Dr Stephen JefferyDr Stephen Jeffery

Groote Schuur HospitalGroote Schuur Hospital

Cape TownCape Town

Recent Advances in the Management

of the Overactive Bladder

Relative proportions of Relative proportions of incontinence by ageincontinence by age

Per

cen

tag

e o

f P

erce

nta

ge

of

inco

nti

nen

t w

om

en (

%)

inco

nti

nen

t w

om

en (

%)

Stress urinary incontinence (SUI)

Urge urinary incontinence (UUI))

Age (years)Age (years)n=6876n=6876

Hannestad YS et al. Hannestad YS et al. J Clin EpidemiolJ Clin Epidemiol 2000; 53: 1150–1157. 2000; 53: 1150–1157.Reproduced with permission from Professor David Castro-Diaz. Reproduced with permission from Professor David Castro-Diaz.

Total

20–2

425

–29

30–3

4

35–3

9

40–4

4

45–4

9

50–5

4

55–5

9

60–6

465

–69

70–7

4

75–7

9

80–8

4

85–8

990

+

Mixed urinary incontinence (MUI)

80

60

40

20

0

100%

Why do patients stop taking Why do patients stop taking antimuscarinic therapy?antimuscarinic therapy?

2

18

9

14

10

10

13

57

47

50

50

50

58

61

66

30

39

24

31

30

26

24

16

4

3

7

4

2

3

2

9

8

0% 10% 20% 30% 40% 50% 60% 70% 80% 90%

Insufficient efficacy Intolerable side effects Dosing convenience Other reasons

Female ≤55 Years of Age

Female >55 Years of Age

Male

In Employment/Activity Working

Retired/Unemployment

OAB Dry

Pure UUI

Mixed UI

Reference: Global Market Research Study (Yamanouchi Pharma Ltd, December 2003:n=736).

International web survey

What Percentage of Urge Incontinent Patients What Percentage of Urge Incontinent Patients achieve Long-Term Benefit From Drugs?achieve Long-Term Benefit From Drugs?

Kelleher et al. Br J Obstet Gyn. 1997;104:988-93..

0

10

20

30

40

50

60

70

80

90

100

All Patients With DO and UI

CuredCured/Improved

RespondersUsing Drugs>6 Months

Urg

e In

con

tin

ent

Pat

ien

ts (

%)

Persistence on Specific Medications for OAB Based on Prescription Data

Chui M, et al. Value in Health. 2004;7:366.

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12

Tolterodine

Tolterodine XL

Oxybutynin

Oxybutynin XL

Per

cen

t

Months

SacroneuromadulationSacroneuromadulation

PTNSPTNS

AcupunctureAcupuncture

PhysiotherapyPhysiotherapy

BotoxBotox

When Anticholinergics Fail

IntroductionIntroductionOptionsOptions

NeuromodulationNeuromodulation Augmentation / Ileocystoplasty Augmentation / Ileocystoplasty

Botulinum Toxin

IntroductionIntroduction

Schurch 2000Schurch 2000 21 Neurogenic Detrusor Overactivity (NDO)21 Neurogenic Detrusor Overactivity (NDO) Botox 200-300uBotox 200-300u 17/19 achieved continence17/19 achieved continence Bladder capacity increased 296ml to 480mlBladder capacity increased 296ml to 480ml Reflex volume 215ml to 415 mlReflex volume 215ml to 415 ml

Schurch et al . J. Urol 2000; 164: 692-697

21st Century Penicillin for the Bladder !

IntroductionIntroduction

Clostridium botulinum Gram positiveGram positive

AnaerobicAnaerobic

1 g kills I million 1 g kills I million peoplepeople

Introduction

19461946Purified botulinum toxin type A in Purified botulinum toxin type A in a crystalline form (Schantz)a crystalline form (Schantz)

1960s1960s Neuromuscular toxin (Schantz)Neuromuscular toxin (Schantz)

19801980 Strabismus (Scott)Strabismus (Scott)

TypesTypes

7 Subtypes A, B, C, D, E, F, G7 Subtypes A, B, C, D, E, F, G

Only A and B available commerciallyOnly A and B available commercially

TypesTypes

Botulinum A Botox® (Allergan Inc.) Dysport® (Ipsen Pharma)

Botulinum B Neurobloc ® (Solstice Neurosciences Inc.)

