Transcript PROF. Rosita Aniuliene LITHUANIAN UNIVERSITY OF HEALTH

PROF. Rosita Aniuliene
LITHUANIAN UNIVERSITY OF HEALTH SCIENCES
President of Lithuanian Association of Urogynecology
Lithuanian Statistics, 2009
Population
3,5 million
GDP per capita in USD
17,7
Total expenditures on health as %
of GDP
5,9
Literacy
99,6%
Birth rate per 1,000 pop.
9,11
Mortality per 1,000 pop.
11,18
Natural increase per 1000 pop.
- 2,6
Life expectancy (years)
74,9 (male-70, female-80)
Total fertility rate
1,23
https://www.cia.gov/cia/publications/factbook/reference_maps/europe.html
http://hdr.undp.org/hdr2006/statistics/indicators/50.html
Perinatal mortality
14
12
Perinatal mortality
Stillbirths
12,5
10,9
10
10,3
10,3
10
9,63
9,3
8
8,1
6
6,9
6
4
6,5
6,4
6,4
5,7
8,03
8,3
7,6
7,26
7,38
6,61
6,39
5,3
5,46
5,2
5,3
4,95
4,36
4,66
2
0
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Infant Mortality 4,9/1000 live births 2008
Maternal mortality in Lithuania
in 1989-2008 (100 000 live births)
50
45
44,4
40
35
30
25
20
15
10
5
0
29,3
27,4
19,5
21,3
19,1
23,8
17,9
18,9
20,4
16,4
13,811,8
12,9
13,4
3,3
6,2
8,6
0
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Maternal Mortality in Lithuania and the
world
100%
90%
80%
70%
60%
50%
Other direct causes
40%
Abortion
Indirect causes
30%
Obstructed labour
20%
Eclampsia
10%
Sepsis
Heamorrhage
0%
World
Lithuania
"Maternal health around the world" poster. World Health Organization and World Bank, 1997
Overactive bladder syndrome
 Symptom complex, not a urodynamic diagnosis (ICS)
 “Urgency with or without urge incontinence, ussually
with frequency and nocturia” (Abrams et al.. 2002)
Detrusor overactivity
 “A urodynamic observation characterised by
involuntary detrusor contractions during the filling
phase which may be spontaneous or provoked”
(Abrams et al., 2002)
Diagnostic
 History-taking and physical examination
 Assessment of pelvic floor muscles
 Assessment of prolapse
 Urine testing
A urine dipstick test should be undertaken in all
women presenting with Ul to detect the presence of
blood, glucose, protein, leucocytes and nitrites in the
urine.
Diagnostic
 Assessment of residual urine
 Symptom scoring and quality-of-life assessment
 Bladder diaries
Women should be encouraged to complete a minimum
of 3 days of the diary covering variations in their usual
activities, such as both working and leisure days.
Diagnostic
 Pad testing
Pad tests are not recommended in the routine assessment of women
with Ul.
 Urodynamic testing
The use of multi-channel cystometry, ambulatory urodynamics or video
urodynamics is not recommended before starting conservative
treatment.
 Imaging
Imaging (magnetic resonance imaging, computed tomography, X-ray) is
not recommended for the routine assessment of women with Ul.
Ultrasound is not recommended other than for the assessment of
residual urine volume.
Non-invasive treatment for OAB
 Lifestyle modification
 Behavioural intervention
 Electrical stimulation
 Acupuncture
 Hypnotherapy
 Drugs
Life style intervention
(fluid intake, caffeine, tea, coke, water reduction)
 Significant reduction in urination frequency and nocturia with 25%
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


reduction in fluid intake, increasing fluid intake worsened frequency
(Haskim et al., 2008)
High caffeine intake is an independent risk factor for detrusor
overactivity. The relationship may be dose dependent (Myers et al.,
2008)
Tea drinking (but not coffee) epidemiologically associated with all
forms of incontinence (Hannested et al., 2003)
Diet Coke and caffeine – free diet coke cause greater urination and
frequency than carbonated water or classic coke (Cartwright, ICS 2007)
Weigt loss decreases incontinence in moderately and morbidly obese
women (4th ICI 20008, Level 1)
Pelvic floor muscle training
Bladder training
4th ICI 2008 (ICI 0 imperial chemical industry)
 PFMT is better than no treatment, placebo drug or inactive control
treatment for women with SUI, urge or mixed urinary incontinence
(LEVEL 1)
 Supervise PFMT should be offered as a first line therapy in all patients
with SUI, urge or mixed urinary incontinence (GRADE A)
 Not clear whether body training is more effective than drug therapy for
women with detrusor overactivity or urge urinary incontinence (LEVEL
1)
 In a choice between body training and anticholinergic drug for women
with detrusor overactivity or urge urinary incontinence, either may be
effective (GRADE B)
Behavioral intervention
 Improves central control
 Underlying psychological abnormality
 Learn/re-learn both consious and unconscious
physiological proccesses
 Avoids side effects of drugs
