Management of Male OAB; Current Status in Japan Department of Urology University of Occupational and Environmental Health, Japan Hisae NISHII

Lower Urinary Tract Symptoms Introduction; LUTS Lower Urinary Tract Symptoms LUTS Storage symptoms Daytime urinary frequency Urgency Nocturia Urinary incontinence Voiding symptoms Slow stream Intermittency Heitency Straining　 Post micturition symptoms Sensation of incomplete emptying Postmicturition dribble

Overactive Bladder (OAB) Introduction; OAB Overactive Bladder (OAB) Urgency, with or without urge(ncy) incontinence, usually with frequency and nocturia Frequency Urgency Urge incontinence OAB is a gender-independent, multifactorial process with local stuructual and functional changes of the bladder, and also systemic medical co-morbidity

Introduction; Male OAB 　The treatment of male LUTS is complicated, because the storage and voiding symptoms frequently coexist. 　Storage symptoms have stronger impact on QOL in men than voiding symptoms, however, voiding symptoms are most prevalent in male LUTS 　Storage symptoms often occur independently of (Bladder outlet obstruction) BOO and persist in many men despite pharmacologic and surgical treatment. 　It is unclear whether storage symptoms may develop secondary to BOO or detrusor dysfunction. BPE BOO Histologic BPH LUTS

Epidemiology-Europe EU SIFO Study US NOBLE Study Over 40y/o 16.6% OAB Male Female 40-44 45-49 50-54 45-59 60-64 65-69 70-74 75+ 5 10 15 20 25 30 35 40 45 　(%) EU SIFO Study US NOBLE Study 40 35 Male Female 30 25 20 15 10 5 18-24 25-34 35-44 45-54 55-64 65-74 75+ Age ( y/o) Age (y/o) Over 40y/o 16.6% OAB Over 18y/o Male 16.0% OAB Female 16.9% OAB EPIC study LUTS were highly prevalent in both men and women to a similar extent in both sexes storage LUTS men 51.3%, women 59.2% voiding LUTS men 25.7%. women 19.5% postmicturion LUTS men 16.9%, women 14.2%

Epidemiology-Japan 2002 Daytime urinary frequency ％ y/o

Epidemiology-Japan 2002 Nighttime urinary frequency ％ y/o

Epidemiology-Japan 2002 Frequency of Urgency ％ y/o

Epidemiology-Japan 2002 Grade of Urgency ％ y/o

Epidemiology-Japan 2002 Social impact

Epidemiology-Japan 2002 Prevalence of OAB ％ y/o

Epidemiology-Japan 2002 Prevalence of OAB 12.4％ of total

Epidemiology-Japan 2002 Patients’ cost for treatment of OAB

Epidemiology-Japan 2002 y/o Percentage of OAB patients treated at clinic y/o

Treatment of male OAB in JAPAN Alpha1-adrenoceptor antagonists Phosphodiesterase inhibitors Prazosin Terazosin Urapidil Tamsulosin Naftopidil Silodosin Phytotherapeutic drug Eviprostat Antimuscarinic agents Oxybutinin Propiverine Tolterodine Solifenacin Imidafenacin$ Combination therapy

Treatment of male OAB; A1-adrenoceptor antagonists Tamsulosin 0.2mg Naftopidil 50mg Naftopidil 75mg Silodosin Comparison of Tamsulosin, Natdopidil, Silodosin

Treatment of male OAB; Alpha1-adrenoceptor antagonists Tamsulosin 0.2mg Naftopidil 50mg Naftopidil 75mg Silodosin Comparison of Tamsulosin, Natdopidil, Silodosin

Tamsulosin, 0.2mg/day, daily 　Entry criteria ・Male over 50y/o ・Clinical BPH ・IPSS≧8 ・OABSS≧3 and 　Q3≧2 ・QOL≧2 0 week 4weeks Tamsulosin, 0.2mg/day, daily Evaluation IPSS QOL Index OABSS Evaluation IPSS QOL Index OABSS Yoshida M et al., 2008

** ** ** ** * IPSS-subscore 0 week 4weeks 3.5 3.2 2.9 2.9 2.2 2.2 1.8 4.0 ** 0 week 4weeks 3.5 ** ** 3.2 2.9 2.9 3.0 2.2 2.2 * 2.0 1.8 1.7 1.6 1.6 1.2 1.1 1.0 1.0 0.9 0.0 Sensation of imcomplete emptying Daytime Urinary Frequency Intermittency Urgency Slow stream Straining Nocturia *：p<0.05、**：p<0.01（Wilcoxon signed-rank test）