Botulinum Toxin A

Botox® Dysport ®

MW (kDa)MW (kDa) 900 900

Target proteinTarget protein SNAP 25 SNAP 25

Units / vialUnits / vial 100 500

Price / vialPrice / vial ~£135 ~£173

Dose IDODose IDO ~200 units ~500 unit

NDONDO ~300 units ~750 units

Dosages Dosages

Botox NDO 300u IDO 200u

Dysport 500 to 1000u Fewer studies

Administration

Rigid

Flexible

Administration

Administration

Normal SalineNormal Saline

Do not shake Do not shake

Administration

Trigone or not?Trigone or not? Lucioni et alLucioni et al

• 16 intratrigonal and 24 trigone sparing16 intratrigonal and 24 trigone sparing• Similar results at 3 weeks & 6 months on UDI and Similar results at 3 weeks & 6 months on UDI and

SIIQ SIIQ Karsenty et alKarsenty et al

• VCU 1hr before & @ 6 weeksVCU 1hr before & @ 6 weeks• N=10 N=10 • No new cases of reflux with similar efficacyNo new cases of reflux with similar efficacy

Lucioni et al Can J Urol 2006;13(5): 3291-5.Karsenty et al J Urol 2007; 177(3):1011-4

Contraindications

Neuromuscular DisordersNeuromuscular Disorders

Previous Failure of Botulinum InjectionsPrevious Failure of Botulinum Injections

Bleeding TendenciesBleeding Tendencies

Efficacy: NDO

Efficacy: NDOEfficacy: NDO

Schurch 2005Schurch 2005 N=59 (NDO)N=59 (NDO) Double blind placebo controlled parallel Double blind placebo controlled parallel

group studygroup study

Schurch et al J Urol 2005; 174: 196-200.

BOTOX

Efficacy: NDOEfficacy: NDO

Schurch 2005Schurch 2005

Schurch et al J Urol 2005; 174: 196-200.

Dose F u Urodynamics Incontinence episodes

Dry QOL

300u (n=19)

200u (n=19)

placebo (n=21)

6 m Increase in MCC, RVDecrease in Max Det Pressure

50 % reduction for 200 and 300u

49% Mean I-QOL scoes improved(p<0.002)

BOTOX

Increase in Maximum Cystometric Increase in Maximum Cystometric Capacity (MCC)Capacity (MCC)

Schurch et al J Urol 2005; 174: 196-200.

0

50

100

150

200

250

Week 2 Week 6 Week 24

200u300uPlacebo

Mea

n in

crea

se in

MC

C f

rom

bas

elin

e (in

ml)

Efficacy: NDOEfficacy: NDO

Reitz 2004 Large European study

10 Centres

N=231(NDO)

12 week and 24 week follow up

Reitz et al Eur Urol 2004; 45: 510-515.

BOTOX

Efficacy: NDOEfficacy: NDO

Reitz et al 2005Reitz et al 2005

Dose F u Urodynamics Dry

Botox 300u 3m&9 m

Increase in MCC, RVand compliance

79% @ 3 m31% @ 9 m

BOTOX

Study N Dose FU Improved Dry Urodynamics

Kuo 2005 24 BTX 200u

3m & 6m

70 % improved 25% Increased Reflex volume and MCC

Klaphajone 2005

10 NDO

BTX300

9 70% Increased MCC, compliance, reflex volume, decrease in detrusor pressure

Schulte-Baukloh 2006

16 MS BTX300

Reduction in daily pad use from 1.75 to 1.08 (4 weeks) and 0.63 (3 months)

Increased Reflex volume and MCC. Decreased Detrusor pressure

Efficacy: NDOEfficacy: NDO BOTOX

Introduction

19461946Purified botulinum toxin type A in Purified botulinum toxin type A in a crystalline form (Schantz)a crystalline form (Schantz)

1960s1960s Neuromuscular toxin (Schantz)Neuromuscular toxin (Schantz)

19801980 Strabismus (Scott)Strabismus (Scott)

TypesTypes

7 Subtypes A, B, C, D, E, F, G7 Subtypes A, B, C, D, E, F, G

Only A and B available commerciallyOnly A and B available commercially

TypesTypes

Botulinum A Botox® (Allergan Inc.) Dysport® (Ipsen Pharma)

Botulinum B Neurobloc ® (Solstice Neurosciences Inc.)

Botulinum Toxin A

Botox® Dysport ®

MW (kDa)MW (kDa) 900 900

Target proteinTarget protein SNAP 25 SNAP 25

Units / vialUnits / vial 100 500

Price / vialPrice / vial ~£135 ~£173

Dose IDODose IDO ~200 units ~500 unit

NDONDO ~300 units ~750 units

Dosages Dosages

Botox NDO 300u IDO 200u

Dysport 500 to 1000u Fewer studies

Administration

Rigid

Flexible

Administration

Administration

Normal SalineNormal Saline

Do not shake Do not shake

Administration

Trigone or not?Trigone or not? Lucioni et alLucioni et al

• 16 intratrigonal and 24 trigone sparing16 intratrigonal and 24 trigone sparing• Similar results at 3 weeks & 6 months on UDI and Similar results at 3 weeks & 6 months on UDI and

