Sussman AAPA OAB by mikeholy



                                                                                      ICS Definition: Overactive Bladder
                                                                                     • OAB is defined as urgency, with or
         Overactive Bladder:                                                           without urgency incontinence, usually
        It is Not Just Women                                                           with frequency and nocturia

         David O. Sussman, DO, FACOS
                  Department of Surgery
                    Division of Urology
    University of Medicine and Dentistry of New Jersey
                   Stratford, New Jersey
                   Section Head, Urology
                  Kennedy Health System
                    Sewell, New Jersey
                                                                                  ICS = International Continence Society.                Abrams P et al. Urology.2003;61:37-49.

                                                                              3                                                                                                       4

                                                                                       OAB Is Underdiagnosed and Undertreated:
  Symptoms That Define OAB                                                             Physicians and Sufferers Both Contribute
                                                                                     • Reasons for those with OAB not seeking care
    Storage           Voiding        Postmicturition                                       –   Embarrassment
    Urgency            Hesitancy       Postvoid dribble                                    –   Failure to see symptoms as abnormal
                                          Sense of                                         –   Belief that symptoms are mild or self -limited
    Frequency          Poor flow
                                     incomplete emptying                                   –   Perception of lack of available treatment
    Nocturia         Intermittency                                                         –   Low expectations for treatment
                                                                                           –   Fear of invasive procedure
                       Straining                                                           –   Fear of high cost of treatment
                                                                                     • Physician lapses
Other incontinence                                                                         – Physicians infrequently initiate discussions about OAB
                        dribble                                                              symptoms
                                                                                           – Physicians often fail to offer medication

                                                                                                                                     Ricci JA et al. Clin Ther. 2001;23:1245 -1259.
                                         Abrams P et al. Urology.2003;61:37-49.                                                         Milsom I et al. BJU Int. 2001;87:760-766.

                                                                                                         5                                                                                                                  6

                                                                                                                Male Lower Urinary Tract Symptoms Can Be
                                                                                                                             Associated With
                 Anatomy of the Bladder                                                                              the Bladder, the Prostate, or Both
               Female                       Ureter
                                                                        Male                                     Bladder Condition                      Lower Urinary                 Prostate Condition
                                                                                                                                                         Tract System
                                       Peritoneal coat                                                         Detrusor Overactivity (DO)
                                                                                                             Urodynamic observation of
                                         Detrusor                                                            involuntary detrusor
                                                                                                                                                                               Benign Prostatic Enlargement (BPE)
                                       smooth muscle                                                         contractions during the filling
                                                                                                             phase, which may be                                                                 Size
                                      Transitional cell                                                      spontaneous or provoked
                                                                                                                                                                               Benign Prostatic Obstruction (BPO)
                                          Trigone                                                                         OAB                      Prostate                         Obstruction due to size
                                                                                       Prostate              Urgency, with or without
                                        Bladder neck                                   gland                 urgency incontinence, usually                                                       BOO
                                                                                                             with frequency and nocturia
                                          External                                                                                                                                 Obstruction during voiding
                                      urethral sphincter                                                                                                                       characterised by increased detrusor
                                                                                                                                                                                 pressure and reduced urine flow
                                         Pelvic floor
                                                                                                                                                                                   Abrams P et al. Urology.2003;61:37-49.

                                                                                                         7                                                                                                                  8

           The Normal Micturition Cycle                                                                                             Detrusor Overactivity
             Storage phase                                  phase                                                         Normal bladder                  Patients with                 Patients with
                                                                                                                                                           urgency or                      urgency

                                                                                                                                                           frequency                    incontinence

                             First sensation    Normal desire
           Bladder filling       to void           to void                    Bladder filling

                                                               Abrams P et al. The Overactive Bladder:
                                                           A Widespread and Treatable Condition. 1998.            Involuntary detrusor contractions.                      Ouslander J. N EnglJ Med . 2004;350(8):786-799.

