International Journal of Urology (2018) 25, 501--506 doi: 10.1111/iju.13558 Original Article: Clinical Investigation Long-term persistence with in a real-world clinical setting Naoki Wada, Masaki Watanabe, Hiroko Banjo, Miyu Tsuchida, Junichi Hori, Gaku Tamaki, Makoto Azumi, Masafumi Kita and Hidehiro Kakizaki Department of Renal and Urologic Surgery, Asahikawa Medical University, Asahikawa, Japan Abbreviations & Acronyms LUTD = lower urinary tract dysfunction OAB = overactive bladder OABSS = Overactive Bladder Symptom Score PV = prostatic volume Correspondence: Naoki Wada M.D., Ph.D., Department of Renal and Urologic Surgery, Asahikawa Medical University, 2-1-1-1 Midorigaoka Higashi, Asahikawa 078-8510, Japan. Email: nwada@asahikawamed.ac.jp Received 27 December 2017; accepted 9 February 2018. Online publication 12 April 2018 Objectives: To examine the long-term persistence rate with in a real-world clinical setting. Methods: We retrospectively collected the data of patients who were prescribed. We investigated the persistence rate and the reason for the discontinuation. The analysis included patient s age, diagnosis, Overactive Bladder Symptom Score, prostatic volume, the prescription by specialists for lower urinary tract dysfunction, drug-na ıve patients, replacement of antimuscarinics or add-on therapy to antimuscarinics. Results: A total of 556 patients were included. Among them, 401 patients (72%) had overactive bladder and the other 155 (28%) were categorized as having other storage symptoms. During the observation period, 170 patients (42%) with overactive bladder discontinued. The reasons for discontinuation in patients with overactive bladder included unmet expectation of treatment (45 patients, 26%), any adverse events (38 patients, 22%) or symptom improvement (37 patients, 22%). The persistence or discontinuation was not related with age, Overactive Bladder Symptom Score, prostatic volume or the prescription by specialists, while older male patients tended to continue. The 3-year persistence rates in female and male overactive bladder patients were 46% and 51%, respectively, and these were better than those in patients with storage symptoms without urgency. In female overactive bladder patients, the persistence rate with used as add-on therapy to antimuscarinics was higher than that in the drug-na ıve patients on the Kaplan Meier curve. Conclusions: The present study shows a relatively good long-term persistence rate with in overactive bladder patients, notwithstanding the retrospective study in an academic hospital. The combined treatment with antimuscarinics could result in a good persistence rate with. Key words: antimuscarinic, combination therapy,, overactive bladder, persistence. Introduction OAB is chronic dysfunctional status of the bladder and defined as urinary urgency with or without urgency incontinence. 1 Behavioral therapies including bladder training, pelvic floor muscle training and fluid management should be offered to all as the first-line treatment. Oral or transdermal medicines, such as antimuscarinics and b3-adrenoceptor agonist, are usually offered as the second-line treatment. OAB is commonly recognized as a chronic condition and long-term treatment is usually necessary. However, previous studies reported a low 1-year persistence rate with antimuscarinics ranging from 17% to 35%. 2 The discontinuation of antimuscarinics could be affected by many factors including unmet expectations of the treatment and adverse events, such as dry mouth or constipation. Unlike antimuscarinics, which act within the parasympathetic nervous system, the recently introduced b3-adrenoreceptor agonist,, targets the sympathetic nervous system and stimulates relaxation of the bladder smooth muscle. Several clinical studies showed that had similar effects to antimuscarinics and fewer adverse events. A systematic 2018 The Japanese Urological Association 501
