Transcript Update On OAB
Update On OAB
Joon Chul Kim The Catholic University of Korea
Overactive Bladder Syndrome : ICS Definition
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Urgency, with or without urge incontinence, usually with frequency and nocturia
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Absence of pathologic or metabolic conditions that might explain these symptoms
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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
Intensity of desire to void Intervoid Interval Void First Sensation 100 cc 300 – 500 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
Desire to Void Reduction in Volume Voided Due to Urgency Urgency Presumed Normal Void Volume Time Void (voluntary and/or involuntary) Reduction of Intervoid Interval Chapple CR et al. BJU Int. 2004; 94:738-744.
Urgency Drives the Other Symptoms of OAB
Urgency 1 Nocturia 2 Increased Frequency and Reduced Intervoid Interval 1 2 Incontinence 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) 25 Men Women 20 15 10 5 *For population 40+ years of age, OAB = 14.9% (male 11.2%; female 18.4%) Estimation of people with OAB in Korea: 5,951,437 0 Korea
Prevalence of OAB by Gender in Korea
Total Men Women 30 25 20 15 10 5 0
Age Group, years
OAB Initiating Treatment
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If there is no significant abnormality of physical exam, urine analysis and PVR, treatment for OAB can be initiated without further workup
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In some cases where abnormalities are found, treatment can be initiated, but abnormality must be worked up (e.g. hematuria)
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UDS in select patients
Antimuscarinics 2008 in Korea
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Oxybutynin IR Oxybutynin ER Tolterodine IR/ER Trospium Solifenacin BID-TID QD BID / QD BID / QD* QD
What’s The Difference??
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Efficacy
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No great differences Dose dependent Tolerability Safety
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Clinical Effectiveness – different for different patients depending on expectations
Differences Among Anticholinergics
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Metabolism
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Hepatic
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Renal Pharmacokinetics
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Delivery system Bioavailability Produce a number of clinically measurable and theoretical differences Receptor selectivity Chemical structure
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Permeability Dose titration
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50-60% of patients will choose higher dose
Why is Efficacy So Hard to Measure in the OAB Population
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Different patients have different:
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Primary bother symptoms Expectations from treatment
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Different studies have different populations
Efficacy of Antimuscarinic Agents vs Placebo
Tolterodine ER (4 mg)* 1 Oxybutynin ER (10 mg)** Oxybutynin TDS (3.9 mg)* 2 Trospium (20 mg BID)** 3 Trospium (20 mg BID)** 4 Solifenacin (5 mg)** 5 Solifenacin (5 mg)** 6 Solifenacin (10 mg)** 5 Solifenacin (10 mg)** 6 Darifenacin (7.5 mg)* 7 Darifenacin (15 mg)* 7 Frequency Drug %
-22 NA -18 -18.1
-20.5
-19.6
-17 -21.9
-20 -16.6
-17.4
Frequency Placebo %
-15 NA -8.7
-8.4
-13.5
-12.8
-8 -12.8
-8 -9.1
-9.9
Ratio
1.47
NA 2.07
2.15
1.52
1.53
2.12
1.71
2.5
1.82
1.76
* Median % change for baseline **Mean % change from baseline.
UUI Drug %
-71 NA -75 -59 -63 -62.7
-65 -57.1
-63 -68.4
-76.8
UUI Placebo %
-33 NA -50 -44 -43 -42.5
-40 -42.5
-40 -53.8
-58.3
Ratio
2.15
NA 1.5
1.34
1.47
1.48
1.63
1.34
1.58
1.27
1.31
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 n.a.
4% <2% 1.9% 1.9% 6.7% 6.7% Ratio 1.5
~1 3.8
4.1
2.2
3.2
Urgency: Defining Symptom of OAB
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How is it measured?
