Management of Lower Urinary Tract

Symptom with Overactive Bladder

(LUTS OAB)

Dr Bambang Sasongko Noegroho, SpB., SpU-K

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 OAB IS UNDERTREATED DUE TO UNDERDIAGNOSIS

Prevalence is similar
in both males and
females and
increases with age2

of the global population

have OAB1,2

Commonly occurs with other

comorbidities:2

of patients with
symptoms don’t seek
treatment2
is how long female patients wait Diabetes Neurological
before consulting a physician3 mellitus disease

OAB, overactive bladder

.

1. Irwin DE, et al. BJU international. 2011;108(7):1132-1138.

2. Chuang YC, et al. Low Urin Tract Symptoms. 2019;11:48-55.
3. Dmochowski RR, et al. Curr Med Res Opin. 2007;23:65-76.
 OAB HAS A CONSIDERABLE FINANCIAL IMPACT ON
PATIENTS
Annual costs associated with OAB for patients in the community setting are estimated to be:

Lost
Productivity

Diagnosis
USD$841.24 Routine Care
million dollars

USD$77.98 USD$1,562.64
million dollars million dollars
Treatment Health-Related

USD$2,798.99 49% of annual USD$3,887.74

million dollars costs are direct1 million dollars

51% considered
indirect costs1

Direct costs are defined as treatment, routine care and diagnosis.

Indirect costs are defined as health-related and lost productivity.
OAB, overactive bladder.

1. Hu TW, et al. Urology. 2003;61:1123-8.

 OAB HAS SHARED SYMPTOMATOLOGY WITH OTHER
COMMON UROLOGIC CONDITIONS1
Misdiagnosis may occur owing to shared symptomatology with recurrent UTIs and BPH

Shared symptoms (OAB/UTI): Shared symptoms (OAB/BPH):

OAB
o Urgency o Urgency
o Frequency o Frequency
o Nocturia

Discrete symptoms:
Discrete symptoms:
o Dysuria
o Hesitancy
o Haematuria
o Intermittency
NOTE:
UTI BPH o Sensation of incomplete voiding
Unlike in OAB, all UTI symptoms tend to be acute

BPH, benign prostatic hyperplasia

OAB, overactive bladder
UTI, urinary tract infection

1. Nik-Ahd F, et al. Current Urology Reports. 2018;19(11):94

 EAU GUIDELINES: APPROPRIATE SCREENING TOOLS
The following methods and tools are recommended by the EAU guidelines as part of the OAB diagnostic evaluation: 1

Patient history and Patient questionnaires Voiding diaries Urinalysis and urinary
physical examination tract infection
including comorbidities

Post-void residual volume Urodynamics Pad testing Imaging

1. EAU Guidelines. Edn. presented at the EAU Annual Congress Amsterdam, 2020. ISBN 978-94-92671-07-3.
 OABSS: A SIMPLE, RELIABLE DIAGNOSTIC TOOL

A self-reported symptom assessment questionnaire designed to quantify four OAB symptoms into a single score,
with higher score:1

Daytime frequency

Night-time
frequency

Urgency

Urge incontinence

If the total score is over 3 points and the Q3 score over 2 points, OAB is diagnosed.
If the total score is 5 or less: Mild, 6‒11: Moderate, 12 or more: Severe

OAB, overactive bladder.

1. Homma Y, et al. Urology. 2006;68(2):318-323.

 CONSIDERATIONS WHEN TREATING OLDER PATIENTS

The prevalence of OAB Patients with OAB are 1.3 –

increases with age1
Reaching an estimated
prevalence of 30% in
people ≥65 years2
2.3x more likely to experience
Management of OAB a fall3
in the elderly requires
best balance between
Falls are the leading
efficacy, tolerability,
cause of injuries in older
and safety2
adults which can lead to
death4

