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Pamela Ellsworth, MD

Professor of Urology/Surgery

Alpert School of Medicine/Brown University

A Case-Based Approach for Overactive Bladder to Evaluate

and Implement Successful Treatment Strategies

• Advisory Board Member:

• Pfizer

• Allergan

• Astellas

• Speaker – Pfizer

• Clinical Trials - Pfizer

Disclosures

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• Recognize at risk patients and understand the prevalence of OAB

• Understand the efficacy, tolerability of new and emerging therapies

• Review guidelines to integrate into a successful management approach

Objectives

Sally and The Wedding Blues

• 53 yr old at routine f/up

• “I am excited but worried about my son’s upcoming wedding”

• What happens if I have the urge to go during the ceremony?“ I don’t want to have to wear a diaper”

• I just can’t control my bladder

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• Diagnostic process to document symptoms and signs that characterize OAB

• Exclude other disorders that could be the cause of the patient’s symptoms

• Minimum requirement – careful history, physical examination and urinalysis

Evaluating OAB –AUA/SUFU Guideline

Gormley EA et al. Diagnosis and treatment of overactive bladder (non‐neurogenic) in adults: AUA/SUFU Guideline. www.auanet.org

Evaluating OAB – A Simplified Approach

Initial Evaluation

• Focused history

• Exam focused physical• Abdominal

• Pelvic

• Neurologic

• Urinalysis

• Degree of bother

Supplemental Aids

• Bladder diary

• Post void residual

• GOAL – to rule out other conditions which may cause/mimic OAB

Wein AJ. Urology. 2003;62 Suppl 2:20-27. Ouslander JG. N Engl J Med. 2004;350:786-799.

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Bladder Diary

NIDDK

• PMH/SH: hypertension, elevated cholesterol

• Med: diuretic, beta-blocker, cholesterol lowering agent

• ROS:• urinary frequency 12-14 times per day

• urgency urinary incontinence 2 -3 times per day• rare episodes of SUI• bowels regular• no frequent UTIs• PE: normal

• Lab evaluation: urinalysis - normal

The Wedding Blues

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• Urodynamics, cystoscopy , US not indicated in initial eval of uncomplicated pt.

• Post void residual –

Not necessary – if being treated with first-line behavioral interventions or uncomplicated patients

Necessary - obstructive sx, hx of incontinence or prostatic surgery, neurologic dz and in men with sx prior to starting antimuscarinic therapy

(Gormley EA et al. Diagnosis and Treatment of Overactive Bladder (Non-neurogenic) in Adults: AUA/SUFU Guideline. www.auanet.org)

Further Evaluation?

• Frequent UTIs

• Sensation of Incomplete emptying, straining to void

• Significant pelvic organ prolapse

• Prior pelvic surgery or radiation therapy

• Hematuria

• Neurologic conditions which may affect bladder function

Red Flags on Evaluation

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• Is NOT a disease

• It is a SYMPTOM COMPLEX

• Urgency -sudden compelling desire to void that is difficult to defer

• Frequency ( 8 or more micturitions in 24 hrs)

• Urgency Urinary Incontinence

• +/- nocturia

Overactive Bladder

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Coping with OAB

OAB Is Prevalent, Underdiagnosed, and Undertreated

OAB Prevalence 33.3 MM

Presenting Patients15.2 MM

Diagnosed Patients6.5 MM

Treated Patients3 MM

• Lengthy period (1 to 3 years) of coping, embarrassment and uncertainty before talking to an HCP

• Lengthy period (1 to 3 years) of coping, embarrassment and uncertainty before talking to an HCP

Stewart WF et al. World J Urol. 2003;20:327-336. Rovner E, Wein A. Curr Urol Rep. 2002;3:434-438.

Milsom I et al. BJU Int. 2001;87:760-766.Benner J et al. J Urol. 2009;181;2591-2598.

Rosenberg M et al. Cleve Clinic J Med. 2007;74;S21-S29. Goepel M et al. Eur Urol. 2002;41:234-239.

Dmochowski RR et al. Curr Med Res Opin. 2007:23:65-76.

• Patient-driven conversation, with multiple office visits required, before prescription

• Patient-driven conversation, with multiple office visits required, before prescription

• More than 66% of patients indicated UUI was primary reason for seeking help

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OAB is more than Urinary Frequency, Urgency and Urgency Urinary Incontinence

OAB Has a Considerable Impact on QoL

Kobelt G, et al. BJU Int 1999;83:583–590.Komaroff AL, et al. Am J Med 1996;101:281–290.

