Medicamenteuze behandeling van aandrang urine-incontinentie is, na of naast conservatieve therapie, de eerste behandeling van keuze. Er zijn verschillende medicamenteuze behandelingen beschikbaar, waarbij de meeste ervaring is met antimuscarinica (ook vaak anticholinergica genoemd). Deze preparaten verschillen in farmacokinetische eigenschappen, maar hebben in meer of mindere mate (anticholinerge) vergelijkbare bijwerkingen, zoals droge mond, wazig zien of een veranderde cognitieve functie. Deze bijwerkingen zijn belangrijk om mee te nemen in de keuze voor deze medicatie, met name bij oudere patiënten. Onder ouderen wordt in vrijwel alle studies mensen boven de 65 verstaan, daarom baseert de werkgroep zich bij het schrijven van deze module op deze definitie. 

Daarnaast is er sinds de laatste herziening van de richtlijn (‘urine-incontinentie voor de 2^e / 3^de lijns zorg’) meer ervaring opgedaan met sympathicomimetica (beta3-agonisten) bij urine incontinentie. Zo is Mirabegron sinds 1 april 2014 in Nederland op de markt, waardoor er nu significant meer praktische ervaring met dit middel is opgedaan. Daardoor kan er een afgewogen advies gegeven worden over de plaats van dit middel in de behandeling van aandrang urine-incontinentie bij ouderen. Daarnaast is er toenemend literatuur over het ook in Nederland te verwachten sympathicomimeticum Vibegron. Kortom het is belangrijk om de plaatsbepaling van de verschillende medicamenteuze behandelmogelijkheden opnieuw te beoordelen voor oudere patiënten met aandrang urine-incontinentie. Bovenstaande ligt ten grondslag aan de herziening van deze module.

