Medial and Surgical Treatment of Incontinence May 6, 2009 Symposium on Challenging Geriatric Issues Satish Rangaswamy, M.D., F.R.C.S.(C)

Disclosures Investigator/Advisory Board Member /or Honoraria provided by the following companies: Pfizer Canada Astellas Pharma Canada Novartis Pharmaceuticals Canada

Overview OAB Incontinence Stress Incontinence

Classification of Urinary Incontinence Stress Urge Mixed Overflow Urethral hypermobility Intrinsic sphincter deficiency Detrusor overactivity Sensitive bladder Combination of urge and stress Hypotonic or acontractile detrusor Obstruction Cause Leakage during  intra- abdominal pressure Involuntary leakage Strong desire to void Often one symptom predominant  with age Bladder distension Frequent to constant dribbling Symptoms 6

Incontinence - acute and potentially treatable causes D Delirium or confusion I Infection A Atrophic vaginitis or urethritis P Pharmaceutical agents (e.g. anticholinergic agents, diuretics, α-adrenoceptor agonists, calcium channel antagonists) P Psychological factors (e.g. depression, dementia) E Excess urine output (e.g. volume-expanded states, retention overflow) R Restricted mobility S Stool impaction

Overactive Bladder Definition Screening and Assessment Management Approach Safety of Pharmacologic agents in the Elderly OAB in Males Emerging therapies/Surgical therapies

DEFINITION The defining symptoms of overactive bladder syndrome (OAB) are: urinary urgency with or without incontinence, frequency nocturia1 Of these, urgency is the cardinal symptom. 1. Abrams P, Cardozo L, Fall M et al., The standardization of terminology of lower urinary tract function: report from the Standardization Sub-committee of the International Continence Society”, Neurourol. Urodyn. (2002);21: pp. 167–178. 2

Etiologies of Bladder Overactivity Obstruction (BPH) Neurological conditions Behavioural Aging-related DHIC (detrusor hyperactivity with impaired bladder contractility) Pelvic floor/urethral disorder Bladder hypersensitivity (sensory) Immature bladder (congenital) Combinations Idiopathic 5

OAB Is Prevalent and Increases With Age Comparison of Data From the SIFO Study 1997 and the EPIC Study 2005 40 35 Men – SIFO 1997 Men – 2005 30 Women – SIFO 1997 25 Women ̶ 2005 Prevalence, % 20 15 10 5 18-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70+ Age, y Milsom I et al. BJU Int. 2001;87:760-766. Irwin DE et al. EAU 2006. EPIC Study. Data of file. Pfizer Inc.

OAB Impact on Quality of Life Physical Decreased ability to maintain an independent lifestyle More discomfort and skin irritation Increased dependence on caregivers Restriction of sexual activity Poor sleep Cause of falls at night 17

OAB Impact on Quality of Life Psychological Loss of self-esteem & self-confidence Feelings of shame, embarrassment Fear of losing “control” (life ruled by bladder) 18

OAB Impact on Quality of Life Social Withdrawal/avoidance/restriction of social activity recreation occupation travel Negative impact on relationships Important influence on decision to institutionalize an elderly person 19

Overactive Bladder Definition Screening and Assessment Management Approach Safety of Pharmacologic agents in the Elderly OAB in Males Emerging therapies/Surgical therapies

Screening for Possible OAB Primary health care providers should question at risk patients to identify OAB Questions should be open-ended e.g. “Are you having any trouble WITH BLADDER CONTROL” 30

Basic Evaluation of OAB Components of the basic evaluation should include patient history-voiding diary physical examination urinalysis PVR - if indicated 32

Basic Evaluation of OAB Postvoid Residual Volume (PVR) patients with symptoms of incomplete emptying longstanding diabetes mellitus past history of urinary retention failure of pharmacological therapy pelvic floor prolapse previous incontinence surgery

Basic Evaluation of OAB Postvoid Residual Volume (PVR) If clinically indicated accurate PVR can be done by catheterization ultrasound PVR of <50 mL is considered normal, repetitive PVR >200 mL is considered abnormal Clinical judgment must be exercised when interpreting PVR results in the intermediate range of 50 - 199 mL Adapted from Clinical Practice Guideline on Urinary Incontinence in Adults. Rockville, MD: Agency for Health Care Policy and Research; March 1996. 36

