Evidence-Based Treatment of Overactive Bladder Syndrome (OAB)

1. Evidence based treatment of OAB PROF. Rosita Aniuliene LITHUANIAN UNIVERSITY OF HEALTH SCIENCES President of Lithuanian Association of Urogynecology

3. KAUNO MEDICINOS UNIVERSITETO AKUŠERIJOS IR GINEKOLOGIJOS KLINIKA

5. Lithuanian Statistics, 2009 https://www.cia.gov/cia/publications/factbook/reference_maps/europe.html http://hdr.undp.org/hdr2006/statistics/indicators/50.html

6. Perinatal mortality

7. Infant Mortality 4,9/1000 live births 2008

8. Maternal mortality in Lithuania in 1989-2008 (100 000 live births)

9. Maternal Mortality in Lithuania and the world "Maternal health around the world" poster. World Health Organization and World Bank, 1997.

10. 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)

11. Detrusor overactivity • “A urodynamic observation characterised by involuntary detrusor contractions during the filling phase which may be spontaneous or provoked” (Abrams et al., 2002)

12. 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.

13. 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.

14. 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.

15. Non-invasive treatment for OAB • Lifestyle modification • Behavioural intervention • Electrical stimulation • Acupuncture • Hypnotherapy • Drugs

16. Life style intervention (fluid intake, caffeine, tea, coke, water reduction) • Significant reduction in urination frequency and nocturia with 25% 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)

17. Pelvic floor muscle training Bladder training4th 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)

18. Behavioral intervention • Improves central control • Underlying psychological abnormality • Learn/re-learn both consious and unconscious physiological proccesses • Avoids side effects of drugs

19. Pharmacological treatment of OAB • Antimuscarinics • Drugs with mixed action • Antidepresants • Alpha – adrenoreceptor antagonists • Beta – adrenoreceptor agonists • Drugs acting on membrane channels • Toxins • Future drugs

20. 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)

21. 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

22. 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

23. Antimuscarinic side effects • Dry mouth • Constipation • Blurred vision • Somnolence Can drug treatment be improved?

24. 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

25. How do we improve compliance and persistence? • Extended release formulations • OxybutyninLyrinel XL • TolterodineDetrusitol XL • PropiverineDetrunorm XL • TrospiumRegurin XL • Selective M3 antagonists • SolifenacinVesicare • DarifenacinEmselex • Bladder selective agents • FesoterodineToviaz • Alternative delivery mechanisms • Oxybutynin patch Kentera • Oxybutinin gel Gelnique

26. Extended release formulations OPERA TRIALOAB: 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

27. STAR study – efficacy summary • Solifenacin equivalent to Tolterodine ER • Micturition frequency (p=0,0681) • Nocturia (p=0,7298) • Solifenacin superior to Tolterodine ER • Urgery episodes (p=0,0353) • Incontinence (p=0,0059) • % dry (p=0,0059) • Pad use (p=0,0023) • Volume voided (p=0,00103) • Patient perception of bladder condition (p=0,0061)

28. 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

29. 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

30. 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

31. 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

32. 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

33. LEVEL 1 drugs4th ICI, 2008

34. Which drug – what evidence?

35. 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

36. DetrusorOveractivity: Botulinum Toxin • 59 patients with detrusoroveractivity • 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 detrusoroveractivity (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

37. Detrusoroveractivity: surgery • Augmentation cystoplasty • Detrusor myectomy • Urinary diversion (to sigma)

38. 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

39. NICE guidelines: detrusoroveractivity • Botulinum toxin A should be used in the treatment of 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

40. NICE guidelines: detrusoroveractivity • Data is currently inadequate to support the use of PTNS (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

41. 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 interactabledetrusoroveractivity • 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

42. 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-to-female pudendal nerve damage during operation, hormone disorders and aging (prostate problem)

43. Thank you for attention