Download Update On OAB

Update On OAB
Joon Chul Kim
The Catholic University of Korea
Overactive Bladder Syndrome
: ICS Definition
• Urgency, with or without urge incontinence,
usually with frequency and nocturia
– Absence of pathologic or metabolic conditions
that might explain these symptoms
• Urgency - Sudden, compelling desire to pass
urine that is difficult to defer
Abrams P et al. Urology. 2003;61:37-49.
Desire to Void (Urge to Void) and
Normal Micturition Process
Void
Intervoid Interval
First
Sensation
Urge Intensity
Volume Voided
Bladder Volume (—)
Intensity of desire to void
300 – 500 cc
100 cc
Time
Urge: A physiological desire to void
•
•
•
Gradual onset
Increases as a function of bladder volume
Can usually be deferred with appropriate strategies
Chapple CR et al. BJU Int. 2004; 94:738-744.
Urgency: Micturition Process in OAB
Urgency
Presumed Normal
Void Volume
Reduction in
Volume Voided
Due to Urgency
Void
Intensity
Bladder Volume (—)
Desire to Void
(voluntary and/or
involuntary)
Time
Reduction of
Intervoid Interval
Chapple CR et al. BJU Int. 2004; 94:738-744.
Urgency Drives
the Other Symptoms of OAB
Urgency
1
Increased Frequency
Nocturia
2
and Reduced
2
Incontinence
Intervoid Interval
1
Reduced Volume Voided per Micturition
1. Proven direct effect
2. Effect correlated with urgency but inconsistent due to multifactorial etiology of the symptom
Chapple CR et al. BJU Int. 2004; 94:738-744.
Prevalence of OAB by Gender in Korea
The Overall Prevalence of OAB in Korea was 12.2%
(10.0% Men and 14.3% Women)
Prevalence,* %
25
Men
Women
20
*For population 40+ years of age,
OAB = 14.9% (male 11.2%; female 18.4%)
15
10
Estimation of people with OAB in Korea:
5,951,437
5
0
Korea
Prevalence of OAB by Gender in Korea
Total
Men
Prevalence of OAB, %
30
25
20
15
10
5
0
Age Group, years
Women
OAB Initiating Treatment
• If there is no significant abnormality of
physical exam, urine analysis and PVR,
treatment for OAB can be initiated without
further workup
• In some cases where abnormalities are found,
treatment can be initiated, but abnormality
must be worked up (e.g. hematuria)
– UDS in select patients
Antimuscarinics 2008 in Korea
•
•
•
•
•
Oxybutynin IR
Oxybutynin ER
Tolterodine IR/ER
Trospium
Solifenacin
BID-TID
QD
BID / QD
BID / QD*
QD
What’s The Difference??
• Efficacy
– No great differences
– Dose dependent
• Tolerability
• Safety
• Clinical Effectiveness – different for
different patients depending on
expectations
Differences Among Anticholinergics
• Metabolism
– Hepatic
– Renal
• Pharmacokinetics
Produce a number of
– Delivery system
clinically measurable
and theoretical
– Bioavailability
differences
• Receptor selectivity
• Chemical structure
– Permeability
• Dose titration
– 50-60% of patients will choose higher dose
Why is Efficacy So Hard to Measure
in the OAB Population
• Different patients have different:
– Primary bother symptoms
– Expectations from treatment
• Different studies have different populations
Efficacy of Antimuscarinic Agents vs Placebo
Frequency
Drug
%
Frequency
Placebo
%
Ratio
UUI
Drug
%
UUI
Placebo
%
Ratio
Tolterodine ER (4 mg)* 1
-22
-15
1.47
-71
-33
2.15
Oxybutynin ER (10 mg)**
NA
NA
NA
NA
NA
NA
Oxybutynin TDS (3.9 mg)*2
-18
-8.7
2.07
-75
-50
1.5
Trospium (20 mg BID)** 3
Trospium (20 mg BID)** 4
-18.1
-20.5
-8.4
-13.5
2.15
1.52
-59
-63
-44
-43
1.34
1.47
Solifenacin (5 mg)** 5
Solifenacin (5 mg)** 6
-19.6
-17
-12.8
-8
1.53
2.12
-62.7
-65
-42.5
-40
1.48
1.63
Solifenacin (10 mg)** 5
Solifenacin (10 mg)** 6
-21.9
-20
-12.8
-8
1.71
2.5
-57.1
-63
-42.5
-40
1.34
1.58
Darifenacin (7.5 mg)* 7
-16.6
-9.1
1.82
-68.4
-53.8
1.27
Darifenacin (15 mg)* 7
-17.4
-9.9
1.76
-76.8
-58.3
1.31
*Median % change for baseline
**Mean % change from baseline.
Side Effects: Dry Mouth Incidence
Oxybutynin ER 10mg
Tolterodine ER 4mg
Oxybutynin TDS
Solifenicin 5 mg
Solifenicin 10 mg
Darifenicin 7.5 mg
Darifenicin 15 mg
Drug
28.1-29.7%
23%
9.6%
14%
21.3%
18.8%
31.3%
Placebo
n.a.
8%
8.3%
4.9%
4.9%
13.2%
13.2%
Ratio
2.9
1.2
2.9
4.3
1.4
2.4
Side Effects: Constipation Incidence
Oxybutynin ER 10mg
Tolterodine ER 4mg
Oxybutynin TDS
Solifenicin 5mg
Solifenicin 10 mg
Darifenicin 7.5mg
Darifenicin 15mg
Drug
6.4-7.0%
6%
<2%
7.2%
7.8%
14.8%
21.3%
Placebo Ratio
n.a.
4%
1.5
<2%
~1
1.9%
3.8
1.9%
4.1
6.7%
2.2
6.7%
3.2
Urgency: Defining Symptom of OAB
• How is it measured?
– Yes/no
– Degree
• VAS, IUSS, UPS
– Warning time
– OAB voids
• Recent studies have shown positive effects on
antimuscarinics on urgency
– Darifenicin and solifenicin using yes/no scales
– Tolterodine and trospium using fixed scales
– Darifenicin using a VAS
Reduction in Urgency Episodes/24 hrs
Episodes
6.15
6.03
End of study mean:
2.24
3.30
Mean change from
baseline to endpoint
Mean baseline:
4
-3.91
63.6%
-2.73
3
2
n=348 †
45.3%
n=336
1
Solifenacin
Placebo
0
P<0.0001
†Flexible dosing with solifenacin 5 or 10mg. Patients were allowed to
dose increase at wk 4 and increase/decrease at wk 8
Serels S et al. Urology 2006; 68 (suppl 5a): 73 MP-04.11
Improvement in IUSS Score:
Baseline to End of Study
IUSS score
Lower IUSS score indicates reduced urgency
2.4%
100
3 = Severe
90
2 = Moderate
18.7%
22.0%
80
1 = Mild
6.8%
18.6%
56.0%
70
Percent
0 = None
60
61.6%
67.8%
50
63.6%
40
50.2%
30
20
10
13.3%
0
Baseline
0.3%
12.0%
End of Study
Solifenacin
Serels S et al. Urology 2006; 68 (suppl 5a):73 MP-04.11
19.5%
Baseline
0.3%
5.9%
End of Study
Placebo
Improvement in Urgency Perception
Score: Baseline to End of Study
1 = Usually not able to hold urine
2 = Usually able to hold urine until I reach the toilet if I go immediately
3 = Usually able to finish what I am doing before going to the bathroom
100
90
15.1%
7.2%
15.2%
9.0%
80
Percent
70
46.7%
60
56.0%
68.4%
73.2%
50
40
30
46.1%
20
35.0%
10
0
16.4%
11.7%
Baseline
End of Study
Solifenacin
Baseline
End of Study
Placebo
Higher UPS score indicates reduced urgency
Serels S et al. Urology 2006; 68 (suppl 5a):73 MP-04.11
Tolterodine LA Nighttime Dosing
Reduced 24-Hour Frequency
Study 037
Placebo (n=421)
Tolterodine LA (n=429)
Total*
Normal†
OAB‡
Median Reduction in
Micturitions, %
0
-10
-20
9.4
14.7
12.3
18.6
-30
11.5
18.1
-40
-50
P=.0068
P=.1571
P=.0012
-60
Micturition episodes defined as:
*Urgency score of 1–5 on urgency scale
†Urgency score of 1–2 on urgency scale
‡Urgency score of 3–5 on urgency scale
P=.0225
Rackley et al. Urology. 2006;67:731-736.