N WADA ET AL. literature review also showed that had similar efficacy to most antimuscarinics and lower incidence of dry mouth, one of the main causes of discontinuation of treatment. 3 In detailed urodynamic studies, had no negative effect on the bladder contractility or post-void residual urine. 4,5 With the emergence of, switching therapy from antimuscarinics and combination therapy with antimuscarinics and could be treatment options for who are not satisfied with antimuscarinics. Favorable profiles of in adverse events and the possible treatment options of might contribute to a better long-term persistence rate with. Thus, we examined the long-term persistence rate with in a real-world clinical setting. Methods We retrospectively collected the data of patients at Asahikawa Medical University Hospital, Asahikawa, Japan, who were prescribed from September 2011 to September 2016. We investigated the continuation or discontinuation of, and the reason for the discontinuation until March 2017. If a patient who had been taking changed hospital, the time of changing hospital was defined as the last observation time-point. The analysis included patient s age, diagnosis (OAB or storage symptoms without urgency), OABSS, PV (only in men), prescription by a specialist for LUTD, drug-na ıve patients, replacement of antimuscarinics or add-on therapy to antimuscarinics. The diagnosis of OAB was made based on OABSS or the presence of urinary urgency. 6 The OABSS is a validated selfassessment questionnaire, and consists of four questions on OAB symptoms (Q1: daytime frequency, Q2: nighttime frequency, Q3: urgency and Q4: urgency incontinence) created by the Japanese Continence Society. 6 A specialist for LUTD was defined as an active member of the Japanese Continence Society who had experience in LUTD treatment for >7 years. Patients sex and age, OABSS, and PV (only in men) were compared between the patients who continued and discontinued using the Wilcoxon matched-pairs signedranks test or the v 2 -test. The persistence rate with was estimated and compared using the Kaplan Meier method. We also used Cox proportional hazards regression to examine factors influencing the persistence rate of. P < 0.05 were regarded as statistically significant. Results A total of 556 patients (female/male: 243/313) were included. There were no differences in age and the observation period between female and male patients. A total of 401 patients (72%) had OAB and the other 155 (28%) were categorized as other storage symptoms, such as urinary frequency without urgency, stress incontinence and interstitial cystitis (Table 1). During the observation period, 170 (42%) and 93 patients (60%) in each group discontinued (Table 2). The main reasons for discontinuation included unmet expectation of treatment, any adverse events or symptom improvement. These three reasons accounted for 26% (unmet expectation), 22% (adverse events) and 22% (symptom improvement) in patients with OAB who discontinued, respectively. The prevalence of patients who discontinued because of unmet expectation of treatment was higher in patients with storage symptoms without urgency (49%) than in (26%) (Table 2). There were no patients who had any cardiovascular events apparently as a result of. The continuation or discontinuation of was not related with age, OABSS or PV, whereas older male patients tended to continue. Male patients who continued were older than those who discontinued (74.2 vs 71.2 years, P = 0.01). The 1- and 3-year persistence rates in female and male were 63% and 46%, and 67% and 51%, respectively, and these were better than those in patients categorized as storage symptoms without urgency (Fig. 1). In male, the persistence rate with prescribed by specialists for LUTD tended to be higher than that by non-specialists, but there was no significant difference (Fig. 2). In female, the persistence rate with used as add-on therapy to antimuscarinics was significantly higher (P < 0.05) than that in the drug-na ıve patients, but was not significantly different from that in the patients receiving as a replacement for antimuscarinics (Fig. 3). In male, there was no significant difference in the persistence rate among the three subgroups of patients (Fig. 3). The details of antimuscarinics combined with are shown in Table 3. In Cox proportional hazards regression, no influencing factors on the persistence rate were detected. Discussion In the present study, the 1- and 3-year persistence rates with for were 63% and 46% in female patients, and 67% and 51% in male patients, respectively. These data were better than the persistence rate with antimuscarinics in previous reports. 2,7 Furthermore, in female OAB Table 1 Patients characteristics Overall Female Male 556 243 (44%) 313 (56%) Age (years) 71.1 (24 93) 69.0 (26 93) 72.8 (24 93) Observation period (months) 14.8 (1 64) 14.5 (1 64) 15.0 (1 63) Diagnosis OAB 401 (72%) 190 (78%) 211 (67%) Storage symptoms without 155 (28%) 53 (22%) 102 (33%) urgency Frequency/nocturia without 71 (13%) 23 (9%) 48 (15%) urgency Stress incontinence/postradical 37 (7%) 4 (2%) 33 (11%) prostatectomy Interstitial cystitis 18 (3%) 14 (6%) 4 (1%) Chronic cystitis/post-extra 12 (2%) 3 (1%) 9 (3%) beam radiotherapy Ureteral stent discomfort 5 (1%) 4 (2%) 1 (1%) Others 12 (2%) 5 (2%) 7 (2%) 502 2018 The Japanese Urological Association
