Urinary Incontinence If you dont ask they wont

Urinary Incontinence: If you don’t ask, they won’t tell! Martha Spencer Division of Geriatric Medicine, Providence Health Care Associate Program Director, Postgraduate Medicine Clinical Instructor, UBC

Objectives Case‐based approach to non‐pharmacological and pharmacological management of: 1. Female community‐dwelling patient with urgency 2. Male patient with nocturia

Case 1: Mrs. S • 84 yo female, widowed, living alone in apartment • Urinary incontinence x 5 years • Symptoms • Frequency‐ 10 x/day, 4 x/night • Leakage with urgency • Occasional leaking with cough, getting out of chair • No hesitancy, intermittency or sensation of incomplete emptying • 4‐ 5 pads/day, 1‐ 2 pads/night • No dysuria, hematuria or recurrent UTI • Soft BM q 1‐ 2 days • Drinks 6 cups of water, 2 cups of tea, 1 cup of coffee/day

Mrs. S • PMHx: • Type 2 diabetes • Hypertension • Chronic venous insufficiency • Chronic pain due to osteoarthritis in hands and knees • History of falls • Mild cognitive impairment • Insomnia • Medications: • Metformin- 1 g po bid • Amlodipine 10 mg po daily • Furosemide 20 mg po bid • Celecoxib 100 mg po bid • Gabapentin 100 mg po tid • Lorazepam 0. 5 mg po qhs

Medications and UI Abrams et al. Incontinence. 5 th International Consultation on Incontinence. 5 th Edition, 2013.

Medications and UI Abrams et al. Incontinence. 5 th International Consultation on Incontinence. 5 th Edition, 2013.

Physical exam n. Difficulty getting up from a chair, undresses slowly n. Slow gait (1. 0 m/s) n. BP 130/70 lying, 100/60 standing (postural dizziness) n 2+ bilateral pedal edema n. Sacral innervation intact n. Anal wink intact, good anal tone, no stool on DRE n. No vaginal prolapse, moderate atrophy n. Weak pelvic floor muscles n. Positive stress test in the upright position n. Post‐void residual urine volume 45 m. L n. Mini‐mental cognitive exam 26/30

Investigations • GFR 60 • Hb. A 1 C= 9. 8% • Urinalysis negative • No indication for invasive tests!

What Type of Incontinence? • Urgency incontinence • Stress incontinence • Functional incontinence Multifactorial Incontinence

Nonpharmacological treatment

What is the Evidence? q q q q December 2015 11 trials (RCT, quasi-randomized) 6000 participants Weight loss interventions- 4 trials Decreasing fluid intake- 3 trials Decreasing caffeine- 3 trials Eliminating soy- 1 trial Imamura M, Williams K, Wells. M, Mc. Grother C. Lifestyle interventions for the treatment of urinary incontinence in adults. Cochrane Database of Systematic Reviews 2015, Issue 12. Art. No. : CD 003505. DOI: 10. 1002/14651858. CD 003505. pub 5.

Other lifestyle interventions • No observational or RTC data to recommend any lifestyle interventions for prevention of UI • Physical activity • Non‐RCT data suggests that moderate exercise may decrease UI/OAB symptoms • Smoking • UI/OAB symptoms may improve with smoking abstinence • Caffeine • Reduction in caffeine intake recommended, but evidence limited (small RCT with n= 14, cross‐sectional data based on self‐report) • Constipation • Small observational trials show association between chronic straining and UI Abrams et al. (2017). Incontinence, 6 th International Consultation on Incontinence.

Behavioural interventions • Pelvic floor muscle training (PFMT) • Effective as a stand‐alone treatment, as part of a multi‐component strategy and as part of more general exercise programs • Supervised PFMT should be offered as a first‐line conservative therapy for women of all ages with UI (Level 1 evidence, Grade A recommendation) • Effective at reducing pelvic floor symptoms in women with prolapse (Level 1 evidence, Grade A recommendation) • Weak evidence suggests that PFMT just as effective as drug therapy and that combination of drug therapy + PFMT more effective than either treatment lone Abrams et al. (2017). Incontinence, 6 th International Consultation on Incontinence.