SIIQ SIIQ Karsenty et alKarsenty et al

• VCU 1hr before & @ 6 weeksVCU 1hr before & @ 6 weeks• N=10 N=10 • No new cases of reflux with similar efficacyNo new cases of reflux with similar efficacy

Lucioni et al Can J Urol 2006;13(5): 3291-5.Karsenty et al J Urol 2007; 177(3):1011-4

Contraindications

Neuromuscular DisordersNeuromuscular Disorders

Previous Failure of Botulinum InjectionsPrevious Failure of Botulinum Injections

Bleeding TendenciesBleeding Tendencies

Efficacy: NDO

Efficacy: NDOEfficacy: NDO

Schurch 2005Schurch 2005 N=59 (NDO)N=59 (NDO) Double blind placebo controlled parallel Double blind placebo controlled parallel

group studygroup study

Schurch et al J Urol 2005; 174: 196-200.

BOTOX

Efficacy: NDOEfficacy: NDO

Schurch 2005Schurch 2005

Schurch et al J Urol 2005; 174: 196-200.

Dose F u Urodynamics Incontinence episodes

Dry QOL

300u (n=19)

200u (n=19)

placebo (n=21)

6 m Increase in MCC, RVDecrease in Max Det Pressure

50 % reduction for 200 and 300u

49% Mean I-QOL scoes improved(p<0.002)

BOTOX

Increase in Maximum Cystometric Increase in Maximum Cystometric Capacity (MCC)Capacity (MCC)

Schurch et al J Urol 2005; 174: 196-200.

0

50

100

150

200

250

Week 2 Week 6 Week 24

200u300uPlacebo

Mea

n in

crea

se in

MC

C f

rom

bas

elin

e (in

ml)

Efficacy: NDOEfficacy: NDO

Reitz 2004 Large European study

10 Centres

N=231(NDO)

12 week and 24 week follow up

Reitz et al Eur Urol 2004; 45: 510-515.

BOTOX

Efficacy: NDOEfficacy: NDO

Reitz et al 2005Reitz et al 2005

Dose F u Urodynamics Dry

Botox 300u 3m&9 m

Increase in MCC, RVand compliance

79% @ 3 m31% @ 9 m

BOTOX

Study N Dose FU Improved Dry Urodynamics

Kuo 2005 24 BTX 200u

3m & 6m

70 % improved 25% Increased Reflex volume and MCC

Klaphajone 2005

10 NDO

BTX300

9 70% Increased MCC, compliance, reflex volume, decrease in detrusor pressure

Schulte-Baukloh 2006

16 MS BTX300

Reduction in daily pad use from 1.75 to 1.08 (4 weeks) and 0.63 (3 months)

Increased Reflex volume and MCC. Decreased Detrusor pressure

Efficacy: NDOEfficacy: NDO BOTOX

What about Dysport in NDO?What about Dysport in NDO? Ruffion et al

45 NDO

Dysport 500 or 1000u

If unsuccessful further 1000u (24%)

76% dry

No difference between 500u and 1000u

Ruffion et al. BJU Int 2006; 97: 1030-1034

What about Dysport in NDO?What about Dysport in NDO? Ruffion et al

1 women muscle weakness

Mean duration• 1000u - 10.4 months• 500u - 4.83 months

Ideal dose ? 750u

Ruffion et al. BJU Int 2006; 97: 1030-1034

Study N Dose FU Improved Dry Urodynamics

Patki 37 Dysport 1000u

7 m Improved ICIQ

Reduced AC use by 80%

82% Increased MCC and decreased voiding pressure

Efficacy: NDOEfficacy: NDO Dysport

Efficacy: IDO

Efficacy IDO : RCTEfficacy IDO : RCT Sahai et alSahai et al

RCT 35 IDORCT 35 IDO Double blind placebo controlled studyDouble blind placebo controlled study 16 Botox 200u, 18 Placebo16 Botox 200u, 18 Placebo Significant improvements in frequency (p=0.003), urge incontinence Significant improvements in frequency (p=0.003), urge incontinence

(p=0.008) at 12 weeks(p=0.008) at 12 weeks

Sahai et al J Urol 2007; 177(6): 2231-36

BOTOX

4 weeks 12 weeks

MCC +144ml

(p<0.0001)

+96ml (p=0.0001)

Efficacy: IDOEfficacy: IDO

Popat 2004 44 NDO and 31 IDO

NDO 300u Botox

IDO 200u Botox

4 week and 16 week follow up

Popat et al J Urol 2005; 174: 984-989.

BOTOX

Dose FU Improved Dry Urodynamics ISC

NDOBTX 300u

4 m 70 % improved

4weeks

64% NDO

16weeks

55% NDO

Increased Reflex volume and MCC

69%

IDOBTX 200u

4m 4weeks

54% IDO

16weeks

57% IDO

19%

Efficacy: NDOEfficacy: NDO BOTOX

Popat et al J Urol 2005; 174: 984-989.