Persistence with Table 2 Reasons for discontinuation of Patients with storage symptoms without urgency Overall Female Male Overall Female Male 401 190 211 155 53 102 who discontinued 170 (42%) 84 (44%) 86 (41%) 93 (60%) 36 (64%) 57 (56%) Reasons for discontinuation Unmet expectation of treatment 45 (26%) 26 (31%) 19 (22%) 46 (49%) 19 (53%) 27 (47%) Adverse effects 38 (22%) 14 (17%) 24 (28%) 15 (16%) 7 (19%) 8 (14%) Poor stream/strain void 11 (29%) 4 (29%) 7 (29%) 5 (33%) 2 (29%) 3 (38%) Increase in post-void residual/urinary retention 8 (21%) 4 (29%) 4 (17%) 4 (27%) 3 (43%) 1 (12%) Constipation 8 (21%) 2 (13%) 6 (25%) 3 (20%) 1 (14%) 2 (25%) Others 11 (29%) 4 (29%) 7 (29%) 3 (20%) 1 (14%) 2 (25%) Improvement of symptoms 37 (22%) 17 (20%) 20 (23%) 14 (15%) 6 (17%) 8 (14%) Unknown 50 (29%) 27 (32%) 23 (27%) 18 (19%) 4 (11%) 14 (25%) patients, add-on treatment with to antimuscarinics resulted in much better continuation compared with drugna ıve patients. Combination therapy with antimuscarinics and could be a better treatment option for female patients satisfaction. Mirabegron was first approved in 2011 for the treatment of OAB in Japan, and is now used worldwide. A placebocontrolled phase 3 study of showed the similar incidence of adverse events and the greater efficacy compared with a placebo. 8 The incidence rate of any adverse events of placebo, and tolterodine was 24.0%, 24.5% and 34.9%, respectively. The prevalence of constipation in (3.4%) and tolterodine (3.5%) was similar, whereas dry mouth developed more frequently in the tolterodine group (2.6% vs 13.3%). Previous clinical trials for antimuscarinics showed a higher incidence rate of dry mouth and constipation 9,10 compared with. 8 A recent randomized cross-over study also showed that had the same efficacy and a lower rate of dry mouth, blurred vision and constipation compared with an antimuscarinic agent imidafenacin. 11 The differences in tolerability with these two types of medication could greatly influence the continuation of medication. In the present study, the reasons for discontinuation of were unmet expectation of treatment (26%), adverse events (22%) or improvement of symptoms (22%) in OAB patients. Benner et al. reported the patient-reported reasons for discontinuation of antimuscarinics. According to their study, among the patients who discontinued antimuscarinics, the reasons were Didn t work as expected in 46.2%, I had sideeffects in 21.1% or Bladder symptoms have stopped/bladder problem is cured in 14.5%. 12 The multicenter clinical study reported by Martan et al. showed that the 1-year persistence rate with was 71%, but 40.0% and 16.7% of the study patients discontinued because of insufficient treatment efficacy and side-effects, respectively. 13 Taken together, the proportion of the reasons for discontinuation seems to be similar between and antimuscarinics. In the present study, the most frequent reason for discontinuation was unmet expectation of treatment. Of the patients categorized as storage symptoms without urgency, 49% discontinued as a result of unmet expectation of treatment, whereas 26% of discontinued. Mirabegron and antimuscarinics are medication for OAB. There is no clear evidence indicating the efficacy of or antimuscarinics for urinary frequency or nocturia without OAB, stress urinary incontinence or interstitial cystitis, although we have no highly recommended medications for these symptoms or diseases. These unfit medications understandably lead to disappointing consequences for patients expectation. The persistence rate with at 1 year varies widely from 12% to 71% in previous studies. 13 19 A smallscaled study at a urology clinic reported a low persistence rate with (12.2%; n = 76) and solifenacin (20.1%; n = 72). 14 In several large cohort studies using clinical databases (n = 1203 4037), just 19 38% of the patients continued. 15 17 Single or multicenter clinical studies including hundreds of patients showed better persistence rates ranging from 63% to 71%. 13 The continuation or discontinuation of medication is affected by several factors other than the efficacy and adverse events, including prescribing doctors, inadequate patients counseling, insufficient recognition of the condition by patients, cost problems and unwillingness to take long-term treatment. In the studies using clinical databases, not only urologists and urogynecologists, but also general practitioners, might be included as prescribing doctors. 