Individual Agents
Advantages and Drawbacks
Oxybutynin - ER
• Advantages
– Widest range of dose titration
– Only compound approved for “high dose”
administration
• Drawbacks
– Effects on cognitive function
Tolterodine
• Advantages
– Long safety record
– Number 1 prescribed drug
– New CNS data favorable
– Data on male OAB
• Drawbacks:
– Lack of titration
– Mild increase in QT interval at super therapeutic
doses
Trospium
• Advantages
– No hepatic
metabolism
• Less drug-drug
interactions
– Less crossing of
blood-brain barrier
• ? Clinical
correlation at this
time
– Higher urine
concentration
• ? Clinical meaning
• Drawbacks
BID dosing
No dose titration
Slight increase
in heart rate
Solifenicin
• Advantages
– Dose titration
– Relatively low dry mouth incidence
• Drawbacks
– Mild increase in QT interval at super therapeutic
doses
Antimuscarinics Summary
• Efficacy among antimuscarinic agents is similar
• There are several different advantages (some
theoretical) which may influence drug choice in a
particular patient
• Expect in cases of high dose antimuscarinics,
decisions are more likely to revolve around
tolerability and safety (or perceived safety)
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
Pharmacologic Therapy
for OAB:
Antimuscarinics
BPH = benign prostatic hyperplasia;
OAB = overactive bladder;
5-ARI = 5-alpha-reductase inhibitor.
Prostate Condition:
BPH
Term used and reserved
for the typical histological
pattern that defines
the disease
Pharmacologic Therapy
for BPH:
alpha-Blockers
5-ARIs
Abrams P et al. Urology. 2003;61:37-49.
Timing of combination treatment
• Primary vs. Add-on
: Many patients with BPH and OAB have benefit
from alpha blocker only
: Initially treated with an alpha blocker
: Anticholinergics is added in patients who report
partial response to the alpha blocker but still
have persistent OAB symptoms
In Men With OAB, Treatment With
Tolterodine Was Not Associated
With Increased Incidence of AUR
Subanalyses of Male Patients With OAB in Tolterodine ER Studies
Withdrawal Because of
Symptoms Suggestive of
Urinary Retention,
% (n/N)
AUR, %
Registration study (N = 163)
Tolterodine ER*
Placebo
1.3 (1/77)
0.0 (0/86)
0.0
0.0
Studies 037 and 041 (N = 745)
Tolterodine ER*
Placebo
0.8 (3/371)
0.5 (2/374)
0.0
0.0
IMPACT study† (N = 155)
Tolterodine ER*
1.3 (2/155)
0.0
*Tolterodine ER 4 mg/d.
†Open-label study.
Roehrborn CG et al. BJU Int. 2006;97:1003-1006.
Abrams P et al. J Urol. 2006;175:999-1004.
Elinoff V et al. Intl J Clin Pract. 2006;60:745-751.
TIMES Study
: Urinary Retention Summary
Placebo
(n = 220)
Tolterodine ER
(n = 216)
Tamsulosin
(n = 215)
Tolterodine ER/
Tamsulosin
(n = 225)
4
4
0
2
Urinary retention
3
2
0
2
Urinary flow decreased
1
2
0
0
Discontinued due
to AE
2
1
0
1
Catheterisation
necessary (AUR)
0
1
0
1
Reported urinary AEs
Kaplan SA et al. JAMA. 2006;296:2319-2328.
Concerns about the risk of AUR
• Several recent clinical trials have refuted
• But, given the exclusion criteria should be
considered
• Exclusion criteria for PVR in clinical trials
- greater than 30-40% of maximum capacity
- or 50-200ml
Concerns about the risk of AUR
• Post-void residual volume should be
measured to exclude baseline urinary
retention
• The safety in patients with baseline urinary
retention is not known
Recommendation
Low PVR: <40% of functional capacity
Jaffe WI, Te AE, Current Urology Reports 2005
Summary: OAB in Men
• Available data suggests that antimuscarinics
are safe in men with OAB + BOO, but PVR
should be considered
• Optimal way to use + alpha blockers needs
to be sorted out
• It should be evaluated which patient benefit
from adding of antimuscarinics initially in
real life practice