BPH-_CME PPT.ppt

Prostatism – A Syndrome of Aging
Male

Topics Discussed
 Population demographics
 Evolution of medical therapy for LUTS and BPH
 Male overactive bladder OAB &LUTS/BPH
 Treatment of male LUTS/OAB with antimuscarinics – alone or in
combination
 The TIMES trial and its analyses
 Are antimuscarinics safe in men with presumed BPH ?
 Algorithms, Guidelines and some suggestions

A New Term for prostatism
 LUTS is a recent term for what used to be known as
prostatism

LUTS
 Abnormal voiding sensations that occur with a
frequency or severity that affects quality of life.
 Common LUTS include:
 Urinary frequency,
 Urgency,
 Nocturia,
 Intermittency,
 Incomplete emptying, and
 Weak stream.
 Nocturia is the most prevalent - half to two-thirds.

LUTS are common and universal…

Epidemiology
 In the aging male, LUTS are common and can have a
significant effect on quality of life.
 Two-thirds to three-quarters of men experience some
degree of urinary symptoms
 Most symptoms occur with greater frequency and
severity with increasing age.
 20% to 30% of men reported having:
 Weak stream, hesitancy, urgency, incomplete emptying, or
postvoid incontinence at least sometimes.
 5% to 15% of men reported these same symptoms often.

The World’s Population
is Aging

Health, United States 2006
Center for Disease Control (CDC)

BPH and Ca Prostate:
common conditions in ageing men
0
10
20
30
40
50
60
70
80
90
100
Prevalence (% men)
Age (years)
3140 4150 5160 6170 7180 80+
Histological Hyperplasia or BPH
Prostate cancer
Berry SJ et al. J Urol. 1984;132:474479;
Bulletin of the World Health Organization 2002;80:622-628

Evolution of LUTS Timeline
 Surgical treatment of obstruction to
relieve LUTS
 Research initiated to examine
medical treatments
 TURP introduced in the late
1920’s by pioneer advocates:
Davis, Alcock, Stern, McCarthy,
and Nesbit
Obstruction

 Pharmacologic treatment of
symptoms of “BPH” to relieve LUTS
Alpha-blockers
• Caine M. J Urol. 1986;136:1.
• Lepor H. J Urol. 1989;141:1283.
• Hedlund H, Andersson KE.
J Urol. 1989;141:1283.

 Finasteride was the first 5-ARI proven to
reduce obstructive symptoms in men
 Prostate size was reduced along with
symptoms in men with large prostates
 5-ARI’s maybe beneficial in
men with large prostates
 Gormley GJ, Stoner E, et al.
N Engl J Med. 1992;327:1185.
5-Alpha Reductase Inhibitors

 Combination pharmacologic therapy
examined to treat “BPH” symptoms
and relieve obstructive symptoms
 Alpha blockers better at reducing
obstructive symptoms
 5-ARI’s no beneficial effect
to treat symptoms
 VA COOP
Lepor H et al. NEJM. 1996;335:533.
 MTOPS initiated
Combination Therapy

VA COOP Trial –
Changes at 1 Year
Lepor H et al. NEJM. 1996;335:533-539
placebo-controlled, multi-center study in 1,229 men with BPH in US VA system
-3.2
-6.1 -6.2
-2.6
-7
-6
-5
-4
-3
-2
-1
0
AUASI
Mean
Change
(Points)
Finasteride Terazosin Combination Placebo
1.6
2.7
3.2
1.4
0
0.5
1
1.5
2
2.5
3
3.5
Qmax
Mean
Change
(ml/sec)

 Treatment with 5-ARI’s
slow/reverse prostatic disease
progression
 5-ARI’s more beneficial in
larger prostates
 PLESS
McConnell et al. N Engl J Med.
1998;338:557
Prostate Disease Progression

Adapted from: McConnell et al. N Engl J Med. 1998;338:557; Data available, Merck & Co., Inc. DA-PRO19(1).
Finasteride in BPH:
PLESS—Acute Urinary Retention
8
2
4
0
6
0 4 8 12 16 20 24 28 32 36 40 44 48
%
of
Patients
Months
Placebo (n = 1503)
6.6
P < 0.001
Finasteride (n = 1513)
2.8

Finasteride in BPH:
PLESS - BPH-Related Surgery
0
Months
12
10
8
2
4
0
6
4 8 12 16 20 24 28 32 36 40 44 48
10.1
Adapted from: McConnell et al. N Engl J Med. 1998;338:557; Data available, Merck & Co., Inc. DA-PRO19(1).
%
of
Patients
Placebo (n = 1503)
P < 0.001
4.6
Finasteride (n = 1513)

