update on oab joon chul kim the catholic university of korea

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.

First Sensation

Urge: A physiological desire to void• Gradual onset • Increases as a function of bladder volume• Can usually be deferred with appropriate strategies

Time

Bla

dd

er V

olu

me

(—)

Urg

e Inten

sity

Intervoid Interval

Vo

lum

e Vo

ided

Desire to Void (Urge to Void) and Normal Micturition Process

Intensity of desire to void Void

Chapple CR et al. BJU Int. 2004; 94:738-744.

100 cc 300 – 500 cc

Void(voluntary and/or

involuntary)

Bla

dd

er

Vo

lum

e (—

)In

tens

ityUrgency: Micturition Process in OAB

Desire to Void UrgencyPresumed Normal

Void Volume

Reduction ofIntervoid Interval

Reduction in Volume VoidedDue to Urgency

Time


Increased Frequency

and Reduced

Intervoid Interval

Urgency Drives the Other Symptoms of OAB

Nocturia

Urgency

1

Incontinence

Reduced Volume Voided per Micturition

1

2 2

1. Proven direct effect2. Effect correlated with urgency but inconsistent due to multifactorial etiology of the symptom


Pre

vale

nce

,* %

Men

Women

*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

The Overall Prevalence of OAB in Korea was 12.2% (10.0% Men and 14.3% Women)

0

5

10

15

20

25

Korea

Prevalence of OAB by Gender in Korea

Pre

vale

nce

of

OA

B,

%

Age Group, years

0

5

10

15

20

25

30

18-29

30-34

35-39

40-44

45-49

50-54

55-59

60-64

65-69

>=70

Total Men Women

Prevalence of OAB by Gender in Korea

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 BID-TID• Oxybutynin ER QD• Tolterodine IR/ER BID / QD• Trospium BID / QD*• Solifenacin 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– Delivery system– Bioavailability

• Receptor selectivity• Chemical structure

– Permeability• Dose titration

– 50-60% of patients will choose higher dose

Produce a number of clinically measurable and theoretical differences

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

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


-19.6

-17

-12.8

-8

1.53

2.12

-62.7

-65

-42.5

-40

1.48

1.63



-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.

Efficacy of Antimuscarinic Agents vs Placebo

Side Effects: Dry Mouth Incidence

Drug Placebo

Oxybutynin ER 10mg 28.1-29.7% n.a.

Tolterodine ER 4mg 23% 8%

Oxybutynin TDS 9.6% 8.3%

Solifenicin 5 mg 14% 4.9%

Solifenicin 10 mg 21.3% 4.9%

Darifenicin 7.5 mg 18.8% 13.2%

Darifenicin 15 mg 31.3% 13.2%

Ratio

2.9

1.2

2.9

4.3

1.4

2.4

Side Effects: Constipation Incidence

Drug Placebo

Oxybutynin ER 10mg 6.4-7.0% n.a.

Tolterodine ER 4mg 6% 4%

Oxybutynin TDS <2% <2%

Solifenicin 5mg 7.2% 1.9%

Solifenicin 10 mg 7.8% 1.9%

Darifenicin 7.5mg 14.8% 6.7%

Darifenicin 15mg 21.3% 6.7%

Ratio

1.5

~1

3.8

4.1

2.2

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

P<0.0001

Mean baseline: 6.156.03

End of study mean: 2.243.30

†Flexible dosing with solifenacin 5 or 10mg. Patients were allowed to dose increase at wk 4 and increase/decrease at wk 8

SolifenacinPlacebo

Serels S et al. Urology 2006; 68 (suppl 5a): 73 MP-04.11

Mea

n c

han

ge

fro

m

bas

elin

e to

en

dp

oin

t

n=336

-2.73

n=348 †

-3.914

3

2

1

0Episodes

63.6%

45.3%

Improvement in IUSS Score: Baseline to End of Study

Serels S et al. Urology 2006; 68 (suppl 5a):73 MP-04.11

0.3%

Lower IUSS score indicates reduced urgencyIUSS score

Baseline End of Study

Solifenacin


Placebo

Pe

rce

nt

100

90

80

70

60

50

40

30

20

10

0

2.4%

22.0%

63.6%

12.0%

6.8%

56.0%

50.2%

5.9%

18.7%

67.8%

13.3%0.3%

18.6%

61.6%

19.5%

0 = None

1 = Mild

2 = Moderate

3 = Severe

Improvement in Urgency Perception Score: Baseline to End of Study

Serels S et al. Urology 2006; 68 (suppl 5a):73 MP-04.11

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


Solifenacin


Placebo

Pe

rce

nt

Higher UPS score indicates reduced urgency

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%

-60

-40

-30

-20

-10

0

Tolterodine LA Nighttime Dosing Reduced 24-Hour Frequency

14.7

P=.0068

9.4

Study 037

11.518.1

P=.0012

P=.0225

-50

Placebo (n=421)

Tolterodine LA (n=429)

Total* OAB‡

Med

ian

Red

uct

ion

in

Mic

turi

tio

ns,

%

18.612.3

P=.1571

Normal†

Rackley et al. Urology. 2006;67:731-736.

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

Individual AgentsAdvantages 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

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-Blockers5-ARIs

Pharmacologic Therapy for BPH:

alpha-Blockers5-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

• 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

*Tolterodine ER 4 mg/d.†Open-label study.

In Men With OAB, Treatment With Tolterodine Was Not Associated With Increased Incidence of AUR

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)

0.00.0

Studies 037 and 041 (N = 745)Tolterodine ER*

Placebo 0.8 (3/371)0.5 (2/374)

0.00.0

IMPACT study† (N = 155)Tolterodine ER* 1.3 (2/155) 0.0

Subanalyses of Male Patients With OAB in Tolterodine ER Studies

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)

Reported urinary AEs 4 4 0 2

Urinary retention 3 2 0 2 Urinary flow decreased

1 2 0 0

Discontinued dueto AE

2 1 0 1

Catheterisation necessary (AUR) 0 1 0 1

Kaplan SA et al. JAMA. 2006;296:2319-2328.

• 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

Concerns about the risk of AUR

Jaffe WI, Te AE, Current Urology Reports 2005Low PVR: <40% of functional capacity

Recommendation

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

update on oab joon chul kim the catholic university of korea

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