Lower Urinary Tract Symptoms and Conditions

LUTS NOCTURIA & INCONTINENCE RECURRENT UTI S St George Education Forum

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

LUTS Overactive Bladder Incontinence

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.

Lower urinary tract symptoms can be divided into three groups 1. Storage/irritative Daytime frequency; nocturia; urgency; urge incontinence 2. Voiding/obstructive Slow stream; spraying of the urine stream; intermittent stream; hesitancy; straining; terminal dribble 3. Post-micturition Feeling of incomplete emptying; post-micturition dribble

Overactive bladder a syndrome of lower urinary tract symptoms Components of overactive bladder 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 Urgency The complaint of a sudden compelling desire to pass urine that is difficult to defer 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 1. Abrams P et al. Neurourol Urodyn 2009;28:287. 2. Ellsworth P et al. J Fam Practice 2009;58(10 Suppl):S1 S12.

Chronic Condition: Detrusor Overactivity There are three types of detrusor overactivity: 1) Neuropathic 2) Obstructive 3) Idiopathic Ureter Peritoneum Detrusor muscle Opening of ureter Trigone Bladder neck Pelvic floor musculature External sphincter Urethra

Overactive bladder is highly prevalent 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 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 Urol 2003;20:327 36. 2. Irwin DE et al. Eur Urology 2006;50:1306-15. 3. Milsom I et al. BJU Int 2001;87:760 6. 4. Larocque P. CME Bulletin 2010;9:1 6.

Risk factors for urinary incontinence 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 Continence Foundation of Australia. The economic impact of incontinence in Australia 2011.

Comorbidities associated with overactive bladder Adapted from Darkow et 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.

Neurogenic causes or contributors to overactive bladder Cause Factors affecting the brain: Tumours MS Stroke Parkinson s Dementia Factors affecting the spinal cord: Spinal cord injury Spina bifida (usually occulta in adults) Cauda equina Trauma Presentation Usually more sudden onset (except dementia states) Look for neurological symptoms/signs Usually obvious Abnormality of function will depend on level of injury Childbirth Surgery

Local bladder causes or contributors of overactive bladder Cause Presentation Tumours Change in severity Polyps Sudden onset Stones Haematuria Infections Positive culture for UTI Positive cytology for tumours Obviously requires referral!

Systemic conditions that may contribute to overactive bladder Cause Congestive heart failure, venous insufficiency Mechanism of effect Volume overload can contribute to urinary frequency and nocturia when patient is supine Poor blood glucose control can contribute to osmotic diuresis and polyuria Sleep disorders can contribute to nocturia Diabetes mellitus Sleep disorders (sleep apnoea, periodic leg movements) Abnormalities of arginine vasopressin Impaired secretion or action of vasopressin may cause polyuria and nocturia Ouslander JG. N Engl J Med 2004;350:786-99.

Functional and behavioural conditions that may contribute to overactive bladder Cause Excess intake of caffeine, alcohol; polydipsia Poor bowel habits and constipation Impaired mobility (e.g. in patients with degenerative joint disease, Parkinson s disease, severe osteoporosis, or muscle weakness) Psychological conditions Mechanism of effect Polyuria and urinary frequency can result Faecal impaction can contribute to symptoms Impaired mobility can interfere with toileting ability and precipitate urge incontinence Chronic anxiety and learned voiding dysfunction can cause symptoms of overactive bladder Ouslander JG. N Engl J Med 2004;350:786-99.

Drugs implicated in overactive bladder Medication class Diuretics (especially rapid-acting agents) Mechanisms or effect Cause a rapid increase in bladder volume, which may precipitate urgency and detrusor overactivity These agents decrease bladder contractility and may cause urinary retention, with a decreased functional bladder capacity These agents could theoretically contribute to detrusor overactivity by increasing acetylcholine levels Anticholinergic agents, narcotics, calcium-channel blockers Cholinesterase inhibitors Ouslander JG. N Engl J Med 2004;350:786-99.