Cochrane Review 2018: PFPT Dumoulin C, Cacciari L, Hay‐Smith EC. Pelvic floor muscle training versus no treatment, or inactive control treatments, for urinary incontinence in women. Cochrane Database of Systematic Reviews 2018, Issue 10. Art. No. : CD 005654. DOI: 10. 1002/14651858. CD 005654. pub 4

Behavioural interventions Scheduled voiding regimens: • Bladder training (BT)‐ should be recommended as a first‐line conservation therapy for UI in women • Start with 1 hr intervals and increase by 15‐ 30 min intervals until q 2‐ 3 hr voiding intervals achieved • Consider self‐monitoring with diary/log • Importance of supervising HCP • Consider different strategy if no improvement after 3 weeks • BT likely as effective as drug therapy • Timed voiding • No high quality evidence to support efficacy in cognitively intact women Abrams et al. (2017). Incontinence, 6 th International Consultation on Incontinence.

Abrams et al. (2017). Incontinence, 6 th International Consultation on Incontinence.

Back to Ms. S…. .

Evidence-based conservative management • Trial caffeine reduction • Physical exercise‐ to increase gait speed and decrease falls risk • Referral to pelvic floor muscle physiotherapist • Instruction + self‐management tools for bladder training • Medication review: n. Taper Lasix, taper Lorazepam n. Replace NSAID with Acetominophen n. Replace Amlodipine with Ramipril (lower dose) n. Add Gliclizide ER 30 mg po daily to optimize DM control • Pharmacological Rx?

Pharmacological Rx? If so, when? • For most, consider 6‐ 8 weeks trial of non‐pharmacological treatment • Who to consider starting on pharmacological therapy earlier: • Younger patients (more evidence about adverse effects, fewer adverse effects) • Few comorbidities • Few medications • Cognitively intact • Severe bother

Drug therapy for urgency urinary incontinence Two targets: n. Reduce the strength and frequency of bladder contractions during the voiding phase n. Antimuscarinic agents n. Botulinum toxin n. Enhance bladder relaxation during the bladder storage phase n. Beta 3 receptor agonists

Pharmacological Rx n. Antimuscarinics: ‐Oxybutynin (Ditropan) ‐Tolterodine (Detrol) ‐Darifenacin (Enablex) ‐Solifenacin (Vesicare) ‐Fesoterodine (Toviaz) ‐Trospium (Santura) n. Beta‐ 3 agonist: ‐Mirabegron (Myrbetriq)

Anticholinergic Agents for OAB: Potential Crossing of Blood-Brain Barrier BBB Vasculature CNS P-g. P • ++ • • • Trospium (Trosec) Darifenacin (Enablex) Fesoterodine (Toviaz) Tolterodine (Detrol) + Solifenacin (Vesicare) Oxybutynin (Ditropan) + Low lipophilicity Charged Relatively bulky (> 400) P-g. P Substrate • Low lipophilicity • Charged • Relatively bulky (> 400) • Lipophilic • Charge unknown • Relatively bulky (> 400) • High lipophilicity • Neutral charge • Relatively small (≤ 400) Adapted from: Todorova A et coll. J Clin Pharmacol. 2001; 41: 636‐ 644. Callegari et al. Br J Clin Pharmacol. 2011; 72: 2: 235‐ 246 Chancellor MB et al. Drugs Aging. 2012 April; 29(4): 259‐ 273 ++ ++ ++ + + ++ + +

FORTA Classifications Class A (absolutely) Indispensable drug, clear‐cut benefit in terms of efficacy/safety ratio proven in elderly patients for a given indication Class B (beneficial) Drugs with proven or obvious efficacy in the elderly, but limited extent of effect or safety concerns Class C (careful) Drugs with questionable efficacy/safety profiles in the elderly, to be avoided or omitted in the presence of too many drugs, lack of benefits or emerging side effects; review/find alternatives Class D (don’t) Avoid in the elderly, omit first, review/find alternatives Wehling M. J Am Geriatr Soc. 2009; 57(3): 560 ‐ 1.

LUTS FORTA Classification: OAB drugs Class A (absolutely) Indispensable drug, clear‐cut benefit in terms of efficacy/ safety ratio proven in elderly patients for a given indication Class B (beneficial) Drugs with proven or obvious efficacy in the elderly, but limited • extent of effect or safety concerns Fesoterodine Drugs with questionable efficacy/safety profiles in the elderly, to be avoided or omitted in the presence of too many drugs, lack of benefits or emerging side effects; review/find alternatives • • • Darifenacin Mirabegron Extended-release oxybutynin Solifenacin Tolterodine Trospium Class D (don’t) Avoid in the elderly, omit first, review/find alternatives • • Immediate release oxybutynin Propiverine Class C (careful) Oelke M et al. Age Aging 2015: 1 -11.