Nocturia vs Nocturnal Polyuria Nocturia is frequency of urination waking up the individual greater than once per night. It may be due to: Nocturnal Polyuria Decreased nocturnal bladder capacity or Combination. Nocturnal Polyuria is passage of greater than 33% of total voided volume during sleeping hours. Multiple causes

Causes of Nocturnal Polyuria Congestive heart failure Hypoalbuminemia  Venous insufficiency  Excessive fluid intake Use of long-acting diuretics Chronic Renal Disease Sleep apnea  Nocturnal Polyuria Syndrome

Sleep Apnea The nocturnal polyuria of sleep apnea is an evoked response to conditions of negative intrathoracic pressure due to inspiratory effort posed against a closed airway. The mechanism for this natriuretic response is the release of atrial natriuretic peptide due to cardiac distension caused by the negative pressure environment. This cardiac hormone increases sodium and water excretion and also inhibits other hormone systems that regulate fluid volume, vasopressin and the renin-angiotensin-aldosterone complex. Mary Umlauff, Eileen Chasens Sleep disordered breathing and nocturnal polyuria: nocturia and enuresis SLEEP MEDICINE REVIEWS Volume 7, Issue 5, Pages 403-411 (October 2003)

Nocturnal Polyuria Syndrome A disorder of the vasopressin system with very low or undetectable levels of vasopressin at night and in some cases throughout the entire 24-hour period has been designated the ‘nocturnal polyuria syndrome’, a condition characterised by an increase in the nocturnal urine output, which in the most extreme cases accounts for 85% of the 24-hour diuresis. It has been estimated that the nocturnal polyuria syndrome occurs in 3–4% of the population aged > 65 years Pharmacotherapy for Nocturia in the Elderly Patient Ragnar Asplund Drugs Aging 2007; 24 (4): 325-343

Voiding Diary 1 Time of Day Amount voided (ml) Amount Intake (ml) 0700h 400 1100h 250 300 1400h 200 500 1800h 350 2100h 2200h 150 Total 1750 ml 1900 ml

Voiding Diary 2 Time of Day Amount voided (ml) Amount Intake (ml) 0700h 250 400 1100h 1600h 200 500 2000h 300 0100h 0200h 150 0300h 0500h 0600h Total 1900ml 2200 ml

Overactive Bladder Definition Screening and Assessment Management Approach Safety of Pharmacologic agents in the Elderly OAB in Males Emerging therapies/Surgical therapies

Treatment approaches for overactive bladder OAB Management Treatment approaches for overactive bladder Lifestyle changes and/or management Behavioral therapy Pharmacological therapy 51

Lifestyle changes Moderate fluid intake Reduce or eliminate caffeine Avoid fluids before bed 52

Behavioral Treatments Pelvic floor muscle exercises Kegel Biofeedback Electrical stimulation 53

Behavioral Treatments Toileting assistance scheduled toileting prompted voiding Bladder education/retraining delayed/timed voiding urge suppression exercises This slide emphasizes the major role that caregivers can play. 52

Pharmacologic Therapy

Pharmacologic Therapy for Bladder Overactivity In addition to antimuscarinic effect oxybutinin has a direct smooth muscle inhibitory and topical local anaesthetic effect

Overactive Bladder Definition Screening and Assessment Management Approach Safety of Pharmacologic agents in the Elderly OAB in Males Emerging therapies/Surgical therapies

OHIP Limited Use 290 For patients with urinary frequency, urgency or urge incontinence who have: Failed to respond to behavioral techniques AND An adequate trial of oxybutynin with gradual dose escalation has shown to be either ineffective or resulted in unaccepatable side effects. Note: If after a trial of 2 weeks patients continue to experience similar side effects and no greater efficacy than oxybutynin, continued therapy with this more costly agent should be reassessed. Authorization Period: Indefinite TOLTERODINE L-TARTRATE Detrol LA 2mg SR Cap Detrol LA 4mg SR Cap Detrol 1mg Detrol 2mg Tab

Overactive Bladder Definition Screening and Assessment Management Approach Safety of Pharmacologic agents in the Elderly OAB in Males Emerging therapies/Surgical therapies

Men and Women Are Both Bothered by OAB Symptoms Percentage of Respondents With OAB Symptoms Who Reported That OAB Had an Effect on Daily Living 100 Men Women 80 65% 67% 60 Percentage of Respondents 40 20 Bothered by OAB From a survey of 16,776 adults. Milsom I et al. BJU Int. 2001;87:760-766.