                                                                                                                                            9                                                                                                         10

                                  OAB: Pathophysiology                                                                                                            OAB: Pathophysiology (cont)
   • Storage                                                                                                                                     • Voiding
                    – Sympathetic nerve fibers originating from                                                                                                  – Upon filling, sensory stretch receptors in the
                                                                                                                                                                   bladder wall trigger a central nervous system
                      the TH11 to L2 segments of the spinal cord
                                                                                                                                                                   (CNS) response
                      innervate smooth muscle fibers around the
                                                                                                                                                                 – The parasympathetic nervous system (PNS), from
                      bladder neck and proximal urethra                                                                                                            S2-S4 segment, causes contraction of the
                           • Muscle fibers contract for normal filling                                                                                             detrusor muscle; muscles of the pelvic floor and
                    – Somatic fibers innervate the external                                                                                                        external sphincter relax
                      sphincter and are responsible for the                                                                                                      – Urination can be prevented by cortical
                      voluntary control of continence during a                                                                                                     suppression of the PNS or by voluntary
                                                                                                                                                                   contraction of the external sphincter
                      pressing desire to void

                                                                                                                                            11                                                                                                        12

               Prevalence of OAB in EU and US                                                                                                                         Prevalence of OAB by Age
                                   EU SIFO Study                                          US NOBLE Study                                                                Comparison of data from the SIFO study 1997
                                                                                                                                                                                 and the EPIC study 2005
                    45                                                     40                                                                                    40
                                    Milsom I et al. 2001                                      Stewart et al. 2003
                    40                                                     35                                                                                                 Men – SIFO 1997
                                 Men                                                     Men
    Prevalence, %

                    35                                                                                                                                                        Men – 2005
                                                                           30                                                                                    30
                                                                                                                                                 Prevalence, %

                    30           Women                                                   Women                                                                                Women – SIFO 1997
                    25                                                                                                                                           25           Women ?2005
                    20                                                                                                                                           20
                    15                                                                                                                                           15
                    10                                                                                                                                           10
                    0                                                      0
                         40–44 45–49 50–54 55–59 60–64 65–69 70–74   75+        18-2 4   25-3 4   35-4 4   45-5 4   55-6 4   65-7 4   75+                         0
                                          Age, years                                                 Age, years                                                       18-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69             70+
                                                                                                                                                                                             Age, years
                                                                                               Milsom I et al. BJU Int. 2001;87:760-766.                                                                       Milsom I et al. BJU Int. 2001;87:760-766.
EU = European Union.                                                                     Stewart W et al. World J Urol . 2003;20:327-336.                                                               Irwin DE et al. Abstract presented at EAU 2006.

                                                                                                                         13                                                                                                                         14

              OAB Has a Considerable Impact
                    on Quality of Life                                                                                                   Components of Patient Bother
                                80                                                                                                                                                    Physical symptoms

                                70                                                                                                                                             • Gradual increase in frequency
                  SF-36 Score

                                60                                                                                                                                             • Increase in urgency
                                                                                                                                                                               • Loss of sleep
                                50                                                                Depression
                                                                                                                                                                               • Wetting accidents
                                40                                                                OAB
                                                                                                                                            Concerns                                       Emotional                     Behavioral
                                                                                                                                   • Women: Am I sick–                               • Embarrassment             • Job performance

                                                                                                                                     do I have cancer?

                                                                                                                                                                                     • Fear                      • Relationship stress
                                                                      (em ing

                          (ph g






                                                                                                                                     I want information.




                                                                                                                                                                                     • Frustration               • Social activities




                                                                                                                                   • Men: Do I have a

                                                                                                                                                                                     • Anger                     • Sexual activities


                                                                                                                                     prostate problem?




                                                                                                                                                                                     • Loss of self-esteem       • Drinking behavior



                                                                                 Kobelt G et al. BJU Int. 1999;83:583-590.

                                                                            Komaroff AL et al. Am J Med. 1996;101:281-290.

