Management of Urgency Incontinence

October 26, 2016

Leslee L. Subak, MDProfessor, UCSF Departments of Obstetrics, Gynecology & Reproductive ScienceEpidemiology & Biostatistics, and UrologyChief, SFVAMC GynecologyCo-Director, UCSF Women’s Health Clinical Research Center

Speaker Disclosure:Astellas: Research grant to UCSF (ITT)NIH/NIDDK

Urinary Incontinence

&Overactive

Bladder(OAB)

High prevalence,

High cost, >$60 billion/yr

High impact on QOL

Chronic Conditions

Kaiser Family Foundation, 2008

50%50%

Urinary Incontinence

Urinary Incontinence

�Common- 25% reproductive age women- 40% postmenopausal women

�Chronic ‒Social seclusion‒ Falls & Fractures‒ 3x Nursing home admissions‒Depression, anxiety, poor QOL

UI: Who is at Risk?Risk Factor � RiskAge (per 5 years) 30%Live birth 30%Modifiable or PreventableOral estrogen 90%Stroke 90%Diabetes 70%BMI (per 5 units) 60%Poor overall health 60%Hysterectomy 40%COPD 40%

Sampselle 2002; Jackson 2004; Hannestad 2003; Waetjen 2006; Melville 2005; Danforth 2006; Ebbesen 200; Wetle 1995; Brown 1996

Stress vs. Urgency IncontinenceSymptom Stress UI Urgency UI

Precipitant Activity Urge

Timing Immediate Delayed

Amount Small-mod Small-large

Urinary Frequency Rare Common

Nocturia Rare Common

Overactive Bladder (OAB)Prevalence: 8-31% of women�Frequency: frequent urination

• >8x per day

�Urgency: sudden compelling desire to void• Difficult to defer

�Nocturia: need to wake during sleep to void• >2x per night

�Urgency urinary incontinence (UUI): involuntary leakage of urine usually associated with urgency

Abrams P et al. Neuourol Urodyn. 2002;21:167

Don’t Tell : Patients

•Few women seek care: 20-30%

•Not discussed with other women

•Treatments: lack knowledge, fear of surgery

•Failed communication with provider

Shaw 2001; Roe 1999; Seim 1995; Mitteness 1995; Burgio 1994

Don’t Ask: PCC

Practice Guidelines:

History, diary, pelvic exam, stress cough test, post void residual (PVR), U/A, 24 hr pad test

•U.S. PCC reality check:

−15 minute appointments

−no pelvic exam tables

−PVR not possible

Too cumbersome for US primary care

Diagnostic Aspects of Incontinence Study (DAISy)

•Multi-center study (N=301)

•3 Incontinence Questions (3 IQ) vs. Extended Evaluation

− US, UK, WHO: Clinical Practice Guidelines

− Extensive History

− Exam: Neuro S2-S4, Pelvic exam

− Tests: PVR, Cough Stress Test, UA

− 3-Day Diary

Brown JS et al. Annals Internal Med 2006;144:715

3 Incontinence Questions (3IQ)

1. During the last 3 months, have you leaked urine, even a small amount? If yes:

2. Does the leak happen with:• Physical activity, coughing, sneezing, lifting, or exercise

(Stress UI)• Urge, feeling need to empty but could not get to the

toilet fast enough (Urge UI)• Don’t know (Other UI)

3. Type of UI MOST OFTEN:• Categorize as Stress, Urge, Mixed (=), Other

12 Brown JS et al. Annals Internal Med 2006;144:715

3 Incontinence Questions (3 IQ)1. During the last 3 months, have you leaked urine, even a small

amount? � Yes � No � Questionnaire Completed.

2. During the last 3 months, did you leak urine: (Check ALL that apply.)� When you were performing some physical activity such as coughing,

sneezing, lifting or exercise?� When you had the urge or the feeling that you needed to empty your

bladder but you could not get to the toilet fast enough? � Without physical activity and without a sense of urgency?

3. During the last 3 months, did you leak urine most often: (Check only ONE)� When you were performing some physical activity such as coughing,

sneezing, lifting or exercise? [STRESS]� When you had the urge or the feeling that you needed to empty your

bladder but you could not get to the toilet fast enough? [URGENCY]� Without physical activity and without a sense of urgency? [OTHER]� About equally as often with physical activity as with a sense of urgency?