Fewer Men than Women Are Treated with Antimuscarinics 25 ‘OAB’ prescriptions 20 ‘BPH’ prescriptions 15 Prescriptions, in thousands 10 5 Female Male Male Women with OAB symptoms get treatment more than men (4:1) Men with LUTS are treated mainly for prostate conditions Data collected over 12 months. ‘OAB’ prescriptions include all antimuscarinics ‘BPH’ prescriptions include all alpha blockers and 5-alpha reductase inhibitors. Verispan Patient Longitudinal Data, MAT. 2005. IMS NPA, MAT. 2005.

Safety of Tolterodine IR in Men With OAB/DO and BOO: Study Design Multinational, double-blind study comparing 12 weeks of tolterodine 2 mg bid with placebo Study objective Evaluate the safety of tolterodine IR in men with urodynamically proven BOO and DO (Abrams-Griffiths >20) and no prior therapy for BPH Patient population 221 men with BOO and DO PVR <40% of maximum cystometric capacity No history of urinary retention in the preceding 12 months 2:1 randomization Abrams P et al. J Urol 2006; 175:999-1004.

Safety of Tolterodine IR in Men With OAB/DO and BOO: Results No difference between tolterodine and placebo effect on Qmax and PdetQmax at 12 weeks No difference in AUR between tolterodine and placebo Abrams P et al. J Urol 2006; 175:999-1004.

Tolterodine ER as Monotherapy in -Blocker Failures: Results Open-label, 6-month study Objective To ascertain safety and efficacy of tolterodine ER in men with LUTS who previously discontinued an α-blocker Patient population 43 men with BPE and LUTS (50-83 years) Failed an α-blockers due to AEs (11pts) or lack of efficacy (32 pts) PSA <10 mg, no history of urologic surgery Kaplan S et al. J Urol. 2005; 174:2273-76

Tolterodine ER as Monotherapy in -Blocker Failures: Results Symptomatic improvement Frequency decreased from 9.8 to 6.3 micturitions/day Night-time frequency decreased from 4.1 to 2.9 per night AUA-SS decreased from 17.3 to 11.2 Urodynamic results Qmax increased from 9.8 mL/s to 11.7 mL/s (P < .001) PVR decreased from 97 mL to 75 mL (P < .03) Safety 4 men (9%) discontinued therapy because of dry mouth No incidence of AUR Kaplan S et al. J Urol. 2005; 174:2273-76

Recent Studies of Anticholinergics in Men with OAB/LUTS: Safety Incidence of Urinary Retention in trials Tolterodine + alpha blocker (3 months) 0/25 (Athanasopoulos) 1/60 (Lee) Tolterodine monotherapy (3-6 months) 0/149 (Abrams) 27 ml average increase in PVR not considered clinically significant 1/72 on placebo 0/43 (Kaplan) 1/77 (Roehrborn) Propiverine + alpha blocker (2 months) 0/142 (Lee) Incidence of Urinary Retention in BPH Patients: 0.5-2.5% /year Roehrborn, 2001 Athanasopoulos A et al., J Urol 2003: 169:2253-6 Kaplan SA, Walmsley K, Te AE, J Urol 2005: 174:2273-6 Lee JY, Kim HW, Lee SJ, et al., BJU Int 2004: 94:817-20 Abrams P, J Urol 2006; 175: 999-1004. Lee K-S, Choo M-S, Kim D-Y, et al. J Urol 2005; 174: 1334-8 Roehrborn C, et al. BJUI 2006; 97:1003

Conclusions - OAB in Men Prevalence of OAB is similar in men and women and increases with age In both men and women with LUTS, storage symptoms are more bothersome than voiding symptoms Physicians are more likely to use BPH agents than OAB agents as a first-line therapy for OAB symptoms in men Early evidence that anti-muscarinics are safe and efficacious in males with OAB/LUTS Caution in patients with neurological disorders

Overactive Bladder Definition Screening and Assessment Management Approach Safety of Pharmacologic agents in the Elderly OAB in Males Emerging therapies/Surgical therapies

β3 Adrenoceptor The b3-AR is the most abundant of the AR subtypes in human detrusor muscle, suggesting that this subtype mediates detrusor relaxation.