Pharmacological treatment of OAB
 Antimuscarinics
 Drugs with mixed action
 Antidepresants
 Alpha – adrenoreceptor antagonists
 Beta – adrenoreceptor agonists
 Drugs acting on membrane channels
 Toxins
 Future drugs
Pharmacological treatment of OAB
 Antimuscarinic agents
 After lifestyle changes antimuscarinic agents are the most common
and currently the most widely used therapy for OAB syndrome
(Anderson, 2004)
 Antimuscarinics
 Reduce intra-vesical pressure
 Increase compliance
 Raise volume thershold for micturition
 Reduce uninhibited contractions (Abrams et al., 2002)
OAB: antimuscarinics
 Oxybutinin (oral, transdermal, intra-vesical, gel)
 Ditropan 2,5–5 mg x3/day per os
 Kentera-wk 3,9 mg x 2/wk transdermal patch
 Lyrinel XL 5-20 mg per day intra-vesical
 Oxybutinin in water 10 mg transdermal gel
 Tolterodine (oral)
 Detrusitol 2 mg x 2/day per os
 Detrusitol XL 4 mg x 1/day per os
 Propiverine (oral)
 Detrunorm 15 mg
OAB: antimuscarinics
 Solifenacin (oral)
 Vesicare 5-10 mg per os
 Trospium (oral)
 Regurin 20-60 mg per os
 Darifenacin (oral)
 Emselex, Enablex 7,5-15 mg per os
 Fesoterodine (oral)
 Toviaz 4-8 mg per os
Antimuscarinic side effects
 Dry mouth
 Constipation
 Blurred vision
 Somnolence
Can drug treatment be improved?
What is desirable in a drug?
 Specificity of action
 Maximisation of efficacy-dose relationship
 Reduction of adverse side effects
 Enhancement of patient compliance
 Controlled administration of a therapeutic dose at
a desirable rate of delivery
 Maintenance of drug concentration within optimal
therapeutic range
How do we improve compliance and
persistence?
 Extended release formulations
 Oxybutynin
 Tolterodine
 Propiverine
 Trospium
Lyrinel XL
Detrusitol XL
Detrunorm XL
Regurin XL
 Selective M3 antagonists
 Solifenacin
Vesicare
 Darifenacin Emselex
 Bladder selective agents
 Fesoterodine Toviaz
 Alternative delivery mechanisms
 Oxybutynin patch
 Oxybutinin gel
Kentera
Gelnique
Extended release formulations
OPERA TRIAL
OAB: Performance of extended release agents
Oxybutynin ER (10 mg/day) vs. Tolterodine ER (4 mg/day)
 Improvement in urge incontinence similar in both groups
 Oxybutynin more effective in reducing frequency
 No episodes of urinary incontinence (dry): Oxybutynin
ER:23% vs. Tolterodine ER:16,8%
 Dry mouth was more common with Oxybutynin ER, but
tolerability was otherwise comparable
Diokno et al., 2003
STAR study – efficacy summary
 Solifenacin equivalent to  Solifenacin superior to
Tolterodine ER
Tolterodine ER
 Micturition frequency
 Urgery episodes (p=0,0353)
(p=0,0681)
 Nocturia (p=0,7298)
 % dry (p=0,0059)
 Incontinence (p=0,0059)
 Pad use (p=0,0023)
 Volume voided (p=0,00103)
 Patient perception of bladder
condition (p=0,0061)
Darifenacin
 Quality of life assessed using KHQ in 2 year open
label study
 7,5mg/15mg: 303 patients/85 elderly, 41 men
 2/3 of Darifenacin continuation groups either satisfied
or extremely satisfied with treatment
Dwyer et al., 2008
 Darifenacin did not impair cognition
Kay and Ebinger, 2008
Trospium ER
 12 weeks randomised trial
 989 women (Trospium = 484, placebo = 505)
 60 mg oral per day
 End point: No of toilet voids, urge urinary incontinence
episodes/day
 Significantly greater mean reductions (p=0,0001)
 Adverse events: dry mouth (11,4%), constipation (8,9%)
Sand et al., 2009
Fesoterodine
 12 week post hoc analysis from 2 clinical trials
 4/8 mg fesoterodine or tolterodine ER 4 mg or placebo:
1548 women
 3 day bladder diary at baseline, 2 weeks and 12 weeks
 Fesoterodine 8 mg more efficacious than 4 mg and
tolterodine ER in improving
 Urgency urinary incontinence episodes
 Continent days/week
Sand et al., 2009
Oxybutinin Gel: Gelnique
 12 week parallel group, double-blind placebo controlled
study
 789 patients in 76 centers (89,2% women)
 Randomised to: oxybutynin gel, placebo
 Significant reduction in:
 Urge incontinence episodes (-3.0, p<0,0001)
 Frequency (-2,7, p=0,0017)
 Significant increase in voided volume (21 ml; p=0,0018)
 Dry mouth higher with oxybutynin (6,9% vs. 2,8%)
 No difference in skin site reaction (5,4% vs. 10%)
Staskin et al., 2009
Desmopressin
 Double-blind, placebo controlled
 Oral Desmopressin 0,2 mg
 Adults with OAB
 Increase in the time to first urgency episode compared to placebo
 Subjective improvement in frequency, urgency, QOL
 Side effects
 All mild
 Headache being the commonest
 No hyponatraemia was recorded
Haskin et al., 2009
LEVEL 1 drugs
4th ICI, 2008
Drug
Level of evidence
Grade of
recommendation
Darifenacin
1
A
Oxybutynin
1
A
Propiverine
1
A
Solifenacin
1
A
Fesoterodine
1
A
Tolterodine
1
A
Trospium
1
A
Which drug – what evidence?