[MIXED]

Accuracy of 3 IQ Compared to Extended Evaluation

> Similar to other diagnostic tests

Sensi-tivity

Speci-ficity

PPV LR+

Urgency UI

0.75 0.77 0.79 3.26

Stress UI 0.86 0.60 0.74 2.13

Brown JS et al. Annals Internal Med 2006;144:715

VALIDATION OF 3IQ

•3IQ: simple, inexpensive, feasible

− Reproducible (kappa 70% for urge and stress)

− Acceptable accuracy for classification of incontinence type

• Include a urinalysis (UA) in the evaluation

•Take Home Message

− 3IQ is a good test for type of UI in women

− With 3IQ + UA, the risk of missed Dx and Rx is low

Brown JS et al. Annals Internal Med 2006;144:715

Patient Resources

National Association For Continence

•www.nafc.org

•Diagnostic quiz

•Disease state and treatment information

•FAQs, Q&A forum

•1-800-BLADDER

NIDDK�http://kidney.niddk.nih.gov/kudiseases/pubs/uiwomen/

UI: Modifiable Contributing Factors�UTI�Constipation�Obesity�Diabetes�Mobility impairment�Liquids, caffeine, EtOH�Drugs: diuretics, ACE inhibitors, sedatives, hypnotics

Urinary Diary

�Simple form for recording voids, incontinent episodes, fluid intake

�Excellent education & intervention!• � UI episodes by 25-45%

�Very useful in planning therapy• fluid adjustment

• timing and type of medications

Behavioral Treatment for UI

Lifestyle changes

1. Fluids management

2. Avoid Caffeine, carbonated beverages, alcohol

3. Bedside commode, night light

4. Weight loss, diabetes control

Weight Reduction & UI

Program to Reduce Incontinence by Diet & Exercise (PRIDE)• NIDDK-funded multi-site RCT

• 338 obese women with UI

• 6-month lifestyle intervention vs. control

Weight Loss similar to medications for UI

Subak LL et al. N Engl J Med. 2009;360:481-90

Intervention Control P-Value

Weight -8.2% -1.8%

25 Holroyd-Leduc JM et al. JAMA 2004;291:986-95 26

Medication

OAB Medications

�Relax the bladder�Symptom relief�Patient-Directed Balance:

OAB Medications

Anticholinergic/Antimuscarinic mechanism

Adverse effects: dry mouth/eyesconstipation, urinary retentionconfusion, anxiety, somnolenceheadache, dizzinessnausea, dyspepsiatachycardia, palpitations

Contraindications: narrow angle glaucomahepatic/renal disease

Holroyd-Leduc JM et al. JAMA 2004;291:986-95

Pharmacologic Therapies Indicated for OAB with or without UUI

Nygaard I. N Engl J Med 2010;363:1156-1162

Mirabegron (Myrbetriq, Astellas Pharmaceuticals) 25, 50 mg by mouth once daily

Cochrane Review: OAB Drug Effectiveness

61 RCTs; 12,000 adults; 9 meds�Medication vs. placebo RR (95% CI)

• Cure or improvement 1.39 (1.28, 1.51)

• UI episodes/dy 0.54 (0.41, 0.67)

• Voids/dy 0.69 (0.54, 0.84)

• Improved QOL

• � Dry mouth 3.00 (2.70, 3.34)• No increase in withdrawal

Nabi G et al. Cochrane Database Syst Rev 2006

Meta-analyses: AntimuscarinicEfficacy:�Placebo controlled trials

• ~ all meds better than placebo• UI episodes, urgency, voids, volume voided

�Active comparator trials• UI episodes: oxybutynin ER 10mg > tolterodine ER 4mg• Urgency: solifenacin 5-10 mg > tolterodine IR 4 mg• Void frequency: solifenacin 10 mg > tolterodine IR 4 mg

Quality of Life• ~ all meds greater improvements in QOL than placebo

Most common AE = dry mouth• � incidence and severity vs. placebo • � incidence and severity oxybutynin IR

Nabi G et al. Cochrane Database Syst Rev 2006; Chapple et al. Eur Urol 2005

Mirabegron (Myrbetriq)

�Mirabegron: selective β3-adrenoceptor agonist�Systematic review and meta-analysis

• Randomized double-blind, placebo-controlled trials• Four publications, N=5,761 patients

• No increased risk: htn, arrythmia, retention, discontinuation 2o AE

Variable (per 24 hours) Std Mean Difference

UI Episodes -0.4 (-0.6, -0.3)

Voids -0.6 (-0.8, -0.4)

Volume voided 13 ( 10, 16)

Urgency episodes -0.6 (-0.8, -0.4)

Nocturia -0.1 (-0.2, -0.01)

Cui Y. Int J Nephrol. 2013

Behavioral Rx vs. Medications

•197 women with Urge UI: RCT

� UIPlacebo 40%

Medication 69%+

Biofeedback/behavioral 81%*’

+

* P < 0.05 vs. medication; + P < 0.05 vs. control

•Greater satisfaction in behavioral group

Bottom line: Educate & Empower

Burgio KL et al. JAMA 1998;280:1995-2000

Which Rx First?