 Precedence of combination therapy
set in MTOPS
 Pharmacologic therapy targeted to
relieve LUTS, including OAB
 Response by prostate size
& PSA
 MTOPS
 TIMES
 ADAM
Bladder vs Prostate

 Symptom clusters
 Metabolic syndrome
 Inflammation
 Central obesity
 Role of sexual dysfunction
as a component of LUTS?
 3 agonist
 PDE-5 inhibitors
 EpiLUTS
 BACH
 Scientific research
Future Concepts
Optimize Diagnosis,
Treatment, and
Patient Outcomes

Evolution of Medical Therapy for
LUTS/BPH/BOO/BPE
 In recent years the recognition grew that some men with
“LUTS” actually suffer from the same symptoms as
women with OAB, thus creating the term “male OAB”
 While previously viewed as contraindicated, the use of
antimuscarinics is now being seriously investigated in
many studies
 The term BPH is reserved to describe the histological
presence of hyperplasia in the prostate

Prevalence of LUTS in Men Is High
6 of 10 men in the general population
(N = 5460) reported at least 1 type of LUTS
38.7%
61.3%
Men without LUTS
Men with LUTS
Post-
micturition
Total
16.5%
Voiding
Total
25.7%
Storage
Total
49.7%
Percentage of men in the general male
population who report at least 1 symptom
representative of a particular type of LUTS
Irwin DE et al. Eur Urol. 2006;50:1306-1315.

Prevalence of Individual LUTS in Men
Irwin DE et al. Abstract presented at EAU 2006.
EPIC Study. Data on file. Pfizer Inc.
Storage Voiding
Post-
micturition
Prevalence,
%
20.8
14.8 13.3
11.1
8.9
5.1
6.4 6.4
5.1
2.8
0
5
10
15
20
25
30
35
40
45
50
Nocturia: waking to void ≥2 times per night.
Frequency: subject feels he/she urinates too often during the day.

Storage
Symptoms Relate
to the Bladder
• Urgency
• Frequency
• Nocturia
• Urgency urinary
incontinence
• Other incontinence
OAB is defined as urgency, with or without urgency incontinence,
usually with frequency and nocturia (ICS definition).
Abrams P et al. Urology. 2003;61:37-49.
OAB = overactive bladder.
Most Men with LUTS Have Both Storage
and Voiding/Post-micturition Symptoms
67%
of Men
Experience
Symptoms of both
OAB and BPH
Voiding/Post-
micturition
Symptoms Relate
to the Prostate
• Slow stream
• Intermittency
• Straining
• Terminal dribble
• Post-micturition dribble
• Incomplete emptying

OAB Symptoms Are as Prevalent in Men as
in Women and Increase with Age
Comparison of Data from the SIFO Study 1997
and the EPIC Study 2005
Prevalence,
%
0
5
10
15
20
25
30
35
40
Age, years
18-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70+
Men – SIFO 1997
Men – 2005
Women – SIFO 1997
Women ̶ 2005
16.6
11.8
Milsom I et al. BJU Int. 2001;87:760-766.

OAB Has a Considerable
Impact on Quality of Life
Kobelt G et al. BJU Int. 1999;83:583-590.
Komaroff AL et al. Am J Med. 1996;101:281-290.
Healthy
Diabetes
Depression
OAB
SF-36
Score
0
10
40
50
60
70
80
90

Men with OAB Report a Greater Degree
of Impairment in HRQL
EQ-5D: Percentage of Respondents
Reporting Any Problems—Men
OAB without UI OAB with UI
Control male
*
*
*
*
*
*
0
5
10
15
20
25
30
35
40
45
Mobility Self-care Usual
activities
Pain/
discomfort
Anxiety
depression
Patients,
%
The EQ-5D is a 5-item generic QOL instrument used to measure overall QOL.
*P ≤ .05 OAB with UI vs controls and OAB without UI vs controls.
HRQL = health-related quality of life; QOL = quality of life; UI = urinary incontinence. Irwin DE. ICS 2006.

Men with LUTS Are Treated Predominantly
with BPH Agents Rather than OAB Agents
OAB Rx
only
BPH Rx
only
OAB &
BPH Rx
No Rx
Patients
Receiving
Treatment,
%
0
10
20
30
40
50
60
70
OAB & BPH (n = 4806)
9 11
36
22
8
6
47
61 Diagnosis
Type of Treatment
Data were obtained from medical and pharmacy claims database of diverse managed care plans.
BPH prescriptions include all alpha-blockers and 5-ARIs; OAB prescriptions include all antimuscarinics.
OAB & No BPH (n = 12,192)
Jumadilova Z et al. Abstract. ICS 2005.

