11 Male OAB Japan status by 3TGsB50a

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									Management of Male OAB;
      Current Status in Japan


Department of Urology
University of Occupational and Environmental Health, Japan

                   Hisae NISHII
                       Introduction; LUTS


                   Lower Urinary Tract Symptoms
                               LUTS
Storage symptoms         Voiding symptoms         Post micturition
                                                    symptoms

Daytime urinary         Slow stream         Sensation of
 frequency              Intermittency        incomplete emptying
Urgency                 Heitency            Postmicturition
Nocturia                Straining            dribble
Urinary incontinence
                            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                                     Histologic BPH
• Storage symptoms often occur independently
                                                          BPE
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                BOO

detrusor dysfunction.

                                                            LUTS
                                      Epidemiology-Europe
 EU SIFO Study                                          US NOBLE Study
      45                                                40
(%)




      40                                                35         Male
                 Male
      35         Female                                 30         Female
      30
                                                        25
      25
                                                        20
      20
                                                        15
      15
                                                        10
      10
       5                                                 5

       0                                                 0
        40-44 45-49 50-54 45-59 60-64 65-69 70-74 75+        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
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       Phytotherapeutic drug
                 Silodosin
                                                   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
 Entry criteria    0 week                        4weeks

・Male over 50y/o        Tamsulosin, 0.2mg/day, daily
・Clinical BPH
・IPSS≧8
・OABSS≧3 and          Evaluation           Evaluation
 Q3≧2                 IPSS                 IPSS
                      QOL Index            QOL Index
・QOL≧2                OABSS                OABSS




                                                Yoshida M et al., 2008
IPSS-subscore


 4.0
                        **
                      3.5                                        **              0 week      4weeks

                                                   **           3.2                           **
 3.0                                              2.9                                       2.9


                            2.2                                                                   2.2
 2.0                                  *                 1.7
                                                                      1.8
          1.6                       1.6

                1.1                                                           1.2
                                          1.0
 1.0                                                                                0.9




 0.0
       Sensation of   Daytime     Intermittency   Urgency     Slow stream      Straining    Nocturia
       imcomplete     Urinary
       emptying       Frequency                           *:p<0.05、**:p<0.01(Wilcoxon signed-rank test)
OABSS

                      **
        10

              8.1
        8

                           6.1
        6


        4


         2                           **:p<0.01
                                     (Wilcoxon signed-
                                     rank test)

         0
             0 week        4 weeks
OABSS-subscore


        4.0
                                                         04週後
                                                          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        Nocturia     Urgency                Urgent
              Urinary                                         incontinence
              Frequency                                **:p<0.01(Wilcoxon signed-rank test)
OAB severity


     (%)
      100                              Severe(12≦OABSS)
                 10               2
                                       Moderate(6≦OABSS≦11)

                                       Mild(OABSS≦5)
                          51
                                      n=41

       50        73



                          46

                 17
        0
               0 week   4 weeks
Treatment of male OAB; Alpha1-adrenoceptor antagonists




 Tamsulosin 0.2mg

 Naftopidil 50mg

 Naftopidil 75mg

 Silodosin

 Comparison of Tamsulosin, Natdopidil, Silodosin
IPSS ≧8 and QOL-Index ≧2                    0 week                                        12 weeks
Prostate volume ≧15mL
Clinical BPH with OAB symptoms                         Naftpidil, 50mg/day, daily


                                               Evaluation                               Evaluation


    IPSS


                                                                            0 week


                                                                        12 weeks
                      ***                        ***                 ***
             ***                 ***
                                        ***
                                                           ***
                                                                            n=36
                                                                              (Wilcoxon signed-rank test)
           Sensation of                                                     ***:p<0.001
           imcomplete
           emptying         Intermittency    Slow stream         Nocturia
                     Daytime           Urgency          Straining
                     Urinary
                     Frequency
                                                                                                 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
                                      0 week              4 weeks                8 weeks
  IPSS ≧8 and QOL-Index ≧2
  Prostate volume ≧15mL                            Naftpidil, 75mg/day, daily
  Clinical BPH with OAB symptoms

                                     Evaluation            Evaluation             Evaluation
IPSS               ***                       ***

             ***                       ***                                 ***
                                                                     ***




                                                                                       n=31
                                                                                       Mean±S.D.
                                                                                       (Wilcoxon signed-
                                                                                              rank test)
                                                                                       ***:p<0.0001




             Storage                  Voiding                  Postmicturition
            Symptom                  Symptom                     symptom
              Score                    Score                       Score
       0 week 4 weeks 8 weeks   0 week 4 weeks 8 weeks       0 week 4 weeks 8 weeks
                                                                                 Miyamoto K. et al. 2009
Voiding diary


         Daytime frequency     Nighttime frequency             Urgency
                 (n=17)              (n=17)                        (n=14)
      (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
  Entry criteria   0 week       4weeks                  12weeks

・Clinical BPH               Silodosin, 8mg/day, daily
・Naftopidil or
  Tamsulosin
  treatment more        Evaluation
  than 6 months         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
 Entry criteria      Tamsulosin 0.2mg/day, daily
  (n=90)
・Clinical BPH        Naftopidil 50mg/day, Daily
・Over 50 y/o
・IPSS≥3              Silodosin, 8mg/day, daily
・Prostate volume
  ≥50ml
・Residual urine                Evaluation
  volume ≤100ml                IPSS, QOL Index




