World J Urol DOI 10.1007/s00345-013-1179-z
ORIGINAL ARTICLE
Efficacy and tolerability of solifenacin in men with overactive bladder: results of an observational study Maximilian Burger • Dietmar Betz Christian Hampel • Monika Vogel
•
Received: 17 May 2013 / Accepted: 3 October 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose To evaluate the efficacy and safety of solifenacin for the treatment of OAB in men. Methods This prospective observational study, reflective of actual practice patterns, was conducted in men older than 18 years who were prescribed solifenacin for the treatment of OAB symptoms. Men with suspected bladder outlet obstruction were excluded. The primary efficacy measure was change in OAB symptoms after 12 weeks of solifenacin. Also assessed were changes in severity of urinary urgency, IPSS, quality of life, cognitive function, and adverse events. Data were analyzed using descriptive methods. Results A total of 799 men recruited at 251 centers, average age 67 years (range 27–92), received solifenacin 5 mg or 10 mg/day. Mean episodes of urinary urgency, This study was registered at www.vfa.de/nis, number NIS Vesi 10 (MOVE).
frequency, and nocturia decreased by 4.4, 3.6, and 1.4 episodes/24 h, respectively. As per IPSS, severe urinary symptoms were reported by 20.4 % at baseline versus by 2.3 % at week 12. Both voiding and storage symptoms showed improvement. Patient-reported general health condition was excellent/good for 39 % at baseline increasing to 76 % at week 12. Adverse event rate was 5.5 %, and discontinuation of solifenacin due to an event was 1.6 %. No change in post-void residual urine volume was experienced in 80%, while an increase of C50 mL was observed in 2.2 %; no cases of acute urinary retention occurred. Baseline mean MMSE was 27.5 points versus 27.9 points at week 12. Conclusions Solifenacin reduced all OAB symptoms, was well tolerated, and had no apparent effect on post-void residual urine volume. Cognitive function was unaltered in this population of older men with OAB. Keywords Antimuscarinic Cognitive function Men Urinary retention
Electronic supplementary material The online version of this article (doi:10.1007/s00345-013-1179-z) contains supplementary material, which is available to authorized users.
Introduction M. Burger (&) Department of Urology and Pediatric Urology, Julius-Maximilians-University Medical Center, Oberdu¨rrbacher Straße 6, 97080 Wu¨rzburg, Germany e-mail: [email protected] D. Betz Urology Center, Du¨sseldorf, Germany C. Hampel Department of Urology, University Medical Center of the Johannes-Gutenberg University, Mainz, Germany M. Vogel Astellas Pharma GmbH, Munich, Germany
Lower urinary tract symptoms (LUTS) in men are often attributed to benign conditions of the prostate but may in fact stem from the entire lower urinary tract. Thus, symptoms such as urinary urgency with or without urgency incontinence in men are suggestive of overactive bladder (OAB) [1]. The prevalence of LUTS in men aged 50–80 years was 90 % in a large multinational study [2]. In the multinational EPIC study, 26 % of men [18 years had voiding symptoms, 51 % storage symptoms, and 12 % OAB [3]. The European Association of Urology (EAU) guidelines
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recommend antimuscarinics in men with moderate to severe LUTS with predominant storage symptoms [4]. Undertreatment of men with OAB occurs frequently because male LUTS is commonly attributed to prostate problems and because antimuscarinics are believed to precipitate acute urinary retention [4–8]. Concerns about urinary retention in men receiving antimuscarinics are unfounded according to clinical evidence [9–11]. The symptoms of OAB can interrupt normal daily routines and negatively impact quality of life (QoL) [12, 13]. Solifenacin has been shown to reduce OAB symptoms while maintaining good safety and tolerability profiles [14, 15] and provide significant short- and long-term improvement in QoL [16]. Recent research has focused on a possible relationship between antimuscarinics and cognitive impairment in older persons [17, 18]. The primary study objective was to evaluate the efficacy and safety of flexible dose solifenacin in men with LUTS. We also investigated changes in voiding symptoms and urinary urgency severity, and changes in QoL and cognitive status following a 12-week administration of solifenacin.
Methods
Table 1 Baseline characteristics and medical history of participants N = 799 Age, mean (SD), year
Urinary urgency
365 (45.7)
Increased frequency of micturition
356 (44.6)
Nocturia
187 (23.4)
Incontinence
101 (12.6)
Diagnosisa OAB, without urgency incontinence
286 (35.8)
BPS/LUTS (storage, not purely voiding)
228 (28.5)
Other diagnosis/missing data
15.4 (5.2)
Post-void residual urine volume, median (range), mL
21.6 (0–300)
Previous nonpharmacological treatment for LUTS
308 (38.5)
Previous pharmacological treatment for LUTS
582 (72.8)
Continuing pharmacological treatment for LUTS
254 (31.8)
5-a-Reductase inhibitor Anticholinergic agent
The primary endpoint was the effectiveness of solifenacin at week 12 in reducing OAB symptoms. Secondary endpoints were solifenacin tolerability, change in QoL, urinary
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93 (11.6)
Total IPSS, mean (SD)
Participants and design
Outcome measurements
319 (40)
OAB, with urgency incontinence
a-Blocker
This noninterventional, observational study (MOVE: men with OAB taking VesicareÒ [Astellas GmbH, Munich, Germany]), conducted from March to November 2011 in urology practices in Germany, recruited men older than 18 years without suspected bladder outlet obstruction or significant post-void residual (PVR) urine volume who were prescribed solifenacin. Best medical practice procedures, as judged by the treating physician, were used to assess and diagnose bladder outlet obstruction and PVR and screen out patients with relevant findings. Dosing choice (5 or 10 mg once daily) was made by the treating physician based on ICS standardizations to diagnose OAB [1]. Data were collected during routine medical care at baseline and 12 weeks after starting solifenacin. Pseudonymous names were used to secure privacy. Additional diagnostic tests were conducted at physician discretion in accordance with standard medical practice. Participants provided written consent, and appropriate ethical approval was obtained before study initiation.