Patient Bother Is High;
Treatment Rates Are Low
 Although symptoms are bothersome, OAB often remains under-
diagnosed and under-treated
 In a survey of patients who informed their physicians about OAB
symptoms, only 27% were treated with medication
 Patient- and physician-related barriers exist, making recognition and
treatment of OAB in men challenging
 Complex clinical presentation of OAB symptoms in combination with other
LUTS (voiding symptoms)
 Complex terminology
 Significant regional and country differences
 Alternative potential pathophysiology
 Bladder dysfunction or prostate conditions, or both
 Concerns about safety
 Clinical effect of a significant increase in PVR
 Presumed increased risk for AUR Elinoff V et al. Int J Clin Pract. 2006;60:745-751.
Ricci JA et al. Clin Ther. 2001;23:1245-1259.
Milsom I et al. BJU Int. 2001;87:760-766.
Chapple CR et al. Eur Urol. 2006;49:651-659.
Steers WD. Rev Urol. 2002;4:S7-S18.
AUR = acute urinary retention;
PVR = post-void residual.

Symptoms of OAB May Be Associated
with Several Possible Etiologies
Ouslander J. N Engl J Med. 2004;350:786-799.
Myogenic
Unknown
Neurogenic
Combination

Increased electrical
coupling between cells
Hypertrophy/hyperplasia
Instability of membrane
potential
Altered intracellular
Ca2+ regulation
OAB/
Detrusor Overactivity
Detrusor
muscle
Outlet
Obstruction
Ischaemia
Supersensitivity to
acetylcholine
Reduced response to
intramural nerve
stimulation
Partial
denervation
OAB/
Outlet
Obstruction
Re-organization of
spinal micturition reflex
(C-fibre–mediated)
Altered Na+ channel
expression/function
Hypertrophy of
afferent and efferent
neurons
Expression of
nerve
growth factor
OAB/
Outlet
Obstruction
Male OAB Symptoms/DO May be Primary
or May Develop Secondary to BOO
BOO = bladder outlet obstruction; DO = detrusor overactivity. Steers WD. Rev Urol. 2002;4:S7-S18.
Potential Etiology of OAB/DO in Men with BOO

Evaluation of Symptoms
 OAB
 No. micturition
episodes/24 h
 No. urge
incontinence
episodes
 Nocturnal voids
 Effect on urgency
 LUTS in men
 IPSS
 Flow rate
 Postvoid residual
(PVR)

Instruments for Evaluation of
LUTS & Bother

Bladder Diaries
Patient-completed instrument capturing time and
number of micturitions, urgency, and urgency
incontinence episodes, as well as voided volume
over at least 3 days
Urgency is recorded according to the ICS definition
and can be classified using a five-point urinary
sensation scale
The scale helps patients interpret various sensations
associated with a micturition, by grading urgency from 0
(no urgency) to 5 (urgency resulting in a leak)
Rackley R et al. Urology. 2006;67:731-736.
Recommendations of the ISC: Evaluation and Treatment of LUTS in
Older Men 6th International Consultation on New Developments in
Prostate Cancer and Prostate Diseases: June 24-28, 2005; Paris,
France

Bladder Diary: Assessment of Urgency
During Micturition
Date:
What time did you start your day today (time
arose)?
What time did you go to bed for the night?
Urinary Sensation Scale*
Urinary urgency is defined as an intense and/or sudden
need to urinate. Please rate the feeling of urinary urgency
that was associated with this urination using the following
scale:
1. No feeling of urgency: I could continue activities until I
chose to use the bathroom
2. Mild feeling of urgency: I could feel the need to urinate,
but it was easily tolerated. I could finish my activity or task
before going to the bathroom
3. Moderate feeling of urgency: My urgency caused
discomfort. I needed to stop my activity or task and go to
the bathroom.
4. Severe feeling of urgency: My urgency cause much
discomfort. I had difficulty holding my urine. I had to stop
my activity or task and hurry to the bathroom to avoid a
wetting accident
5. Unable to hold; leak urine: I had a wetting accident before
arriving to the bathroom
BLADDER

Complex Clinical Presentation:
Male LUTS Can Be Associated with the Bladder, the Prostate, or
Both
Bladder Condition:
OAB
Urgency, with or without
urgency incontinence,
usually with frequency
and nocturia
Pharmacological Therapy
for OAB:
Antimuscarinics
Prostate Condition:
BPH
Term used and reserved
for the typical histological
pattern that defines
the disease
Pharmacological Therapy
for BPH:
alpha-Blockers
5-ARIs
5-ARI = 5-alpha-reductase inhibitor. Abrams P et al. Urology. 2003;61:37-49.