OAB, overactive bladder

1. Eapen RS, et al. Res Rep Urol. 2016, 8, 71-6.
2. Macdiarmid SA, et al. Rev Urol. 2008, 10, 6-13.
3. Szabo SM, et al. Adv Ther. 2018, 35, 1831-1841.
4. Soliman Y, et al. Rev Urol. 2016;18:28-32
 THE IMPORTANCE OF TREATING OAB IN OLDER
PATIENTS
Phase IV Pillar Study1
• Study assessing the efficacy, safety, and
tolerability of mirabegron compared to
placebo.
• Patients ≥65 years with OAB and
incontinence.
• Patients had a mean of 8.2 comorbid GORD
Hypertonic
Bladder
Osteoarthritis Hypertension
conditions and 6.5 concomitant
Mirabegron 29.4% 35.5% 33.0% 58.2%
medications at baseline.
Placebo 30.5% 32.8% 39.1% 55.0%
• Likely to have impairment in daily
activities and to be at increased risks of
falls and fracture.

GORD, Gastro-oesophageal reflux disease

OAB, overactive bladder.

1. Wagg A, et al. Eur Urol. 2020 Feb;77:211-220. 2. Macdiarmid SA, et al. Rev Urol. 2008, 10, 6-13.
 RISKS OF ANTICHOLINERGIC ADVERSE EVENTS

While effective, treatment with antimuscarinics may lead to anticholinergic adverse events
in older patients with OAB1,2
Dry Mouth
Systematic review and meta-
AEs3
analysis of 16 RCTs in adults ≥65
with OAB:3 Constipation

• AEs and discontinuations more

Any AE
common in patients given
antimuscarinics than placebo. Discontinuations3

Dry Mouth
• Higher incidence of dizziness,
dyspepsia, urinary retention,
headache, and urinary tract
infection in patients given
antimuscarinics. Adapted from Vouri et al. 2017

AE, Adverse event; OAB, Overactive bladder.

1. Wagg A, et al. Eur Urol. 2020 Feb;77:211-220. 2. Kachru, N.; et al. Drugs aging. 2016, 33; 755-763. 3. Vouri SM, et al. Arch Gerontol Geriatr. 2017 Mar-Apr;69:77-96.
 RISK OF COGNITIVE DECLINE AND IMPAIRMENT

Antimuscarinic drug usage is associated with and impairment in elderly patients.1

• Long-term use is associated with increased cognitive impairment.2
Retrospective case-control analysis of 20,246 patients from Taiwan National Health Insurance Research
Database.1
• Risk of cognitive impairment was 2.46-fold higher in patients who used bladder antimuscarinic for ≥1 year
than unexposed patients.
• Risk increased proportionally with dose of antimuscarinic drugs used.

1. Harnod T, et al. Sci Rep. 2021, 11 (1), 4827.

2. Perry EK, et al. Ann Neurol. 2003, 54 (2), 235-238.
 RISK OF FALLS AND FRACTURES

Retroactive claims database study in 154,432 patients with OAB in the US.
• High anticholinergic burden significantly associated with 1.4-fold higher risk of falls and fractures
compared to no burden.1
• Healthcare cost associated with fall or fracture is 50% higher in patients with OAB with high
anticholinergic burden compared to patients without burden.2

Treatment considerations need to be tailored to reflect the higher risk of anticholinergic

adverse events in older patients with OAB.

1. Szabo SM, et al. BMJ Open. 2019, 9 (5), e026391.

2. Lozano-Ortega G, et al. Pharmacoecon Open. 2021, Mar;5(1):45-55.
 GUIDELINE RECOMMENDATION
EAU 2020 recommendation for use of antimuscarinic drugs for urinary incontinence in the elderly. 1

Recommendations from the 2020 EAU Guidelines on urinary incontinence in adults

Summary of evidence for use of antimuscarinics in the elderly Evidence level

Long-term antimuscarinic treatment should be used with caution in elderly

Strong
patients especially those who are at risk of, or have, cognitive dysfunction