67.4 (10.3)
Most compromising symptom of LUTSa
216 (27) 25 (3.1) 13 (1.6)
Concomitant disease
472 (59.1)
Concomitant medication use
418 (52.3)
Responses presented as number (%) unless indicated otherwise a
Multiple responses possible
LUTS lower urinary tract symptom, OAB overactive bladder, BPS benign prostatic symptom, IPSS International Prostate Symptom Score (scored as 0 = no symptoms to 35 = severe symptoms)
urgency severity, cognitive status, and post-void residual urine volume between baseline and week 12. The International Prostate Symptom Score (IPSS) was used to measure efficacy [19]. This scale uses seven items to assess feelings of incomplete bladder emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia with a score between 1 and 5 points for a maximum score of 35, and one item to assess QoL scored between 1 and 6 points. Urinary urgency was measured using the Indevus Urgency Severity Scale (IUSS) [20]. This four-item patient-reported scale rates the severity of urinary urgency per void using a score of 0–3. To facilitate the collection of data in the clinical setting, three questions from the King’s Health Questionnaire (KHQ) [21] were selected to measure the impact of lower urinary tract symptoms on health-related QoL. These questions were: ‘‘How would you describe your health at present?’’
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(general health QoL assessment), ‘‘How much do you think your bladder problem affects your life?’’ and ‘‘How would you feel if your symptoms remained untreatable?’’ The Mini Mental State Exam (MMSE) [22] was used to evaluate cognitive status (orientation, immediate recall, attention and calculation, and language). A score C27 (out of a possible score of 30) indicates normal cognitive function, 18–26 indicates mild cognitive impairment, 10–17 moderates impairment, and B9 is indicative of severe cognitive impairment. To capture information on drug safety, participants were asked at each visit whether they had experienced any adverse events related to solifenacin and physically examined for possible adverse events. An increase in postvoid residual urine volume was defined as C20 mL.
Fig. 1 Changes in symptoms of overactive bladder over 12 weeks following the administration of solifenacin. A decrease in all symptoms of OAB was evident at week 12. Of clinical relevance are the marked decreases in episodes of urinary urgency (-4.4 episodes) and voiding frequency (-3.7 episodes) over 24 h
Data analysis
Results
participants continued to receive the lower dose at week 12 when 71 % were taking solifenacin 5 mg and 23.5 % were taking 10 mg. In total, 1.9 % discontinued taking solifenacin; there was no single causative factor attributed to the discontinuations. Physicians rated medication compliance as excellent or good for 93.6 % of the participants.
Participant characteristics
Efficacy
The full analysis set comprised 799 men from 251 centers. Mean age was 67 years (range 27–92 years). Median time since diagnosis of urinary dysfunction was 2.4 months (range \1 week to 20 years) although the median duration of symptoms was much longer at 11.3 months (range \1 week to 26 years). Most commonly, participants identified urinary urgency followed by micturition frequency as the most bothersome storage symptoms (Table 1). More than two-thirds of participants had received previous pharmacological treatment for urinary symptoms, including treatment with a-blockers (44.6 %), 5-a-reductase inhibitors (5 %), and anticholinergic agents (29.4 %). Herbal remedies and behavioral therapies, including bladder and pelvic floor muscle training, had been implemented by 19 and 22 %, respectively. Pharmacological agents (mainly a-blockers) prescribed for urinary dysfunction were continued in 32 %. A small percentage of participants, 15 %, had had surgical treatment for pathologic conditions of the lower urinary tract. Commensurate with the age of participants, concomitant disease was reported in approximately 60 % and a majority was taking concomitant medications including, most commonly, acetylsalicylic acid (24 %) and ramipril (22 %). Initially, solifenacin 5 mg was prescribed for 87 % of participants and solifenacin 10 mg for 12.5 %. More
All OAB symptoms clearly decreased at week 12 (Fig. 1). Most notably, mean episodes of urinary urgency decreased from 9.2 to 4.8 episodes/24 h and nocturia from 3.2 to 1.8 episodes/night, while voiding frequency decreased from 12 to 8.3 episodes/24 h. Severity of urinary symptoms also decreased markedly. Mean total IPSS was 15.4 points at baseline and 9.4 points at week 12. Severe symptoms were reported by 20.4 % at baseline but by 2.3 % at week 12 (Fig. 2a). Decreases in storage symptoms were more pronounced than decreases in voiding symptoms. Mean scores for voiding symptoms were 4.4 at week 12, a decrease of 1.7 points from baseline, and mean scores for storage symptoms were 5 points at week 12, a decrease of 4.2 points from baseline (Fig. 2b). A decrease in urinary urgency severity was observed as shown by IUSS scores. While 24.3 % of participants experienced severe urgency at baseline (194 of 799), the rate decreased to 1.8 % (14 of 799) at week 12.