Treatment Response May Vary in Men with
LUTS Because of Different Pathologies
LUTS (n = 144; 100%)
Urodynamic Evaluation
Doxazosin  3 mo
BOO (n = 76; 52.8%)
Improved
n = 60
79%
NOT Improved
n = 16
21%
Doxazosin  3 mo
BOO and DO (n = 68; 47.2%)
Improved
n = 24
35%
NOT
Improved
n = 44
65%
Lee JY et al. BJU Int. 2004;94:817-820.
Patients with DO had involuntary detrusor contractions 10 cm H2O.
Improvement was defined as at least a 3-point reduction in International
Prostate Symptom Score (IPSS).

Tolterodine Alone or in Combination
with alpha-Blockers for the Treatment
of Men with OAB and Other LUTS
Evaluated Urodynamically

Combination Treatment
With an -Blocker
Plus an Anticholinergic
for BOO
Athanasopoulos A, et al, 2003

Athanasopoulos A et al. 2002 Neurourol Urod 19; 308-309.
• Randomised, controlled trial
• 50 men
• mild/moderate BOO on UDS
• concomitant idiopathic detrusor overactivity
• Study design
• complete QoL9 UROLIFE questionnaire prior to
study onset
• 1 week tamsulosin 0.4 mg qd, then randomly
assigned to receive concomitant tolterodine 2 mg
bid or continue tamsulosin monotherapy
• repeat QoL9 and UDS at 12 weeks
Antimuscarinic and -Adrenergic Blocking
Combination Therapy in Men with BOO

542.2
525
548.2
628.4
0
480
500
520
540
560
580
600
620
640
Tamsulosin Tamsulosin + Tolterodine
Baseline
12 Weeks
Mean
Score
(QoL
9
UROLIFE)
P = NS
P =
0.0003
(n = 25) (n = 25)
Improved
QoL
Athanasopoulos A et al. 2002 Neurourol Urodyn. 19;308-309.
Antimuscarinic and -Adrenergic Blocking Combination
Therapy in Men with BOO: Effects on QoL

Effect on Urodynamic Parameters
Tamsulosin
(n = 25)
Tamsulosin +
Tolterodine (n = 25)
Mean Change
from Baseline
P value
Mean Change
from Baseline
P value
Maximum detrusor
pressure (cm H2O)
–5.2 0.0827 –8.24 0.0082
Maximum flow rate
(mL/second)
+1.16 0.0001 +1.32 0.0020
Pressure at maximum
overactivity (cm H2O)
–2.16 0.05690 –11.16 0.0001
Volume at first overactive
contraction (mL)
+30.40 0.0190 +100.40 0.0001
Athanasopoulos A et al.2002 Neurourol Urodyn 19; 308-309.

Safety and Efficacy of tolterodine extended release in men with
overactive bladder symptoms and presumed non-obstructive
benign prostatic hyperplasia
Hoefner et al: World J Urol 25:627, 2007
• Patients with presumed non-obstructive BPH (Qmax¸ 15
ml/s) treated with tolterodine ER 4 mg/day for OAB
symptoms, alone or added to unsuccessful alphablocker
treatment of 6 weeks duration, were observed for 12 weeks
• The study was completed by 926 patients of the safety
set (85.7%).
• In the FAS, 661 (89.2%) subjects completed the study. Of
80 (10.9%) who discontinued prematurely, in 59 (8.0%)
the cause was treatment related:
• 1.1% due to adverse events,
• 1.6% due to lack of efficacy and
• 5.3% for complete response.

Safety and Efficacy of tolterodine extended release in men with
overactive bladder symptoms and presumed non-obstructive
benign prostatic hyperplasia
Hoefner et al: World J Urol 25:627, 2007

Well-Designed, Double-Blind,
Placebo-Controlled Trials
• Efficacy and safety of tolterodine ER
4 mg in men with LUTS that include
OAB symptoms
• 4-arm study (200 patients/arm)
– Placebo
– Tamsulosin
– Tolterodine ER
– Tolterodine ER + Tamsulosin
• Efficacy and safety of tolterodine
ER 4 mg in men with persistent
OAB symptoms undergoing stable
alpha-blocker therapy
• 2 arms (304 patients/arm)
– Placebo + alpha-blocker
(stable dose for ≥1 month)
– Tolterodine ER + alpha-blocker
(stable dose for ≥1 month)
Studies collect OAB end points, IPSS, and data on PSA, PVR, flow rate, and prostate volume
Ongoing Trial Completed Trial
PSA = prostate-specific antigen. Kaplan SA et al. JAMA. 2006;296:2319-2328.

