Duloxetine for Mild to Moderate Postprostatectomy Incontinence: Preliminary Results of a Randomised, Placebo-Controlled Trial

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1 EUROPEAN UROLOGY 59 (2011) available at journal homepage: Incontinence Duloxetine for Mild to Moderate Postprostatectomy Incontinence: Preliminary Results of a Randomised, Placebo-Controlled Trial Jean-Nicolas Cornu a, *, Benoit Merlet a, Calin Ciofu a, Stéphane Mouly b, Laurence Peyrat a, Philippe Sèbe a, René Yiou c, Guy Vallancien d, Isabelle Debrix e, Karim Laribi e, Olivier Cussenot a, François Haab a a Department of Urology, Tenon Hospital, University Paris VI, Paris, France b Department of Internal Medicine, Lariboisière Hospital, University Paris VII, Paris, France c Department of Urology, Henri Mondor Hospital, University Paris XII, Créteil, Paris, France d Department of Urology, Institut Mutualiste Montsouris, Paris, France e Department of Pharmacy, Tenon Hospital, University Paris VI, Paris, France Article info Article history: Accepted October 13, 2010 Published online ahead of print on October 27, 2010 Keywords: Duloxetine Urinary incontinence Stress Prostatectomy Randomised controlled trial Abstract Background: Duloxetine is effective in the management of stress urinary incontinence (SUI) in women but has been poorly evaluated in the treatment of SUI following radical prostatectomy (RP). Objective: To establish the superiority of duloxetine over placebo in SUI after RP. Design, setting, and participants: We conducted a prospective, randomised, placebocontrolled, double-blind, monocentric superiority trial. After a placebo run-in period of 2 wk, patients with SUI after RP were randomised to receive either 80 mg of duloxetine daily or matching placebo for 3 mo. Measurements: The primary outcome measure was the relative variation in incontinence episodes frequency (IEF) at the end of study compared to baseline. Secondary outcomes included quality of life (QoL) measures (Incontinence Impact Questionnaire Short Form [IIQ-SF], Urogenital Distress Inventory Short Form [UDI-SF], Incontinence Quality of Life [I-QoL]), symptom scores (Urinary Symptom Profile [USP] questionnaire, International Consultation on Incontinence/World Health Organisation Short Form questionnaire [ICIQ- SF], the Beck Depression Inventory [BDI-II] questionnaire), 1-h pad test, and assessment of adverse events. Results and limitations: Thirty-one patients were randomised to either the treatment (n = 16) or control group (n = 15). Reduction in IEF was significant with duloxetine compared to placebo (mean standard deviation [SD] variation: 52.2% 38.6 [range: 100 to +46] vs +19.0% 43.5 [range: 53 to +104]; mean difference: 71.2%; 95% confidence interval [CI] for the difference: ; p < ). IIQ-SF total score, UDI-SF total score, SUI subscore of the USP questionnaire, and question 3 of the ICIQ-SF questionnaire showed improvement in the duloxetine group ( p = 0.006, p = 0.02, p = , and p = 0.003, respectively). Both treatments were well tolerated throughout the study period. Conclusions: Duloxetine is effective in the treatment of incontinence symptoms and improves QoL in patients with SUI after RP. # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, Tenon Hospital, 4 rue de la Chine, Paris Cedex 20, France. Tel ; Fax: address: jncornu@hotmail.fr (J.-N. Cornu) /$ see back matter # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 EUROPEAN UROLOGY 59 (2011) Introduction Stress urinary incontinence (SUI) following radical prostatectomy (RP) has been described as a major side-effect that can affect patient quality of life (QoL) [1] and remains a daily challenge for urologists [2,3]. After initial assessment, the first-line treatment is noninvasive and based on supervised pelvic floor muscle training (PFMT) [4]. Behavioural therapies (reduction of bladder irritants, reduction of fluid intake, timed voiding, and bladder training) are also recommended [4,5], although no high level-of-evidence work has established their efficiency [4]. In the case of refractory SUI, more specialised management using invasive options is recommended. An effective drug treatment with acceptable side-effects is needed to fill