Percentage change in leak:Percentage change in leak:Popat et al.Popat et al.

0102030405060708090

100

4 weeks 16 weeks

NDO

IDO

Per

cen

tag

e ch

ang

e in

lea

k

Study N Dose FU Improved QOL Urodynamics Voiding Dysf

Schulte-Baukloh 2005

44 BTX 300u

9m Daily Pad use reduced 4.2 to 2.4 per day

Improvements in UDI-6, SSI, SII up to 6 months

Increased RV, MCC and reduced detrusor pressure

NoneNone

Werner 2005

26 BTX100

9 69% at 4 weeks

80% at 12

weeks

Improvement on all urge related parameters on KHQ

Increased MCC, compliance,

decreased DO,

2 ISC

Rajkumar 15 300u 6 Improved on all domains in KHQ and BFLUTS

Increased MCC, Increased MCC, FDV, Reflex FDV, Reflex

volumevolume

None

Efficacy: IDOEfficacy: IDO BOTOX

Weekly incontinence episodes

*

*

*

5.7

2.1

2.4

1.7

2.7

0

1

2

3

4

5

6

Pre 6 weeks 3 months 6 months 9 months

**

*

*

Efficacy: IDOEfficacy: IDO Dysport

Jeffery et al BJU 2007; 174: 984-989.

0

50

100

150

200

250

300

350

400

MCC FD Reflex volume

Pre 3 Months

Results: Urodynamics

Jeffery et al BJU 2007; 174: 984-989.

Results: Voiding Dysfunction

Pre6 weeks

3 months6 months

9 months

S1

0

42%36%

17% 18%

0

20

40

60

80

100

Jeffery et al BJU 2007; 174: 984-989.

Efficacy

Repeat Injections

Study N Dose FU Improved Urodynamics

Grosse 66Repeat

Botox 300u

Dysport750 u or

1000u

15m Subjective high satisfaction rates

Similar efficacy

Increased MCC and Reflex volume

Efficacy Repeat Injections: NDOEfficacy Repeat Injections: NDO

Grosse et al. Eur Urol 2005; 47: 653-659

Transient Muscle weakness in 4 patients after Dysport 1000u

Efficacy Repeat Injections: NDOEfficacy Repeat Injections: NDO

Grosse et al. Eur Urol 2005; 47: 653-659

0

2

4

6

8

10

12

14

Inj 1 to 2 Inj 2 to 3 Inj 3 to 4

Tim

e be

twee

n in

ject

ions

(in

m

onth

s)

Efficacy

Sensory Urgency

Study N Dose FU Improved QOL Urodynamics Voiding Dysf

Schulte-Baukloh 2005

7 BTX 300u

6m Daily Pad use reduced

Improved UDI -6, SII scores

No significant changes

NoneNone

Efficacy: No Do on CMGEfficacy: No Do on CMG

Schulte-Baukloh et al. Urology 2005; 66(1): 82-87

Long Term EfficacyLong Term Efficacy

Kuschel et alKuschel et al 2 yr follow up2 yr follow up Botox Botox 100 u N=26 N=26

• 11 single injection• 1 primary failure• 3 lost to follow up• 11 repeat injection

Long Term EfficacyLong Term Efficacy

Kuschel et alKuschel et al

11 single injection

4 very satisfied

7 had other treatments

Newer data: Site of injectionNewer data: Site of injection

Kuo et alKuo et al N=45N=45 Suburothelial vs Detrusor vs Trigonal InjectionSuburothelial vs Detrusor vs Trigonal Injection VCU at 3 month showed no refluxVCU at 3 month showed no reflux Success Success

• Suburothelial Suburothelial 80%80%• Detrusor Detrusor 93%93%• Trigonal InjectionTrigonal Injection 67%67%

CostCost EffectivenessEffectiveness

Kalsi et alKalsi et al IDO IDO ££745 per treatment745 per treatment NDO NDO ££874 per treatment874 per treatment

Viewed in the context of the alternativesViewed in the context of the alternatives SacroneuromodulationSacroneuromodulation CystoplastyCystoplasty

ConclusionConclusion

Botulinum Toxin A – highly effectiveBotulinum Toxin A – highly effective

Improvements in multiple parameters Improvements in multiple parameters

No loss of efficacy with repeat injectionsNo loss of efficacy with repeat injections

Main problem is voiding dysfunction Main problem is voiding dysfunction

IssuesIssues

Correct dose esp Correct dose esp dysportdysport

Trigonal injectionsTrigonal injections

Sphincter injectionsSphincter injections

No. and dilution of No. and dilution of injections injections