Tolterodine and Tamsulosin In
Men With LUTS Including
OAB: Evaluation of Efficacy
And Safety
TIMES

Study Objectives
• Primary objective
– Evaluate the effect of tolterodine ER plus
tamsulosin versus placebo on patient perception
of treatment benefit at week 12
• Secondary objective
– Evaluate the effect on efficacy, safety, patient
perception, and health-related quality of life
(HRQL) among the various treatment groups
Kaplan SA et al. JAMA. 2006;296:2319-2328.
BOO = bladder outlet obstruction; ER = extended release; UUI =
urgency urinary incontinence.

Study Design
• Design
– 12-week, randomised, double-blind, active- and placebo-controlled, 4-
arm (placebo, tolterodine ER, tamsulosin, and tolterodine ER plus
tamsulosin) multi-centre study
– 876 adult male subjects (≥40 years of age)
• Setting
– 95 centres (urology offices/clinics) throughout the US
• Treatment
– Equally randomised into 4 groups with night-time dosing
• Placebo
• Tolterodine ER 4mg
• Tamsulosin 0.4 mg
• Tolterodine ER plus tamsulosin

TIMES: Study Timeline
Week 1 Week 6 Week 12
Visit 1 Visit 3
Visit 2 Visit 4 Visit 5
Screen
Placebo
Tolterodine ER
Tamsulosin
Combination
Week –1

652 Excluded:
Did not meet inclusion/exclusion criteria: 481
Lost to follow
-
Other: 29
Refusal to participate further: 118
879 Randomized
tolterodine ER = 217 Tamsulosin = 215
Discontinued: 27
Adverse event: 5
Lack of efficacy: 8
Consent withdrawn: 9
Protocol deviation: 2
Lost to follow
-up: 1
Death: 1
Other: 1
Discontinued: 29
Adverse event: 7
Lost to follow
-up: 4
Other: 5
tolterodine ER /
Tamsulosin = 225
Discontinued: 34
Adverse event: 20
Lack of efficacy: 4
Lost to follow
-up: 6
Other: 2
Efficacy Analysis = 217
Placebo = 222
Discontinued: 32
Adverse event : 7
Lack of efficacy: 7
Lost to follow
-up: 4
Other: 5
Safety Analysis = 216 Safety Analysis = 215 Safety Analysis = 225
1531 Assessed for Eligibility
652 Excluded:
Did not meet inclusion/exclusion criteria: 481
Lost to follow
- up: 24
Other: 29
Refusal to participate further: 118
879 Randomized
tolterodine ER = 217 Tamsulosin = 215
Discontinued: 27
Adverse event: 5
Lack of efficacy: 8
Lost to follow: 1
-
Death: 1
Other: 1
Discontinued: 29
Adverse event: 7
Lost to follow: 4
-
Other: 5
Efficacy Analysis = 210 Efficacy Analysis = 209
tolterodine ER /
Tamsulosin = 225
Discontinued: 34
Adverse event: 20
Lack of efficacy: 4
Lost to follow: 6
-
Other: 2
Placebo = 222
Discontinued: 32
Adverse event : 7
Lack of efficacy: 7
Lost to follow: 4
-
Other: 5
Safety Analysis = 216 Safety Analysis = 215 Safety Analysis = 225
Safety Analysis = 220
Disposition of Study
Participants

Measurement Instruments Used
• Patient perception of treatment benefit (PPTB,
primary outcome)
– The following questions were asked to capture patient
perception of treatment benefit
• Have you had any benefit from your treatment?
• If yes, have you had little benefit or much benefit?
• Bladder diary (3-day)
– Patient-recorded micturitions and episodes of urgency
and UUI
• International Prostate Symptom Score IPSS (0-35
score)
– Storage (0-15) and voiding (0-20) sub-scores
Data on file. Pfizer Inc.

Baseline Characteristics Suggest Subjects Had
Moderate-Severe Storage and Voiding Symptoms
Placebo
(n = 215)
Tolterodine ER
(n = 210)
Tamsulosin
(n = 209)
Tolterodine ER/
Tamsulosin
(n = 217)
Diary variables, mean
UUI episodes/24 h* 1.0 0.0 0.7 1.4
Urgency
episodes/24 h
7.3 7.6 7.1 6.7
Micturitions/24 h 11.9 11.8 12.1 11.9
Micturitions/night 2.0 2.0 1.7 2.1
Total IPSS score† 20.0 19.5 20.0 20.1
Storage IPSS 10.2 9.9 10.3 10.2
Voiding IPSS 9.9 9.6 9.7 9.9
IPSS QOL 4.6 4.6 4.6 4.6
Mean Qmax , ml/s 12.2 13.3 13.4 12.7
Mean PVR, ml 47.1 50.5 56.5 58.8
*Patients who had incontinence at baseline.
PVR = post-void residual; Qmax = maximum flow rate. Kaplan SA et al. JAMA. 2006;296:2319-2328.
†Total IPSS score: 0-7, mildly symptomatic; 8-19, moderately symptomatic; 20-35, severely symptomatic.