the gap between physical/behavioural therapies and surgical options. To date, no pharmacologic therapy has been approved for male SUI. Duloxetine, a serotonin noradrenalin reuptake inhibitor, has proven its efficacy for SUI management in women [6] and has been proposed for use in men. This product acts in the Onuf s nucleus by blocking the reuptake of noradrenalin and serotonin. The increased concentration of these two neurotransmitters raises the activity of pudendal motor neurons, leading to an increase in striated urethral sphincter tonus and detrusor relaxation [7]. However, no clear data with a high level of evidence have yet been reported about duloxetine in male SUI after RP. Indeed, two case series with no control group evaluated the clinical efficacy of 40 mg of duloxetine daily after RP in 15 and 18 patients, respectively, with promising results [8,9]. One prospective, randomised study has been conducted [10], but it was single-blinded and conducted immediately after RP, and the drug was combined with PFMT for all patients. Thus, duloxetine is not recommended for management of SUI after RP and is currently used off-label by some practitioners [4]. To overcome these doubts and assess the clinical efficacy of 80 mg of duloxetine daily in men, we conducted a prospective, placebo-controlled, double-blind, randomised, superiority study in men with mild to moderate SUI persistent at least 1 yr after RP. 2. Patients and methods 2.1. Study overview This pilot randomised controlled trial (RCT) was conducted in one tertiary reference centre from March 2009 to March The study was conducted in accordance with good clinical practice guidelines and the Declaration of Helsinki, and our local institutional review board approved the protocol. All subjects gave written informed consent before enrolment in the study. The sponsors of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report Participants Male patients between 53 and 81 yr of age who had undergone RP for prostate cancer >1 yr before enrolment and who suffered from SUI or mixed incontinence with predominant SUI (7 28 leakage episodes per week certified on a 3-d bladder diary) were eligible to participate in the study. Exclusion criteria related to urologic condition or duloxetine mechanism of action are detailed in Table 1. Table 1 Exclusion criteria Related to urologic condition Severe SUI defined as >28 incontinence episodes mentioned in the 3-d bladder diary Previous surgical treatment of SUI except male sling Active or recent history (6 mo) of urethral stenosis Active or recurrent history (more than three episodes yearly) of UTI History of pelvic floor RT PFMT in the last month or scheduled in the next 3 mo Maximum urinary flow rate <15 ml/s PVR volume >100 ml identified with bladder scan Diuresis >2500 ml Medication regimen that includes diuretics where dose and/or frequency have not been stable for at least 12 wk prior to randomisation or are anticipated to change during the course of the study Known neurologic disease associated to LUTS Related to duloxetine effects Treatment with alpha agonists, serotonin-capture inhibitors, or anticholinergic-antimuscarinic drugs in the past 2 wk Hepatic impairment with hepatic insufficiency (In general, the test criteria are either alanine aminotransaminase 3 times the ULN of the laboratory performing the evaluation or total bilirubin 1.5 times the ULN of the laboratory performing the tests.) Patient rating a score of 2 or 3 on item 9 of the BDI-II Use of monoamine oxidase inhibitors, duloxetine, fluvoxamine, ciprofloxacine, enoxacine, or other medications with a potential undesirable interaction with duloxetine within 14 d prior to randomisation or at any time during the study or within 5 d of discontinuation of study drug Uncontrolled narrow-angle glaucoma Hypersensitivity to duloxetine or any of the inactive ingredients Severe renal impairment (creatinine clearance <30 ml/min) Uncontrolled hypertension SUI = stress urinary incontinence; UTI = urinary tract infection; RT = radiation therapy; PFMT = pelvic floor muscle training; PVR = postvoid residual; LUTS = lower urinary tract symptoms; ULN = upper limit of normal; BDI-II = Beck Depression Inventory.