Antimuscarinic treatment versus placebo

1. Darifenacin versus placebo

1.1. Improvement of urine incontinence complaints (critical)

1.2. Quality of life (critical)

1.3. Adverse event (important)

1.3.1. Adverse event: dry mouth

1.3.2. Adverse event: obstipation

1.3.3. Adverse event: cognitive decline

2. Fesoterodine versus placebo

2.1. Improvement of urine incontinence complaints (critical)

2.2. Quality of life (critical)

2.3. Adverse event (important)

2.3.1. Adverse event: dry mouth

2.3.2. Adverse event: obstipation

2.3.3. Adverse event: cognitive decline

3. Oxybutynin versus placebo

3.1. Improvement of urine incontinence complaints (critical)

3.2. Quality of life (critical)

3.3. Adverse events (important)

3.3.1. Adverse event: dry mouth

3.3.2. Adverse event: obstipation

3.3.3. Adverse event: cognitive decline

4. Solifenacin versus placebo

4.1. Improvement of urine incontinence complaints (critical)

4.2. Quality of life (critical)

4.3. Adverse events (important)
4.3.1. Adverse event: dry mouth

4.3.2. Adverse event: obstipation

4.3.3. Adverse event: cognitive decline 

5. Tolterodine versus placebo

5.1. Improvement of urine incontinence complaints (critical)

5.2. Quality of life (critical)

5.3. Adverse events (important)

5.3.1. Adverse event: dry mouth

5.3.2. Adverse event: obstipation

5.3.3. Adverse event: cognitive decline

2. Mirabegron versus placebo or antimuscarinic treatment

1. Mirabegron versus placebo

1.1. Improvement of urine incontinence complaints (critical)

1.2. Quality of life (critical)

1.3. Adverse events (important)

1.3.1. Adverse event: dry mouth

1.3.2. Adverse event: obstipation

1.3.3. Adverse event: cognitive decline

2. Vibegron versus placebo

2.1. Improvement of urine incontinence complaints (critical)

2.2. Quality of life (critical)

2.3. Adverse events (important)

2.3.1. Adverse event: dry mouth

2.3.2. Adverse event: obstipation

2.3.3. Adverse event: cognitive decline

3. Vibegron versus tolterodine

3.1. Improvement of urine incontinence complaints (critical)

3.2. Quality of life (critical)

3.3. Adverse events (important)

3.3.1. Adverse event: dry mouth

3.3.2. Adverse event: obstipation; 3.3.3. Adverse event: cognitive decline

4. Mirabegron versus solifenacin

4.1. Improvement of urine incontinence complaints (critical)

4.2. Quality of life (critical)

4.3. Adverse events (important)
4.3.1. Adverse event: dry mouth

4.3.2. Adverse event: obstipation

4.3.3. Adverse event: cognitive decline

1. Antimuscarinic treatment versus placebo

Description of studies

Samuelsson (2015) performed a systematic review to assess the effects of pharmacotherapy for urinary incontinence in elderly and frail elderly populations. Randomized controlled trials and prospective controlled observational studies that evaluated interventions for drug treatment of urinary incontinence in the elderly and frail elderly population were included.

PubMed, EMBASE, Cochrane library and Cinahl databases were searched up to October 2013. In total, 13 studies were included in the review. The review by Samuelsson (2015) was used for the description of all published studies up until 2010. For the purpose of this guideline, the results of four RCTs matching de predefined PICO are summarized below (Chapple, 2007; Ouslander, 1995; Szony, 1995, Zinner, 2002). Chapple (2007) compared darifenacin with placebo, Ouslander (1995) and Szonyi (1995) compared oxybutynin with placebo, and Zinner (2002) compared tolterodine with placebo. Outcomes included urinary leakage, quality of life and adverse events.

1. Darifenacin versus placebo

Samuelsson (2015) included one RCT that compared darifenacin versus placebo (Chapple, 2007). Patients received 7.5 mg darifenacin daily with voluntary up-titration to 15 mg after 2 weeks for 12 weeks. 

2. Fesoterodine versus placebo

Dubeau (2014) performed a randomized, double-blind, placebo controlled, parallel group, multicentre trial to assess the efficacy and safety of flexible dose fesoterodine in medically complex vulnerable elderly subjects with urgency urinary incontinence (UUI). Men or women who were 65 years old or older with self-reported UUI symptoms for 3 or more months, a mean of 2 to 15 UUI episodes (voids that subjects rated with a score of 5 on the Urinary Sensation Scale), 8 or more micturitions per 24 hours on baseline 3-day bladder diary, and at least some

moderate bladder related problem on the Patient Perception of Bladder Condition (PPBC) who were determined to be vulnerable (at risk of deteriorating health) by a score of 3 or more on the VES-13 at screening were included. Besides, subjects had to be capable of adequate mobility for independent toileting (could use cane or walker) and independent completion of bladder diaries and study related questionnaires. Exclusion criteria were:

• Any condition contraindicating the use of fesoterodine
• Clinically significant hepatic disease or liver enzymes greater than 2 times the upper limit of normal
• Clinically significant renal disease and/or estimated creatinine clearance less than 30 ml per minute
• Neurological conditions that may specifically affect bladder function
• Previous surgery that might alter bladder function
• Advanced malignancy
• Clinically significant bladder outflow obstruction
• Post-void residual urinary volume (PVR) greater than 200 ml
• Predominant stress urinary incontinence
• Recurrent urinary tract infection
• Significant constipation
• Mini-Mental State Examination (MMSE) score less than 20
• Behavioural interventions or electrical stimulation within 8 weeks
• Antimuscarinic medication use within 3 weeks
• Initiation or variable dose of tricyclic antidepressants, a-blockers, oestrogens (within 4 weeks) or diuretics (within 2 weeks)
• An unstable medical condition
• Average resting heart rate of 90 beats per minute or greater

In total, 281 subjects were randomized to fesoterodine treatment, and 281 subjects received a placebo once daily for 12 weeks. Subjects started at a dose of 4 mg, and this could be increased to 8 mg at the 4-week visit. For subjects that escalated their dose to 8 mg, it could be returned to 4 mg at any time but could not increase it again to 8 mg. Groups were comparable at baseline. Outcomes of interest were mean number of UUI episodes per 24 hours, quality of life and adverse events.