Placebo
(n = 215)
Tolterodine ER
(n = 210)
Tamsulosin
(n = 209)
Tolterodine ER/
Tamsulosin
(n = 217)
UUI episodes/24 h* 1.0 0.0 0.7 1.4
Urgency
episodes/24 h
7.3 7.6 7.1 6.7
Micturitions/24 h 11.9 11.8 12.1 11.9
Total IPSS score† 20.0 19.5 20.0 20.1
Storage IPSS 10.2 9.9 10.3 10.2
Voiding IPSS 9.9 9.6 9.7 9.9
IPSS QOL 4.6 4.6 4.6 4.6
Mean Qmax , ml/s 12.2 13.3 13.4 12.7
Mean PVR, ml 47.1 50.5 56.5 58.8
10 of possible 15 Storage
Vs
10 of possible 20 Voiding

Placebo
(n = 215)
Tolterodine ER
(n = 210)
Tamsulosin
(n = 209)
Tolterodine ER/
Tamsulosin
(n = 217)
UUI episodes/24 h* 1.0 0.0 0.7 1.4
Urgency
episodes/24 h
7.3 7.6 7.1 6.7
Micturitions/24 h 11.9 11.8 12.1 11.9
Total IPSS score† 20.0 19.5 20.0 20.1
Storage IPSS 10.2 9.9 10.3 10.2
Voiding IPSS 9.9 9.6 9.7 9.9
IPSS QOL 4.6 4.6 4.6 4.6
Mean Qmax , ml/s 12.2 13.3 13.4 12.7
Mean PVR, ml 47.1 50.5 56.5 58.8
Due to the exclusion of pts who score
“delighted”, “very pleased” or
“pleased” to this question

Placebo
(n = 215)
Tolterodine ER
(n = 210)
Tamsulosin
(n = 209)
Tolterodine ER/
Tamsulosin
(n = 217)
UUI episodes/24 h* 1.0 0.0 0.7 1.4
Urgency
episodes/24 h
7.3 7.6 7.1 6.7
Micturitions/24 h 11.9 11.8 12.1 11.9
Total IPSS score† 20.0 19.5 20.0 20.1
Storage IPSS 10.2 9.9 10.3 10.2
Voiding IPSS 9.9 9.6 9.7 9.9
IPSS QOL 4.6 4.6 4.6 4.6
Mean Qmax , ml/s 12.2 13.3 13.4 12.7
Mean PVR, ml 47.1 50.5 56.5 58.8
No upper threshold for Qmax
had to be > 5 ml/sec
This likely prevented an effect of Rx
on Qmax

*P < .001 between-group comparisons.
†P = .001 between-group comparisons.
‡P < .05 between-group comparisons.
Treatment with Tolterodine ER plus Tamsulosin Resulted in
Significant Treatment Benefit at Week 12
‡
†
*
62
65
35
71
30
80
20
38
0
10
20
30
40
50
60
70
80
90
100
Placebo Tolterodine ER Tamsulosin Tolterodine ER /
Tamsulosin
Patients,
%
Benefit No Benefit
Only Combination Therapy
Was superior to Placebo!

–1.24
–1.75 –1.75
Treatment with Tolterodine ER plus Tamsulosin
Significantly Reduced Frequency
*P < .05 versus placebo.
†P < .01 versus placebo.
‡P < .001 versus placebo.
LS = least squares. Kaplan SA et al. JAMA. 2006;296:2319-2328.
0
–3.0
–2.5
–2.0
–1.5
–1.0
–0.5
0.0
Week 0 Week 1 Week 6 Week 12
Episodes,
n
per
day
(LS
mean)
Tamsulosin (n = 209, baseline: 12.1) Tolterodine ER / Tamsulosin (n = 217, baseline: 11.92)
Tolterodine ER (n = 210, baseline: 11.79)
Placebo (n = 215, baseline: 11.86)
Change in Micturition Frequency per 24 Hours
–0.8*
–1.41
–1.46
–0.51
–1.67
–1.42
–1.41†
–2.36‡
–2.54‡