                                                                                                                         15                                                                                                                         16

                  Individuals With OAB Symptoms Report                                                                            Although Prevalence Is Similar, Fewer Men Are
                              More Depression                                                                                           Treated for OAB Than Are Women
                                                                                                                                            Prescriptions, in thousands

                                     Controls (n = 3018)          OAB With Incontinence (n = 692)                                                                         10
                  25                 Total OAB (n = 1487)         OAB Without Incontinence (n = 795)
                  20                                                                *
    Subjects, %

                                                *                                                                                                                          6
                  15                                                           *
                     People with OAB, with or without incontinence,
                                                        *                                                                                                                  4
                        reported higher depression scores and a
                  10                 *
                   higher self-reported diagnosis of depression than                                                                                                       2
                   5                a control group                                                                                                                        0
                        0                                                                                                                                                         Female                 Male
                                           CES-D                  Self-reported                                                                                                  Women with OAB are treated
                                            > 21               depression diagnosis                                                                                                 more than men (4:1)
1487 OAB cases (66% female; mean age 54 years);
3018 controls (51% female; mean age 50 years)                                                                                 Data collected over 12 months.
*P = .05 OAB vs controls.                                                                       EPIC Study. Data on File.     BPH prescriptions include 5 -α reductase inhibitors.                      Verispan Patient Longitudinal Data, MAT. 2005.
CES-D = depressive symptoms measurement tool; >21 indicates major depression.                                  Pfizer Inc.    BPH = benign prostatic hyperplasia.                                                                IMS NPA, MAT. 2005.

                                                                                                           17                                                                                                         18

     Men With LUTS Are Predominantly Treated                                                                         Prostate Treatment Leaves Subset of
     With BPH Agents Rather Than OAB Agents                                                                         LUTS Patients With Inadequate Control
                                          61                        Diagnosis                                       • 65% of patients with BOO and DO treated with an α-blocker
                              60                                                                                      for 3 months did not show improvement in symptoms,
         Patients Receiving

                                                                    OAB & BPH (n = 4806)
            Treatment, %

                              50     47                                                                               defined as >3 point reduction in IPSS
                              40                                    OAB & No BPH (n = 12,192)
                                                 36                                                                       – 73% of these non-responders improved after adding
                              30                                                                                            tolterodine IR
                                                            9 11                                                    • 19% of men have persistent OAB symptoms after TURP
                              10                                          8
                               0                                                                                    • Despite reports of short-term resolution of DO symptoms in
                                    No Rx       BPH Rx     OAB Rx     OAB &
                                                 only       only      BPH Rx                                          men with BOO following TURP, a significant increase in
                                               *Type of Treatment                                                     number of patients with DO has been observed at long-term
*Data were obtained from medical and pharmacy claims                                                                                                                                 Lee JY et al. BJU Int. 2004;94:817.
databases of diverse managed care plans.                                                                        IPSS = International Prostate Symptom Score;      Dmochowski et al. Urology. 2002;60(suppl 5A):56-62.
Rx = treatment.                                                       Jumadilova Z et al. Abstract. ICS 2005.   TURP = transurethral resection of the prostate.        Thomas AW et al. BJU Int. 2004;93(6):745-750.


    Why Do We Treat Men Differently Than
      Women When It Comes to OAB?
                                     Female                        Male

                                                                                                                               Assessment of OAB in Men
                                                                                                                                       Importance of Objective and
                                                                                                                                          Subjective Measures
   • While OAB symptoms are the same for both men
     and women:
                               – Women are diagnosed and treated for OAB
                               – Men are often diagnosed with conditions related to the

                                                                      Jumadilova Z et al. Abstract. ICS 2005.

