LUTS – Nocturia & Incontinence Recurrent UTI ’s

1. LUTS – Nocturia & IncontinenceRecurrent UTI’s St George Education Forum

2. LUTS = Lower Urinary Tract Symptoms • OAB = OverActive Bladder • Incontinence • Nocturia • Approach • Newer therapies • Recurrent Urinary Tract Infections • Strategy Agenda

3. LUTS Overactive Bladder Incontinence

4. Lower urinary tract symptoms are highly prevalent and expected to increase as our population ages Projected prevalence of incontinence in Australians aged 15 years and over, 2010 to 2030 Residential aged care (RAC) Community Reproduced from Continence Foundation of Australia, 2011.

5. Lower urinary tract symptoms can be divided into three groups • Storage/irritative • Daytime frequency; nocturia; urgency; urge incontinence • Voiding/obstructive • Slow stream; spraying of the urine stream; intermittent stream; hesitancy; straining; terminal dribble • Post-micturition • Feeling of incomplete emptying; post-micturition dribble

6. Overactive bladder – a syndrome of lower urinary tract symptoms Components of overactive bladder Urgency The complaint of a sudden compelling desire to pass urine that is difficult to defer Urgency Urinary Incontinence The complaint of involuntary loss of urine that is accompanied by or immediately preceded by urgency International Continence Society (ICS) definition of overactive bladder Urgency with or without urge incontinence, generally usually with increased frequency and nocturia Urinary Frequency The need to void more than 8 times in a 24-hour period Nocturia The complaint of having to void more than once per night • Abrams P et al. NeurourolUrodyn 2009;28:287. • Ellsworth P et al. J Fam Practice 2009;58(10 Suppl):S1–S12.

7. Ureter Peritoneum Detrusor muscle Opening of ureter Trigone Bladder neck Pelvic floor musculature External sphincter Urethra Chronic Condition: Detrusor Overactivity There are three types of detrusor overactivity: • Neuropathic • Obstructive • Idiopathic

8. Reported prevalence of OAB varies from 12% to 17% • Prevalence is similar in men & women, butgenerally develops later in life in men • Up to ~55% of women and ~16% of men with OAB have urge urinary incontinence1* • Overactive bladder symptoms are reported in: • 22% of men and women aged 70–74 years • 31% of females and 42% of males aged 75 years Overactive bladder is highly prevalent Although prevalence increases with age, overactive bladder is treatable and should not be considered a normal part of ageing *Data from the US National Overactive Bladder Evaluation (NOBLE) Program involving 5204 adults aged 18 years and representative of the US population by sex, age and geographical region. ^Data from a cross-sectional survey of 19,165 individuals in Canada, Germany, Italy, Sweden and UK. †Data from a random sample of 16,776 subjects aged 40 years from six European countries. 1. Stewart WF et al. World J Urol2003;20:327–36. 2. Irwin DE et al. Eur Urology 2006;50:1306-15. 3. Milsom I et al. BJU Int2001;87:760–6. 4. Larocque P. CME Bulletin 2010;9:1–6.

9. Female gender, in particular pre- and post-natal women Advanced age Menopause Obesity Recurrent urinary tract infections Specific types of surgery such as prostatectomies, hysterectomies Neurological diseases such as multiple sclerosis Reduced mobility Some medications Risk factors for urinary incontinence Continence Foundation of Australia. The economic impact of incontinence in Australia 2011.

10. Comorbidities associated with overactive bladder Adapted from Darkowet al, 2005 Retrospective analysis of US claims database. Prevalence of all comorbid conditions shown was significantly higher (p<0.0001) for patients with overactive bladder than for control subjects.

11. Neurogenic causes or contributorsto overactive bladder

12. Local bladder causes or contributors of overactive bladder

13. Systemic conditions that may contribute to overactive bladder OuslanderJG. N Engl J Med 2004;350:786-99.

14. Functional and behavioural conditions that may contribute to overactive bladder OuslanderJG. N Engl J Med 2004;350:786-99.