Treatment with Tolterodine ER plus Tamsulosin
and Tolterodine ER Alone Significantly Reduced UUI
* Only those patients with UUI at baseline
UUI = urgency urinary incontinence
Placebo (n = 48, baseline: 0.98)
0
–0.26
–0.13
–0.38
–0.35
–0.85*
–0.83*
–0.39
–0.78*
–0.70
–0.63
–0.81*
–0.88*
Tolterodine ER (n = 53, baseline: 0.84)
Tamsulosin (n = 50, baseline: 0.71) Tolterodine ER / Tamsulosin (n = 52, baseline: 1.4)
Change in Urgency Incontinence Episodes / 24 Hours*
Week 0 Week 1 Week 6 Week 12
*P < .01 vs placebo.
Episodes,
n
per
day
(LS
mean)
–1.0
–0.9
–0.8
–0.7
–0.6
–0.5
–0.4
–0.3
–0.2
–0.1
0.0

TIMES: Efficacy Summary
Tolterodine ER Tamsulosin
Tolterodine ER/
Tamsulosin
Patient perception of treatment benefit ++
Frequency/24 h ++
Night-time frequency +
Urgency incontinence/24 h ++ ++
Urgency episodes/24 h +
IPSS total ++ ++
IPSS storage ++
IPSS voiding ++
IPSS QOL ++
PPBC +
OAB-q/Symptom Severity score ++
OAB-q/HRQL total score +
++P < .01 versus placebo.
+P < .05 versus placebo.

TIMES: Efficacy Summary
• In bothered male patients with LUTS, including diary-
documented OAB
– Tolterodine ER and tamsulosin were used according to
their indications
• Tolterodine is indicated for the treatment of OAB with symptoms
of UUI, urgency, and frequency
• Tamsulosin is indicated for the treatment of signs and symptoms
of BPH
– Tolterodine ER, administered with tamsulosin, was an
efficacious treatment
– Tolterodine ER or tamsulosin therapy alone was not
sufficient to show significant clinical efficacy

Conclusions
• In this stratified analysis of the TIMES study,
tolterodine ER alone was an effective therapy
for OAB in men with smaller glands and lower
PSA
• Tolterodine ER administered with an alpha-
blocker was an effective treatment for OAB
symptoms in men with larger glands and
higher PSA

Are antimuscarinics safe in men with presumed
BPH and possible bladder outlet obstruction?
 In the past there had been concerns that the use of
antimuscarinic agents might negatively affect
detrusor muscle function and result in:
 Increased postvoid residual urine (PVR)
 Worsening of voiding efficiency
 Episodes of acute urinary retention (AUR)
 Need for BPH related surgery

Can MOA of Antimuscarinics Aggravate Voiding
Difficulties?
 Antimuscarinics inhibit detrusor contractions
 Theoretical risk for AUR
 However, it is postulated that
 Antimuscarinics inhibit detrusor contractions during the filling
phase and are displaced during the emptying phase
 During normal voiding, massive release of acetylcholine occurs from
parasympathetic nerves, displacing antimuscarinics via competitive
binding (resulting in normal voiding)
 At therapeutic doses of antimuscarinics, there is no effect on
normal voiding and no increased occurrence of AUR
 This hypothesis is supported by clinical evidence on the
urinary safety of antimuscarinics at recommended doses
Andersson KE et al. Eur Urol. 2003;43:1-5.
Reynard JM. Cur Opin Urol. 2004,14:13-16.
MOA = mechanism of action.

In Men with Symptoms of OAB and BOO, Tolterodine IR
Was Not Associated with Increased Incidence of AUR
 ≤12-Week Studies in Men Evaluated Urodynamically for
BOO and DO
AUR, % (n/N)
Abrams et al study (N = 221)
Tolterodine IR*
Placebo
0.0 (0/149)
1.4 (1/72)
Lee et al study (N = 144)
Doxazosin + Tolterodine IR*
Doxazosin†
3.3 (2/60) ‡
0.0 (0/84)
Athanasopoulos et al study (N = 50)
Tamsulosin + Tolterodine IR*
Tamsulosin†
0.0 (0/25)
0.0 (0/25)
Abrams P et al. J Urol. 2006;175:999-1004.
Lee JY et al. BJU Int. 2004;94:817-820.
Athanasopoulos A et al. J Urol. 2003;169:2253-2256.
Data on File. Pfizer Inc.
*Tolterodine IR 2 mg 2 times daily (BID).
†Doxazosin 4 mg/d or tamsulosin 0.4 mg/d.
‡An erratum submitted to the journal stated that only 1 of the 2 patients
who experienced AUR was taking tolterodine IR + doxazosin, whereas
the other received doxazosin monotherapy.
IR = immediate release.

