dr stephen jeffery groote schuur hospital cape town recent advances in the management of the...
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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