UTIs and overactive bladder Cause Management Asymptomatic bacteriuria Opinion divided as to what culture numbers are significant and when treatment is necessary Consider treating in at risk states e.g. pregnancy, immunologically compromised 1. Ouslander JG. N Engl J Med 2004;350:786-99. 2. Walsh CA, Moore KH. Neurourol Urodyn 2011;30:32-7. 3. Information provided by the Steering Committee.

Identifying low-count bacteriuria in women with suspected overactive bladder 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 It is likely that many cases of low-count bacteriuria are under-recognised in women attending for urodynamic testing or worsening urinary symptoms

Recurrent UTIs and overactive bladder Cause There is usually a reason why a patient is vulnerable to UTIs Management treat aggressively correct predisposing factors such as constipation diabetic, stress, constipation, etc > 2 UTIs in 12 months look at prevention (prophylactic antibiotic) immune compromised steroids refer if problems persist Oestrogen deficient tissue poor choice of antibiotic

Overactive bladder remains undertreated 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 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. Milsom I et al. BJU Int 2001;87:760 6. 3. Rosenberg MT et al. Cleve Clin J Med 2007;74 Suppl 3:S21 9.

Distinguishing different types of incontinence Urgency incontinence Stress incontinence Mixed incontinence Involuntary leakage accompanied or immediately preceded by urgency Involuntary leakage on effort or exertion, or on sneezing or coughing The coexistence of urge and stress 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

Quantification of symptoms 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 1. Rosenberg MT et al. Cleve Clin J Med 2007;74 Suppl 3:S21 9. 2. Drutz HP. J Multidiscip Healthc 2011;4:233 7.

MANAGEMENT - OAB

Algorithm for managing overactive bladder Confirmation of diagnosis Baseline measurements of severity Initial behavioural measures Pharmacotherapy (antimuscarinics/anticholinergics) If refractory overactive bladder diagnosed, refer to specialist for alternative management options

Algorithm for the treatment of overactive bladder Urgency, frequency, nocturia incontinence (stress incontinence ruled out) 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 Improved change Improved Poor efficacy Complete Treatment Continue treatment Specialist evaluation

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

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

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 and Resources/Quick-Reference-Guide-for-Clinicians/OAB/Introduction.

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

Reviewing lifestyle changes as part of a bladder training program 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

PHARMACOLOGICAL MX Anti-Muscarinics Beta-3 Agonist

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

Effects of anti-muscarinic blockade Muscarinic receptors types and potential effects from their blockade* Receptor s anticholinergic blockage Effects and/or adverse effects from Organ System Bladder (detrusor muscle) Decreased contraction, urinary retention M2, M3 M1, M3, M4 Salivary glands Dry mouth Cardiac tissue M2 Tachycardia, palpitations Eye (ciliary muscle, iris) M3, M5 Dry eyes, blurred vision, mydriasis M1, M2, M3 Slowing of transit time, constipation, effects on sphincter tone and gastric acid secretion Gastrointestinal tract Central nervous system, brain (cortex and hippocampus) M1, M2, M3, M4, M5 Effects on memory, cognition and psychomotor speed, Other: confusion, delirium, sedation, hallucinations, sleep disruption

Selecting an anti-muscarinic agent 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

Available anti-cholinergic agents and their predominant receptor affinity Predominant receptor Medication Metabolism affinity* Oxybutynin M1, M2, M3, M4 Hepatic Propantheline M1, M2, M3, M4 Hepatic Tolterodine M1, M2, M3, M4, M5 Hepatic Solifenacin M3 Hepatic Darifenacin M3 Hepatic

Overview of contraindications and precautions for anti-muscarinic agents 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

BETA3 AGONIST Mirabegron

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 mirabegron 50 mg 11.15 2.65 tolterodine SR 4 mg 11.10 2.57 Week 12 Final visit Baseline 0 4 8 11.29 2.75 0.0 0.0 (n=368) (n=369) (n=368) Mean change from baseline 0.5 0.86 1.0 1.0 1.40 1.5 1.67 NT P 0.001* 2.0 2.0 n=368 n=369 n=368 n=368 n=369 n=368 n=349 n=349 n=355 n=368 n=369 n=368 n=357 n=352 n=361 SE, standard error. NT, not tested. *2-sample t-test vs placebo (0.05% significance level, 2-sided)