Summary of evidence for use of antimuscarinics in the elderly Evidence level

Oxybutynin may worsen cognitive function in elderly patients. 2

Mirabegron has been shown to be efficacious and safe in elderly patients. 1b

Long-term antimuscarinic treatment should be used with caution in elderly patients

especially those who are at risk of, or have, cognitive dysfunction

EAU: European Association of Urology

1. EAU Guidelines. Edn. presented at the EAU Annual Congress Amsterdam, 2020. ISBN 978-94-92671-07-3.
 ANTIMUSCARINICS IN OAB MANAGEMENT

Central Nervous
System
Antimuscarinics act through
inhibition of muscarinic receptors on
the detrusor myocyte, responsible Safety and tolerability
for bladder contraction, leading to
less spontaneous detrusor Iris/ciliary body
Reduce involuntary
activity voiding.1 Central bladder contractions
Lacrimal gland
Nervous
System Salivary glands Examples:3,4
Reduce OAB
Muscarinic receptors are distributed symptoms including: • Oxybutynin
Heart Quality • Solifenacin
at multiple sites in the body, which of life • Tolterodine
can lead to a variety of side effects:2 Gallbladder Micturition frequency • Trospium chloride
nocturia
Stomach

Colon Urge urinary

incontinence
Bladder
(detrusor muscle)

1. Chung E, et al. Med J Aust 2018;208:41-45.

2. Abrams P, et al. Br J Pharmacol 2006;148:565-578.
3. Corcos J, et al. Can Urol Assoc J. 2017;11:e142-e73.
4. Leron E, et al. Curr Urol. 2018;11:117-25.
 CHALLENGES WITH ANTIMUSCARINIC THERAPY

Poor Persistence1 Antimuscarinic cycling1

Adherence to antimuscarinic therapy is reportedly
low (18%) and almost half discontinue their first
prescribed antimuscarinic.
Most discontinue within the first year due to lack of
efficacy, adverse events, and/or cost.
Discontinuation of an antimuscarinic is followed by a
switch to another antimuscarinic.
Patient can cycle from 1 to 6 antimuscarinics with
out addition benefit, leading to sub-optimal care.

Polypharmacy and anticholinergic burden2,3

Antimuscarinics can increase the anticholinergic burden in
patients.

Elderly patients have higher risk of cognitive dysfunction and

alteration in CNS metabolism.

CNS = Central Nervous System

1. Chancellor MB, et al. Int Urol Nephrol. 2016;48:1029-1036.

2. Nambiar AK, et al. Eur Urol. 2018;73:596-609.
3. Wagg A, et al. Eur Urol. 2020;77:211-20.
 MIRABEGRON: A FIRST-IN-CLASS BETA-3 AGONIST

Proven efficacy1,2,3,4 Favourable safety profile5

As monotherapy Does not contribute to anticholinergic burden

Improved QoL6,7 Cost-effectiveness8

Clinically meaningful improvements MIRABEGRON Low healthcare utilisation
in QoL and health status

Quick onset of action9 Better persistence10,11

Reported as early as 2 weeks, Observed up to 3 years, significantly longer
similar to antimuscarinics when administered in first‐ or second‐line

QoL, Quality of life.

1. Nitti VW, et al. J Urol. 2013;189:1388-1395. | 2. Kelleher C, et al. European urology. 2018;74(3):324-333.
3. Chapple C, et al. European urology. 2015;67(1):11-4. | 4. Drake MJ, et al. European urology. 2016;70(1):136-45.
5. Lozano-Ortega G, et al. Drugs Aging. 2020;37:801-816. | 6. Chapple CR, et al. Int Urogynecol J. 2013;24:1447-1458
7. Freeman R, et al. Curr Med Res Opin. 2018;34:785-793 | 8. Nazir J, et al. Pharmacoecon Open. 2017;1:25-36
9. Kato D, et al. Low Urin Tract Symptoms. 2019;11:O152-O161. 10. Soda T, et al. Neurourol Urodyn. 2020;39:2527-2534. 11. Andersson KE, et al. Ther Adv Urol. 2018;10:243-256.
 MIRABEGRON IS ASSOCIATED WITH A FAVOURABLE
TOLERABILITY IN PATIENTS WITH OAB
According to a meta-analysis of randomised
control trials from 2000–2017, mirabegron
was significantly better tolerated regarding:

Dry Mouth
(21/22 active comparators)

Constipation
(9/20 active comparators)

Urinary Retention
(7/10 active comparators)

Mirabegron is as effective as antimuscarinic therapy with fewer bothersome side effects

1. Kelleher C, et al. Eur Urol. 2018;74:324-333.

 MIRABEGRON HAS SIMILAR CARDIOVASCULAR
SAFETY WHEN COMPARED WITH ANTIMUSCARINICS
Comparison of cardiovascular and mortality outcomes
In a real-world observational post-marketing during current use of mirabegron or antimuscarinics1
safety study, rates of:

• MACE
• AMI
• Stroke

were no higher with mirabegron versus

antimuscarinics.1

AMI, acute myocardial infarction; CI, confidence interval;

CV, cardiovascular; MACE, major adverse cardiovascular event; Ref, reference group.
1. Hoffman V, et al. Drug Safety. 2021;44:899-915
 MIRABEGRON IS ASSOCIATED WITH HIGHER LEVELS
OF TREATMENT PERSISTENCE

Post-marketing survey1
• OAB is a chronic Persistence rates with mirabegron were:
condition requiring 65.8% → 52.9% → 46.7%
long-term treatment
1 year 2 years 3 years
and persistence1
• 65%–86% of patients
under antimuscarinics Retrospective review3
discontinue treatment “Treatment persistence with
mirabegron was significantly longer
after one year2
than that with antimuscarinics when
administered as either the first‐ or
second‐line medication”

OAB, Overactive bladder

1. Kato D, et al. Low Urin Tract Symptoms. 2019;11:O152-O161.
2. Dhaliwal P, et al. Clin Interv Aging. 2016;11:755-760.
3. Soda T, et al. Neurourol Urodyn. 2020;39:2527-2534.
Efficacy and safety of mirabegron in
older patients
 POOLED 12-WEEKS TRIALS

Pooled data from three 12-weeks, Phase 3 RCTs in patients with OAB1
• ≥8 micturitions/24 h and ≥3 urgency episodes with or without urgency incontinence over 3 days before
randomisation.

Run-in period (2 weeks) Treatment period (12 weeks)

Randomisation n = 1324 with

Treatment arm mirabegron 50 mg

Placebo

Placebo arm n = 1328

Single-blinded

OAB, overactive bladder.

1. Wagg, A, et al. Age Ageing. 2014, 43; 666-675.
 POOLED 12-WEEKS TRIALS: MICTURITIONS

Mirabegron
Placebo

Mirabegron 50 mg significantly reduced

micturition frequency vs placebo in patients ≥65
years and ≥75 years.1

1. Wagg, A, et al. Age Ageing. 2014, 43;666-675.

 POOLED 12-WEEKS TRIALS: INCONTINENCE

Mirabegron
Placebo

Significantly reduced daily incontinence

episodes in patients ≥65 years and ≥75 years1

No loss of efficacy with mirabegron

in older patients with OAB

§Statistically
significant difference versus placebo at the 0.05 level with multiplicity adjustment .
1. Wagg, A, et al. Age Ageing. 2014, 43;666-675.
POOLED 12-WEEKS TRIALS: SAFETY AND TOLERABILITY

Incidence of dry mouth:1 Well-tolerated:1

• Similar to placebo. • No age-related differences in tolerability
• Compared to tolterodine: Up to six times over a 1 year follow-up in older patients
lower for people aged ≥ 65 years and four aged ≥ 65 and ≥ 75 years old.
times lower for people aged ≥ 75 years.