                                                                                                        21                                                                                                                    22

          Overactive Bladder-Validated 8
           Question Screener (OAB-V8)                                                                                                      OAB-V8 Screener
                                                                                                                                    8 Simple, Self-Administered Questions
    • 8-item symptom bother scale of the original OAB
      questionnaire (OAB-q)                                                                                      How bothered have you been by …
                                                                                                                 1. Frequent urination during the
    • An awareness tool validated in 1260 patients                                                                  daytime hours?
                                                                                                                 2. An uncomfortable urge to urinate?
    • Simple scoring by addition                                                                                 3. A sudden urge to urinate with little
                                                                                                                    or no warning?
    • Accommodates gender differences                                                                            4. Accidental loss of small amounts
                                                                                                                    of urine?
    • Available and linguistically validated in more                                                             5. Nighttime urination?
      than 20 languages                                                                                          6. Waking up at night because you
                                                                                                                    had to urinate?
    • Other than the OAB-V8, few validated patient                                                               7. An uncontrollable urge to urinate?
      screening tools are available for OAB                                                                      8. Urine loss associated with a
                                                                      Coyne KS et al. ICS Abstract. 2004.           strong desire to urinate?
                                               Overactive Bladder Questionnaire Family Web site. Available
                                                         at: Accessed November 30, 2005.                                                                                       Coyne KS et al. ICS Abstract. 2004.

                                                                                                        23                                                                                                                    24

     OAB in Men Can Be Diagnosed Using LUTS
      Assessment Protocol, Plus Voiding Diary                                                                         Initial Evaluation for Male LUTS
                                                         LUTS                       OAB                          • Patient history
                                                      Assessment                 Assessment
                                                                                                                 • Assessment of symptoms and bother
                                                                                                                       – IPSS
    IPSS Questionnaire (storage and voiding)                                                                           – Voiding diary
                                                                                                                       – OAB-V8 Screener
    Voiding diary
                                                                                                                 •   Physical and digital rectal examination
    Physical examination
                                                                                                                 •   Urinalysis
                                                                                                                 •   Frequency – volume chart (voiding diary)
    PSA (as indicated, based on age)                                                                             •   Serum PSA
                                                                                                             Recommendations of the ISC: Evaluation and Treatment of LUTS in Older Men 5 th International
IPSS = International Prostate Symptom Score.                                                                 Consultation on New Developments in prostate Cancer and Prostate Diseases: June 24-28, 2005

                                                                                                                  25                                                                                                                     26

      Further Evaluation for Male LUTS                                                                                      Optional Evaluation for Male LUTS
    • Flow rate recording                                                                                                  • Imagining of the prostate by
    • Residual urine                                                                                                         ransabdominal or
                                                                                                                             transrectal ultrasound
    • Pressure flow studies (PFS) prior to
      invasive therapy unless the Q max is                                                                                 • Imaging of the upper urinary tract by
      <10 ml as specificity of PFS is                                                                                        ultrasonography or intravenous
      then inadequate *                                                                                                      uro-graphy (IVU)
                                                                                                                           • Endoscopy of the lower urinary tract

Recommendations of the ISC: Evaluation and Treatment of LUTS in Older Men 5 th International                           Recommendations of the ISC: Evaluation and Treatment of LUTS in Older Men 5 th International
Consultation on New Developments in prostate Cancer and Prostate Diseases: June 24-28, 2005                            Consultation on New Developments in prostate Cancer and Prostate Diseases: June 24-28, 2005

                                                                                                                  27                                                                                                                     28

          Current Strategies for Treating                                                                                          Current Therapeutic Options:
                 Men With LUTS                                                                                                      Men With OAB Symptoms
    • Watchful Waiting                                                                                                     • Although other pharmacologic
                                                                                                                             mechanisms are theoretically attractive
    • Minimally Invasive Therapies                                                                                           and some show promise in animal
    • Surgical Therapies                                                                                                     models, strong clinical proof of concept is
                                                                                                                             lacking for all except
    • Pharmacologic Therapies
                                                                                                                                 – Alpha 1-Adrenergic receptor antagonists
                                                                                                                                 – Antimuscarinic agents
                                                                                                                                 – 5α-Reductase inhibitors (5-ARIs)
                                                                                                                                                                                       Athanasopoulos A et al. J Urol. 2003;169:2253-2256.
                                                                    Kaplan SA et al. Rev in Urol. 2004;6(9):S45-S52.                                                                         Naderi N et al. Curr Opin Urol. 2004;14:41-44.