The study data were analyzed using descriptive methods, and no testing for statistical significance was performed.
Quality of Life At baseline, general condition of health as assessed from the KHQ was rated as excellent and good by 39.4 and 76.1 %, respectively, at week 12. Urinary urgency had a severe effect on daily life for 43.6 % of participants at baseline but for far fewer, 5.4 %, at week 12. In the presence of current OAB symptoms, 11.8 % at baseline versus
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World J Urol Fig. 2 Comparison of mean total scores and subdomain scores of the IPSS measured at baseline and at week 12 in men with overactive bladder, N = 799. a Classification of total IPSS. At week 12, the number of participants reporting severe urinary symptoms decreased while the number of participants reporting mild urinary symptoms increased in comparison with baseline. b IPSS subdomain scores. In comparison with baseline, reductions in the severity of voiding symptoms, especially incomplete emptying, and reductions in the severity of storage symptoms, most especially nocturia, were observed at week 12. IPSS International Prostate Symptom Score
48.7 % at week 12 reported satisfaction with QoL. Using the IPSS to assess QoL, mean score at baseline was 3.5 points (predominantly unsatisfied) and decreased to 1.8 points (predominantly satisfied) at week 12. Cognition MMSE data were provided at baseline and week 12 and were complete for 532 (66.6 %) participants. MMSE
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scores showed no meaningful change with treatment: Mean scores changed by 0.4 points between baseline and week 12 (range -5 to 10 points) (Table 2). Changes in MMSE scores for a subset of participants with mild or moderate dementia at baseline (i.e., a score between 10 and 26 points at baseline, n = 59) were analyzed. MMSE total scores for this subset remained unchanged: Baseline mean was 20.4 points versus 21.7 points at week 12.
World J Urol Table 2 Changes in cognition at week 12 as measured using the Mini Mental State Exam n = 532a Change in score ± 1 point
389 (73.1)
Increase in score C 2 points
102 (19.2)
Decrease in score C 2 points
41 (7.7)
Decrease of 2 points
24 (4.5)
Decrease of 3 points
12 (2.3)
Decrease of 4 points
4 (0.8)
Decrease of 5 points
1 (0.2)
Data in table are presented in numbers (percentage) a
Participants with measurements of Mini Mental State Exam (MMSE) at both baseline and week 12
Safety Adverse events occurred in 5.5 % (44 of 799) of participants; no participants experienced a serious adverse event. The most common event was dry mouth reported in nine participants (1.1 %) followed by hematuria and proteinuria, each reported in eight participants (1 %), and leukocyturia in six participants (0.8 %). An adverse event was the reason for the discontinuation of solifenacin in 13 (1.6 %) participants, and one adverse event was causally related to solifenacin. Measurements of PVR were available for 555 men at both baseline and week 12; mean (SD) PVR was 20.5 mL (24.4) and 19.6 mL (22.6), respectively. There was no change in PVR in 80 %. An increase of C50 mL was observed in 2.2 % (Table 3). Four men had an increase of C80 mL: Three had no PVR at baseline and amounts ranging from 80 to 100 mL at week 12, and one had a PVR of 20 mL at baseline and 130 mL at week 12. No participant experienced acute urinary retention. Table 3 Change in post-void residual urine volume at week 12 n = 555a No change in post-void residual urine volume
444 (80)
Decrease in post-void residual urine volume
67 (12.1)
Increase in post-void residual urine volume
44 (7.9)
20–29 Ml
18 (3.2)
30–39 mL
12 (2.2)
40–49 mL
2 (0.4)
50–59 mL
3 (0.5)
60–69 mL
4 (0.7)
70–79 mL
1 (0.2)
[80 mL
4 (0.7)
Data in table are presented in numbers (percentage) a
Participants with measurements of post-void residual urine volume at both baseline and week 12
Discussion This observational study is one of a few to evaluate an antimuscarinic agent for the treatment of storage symptoms indicative of OAB in men. The results show that flexible dosing with both 5 and 10 mg solifenacin is efficacious and well tolerated in this population. All symptoms of OAB, but most notably urinary urgency and frequency, were reduced after 12 weeks. We observed a clinically relevant improvement in storage symptoms and a weaker improvement in voiding symptoms as measured using subdomain scores of the IPSS. The results corroborate our statement of an improvement in OAB symptoms with solifenacin. For the majority of men, efficacy was obtained using the 5 mg dose of solifenacin. To approximate daily medical practice, participants were allowed to continue a-blocker therapy. The majority of participants, however, began antimuscarinic monotherapy: There was no notable difference in efficacy results between these two groups (data not presented). Approximately three-quarters of participants rated their QoL after 12 weeks of treatment with solifenacin as good or excellent. It is desirable that patients with OAB have improvements in QoL in parallel with those in efficacy variables [16]; our results support this relationship. The inhibitory effect of antimuscarinics on detrusor muscle contraction could cause acute urinary retention in men [23]. Results of a meta-analysis of randomized trials of antimuscarinics showed that only oxybutynin IR significantly increased the risk of urinary retention compared with placebo [24]. A randomized trial using solifenacin added to tamsulosin reported 3 % urinary retention in male participants [25]. Although post-void residual urine volume has been shown to increase in older men [24], in our cohort with a mean age of 67 years, only 2.2 % had an increase in PVR of C50 mL and there was no acute retention. Our results contribute to the safety profile of solifenacin use in men and thus provide further substantiation for the proposal by Oelke and colleagues [6] to use antimuscarinics in men without BOO without the risk of increasing AUR. Treatment tolerability was good as demonstrated by the very low number of participants who experienced an adverse event or prematurely discontinued solifenacin. It is worth mentioning that the low number of events occurred in a population with extended use of concomitant medications. Persistence with taking solifenacin for the control of OAB symptoms was high, which may indicate a positive balance between tolerability and efficacy as viewed by study participants. There are reports of changes in cognitive function, particularly memory, associated with antimuscarinics, and the American Urological Association recommends that an MMSE should be conducted on all patients at risk of