Drug
Advantages
Disadvantages
Oxybutynin IR
Flexible dosing, rapid,
onset of action, cheap
Persistence limited by dry
mouth
Oxybutynin ER
Flexible dosing
Cognitive impairment
Oxybutynin TDS
Placebo rate of side
effects
15-20% rate of pruritus
Tolterodine ER
Well tolerated
Single dose
Solifenacin
Superior efficacy to
Tolterodine ER
High rate of dry mouth at
10 mg dose
Darifenacin
Low rate of cognitive
impairment
High rate of constipation
Trospium
Does not cross blood
brain barrier
Single dose
Propiverine
Well tolerated
Efficacious only for
frequency
Fesoterodine
Flexible dosing
Limited experience
OAB: new directions
 Calcium antagonists
 Potassium channel openers
 NK1/NK2 receptor antagonists
 B3 adrenergic receptor agonist
 Vitamin D3 receptor analogues
 Combination therapy
 Antimuscarinic and alfa antagonist
Detrusor Overactivity: Botulinum Toxin
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59 patients with detrusor overactivity
Botox (200/300µ) or placebo
Single treatment, randomised, placebo controlled study
Significant reduction in incontinence episodes
Significant improvement in QOL
Schurch et al., 2005
 Systemic review of 18 papers in detrusor overactivity (normal and
idiopathic)
 40-80% of patients subjectively dry
Karsentry et al., 2008
 Multicenter double blind placebo controlled trial
 Dose dependent efficacy in OAB
 No benefit in efficacy of doses > 150µ
Brubaker et al., 2008
Detrusor overactivity: surgery
 Augmentation cystoplasty
 Detrusor myectomy
 Urinary diversion (to sigma)
NICE guidelines : overactive bladder
 Caffeine reduction
 6 weeks bladder retraining
 Oxybutynin IR first line
 Darifenacin, salifenacin, tolterodine, trospium or
oxybutynin ER/transdermal second life
 Topical oestrogens
 Sacral neuromodulation
NICE – National Institute for health and clinical excellence
NICE guidelines: detrusor overactivity
 Botulinum toxin A should be used in the treatment of
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idiopathic detrusor overactivity who have not responded to
conservative therapy
Use not currently licensed in UK for detrusor overactivity
Botulinum toxin B is not recommended for idiopathic OAB
Sacral nerve stimulation is recommended in women who
have not responded to conservative therapy
Sacral nerve stimulation should be offered based on the
response to preliminary percutaneous nerve evaluation
NICE guidelines: detrusor overactivity
 Data is currently inadequate to support the use of PTNS
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(percuatneous tibial nerve stimulation)
Augmentation cystoplasty should be restricted to those
women who have failed conservative therapy
Should be able to self catheterize and should be warned
about long-term complications
Role of detrusor myectomy not established
Urinary diversion should only be considered if sacral
nervous stimulation and cystoplasty are not appropriate
Conclusions
 Conservative therapy is indicated as primary treatment
 Antimuscarinic agents are most commonly used drugs
 Limited by tolerability and efficacy
 Significant effect on compliance and resistance
 Newer bladder specific agents may offer advantages
 Possible to individualise treatment for each patient
 New drugs currently remain under development
 Neuromodulation and botulinum toxin may be useful in patients with
interactable detrusor overactivity
 Reconstructive surgery should be considered in those women who have
failed other treatments
 Patients can be advised to reduce their fluid input by 25% to help control
all OAB symptoms, providing they do not drink <1l/day, remembering
that 300-500ml of fluids is provided by food
General conclusions
 Anticholinergics are the gold standard for the
treatment of OAB
 Patient history, examination, urinanalysis,
micturation diary is very important
 Bladder training programs
 Special treatment needs for transsexuals male-tofemale pudendal nerve damage during operation,
hormone disorders and aging (prostate problem)
Thank you for attention