CUA: Overactive Bladder (2017)

See Original Guideline

Definitions

• ICS Definition of OAB
  1. Urinary urgency
  2. With or without urgency urinary incontinence (UUI)
  3. Often accompanied by frequency and nocturia
  4. In the absence of urinary tract infection (UTI) or other obvious pathology

Epidemiology

• Prevalence in Canada: 13.9% (Herschorn et al. population-based study)
• Prevalence similar in men and women, however, sex-specific differences in OAB symptoms
  • Women: prevalence of OAB with and without UUI in women is similar
  • Men: prevalence of OAB without UUI (OAB "dry) >> with UUI (OAB "wet")
• Prevalence of OAB symptoms increases with age in both sexes

Natural History

• OAB is not life-threatening but has a significant negative impact on daily activities, mental health, sexual function, and marital satisfaction. Its impact on QOL plays a major role in the decision to treat patients. Furthermore, OAB symptoms are linked to depressive illness.
  • Domains affected by OAB: P-SWORD
    1. Psychological concerns
    2. Sexuality
    3. Work productivity
    4. IsOlation
    5. Recreational life
    6. Daily life

Diagnosis and Evaluation

• Recommended (4): H+P, urinalysis, questionnaire, voiding diary (3-7 days)
  1. History and Physical Exam
     • History
       • Symptoms and signs that characterize OAB
         • Questions about urinary symptoms associated with OAB should be subdivided into (SVPMO):
           • Storage problems (frequency, urgency, nocturia, incontinence)
           • Voiding symptoms (hesitancy, straining, poor and intermittent flow)
           • Post-micturition symptoms (sensation of incomplete emptying, post-micturition dribble)
           • Other symptoms (nocturnal enuresis, dysuria)
         • Rapidity of onset, duration of symptoms, and baseline symptom levels
       • Severity of bladder symptoms and influence on patient’s QOL and day-to-day activities
         • Severity can be assessed by asking about pad usage, including pad weight, size, number of used pads, and number of urinary incontinence episodes per day.
       • Fluid intake habits
         • Patients should be asked about how much fluid they drink each day, what type of fluids they prefer (with a special consideration for caffeine intake as an exacerbating factor for urgency and frequency), and how many times they void over a 24-hour period.
           • Excessive or inadequate intake can produce or exacerbate some of the OAB symptoms.
         • Assessment of other potential bladder irritants (alcohol, carbonated drinks) is also important and provide an opportunity to educate the patients about modifiable habits
       • In women, a thorough obstetric and gynecological history may help to understand the underlying cause and identify factors that may influence treatment decisions.
       • Comorbidities
         • May produce or worsen OAB symptoms including neurological diseases (i.e., stroke, Parkinson’s disease, multiple sclerosis, spinal cord injury), endocrine disorders (i.e., complicated and uncontrolled diabetes, diabetes insipidus), urological conditions (i.e., BPH, urolithiasis, recurrent urogenital infections, bladder/prostate cancer), respiratory dysfunctions with chronic cough (i.e., chronic obstructive pulmonary disease), fecal motility disorders (constipation or fecal incontinence), chronic pelvic pain, mobility deficits, prior pelvic surgeries, pelvic cancers, and pelvic radiation.
           • OAB and bladder outlet obstruction (BOO) due to benign prostatic hyperplasia are common comorbid conditions
         • Psychiatric disorders such as depression, dementia and anxiety can contribute to abnormal voiding patterns.
         • Ensure that there are no contraindications or risk factors for potential complications with the introduction of OAB pharmacotherapy. Conditions to consider include
           • Cardiac history, in particular a prolonged QT interval, functional gastrointestinal pathology, myasthenia gravis, or uncontrolled narrow angle glaucoma, due to concerns with anticholinergics
           • Uncontrolled hypertension due to concerns with beta-3 agonist
           • Renal and liver impairment due to metabolism of anticholinergics and beta-3 agonists.
       • Medication use
         • Both prescribed and over-the-counter may precipitate or worsen OAB symptoms. Diuretics and sympathomimetics can cause urgency, frequency, and urgency incontinence.
       • Exclude other disorders that could be the cause of the patient’s symptoms
     • Physical exam