15 17 Patients should recognize the chronic nature of OAB and the need for long-term treatment, and medical specialists for LUTD should counsel patients adequately to take medicines for a long time. In the present study, the add-on therapy with to antimuscarinics in female provided a better persistence rate than that in drug-na ıve patients, although the multivariable analysis failed to detect it as a significant factor. Martan et al. also showed that the use of as combination therapy with antimuscarinics resulted in better persistence. 13 Other factors associated with better persistence with were female patients, older aged patients or polypharmacy according to the previous studies. 15,16 One reason why combination therapy with and 2018 The Japanese Urological Association 503
N WADA ET AL. (a) Female 1 year (b) Male 3 years 1 year 3 years 63% 29% 46% 10% P < 1 67% 43% 51% 39% P < 1 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 OAB 190 104 63 36 26 16 7 OAB 211 125 70 42 23 9 3 Storage symptoms 53 11 5 3 3 1 1 Storage symptoms 102 37 19 12 7 2 1 without urgency without urgency Fig. 1 Kaplan Meier estimates of the persistence rate with in (a) female and (b) male patients. (a) Female (b) Male Specialist Non specialist 64% 58% 46% 43% P = 0.62 Specialist 74% Non specialist 67% 59% 49% P = 0.09 Non-specialists Specialists Non-specialists Specialists Specialist Non specialist 0 10 20 30 40 147 82 52 43 21 11 31 22 15 4 4 1 50 60 70 7 0 10 20 30 40 50 60 70 Specialist 134 82 44 30 18 8 2 Non specialist 77 43 26 13 6 3 Fig. 2 Kaplan Meier estimates of the persistence rate with in (a) female and (b) male patients who were prescribed by specialists or non-specialists for lower urinary tract dysfunction. (a) Female (b) Male Add-on 61% 45% 58% 41% 73% 51% P = 0.17 Add-on therapy P < 0.05 66% 53% 65% 46% Add-on 72% 49% Add-on therapy 0 10 20 30 40 50 60 Add-on 102 41 47 51 26 27 29 17 19 14 11 11 10 7 10 6 4 7 3 2 3 70 0 10 20 30 40 50 60 70 130 73 41 23 13 7 4 34 21 10 8 5 1 Add-on 47 30 20 12 7 3 1 Fig. 3 Kaplan Meier estimates of the persistence rate with in (a) female and (b) male patients who received as the first medication (drugna ıve), replacement of antimuscarinics or add-on to antimuscarinics. 504 2018 The Japanese Urological Association
Persistence with Table 3 Antimuscarinics combined with for Female Male Combined antimuscarinics Who continued Who discontinued Who continued Solifenacin 17 10 20 15 Propiverine 4 6 1 0 Tolterodine 5 0 3 3 Imidafenacin 3 0 4 0 Fesoterodine 1 1 0 1 Who discontinued antimuscarinic resulted in better persistence might be that the patients receiving combination therapy included a greater number of patients with severe OAB. Furthermore, the greater efficacy of combination therapy with and antimuscarinics for has already been reported. 20 Small-scaled clinical studies and basic research showed that combination therapy with and antimuscarinics was effective for treatment of bladder dysfunction and bladder remodeling in neurogenic bladder. 21 23 Thus, better efficacy of combination therapy could result in a better persistence rate with. In the present study, most patients received solifenacin combined with. We require further clinical study to know which antimuscarinics work better with. Limitations of the present study include the retrospective nature of the data collection in a single academic hospital. OAB definition was based on the description in medical records. The use of as add-on to or replacement of antimuscarinics was decided at the doctors discretion. The present study included some patients who were of reproductive age and had severe neurogenic OAB as a result of spinal disorders, including spinal cord injury or spina bifida. Mirabegron should be avoided as far as possible by people of reproductive age according to the package insert. We always informed those patients of that issue and gained their agreement. Despite these limitations, the present study showed a better persistence rate with in a real-world clinical setting, and the combination treatment with antimuscarinics in female is one of the treatment options yielding the patients satisfaction. In conclusion, the present study shows a relatively good long-term persistence rate with in. Combined treatment with antimuscarinics, especially in female, could result in a good persistence rate with. Conflict of interest Hidehiro Kakizaki has received consultancy, lectureship, advisory board membership fees and grants from Astellas Pharma. References 1 Abrams P, Artibani W, Cardozo L, Dmochowski R, van Kerrebroeck P, Sand P. Reviewing the ICS 2002 terminology report: The ongoing debate. Neurourol. Urodyn. 2009; 28: 287. 