Management of Urgency Speaker Disclosure: Incontinence Astellas: - - PowerPoint PPT Presentation

Management of Urgency Incontinence

October 26, 2016

Leslee L. Subak, MD Professor, UCSF Departments of Obstetrics, Gynecology & Reproductive Science Epidemiology & Biostatistics, and Urology Chief, SFVAMC Gynecology Co-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 Risk

Age (per 5 years) 30% Live birth 30% Modifiable or Preventable Oral 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 Incontinence

Symptom 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

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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%

<0.001 Total UI

• 46%
• 25%

0.04

Behavioral Treatment for UI

• 5. Pelvic Floor Exercises
• Squeeze your bottom like you are trying to hold back

gas (should feel around your vagina as well)

• Hold for 2 seconds and relax for 2 seconds (increase

each by 1 second each week until 10 seconds each)

• 6. Timed voiding / bladder retraining
• 7. Bladder control strategies
• Urge control: “Freeze and Squeeze”
• Stress control: “Squeeze before you Sneeze” (lift, etc.)

Verbal and written instructions

Burgio KL. 2002; Goode PS. 2003; Dumoulin C 2010; Fantyl 1991

Meta-analysis: PFMT vs. no Rx

12 RCT’s with 672 women

• moderate to high risk of bias
• variation in interventions used, study

populations, and outcome measures report of cure or improvement with PFMT

• better continence specific quality of life
• less leakage on office pad test.
• longer training period α greater benefit

Dumoulin C, Hay-Smith J. Cochrane Database Syst Rev 2010

Patient Information vs. Behavioral Rx

• 222 women with Urge UI: RCT

Improvement

• Self-help booklet

59%

• Verbal/vaginal instruct

69%

• Biofeeback

63% Not statistically different

Bottom line: Educate & Empower!

Burgio KL. JAMA. 2002;288:2293

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

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Medication

OAB Medications

Relax the bladder Symptom relief Patient-Directed Balance:

OAB Medications

Anticholinergic/Antimuscarinic mechanism

Adverse effects: dry mouth/eyes constipation, urinary retention confusion, anxiety, somnolence headache, dizziness nausea, dyspepsia tachycardia, palpitations Contraindications: narrow angle glaucoma hepatic/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: Antimuscarinic

Efficacy: Placebo controlled trials

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

Active comparator trials

• UI episodes:
• xybutynin 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

UI Placebo 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 UI Behav 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. YOGA
• 2. 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
• veractivity 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 Syst Rev 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<0.001):

− urinary tract infection (21% v. 7%) − intermittent self-catheterisation (12% v. 0%)

Intervention N studies/pts %∆ daily Frequency %∆ daily urgency %∆ daily leak Placebo 9/772 −5 (2) −19 (3) −13 (5) Botox 16/1380 −29 (3) −38 (6) −59 (4) P-Value <0.001 0.02 <0.001

Mangera et al. Eur Urol 2014

Leslee L. Subak, MD Non- Surgical Treatment of UI

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 intradetrusor injection 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

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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 References

Holroyd-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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