• 13 trials of high/moderate quality • 11‐ Antimuscarinic • 2‐ Duloxetine

Systematic review- pharmacological Rx elderly/frail elderly Results • Oxybutynin (only drug studied in frail elderly at time of publication)‐ no effect on UI or QOL (4 trials) • Anticholinergics (Darifenacin, Fesoterodine, Solifenacin, Tolterodine, Trospium)‐ decrease in UI (mean= 1/2 leak/24 hrs) (7 trials) • Adverse effects‐ dry mouth, constipation • Data insufficient for quality of life, cognitive effects • Data insufficient for Duloxetine (SUI) • No studies on Mirebegron or estrogen (at time of publication)

Fesoterodine in the Frail Elderly 562 frail elderly with urgency urinary incontinence, average 75 (range 65 -91) with a mean of 8 -9 health conditions, 1 -in-4 taking > 11 meds Placebo Fesoterodine Mean change from baseline in LS Mean (SE) Change UUI Episodes/24 h (n=248) (n=255) Week 4 (n=250) (n=256) Week 12 3‐day diary dry‐rate at 12 weeks P <0. 001 P = 0. 002 36% placebo 51% Fesoterodine Du. Beau CE, Kraus SR, Griebling TL et. al. Effect of Fesoterodine in Vulnerable Elderly Subjects with Urgency Incontinence: A Double-Blind, Placebo Controlled Trial. J Urol (2014). 191: 2; 395 -404)

Du. Beau CE, Kraus SR, Griebling TL et. al. Effect of Fesoterodine in Vulnerable Elderly Subjects with Urgency Incontinence: A Double-Blind, Placebo Controlled Trial. J Urol (2014). 191: 2; 395 -404)

Wagg, A. , Arumi, D. , Herschorn, S. , Angulo Cuesta, J. , Haab, F. , Ntanios, F. , . . . & Oelke, M. (2017). A pooled analysis of the efficacy of fesoterodine for the treatment of overactive bladder, and the relationship between safety, co‐morbidity and polypharmacy in patients aged 65 years or older. Age and ageing, 46(4), 620‐ 626.

Fesoterodine- pooled analysis, Wagg 2017 • 10 double‐blind RCTs • N=4040, >65 years old • Logistic regression analysis of different variables in the prediction of treatment emergent adverse effects (TEAEs) Wagg, A. , Arumi, D. , Herschorn, S. , Angulo Cuesta, J. , Haab, F. , Ntanios, F. , . . . & Oelke, M. (2017). A pooled analysis of the efficacy of fesoterodine for the treatment of overactive bladder, and the relationship between safety, co-morbidity and polypharmacy in patients aged 65 years or older. Age and ageing, 46(4), 620 -626.

Wagg, A. , Arumi, D. , Herschorn, S. , Angulo Cuesta, J. , Haab, F. , Ntanios, F. , . . . & Oelke, M. (2017). A pooled analysis of the efficacy of fesoterodine for the treatment of overactive bladder, and the relationship between safety, co-morbidity and polypharmacy in patients aged 65 years or older. Age and ageing, 46(4), 620 -626.

TEAEs- Comorbidity Wagg, A. , Arumi, D. , Herschorn, S. , Angulo Cuesta, J. , Haab, F. , Ntanios, F. , . . . & Oelke, M. (2017). A pooled analysis of the efficacy of fesoterodine for the treatment of overactive bladder, and the relationship between safety, co-morbidity and polypharmacy in patients aged 65 years or older. Age and ageing, 46(4), 620 -626.

TEAE- Concomitant medications Wagg, A. , Arumi, D. , Herschorn, S. , Angulo Cuesta, J. , Haab, F. , Ntanios, F. , . . . & Oelke, M. (2017). A pooled analysis of the efficacy of fesoterodine for the treatment of overactive bladder, and the relationship between safety, co-morbidity and polypharmacy in patients aged 65 years or older. Age and ageing, 46(4), 620 -626.

Mirebegron Wagg, A. , Cardozo, L. , Nitti, V. W. , Castro‐Diaz, D. , Auerbach, S. , Blauwet, M. B. , & Siddiqui, E. (2014). The efficacy and tolerability of the β 3‐adrenoceptor agonist mirabegron for the treatment of symptoms of overactive bladder in older patients. Age and ageing, 43(5), 666‐ 675.

Efficacy Wagg, A. , Cardozo, L. , Nitti, V. W. , Castro‐Diaz, D. , Auerbach, S. , Blauwet, M. B. , & Siddiqui, E. (2014). The efficacy and tolerability of the β 3‐adrenoceptor agonist mirabegron for the treatment of symptoms of overactive bladder in older patients. Age and ageing, 43(5), 666‐ 675.