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cognitive impairment to determine possible cognitive decline with antimuscarinic treatment [26]. We found no changes from baseline measures in mental state at week 12 although the men in our study were older and thus potentially vulnerable to cognitive deficits as a side effect of antimuscarinics [17]. A limitation of this study might be the observational design and the lack of testing for statistically significant differences. In comparison with the randomized studies, observational studies are more likely to provide an indication of what is achieved in daily medical practice [27], and this was our motivation for conducting the study. Meta-analyses have confirmed that observational studies do not overestimate the magnitude of the effects of treatment [28]. In this respect, although the study protocol did not mandate diagnostic instruments for assessing some variables or specify the use of patient diaries, and decisions on patient management were made according to best medical practice and not protocol-driven, we feel the large study sample representing a broad spectrum of men with OAB and the good quality of data collected (the frequency of missing data ranged between 0.6 and 5 %) support the relevance of these results. In conclusion, the administration of flexible dose solifenacin over 12 weeks reduced all measured OAB symptoms, which seemed to positively impact QoL. Solifenacin was well tolerated and appeared not to affect PVR urine volume or cognitive function in this somewhat older male population. The results of this observational study, with its expansive population of men with OAB, are reflective of routine medical practice that may facilitate an easier transfer of findings into daily practice. Acknowledgments We thank the participating urologists for their help in data collection. Astellas GmbH, Germany, provided financial support for this study. Tanja Fielenbach and Michael Mader (Medidata, Germany) conducted the statistical analysis, funded by Astellas. Writing and editing assistance was provided by C. Krcmar, CRKrcmar Medical Communications, and was funded by Astellas. All authors have received consulting and lecture fees from Astellas. M. Vogel is an employee of Astellas GmbH. No remuneration was awarded to the authors for their participation in this study.
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lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 50:1306–1315 Oelke M, Bachmann A, Descazeaud A et al (2013) EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol 64:118–140 Morant SV, Reilly K, Bloomfield GA, Chapple C (2008) Diagnosis and treatment of lower urinary tract symptoms suggestive of overactive bladder and bladder outlet obstruction among men in general practice in the UK. Int J Clin Pract 62:688–694 Oelke M, Burger M, Castro-Diaz D et al (2012) Diagnosis and medical treatment of lower urinary tract symptoms in adult men: applying specialist guidelines in clinical practice. BJU Int 110:710–718 Andersson KE, Chapple CR, Cardozo L et al (2009) Pharmacological treatment of overactive bladder: report from the International Consultation on Incontinence. Curr Opin Urol 19:380–394 Hefland BT, Evans RM, McVary KT (2010) A comparison of the frequencies of medical therapies for overactive bladder in men and women: analysis of more than 7.2 million aging patients. Eur Urol 57:586–591 Kaplan SA, Roehrborn CG, Dmochowski R, Rovner ES, Wang JT, Guan Z (2006) Tolterodine extended release improves overactive bladder symptoms in men with overactive bladder and nocturia. Urology 68:328–332 Roehrborn CG, Abrams P, Rovner ES, Kaplan SA, Herschorn S, Guan Z (2006) Efficacy and tolerability of tolterodine extendedrelease in men with overactive bladder and urgency urinary incontinence. BJU Int 97:1003–1006 Kaplan SA, Goldfischer ER, Steers WD, Gittelman M, Andoh M, Forero-Schwanhaeuser S (2010) Solifenacin treatment in men with overactive bladder: effects on symptoms and patient-reported outcomes. Aging Male 13:100–107 Temml C, Heidler S, Ponholzer A, Madersbacher S (2005) Prevalence of the overactive bladder syndrome by applying the International Continence Society definition. Eur Urol 2005: 622–627 Milson I, Kaplan SA, Coyne KS, Sexton CC, Kopp ZS (2012) Effect of bothersome overactive bladder symptoms on healthrelated quality of life, anxiety, depression, and treatment seeking in the United States: results from EpiLUTS. Urology 80:90–96 Chapple CR, Rechberger T, Al-Shukri S et al (2004) Randomized, double-blind placebo- and tolterodine-controlled trial of the once-daily antimuscarinic agent solifenacin in patients with symptomatic overactive bladder. BJU Int 93:303–310 Cardozo L (2004) Randomized, double-blind placebo-controlled trial of once-daily antimuscarinic agent solifenacin succinate in patients with overactive bladder. J Urol 172:1919–1924 Kelleher CJ, Cardozo L, Chapple CR, Haab F, Ridder AM (2005) Improved quality of life in patients with overactive bladder symptoms treated with solifenacin. BJU Int 95:81–85 Fox C, Richardson K, Maidment ID et al (2011) Anticholinergic medication use and cognitive impairment in the older population: the medical research council cognitive function and ageing study. J Am Geriatr Soc 59:1477–1483 Whalley LJ, Sharma S, Fox HC et al (2012) Anticholinergic drugs in late life: adverse effects on cognition but not on progress to dementia. J Alzheimers Dis 1:253–261 Barry MJ, Fowler FJ Jr, O’Leary MP et al (1992) The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 148:1549–1557 Zinner N, Harnett M, Sabounjian L, Sandage B, Dmochowski R, Staskin D (2005) The overactive bladder-symptom composite score: a composite symptom score of toilet voids, urgency