                                                                                                                    29                                                                                                       30

                               Alpha-blockers:                                                                                         Antimuscarinic Therapy in
                              First-Line Therapy                                                                                      Patients With OAB: Rationale
    • Prescribed first-line medical therapy for BPH                                                                          • Etiology
          – Efficacy documented by multiple clinical                                                                               – Neurogenic
            randomized trials                                                                                                            • Lack of CNS inhibition
          – Long-term efficacy is less well documented                                                                                   • Parasympathetic leak during filling/storage
                                                                                                                                         • Increased afferent input or sensitivity, or both
    • Efficacy comparable among long-acting agents
      at appropriate therapeutic doses                                                                                             – Myogenic
                                                                                                                                         • Denervation with increased spontaneous action
    • Low risk for morbidity                                                                                                               potentials and coupling
          – Can be discontinued at any time                                                                                              • Micromotion (PS leak)
                                                                                                                                         • Exaggerated or uninhibited autonomous activity
                                                 The Italian Alfuzosin Co-Operative Group. Eur Urol. 2000;37:680-686.
                                                               Narayan P, Tewari A. Urology. 1998;51(suppl 4A):38 -45.
                                                                             Vallancien G. Urology. 1999;54:773-775.

                                                                                                                    31                                                                                                       32

     Antimuscarinic Treatment Options                                                                                            Recent Clinical Data Support
          for Patients With OAB                                                                                               the Use of Antimuscarinics in Men
    Drug                                      Dose                           Frequency                                       • Several recent studies evaluated tolterodine in
    Darifenacin                               7.5 – 15 mg                    QD                                                male patients with DO and concomitant BOO
    Oxybutynin                                5 – 30 mg                      BID or TID                                        (symptomatic, urodynamic, or both)
                                                                                                                                   – Tolterodine added to doxazosin in doxazosin
    Oxybutynin XL                             5 – 15 mg                      QD
    Oxybutynin (patch) 3.9 mg/d                                              1 patch × 2W
                                                                                                                                   – Tolterodine LA monotherapy in men who were
    Solifenacin                               5 – 10 mg                      QD                                                      nonresponsive to a-blocker therapy
    Tolterodine LA                            4 mg                           QD                                                    – Tolterodine added to tamsulosin
    Trospium                                  20 mg                          BID                                                   – Safety of tolterodine in men with DO and BOO
                                                                                                                                                                                     Lee JY et al. BJU Int. 2004; 94:817-820.
                                                                                                                                                                                   Kaplan S et al. J Urol. 2005;174:2273 -2276.
QD = once daily; BID = twice daily;                                                                                                                                       Athanasopoulos A et al. J Urol. 2003; 169:2253-2256.
TID = three times daily; 2W = twice weekly.                             Adapted from Medical Letter. 2005; 47:23-24      IR = immediate release; ER = extended release.      Abrams P et al. Neurourol Urodyn. 2001; 547-548.

                                                                    33                                                                                                                 34

        Evidence to Date: Summary                                             Evidence to Date: Summary (cont)
•   65% of patients evaluated urodynamicallyfor BOO and DO,                  • In a predominantly continent male population with OAB
    treated with α -blocker monotherapyfor 3 months, did not show              symptoms, tolterodine was significantly more effective than
                                                                               placebo in reducing
    symptomatic improvement
                                                                                   – 24-hour frequency
     – Of these, 73% improved after adding DETRUSITOL
                                                                                   – Severe OAB nighttime frequency
•   21% of patients with BOO only, treated with                              • Tolterodine achieved significant symptom control in men
    α -blocker monotherapyfor 3 months, did not show                           with OAB without clinically significant BOO (based on
    symptomatic improvement                                                    investigator judgment)
     – Of these, 37.5% improved after adding DETRUSITOL                      • Tolterodine led to substantial improvement in patient
                                                                               perception of bladder condition
• Tolterodine increased bladder capacity and Q max                           • Tolterodine was well tolerated and did not increase the
• Tolterodine showed improvement in AUA   -SS                                  incidence of acute urinary retention or negatively affect PVR
    (P < .01) and daytime and nighttime micturition frequencies              • Tolterodine is a reasonable therapeutic option in men with
                                                                               OAB symptoms (with or without other LUTS) that have not
                                                                               responded to treatment with
                                                                               a -blockers