Healthy

Diabetes

Depression

OABSF

-36

Sco

re

0

10

40

50

60

70

80

90

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Physical

• Limitations or cessation of physical activities

Quality of Life

Sexual

• Avoidance of sexual contact and intimacy

Occupational

• Absence from work

• Decreased productivity

Social

• Reduction in social interaction

• Limit and plan travel around toilet accessibility

Domestic

• Require specialized underwear, bedding

• Special precautions with clothing

Psychological• Guilt/depression• Loss of self-esteem• Fear of

– Being a burden– Lack of bladder control– Urine odor

Impact of Overactive Bladder on Quality of Life

Tubaro A. Urology. 2004;64(6 suppl 1):2-6.

• Sally is worried – the wedding is in 2 months

• “Can you get all of the tests done to find out what is wrong with my bladder”

• “Can you fix my problem in time for the wedding”

• “ I am so worried about this problem, it is so embarrassing”

Back to the Wedding

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Why Is Sally Having This Problem Addressed 2 Months Before the

Wedding?

• Patients don’t discuss with physician• Embarrassment• Fear of invasive procedures or need for surgery• Perception of lack of available treatment

• Physician doesn’t ask• Too busy• One more thing to screen for• Don’t understand the impact• Not life-threatening• Patient will bring it up if bothered

Why are So Few OAB Sufferers Diagnosed and So Few Treated?

Ricci JA, et al. Clin Ther 2001;23:1245–1259.

Milsom I, et al. BJU Int 2001;87:760–766.

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OAB Treatment

Education Management Strategies

Surgical Procedures

MedicationsBehavioral

Modification

Treatment of OAB

Borello-France D, Burgio KL. Clin Obstet Gynecol. 2004;47:70-82. Gross M, et al. Curr Urol Rep. 2002;5:388-395. Rovner ES, et al. Women’s Health in Primary Care. 2000;3:179-186. Sahai A, et al. Neurourol Urodyn. 2005;1:2-12. http://www.emedicine.com/med/topic2781.htm. Accessed April 6, 2005.

• Education regarding normal bladder function

• OAB is a symptom complex with variable and chronic course

• Setting patient expectations

• Getting better versus getting cured

• Often task oriented for patient instead of number (ie watch a movie without interruption)

Management Strategies and Patient Education

Borello-France D, Burgio KL. Clin Obstet Gynecol. 2004;47:70-82. Gross M, et al. Curr Urol Rep. 2002;5:388-395. Rovner ES, et al. Women’s Health in Primary Care. 2000;3:179-186. Sahai A, et al. Neurourol Urodyn. 2005;1:2-12. http://www.emedicine.com/med/topic2781.htm. Accessed April 6, 2005.

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• Education

• Diet

• Modifying bladder function by changing voiding habits– Timed voiding

– Delayed voiding

• Behavioral training– Pelvic floor muscle therapy

– Biofeedback

First- Line Treatments: Behavioral Therapies

Burgio KL, et al. JAMA. 2002;288:2293-2299. Borello-France D, Burgio KL. Clin Obstet Gynecol. 2004;47:70-82.; Gormley EA et al. Diagnosis and Treatment of Overactivbe Bladder (non-neurogenic in adults: AUA/SUFU Guideline. www.auanet.org)

“I need to be better in 2 months”

Sally Needs More than Behavioral Therapy

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• In the detrusor, the postjunctional M3receptor is the predominant subtype mediating contraction

• Role of M2 not fully understood• M3 receptor antagonism

– Stabilizes bladder (detrusor) muscle

– Increases bladder capacity– Diminishes frequency of

involuntary bladder contractions– Delays initial urge to void

Muscarinic Receptor-Mediated Effects In the Detrusor

Andersson KE, Yoshida M. Eur Urol. 2003;43:1-5.