       • General evaluation of mental status, cognitive impairment, obesity, physical dexterity, and mobility
       • Abdominal and pelvic examination
         • Pelvic examination should assess tissue quality and sensation, urethra, pelvic floor supports/pelvic organ prolapse, and stress incontinence (cough test).
       • Digital examination of the vagina and/or rectum should be performed
       • Neurological examination with a special attention to the sacral neuronal pathways from S1 to S4 with the assessment of perineal sensation, bulbocavernosus reflex, rectal sphincter tone, and ability to contract the anal sphincter should be performed in the presence of any neurological symptoms.
  2. Urinalysis
     • If evidence of infection is detected, a urine culture should be performed and the infection treated appropriately.
       • After recovering from infection, patient evaluation should be again performed.
     • Low count bacteriuria (103–105 CFU/ml) might be associated with a wide range of LUTS and thus should be treated in patients with OAB symptoms.
       • Asymptomatic bacteriuria (>105 CFU/ml), highly prevalent in older persons, diabetic and catheterized patients, or in those with neurogenic lower urinary tract dysfunction, should not be routinely treated except in pregnant women and before urological procedures within the urinary tract
  3. Questionnaires
     • Options include:
       • Overactive Bladder Questionnaire (OAB-q)
       • Overactive Bladder Satisfaction Questionnaire (OABS)
       • Overactive Bladder Symptom Scores Questionnaire (OABSS)
       • Incontinence Impact Questionnaire (II-Q)
       • Urogenital Distress Inventory (UDI)
       • Each questionnaire can be used to improve assessment or monitoring of treatment outcomes. There is no evidence to indicate whether use of QOL or condition-specific questionnaires have an impact on outcomes from treatment
  4. Voiding diary
     • Semi-objective method of quantifying fluid intake and urological symptoms, such as frequency and possible episodes of urinary incontinence
     • Should document the time, type, and volume of fluid intake, urine volume voided, urgency episodes, and incontinence episodes
       • Can help the physician to differentiate between real small volume frequency (pollakiuria) and polyuria
     • A voiding diary observation with 3‒7 days duration is recommended
• Not recommended (4): PVR, cystoscopy, imaging, urodynamics
  1. PVR
     • Elevated PVR has a multifactorial etiology, but is usually caused by BOO or detrusor underactivity
     • Measurement of PVR is not mandatory for uncomplicated OAB patients with no risk factors or history of urinary retention.
     • PVR should be evaluated in patients with (3):
       1. Obstructive symptoms
       2. Neurological diagnoses
       3. History of either prostatic or incontinence surgery
       • In these patients, PVR should be measured prior to starting antimuscarinic treatment.
         • PVR >250‒300 ml warrants special attention if antimuscarinic treatment is intended and consideration should be made as to the existence of other possible pathologies.
  2. Cystoscopy
     • May be used to exclude other causes for the symptoms associated with OAB (bladder tumour, carcinoma in-situ, ulcers, bladder stones, foreign bodies, cystitis)
     • Recommended in patients with:
       1. Recurrent UTI
       2. Persistent pyuria
       3. Hematuria
       4. Bladder pain
       5. History of stress incontinence or pelvic surgery
       6. Suspected fistula
       7. Urethral diverticulum
       8. Urinary tract malformation
     • Considered in patients with:
       • Possible obstructive pathology
  3. Imaging
     • Neurological evaluation with spine imaging (CT, MRI) may be considered for patients with associated neurological symptoms.
  4. Urodynamics
     • OAB cannot be precisely and directly measured by UDS and is not recommended in the initial patient assessment
     • UDS is indicated when:
       1. Diagnosis remains uncertain after history and physical examination
       2. Symptoms do not correlate with physical findings
       3. Failed previous treatment
     • UDS should be taken into consideration in initial diagnosis of patients with:
       1. History of radical pelvic surgery and pelvic radiation
       2. Neurogenic voiding dysfunction
       3. Risk of upper urinary tract deterioration
     • The role of videourodynamics in OAB has not been determined and this technique is not currently recommended
     • The primary urodynamic abnormality underlying OAB is detrusor overactivity (DO)