15. Drugs implicated in overactive bladder OuslanderJG. N Engl J Med 2004;350:786-99.

16. UTIs and overactive bladder 1. Ouslander JG. N Engl J Med 2004;350:786-99. 2. Walsh CA, Moore KH. NeurourolUrodyn2011;30:32-7. 3. Information provided by the Steering Committee.

17. Diagnosis of overactive bladder involves excluding infection, thus the precise definition of significant bacteriuria is critical • The traditional definition of ‘significant’ bacteriuria is >105 CFU/ml • However, this is insensitive in women with acute lower urinary tract symptoms • Bacterial counts from 102–105 CFU/ml (low-count bacteriuria) are now considered important in women with acute dysuria and warrant treatment • One recent study showed that low-count bacteriuria is more prevalent among women with severe OAB than bacteriuria >105 CFU/L Identifying low-count bacteriuria in women with suspected overactive bladder It is likely that many cases of low-count bacteriuria are under-recognised in women attending for urodynamic testing or worsening urinary symptoms

18. Recurrent UTIs and overactive bladder

19. One study showed that only 38% of women with urinary incontinence symptoms seeks clinical help • Another study showed that only 27% of all patients with symptoms of overactive bladder receive treatment Overactive bladder remains undertreated Patients want their primary care provider to discuss the issue, yet there appears to be a communication gap *Data from a US national, cross-sectional mailed survey identifying 1,970 women with urinary incontinence symptoms.1 †Data from a random sample of 16,776 subjects aged 40 years from six European countries.2 1. Kinchen KS et al. J Womens Health (Larchmt) 2003;12:687–98.2. MilsomI et al. BJU Int2001;87:760–6.3. Rosenberg MT et al. Cleve Clin J Med 2007;74 Suppl 3:S21–9.

20. Distinguishing different types of incontinence Most commonly associated with overactive bladder Recognising the symptoms and making a proper diagnosis is essential because stress incontinence is primarily treated with surgery, whereas urgency incontinence is managed medically

21. A bladder diary can provide information on: • Times of micturition • Voided volumes • Degree of urgency • Degree of incontinence • Incontinence episodes • Pad usage • Fluid intake • Triggers e.g. coffee or tea Quantification of symptoms 1. Rosenberg MT et al. Cleve Clin J Med 2007;74 Suppl 3:S21–9. 2. Drutz HP. J MultidiscipHealthc2011;4:233–7.

22. Management - OAB

23. Algorithm for managing overactive bladder

24. Urgency, frequency, nocturia ± incontinence (stress incontinence ruled out) Algorithm for the treatment of overactive bladder Secondary causes such as constipation, UTI, diabetes and kidney stone ruled out History of neurological disease(cerebrovascular disorder, spinal cord injury, etc) No Yes Urinalysis No haematuria or pyuria on urinalysis Unexplained haematuria or malignant cells Pyuria Measurement of residual urine volume Little residual urine Treat urinary tract infection Copious residual urine Behavioural or drug therapy using anticholinergic drugs, etc No change Improved Improved Poor efficacy Complete Treatment Continue treatment Specialist evaluation

25. Non-pharmacological • Behavioural therapy • Patient education on fluid intake • Bladder training • Neuromodulation • Surgery • Pharmacological • Anti-muscarinic agents • Tricyclic antidepressants • Botulinum toxin injections* • Other Treatment of overactive bladder

26. Behavioural therapy should be a part of the initial management in all cases of overactive bladder Charts & diaries Fluid & diet management Education reinforcement Behavioural modifications for overactive bladder Timed voiding Pelvic floor exercises & biofeedback Delayed voiding

27. Patient education • All patients should be educated about: • Bladder function • Fluid and dietary management • Timed voiding • Bladder training regimens • Keeping a bladder diary • Pelvic floor exercises • The importance of keeping mobile Association of Reproductive Health Professionals, 2011. Available at: www.arhp.org/Publications andResources/Quick-Reference-Guide-for-Clinicians/OAB/Introduction.