3 150 [()TD$FIG] EUROPEAN UROLOGY 59 (2011) criteria concerning tolerance were any secondary effects reported during the study period (including variation in hepatic blood tests), Q max, PVR volume, and BDI-II at last follow-up. Two senior urologists conducted the visits, and the questionnaires were filled out at each visit Sample size Efficacy data are based on previous results obtained for SUI management in women and on expert opinion. Duloxetine treatment has been shown to be efficient in 50% of subjects in previous studies [6]. Placebo was estimated to reach 20% efficacy. Because of adverse events, the rate of patients stopping the study is around 17% for the duloxetine arm in previous studies [6]. With 90% power and a 0.05 type I error level, we needed to enrol 90 patients Randomisation and blinding 2.3. Procedures Fig. 1 Study design. Patients were randomised 1:1 to each group by blocks of four via a centralised computerised system to ensure a good balance of participant characteristics in each group. The study was double-blinded, as placebo capsules were strictly identical to duloxetine capsules. All patients were seen at the screening visit (V0) to check selection criteria and obtain written informed consent (Fig. 1). This first visit included assessment of the following areas: age, clinical history, clinical examination, prostate-specific antigen and hepatic blood tests, urine culture, 1-h pad test, baseline assessment of symptom scores (the Urinary Symptom Profile [USP] questionnaire and the International Consultation on Incontinence/World Health Organisation Questionnaire Short Form [ICIQ-SF]), QoL scores (Incontinence Impact Questionnaire Short Form [IIQ-SF], Urogenital Distress Inventory Short Form [UDI-SF], Incontinence Quality of Life [I-QoL], and the Beck Depression Inventory questionnaire [BDI-II]), 7-d bladder diary, uroflowmetry parameters (maximum flow rate [Q max ]), and postvoid residual (PVR) volume evaluation by bladder scan. All patients selected entered a 2-wk run-in phase during which they received placebo (Fig. 1). At the first visit (V1), eligible patients were randomly assigned 1:1 to the treatment group or the control group for 12 wk. Patients in the treatment group received duloxetine according to the following schedule: 20 mg twice per day (BID) for a total dose of 40 mg of duloxetine for 7 d, then 40 mg BID for a total dose of 80 mg for 67 d, and 20 mg BID for 14 d. Patients in the placebo arm received placebo given in identical capsules with the same frequency (twice daily). Patients were asked to take their medications at the same hour each day and to bring back boxes and blisters at each visit. Investigators and patients were blinded to the type of medication received. Visits after randomisation were scheduled at 2 wk (V2), 4 wk (V3), 8 wk (V4), and 12 wk (V5). Treatment was interrupted after the last visit. From V2 to V5, patients underwent blood tests for hepatic evaluation and filled out the USP, ICIQ-SF, IIQ-SF, UDI-SF, BDI-II, and I-QoL questionnaires. Clinical examination, 1-h pad test, PVR volume evaluation, and Q max assessment were done at V5 only. Adverse events were collected at each visit Outcome The primary outcome was the relative variation in the mean number of leakage episodes per day (incontinence episodes frequency [IEF]) according to the last voiding diary available (after V1 and before V5, last observation carried forward) and the last voiding diary before randomisation (V1). Secondary outcome measures concerning efficacy were the variation in symptom questionnaires (USP, ICIQ-SF) between V5 and V0, the variation in the 1-h pad test, and the variation in the QoL questionnaires (I-QoL, IIQ-SF, UDI-SF, and ICIQ-SF). Secondary outcome 2.7. Statistical analysis The statistical analysis was performed according to the intent to treat (ITT) principle and included all randomised subjects with at least one postrandomisation outcome measure. For patients lost to follow-up, data were analysed using the last-observation-carried-forward method. Categorical variables were analysed with the x 2 test or Fisher exact test, as appropriate. Primary quantitative outcome variables were compared by thestudent t test afterverification of normality by the Shapiro Wilk test or by the Mann-Whitney U test, as appropriate. The results presented here are issued from an interim analysis, driven by an independent statistician, after randomisation of 31 patients. Interim analysis, although not preplanned in the original protocol, was conducted after withdrawal of written informed consent by three patients (10% of total sample) and threats of withdrawal by others because of ineffectiveness. The study is registered under EudraCT number Results 3.1. Population A total of 31 men were randomised to duloxetine (n = 16) or placebo (n = 15). All patients had