Management of OAB

• First-line (3): lifestyle changes, behavioural therapies, patient education
  1. Lifestyle changes
     • Modifications of fluids/caffeine intake, weight control, dietary modifications, management of bowel regularity, smoking cessation, and optimization of other comorbidities (i.e., diabetes, CHF, OSA)
       • Smoking cessation is a recommendation even though a Cochrane review described the effect of nicotine on OAB as uncertain
     • Restricting fluid intake 2‒4 hours before bedtime, or after 6 pm decreases nocturia and nighttime incontinence
  2. Behavioural therapies
     • Bladder training includes the use of bladder diaries, bladder control strategies, timed voiding, prompted or scheduled voiding, or delayed voiding. These are all used to alter patient voiding patterns.
       • Rapid short pelvic contractions (termed, "quick flicks") have been shown to decrease bladder overactivity and urinary urgency.
     • Pelvic floor muscle therapy may also include urgency suppression, control strategies, and biofeedback
  3. Patient education
     • Education empowers patients to engage and participate in their treatment.

• Second-line (3): oral antimuscarinics, transdermal oxybutynin or oral beta-3 adrenoceptor agonist
  • Antimuscarinics (AM)
    • See Table 2 from Original Guideline
    • Mechanism of action
      • Antagonistic action on muscarinic receptors throughout the body
        • In the bladder, blocks the M2 and M3 receptors in the bladder and urothelium. M2 receptors predominate, but M3 receptors mediate cholinergic contractions.
      • Reduces involuntary detrusor contraction and reduces sensory afferent signalling
    • Available agents
      • 7 AM agents are available for OAB in Canada (daily dosing described):
        1. Oxybutynin [Ditropan] (immediate release [IR], extended release [ER], transdermal) ER: 5 or 10 mg
        2. Tolterodine (IR, ER) [Detrol, Detrol LA] ER 2mg or 4mg
        3. Darifenacin [Enablex] 7.5 or 15mg
        4. Trospium (IR) [Trosec]
        5. Solifenacin [Vesicare] 5 or 10mg
        6. Propiverine [Mictoryl] 30 or 45mg
        7. Fesoterodine [Toviaz] 4 or 8mg
      • Tolterodine has similar efficacy vs. oxybutynin but with less adverse events. ER preparations of oxybutynin or tolterodine provided similar improvement, while having less risk of dry mouth compared to IR. Immediate release formulations of AMs should be avoided if other formulations are available.
      • Transdermal oxybutynin and tolterodine-ER had similar rates of dry mouth, but the transdermal patch was associated with a higher withdrawal rate due to skin reactions. Therefore, tolterodine [Detrol]-ER would be a first choice compared to other formulations of tolterodine and oxybutynin.
      • The highest of the two doses for both solifenacin and fesoterodine (10 mg and 8 mg, respectively) had better clinical efficacy, but with higher rates of dry mouth. Fesoterodine had favourable clinical outcomes compared to tolterodine-ER, but higher rates of withdrawal due to adverse events and risk of dry mouth.
      • The overall adverse event profile is comparable for darifenacin, fesoterodine, transdermal oxybutynin, propiverine, solifenacin, tolterodine, and trospium. However oral oxybutynin, in doses of or exceeding 10 mg/day was associated with the worst adverse event profile
    • Adverse events
      • The most commonly adverse events reported groups are gastrointestinal, followed by neurological, ocular, and renal/genitourinary
      • The most common adverse events are (4):
        1. Dry mouth
        2. Pruritis
        3. Constipation
        4. CNS effects
      • Combining different AMs has limited clinical improvement with much higher adverse events
      • Anticholinergic burden has been linked to cognitive dysfunction but also with increased mortality and cardiovascular risk
    • Contraindications
      1. Uncontrolled narrow-angle glaucoma
         • Can induce or precipitate acute angle-closure glaucoma due to their antagonistic actions on M3 and M5 receptors in the eye
      2. Functional GI obstruction
      3. Myasthenia gravis
    • All require dose adjustment in hepatic or renal impairment, except oxybutynin
    • Tolterodine, darifenacin, tropsium, and solifenacin require dose adjustment with concomitant CYP3A4 inhibitors
    • Tolterodine most likely associated with QT prolongation
    • The potential of AM agents to improve OAB symptoms may not be fully realized for a period of 12 weeks, whereas side effects may present earlier with varying degrees of severity
  • Beta-3 adrenoreceptor agonist
    • Mechanism of action:
      • Activates beta-3 adrenoceptors
      • Increases bladder relaxation, improving bladder filling and storage of urine
    • Available agents
      • Mirabegron is the only approved beta-3 adrenoceptor agonist in Canada for the treatment of OAB
      • A starting dose of 25 mg and increasing to 50 mg, if needed, is recommended. The lowest dose is also recommended for renal and hepatic impairment
    • Efficacy
      • Similar efficacy in patients who were AM-naïve and those with prior use of AM
    • Adverse events:
      • The most common adverse events (3):
        1. Hypertension
        2. Nasopharyngitis
        3. UTI
        • Headache and back pain also occurred in the one-year study.
    • Contraindications (2):
      1. Pregnancy
      2. Severe uncontrolled hypertension
    • Mirabegron vs. AMs
      • Mirabegron 50 mg had a similar efficacy in decreasing the number of frequency, UUI episodes, and overall incontinence episodes, compared to all AM except for solifenacin.
        • Only solifenacin 10 mg had a higher efficacy than mirabegron 50 mg in the improvement of frequency and UUI episodes.
        • Mirabegron 50 mg had a similar rate of dry mouth and constipation compared to placebo. For dry mouth, all other AMs had higher rates than mirabegron 50 mg; for constipation, darifenacin 15 mg, fesoterodine 8 mg, solifenacin 5 mg, solifenacin 10 mg, and trospium 60 mg had higher rates than mirabegron 50 mg.
      • Although there is no direct comparison, mirabegron appears to have similar clinical effectiveness compared to most AMs, but has a different side-effect profile
  • Prescribing second-line treatment
    • The adverse event profile and possible contraindications should be considered when prescribing the drug of choice as second-line treatment.
    • The lowest recommended dose should first be prescribed, followed by dose increases in order to obtain the best clinical improvement while monitoring for adverse events.
    • If the initial selected drug is not tolerated or does not provide adequate symptom relief, patients should be offered an alternative medication, preferably with a different mechanism of action.
    • Patients who remain incontinent after the initial treatment with an AM could be offered combination treatment with solifenacin and mirabegron
    • UrologySchool.com takeaway: start with 50mg mirabegron. If not effective, solifenacin 5mg then 10mg. If still ineffective, consider combination solifenacin and mirabegron

• • Age-related changes in pharmacology
    • See Table 3 from Original Guideline
    • The age-related changes in pharmacology suggest that some UI drugs may be effective at lower than standard doses in frail older persons with concomitant decreased adverse effects
    • Immediate-release oxybutynin may be associated with cognitive impairment

• AMs for treatment of OAB remain as potentially inappropriate medications for frail older people
• Cholinesterase inhibitors treatment is associated with either precipitation or worsening of OAB symptoms. Although intuitively illogical, given the opposing pharmacological actions, there seems to be no reason not to use bladder AMs for older people with dementia, ensuring that the cholinesterase inhibitors is warranted and effective, that the incontinence is sufficiently bothersome to warrant treatment, and that the patient (where possible) and the caregiver are fully informed.

• Third-line treatments (3): Botox, PTNS, SNM
  • Onabotulinum toxin A
    • Mechanism of action
      • Inhibits acetylcholine (ACh) release at the presynaptic neuromuscular junction. Inhibited ACh release results in regionally decreased muscle contractility and atrophy at the injection site
    • Intradetrusor onabotulinum toxinA 100U is an effective, safe, and long-term treatment option for OAB with UUI refractory to second-line OAB pharmacotherapies
      • Doses of onabotulinumtoxinA should not exceed 360U every 12 weeks
      • 200U is recommended in neurogenic overactivity
    • Efficacy
      • Clinical effects begin within 5-7 days of injection, with maximal effects reached within 4-6 weeks
      • Median duration of effect: 7.6 months
    • Adverse events
      • Most common adverse events
        1. UTI
        2. Dysuria (12%)
        3. Bacteriuria (5%)
        4. Urinary retention (5%)
        5. Transient weakness
      • Rate of discontinuation due to lack of efficacy or adverse events was 5.7% and 5.1%, respectively.
    • Long-term treatment with onabotulinumtoxinA is well-tolerated, with no evidence of increasing occurrence of adverse events with repeat treatments.
    • Patients must be carefully counselled regarding the:
      1. Need for close follow-up; patients must be followed closely after initial treatment, with assessment of PVR for the possibility of acute urinary retention and need for catheterization.
      2. Possible need for catheterization (indwelling or CIC)
      3. Likelihood of repeat injections to maintain symptom improvement
    • If deemed effective and safe, a repeat injection can be offered at 6 months and adjusted according to individual response
  • Peripheral tibial nerve stimulation and sacral neuromodulation
    • Treatment effect of PTNS is similar compared to AMs, but with a more tolerable side effect profile
    • The treatment effects duration for SNM responders is similar to the pattern of PTNS in that maintenance of symptom improvement occurs only with continued use of the intervention.
    • Separating SNM from PTNS and onabotulinumtoxinA injections is the different adverse event profile, including the need for surgical re-intervention in up to 40% of patients, with up to 1/3 of patients in the majority of studies requiring revision. SNM was also complicated by pain at the stimulator site (3.3‒19.8%), pain at the lead site (4.5‒19.1%), lead migration (2.2‒8.6%), electric shock (5.5‒7.9%), and infection/irritation

• Additional treatment options
  • Indwelling catheterization, augmentation cystoplasty, or other urinary diversions are rare long-term management strategies for OAB and should only be considered after all other medical and surgical options have been exhausted and only after careful consideration of the likely benefits and risks.
    • Indwelling catheter
      • In the patient with contraindications to other treatment options, including intolerance to medications, allergy, severe debilitation or immobility, and cognitive deficit or expected cognitive decline, indwelling or intermittent catheterization may be tried.
      • However, this carries a high risk of catheter-associated UTIs, long-term issues of urethral erosion (indwelling urethral catheters), and development of bladder calculi, and comes at the requirement of patient compliance and/or caregiver support.

Questions

1. What is the ICS definition of OAB?
2. How does the prevalence of OAB differ between men and women?
3. What are the quality of life domains affected by OAB?
4. As per the 2017 CUA Guidelines on OAB, what is the recommended work-up of a patient with OAB? Not recommended?
5. What are the indications to treat asymptomatic bacteruria? Should a low bacterial count (103–105 CFU/ml) in a patient with OAB be treated?
6. When should PVR be evaluated in a patient with suspected OAB?
7. When is UDS indicated in a patient with suspected OAB?
8. What are the first-line treatment options for OAB?
9. What are the second-line treatment options for OAB?
10. Which receptors do anti-cholinergics act on in the bladder?
11. Which anti-cholinergic agents are available for treatment of OAB in Canada?
12. Which anti-cholinergic agents are associated with cognitive impairment?
13. Which anti-cholinergic agents should be avoided/require dose adjustment with renal dysfunction? Hepatic dysfunction?
14. What are potential adverse events related to the use of anti-cholinergic drugs to treat OAB?
15. What are the contraindications to use of anti-cholinergic drugs?
16. When should a patient expect symptom improvement after initiating an anti-cholinergic for OAB?
17. What are potential adverse events related to the use of beta-3-agonist drugs to treat OAB?
18. What are the contraindications to use of beta-3-agonist drugs?
19. What is the starting dose for the different drugs used in OAB?
20. What are the third-line treatment options for OAB?
21. What is the median duration of effect of intradetrusor botox?
22. What are potential adverse events related to the use of intradetrusor botox to treat OAB?
23. What are the fourth-line treatment options for OAB?

Answers

1. What is the ICS definition of OAB?
   • Urinary urgency, with or without incontinence, often associated with frequency and nocturia, in the absence of infection or other pathology
2. How does the prevalence of OAB differ between men and women?
   • Similar prevalence, women more likely to have OAB-wet
3. What are the quality of life domains affected by OAB?
   1. Daily life
   2. Recreational life
   3. Psychological concerns
   4. Isolation
   5. Sexuality
   6. Work productivity
4. As per the 2017 CUA Guidelines on OAB, what is the recommended work-up of a patient with OAB? Not recommended?
   • Recommended: History + physical, U/A, questionnaire, voiding diary
   • Not recommended: PVR, cystoscopy, imaging, urodynamics
5. What are the indications to treat asymptomatic bacteruria? Should a low bacterial count (103–105 CFU/ml) in a patient with OAB be treated?
   • Pregnancy and patients undergoing urologic procedures involving breach of mucosa
   • Yes since symptomatic
6. When should PVR be evaluated in a patient with suspected OAB?
   1. Obstructive symptoms
   2. Neurological diagnoses
   3. History of either prostatic or incontinence surgery
7. When is UDS indicated in a patient with suspected OAB?
   1. Diagnosis uncertain
   2. Symptoms to not correlate with physical exam
   3. Failure of treatment
   4. Neurogenic voiding dysfunction
   5. Prior pelvic surgery or radiation
   6. High risk bladder storage features
8. What are the first-line treatment options for OAB?
   1. Bladder training
   2. Pelvic floor physiotherapy
   3. Lifestyle changes
   4. Patient education
9. What are the second-line treatment options for OAB?
   1. Oral anti-cholinergics
   2. Beta-3 agonists
10. Which receptors do anti-cholinergics act on in the bladder?
    • M2 and M3 muscarinic receptors; M2 receptors predominate but M3 receptors mediate cholinergic contractions
11. Which anti-cholinergic agents are available for treatment of OAB in Canada?
    1. Oxybutynin
    2. Fesoterodine
    3. Tolterodine
    4. Solifenacin
    5. Darifenacin
    6. Tropsium
    7. Propiverine
12. Which anti-cholinergic agents are associated with cognitive impairment?
    • Oxybutynin
    • Solifenacin
13. Which anti-cholinergic agents should be avoided/require dose adjustment with renal dysfunction? Hepatic dysfunction?
    • Renal: tolterodine, fesoterodine
    • Hepatic: oxybutynin, tolterodine, solifenacin, darifenacin
14. What are potential adverse events related to the use of anti-cholinergic drugs to treat OAB?
    • Dry mouth
    • Pruritis
    • Constipation
    • CNS effects
15. What are the contraindications to use of anti-cholinergic drugs?
    • Uncontrolled narrow-angle glaucoma
    • Functional GI obstruction
    • Myasthenia gravis
16. When should a patient expect symptom improvement after initiating an anti-cholinergic for OAB?
    • 12 weeks
17. What are potential adverse events related to the use of beta-3-agonist drugs to treat OAB?
    1. UTI
    2. Nasopharyngitis
    3. HTN
    4. Back pain
    5. Headache
18. What are the contraindications to use of beta-3-agonist drugs?
    1. Pregnancy
    2. Uncontrolled HTN
19. What is the starting dose for the different drugs used in OAB?
    • Oxybutynin 5mg
    • Fesoterodine 4mg
    • Tolterodine 4mg
    • Solifenacin 5mg
    • Darifenacin 7.5mg
    • Tropsium
    • Propiverine 30mg
20. What are the third-line treatment options for OAB?
    1. Botox
    2. PTNS
    3. SNM
21. What is the median duration of effect of intradetrusor botox?
    • 8 months
22. What are potential adverse events related to the use of intradetrusor botox to treat OAB?
    1. UTI
    2. Dysuria
    3. Bacteruria
    4. Retention
23. What are the fourth-line treatment options for OAB?
    1. Indwelling cathter
    2. Augmentation
    3. Diversion