•35 women with Urge UI: modified crossover extension of RCT

�UIBehav � behav+drug 84%Drug � drug+behav 89%

Bottom line: Be creative!

Burgio KL et al. J Am Geriatr Soc 2000;4:370-4 2000

UI Treatment Effectiveness

Placebo 20-40%

Behavioral 40-80%Pharmacological 40-70%

Side effects, discontinuation 50%

Weight Loss 50-60%

Treatment efficacies similar!

OTHER Rx To consider:1. YOGA2. Slow-Paced

Respiration

• Pilot RCT’s• Significant � in UI• Efficacy RCT’s in

progress• Secondary health

benefits

Estrogen Therapy for UI

�� UI with estrogen Rx in observational studies− Receptors in urethra, bladder

�7 RCTs oral CEE/MPA vs. placebo (N=15,593)− HERS & WHI• For Stress, Urge, & Mixed UI:− Prevalent UI: � frequency 40-50% (4 mo � 4 yrs)− Incident UI at 1 yr: � 15% to 2–fold

�Locally estrogen (vaginal creams or pessaries) may improve incontinence (RR 0.74, 95% CI 0.64 to 0.86)

Oral HT not for prevention or Rx of UI

Grady DG. Obstet Gynecol 2001; Hendrix SL. JAMA 2005;293:935-48; Cody JD. Cochrane Database 2012

Initial Visit

1. Simple Diagnosis - 3 IQ, UA

2. Patient information• Educate and Empower (self-help)

3. Treat modifiable factors• Weight loss• Bedside Commode

4. Reasonable expectations• Ask patient what she wants!

5. 50% reduction in incontinence • Pelvic-floor muscle exercises • Bladder-control strategies • Taught with a booklet

BRIDGEs: Diagnose & Treat UUI•Multicenter, double-blind, 12-week RCT (N=645)

− Urgency-predominant incontinence, primary care− Diagnosis: 3-item questionnaire− UA− Fesoterodine (4-8 mg daily) or placebo

•Women assigned to Drug had- � UUI episodes/day- � Total episodes/day- � Daytime and nighttime voids- � Urgency

•Safe- No difference in AE, elevated PVR

Huang AJ et al. Am J Obstet Gynecol. 2012;20:444.e1-11

When to Refer�Persistent, bothersome symptoms after 2-3 mo trial with behavioral treatment, drug treatment or both

�Patient not satisfied with treatment outcome �UTI > 2 in 12 mo, PVR > 200 cc, hematuria, neurological symptoms, failure to isolate pelvic floor muscles in a patient who desires PFMT, prolapse > hymen

�Refer to a specialist• Urogynecologist• Urologist• Physical therapist/continence specialist• Continence/FPMRS center

Refractory OAB

Next treatment options:

• Intensive behavioral therapy with biofeedback– Possible electrical stimulation

• Sacral nerve neuromodulation

• Posterior tibial nerve stimulation

• Botulinum toxin type A injection

Abrams P. Incontinence. 4th ed. Plymouth, UK: Health Publications, Ltd; 2009

Sacral Nerve modulation

�Refractory UUI�Temporary, percutaneous SN test stimulation �permanent, surgically implanted lead (S3 foramen) and neurostimulator (InterStim, Medtronic)

�In two multicenter trials:• N=41: 59% had > 50% reduction in UUI/dy (46% dry) at

3 years

• N=152: UUI/dy decreased from 10 to 4 at 5 years‒ Voids/day decreased and volume voided increased

Siegle SW. Urology. 2000;56:87-91; van Kerrebroeck PE. J Urol. 2007;178:2029-34; Brazzelli M. J Urol, 2006;175:835–41

Sacral Nerve modulation�Systematic Review, 4 RCT’s, N=120

� Safety: 993 patients, 4 RCT & 20 case control studies‒ Reoperation 33%‒ Implantable device replaced 15%‒ Generator problems 5%‒ Electrode/lead problems 16%‒ Pain 25%‒ Infection, Wound problems 5%‒ Adverse bowel function 6%