                                                     Kikuchi Y et al. 2010
IPSS-subscore

          Total voiding score
     10
     9                              **
     8
     7
     6
     5
     4                               **            **
     3                  **
     2
     1
     0
                 Tamsulosin     Naftopidil   Silodosin
IPSS-subscore

         Total storage score
     8
                                   **
     7
                                            *
     6

     5                                                 *
     4                              **
     3                 **
     2

     1

     0
                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
                                          Tamsulosin 0.2mg, 1C/day, daily


           Tamsulosin 0.2mg               Tamsulosin 0.2mg, 1C/day, daily
          1C/day, daily. 8weeks           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                       Having OAB symptoms after 8 weeks Tamsulosin
 Clinical BPH                 Daitime frequency more than 8 times
 IPSS more than8              Urgency once/ 24 hrs at least
 QOL index more than 2        Except Qmax<5ml/sec, RV>100ml
 Qmax<15ml/sec
 Voiding diary

Average voiding time/24hr                                Urgency




                                                     *
                                      P=0.0261
  Tamsulosin
  Tamsulosin+Propiverine 20mg
  Tamsulosin+Propiverine 10mg                                                                       **
                                                                                         P=0.0093


                   12wks     12wks        12wks(P)                          12wks     12wks     12wks(P)
                    (n)    (mean±SD)                                         (n)    (mean±SD)
  Tamsulosin        46      10.3±2.9       0.004           Tamsulosin        46      2.3±3.3     0.3024
+Propiverine10mg    49      9.4±2.3        <.0001        +Propiverine10mg    49      1.0±1.5     <.0001
+Propiverine20mg    45      10.1±2.8       0.0074        +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                        P=0.0465                                                     *
      Tamsulosin+Propiverine 20mg
                                                                                                          *
      Tamsulosin+Propiverine 10mg                                                     P=0.0252


    割付群            12週        12週           12週(P値)           割付群            12週      12週      12週(P値)
                   (n)     (mean±SD)                                         (n)   (mean±SD)
  Tamsulosin       47         5.7±3.7        0.0009         Tamsulosin       47     1.6±1.6      0.0195
+Propiverine10mg   49         4.7±2.3        <.0001       +Propiverine10mg   49     0.9±1.0      <.0001
+Propiverine20mg   45         4.5±2.8        <.0001       +Propiverine20mg   45     0.9±1.4      <.0001




 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 20mg
 Tamsulosin+Propiverine 10mg




    割付群            12週       12週         12週(P値)       割付群            12週      12週      12週(P値)
                   (n)    (mean±SD)                                   (n)   (mean±SD)
  Tamsulosin       47          3.9±4.2    0.029      Tamsulosin       47     12.7±5.4    0.3259
+Propiverine10mg   49          3.5±3.1    0.0126   +Propiverine10mg   49     12.2±6.2    0.8853
+Propiverine20mg   45          4.9±3.4    0.4823   +Propiverine20mg   45     13.3±8.9    0.0667
Residual urine volume




                                                                  * P=0.0325


                                                                 Tamsulosin
                                                                 Tamsulosin+Propiverine 20mg
                                                                 Tamsulosin+Propiverine 10mg




                      割付群            12週      12週      12週(P値)
                                     (n)   (mean±SD)
                    Tamsulosin       47    38.0±39.6    0.0016
                  +Propiverine10mg   49    59.6±55.3    <.0001
                  +Propiverine20mg   45    62.5±51.9    <.0001




                 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
                               OABSS
                               Q3 (Urgency)≧2 And
                               OABSS≧3



                                          Tamsulosin 0.2mg/day, daiy
Clinical
               Tamsulosin
 BPH
                                          Tamsulosin 0.2mg/day, daiy
                                              +Solifenacine 2.5mg/day, daily
           More than 4 weeks            0 week                                  4 weeks


           Evaluation                                   Evaluation
                IPSS, OABSS                                  IPSS, OABSS
                QOL index                                    QOL index
                Qmax                                         Qmax
                Residual urine volume                        Residual urine volume




                                                                       Kakizaki H et al., 2008
       Total IPSS                     QOL-index            15        OABSS
                               6
25
               **                           *
               NS              5
                                            NS
                                                                         **
20                                                                       **
                                      4.0                  10
                               4
        13.9                                         3.4
15                                    3.7                         7.3
                               3                     3.3
                        11.2
        11.6                                                                      5.0
10                      10.8                                5     6.4
                               2
                                                                                  4.4
 5                             1

 0                             0
     0 week         4 weeks        0 week        4 weeks        0 week        4 weeks

 Mean±SD                                                        Tamsulosin + Solifenacine
 **:p<0.01 *:p<0.05 (Wilcoxon signed-rank test)                 Tamsulosin
                      Qmax                    Residual Urine Volume
    (mL/s)                             (mL)
       30              NS
                                        150               NS

                       NS                                 NS



       20                               100

                13.5            13.2

                13.0                               41.4            52.5
                                12.7
       10                                50

                                                   33.5            31.0
                                                                          Mean±SD
                                                                          paired t-test
        0                                 0
             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
                                                                  Middle aged male
                                                                  likely with BPH are
             Neurogenic disorders                                 recommended to be
                                                                  treated with alpha1-
Neurogenic                               Nonneurogenic            blocker or referred
  OAB                                        OAB                  to urology specialist.

                            Urinalysis and Residual Urine Volume

                Hematuria       Pyuria        Normal urinalysis       Normal urinalysis
                                                 RV<50ml                 RV≥50ml
                                 UTI
                              treatment
                                             Primary treatment

                                      effective              ineffective
                                            Continue

                    Consultation 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.

								
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