• Most common S/E: • HTN (similar to Tolterodine) • UTI • Nasopharyngitis >75 yo group‐ also headache, dry mouth, extremity pain • Lower discontinuation rate with Mirebegron vs. Tolterodine Wagg, A. , Cardozo, L. , Nitti, V. W. , Castro‐Diaz, D. , Auerbach, S. , Blauwet, M. B. , & Siddiqui, E. (2014). The efficacy and tolerability of the β 3‐adrenoceptor agonist mirabegron for the treatment of symptoms of overactive bladder in older patients. Age and ageing, 43(5), 666‐ 675.

Mirabegron- in combination with antimuscarinics • Symphony trial (Abrams et al. , 2015)‐ Mirabegron and Solifenacin, 6 combination groups vs. 5 monotherapy groups vs. placebo • Significantly reduced number of micturitions/24 hrs with all combination groups vs. Solifenacin alone + trend for increasing effect with increasing doses of Solifenacin and Mirabegron • All treatment groups (including placebo) had reductions in UI episodes, no difference between treatment groups vs. placebo Abrams P, Kelleher C, Staskin D, et al. Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double‐blind, dose‐ranging, phase 2 study (Symphony). Eur Urol 2015; 67: 577– 588.

Mirabegron- in combination with antimuscarinics • SYNERGY (Herschorn et al, 2017)‐ Solifenacin 5 mg + Mirabegron 25/50 mg vs. monotherapy • Greater reduction in UI with combination groups vs. monotherapy and placebo (difference of approx. 0. 6 less UI episodes vs. placebo an 0. 25 less than monotherapy) • Overall‐ no. clinically significant difference with combination therapy Herschorn S, Chapple CR, Abrams P, et al. Efficacy and safety of combinations of mirabegron and solifenacin compared with monotherapy and placebo in patients with overactive bladder (SYNERGY study). BJU Int 2017; 120: 562– 575.

Mirabegron- in combination with antimuscarinics • BESIDE study (Drake et al, 2016)‐ non‐responders to Solifenacin 5 mg after 4 weeks • Combination showed greater reduction in UI episodes vs. Solifenacin 5 mg ( ‐ 1. 80 vs. ‐ 1. 53 UI episodes/24 hrs) • Combination non‐inferior to Solifenacin 10 mg • Adverse events highest in Solifenacin 10 mg (mostly anticholinergic side effects) • Sub‐group analysis for older adults (Gibson et al, 2017) • No difference in efficacy for >65 or >75 yo groups • Older groups more likely to have adverse events (especially constipation in >75 yo group), cardiac events <2% across all groups • Cognitive adverse events not reported Drake MJ, Chapple C, Esen AA, et al. Efficacy and safety of mirabegron add‐on therapy to solifenacin in incontinent overactive bladder patients with an inadequate response to initial 4‐week solifenacin monotherapy: a randomised double‐blind multicentre phase 3 b study (BESIDE). Eur Urol 2016; 70: 136– 145. Gibson W, Mac. Diarmid S, Huang M, et al. Treating overactive bladder in older patients with a combination of mirabegron and solifenacin: a prespecified analysis from the BESIDE study. Eur Urol Focus 2017; 3: 629– 638.

Mirabegron- in combination with antimuscarinics Bottom line • No data to suggest clinically relevant difference between monotherapy vs. combination therapy (and even vs. placebo? ) • MAY be able to avoid some anticholinergic side effects by opting for combination therapy • Some evidence that patient‐reported outcomes may be better with combination therapy group (greater chance of achieving >50% reduction in UI episodes and complete cure of UI) (Macdiarmid et al, 2016) Mac. Diarmid S, Al‐Shukri S, Barkin J, et al. Mirabegron as add‐on treatment to solifenacin in patients with incontinent overactive bladder and an inadequate response to solifenacin monotherapy. J Urol 2016; 196: 809– 818.

Case 2: Mr. B • 80 yo male, living with his wife • Avid gardener, walks his dog 60 min/day • No falls, no cognitive concerns “Doctor, I wake up at least 4 times/night to empty my bladder and it is driving me crazy!”