• 1965 – Oxybutynin• 1998 – Tolterodine IR, Oxybutynin ER• 2000 – Tolterodine ER• 2003 – Transdermal Oxybutynin• 2004 – Trospium chloride, Solifenacin, Darifenacin• 2007 - Trospium chloride once daily (Sanctura XR)• 2008 (Nov) – Fesoterodine (Toviaz)• 2009 (Jan) – Oxybutynin gel (Gelnique)

• 2012 (Jun) – Mirabegron (Myrbetriq) – first beta-agonist

Pharmacologic Therapy: The Evolution

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• All antimuscarinics are effective for treatment of OAB symptoms

• Individual differences exist in the profiles of antimuscarinics

• There is some evidence of differences among AE profiles

• There are differences in tolerability profiles

Not All Antimuscarinic Agents Are the Same

Chapple C et al. Eur Urol. 2005;48(1):5-26.Staskin DR. Drug Aging. 2005;22:1013-1028.

Comparison of Anticholinergic Agents

DRUG DOSE DELIVERY MECH

Darifenacin 7.5mg, 15mg pill Can’t cut, crush, chew

Fesoterodine 4mg, 8mg pill Can’t cut, crush, chew

Oxybutynin 3.8mg -30mg pill,liquid, patch, gel

Patch 2x/wk, gel QD, oral once(XL) to TID (IR)

Solifenacin 5mg, 10mg pill Can’t cut, crush, chew

Tolterodine LA 2mg, 4mg pill Can open

Trospium chloride XR

60 mg pill Can’t cut, crush, chew –can’t pm dose

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• asad

Antimuscarinic Agents - Efficacy

1) Gormley EA et al. Diagnosis and Treatment of Overactive Bladder (Non-neurogenic) in Adults: AUA/SUFU Guideline.

Mirabegron

• Selective beta-3 adrenoceptor agonist

• Activates beta-3 adrenoceptor on the detrusor muscle of bladder to facilitate filling of bladder and storage

• Does not affect detrusor contractility

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• Starting dose – 25mg with or without food

• Effective within 8 wks, may increase to 50mg

• Do not cut, crush or chew

• Max dose 25mg with severe renal impairment or moderate hepatic impairment

• ESRD and severe hepatic impairment – not recommended

• Mirabegron is a CYP2D6 inhibitor

• May increase BP – BP checks rec – don’t use in severe uncontrolled HTN

• (prescribing information Mirabegron (Myrbetriq), Astellas)

Mirabegron – Prescribing Information

• 1329 pts were randomized 1:1:1 to placebo, Mirabegron 50mg, and Mirabegron 100mg

• Efficacy data -> patient diaries and QoLassessments

• Incidence of HTN, UTI, headache & nasopharyngitis was similar in all groups

Mean reduction number of micturitions per 24hrs

Mean reduction of incontinent episodes per 24hrs

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Mirabegron – Adverse Events –Phase III trials

• No significant CV events in the mirabegron groups

• Overall incidence HTN similar across groups

• No effect on QT interval

• Dry mouth, sim to PBO 3%, tolt 10%

• Overall, treatment-emergent AEs similar btn PBO, mirabegron (50 and 100mg) and tolt (

EAU 26th Annual Congress: Posters 885 and 886. March 21, 2011)

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• Onset of action• Significant improvements over placebo as early as 1 week with

anticholinergic agents• Maximum improvement btn 4-12 weeks with all agents

• Timing of dose titration varies• Prescribing information recommendations• Naïve vs non-naïve• Patient tolerance and preference

(Siami P et al. Clin Ther 2002; 24(4): 616-628)

“Will it work in 2 Months?”

•70 yr old female with multiple medical problems and OAB

•Meds – hydrochlorothiazide, amlodipine, sertraline, calcium, vitamin D, laxative prn

•Lives alone –depends on daughter

“I worry about being a burden to my daughter, she has enough to do”

•Her OAB is bothersome and pads/diapers are expensive

•Tried oxybutynin 5mg BID– not effective enough and intolerable dry mouth and constipation

Case 2: Sylvia

“I take enough medications –Can something else be done?”

“I don’t drink much fluids during the day – why do I still have to go so frequently?”