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Yes/no
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Degree
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VAS, IUSS, UPS
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Warning time OAB voids
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Recent studies have shown positive effects on antimuscarinics on urgency
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Darifenicin and solifenicin using yes/no scales
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Tolterodine and trospium using fixed scales
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Darifenicin using a VAS
Reduction in Urgency Episodes/24 hrs Mean baseline: End of study mean: 6.15
Episodes
2.24
6.03
3.30
-3.91
4
63.6%
3
-2.73
45.3%
2
n=348 † n=336
1 0 Solifenacin Placebo
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
IUSS score
Improvement in IUSS Score: Baseline to End of Study
Lower IUSS score indicates reduced urgency 2.4% 3 = Severe 2 = Moderate 1 = Mild 0 = None
100 90 80 70 60 50 40 30 20 10 0
18.7% 67.8% 22.0% 63.6% 13.3% 0.3% Baseline 12.0% End of Study Solifenacin 18.6% 61.6% 6.8% 56.0% 50.2% 19.5% 0.3% Baseline 5.9% End of Study Placebo
Serels S et al.
Urology
2006; 68 (suppl 5a):73 MP-04.11
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 80 70 60 50 40 30 20 10 0
15.1% 73.2% 11.7% 7.2% 46.7% 46.1% 15.2% 68.4% 16.4% 9.0% 56.0% 35.0% Baseline End of Study Baseline End of Study Solifenacin 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
Total* 0 -10 -20 -30 -40 -50 -60 9.4
14.7
P=.0068
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 Normal 18.6
P=.1571
† 12.3
11.5
OAB ‡ Placebo (n=421) Tolterodine LA (n=429) 18.1
P=.0012
P=.0225
Rackley et al.
Urology
. 2006;67:731-736.
Individual Agents Advantages and Drawbacks
Oxybutynin - ER
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Advantages
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Widest range of dose titration
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Only compound approved for “high dose” administration
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Drawbacks
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Effects on cognitive function
Tolterodine
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Advantages
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Long safety record
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Number 1 prescribed drug New CNS data favorable Data on male OAB
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Drawbacks:
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Lack of titration
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Mild increase in QT interval at super therapeutic doses
Trospium
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Advantages
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No hepatic metabolism
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Less drug-drug interactions
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Less crossing of blood-brain barrier
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? Clinical correlation at this time
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Higher urine concentration
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? Clinical meaning
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Drawbacks BID dosing No dose titration Slight increase in heart rate
Solifenicin
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Advantages
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Dose titration
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Relatively low dry mouth incidence
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Drawbacks
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Mild increase in QT interval at super therapeutic doses
Antimuscarinics Summary
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Efficacy among antimuscarinic agents is similar
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There are several different advantages (some theoretical) which may influence drug choice in a particular patient
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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 Prostate Condition: BPH Term used and reserved for the typical histological pattern that defines the disease Pharmacologic Therapy for BPH: alpha-Blockers 5-ARIs BPH = benign prostatic hyperplasia; OAB = overactive bladder; 5-ARI = 5-alpha-reductase inhibitor.
Abrams P et al. Urology. 2003;61:37-49.
Timing of combination treatment
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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
Studies 037 and 041 (N = 745)
Tolterodine ER * Placebo
IMPACT study † (N = 155)
Tolterodine ER * 1.3 (1/77) 0.0 (0/86) 0.8 (3/371) 0.5 (2/374) 0.0
0.0
0.0
0.0
*Tolterodine ER 4 mg/d.
† Open-label study.
1.3 (2/155) 0.0
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
Reported urinary AEs Urinary retention Urinary flow decreased Discontinued due to AE Catheterisation necessary (AUR)
Placebo (n = 220)
4 3 1
Tolterodine ER (n = 216)
4 2 2
Tamsulosin (n = 215)
0 0 0 2 1 0 0 1 0
Tolterodine ER/ Tamsulosin (n = 225)
2 2 0 1 1 Kaplan SA et al. JAMA. 2006;296:2319-2328.
Concerns about the risk of AUR
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Several recent clinical trials have refuted But, given the exclusion criteria should be considered
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Exclusion criteria for PVR in clinical trials - greater than 30-40% of maximum capacity - or 50-200ml
Concerns about the risk of AUR
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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
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Available data suggests that antimuscarinics are safe in men with OAB + BOO, but PVR should be considered
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Optimal way to use + alpha blockers needs to be sorted out
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It should be evaluated which patient benefit from adding of antimuscarinics initially in real life practice