Mr. B • Frequency 5 x/day, 4‐ 5 x/night • Occasional urgency (not bothersome), no urgency incontinence • Had TURP 10 years ago (no complications) that resolved prior weak stream, hesitancy and intermittency • No other abdominal/pelvic surgeries • No hematuria, UTIs • Normal bowel habits (soft, q 1‐ 2 days) • Trialed on Flomax by GP but no improvement in nocturia

What would you do next? 1. 2. 3. 4. Add Finasteride Send him for urodynamic studies Do a bladder diary Trial Mirabegron

BLADDER DIARY DAY 1 Time DRINKS What kind/how much? TRIPS TO THE BATHROOM How much urine did you pass (m. L)? DID YOU FEEL A STRONG URGE TO GO? Urine leakage Circumstances of urine leakage (yes, no) 6: 30 a. m. ½ glass water 200 ml yes � On the way to the bathroom 7: 00 a. m. 1 cup tea, ½ glass juice 8: 00 a. m. 9: 00 a. m. 1 glass water 75 ml yes 150 ml yes 10: 30 a. m. 75 ml yes � Coughing 12 p. m. 1 cup tea, 1 glass milk 1 p. m. 100 ml yes � Running water, washing dishes 2: 30 p. m. ½ glass water 150 ml yes 3: 30 p. m. 1 cup tea 250 ml yes � Coming home from the store 5 p. m. 1 cup tea 6 p. m. 1 glass water 125 ml yes 7 p. m. 1 glass cola 125 ml yes � On the way to the bathroom 8 p. m. 100 ml yes 10 p. m. 1 glass water 150 ml yes Midnight 300 ml yes 2 a. m. Don’t know � While asleep 3: 30 a. m. ½ glass water 300 ml yes 5 a. m. 300 ml yes TOTAL 11 cups (2625 m. L) 11 daytime voids/4 night-time voids. Vol 2400 m. L 14 Urgency episodes 6 incontinence episodes

Mr. B • Bladder diary summary (1 day): • Total fluid consumed= 1550 ml (none after 6 pm)‐ water, milk, 1 cup of coffee • Total urine output= 1530 ml • Daytime frequency= 5 voids • Nighttime frequency= 4 voids • Daytime urine output= 918 ml • Nighttime urine output= 612 ml >30% of total 24 hr urine production occurring at night= nocturnal polyuria! • Mild daytime urgency x 1, no incontinence episodes

Nocturnal polyuria • “Flat‐lining” of normal nocturnal ADH peak • Other possible contributors= decline in GFR and reduced renal concentrating ability (lower daytime urine production) • Occurs in ¼ adults >60 years old • Most common LUTS‐ >70% for males and females • Nocturnal polyuria is the main cause of nocturia in older adults (75% of cases) • Nocturia associated with: • • Poor concentration Poor work performance Daytime somnolance Poor sleep for bed partner Gibson, W. , & Wagg, A. (2017). Incontinence in the elderly, 'normal'ageing, or unaddressed pathology? . Nature Reviews Urology, 14(7), 440.

Treatment • Lifestyle/behavioral‐ avoid drinking excessively or late at night, avoid caffeine/alcohol around bedtime, proper sleep hygiene • Rule our underlying medical causes • Pedal edema (CHF, venous insufficiency, etc) • Obstructive sleep apnea • Central cause of reduced ADH • Consider concurrent OAB and BPH (but do not always blame the prostate in men!!!) • Desmopressin

Desmopressin • Desmopressin‐ 0. 1 mg po daily (starting dose) • Monitor for hypo. Na within 1 week (ideally within 72 hrs), consider checking Na prior to initiating Rx especially if history of hypo. Na • Women, elderly at at higher risk • Caution of concurrent drugs that may cause hypo. Na • Other formulations: • Low‐dose oral disintegrating tablets (25, 50 mcg) available in Canada (Nocdurna)‐ $$$ • Intranasal (emulsified, microdose) formulations available (Noctiva)‐not in Canada

54% of Desmopressin group vs. 16% of placebo group obtained >40% reduction in nocturnal voids (intention‐to‐treat analysis) Mattiasson, A. , Abrams, P. , Van Kerrebroeck, P. , Walter, S. , & Weiss, J. (2002). Efficacy of desmopressin in the treatment of nocturia: a double‐blind placebo‐controlled study in men. BJU international, 89(9), 855‐ 862.

• • Increase in mean time to first nocturnal void= 49 min Response seen in 1 week and sustained OR of achieving >33% reduction in nocturnal voids= 1. 85 No Na<125, 3 patients with Na <130 Sand, P. K. , Dmochowski, R. R. , Reddy, J. , & van der Meulen, E. A. (2013). Efficacy and safety of low dose desmopressin orally disintegrating tablet in women with nocturia: results of a multicenter, randomized, double‐blind, placebo controlled, parallel group study. The Journal of urology, 190(3), 958‐ 964.

Nocturia- Summary • Most commonly caused by nocturnal polyuria • Very common in older adults • Do bladder diary to diagnose nocturnal polyuria (>30% of 24 hr urine production at night) • No strong evidence for non‐pharmacological treatment • Consider desmopressin‐ quite effective but watch Na, especially in older women

Questions?