28. Bladder diary example Continence Foundation of Australia. Available at: http://www.continence.org.au/data/files/Factsheets/bladderdiary.pdf. Accessed March 2012.

29. Reduce or cease intake of caffeine, alcohol and sweet drinks Manage constipation Only go to the toilet when needed (i.e. don’t go “just-in-case”) Drink ~1.5 L of fluid per day (mostly water) Aim to regularly pass 300 ml or more of urine Exercise pelvic floor muscles Maintain a healthy weight Reviewing lifestyle changes as part of a bladder training program

30. Pharmacological Mx Anti-Muscarinics Beta-3 Agonist

31. Anti-muscarinic drugs inhibit involuntary detrusor contractions and thus reduce urgency Transmitter: acetylcholine Antimuscarinic drugs Muscarinic receptors – contraction Pelvic Nerve Contraction

32. Effects of anti-muscarinic blockade

33. Agents differ at the structural and molecular level, resulting in different metabolism, absorption, potency and selectivity profiles • Antimuscarinic agents can be divided into two main groups: • Non-selective – have affinity for all muscarinic receptors • Selective – have relatively more affinity for M2 and M3 receptors • Understanding how these differences impact efficacy and safety allows clinicians to make informed decisions about the most suitable treatment option for their patients Selecting an anti-muscarinic agent

34. Available anti-cholinergic agents and their predominant receptor affinity

35. Uncontrolled narrow-angle glaucoma • Urinary retention • Hypersensitivity to the product • Gastric retention • Obstructive GI conditions, toxic megacolon, ulcerative colitis • Myasthenia gravis; autonomic neuropathy • Renal impairment (oxybutynin, solifenacin, tolterodine) • Hepatic impairment • Caution/dose reduction may be required in moderate impairment • Severe hepatic impairment (darifenacin/solifenacin not recommended) • Cardiac (pre-existing cardiac diseases; prolongation QT interval) • Anticholinergics may cause blurred vision • Other Overview of contraindications and precautions for anti-muscarinic agents

36. Beta3 Agonist Mirabegron

37. RESULTS: MEAN CHANGE IN NUMBER OF MICTURITIONS/DAY RESULTS: PRIMARY ENDPOINTS From baseline to end of study From baseline to each visit tolterodine SR 4 mg Placebo mirabegron 50 mg Placebo mirabegron50 mg tolterodineSR 4 mg Week Baseline 11.29±2.75 11.15±2.65 11.10±2.57 • Final visit 0 • 4 • 8 • 12 0.0 0.0 (n=368) (n=369) (n=368) －0.5 －0.86 －1.0 • Mean change from baseline －1.0 －1.40 －1.5 NT －1.67 P ＜0.001* －2.0 －2.0 n=368 n=368 n=349 n=368 n=357 n=369 n=369 n=352 n=349 n=369 n=368 n=368 n=361 n=355 n=368 SE, standard error. NT, not tested. *2-sample t-test vs placebo (0.05% significance level, 2-sided)

38. RESULTS: MEAN CHANGE IN URGENCY EPISODES/24 H From baseline to end of study From baseline to each visit tolterodine SR 4 mg Placebo mirabegron 50 mg Placebo tolterodineSR 4 mg mirabegron50 mg Week Baseline • Final visit 4.42±2.99 4.27±2.85 4.13±2.81 0 • 4 • 8 • 12 0.0 0.0 (n=369) (n=368) (n=368) －0.5 －1.0 • Mean change from baseline －1.0 －1.37 －1.5 －1.66 －1.85 NT • －2.0 －2.0 P＝0.025* n=368 n=368 n=357 n=349 n=368 n=369 n=369 n=352 n=349 n=369 n=368 n=368 n=361 n=355 n=368 SE, standard error. NT, not tested .*2-sample t-test vs placebo (0.05% significance level, 2-sided)