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• Fluid intake

• One cup of caffeinated coffee in am

• One cup of tea in the afternoon

• One glass of milk with dinner

• Bowel history

• Moves her bowels 2 times per week

• Takes a stool softener and laxative prn

Sylvia

“Clinicians should manage constipation and dry mouth before abandoning effective antimuscarinictherapy”

AUA/SUFU Guidelines

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• Baseline bowel function

• Ask about bowel frequency and stools

• Many pts fluid restrict in hopes of decreasing frequency, incontinence

• If infrequent stools/constipation

• Increase fluid intake

• Increase dietary fiber

• Osmotic laxative

• No improve consider GI evaluation• (Toney, Agrawal. Practical Gastroenterology, May 2008)

Minimizing AEs in Patients on Anticholinergics for OAB

Don’t Just Ask Are You Constipated? Character and Frequency

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• www.essology.com has a 23 page list of medications that can cause xerostomia

• Tips for treating dry mouth

• Sips cool water throughout the day

• Drink milk – lubricates oral mucosa

• Restrict caffeine and alcohol intake both cause dry mouth

• Use of sugar-free gum stimulates saliva flow

• Saliva sure tables, oral balance, biotene toothpaste, recaldent

Minimizing AEs in Patients on Anticholinergics for OAB- Xerostomia

Xerostomia Therapies

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• Education

• Timed voiding

• Diet

• Delayed voiding

• Pelvic floor muscle therapy

Behavioral Modification – First Line Therapy

Burgio KL, et al. JAMA. 2002;288:2293-2299. Borello-France D, Burgio KL. Clin Obstet Gynecol. 2004;47:70-82.

• Fluids• Alcoholic beverages

• Carbonated beverages

• Soda—caffeine

• Milk—milk products

• Coffee—even decaffeinated

• Tea

• Citrus juice

• Fluid restriction

• WATER IS THE BEST

Dietary Regulation

• Foods– Citrus fruits

– Tomatoes

– Tomato-based products

– Highly spiced foods

– Sugar

– Honey

– Chocolate

– Corn syrup

– Artificial sweeteners

• Foods– Citrus fruits

– Tomatoes

– Tomato-based products

– Highly spiced foods

– Sugar

– Honey

– Chocolate

– Corn syrup

– Artificial sweeteners

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• 8% weight loss in obese women reduced incontinence episodes per week by 47% (28% in control group) , decreased UUI episodes by 42% (26% in controls)

• 25% reduction in fluid intake reduced frequency and urgency

• Reducing caffeine intake decreases voiding frequency• (Subak LL et al. NEJM 2009; 360: 481; Hashim H, Abrams P. BJU Intl 2008, 102: 62; Bryant

CM et al. Br J Nurs 2002; 11: 560)

Impact of Behavioral Modifications

• Generally equivalent to or superior to medications in reducing incontinence episodes, improving voiding parameters and QoL

(Jarvis GJ. BJU 1981; 53: 565; Burgio KL et al. J Am Geriatr Soc 2011; 59: 2209; Goode PS et al. J Am Geriatr Soc 2002; 50: 808; Kaya S et al. Clin Rehabil 2011; 25: 327;Arruda RM et al. IntUrogynecol J Pelvic Floor Dysfunct 2008; 19: 1055; Colombo M et al. Int Urogynecol J 1995; 6: 63; Burgio KL et al. JAMA 1998; 280: 1995; Song C et al. J Korean Med Sci 2006; 21: 1060; Kafri R et al. Int Urogynecol J Pelvic Floor Dysfunct 2007; 18: 407; Johnson TM et al. J Am Geriatr Soc2005; 53: 846; Gormely EA et al. Diagnosis and Treatment of Overactive Bladder (non-neurogenic) in Adults: AUA/SUFU Guideline. www.auanet.org)

Behavioral Therapies

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Additive Effect of Combining Behavioral And Drug Therapies

Burgio KL, et al. J Am Geriatr Soc. 2000;48:370-374.

–100

–80

–60

–40

–20

0

Mea

n R

edu

ctio

n i

n U

I, %

BehavioralTherapy

Combined Therapy

Drug Therapy

Combined Therapy

P < .05 P = .001

–57.5%

–88.5%

–72.7%

–84.3%

• “Those pills don’t work and they made my mouth dry”

• “I don’t want another pill – I take so many already”

• “I have given up coffee, tea, chocolate and I am no better”

• She does not want further pharmacologic therapy

Case 3 – Mildred: The Refractory OAB Patient

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• First line – behavioral - on it but not adequate

• Second line• Pharmacologic

• Anticholinergic agents – TRIED – No success, side effects• Beta agonist – TRIED – No success

• Third line• Neuromodulation

• PTNS• Sacral nerve stimulation

• Onabotulinum toxin A

What Options are Available for Mildred?