Wagg (2013) performed a randomized, double-blind, placebo-controlled trial to determine the efficacy and safety of flexible-dose fesoterodine in elderly adults with overactive bladder (OAB). Men and women aged 65 years or older with OAB symptoms for 3 months or longer, a mean of eight or more micturitions and three or more urgency episodes per 24 hours on a 3-day bladder diary at baseline who self-reported at least some moderate problems on the Patient Perception of Bladder Condition (PPBC) questionnaire and had a MMSE score of 20 or greater were included. Besides, participants need to be able to complete micturition diaries and study-related questionnaires and adhere to study procedures. Exclusion criteria were:

• Hypersensitivity to the active substance (fesoterodine fumarate) or to peanut, soya, or any of the excipients
• Predominant stress incontinence as determined according to the investigator
• Significant bladder outlet obstruction
• Previous history of acute urinary retention requiring catheterization, severe voiding difficulties, or active urinary tract infection
• Clinically significant renal disease
• Multiple sclerosis or spinal cord injury
• Treatment with other antimuscarinics within 2 to 3 weeks before baseline
• Treatment with potent CYP3A4 inhibitors
• Intermittent or unstable use of diuretics or alpha-blockers or initiation of treatment within 2 weeks of baseline

In total, 392 patients received fesoterodine and 393 patients received placebo for 12 weeks. Subjects started at a fesoterodine dose of 4 mg, and this could be increased to 8 mg at 4 and 8 weeks. For subjects that escalated their dose to 8 mg, it could be de-escalated to 4 mg at 8 weeks. Groups were comparable at baseline. Outcomes of interest were urgency urinary incontinence episodes per 24 hours, quality of life, and adverse events.

3. Oxybutynin versus placebo

Lackner (2011) performed a randomized controlled trial to assess the efficacy of oral extended-release oxybutynin for urge urinary incontinence in older female nursing home residents with mild to severe cognitive impairment. Female nursing home residents of 65 years or older with urge urinary incontinence and mild to severe cognitive impairment (no delirium or diagnosis of dementia with Lewy bodies) were included. Besides, participants were ambulatory, able to communicate, had a post void residual urine volume of less than 150 mL and remain incontinent following a 2-day prompted voiding program conducted by investigators. Exclusion criteria were males, participants with unstable or severe medical conditions that precluded the use of oxybutynin, a terminal illness and the use of antimuscarinic, bisphosphonate, or acetylcholinesterase inhibitors during the month before or during treatment. In total, 26 subjects were allocated to extended-release oxybutynin 5 mg/day and 24 subjects received placebo for 4 weeks. Groups were comparable at baseline. The outcome of interest were urinary incontinence episodes.

Samuelsson (2015) included two RCTs that compared oxybutynin versus placebo (Ouslander, 1995; Szonyi, 1995). Patients included in Ouslander (1995) received oxybutynin 2.5-5 mg three times daily with prompted voiding for 20 days. Patients included in Szonyi (1995) received oxybutynin 2.5 mg twice daily and bladder training or a placebo and bladder training for 6 weeks.

4. Solifenacin versus placebo

Kosilov (2015) performed a randomized controlled trial to assess the effectiveness and safety of mirabegron and solifenacin for managing heavy symptoms of overactive bladder. Patients with severe symptoms of overactive bladder (the frequency of episodes of incontinence (EI) ³3/day) with an age over 65 years were included. Exclusion criteria were chronic active diseases including hypertension and intolerance to antimuscarinics and agonists of b3-adrenoreceptors. Sixty-three patients were treated with mirabegron (50 mg/day), 52 patients were treated with solifenacin (10 mg/day), and 59 patients were treated with placebo for 6 weeks. Outcomes of interest were the frequency of episodes of incontinence and adverse events.