                                                                    35                                                                                                                 36

     Clinical Issues: Antimuscarinic                                                 Perception of Antimuscarinic
     Therapy in Male OAB Patients                                                           Safety in Men
                                                                                                                                         Antimuscarinic safety:
                                                                                 Antimuscarinic Class Label
• Efficacy:                                                                                                                             MOA and Clinical Evidence
                                                                            • “Should be administered with caution in                   By blocking muscarinic receptors,
     – Who should be treated:                                                 patients with clinically significant bladder         antimuscarinics inhibit detrusor contraction
                                                                              outlet obstruction at risk for urinary
        • OAB without BOO                                                     retention”
                                                                            • “Contraindicated in patients with urinary         Theoretical risk of urinary retention or aggravation
        • OAB with BOO                                                                                                                     of voiding difficulties in men
                                                                                                                                                      with BOO
                                                                                   Physician Perception
        • Combined with BPH treatments                                          as Result of Medical Training
                                                                                                                                • However:
                                                                                                                                   – At therapeutic doses, antimuscarinics
                                                                                                                                     reduce uninhibited detrusor contractions
• Safety:                                                                   • Most perceive a risk of urinary retention
                                                                              associated with the use of antimuscarinics in
                                                                                                                                     during filling/storage phase
                                                                              men                                                  – During voiding, massive release of ACh
     – Urinary retention, predominantly in                                      – Level of concern varies by market                  from parasympathetic nerves displaces
                                                                                                                                     antimuscarinics (which are competitive
       patients with BOO                                                    • Need for guidance on patient selection for less
                                                                              confident prescribers
                                                                                                                                     antagonists), decreasing their effect

                                                                         BOO = Bladder Outlet Obstruction
                                                                         ACh = acetylcholine                                            Andersson KE, Yoshida M. Eur Urol. 2003; 43:1-5.

                                                                                            37                                                                                                              38

             Safety of Tolterodine in Men With                                                          Safety of Tolterodine in Men With
             OAB/DO and BOO: Study Design                                                                 OAB/DO and BOO: Baseline
                                                                                                               Patient Population (Baseline Characteristics)
    • Multi-national, double-blind study comparing 12 weeks of
      tolterodine 2 mg bid with placebo                                                                                                             Placebo               Tolterodine
    • Study objective
                                                                                                     PdetQmax, cm H2O                                  60.0                      69.0
           – Evaluate the safety of tolterodine IR in men with
             urodynamically proven BOO and DO (Abrams- Griffiths >20)
             and no prior therapy for BPH
                                                                                                     Qmax, mL/s                                         8.0                        8.5
    • Patient population
           – 221 men with BOO and DO
           – PVR <40% of maximum cystometric capacity                                                PVR, mL                                           27.5                      22.0
           – No history of urinary retention in the preceding
                                                                                                                                                   More than half the enrolled patients
             12 months
                                                                                                                                                      had moderate to severe BOO
                                                                                                 PdetQm a x = detrusor pressure at maximum flow.
Please see full prescribing information.           Abrams P et al. J Urol. 2006;175:999 -1004.   Please see full prescribing information.                          Abrams P et al. J Urol. 2006;175:999 -1004.