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25. Kaplan SA, McCammon K, Fincher R, Fakhoury A, He W (2009) Safety and tolerability of solifenacin add-on therapy to a-blocker treated men with residual urgency and frequency. J Urol 182:2825–2830 26. Gromley EA, Lightner DJ, Burgio KL et al (2012) Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/ SUFU guideline. J Urol 188(6 Suppl):2455–2463 27. Theobald K, Capan M, Herbold M, Schinzel S, Hundt F (2009) Quality assurance in non-interventional studies. Ger Med Sci 7: Doc29. doi:10.3205/000088 28. Concato J, Shah N, Horwitz RI (2000) Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 342:1887–1892
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ORIGINAL ARTICLE
Efficacy and tolerability of solifenacin in men with overactive bladder: results of an observational study Maximilian Burger • Dietmar Betz Christian Hampel • Monika Vogel
•
Received: 17 May 2013 / Accepted: 3 October 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose To evaluate the efficacy and safety of solifenacin for the treatment of OAB in men. Methods This prospective observational study, reflective of actual practice patterns, was conducted in men older than 18 years who were prescribed solifenacin for the treatment of OAB symptoms. Men with suspected bladder outlet obstruction were excluded. The primary efficacy measure was change in OAB symptoms after 12 weeks of solifenacin. Also assessed were changes in severity of urinary urgency, IPSS, quality of life, cognitive function, and adverse events. Data were analyzed using descriptive methods. Results A total of 799 men recruited at 251 centers, average age 67 years (range 27–92), received solifenacin 5 mg or 10 mg/day. Mean episodes of urinary urgency, This study was registered at www.vfa.de/nis, number NIS Vesi 10 (MOVE).
frequency, and nocturia decreased by 4.4, 3.6, and 1.4 episodes/24 h, respectively. As per IPSS, severe urinary symptoms were reported by 20.4 % at baseline versus by 2.3 % at week 12. Both voiding and storage symptoms showed improvement. Patient-reported general health condition was excellent/good for 39 % at baseline increasing to 76 % at week 12. Adverse event rate was 5.5 %, and discontinuation of solifenacin due to an event was 1.6 %. No change in post-void residual urine volume was experienced in 80%, while an increase of C50 mL was observed in 2.2 %; no cases of acute urinary retention occurred. Baseline mean MMSE was 27.5 points versus 27.9 points at week 12. Conclusions Solifenacin reduced all OAB symptoms, was well tolerated, and had no apparent effect on post-void residual urine volume. Cognitive function was unaltered in this population of older men with OAB. Keywords Antimuscarinic Cognitive function Men Urinary retention
Electronic supplementary material The online version of this article (doi:10.1007/s00345-013-1179-z) contains supplementary material, which is available to authorized users.
Introduction M. Burger (&) Department of Urology and Pediatric Urology, Julius-Maximilians-University Medical Center, Oberdu¨rrbacher Straße 6, 97080 Wu¨rzburg, Germany e-mail: [email protected] D. Betz Urology Center, Du¨sseldorf, Germany C. Hampel Department of Urology, University Medical Center of the Johannes-Gutenberg University, Mainz, Germany M. Vogel Astellas Pharma GmbH, Munich, Germany
Lower urinary tract symptoms (LUTS) in men are often attributed to benign conditions of the prostate but may in fact stem from the entire lower urinary tract. Thus, symptoms such as urinary urgency with or without urgency incontinence in men are suggestive of overactive bladder (OAB) [1]. The prevalence of LUTS in men aged 50–80 years was 90 % in a large multinational study [2]. In the multinational EPIC study, 26 % of men [18 years had voiding symptoms, 51 % storage symptoms, and 12 % OAB [3]. The European Association of Urology (EAU) guidelines
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recommend antimuscarinics in men with moderate to severe LUTS with predominant storage symptoms [4]. Undertreatment of men with OAB occurs frequently because male LUTS is commonly attributed to prostate problems and because antimuscarinics are believed to precipitate acute urinary retention [4–8]. Concerns about urinary retention in men receiving antimuscarinics are unfounded according to clinical evidence [9–11]. The symptoms of OAB can interrupt normal daily routines and negatively impact quality of life (QoL) [12, 13]. Solifenacin has been shown to reduce OAB symptoms while maintaining good safety and tolerability profiles [14, 15] and provide significant short- and long-term improvement in QoL [16]. Recent research has focused on a possible relationship between antimuscarinics and cognitive impairment in older persons [17, 18]. The primary study objective was to evaluate the efficacy and safety of flexible dose solifenacin in men with LUTS. We also investigated changes in voiding symptoms and urinary urgency severity, and changes in QoL and cognitive status following a 12-week administration of solifenacin.