5. Tolterodine versus placebo

Samuelsson (2015) included one RCT that compared tolterodine with placebo (Zinner, 2002). Patients received tolterodine extended release capsules 4 mg once daily for 12 weeks.

Results

1.     Darifenacin versus placebo

1.1  Improvement of urine incontinence complaints (critical)

Chapple (2007) reported the urgency urinary incontinence episodes per week after 12 weeks of treatment. Patients receiving darifenacin experienced between 14 and 19.8 episodes/week as compared to 13 to 21 episodes/week for patients treated with placebo. However, since no standard deviations were presented, no GRADE-assessment could be performed. 

1.2  Quality of life (critical)

Chapple (2007) reported the quality of life with the overactive bladder questionnaire (OABq). The mean change at week 12, was 22.9 (estimated SD 17.44) for patients receiving darifenacin (n= 266) and 16.8 (estimated SD 17.44) for patients receiving placebo (n= 133). This resulted in a mean difference of 6.10 (95%CI 2.47 to 9.73), translating in an SMD of 0.35 (95% CI 0.14 to 0.56), which was not clinically relevant.

1.3  Adverse events (important)

1.3.1. Dry mouth

Chapple (2007) reported that 59 of the 266 patients (22.2%) who received darifenacin had a dry mouth as compared to 5 of the 133 patients (3.8%) who received placebo (RR=9.83, 95%CI 3.14 to 30.78). This difference is clinically relevant favouring placebo.

1.3.2. Obstipation

Chapple (2007) reported that 41 of the 266 patients (15.4%) who received darifenacin had constipation as compared to 11 of the 133 patients (8.3%) who received placebo (RR=1.86, 95%CI 0.99 to 3.51). This difference is clinically relevant favouring placebo.

1.3.3. Cognitive decline

Not reported.

2. Fesoterodine versus placebo

2.1 Improvement of urine incontinence complaints (critical)

Dubeau (2014) reported the reduction in UUI episodes per 24 hours. At 4 weeks, a mean change of -2.36 episodes was found for patients treated with fesoterodine as compared to a mean change of -1.54 episodes for patients receiving placebo (p<0.001). At 12 weeks, a mean change of -2.84 episodes was found for patients who received treatment with fesoterodine as compared to a mean change of -2.20 episodes for patients who received placebo (p=0.002). Since no standard deviations have been reported, no GRADE assessment can be performed.

Wagg (2013) reported that the median number of UUI episodes per 24 hours decreased from 1.3 at baseline to 0.0 at week 12 for patients receiving fesoterodine and from 1.7 at baseline to 0.0 at week 12 for patients treated with placebo. Since no interquartile ranges were reported, no GRADE assessment can be performed.

2.2 Quality of life (critical)

Dubeau (2014) reported the total health-related quality of life (HRQL) score measured with the Overactive Bladder Questionnaire (OAB-q) which contained a 25-item HRQL scale with 4 domains. Higher scores indicated improvements. At 4 weeks, a mean HRQL of 17.8 (SE=1.4) was reported for patients treated with fesoterodine, as compared to a mean HRQL of 12.0 (SE=1.4) for patients who received placebo, resulting in an SMD of 0.25 (95% CI 0.08 to 0.41). At 12 weeks, a mean HRQL of 23.1 (SE=1.5) was reported for patients treated with fesoterodine, as compared to a mean HRQL of 17.6 (SE=1.5) for patients who received placebo, resulting in an SMD of 0.22 (95% CI 0.05 to 0.38). This difference is not clinically relevant.

Wagg (2013) reported the least squares (LS) mean change in HRQL from baseline to week 12. For patients receiving fesoterodine, the LS mean change for total HRQL was 11.6 as compared to 7.1 for patients receiving placebo. Since no standard deviations have been reported, no GRADE assessment can be performed.