2 Wagg A, Compion G, Fahey A, Siddiqui E. Persistence with prescribed antimuscarinic therapy for overactive bladder: A UK experience. BJU Int. 2012; 110: 1767 74. 3 Maman K, Aballea S, Nazir J et al. Comparative efficacy and safety of medical treatments for the management of overactive bladder: A systematic literature review and mixed treatment comparison. Eur. Urol. 2014; 65: 755 65. 4 Nitti VW, Rosenberg S, Mitcheson DH et al. Urodynamics and safety of the b3-adrenoceptor agonist in males with lower urinary tract symptoms and bladder outlet obstruction. J. Urol. 2013; 190: 1320 7. 5 Wada N, Iuchi H, Kita M, Hashizume K, Matsumoto S, Kakizaki H. Urodynamic efficacy and safety of add-on treatment with tamsulosin for Japanese male patients with overactive bladder. Low Urin. Tract Symptoms 2016; 8: 171 6. 6 Yamaguchi O, Nishizawa O, Takeda M et al. Clinical guidelines for overactive bladder. Int. J. Urol. 2009; 16: 126 42. 7 Veenboer PW, Bosch JL. Long-term adherence to antimuscarinic therapy in everyday practice: A systematic review. J. Urol. 2014; 191: 1003 8. 8 Yamaguchi O, Marui E, Kakizaki H et al. Phase III, randomised, doubleblind, placebo-controlled study of the b3-adrenoceptor agonist, 50 mg once daily, in Japanese patients with overactive bladder. BJU Int. 2014; 113: 951 60. 9 Yamaguchi O, Marui E, Kakizaki H et al. Japanese Solifenacin Study Group. Randomized, double-blind, placebo- and propiverine-controlled trial of the once-daily antimuscarinic agent solifenacin in Japanese patients with overactive bladder. BJU Int. 2007; 100: 579 87. 10 Homma Y, Paick JS, Lee JG. Kawabe K; Japanese and Korean Tolterodine Study Group. Clinical efficacy and tolerability of extended-release tolterodine and immediate-release oxybutynin in Japanese and Korean patients with an overactive bladder: A randomized, placebo-controlled trial. BJU Int. 2003; 92: 741 7. 11 Torimoto K, Matsushita C, Yamada A et al. Clinical efficacy and safety of and imidafenacin in women with overactive bladder: a randomized crossover study (the MICRO study). Neurourol. Urodyn. 2017; 36: 1097 103. 12 Benner JS, Nichol MB, Rovner ES et al. Patient-reported reasons for discontinuing overactive bladder medication. BJU Int. 2010; 105: 1276 82. 13 Martan A, Masata J, Krhut J, Zachoval R, Hanus T, Svabik K. Persistence in the treatment of overactive bladder syndrome (OAB) with in a multicenter clinical study. Eur. J. Obstet. Gynecol. Reprod. Biol. 2017; 210: 247 50. 14 Kinjo M, Sekiguchi Y, Yoshimura Y, Nutahara K. Long-term persistence with versus solifenacin in women with overactive bladder: Prospective, randomized trial. Low Urin. Tract Symptoms. 2016. https://doi. org/10.1111/luts.12151. 15 Wagg A, Franks B, Ramos B, Berner T. Persistence and adherence with the new beta-3 receptor agonist,, versus antimuscarinics in overactive bladder: early experience in Canada. Can. Urol. Assoc. J. 2015; 9: 343 50. 16 Chapple CR, Nazir J, Hakimi Z et al. Persistence and adherence with versus antimuscarinic agents in patients with overactive bladder: A Retrospective Observational Study in UK Clinical Practice. Eur. Urol. 2017; 72: 389 99. 17 Sussman D, Yehoshua A, Kowalski J et al. Adherence and persistence of and anticholinergic therapies in patients with overactive bladder: A real-world claims data analysis. Int. J. Clin. Pract. 2017; 71: e12824. 2018 The Japanese Urological Association 505
N WADA ET AL. 18 Duckett J, Balachandran A. Tolerability and persistence in a large, prospective case series of women prescribed. Int. Urogynecol. J. 2016; 27: 1163 7. 19 Pindoria N, Malde S, Nowers J, Taylor C, Kelleher C, Sahai A. Persistence with therapy for overactive bladder: A real life experience. Neurourol. Urodyn. 2017; 36: 404 8. 20 Abrams P, Kelleher C, Staskin D et al. Combination treatment with and solifenacin in patients with overactive bladder: Efficacy and safety results from a randomized, double-blind, dose-ranging, phase 2study (Symphony). Eur. Urol. 2015; 67: 577 88. 21 Wada N, Okazaki S, Kobayashi S et al. Efficacy of combination therapy with for anticholinergic-resistant neurogenic bladder: Videourodynamic evaluation. Act. Urol. Jpn 2015; 61: 7 11. 22 Kamei J, Furuta A, Akiyama Y et al. Video-urodynamic effects of, a b3-adrenoceptor agonist, in patients with low-compliance bladder. Int. J. Urol. 2015; 22: 956 61. 23 Wada N, Shimizu T, Takai S et al. Combinational effects of muscarinic receptor inhibition and b3-adrenoceptor stimulation on neurogenic bladder dysfunction in rats with spinal cord injury. Neurourol. Urodyn. 2017; 36: 1039 45. 506 2018 The Japanese Urological Association