                                                                                            39                                                                                                              40

       Safety of Tolterodine in Men With                                                                Safety of Tolterodine in Men With
           OAB/DO and BOO: Qmax                                                                          OAB/DO and BOO: PdetQmax
                                           Placebo           Tolterodine                                                                                  Placebo            Tolterodine
     Qmax, mL/s                            (n = 72)           (n = 149)                              PdetQ max, cm H2O                                    (n = 72)               (n = 149)
                                              8.0                  8.5                                                                                      60.0                   68.0
     Baseline, median (range)                                                                        Baseline, median (range)
                                           (2.4-15.0)           (2.0-20.0)                                                                              (27.0-132.0)           (20.0-195.0)
                                              8.8                  8.5
     Week 12, median (range)                                                                                                                                60.0                   59.5
                                           (2.5-17.0)           (2.0-32.0)                           Week 12, median (range)
                                                                                                                                                        (22.0-112.0)           (15.0-139.0)
     Estimated difference (95% CI)
                                                                                                     Estimated difference (95% CI)
     in median change                            –0.7 (–1.6 to 0.4)
                                                                                                     in median change                                            –7.0 (11 to –3)
     (Tolterodine vs placebo)
                                                                                                     (Tolterodine vs placebo)
*Defined in protocol as ≥ 3 mL/s.
CI = confidence interval.                                                                        *Defined in protocol as ±15 cm H 2 O.
Please see full prescribing information.           Abrams P et al. J Urol. 2006;175:999 -1004.   Please see full prescribing information.                          Abrams P et al. J Urol. 2006;175:999 -1004.

                                                                                           41                                                                                                                   42

       Safety of Tolterodine in Men With                                                                  Safety of Tolterodine in Men With
       OAB/DO and BOO: PVR Results                                                                       OAB/DO and BOO: Adverse Events
                                                                                                                                                Urinary Symptom Adverse Events
                                           Placebo        DETRUSITOL                                                                       Placebo (n = 72)              DETRUSITOL (n = 149)
    PVR, mL                                (n = 72)        (n = 149)                                                                        N          (%)                  N         (%)
                                                                                                    Micturition disorder                    2              2.8                7                  4.7
                                              27.5                 22.0
    Baseline, median (range)                                                                        Urinary tract infection                 3              4.2                6                  4.0
                                            (0-300)               (0-374)
                                                                                                    Dysuria                                 1              1.4                3                  2.0
                                                                                                    Micturition frequency                   2              2.8                3                  2.0
                                              27.0                 60.0
    Week 12, median (range)                                                                         Micturition urgency                     1              1.4                2                  1.3
                                            (0-435)               (0-670)                           Strangury                               0               –                 2                  1.3
                                                                                                    Urinary retention                       1              1.4                0                  0.0
    Estimated difference (95% CI)                                                                   Bladder discomfort                      0               –                 1                  0.7
    in median change                                  27 (8-50)                                     Urethral disorder                       0               –                 1                  0.7
    (DETRUSITOL vs placebo)                                                                         Urinary incontinence                    2              2.8                0                   –
                                                                                                    Overall                                 9             12.5               19                 12.8
P < .01.                                                                                                                                                                                 Data on file. Pfizer Inc.
Please see full prescribing information.          Abrams P et al. J Urol. 2006;175:999 -1004.   Please see full prescribing information.                             Abrams P et al. J Urol. 2006;175:999 -1004.

                                                                                           43                                                                                                                   44

       Safety of Tolterodine in Men With                                                                 Experimental Pharmacotherapy
       OAB/DO and BOO: Conclusions                                                                            Alternatives in OAB
    • No difference between tolterodine and placebo                                                 Agent                                  Proposed Mechanism of Action

      effect on Qmax and PdetQmax at                                                                GABA receptor agonists                 Inhibits voiding reflex
                                                                                                                                           Inhibits acetylcholine release at neuromuscular
      12 weeks                                                                                      Botulinum toxin