Safety of Tolterodine® IR in Men with OAB/DO and
BOO: AEs
Urinary Symptom AEs
Placebo n = 72
Tolterodine IR
n = 149
n % n %
Micturition disorder 2 2.8 7 4.7
Urinary tract infection 3 4.2 6 4.0
Dysuria 1 1.4 3 2.0
Micturition frequency 2 2.8 3 2.0
Micturition urgency 1 1.4 2 1.3
Strangury 0 – 2 1.3
Acute urinary retention 1 1.4 0 0.0
Bladder discomfort 0 – 1 0.7
Urethral disorder 0 – 1 0.7
Urinary incontinence 2 2.8 0 –
Overall 9 12.5 19 12.8
AE = aderse event; IR = immediate release.

Safety of Tolterodine® IR in Men with OAB/DO and
BOO: Conclusions
 Tolterodine IR did not affect urinary function in men with OAB/DO
and BOO
 No difference between Tolterodine IR and placebo on Qmax and PdetQmax
 Tolterodine IR did not adversely affect urinary flow or detrusor
muscle function
 27-ml increase in median PVR for Tolterodine IR over placebo
 No subjects in the Tolterodine IR–treated group reported AUR
 1 (1.4%) of 74 patients reported AUR in the placebo-treated group
 Results suggest Tolterodine IR is safe in men with OAB/DO and mild
to severe BOO
 Tolterodine was well tolerated and did not aggravate voiding difficulties or
increase the incidence of AUR

TIMES: Safety and Tolerability Profile Furthers Evidence
for Urinary Safety in Men with OAB and Other LUTS
Treated with Tolterodine®
 In this study population, Tolterodine SR, administered with or without
tamsulosin, was well tolerated, and the risk for AUR was low
 LUTS/OAB patients with PVR <200 ml and Qmax >5 ml/s
 No increase in PVR
 No decrease of Qmax
 Low incidence of AUR

Longer term studies with antimuscarinics
 Abrams P, Malone-Lee J, Jacquetin B, et al. Twelve-month treatment
of overactive bladder: efficacy and tolerability of tolterodine. Drugs
Aging 2001;18:551-60
 Van Kerrebroeck P. Long-term (12-months) efficacy and tolerability of
tolterodine once daily in the treatment of overactive bladder. ICS
2001. Neurourol Urodyn 2001;20:401-2 (Abstr)
 Appell RA, Diokno A, Antoei J, Labasky RF for the Ditropan XL Study
Group. One-year prospective, open-label trial of controlled-release
oxybutynin for overactive bladder in a community- based population.
Neurol Urodyn 2000;19:528-9 (Abstr)

Practical guide to the evaluation and treatment of male lower
urinary tract symptoms in the primary care setting.
Rosenberg
et
al:
International
Journal
of
Clinical
Practice
61
(9),
1535-1546

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

Specialized Management for Persistent
Bothersome LUTS after Basic Management
OAB
(Overactive Bladder)
(Storage Symptoms)
No Evidence
of BOO
• Lifestyle
Intervention
• Behavioral
Therapy
• Antimuscarinics
Recommended Tests:
• Validated Questionnaires
• FVC (Frequent Volume Chart)
• Flowrate Recording
• Residual Urine
Evidence of BOO
Discuss Rx Options
Shared Decision
Medical Therapy Option
Predominant BOO
MIST
(Minimally Invasive
Surgical Treatment)
OR
Surgery Option
Mixed OAB
And BOO
Failure
Reassess and
Consider Invasive
Therapy of OAB
Antimuscarinic*
&
α-Blockers
Small Gland and/or
Low PSA
α-Blockers
Larger Gland and/or Higher
PSA
α-Blockers +
5α-Reductase Inhibitors
Failure
Offer MIST or Surgery to Patient
Evaluation clearly suggestive of
Obstruction? (Qmax < 10 ml/s)
Pressure-Flow Studies
Obstruction?
NO YES
NO YES
Proceed with
selected technique
Treat appropriately. If interventional therapy is
pursued, patients need to be informed of possible
higher failure rates
OAB: Overactive Bladder
MIST: Minimally Invasive
Surgical Treatment
BOO: Bladder Outlet
Obstruction

Obstructive
Voiding
Irritative
Storage
Larger
Higher PSA
Smaller
Lower PSA

Obstructive
Voiding
Irritative
Storage
Larger
Higher PSA
Smaller
Lower PSA
Antimuscarinics
Antimuscarinics
Alpha Blocker
5 ARIs
Alpha Blocker
Alpha Blocker
5 ARIs
Alpha Blocker
5 ARIs
Alpha Blocker

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