimer G, Ulmsten U. DiHA Dextran Copolymer, a new biocompatible material for endoscopic treatment of stress incontinent women. Short term results. Acta Obstet Gynecol Scand 1999;78: