Weidner OAB Rx in Elderly

9/12/18

Urge urinary incontinence in the elderly: Evaluation, Medications, and Office Procedures ALISON C WEIDNER, MD OCTOBER 10 2018

I have no relevant financial disclosures

1 9/12/18

OAB in the elderly

• OAB is twice as prevalent in those >65 years old than those <45 years of age ◦ NOBLE Study, a population based survey in the US • Urinary symptoms have significant impact on QOL ◦ Increase risks of falls and fractures ◦ Increased risk of major depression • Costs of treatment are significant • By 2025 there will be 52 million adults in the US with lower urinary tract symptoms due to aging of the population

Stewart, World J Urol 2003 Littman, BJU Intl 2007

OAB in the elderly

• Pathways for treatment even for the general population can be less than effective • Co-morbidities in the elderly can make clinical paradigms for the general population a further challenge • The frail elderly are a special subpopulation meriting special caution • There is a dearth of level I evidence for interventions for OAB in the frail elderly ◦ There are no evidence-based guidelines for the assessment of UI in the frail elderly

DuBeau, Report of the 4th ICS Consultation Neurourol and Urodyn 2010

2 9/12/18

After this presentation, the participant will:

• Be able to describe the mechanisms of action of common pharmaceuticals for OAB in the lower urinary tract • Be able to describe systematic review evidence for the level of effectiveness for these therapies for OAB • Be able to discuss a paradigm for treatment of OAB tailored to the elderly • Be able to discuss the evidence to support second and third tier treatments for OAB in the elderly

After this presentation, the participant will:

3 9/12/18

Pharmaceutical treatment of OAB: Anti-muscarinics

• M 2 muscarinic receptors are the predominant subtype (comprising about 80% of all muscarinic receptors) in the bladder (detrusor and urothelium) • However, contraction of smooth muscle, including muscles in the urinary bladder, is mediated mainly by M3 receptors. • M 3 receptors are also involved in contraction of the gastrointestinal smooth muscle, saliva production, and iris sphincter function à side effects

[1]

Anti-muscarinics

•Mechanism of action: Antagonize the effects of acetylcholine at muscarinic receptors on the detrusor muscle •Potently and selectively bind to the M2 and M3 receptor subtypes > other muscarinic receptor subtypes •Inhibit involuntary detrusor contractions

[2]

4 9/12/18

Anti-muscarinics – currently available in US ◦ Darifenacin 7.5-15 mg daily ◦ Fesoterodine : 4-8 mg daily ◦ Oxybutynin: 5-15 mg daily ER ◦ Solifenacin: 5-10 mg daily ◦ Tolterodine: 2-4 mg daily ER ◦ Trospium: 20 mg BID or 60 mg daily ER

[2]

Anti-muscarinics

• Indications: • AUA/SUFU Guidelines 2015 [4]: First-line therapy for overactive bladder includes behavior and lifestyle modifications; however, when these approaches are insufficient, the mainstay of second-line therapy is pharmacologic treatment with either anti-muscarinics or !3 agonist

• With appropriate patient counseling, may be offered as a first line treatment option for OAB [2] • Contraindications: [1] • Untreated narrow (closed) angle glaucoma • GI obstruction: ileus, SBO, gastroparesis • Myasthenia gravis • Tachyarrhythm ias • Urinary retention (relative) • Dementia

5 9/12/18

!3-adrenergic agonists ◦ Mirabegron: 25-50 mg daily ◦ Solabegron (available in Europe) • Indication ◦ Mirabegron is FDA approved for the treatment of overactive bladder ◦ AUA/SUFU 2015 Guidelines for treatment of non-neurogenic OAB: “Clinicians should offer oral anti-muscarinics or oral b3 adrenoceptor agonists as second-line therapy.” [4]

• Mechanism of action: ◦ Acts on !3 adrenoreceptors of of the bladder wall and leads to detrusor relaxation during filling and storage phase of micturition

!3-adrenergic agonist • Contraindications: • Uncontrolled HTN (> 180/100) • Patients with bladder outlet obstruction (relative) • Use with caution in patients taking medications that are metabolized by CYP2D6 (metoprolol, desipramine, amitriptyline) as mirabegron inhibits this enzyme • Use with caution in patients taking digoxin or warfarin mirabegron has been shown to increase the systemic effects of these medications à monitor drug levels closely Side effects: • Most commonly reported adverse reactions (> 2%) were hypertension, nasopharyngitis, UTI and headache. [1]

6 9/12/18

Comparison of anti-muscarinics

• Objective: Examine the evidence available from randomized clinical trials about outcomes of pharmacologic management of overactive bladder in women and to summarize the comparative effectiveness evidence of available drugs for reducing voiding and resolving urine loss. • Relevant population: Non-neurogenic OAB undergoing pharmacotherapy with medication available in US, at least 75% women • Methods: Included only RCTs comparing drug to placebo and those that provided information on # daily voids and # UUI episodes per day with sample size of at least 50 [3]

7 9/12/18

Comparison of anti-muscarinics

• 50 RCTs included • 27,000 women • Median follow up 12 weeks • 98% studies were industry-funded • All medications were effective at improving one or more OAB symptoms. • Reductions in daily UUI episodes ranged from no improvement to up to 2.5 fewer episodes (95% confidence interval [CI] 1.82– 3.12) across all drug treatments. [3]

Comparison of anti-muscarinics

• Reductions in voids per day ranged from no change to 2.5 fewer (95% CI 1.39– 3.5). • Placebo significantly improved both UUI episodes (1.06, 95% CI 0.7– 1.4) and daily voids (1.2, 95% CI 0.72– 1.67). • Even with small-moderate effect on symptoms, medications were generally associated with fewer UUI episodes compared to placebo

[3]

8 9/12/18

Comparison of anti-muscarinics

• 18 studies compared drugs in pairs à generally designed to study noninferiority, would need larger sample sizes to eval for small differences between agents • In the majority of comparisons, neither drug was reported more effective at reducing either UUI episodes or voids per day with a few exceptions.

[3]

Comparison of anti-muscarinics

• Both oxybutynin extended release and tolterodine extended release demonstrated superiority in reducing incontinence episodes over tolterodine immediate release (4 studies) • Fesoterodine resulted in greater reductions in mean daily UUI episodes over tolterodine extended release.

[3]

9 9/12/18

Side effects of anti-muscarinics

[3]

Side effects of anti-muscarinics

[3]

10 9/12/18

Comparison of anti-muscarinics

• Conclusions: • Improvement in symptoms associated with medical management of OAB is modest and rarely fully resolves symptoms. • Relative paucity of data directly comparing agents, it is impossible to report that any specific agent is superior to any other in terms of efficacy or harms. • Almost all of these studies are industry-sponsored trials of relatively short duration with only modest improvements in outcome parameters. • Well-conducted trials of greater duration and sophistication, apart from industry, are crucial. [3]

Anti-muscarinics

• Poor long term compliance • Based on a systematic review of compliance, 60% of patients discontinue therapy within 6 months (Sexton et al 2011) [5] • Cost : • see table to right from a 2007 review of OAB pharmacotherapy at Baylor (Hesch 2007)

[3]

11 9/12/18

!3-adrenergic agonists

• Objective: To determine efficacy and safety of nonantimuscarinic treatments for overactive bladder • Included any study design and n>100 if at least one arm was a nonantimuscarinic therapy, or any comparative trial, regardless of number, if at least 2 arms were nonantimuscarinic therapies for OAB • 11 reviewers double-screened citations and extracted eligible studies • 99 comparative studies met inclusion criteria [8]

!3-adrenergic agonist ◦ Three RCTs of mirabegron, 1 RCT of solabegron ◦ Mirabegron vs placebo: Mirabegron (25-50 mg) is superior to placebo in 1 RCT for decreasing the # of UUI episodes at 12 months, and mirabegron (50-100 mg) was superior to placebo in decreasing # UUI episodes on diary at 12 weeks in another RCT but with increase in adverse events (URI, dizziness, nausea). ◦ Solabegron vs placebo: In 1 RCT, solabegron was superior to placebo in decreasing # of daily UUI episodes at 4 weeks with an increase in advers events (headache, nasopharangitis, dry mouth, constipation, hypertension) ◦ Mirabegron vs antimuscarinic (tolterodine): Mirabegron (100 mg) was similar to tolterodine extended-release (4 mg) at 12 weeks in an RCT for subjective outcomes (nocturia) and bladder diary outcomes (daily incontinence episodes, number of daily voids, and urine volume per void). ◦ Adverse events similar between mirabegron and tolterodine : HTN, UTI, dry mouth, nasopharangitis, headache, tachycardia, etc) ◦ Mirabegron vs other intervention: no studies identified [8]

12 9/12/18

OAB in the elderly: a perceptual syndrome

• ICS defines OAB as a symptom complex: “urgency, with or without urge incontinence, usually with increased frequency and nocturia”

• Normal control of bladder volume requires: ◦ A low pressure, compliant bladder reservoir ◦ The ability to relax the sphincteric mechanism and contract the detrusor smooth muscle to achieve voiding at an appropriate time and place ◦ Central abilities to perceive and control these relationships

Abrams et al, Urol, 2003

13 9/12/18

Paradigm for evaluation and treatment in the elderly:

• Who is the patient? • What are feasible treatment options? • What is a reasonable diagnostic evaluation, given these concerns?

Who is the patient?

• The patient ◦ The patient themselves may not perceive a problem with urinary control • Family • Nursing home ◦ Staffing or facilities may not permit necessary support for toileting assistance • Examples: ◦ The frail patient with incontinence and high PVR ◦ The patient with dementia and inattention to toileting

14 9/12/18

Frailty: frail patients are more likely to have:

• Depression • Poor cognition • Polypharmacy • Fecal incontinence

In managing the frail incontinent patient, the impact of comorbid diseases and their treatments should be considered

Wang, Rejuvenation Res 2017

Prevalence of OAB increases in the elderly and is associated with frailty

• 19.1% of men and 18.3% of women 60 years and older in the EPIC study • UUI is associated with impairments in QOL, anxiety, and depression • Patients with OAB in community or in nursing facilities have more morbidity and impairments than their counterparts without OAB • OAB and UUI may be an early marker for frailty • Frailty is much more common in patients with UI vs those without UI • 60% of men in Taiwanese study vs 32.3% for those without UI

Irwin, Eur Urol 2006 Wang, Rejuvenation Res 2017

15 9/12/18

What are feasible treatment options?

• What are the patient’s priorities and which treatments might best address them? • Functional decline or mobility issues may limit ability to cooperate with treatment • Transportation dependence may limit repeated visits • Diminished ability to withstand invasive treatments

• All of these may render some standard evaluation and treatment pathways unnecessary

What is a reasonable diagnostic evaluation?

• Guidelines for the general population must be tempered for the elderly • Individualize the evaluation: a multichannel urodynamic study may not be tolerable or inform treatment options • Assess patient expectations, goals, frailty, comorbidities

16 9/12/18

Treatment principles: first line therapy

• Lifestyle and behavioral modifications • This includes various forms of non-pharmacologic therapy • Four elements of non pharmacologic therapy for older adults: ◦ Communication (Education about OAB and treatment options) ◦ Behavior (Bladder training, timed voiding) ◦ Training (pelvic floor muscle training and techniques for urge suppression) ◦ Supportive measures (biofeedback or PTNS)

Treatment principles: first line therapy

• Address modifiable risk factors • Mobility • Falls risks • The four elements of non pharmacologic therapy can be successful especially for the community dwelling patient

• Many patients with OAB have immediate UI without warning For these patients, pharmaceutical management can be most effective

Burgio, Clin Geriatr Med 1986

17 9/12/18

Pharmacologic therapy: special issues

• First line therapy generally is with antimuscarinics • Efficacy is via M3 and M2, which also cause the most common side effects • Cognitive impairment is via the M1 in the CNS

• The ideal molecule would be highly specific for M3, and not cross into the CNS

• What is the evidence for specific antimuscarinics in the elderly?

Minimizing side effects

• Diminished penetration has been demonstrated by quaternary amines such as trospium chloride but this has not been conclusively demonstrated clinically • Darifenacin proposes to specifically target bladder M3 receptors • Limited data supports lack of negative effect of Darifenacin on cognition in older patients ◦ Evaluation of cognitive function was only tested in healthy elderly and not the frail or those with impaired cognition

Callegari, B J Clin Pharmacol 2011 Cetinel, Korean J Urol 2013 Wagg, Int J Clin Pract 2010 Kay, Eur Urol 2006

18 9/12/18

Minimizing side effects

• Dubeau et al published a trial specifically targeting OAB in community dwelling elderly with comorbidities and polypharmacy • A first study of OAB medical therapy in the elderly • RCT of fesoterodine vs placebo in 562, 82% were women • Fesoterodine group had significant decreases in UUI/24 hrs, voids, urgency, and had higher “dry diary” rates

• No decrease in Mini-Mental State Exam

Dubeau, J Urol 2014

Minimizing side effects

• What is the risk of long term anticholinergic medications use? • Anticholinergic exposure and cognitive decline in older adults: Effect of anticholinergic exposure definitions in a 3-year analysis of the Multidomain Alzheimer Preventive Trial (MAPT) study • 1400 patients 70 years of age and older • 7- 23% exposed to various anticholinergic medications depending on the scle used to define exposure • 64% experienced cognitive decline over 3 years • Regardless of the mental status scale used, there was no association with anticholinergic burden

Andre et al, Br J Clinc Pharmacol, 2018

19 9/12/18

B3 Agonists in the elderly

• Prospective subanalysis of 3, 12 week Phase III trials of Mirabegron in elderly • Mirabegron significantly decreased UUI episodes and frequency vs placebo with no loss of efficacy with age • Most common side effects HTN, nasopharyngitis, UTI (3-9%) • Dry mouth was 6x less common than with tolterodine

• Mirabegron was well tolerated in subjects with renal or hepatic impairment in one small pharmacokinetic study

Wagg et al, Int J Clin Prac 2010 Dickinson, Clin Drug Invest 2013

• Be able to describe the mechanisms of action of pharmaceuticals for OAB in the lower urinary tract • Be able to describe systematic review evidence for the level of effectiveness for these therapies for OAB • Be able to discuss important considerations regarding treatment of OAB in the elderly • Be able to discuss the evidence to support second and third tier treatments for OAB in the elderly

20 9/12/18

OnabotulinumtoxinA (Botox)

Indication • Axillary hyperhidrosis • Blepharospasm • Cervical dystonia • Chronic migraine • Limb spasticity • FDA approved for detrusor overactivity in patients with associated neurologic conditions such as MS or spinal cord injury in 2011 (200 units) • Approved in 2013 for idiopathic refractory OAB (100 units)

[15]

OnabotulinumtoxinA (Botox) Mechanism of action • Potent neurotoxin derived from anaerobic bacteria Clostridium botulinum • Acts primarily as a muscle paralytic by inhibiting presynaptic release of acetylcholine from motor neurons at the neuromuscular junction • Also affects afferent side by decreasing sensory response of c fibers

[15]

21 9/12/18

OnabotulinumtoxinA (Botox)

Technique* • Perform urinalysis to rule out UTI • Anticoagulation such as Coumadin/Plavix should be discontinued x 5-7 days prior • Prophylactic antibiotics administered at the discretion of the surgeon • Lithotomy position • Instill local anesthetic x 30 minutes prior • Reconstitute 100 units Botox in 10 ml of sterile 0.9% NS • Inject reconstituted Botox into detrusor muscle via flexible or rigid cystoscope • Needle should be inserted approximately 2 mm into detrusor, injections spaced 1 cm apart, approximately 20 injections of 1 ml • For final injection, 1 ml of sterile saline should be injected in order to deliver remaining Botox from needle into detrusor [*From Botox package insert] • Drain saline used for bladder visualization

OnabotulinumtoxinA (Botox): Response rates

• Duthie et al 2011 – Cochrane review of Botox for adults with OAB, 19 RCTs included

• The meta-analysis for urinary frequency and incontinence episodes favored Botox at both the 4-6 week and 12 week follow up points. • reduction in urinary frequency of - 6.50 episodes per day (- 8.92 to - 4.07), (P = < 0.00001) at 4 to 6 weeks. and - 3.37 episodes per day (- 5.15 to - 1.59), (P= 0.0002) at 12 weeks. • reduction in incontinence episodes of -1.58 (- 2.16 to -1.01), (P = 0.00001) at 4 to 6 weeks and - 2.74 (- 4.47 to -1.01), (P = 0.002) at 12 weeks • change in PVR favors placebo with an increase of PVR of 70.22 ml (30.63 to 109.81) in the Botox group, (P = 0.0005). [16]

22 9/12/18

OnabotulinumtoxinA (Botox): side effects • Urinary retention: Rovner et al 2011 - multicenter double blind dose response study of 5 doses (50-300 units). Reported efficacy, UDS parameters, safety. • For idiopathic OAB, rates of urinary retention with need for CISC increase with dose • 50 units – 0% • 100 units – 3.6% • 150 units – 9.1% • 200 units - 12.7% • 300 units -18.2% • Urinary tract infection: Feb 2017 Systematic Review and Meta-analysis of Botox for OAB: (RR: 2.73; 95% CI: 1.98- 3.78; P ≤ 0.00001) • Rate of UTI varies with each study – 44% in Brubaker et al 2008 study, 25% in other studies

Percutaneous Tibial Nerve Stimulation (PTNS)

• Indications: ◦ Idiopathic and neurogenic OAB ◦ Per AUA/SUFU 2015 Guidelines for treatment of OAB, “Clinicians may offer peripheral tibial nerve stimulation (PTNS) as third-line treatment in a carefully selected patient population.” ◦ Received FDA approval in 2000

23 9/12/18

Percutaneous Tibial Nerve Stimulation (PTNS)

• Mechanism of Action: ◦ Posterior tibial nerve is a mixed sensory-motor nerve arising from spinal roots L4-S3 ◦ Indirectly stimulates somatosensory afferent fibers of the sacral plexus (parasympathetics) thereby influencing signals to the bladder ◦ Involves specific receptors in the spinal cord which contribute to the effectiveness of neuromodulation ◦ Induces neural plasticity in the CNS

[20]

Percutaneous Tibial Nerve Stimulation (PTNS)

Technique: ◦ Treatment requires weekly 30 minute sessions x 12 consecutive weeks then monthly maintenance therapy

◦ 34 gauge needle electrode placed into the lower inner aspect of either leg 3-5 cm cephalad to the medial malleolus.

◦ Surface electrode placed using sticker adhesive and then the needle electrode is connected to a stimulator.

◦ Stimulation is low voltage (9 V) with 0–10 mA at a fixed frequency of 20 Hz and pulse width of 200 ms. • The amplitude is increased until the toes are seen to fan or the big toe to flex. Usually this is accompanied by a sensory response across the sole of the foot. • The current is set at the highest tolerated level and the stimulation is then continued for 30 min. The amplitude can be increased during the session as necessary. • Generated electrical pulse travels to the sacral plexus via posterior tibial nerve [20]

24 9/12/18

Percutaneous Tibial Nerve Stimulation (PTNS): response • Burton et al 2012 – Systematic Review and meta-analysis of PTNS for idiopathic OAB • Four RCTs compared PTNS with sham treatment showing a significant difference favoring PTNS [RR 7.02 95% confidence interval (CI) 1.69– 29.17] in improvement in UUI episodes/day by bladder diary • Two randomized trials compared PTNS with antimuscarinic medication with no significant difference in the change in bladder diary parameters between the treatments. • The pooled subjective success rate was 61.4% (95% CI 57.5–71.8) and objective success rate was 60.6% (95% CI 49.2–74.7). [20]

Percutaneous Tibial Nerve Stimulation (PTNS): AEs • Burton et al 2012 – Systematic Review and meta- analysis of PTNS for idiopathic OAB • No serious adverse events were reported. • Occasional transient side effects included pain, bruising, tingling or bleeding at insertion site, and leg cramp and numbness/pain under the sole of the foot. • In the studies that recorded actual numbers, 20/236 (8.5%) patients experienced the above-mentioned side effects. • When compared to antimuscarinic therapy, patients receiving PTNS reported significantly less constipation and dry mouth.