    • Tolterodine did not adversely affect urinary flow                                             Vanilloids/afferent nerve
                                                                                                    inhibitors                             Desensitize unmyelinated C fibers

      or detrusor muscle function at 12 weeks                                                       Calcium channel blockers
                                                                                                                                           Decrease Ca++ available for smooth
                                                                                                                                           muscle contraction
          – 27-mL increase in median PVR for tolterodine                                            Inhibitors of prostaglandin            May increase contraction of bladder
            over placebo was not deemed clinically                                                  synthesis                              smooth muscle
            significant by authors                                                                  Potassium channel openers              Decrease spontaneous smooth
                                                                                                                                           muscle contractions
    • No subjects in the tolterodine -treated group                                                 Dopamine D1 receptor agonists          Inhibits the voiding reflex
      reported AUR; 1 of 74 patients (1.4%) reported                                                Nerve growth factor inhibitors         Modulates sensory afferent function

      AUR in the placebo-treated group                                                              Enkephalins                            Suppress the voiding reflex

Please see full prescribing information.          Abrams P et al. J Urol. 2006;175:999 -1004.                                                                 Ouslander JG. N EnglJ Med. 2004;350:786-799.

                                                                                    45                                                                                           46

        Gaps in Current Data on                                                            Redefining the Treatment of Men
         Treating OAB in Men                                                                    With OAB: Summary
• Efficacy                                                                               • In men with LUTS, BPH is the presumed diagnosis, and the
                                                                                           initial treatment is with α -blockers, often leaving a subset of
   – Small, open-label, non–placebo-controlled studies                                     men with inadequate control of their symptoms
   – Patients enrolled based on a urodynamic rather                                      • Men with LUTS may have OAB
     than a symptomatic OAB diagnosis
                                                                                            – OAB and prostatic conditions may coexist
   – No data collected via OAB instruments (eg,
     micturition diary, patient-centric end points, QOL)                                 • The prevalence of OAB is as high in men as in women
                                                                                         • Many men with LUTS and OAB treated with α-blockers
• Safety                                                                                   continue to have persistent storage (or OAB) symptoms
   – The number of patients treated with                                                   after pharmacologic or surgical prostate treatment
     antimuscarinics alone or in combination with a-
     blockers is small
   – Duration is mostly 3 months (43 patients—for 6                                                                                                Irwin et al. Abstract. EAU 2006.
     months)                                                                                                                     Stewart WF et al. World J Urol . 2003;20:327-336.
                                                                                                                                 Knutson T et al. Neuro Urodyn. 2001;20:237 -247.
                                                                                                                                                      Jumadilova Z et al. ICS 2005.
                                          Kaplan S et al. J Urol. 2005;174:2273 -2276.                                        Machino R et al. Neurourol Urodyn. 2000;21:444 -449.

                                                                                    47                                                                                           48

 Redefining the Treatment of Men                                                           Redefining the Treatment of Men
  With LUTS: Summary (cont’d)                                                               With LUTS: Summary (cont’d)
• Tolterodine LA is approved for the treatment of OAB                                    • Published open-label and active -comparator
  in men and women                                                                         studies show that tolterodine LA is associated
• Treatment with tolterodine of OAB in men and                                             with no increased risk for AUR
  women showed significant effectiveness on OAB
  symptoms                                                                               • Placebo-controlled studies show that tolterodine
• Male patients with LUTS and presumed BOO are                                             LA is associated with no increased risk for AUR
  generally treated for prostate-related conditions first                                  (versus placebo)
• An antimuscarinic can be added if OAB symptoms

                                            Kaplan S et al. J Urol. 2005;December.
                                                      Jumadilova Z et al. ICS 2005.                                                   Kaplan S et al. J Urol. 2005;174:2273 -2276.
                                                  Lee JY et al. BJU Int. 2004;94:817                                                            Lee JY et al. BJU Int. 2004;94:817.
                                Athanasopoulos A et al. J Urol. 2003;169:2253-2256.                                           Athanasopoulos A et al. J Urol. 2003;169:2253-2256.
                                Abrams P et al. Neurourol Urodyn. 2001;20:547 -548.                                           Abrams P et al. Neurourol Urodyn. 2001;20:547 -548.


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