39. RESULTS: MEAN CHANGE IN URGENCY INCONTINENCE EPISODES/24 H From baseline to end of study From baseline to each visit tolterodine SR 4 mg Placebo mirabegron 50 mg tolterodineSR 4 mg Placebo mirabegron50 mg Week • Final visit Baseline 1.67±1.37 1.78±1.75 1.71±1.57 • 12 0 • 4 • 8 0.0 0.0 (n=258) (n=254) (n=230) －0.5 －0.5 －0.60 • Mean change from baseline －0.95 －1.01 －1.0 －1.0 NT P＝0.008* －1.5 • －1.5 n=258 n=258 n=250 n=246 n=258 n=254 n=254 n=244 n=241 n=254 n=230 n=230 n=224 n=222 n=230 SE, standard error NT, not tested. *Wilcoxon rank sum test vs placebo (0.05% significance level, 2-sided)

40. RESULTS: MEAN CHANGE IN NOCTURIA EPISODES/24 H From baseline to end of study From baseline to each visit tolterodine SR 4 mg Placebo mirabegron 50 mg Placebo mirabegron50 mg tolterodineSR 4 mg Week Baseline 1.81±1.20 1.72±1.00 1.71±1.08 0 • 4 • 8 • 12 Final visit 0.0 0.0 (n=322) (n=323) (n=332) －0.1 • －0.1 • －0.2 －0.2 • Mean change from baseline －0.3 • －0.3 －0.36 －0.42 －0.4 • －0.4 －0.44 NT NS －0.5 • －0.5 n=311 n=322 n=322 n=304 n=322 n=307 n=323 n=323 n=304 n=323 n=325 n=332 n=332 n=319 n=332 SE, standard error. NS, not significant, NT, not tested. *2-sample t-test vs placebo (0.05% significance level, 2-sided)

41. RESULTS: SAFETY─Treatment-related adverse events Treatment-related adverse events occurring in ≥2% of patients in any treatment group Data are for the Safety Analysis Set. ALT, alanine aminotransferase. AST, aspartate aminotransferase. CPK, creatine phosphokinase. γ-GTP, gamma-glutamyltransferase. AP, alkaline phosphatase.

42. Other …

43. Botulinum toxin injections into bladder • Botulinum toxin injection into the bladder results in detrusor muscle paralysis, which reduces or eradicates detrusor overactivity Source: McKertich et al, 2008.1 McKertichK. AustFam Physician 2008;37:122-31 2. Botox Product Information. Date of TGA approval: 20 March 2012.

44. Neuromodulation: sacral nerve stimulation • involves chronic electrical stimulation of the S3 or S4 nerve root via an electrode which modulates abnormal reflexes between the bladder, urethral sphincter and pelvic floor muscles

45. Management of men with lower urinary tract symptoms Lower urinary tract symptoms Benign prostatic hyperplasia likely Overactive bladder likely Benign prostatic hyperplasia/overactive bladder unlikely Benign prostatic hyperplasia/overactive bladder complications* Consider referral Treat for benign prostatic hyperplasia Treat for overactive bladder No improvement? Treat for benign prostatic hyperplasia No improvement? Treat for overactive bladder *Benign prostatic hyperplasia and overactive bladder complications include urinary retention, benign prostatic bleeding and urinary tract infection. A history of haematuria always warrants investigation and referral, regardless of the number of episodes and whether it has resolved. Still no improvement? Consider referral Adapted from 1. Woo HH et al. Med J Aust2011;195:34–9.

46. Nocturia

49. Bladder Diary

50. Prevalence • 20-40 yrs: 2-20% • > 70 yrs: 28-60% • Quality of Life Issues: • increased no. of falls • increased no. of fractures • mood disturbances • increased daytime fatigue • decreased alertness • nocturnal polyuria contributory factor in ≈83% of people with nocturia Nocturia