at least one complete follow-up evaluation, and all patients were included in ITT analysis. Four patients were lost to follow-up during the study. The flowchart is presented in Fig. 2. Table 2 lists baseline demographic and incontinence data gathered at the time of screening and randomisation, which indicated no significant differences between the treatment groups. Seventy-five percent of patients had more than two incontinence episodes per day at baseline Primary outcome The decrease in IEF at the end of the study (V5) was significantly greater in the duloxetine group (mean standard deviation [SD] variation: 52.2% 38.6 [range: 100 to +46] vs +19.0% 43.5 [range: 53 to +104]; mean difference: 71.2%; 95% confidence interval [CI], ; p < ). Median relative reduction in IEF during the study

4 [()TD$FIG] EUROPEAN UROLOGY 59 (2011) SCREENED, assigned for eligibility (n = 38) EXCLUDED (n = 7) - Incomplete data (n = 1) - PSA >0.1 ng/ml (n = 1) - Refused to participate (n = 5) RANDOMISED (n = 31) PLACEBO (n = 15) DULOXETINE (n = 16) Withdrew written informed consent and quit study because of: - adverse events (n = 1) - inefficiency (n = 2) Lost to follow-up (n = 1) 15 patients analysed 16 patients analysed Fig. 2 Study flowchart. Data concerning dropouts were analysed with the last-observation-carried-forward method. PSA = prostate-specific antigen. is shown in Fig. 3. Significant, superior IEF improvements with duloxetine compared to placebo were observed after 8 wk and 12 wk but not at the 4-wk visit. treatment ( p = 0.019). Other secondary parameters concerning efficacy show a significant improvement in the duloxetine group, except for 1-h pad test (Table 3) Secondary efficacy outcomes QoL measured by the I-QoL questionnaire was improved in the duloxetine group compared to placebo (Fig. 4). However, this difference was only significant at V5 after 12 wk of 3.4. Tolerance Treatment-emergent adverse events are described in Table 4. The only adverse event associated with duloxetine was fatigue. Mean BDI-II score variation between V1 and V5 were Table 2 Baseline characteristics of the 31 randomised patients Characteristics Duloxetine (n = 16) Placebo (n = 15) p value Age, yr, mean SD (range) (53 81) (55 75) 0.46 Previous surgical management of SUI by male sling, no Interval after RP, yr, mean SD (range) (1 10) (2 8) 0.92 RP with neurovascular bundles preservation, no Mixed urinary incontinence, no No. of PFMT sessions, mean SD (range) (0 200) (20 100) 0.58 Weight, kg, mean SD (range) (65 91) (65 90) 0.98 Height, cm, mean SD (range) ( ) ( ) 0.26 BMI, mean SD (range) ( ) ( ) h pad test, median (IQR) 4.5 ( ) 3.5 (2.2 7) 0.99 I-QoL (V1), mean SD (range) (60 105) (54 105) 0.41 IEF at baseline (V1), median (IQR) 3 (2 4) 3 (2 4) 0.98 SD = standard deviation; SUI = stress urinary incontinence; RP = radical prostatectomy; PFMT = pelvic floor muscle training; BMI = body mass index; IQR = interquartile range; I-QoL = Incontinence-Quality of Life; V1 = first visit; IEF = incontinence episodes frequency.

5 152 EUROPEAN UROLOGY 59 (2011) [()TD$FIG] Table 3 Secondary efficacy parameters and their variation from baseline; all values calculated as differences between the last value and the baseline value Duloxetine (n = 16) Placebo (n = 15) p value* Baseline value Value at V5 Difference (V5 V1) Baseline value Value at V5 Difference (V5 V1) IIQ-SF total score, mean SD (range) (1 14) (0 11) ( 13 to +2) (2 18) (1 14) ( 6 to +5) UDI-SF total score, mean SD (range) (1 9) (1 10) ( 8 to +2) (3 11) (3 11) ( 3 to +2) 0.02 SUI subscore of the USP questionnaire, (2 9) (0 9) ( 6 to0) (3 9) (3 9) ( 7 to +3) mean SD (range) ICIQ-SF question 3, mean SD (range) (0 9) (0 8) ( 7 to +1) (1 10) (0 10) ( 3 to +3) h pad test, median (IQR) 4.5 ( ) 2 (0 6) 1 ( 5.5 to 0) 3.5 (2.2 7) 4 (4 5.5) 0.5 ( 4 to +2) 0.48 V5 = visit 5; V1 = visit 1; IIQ-SF = Incontinence Impact Questionnaire Short Form; SD = standard deviation; UDI-SF = Urogenital Distress Inventory Short Form; SUI = stress urinary incontinence; USP = Urinary Symptom Profile; ICIQ-SF = International Consultation on Incontinence/WHO Questionnaire Short Form; WHO = World Health Organization. Fig. 3 Median percent decrease in incontinence episodes frequency for duloxetine and placebo at each of the three visits conducted during follow-up. The difference between duloxetine and placebo response was significant at visit 4 (8 wk) and visit 5 (12 wk). IEF = incontinence episodes frequency. [()TD$FIG] Fig. 4 Mean improvement in Incontinence Quality of Life total score for the duloxetine and placebo groups at each follow-up visit. QoL = quality of life. not different between the duloxetine and placebo groups ( [range: 10 to +7] and [range: 15 to +9], respectively; p = 0.27). The International Index of Erectile Function score and dysuria subscore of the USP questionnaire Table 4 Emergent side-effects during the study and secondary outcomes concerning tolerance ( p values issued from Fisher exact test) Side-effect Duloxetine (n = 16) Placebo (n = 15) Fatigue 8 (50%) 2 (13%) Sweat 4 (25%) 3 (20%) Insomnia 4 (25%) 1 (7%) Loss of libido 3 (19%) 1 (7%) Constipation 2 (13%) 1 (7%) Nausea 2 (13%) 1 (7%) Diarrhoea 2 (13%) 1 (7%) Dry mouth 1 (6%) Anorexia 1 (6%)