Surgical Procedures: Sacral Nerve Stimulation (Neuromodulation)

• 2-step process

• Initial test stimulation

• If good response, permanent stimulator implanted

• Small doses of electric current sent to sacral nerve

• FDA approval

• 1997: Urge incontinence

• 1999: Urinary retention and urgency/frequency symptoms

Borello-France D, Burgio KL. Clin Obstet Gynecol. 2004;47:70-82. Gross M, et al. Curr Urol Rep. 2002;5:388-395. Rovner ES, et al. Women’s Health in Primary Care. 2000;3:179-186. http://www.emedicine.com/med/topic2781.htm. Accessed April 6, 2005.

Image reprinted with permission of Medtronic, Inc. ©

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Interstim

Interstim

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Sacral Nerve Stimulation• Systematic review - 1996-2003

• 4 RCTS -80% achieved continence or > 50% improvement in main incontinence sxs after SNS vs 3% of ctrls

• 30 Case series - 67% patients dry of > 50% improvement in sx

• Benefits persisted 3-5 yrs after implantation

• Reoperation rate in implanted cases 33%

• Relocation of generator due to pain or infection (Brazzelli M et al. J Urol 2006; 175(3 pt 1): 835-41

• Sustained long-term benefit through average of 30.8 months (Janknegt RA et al. Eur urol 2001; 39(1): 101-6)

Percutaneous Tibial Nerve Stimulation (PTNS)

• RX protocol – once/wk for 12 wks, 30 min/session

• Pts who respond may require occ rxs to sustain

• 2010 – FDA clearance inclOAB

• OrBIT Trial – 73% pts who responded to rx cont for 1 yrand were able to sustain improvement with rx Q 21 days (MacDiarmid SA et al. J Urol2010; 183: 234-240)

• Urgent PC NeuromodulationSystem

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PTNS

Onabotulinum Toxin A

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Onabotulinum Toxin A for OAB and UUI

• Results of phase 3 RCT• Significant decrease in

frequency of UUIs/day vsPBO (-2.65 vs -0.87, p<0.001)

• 22.9% treated with botoxbecame dry vs 6.5% PBO

• 60.8% treated with botoxreported (+) response on treatment benefit scale vs29.2% PBO, p<0.001

• Most common AE – UTI• 5.4% rate of urinary retention

Nitti VW et al. J Urol 2013; 189(6): 2186-93

• Objective: Assess the impact on efficacy, safety, and HRQOL of onabotulinumtoxinA in patients with OAB with UI

• Design, setting, and participants: multicentre, double-blind, randomized, placebo controlled

• Idiopathic OAB with 3 urgency UI episodes over 3 d and ≥8 voids per day who failed anticholinergic

• PVR < 100cc• Willing to perform CIC

• Intervention: OnabotulinumtoxinA at a 100 U dose (n = 280) or placebo (n = 277), administered as 20 intradetrusor injections of 0.5 ml.

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No CICCIC for 6 -12 weeks

5.4% Required CIC

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• Repeat injections• Median Time Between

Injections• 1 to 2 = 377 days• 2 to 3 = 378 days• 3 to 4 = 256 days

• Equivalent Efficacy• Frequency• Urgency Episodes• UUI Episodes• QOL Improvement

• Re-injection timing not well studied

1) Sahai A, Dowson C, Khan MS et al: Repeated injections of botulinum toxin-A for idiopathic detrusor overactivity. Urology 2010; 75: 552.2) Gamé X, Khan S, Panicker JN et al: Comparison of the impact on health-related quality of life of repeated detrusor injections of botulinum toxin

in patients with idiopathic or neurogenic detrusor overactivity. BJU Int 2010; 107: 1786

Frequency Urgency Episodes

UUI EpisodesUDI-6 QOL

• Simplified evaluation

• 3 tiers of therapy

• First line – behavioral

• Second line – pharmacologic

• Anticholinergic agents

• Beta3 agonists

• Third lines

• Onabotulinum toxin A intradetrusor injections

• Neuromodulation

• Sacral nerve stimulation

• Percutaneous tibial nerve stimulation

Conclusion

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• Setting appropriate goals and treatment expectations are important

• Managing side effects is critical

• No single therapy is ideal for all

OAB