8.1 6.1 ** 10 8 6 4 2 OABSS 0 week 4 weeks **：p<0.01 （Wilcoxon signed-rank test） 0 week 4 weeks

** ** ** OABSS-subscore 4週後 0 week 4weeks 3.2 2.3 2.1 1.8 1.5 1.0 1.0 4.0 4週後 0 week 4weeks ** 3.2 3.0 ** 2.3 2.1 ** 2.0 1.8 1.5 1.0 1.0 1.0 0.9 0.0 Daytime Urinary Frequency Nocturia Urgency Urgent incontinence **：p<0.01（Wilcoxon signed-rank test）

10 2 51 73 46 17 0 week 4 weeks OAB severity （％） 100 50 Severe（12≦OABSS） 10 2 Moderate（6≦OABSS≦11） Mild（OABSS≦5） 51 n＝41 73 50 46 17 0 week 4 weeks

Treatment of male OAB; Alpha1-adrenoceptor antagonists Tamsulosin 0.2mg Naftopidil 50mg Naftopidil 75mg Silodosin Comparison of Tamsulosin, Natdopidil, Silodosin

Naftpidil, 50mg/day, daily IPSS ≧8　and QOL-Index ≧2 Prostate volume ≧15mL Clinical BPH with OAB symptoms 0 week 12 weeks Naftpidil, 50mg/day, daily Evaluation Evaluation IPSS 0 week 12 weeks *** *** *** *** *** *** *** n＝36 （Wilcoxon signed-rank test） ***：p＜0.001 Sensation of imcomplete emptying Intermittency Slow stream Nocturia Daytime Urinary Frequency Urgency Straining Awa Y.,et al.. 2008

Treatment of male OAB; Alpha1-adrenoceptor antagonists Tamsulosin 0.2mg Naftopidil 50mg Naftopidil 75mg Silodosin Comparison of Tamsulosin, Natdopidil, Silodosin

Naftpidil, 75mg/day, daily 0 week 4 weeks 8 weeks IPSS ≧8　and QOL-Index ≧2 Prostate volume ≧15mL Clinical BPH with OAB symptoms Naftpidil, 75mg/day, daily Evaluation Evaluation Evaluation IPSS *** 0 week 8 weeks 4 weeks *** 0 week 8 weeks 4 weeks *** 0 week 8 weeks 4 weeks n＝31 Mean±S.D. （Wilcoxon signed-rank test） ***：p＜0.0001 Storage Symptom Score Voiding Symptom Score Postmicturition symptom Score Miyamoto K. et al. 2009

Voiding diary Daytime frequency Nighttime frequency Urgency （n＝17） (回） (点） (点） ** ** * ** ** * Mean±S.D. （Wilcoxon signed-rank test） **：p＜0.005 * ：p＜0.05 0 week 8 weeks 0 week 8 weeks 0 week 8 weeks 4 weeks 4 weeks 4 weeks Miyamoto K. et al. 2009

Treatment of male OAB; Alpha1-adrenoceptor antagonists Tamsulosin 0.2mg Naftopidil 50mg Naftopidil 75mg Silodosin Comparison of Tamsulosin, Natdopidil, Silodosin

Silodosin, 8mg/day, daily 　Entry criteria ・Clinical BPH ・Naftopidil or Tamsulosin treatment more than 6 months 0 week 4weeks 12weeks Silodosin, 8mg/day, daily Evaluation IPSS, QOL Index, OABSS,Qmax, Residual urine volume IPSS Tanaka M et al. 2010

IPSS-subscore No significant changes in the OABSS (4.4 ± 2.4–4.4 ± 2.6, p = 0.897) Qmax (11.7 ± 6.1 to 12.7 ± 6.3, P = 0.259) residual urine volume (38.0 ± 59.4–40.0 ± 58.7, P = 0.526)  

Treatment of male OAB; Alpha1-adrenoceptor antagonists Tamsulosin 0.2mg Naftopidil 50mg Naftopidil 75mg Silodosin Comparison of Tamsulosin, Natdopidil, Silodosin