1. Wagg, A, et al. Age Ageing. 2014, 43;666-675.

 PILLAR PHASE IV

Phase IV study assessing efficacy, safety, and tolerability of mirabegron in patients

≥65 years with OAB and urgency incontinence

Treatment period Completed

Placebo run-in
(12 weeks) follow up
(2 weeks)
Patients

Randomisation
• ≥65 years
• ≥1 incontinence Co-primary endpoints
episodes Mirabegron, (25 mg
Change from baseline
• ≥3 urgency with option to dose-up n = 405
to end of treatment in
episodes grade to 50 mg at wk 4 or 8)
mean number of:
3 or 4 Placebo • Micturitions/24h
• ≥8 micturition • Incontinence
episodes/day episodes/24h
Placebo n = 396

Double-blinded

OAB, overactive bladder.

1. Wagg A, et al. Eur Urol. 2020 Feb;77:211-220.
PILLAR PHASE IV: MICTURITIONS

Mirabegron Mirabegron

Significant reduction in micturition

frequency/24 h in both patients <75 years
and ≥75 years1

CI, confidence interval; SE, standard error.

1. Wagg A, et al. Eur Urol. 2020 Feb;77:211-220.
PILLAR PHASE IV: INCONTINENCE EPISODES

Mirabegron Mirabegron

Significant reduction in incontinence

episodes/24 h in both patients <75 years
and ≥75 years1

CI, confidence interval; SE, standard error.

1. Wagg A, et al. Eur Urol. 2020 Feb;77:211-220.
 PILLAR PHASE IV: IMPACT ON COGNITION
Percentage of patients with MoCA score change at Week 12
No significant change in MoCA total
score from baseline to EoT in
mirabegron compared to placebo1

Adapted from Griebling et al. 2020

Mirabegron did not contribute to drug-related cognitive side-effects in patients ≥65 years of age with OAB

EoT, End of treatment; MoCA, Montreal Cognitive Assessment; OAB, Overactive bladder
1. Griebling TL, et al. BMC Geriatr. 2020;20:109.
 BELIEVE: QUALITY OF LIFE
Prospective, non-interventional, real-world study of 848 patients prescribed Mirabegron for
OAB in Europe.

OAB-q subscores from baseline to 10-12 months1

Improved symptom bother score and total

HRQoL Score 10-12 months after mirabegron
use in patients ≥65 years.1

*≥10 points difference from baseline. MID: Minimally important difference; HRQoL, Health-related quality of life; OAB-q, Overactive bladder questionnaire.
1. Foley S, et al. Int J Urol. 2019;26:890-896.
 NETWORK META-ANALYSIS: SAFETY OF MIRABEGRON

Network meta-analysis of 11 RCTs (n = 7170 patients ≥65 years) with dry mouth and constipation incidence data.

Odds Ratio (95% CI)*

TEAE
Dry mouth Constipation
Mirabegron 0.76 (0.26–2.37) 1.08 (0.39–3.02)
Antimuscarinics 3.78 to 7.85 2.12 to 4.66
(4.18–11.86 to 0.86–33.08) (1.97–5.24 to 0.98–23.76)
*Compared with placebo

Favourable safety profile compared to antimuscarinics.

Does not contribute to adverse events typically associated with anticholinergic burden.1

RCT, Randomized controlled trial.

1. Lozano-Ortega, et al. Drugs aging. 2020, 37; 801-816.
SUMMARY

• OAB is undertreated due to underdiagnose and OAB has shared symptoms with other
common urologic conditions
• Guideline recommendation mentioned that OAB commonly treated with antimuscarinic,
even though it came with several challenges
• Mirabegron associated with better safety compare to antimuscarinic, come with higher
persistance but similar cardiovascular safety
• Mirabegron 50 mg significantly reduced micturition frequency, improved symptom bother
score and total HRQoL Score in elderly patients
• Mirabegron did not contribute to drug-related cognitive side-effects in patients ≥65 years
of age with OAB
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