Methods
Table 1 Baseline characteristics and medical history of participants N = 799 Age, mean (SD), year
Urinary urgency
365 (45.7)
Increased frequency of micturition
356 (44.6)
Nocturia
187 (23.4)
Incontinence
101 (12.6)
Diagnosisa OAB, without urgency incontinence
286 (35.8)
BPS/LUTS (storage, not purely voiding)
228 (28.5)
Other diagnosis/missing data
15.4 (5.2)
Post-void residual urine volume, median (range), mL
21.6 (0–300)
Previous nonpharmacological treatment for LUTS
308 (38.5)
Previous pharmacological treatment for LUTS
582 (72.8)
Continuing pharmacological treatment for LUTS
254 (31.8)
5-a-Reductase inhibitor Anticholinergic agent
The primary endpoint was the effectiveness of solifenacin at week 12 in reducing OAB symptoms. Secondary endpoints were solifenacin tolerability, change in QoL, urinary
123
93 (11.6)
Total IPSS, mean (SD)
Participants and design
Outcome measurements
319 (40)
OAB, with urgency incontinence
a-Blocker
This noninterventional, observational study (MOVE: men with OAB taking VesicareÒ [Astellas GmbH, Munich, Germany]), conducted from March to November 2011 in urology practices in Germany, recruited men older than 18 years without suspected bladder outlet obstruction or significant post-void residual (PVR) urine volume who were prescribed solifenacin. Best medical practice procedures, as judged by the treating physician, were used to assess and diagnose bladder outlet obstruction and PVR and screen out patients with relevant findings. Dosing choice (5 or 10 mg once daily) was made by the treating physician based on ICS standardizations to diagnose OAB [1]. Data were collected during routine medical care at baseline and 12 weeks after starting solifenacin. Pseudonymous names were used to secure privacy. Additional diagnostic tests were conducted at physician discretion in accordance with standard medical practice. Participants provided written consent, and appropriate ethical approval was obtained before study initiation.
67.4 (10.3)
Most compromising symptom of LUTSa
216 (27) 25 (3.1) 13 (1.6)
Concomitant disease
472 (59.1)
Concomitant medication use
418 (52.3)
Responses presented as number (%) unless indicated otherwise a
Multiple responses possible
LUTS lower urinary tract symptom, OAB overactive bladder, BPS benign prostatic symptom, IPSS International Prostate Symptom Score (scored as 0 = no symptoms to 35 = severe symptoms)
urgency severity, cognitive status, and post-void residual urine volume between baseline and week 12. The International Prostate Symptom Score (IPSS) was used to measure efficacy [19]. This scale uses seven items to assess feelings of incomplete bladder emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia with a score between 1 and 5 points for a maximum score of 35, and one item to assess QoL scored between 1 and 6 points. Urinary urgency was measured using the Indevus Urgency Severity Scale (IUSS) [20]. This four-item patient-reported scale rates the severity of urinary urgency per void using a score of 0–3. To facilitate the collection of data in the clinical setting, three questions from the King’s Health Questionnaire (KHQ) [21] were selected to measure the impact of lower urinary tract symptoms on health-related QoL. These questions were: ‘‘How would you describe your health at present?’’
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(general health QoL assessment), ‘‘How much do you think your bladder problem affects your life?’’ and ‘‘How would you feel if your symptoms remained untreatable?’’ The Mini Mental State Exam (MMSE) [22] was used to evaluate cognitive status (orientation, immediate recall, attention and calculation, and language). A score C27 (out of a possible score of 30) indicates normal cognitive function, 18–26 indicates mild cognitive impairment, 10–17 moderates impairment, and B9 is indicative of severe cognitive impairment. To capture information on drug safety, participants were asked at each visit whether they had experienced any adverse events related to solifenacin and physically examined for possible adverse events. An increase in postvoid residual urine volume was defined as C20 mL.
Fig. 1 Changes in symptoms of overactive bladder over 12 weeks following the administration of solifenacin. A decrease in all symptoms of OAB was evident at week 12. Of clinical relevance are the marked decreases in episodes of urinary urgency (-4.4 episodes) and voiding frequency (-3.7 episodes) over 24 h
Data analysis
Results
participants continued to receive the lower dose at week 12 when 71 % were taking solifenacin 5 mg and 23.5 % were taking 10 mg. In total, 1.9 % discontinued taking solifenacin; there was no single causative factor attributed to the discontinuations. Physicians rated medication compliance as excellent or good for 93.6 % of the participants.