0 week 12weeks Evaluation Tamsulosin 0.2mg/day, daily 　Entry criteria (n=90) ・Clinical BPH ・Over 50 y/o ・IPSS≥3 ・Prostate volume ≥50ml ・Residual urine volume ≤100ml Tamsulosin 0.2mg/day, daily Naftopidil 50mg/day, Daily Silodosin, 8mg/day, daily Evaluation IPSS, QOL Index Kikuchi Y et al. 2010

** ** ** ** 10 9 8 7 6 5 4 3 2 1 IPSS-subscore Total voiding score Tamsulosin Naftopidil Silodosin

** * * ** ** 8 7 6 5 4 3 2 1 IPSS-subscore Total storage score Tamsulosin Naftopidil Silodosin

Treatment of male OAB; Alpha1-adrenoceptor antagonists Tamsulosin 0.2mg Naftopidil 50mg Naftopidil 75mg Silodosin Comparison of Tamsulosin, Natdopidil, Silodosin

Treatment of male OAB; Combination therapy Trial of combination treatment with an Alpha-blocker plus an Anticholinergic for BPH with OAB (TAABO) Combination treatment with Tamsulosin and Solifenacine to OAB symptoms with BPH

Treatment of male OAB; Combination therapy Trial of combination treatment with an Alpha-blocker plus an Anticholinergic for BPH with OAB (TAABO) Combination treatment with Tamsulosin and Solifenacine to OAB symptoms with BPH

Having OAB symptoms after 8 weeks Tamsulosin Tamsulosin 0.2mg, 1C/day, daily Tamsulosin 0.2mg 1C/day, daily. 8weeks Tamsulosin 0.2mg, 1C/day, daily Propiverine 10mg, 1T/day, daily Tamsulosin 0.2mg, 1C/day, daily Propiverine 20mg, 1T/day, daily N=516 N=214 Session Ⅰ Session Ⅱ Registration －8weeks 4weeks 8weeks 12weeks Age>50 Clinical BPH IPSS more than8 QOL index more than 2 Qmax<15ml/sec Having OAB symptoms after 8 weeks Tamsulosin Daitime frequency more than 8 times Urgency once/ 24 hrs at least Except Qmax<5ml/sec, RV>100ml

Combination therapy with Tamsulosin and propiverine 10mg significantly Voiding diary Average voiding time/24hr Urgency * P=0.0261 Tamsulosin Tamsulosin+Propiverine 10mg Tamsulosin+Propiverine 20mg ** P=0.0093 12wks（n） 12wks（mean±SD） 12wks（P） Tamsulosin 46 10.3±2.9 0.004 +Propiverine10mg 49 9.4±2.3 <.0001 +Propiverine20mg 45 10.1±2.8 0.0074 12wks（n） 12wks（mean±SD） 12wks（P） Tamsulosin 46 2.3±3.3 0.3024 +Propiverine10mg 49 1.0±1.5 <.0001 +Propiverine20mg 45 1.4±3.0 0.0103 Combination therapy with Tamsulosin and propiverine 10mg significantly decrease the average voiding time and urgency times in voiding diary.

Total storage symptoms score in IPSS IPSS Q4 Urgency * Tamsulosin Tamsulosin+Propiverine 10mg Tamsulosin+Propiverine 20mg * P=0.0465 * P=0.0252　 割付群 12週（n） 12週（mean±SD） 12週（P値） Tamsulosin 47 5.7±3.7 0.0009 +Propiverine10mg 49 4.7±2.3 <.0001 +Propiverine20mg 45 4.5±2.8 割付群 12週（n） 12週（mean±SD） 12週（P値） Tamsulosin 47 1.6±1.6 0.0195 +Propiverine10mg 49 0.9±1.0 <.0001 +Propiverine20mg 45 0.9±1.4 Combination therapy with Tamsulosin and propiverine 10mg significantly decrease the storage symptoms scores and urgency score in IPSS.

Total voiding symptoms scores in IPSS Qmax Tamsulosin Tamsulosin+Propiverine 10mg Tamsulosin+Propiverine 20mg 割付群 12週（n） 12週（mean±SD） 12週（P値） Tamsulosin 47 3.9±4.2 0.029 +Propiverine10mg 49 3.5±3.1 0.0126 +Propiverine20mg 45 4.9±3.4 0.4823 割付群 12週（n） 12週（mean±SD） 12週（P値） Tamsulosin 47 12.7±5.4 0.3259 +Propiverine10mg 49 12.2±6.2 0.8853 +Propiverine20mg 45 13.3±8.9 0.0667