6 EUROPEAN UROLOGY 59 (2011) remained stable in the two groups. Hepatic blood tests, Q max, and PVR volume were not significantly different from baseline in any study group. 4. Discussion Our results show that using several measures of efficacy, duloxetine was significantly more effective than placebo. On ITT analysis, a decrease of % in IEF was seen at the end of the study in more than half of the patients treated with duloxetine. These results were largely significant. In line with previous analysis of the impact of IEF modification in patients treated by duloxetine [11], reduction in IEF was associated with intense and significant improvement in various QoL scores, including the I-QoL, UDI-SF, IIQ-SF, ICIQ- SF, and USP questionnaires. These data help put the IEF into clinical perspective. One-hour pad test decrease was not different in the groups, but this test has been shown to have intrinsic limitations and reproducibility problems that may explain these data [12,13]. Emerging adverse events were comparable to those reported by previous work, although statistical significance could not be reached in our data. This discrepancy may be the result of the relatively small number of patients randomised, because it was previously reported that each adverse event occurred in <25% of cases [14 17]. Although adverse events in our study did not required treatment interruption or specific medical management, they are not negligible and should be investigated by larger studies. We also noted an absence of placebo effect, contrary to previous studies conducted in women. This difference may be explained by the washout period in our study, but no reference is available, because our study is the first RCT of duloxetine in men. These results have to be considered in the field of postprostatectomy incontinence management after failure of conservative measures. Bothering SUI after RP is currently mainly managed by surgical options, including artificial urinary sphincter, male slings, periurethral inflatable balloons, and periurethral injections [4]. The present results thus give evidence to introduce a new pharmacologic category of efficient management of male SUI after RP. This alternative should be useful to patients reluctant to undergo surgery, especially in cases of mild incontinence. It may also provide a means to treat patients with incomplete results after mini-invasive therapy, such as tapes and balloons. For instance, in the present study, seven patients were included after failure of AdVance male sling (American Medical Systems, Minnetonka, MN, USA) implantation. One of the three patients randomised to the duloxetine group experienced an 86% reduction in IEF at last follow-up and was fully satisfied. Our study is based on an interim analysis and thus includes only 31 randomised patients. However, this fact should not be seen as a dramatic flaw for many reasons. This analysis was conducted by an independent statistician, because an increasing number of patients were willing to drop out during the study because of the inefficiency of the placebo medication and the absence of side-effects in this group. Indeed, written informed consent withdrawal occurred in two cases during follow-up, and other patients threatened to do so. We therefore postulated that we underestimated the efficacy of duloxetine and produced the interim analysis on the advice of our internal review board. Our results confirmed our hypothesis by showing a major statistical difference between the two groups on the primary outcome criteria ( p < ). This strong effect of duloxetine explains the overestimation of our necessary number of subjects presented in the Patients and methods section. Moreover, this result was resistant to a Bonferroni correction that, applied to our analysis, should lead to a upper limit of statistical significance for the p value. In the context of a superiority study, this p value allows us to draw conclusions about the primary outcome criterion and take into account results from secondary criteria. Therefore, our study is plainly valid from a methodologic point of view. Potential limitations of this study are its monocentric design and the heterogeneity of patient characteristics. In particular, because duloxetine increases neurotransmitter levels in the central nervous system, branches of the pudendal nerve play a crucial role by transmitting the message at the sphincter and bladder level. Hence, inclusion of patients with or without neurovascular bundle sparing could have biased the results, although the two groups were comparable. Furthermore, although the small number of subjects did not limit the evidence for treatment efficacy, it limited interpretation of adverse events. Side-effects are probably identical to those observed in women, but this remains to be established in a large sample of patients. 