Participant characteristics
Efficacy
The full analysis set comprised 799 men from 251 centers. Mean age was 67 years (range 27–92 years). Median time since diagnosis of urinary dysfunction was 2.4 months (range \1 week to 20 years) although the median duration of symptoms was much longer at 11.3 months (range \1 week to 26 years). Most commonly, participants identified urinary urgency followed by micturition frequency as the most bothersome storage symptoms (Table 1). More than two-thirds of participants had received previous pharmacological treatment for urinary symptoms, including treatment with a-blockers (44.6 %), 5-a-reductase inhibitors (5 %), and anticholinergic agents (29.4 %). Herbal remedies and behavioral therapies, including bladder and pelvic floor muscle training, had been implemented by 19 and 22 %, respectively. Pharmacological agents (mainly a-blockers) prescribed for urinary dysfunction were continued in 32 %. A small percentage of participants, 15 %, had had surgical treatment for pathologic conditions of the lower urinary tract. Commensurate with the age of participants, concomitant disease was reported in approximately 60 % and a majority was taking concomitant medications including, most commonly, acetylsalicylic acid (24 %) and ramipril (22 %). Initially, solifenacin 5 mg was prescribed for 87 % of participants and solifenacin 10 mg for 12.5 %. More
All OAB symptoms clearly decreased at week 12 (Fig. 1). Most notably, mean episodes of urinary urgency decreased from 9.2 to 4.8 episodes/24 h and nocturia from 3.2 to 1.8 episodes/night, while voiding frequency decreased from 12 to 8.3 episodes/24 h. Severity of urinary symptoms also decreased markedly. Mean total IPSS was 15.4 points at baseline and 9.4 points at week 12. Severe symptoms were reported by 20.4 % at baseline but by 2.3 % at week 12 (Fig. 2a). Decreases in storage symptoms were more pronounced than decreases in voiding symptoms. Mean scores for voiding symptoms were 4.4 at week 12, a decrease of 1.7 points from baseline, and mean scores for storage symptoms were 5 points at week 12, a decrease of 4.2 points from baseline (Fig. 2b). A decrease in urinary urgency severity was observed as shown by IUSS scores. While 24.3 % of participants experienced severe urgency at baseline (194 of 799), the rate decreased to 1.8 % (14 of 799) at week 12.
The study data were analyzed using descriptive methods, and no testing for statistical significance was performed.
Quality of Life At baseline, general condition of health as assessed from the KHQ was rated as excellent and good by 39.4 and 76.1 %, respectively, at week 12. Urinary urgency had a severe effect on daily life for 43.6 % of participants at baseline but for far fewer, 5.4 %, at week 12. In the presence of current OAB symptoms, 11.8 % at baseline versus
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World J Urol Fig. 2 Comparison of mean total scores and subdomain scores of the IPSS measured at baseline and at week 12 in men with overactive bladder, N = 799. a Classification of total IPSS. At week 12, the number of participants reporting severe urinary symptoms decreased while the number of participants reporting mild urinary symptoms increased in comparison with baseline. b IPSS subdomain scores. In comparison with baseline, reductions in the severity of voiding symptoms, especially incomplete emptying, and reductions in the severity of storage symptoms, most especially nocturia, were observed at week 12. IPSS International Prostate Symptom Score
48.7 % at week 12 reported satisfaction with QoL. Using the IPSS to assess QoL, mean score at baseline was 3.5 points (predominantly unsatisfied) and decreased to 1.8 points (predominantly satisfied) at week 12. Cognition MMSE data were provided at baseline and week 12 and were complete for 532 (66.6 %) participants. MMSE
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scores showed no meaningful change with treatment: Mean scores changed by 0.4 points between baseline and week 12 (range -5 to 10 points) (Table 2). Changes in MMSE scores for a subset of participants with mild or moderate dementia at baseline (i.e., a score between 10 and 26 points at baseline, n = 59) were analyzed. MMSE total scores for this subset remained unchanged: Baseline mean was 20.4 points versus 21.7 points at week 12.