The increase of residual urine volume was 20-25ml P=0.0325　 * Tamsulosin Tamsulosin+Propiverine 10mg Tamsulosin+Propiverine 20mg 割付群 12週（n） 12週（mean±SD） 12週（P値） Tamsulosin 47 38.0±39.6 0.0016 +Propiverine10mg 49 59.6±55.3 <.0001 +Propiverine20mg 45 62.5±51.9 The increase of residual urine volume was 20-25ml

Voiding times and urgency times in voiding diary, storage symptom scores and urgency in IPSS were significantly decreased with combination therapy with Tamsulosin and propiverine 10mg. Voiding symptom scores in IPSS and Qmax in uroflowmetrty did not show any significant difference between Tamsulosin single therapy and combination therapy with Tamsulosin and propiverine. Residual urine volume had tendency to increase in combination therapy group. One case of urinary retention was reported in the combination therapy with Tamsulosin and propiverine 20mg. Adverse effects were observed in 7.6% (15/197) in combination therapy. The combination therapy with Tamsulosin and Propiverine 10mg significantly decreased male OAB symptoms with BPH without major adverse effects.

Treatment of male OAB; Combination therapy Trial of combination treatment with an Alpha-blocker plus an Anticholinergic for BPH with OAB (TAABO) Combination treatment with Tamsulosin and Solifenacine to OAB symptoms with BPH

Clinical BPH Tamsulosin 0.2mg/day, daiy Tamsulosin OABSS Q3 (Urgency)≧2 And OABSS≧3 Tamsulosin Tamsulosin 0.2mg/day, daiy Clinical BPH Tamsulosin 0.2mg/day, daiy ＋Solifenacine 2.5mg/day, daily More than 4 weeks 0 week 4 weeks Evaluation IPSS, OABSS QOL index Qmax Residual urine volume Evaluation IPSS, OABSS QOL index Qmax Residual urine volume Kakizaki H et al., 2008

* ** ** ** Total IPSS QOL-index OABSS 15 6 25 5 20 4.0 10 4 3.4 15 NS NS 5 ** 20 4.0 10 4 3.4 15 13.9 3.7 7.3 3 3.3 11.2 5.0 10 11.6 10.8 6.4 2 5 4.4 5 1 0 week 4 weeks 0 week 4 weeks 0 week 4 weeks Tamsulosin + Solifenacine Tamsulosin Mean±SD **：p＜0.01 *：p＜0.05　（Wilcoxon signed-rank test） 　

Qmax Residual Urine Volume （mL/s） （mL） 30 150 NS NS NS NS 20 100 13.5 13.2 52.5 13.0 12.7 41.4 10 50 33.5 31.0 Mean±SD paired t-test　 0 week 4 weeks 0 week 4 weeks The OAB symptoms which were not released by Tamsulosin monotherapy were significantly released by adding solifenacine, without major adverse effects.

Treatment of male OAB; Combination therapy Trial of combination treatment with an Alpha-blocker plus an Anticholinergic for BPH with OAB (TAABO) Combination treatment with Tamsulosin and Solifenacine to OAB symptoms with BPH Effective, but have to be careful of urinary retention or increase in residual urine volume

Treatment of OAB; Japanese guideline OAB symptoms Neurogenic disorders Neurogenic OAB Nonneurogenic Urinalysis and Residual Urine Volume Hematuria Pyuria Normal urinalysis RV<50ml Normal urinalysis RV≥50ml UTI treatment Primary treatment ineffective effective Continue Consultation to Urology specialist Middle aged male likely with BPH are recommended to be treated with alpha1-blocker or referred to urology specialist.

Treatment of BPH; Japanese guideline (2001) Therapeutic options Alpha1-aderenoceptor antagonist Anti-andorogen drug Others; Phytotherapeutic drugs

Shift in the treatment of male OAB ? Alpha1-receptor antagonist for BOO Antimuscarinic agents for Non-responders 5alpha-reductase inhibitor for BPE Comination therapy Qmax ≥5ml/sec, RV ≤100ml

Resident Manual, Department of Urology, UOEH

Conclusions Lower urinary tract symptoms occur commonly in Japanese population. Storage symptoms, in particular urgency and the symptoms of OAB, are the most bothersome in male LUTS. Alpha1-adrenoceptor antagonist monotherapy improves OAB symptoms in male patients. Combination therapy with alpha1-adrenoceptor antagonist and antimuscarinic agents improve OAB symptoms in male patients.