β3 Adrenoceptor Agonist The mechanism by which b-AR agonists induce relaxation of smooth muscles is not fully understood, but it is believed that an intracellular pathway for smooth muscle relaxation is activated by cAMP

Animal Studies of β3 Adrenoceptor Agonist No change in micturition pressure1 Bladder capacity increased and No change in residual volume.2 1. Fujimura T, Tamura K, Tsutsumi T, et al. Expression and possible functional role of the b3-adrenoceptor in human and rat detrusor muscle. J Urol 1999;161:680–5. 2. Takeda H, Yamazaki Y, Akahane M, et al. Role of the b3-adrenoceptor in urine storage in the rat: comparison between the selective b3-adrenoceptor agonist, CL316,243, and various smooth muscle relaxants. J Pharmacol Exp Ther 2000;293:939–45.

β3 Adrenoceptor Agonist Beta-3 AR agonist Anticholinergic agent M3 β3 β3 M3 Induction of relaxation Inhibition of contraction Bladder β3 β3 M3 M3 α1 α1 α1 α1 Prostate Sphincter muscle of urethra β2 β2 β2 β2 Induction of relaxation without change in maximum micturition pressure Inhibition of contraction with decrease in maximum micturition pressure No affect on residual urine volume ? Increase in residual urine volume The possibility of indication for urge incontinence with BPH ? Contraindication for urge incontinence with BPH

BTX Efficacy: BTX has been shown to decrease or eliminate urge urinary incontinence for 6 to 9 months in 67% to 73% of patients experiencing neurogenic or idiopathic detrusor overactivity. Optimal dosing and duration have yet to be determined Been suggested that BTX will become an accepted therapeutic option in patients with OAB refractory to antimuscarinic therapy. Contraindicated in patients with an infection at the injection site or hypersensitivity to BTX

Normal Neuromuscular transmission THE JOURNAL OF UROLOGY® Vol. 171, 2128–2137, June 2004

Mechanism of Action Botulinum toxin THE JOURNAL OF UROLOGY® Vol. 171, 2128–2137, June 2004

Botox® injection 100 units diluted in 10ml saline in 30 injection sites, sparing the trigone Under local anesthesia (xylocaine 2% in 20ml, 20 minutes) In the absence of a positive urine culture

Interstim Sacral Neuromodulation

Gastric Augmentation Cystoplasty

Detubularized Ileal Augmentation Cystoplasty Augmentation cystoplasty with simultaneous AUS implantation;

Conclusion-Overactive Bladder Definition Urgency Nocturia – NP vs DBC Screening and Assessment History, Physical, Voiding Diary is helpful Management Approach Lifestyle, Behavioural, Pharmacological and Surgical

Conclusion-Overactive Bladder Safety of Pharmacologic agents in the Elderly Use selective M3 anti muscarinics where possible Use agents which don’t cross the BBB OAB in Males Anticholinergics seem safe Surgical and Emerging therapies Newer agents and surgical procedures

Stress Incontinence Female Hypermobility ISD Neurogenic Male Postprostatectomy Neurogenic

Stress Incontinence Assessment History, Physical Examination Pad test Cough stress test Cystoscopy Voiding cystometrogram Abdominal leak point pressure

Stress Incontinence Medical therapy Kegel exercises M/F Alpha adrenergic agonists M/F

Stress Incontinence Surgical therapy Periurethral Bulking Agents M/F Post./Midurethral Slings M/F Open Surgery (rarely)-Pubovaginal Sling, Retropubic Urethropexy F Artificial Sphincter M/F

Stress Incontinence Female Hypermobility ISD Neurogenic

Hypermobility

Hypermobility

ISD Normal mucosal seal Poor mucosal seal

Original TVT

TRANS-OBTURATOR SLINGS

Third Generation Synthetic Midurethral Slings

Peri-Urethral Bulking Agents Autologous fat Hyaluronic acid/Dextranomer Teflon particles Collagen Silicone particles Calcium hydroxylapatite Ethylene vinyl alcohol Carbon spheres Porcine dermal implant

Treatment with Zuidex Implacement 4 x 0.7ml NASHA/Dx

Stress Incontinence Male Postprostatectomy Neurogenic

Male Slings AMS Advance Male Sling

AUS