World J Urol Table 2 Changes in cognition at week 12 as measured using the Mini Mental State Exam n = 532a Change in score ± 1 point
389 (73.1)
Increase in score C 2 points
102 (19.2)
Decrease in score C 2 points
41 (7.7)
Decrease of 2 points
24 (4.5)
Decrease of 3 points
12 (2.3)
Decrease of 4 points
4 (0.8)
Decrease of 5 points
1 (0.2)
Data in table are presented in numbers (percentage) a
Participants with measurements of Mini Mental State Exam (MMSE) at both baseline and week 12
Safety Adverse events occurred in 5.5 % (44 of 799) of participants; no participants experienced a serious adverse event. The most common event was dry mouth reported in nine participants (1.1 %) followed by hematuria and proteinuria, each reported in eight participants (1 %), and leukocyturia in six participants (0.8 %). An adverse event was the reason for the discontinuation of solifenacin in 13 (1.6 %) participants, and one adverse event was causally related to solifenacin. Measurements of PVR were available for 555 men at both baseline and week 12; mean (SD) PVR was 20.5 mL (24.4) and 19.6 mL (22.6), respectively. There was no change in PVR in 80 %. An increase of C50 mL was observed in 2.2 % (Table 3). Four men had an increase of C80 mL: Three had no PVR at baseline and amounts ranging from 80 to 100 mL at week 12, and one had a PVR of 20 mL at baseline and 130 mL at week 12. No participant experienced acute urinary retention. Table 3 Change in post-void residual urine volume at week 12 n = 555a No change in post-void residual urine volume
444 (80)
Decrease in post-void residual urine volume
67 (12.1)
Increase in post-void residual urine volume
44 (7.9)
20–29 Ml
18 (3.2)
30–39 mL
12 (2.2)
40–49 mL
2 (0.4)
50–59 mL
3 (0.5)
60–69 mL
4 (0.7)
70–79 mL
1 (0.2)
[80 mL
4 (0.7)
Data in table are presented in numbers (percentage) a
Participants with measurements of post-void residual urine volume at both baseline and week 12
Discussion This observational study is one of a few to evaluate an antimuscarinic agent for the treatment of storage symptoms indicative of OAB in men. The results show that flexible dosing with both 5 and 10 mg solifenacin is efficacious and well tolerated in this population. All symptoms of OAB, but most notably urinary urgency and frequency, were reduced after 12 weeks. We observed a clinically relevant improvement in storage symptoms and a weaker improvement in voiding symptoms as measured using subdomain scores of the IPSS. The results corroborate our statement of an improvement in OAB symptoms with solifenacin. For the majority of men, efficacy was obtained using the 5 mg dose of solifenacin. To approximate daily medical practice, participants were allowed to continue a-blocker therapy. The majority of participants, however, began antimuscarinic monotherapy: There was no notable difference in efficacy results between these two groups (data not presented). Approximately three-quarters of participants rated their QoL after 12 weeks of treatment with solifenacin as good or excellent. It is desirable that patients with OAB have improvements in QoL in parallel with those in efficacy variables [16]; our results support this relationship. The inhibitory effect of antimuscarinics on detrusor muscle contraction could cause acute urinary retention in men [23]. Results of a meta-analysis of randomized trials of antimuscarinics showed that only oxybutynin IR significantly increased the risk of urinary retention compared with placebo [24]. A randomized trial using solifenacin added to tamsulosin reported 3 % urinary retention in male participants [25]. Although post-void residual urine volume has been shown to increase in older men [24], in our cohort with a mean age of 67 years, only 2.2 % had an increase in PVR of C50 mL and there was no acute retention. Our results contribute to the safety profile of solifenacin use in men and thus provide further substantiation for the proposal by Oelke and colleagues [6] to use antimuscarinics in men without BOO without the risk of increasing AUR. Treatment tolerability was good as demonstrated by the very low number of participants who experienced an adverse event or prematurely discontinued solifenacin. It is worth mentioning that the low number of events occurred in a population with extended use of concomitant medications. Persistence with taking solifenacin for the control of OAB symptoms was high, which may indicate a positive balance between tolerability and efficacy as viewed by study participants. There are reports of changes in cognitive function, particularly memory, associated with antimuscarinics, and the American Urological Association recommends that an MMSE should be conducted on all patients at risk of
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cognitive impairment to determine possible cognitive decline with antimuscarinic treatment [26]. We found no changes from baseline measures in mental state at week 12 although the men in our study were older and thus potentially vulnerable to cognitive deficits as a side effect of antimuscarinics [17]. A limitation of this study might be the observational design and the lack of testing for statistically significant differences. In comparison with the randomized studies, observational studies are more likely to provide an indication of what is achieved in daily medical practice [27], and this was our motivation for conducting the study. Meta-analyses have confirmed that observational studies do not overestimate the magnitude of the effects of treatment [28]. In this respect, although the study protocol did not mandate diagnostic instruments for assessing some variables or specify the use of patient diaries, and decisions on patient management were made according to best medical practice and not protocol-driven, we feel the large study sample representing a broad spectrum of men with OAB and the good quality of data collected (the frequency of missing data ranged between 0.6 and 5 %) support the relevance of these results. In conclusion, the administration of flexible dose solifenacin over 12 weeks reduced all measured OAB symptoms, which seemed to positively impact QoL. Solifenacin was well tolerated and appeared not to affect PVR urine volume or cognitive function in this somewhat older male population. The results of this observational study, with its expansive population of men with OAB, are reflective of routine medical practice that may facilitate an easier transfer of findings into daily practice. Acknowledgments We thank the participating urologists for their help in data collection. Astellas GmbH, Germany, provided financial support for this study. Tanja Fielenbach and Michael Mader (Medidata, Germany) conducted the statistical analysis, funded by Astellas. Writing and editing assistance was provided by C. Krcmar, CRKrcmar Medical Communications, and was funded by Astellas. All authors have received consulting and lecture fees from Astellas. M. Vogel is an employee of Astellas GmbH. No remuneration was awarded to the authors for their participation in this study.
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