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 tolterodine SR 4 mg mirabegron 50 mg Week Baseline 0 4 8 12 Final visit 4.42 2.99 4.27 2.85 4.13 2.81 0.0 0.0 (n=369) (n=368) (n=368) Mean change from baseline 0.5 1.0 1.0 1.37 1.5 1.66 1.85 NT 2.0 2.0 P 0.025* n=368 n=369 n=368 n=368 n=369 n=368 n=357 n=352 n=361 n=349 n=349 n=355 n=368 n=369 n=368 SE, standard error. NT, not tested .*2-sample t-test vs placebo (0.05% significance level, 2-sided)

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

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 mirabegron 50 mg 1.72 1.00 tolterodine SR 4 mg 1.71 1.08 Week Baseline 0 4 8 12 Final visit 1.81 1.20 0.0 0.0 (n=322) (n=323) (n=332) Mean change from baseline 0.1 0.1 0.2 0.2 0.3 0.3 0.36 0.42 0.4 0.4 0.44 NT NS 0.5 0.5 n=311 n=307 n=325 n=322 n=323 n=332 n=322 n=323 n=332 n=304 n=304 n=319 n=322 n=323 n=332 SE, standard error. NS, not significant, NT, not tested. *2-sample t-test vs placebo (0.05% significance level, 2-sided)

RESULTS: SAFETYTREATMENT-RELATED ADVERSE EVENTS Treatment-related adverse events occurring in 2% of patients in any treatment group Placebo (n=379) 91 (24.0) 10 (2.6) 11 (2.9) 2 (0.5) 5 (1.3) 6 (1.6) 14 (3.7) 9 (2.4) 10 (2.6) Mirabegron 50 mg (n=379) 93 (24.5) 13 (3.4) 10 (2.6) 0 9 (2.4) 6 (1.6) 10 (2.6) 15 (4.0) 10 (2.6) Tolterodine SR 4 mg (n=375) 131 (34.9) 13 (3.5) 50 (13.3) 8 (2.1) 9 (2.4) 10 (2.7) 8 (2.1) 6 (1.6) 6 (1.6) Preferred term All, n (%) Constipation Dry mouth Thirst ALT increased AST increased Blood CPK increased -GTP increased Blood AP increased Data are for the Safety Analysis Set. ALT, alanine aminotransferase. AST, aspartate aminotransferase. CPK, creatine phosphokinase. -GTP, gamma- glutamyltransferase. AP, alkaline phosphatase.

OTHER

Botulinum toxin injections into bladder Botulinum toxin injection into the bladder results in detrusor muscle paralysis, which reduces or eradicates detrusor overactivity Advantages Minimally invasive day case procedure Effective in a significant proportion of patients (including neurogenic patients) Disadvantages Expensive Currently limited availability in public hospitals in Australia Requires repeat treatments over time Risk of urinary retention Source: McKertich et al, 2008.1 McKertich K. Aust Fam Physician 2008;37:122-31 2. Botox Product Information. Date of TGA approval: 20 March 2012.

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 Advantages does not cause urinary retention or need for self catheterisation single treatment required may be more cost effective over time than multiple separate interventions such as botulinum toxin Disadvantages Expensive currently limited availability in Australia ie only marginally supported in public health system device replacement required when battery runs out 7-10 years

Management of men with lower urinary tract symptoms Lower urinary tract symptoms Benign prostatic hyperplasia/overactive bladder complications* Benign prostatic hyperplasia/overactive bladder unlikely Benign prostatic hyperplasia likely Overactive bladder likely Treat for benign prostatic hyperplasia Treat for overactive bladder Consider referral No improvement? Treat for overactive bladder No improvement? Treat for benign prostatic hyperplasia *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 Aust 2011;195:34 9.

NOCTURIA

Bladder Diary Nocturia Voiding Diary Nocturnal polyuria Low nocturnal bladder capacity Mixed Polyuria NUV / Total >35% eg BPH; infection; CaB 24hr UO >40mg/kg ?? aetiology

Nocturia Prevalence 20-40 yrs: > 70 yrs: 2-20% 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