Brazzelli M. J Urol, 2006;175:835–41

Cured> 90% Improvement

Improved> 50% Improvement

Stimulation group 50% 37%

Delay group 2% 3%

Percutaneous Tibial Nerve Stimulation

•Electrostimulation of the PTN by a fine needle inserted near the ankle

•Rx for 30 minutes, weekly x 12 weeks

•RCT 220 adults with OAB: PTNS vs. sham− PTNS had sig. � frequency, nocturia, mod/severe

urgency, and UUI episodes vs. sham

•RCT 35 women with UUI PTNS vs. Placebo needle:− 71% vs. 0% had > 50 reduction in UIEF

Peters KM. J Urol. 2010; Finazzi-Agrò E et al. J Urol. 2010; Moossdorff-Steinhauser. Neurourol Urodyn 2013

Botulinum toxin type A injection

• FDA approval for use in neurogenic detrusor overactivity and overactive bladder

• OAB refractory to behavioral & medical Rx

• Binds to receptors on the membrane of cholinergic nerves � temporary denervation � muscle relaxation

Botulinum toxin type A injection

• Intravesical injection through cystoscope- Out- or in-patient setting- 100-200 U injected in 10-20 sites of 0.5-1 ml/injection- injected directly into the detrusor, sparing the trigone

• Repeat Injections- 50% had 2 injections- 20% had 3 injections- 10% had 4 injections- 10% had 5 injections- 10% had >6 injections

Dowson C et al. Eur Urol 2012

Intravesical Botulinum Toxin

•Systematic review

•3 Placebo controlled RCT’s

•Refractory OAB

•BTX vs. sham had:−� 4 UI episodes/dy

(95% CI: 2, 6)

−� QOL−� PVR, retention, UTI

Anger JT et al. J Urol 2010;183:2258-64; Cochrane Database SystRev 2007

Intravesical Botulinum Toxin

• Systematic review, N=16 articles level 1 & 2

• Botox had � % change maximum cystometric capacity and � % change in maximum detrusor pressure

• Botox had � risk (p

Anticholinergic vs. Botox for UUI

�ABC trial, PFDN�RCT, 6 mo, N=247 women with UUI (>5 on 3-day diary)• solifenacin 5-10 mg + intradetrusor saline• Intradetrusor botulinum + Placebo

• QOL improved similarly in both groups

Botox Medication P

Change in UUI/day -3.3 -3.4 0.81

Resolution UUI 27% 13% 0.003

Dry mouth 31% 46% 0.02

Catheter use (2 mo) 5% 0% 0.01

UTI 33% 13% 0.001

Visco AG et al. N Engl J Med. 2012;367:1803-13 Visco AG et al. NEJM 2012

OnabotulinumtoxinA vs. Sacral Neuromodulation

�Multicenter open-label RCT, 6 mo follow-up�381 women with refractory urgency urinary incontinence�OnabotulinumtoxinA 200 U cystoscopic intradetrusorinjection or sacral neuromodulation

�OnabotulinumtoxinA associated with:• Greater decrease in UUI episodes/day (-3.9 vs -3.3; P = .01)

‒ statistically significant but uncertain clinical importance• Greater improvement in symptom bother, satisfaction

• Increased UTI, need for self-cath

51 Amundsen CL et al. JAMA. 2016;316:1366-1374

Summary and Conclusion

Incontinence is common and treatable

�Simple diagnosis: 3IQ and UA�Simple treatments: Info ± Rx�Ask patient what she wants!�Combine treatments, flexibility�Refer if no improvement in 2–6 months

Educate and Empower!

Useful ReferencesHolroyd-Leduc JM, Tannenbaum C, Thorpe KE, Straus SE. What type of urinary incontinence does this woman have? JAMA 2008 Mar 26;299(12):1446-56. Review.

Holroyd-Leduc JM, Straus SEManagement of urinary incontinence in women: scientific review. JAMA 2004 Feb 25;291(8):986-95. Review.

Rogers RG. Urinary Stress Incontinence in Women. N Engl J Med 2008;358:1029-36.

DuBeau C. Treatment of urinary incontinence. Uptodate.com. June 2009.

DuBeau C. Epidemiology, risk factors, and pathogenesis of urinary incontinence. June 2009

Myers DL. Female mixed urinary incontinence: a clinical review. JAMA. 2014;311:2007-14

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