5. Conclusions Data from this study show for the first time in the literature the strong superiority of 80 mg of duloxetine daily over placebo in the treatment of male SUI after RP. Duloxetine is the first potentially widely approved pharmacologic treatment for postprostatectomy incontinence that fills an unmet medical need for patients who want to postpone or avoid surgery. Larger studies will narrow its indications and its modalities of use and surveillance in current clinical practice. Author contributions: Jean-Nicolas Cornu had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Haab, Cussenot. Acquisition of data: Yiou, Peyrat, Merlet, Ciofu, Vallancien, Sèbe. Analysis and interpretation of data: Cornu, Ciofu, Cussenot, Haab. Drafting of the manuscript: Cornu. Critical revision of the manuscript for important intellectual content: Haab, Cussenot, Mouly. Statistical analysis: Mouly, Cornu, Cussenot. Obtaining funding: None. Administrative, technical, or material support: Debrix, Laribi. Supervision: Haab. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/

7 154 EUROPEAN UROLOGY 59 (2011) affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Professor Stephane Mouly received consultancy honoraria from Braun, Pfizer, Sanofi-Aventis, Lilly Research Laboratories, Lundbeck, and Chugai Pharma. Funding/Support and role of the sponsor: None. Acknowledgment statement: The authors acknowledge Lilly for its support. References [1] Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 2008;358: [2] Herschorn S, Bruschini H, Comiter C, et al. Committee of the International Consultation on Incontinence. Surgical treatment of stress incontinence in men. Neurourol Urodyn 2010;29: [3] Loughlin KR, Prasad MM. Post-prostatectomy urinary incontinence: a confluence of 3 factors. J Urol 2010;183: [4] Bauer RM, Bastian PJ, Gozzi C, Stief CG. Postprostatectomy incontinence: all about diagnosis and management. Eur Urol 2009;55: [5] Abrams P, Andersson KE, Birder L, Brubaker L, Cardozo L, Chapple C. Fourth International Consultation on Incontinence Recommendations of the International Scientific Committee: Evaluation and Treatment of Urinary Incontinence, Pelvic Organ Prolapse, and Fecal Incontinence. Neurourolurodyn 2010;29: [6] Mariappan P, Alhasso A, Ballantyne Z, Grant A, N Dow J. Duloxetine, a serotonin and noradrenaline reuptake inhibitor (SNRI) for the treatment of stress urinary incontinence: a systematic review. Eur Urol 2007;51: [7] Boy S, Reitz A, Wirth B, et al. Facilitatory neuromodulative effect of duloxetine on pudendal motor neurons controlling the urethral pressure: a functional urodynamic study in healthy women. Eur Urol 2006;50: [8] Zahariou A, Papaioannou P, Kalogirou G. Is HCl duloxetine effective in the management of urinary stress incontinence after radical prostatectomy? Urol Int 2006;77:9 12. [9] Schlenker B, Gratzke C, Reich O, Schorsch I, Seitz M, Stief CG. Preliminary results on the off-label use of duloxetine for the treatment of stress incontinence after radical prostatectomy or cystectomy. Eur Urol 2006;49: [10] Filocamo MT, Li Marzi V, Del Popolo G, et al. Pharmacologic treatment in postprostatectomy stress urinary incontinence. Eur Urol 2007;51: [11] Yalcin I, Peng G, Viktrup L, Bump RC. Reductions in stress urinary incontinence episodes: what is clinically important for women? Neurourol Urodyn 2010;29: [12] Aslan E, Beji NK, Coskun A, Yalcin O. An assessment of the importance of pad testing in stress urinary incontinence and the effects of incontinence on the life quality of women. Int Urogynecol J Pelvic Floor Dysfunct 2003;14: [13] Soroka D, Drutz HP, Glazener CM, Hay-Smith EJ, Ross S. Perineal pad test in evaluating outcome of treatments for female incontinence: a systematic review. Int Urogynecol J Pelvic Floor Dysfunct 2002;13: [14] Cardozo L, Drutz HP, Baygani SK, et al. Pharmacological treatment of women awaiting surgery for stress urinary incontinence. Obstet Gynecol 2004;104: [15] Dmochowski RR, Miklos JR, Norton PA, et al. Duloxetine versus placebo for the treatment of North American women with stress urinary incontinence. J Urol 2003;170: [16] Millard RJ, Moore K, Rencken R, et al. Duloxetine vs placebo in the treatment of stress urinary incontinence: a four-continent randomized clinical trial. BJU Int 2004;93: [17] Norton PA, Zinner NR, Yalcin I, et al. Duloxetine versus placebo in the treatment of stress urinary incontinence. Am J Obstet Gynecol 2002;187:40 8.