[20]

25 9/12/18

Percutaneous Tibial Nerve Stimulation (PTNS) • Response defined as 25% or 50% reduction in frequency or incontinence episodes1-2

• Maintenance therapy seems to be important3

• More data are needed

1. Govier et al. J Urology, 2001 2. Stoller. Eur Urol, 1999 3. van der Pal et al. BJU Int, 2006.

References

1. Walters, M. D., Karram, M. M.: Urogynecology and reconstructive pelvic surgery, Fourth editio. ed, p. 1 online resource. 2. Urinary Incontinence in Women. Female Pelvic Med Reconstr Surg, 21: 304, 2015 3. Reynolds, W. S., McPheeters, M., Blume, J. et al.: Comparative Effectiveness of Anticholinergic Therapy for Overactive Bladder in Women: A Systematic Review and Meta-analysis. Obstet Gynecol, 125: 1423, 2015 4. Gormley, E. A., Lightner, D. J., Burgio, K. L. et al.: Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline. J Urol, 188: 2455, 2012 5. Sexton, C. C., Notte, S. M., Maroulis, C. et al.: Persistence and adherence in the treatment of overactive bladder syndrome with anticholinergic therapy: a systematic review of the literature. Int J Clin Pract, 65: 567, 2011 6. Hesch, K.: Agents for treatment of overactive bladder: a therapeutic class review. Proc (Bayl Univ Med Cent), 20: 307, 2007 7. Alhasso, A., Glazener, C. M., Pickard, R. et al.: Adrenergic drugs for urinary incontinence in adults. Cochrane Database Syst Rev: CD001842, 2005

26 9/12/18

References

8. Olivera, C. K., Meriwether, K., El-Nashar, S. et al.: Nonantimuscarinic treatment for overactive bladder: a systematic review. Am J Obstet Gynecol, 215: 34, 2016 9. Mariappan, P., Alhasso, A., Ballantyne, Z. et al.: Duloxetine, a serotonin and noradrenaline reuptake inhibitor (SNRI) for the treatment of stress urinary incontinence: a systematic review. Eur Urol, 51: 67, 2007 10. Steers, W. D., Herschorn, S., Kreder, K. J. et al.: Duloxetine compared with placebo for treating women with symptoms of overactive bladder. BJU Int, 100: 337, 2007 11. Woodman, P. J., Misko, C. A., Fischer, J. R.: The use of short-form quality of life questionnaires to measure the impact of imipramine on women with urge incontinence. Int Urogynecol J Pelvic Floor Dysfunct, 12: 312, 2001 12. Guo, C., Yang, B., Gu, W. et al.: Intravesical resiniferatoxin for the treatment of storage lower urinary tract symptoms in patients with either interstitial cystitis or detrusor overactivity: a meta-analysis. PLoS One, 8: e82591, 2013 13. Andersson, K. E.: Treatment of overactive bladder: other drug mechanisms. Urology, 55: 51, 2000

References

14. Chin, H. Y., Lin, K. C., Chiang, C. H. et al.: Combination of baclofen and antimuscarinics to reduce voiding difficulty in treating women with overactive bladders. Clin Exp Obstet Gynecol, 39: 171, 2012 15. ACOG/AUGS Committee Opinion No. 604: OnabotulinumtoxinA and the bladder. Obstet Gynecol, 123: 1408, 2014 16. Duthie, J. B., Vincent, M., Herbison, G. P. et al.: Botulinum toxin injections for adults with overactive bladder syndrome. Cochrane Database Syst Rev: CD005493, 2011 17. Rovner, E., Kennelly, M., Schulte-Baukloh, H. et al.: Urodynamic results and clinical outcomes with intradetrusor injections of onabotulinumtoxinA in a randomized, placebo-controlled dose-finding study in idiopathic overactive bladder. Neurourol Urodyn, 30: 556, 2011 18. Lopez Ramos, H., Torres Castellanos, L., Ponce Esparza, I. et al.: Management of Overactive Bladder With OnabotulinumtoxinA: Systematic Review and Meta-analysis. Urology, 100: 53, 2017 19. Brubaker, L., Richter, H. E., Visco, A. et al.: Refractory idiopathic urge urinary incontinence and botulinum A injection. J Urol, 180: 217, 2008 20. Burton, C., Sajja, A., Latthe, P. M.: Effectiveness of percutaneous posterior tibial nerve stimulation for overactive bladder: a systematic review and meta-analysis. Neurourol Urodyn, 31: 1206, 2012