2.3 Adverse events (important)

2.3.1. Dry mouth

Dubeau (2014) reported that 66 of the 281 patients (23.5%) who received fesoterodine had a dry mouth as compared to 17 of the 281 patients (6.0%) who received placebo (RR=3.88, 95%CI 2.34 to 6.44). This difference is clinically relevant favouring placebo.

Wagg (2013) reported that 133 of the 392 patients (33.9%) who received fesoterodine had a dry mouth as compared to 21 of the 393 patients (5.3%) who received placebo (RR=6.35, 95%CI 4.10 to 9.84). This difference is clinically relevant favouring placebo.

2.3.2. Obstipation

Dubeau (2014) reported that 31 of the 281 patients (11.0%) who received fesoterodine had constipation as compared to 12 of the 281 patients (4.3%) who received placebo (RR=2.58, 95%CI 1.35 to 4.93). This difference is clinically relevant favouring placebo.

Wagg (2013) reported that 35 of the 392 patients (8.9%) who received fesoterodine had constipation as compared to 10 of the 393 patients (2.5%) who received placebo (RR=3.51, 95%CI 1.76 to 6.99). This difference is clinically relevant favouring placebo.

2.3.3. Cognitive decline

Dubeau (2014) reported the Mini-Mental State Examination (MMSE) score. The MMSE is scored on a scale from 0 to 30 with scores ³27 considered as normal cognition, scores from 20 to 26 were considered as some cognitive impairment, scores from 10 to 19 were considered as moderate to severe cognitive impairment and less than 10 was considered as very severe cognitive impairment. No deterioration in mean MMSE scores from baseline to week 12 were found. For patients receiving fesoterodine (n= 281), the LS mean MMSE score from baseline to week 12 was 0.15 (SE=0.12) as compared to 0.33 (SE=0.12) for patients receiving placebo (n= 281). This resulted in an SMD of -0.09 (95% CI -0.25 to 0.08). This difference is not clinically relevant. Subjective memory impairment was reported in two subjects treated with fesoterodine with onset after increase to the 8 mg dose.

Wagg (2013) reported no meaningful change in MMSE score from baseline to week 12. Mean MMSE scores at week 12 were 28.4 (range 20 to 30) for patients receiving fesoterodine and 28.3 (range 19 to 30) for patients treated with placebo. For patients receiving fesoterodine (n= 392), the mean change was 0.24 (SE=1.76) as compared to 0.23 (SE=1.82) in the placebo-group (n= 393), resulting in an SMD of 0.00 (95% CI -0.14 to 0.14). This difference is not clinically relevant.

3. Oxybutynin versus placebo

3.1  Improvement of urine incontinence complaints (critical)

Lackner (2011) reported the median number of urinary incontinence episodes after 4 weeks of treatment. For patients who received extended-release oxybutynin, the median number of urinary incontinence episodes was 6 (range 2 to 12) at baseline and 4 (range 0 to 11) after treatment. For patients receiving placebo, the median number of urinary incontinence episodes was 4.5 (range 3 to 10) at baseline and 2.5 (range 0 to 14) after treatment.  Since no means or measures of dispersion were reported, these results were not GRADE evaluated.

Ouslander (1995) reported the number of incontinence episodes per 3 days at day 20.

Patients receiving oxybutynin (n= 75) had 6.8 episodes (estimated SD 4.03) as compared to 7.7 episodes (estimated SD 4.03) for patients receiving placebo (n= 75). This resulted in a mean difference of -1.10 (95%CI -2.39 to 0.19), translating in an SMD of -0.22 (95% CI -0.54 to 0.10), which was not clinically relevant.

Szonyi (1995) reported the change in incontinence episodes/day during first 14 days versus last 14 days. Patients receiving oxybutynin had a difference of 8 (IQR=8 to 10) as compared to a difference of 7 (IQR = 7 to 7) for patients receiving placebo. No GRADE assessment could be performed.

Due to heterogeneity in reporting of data, it was not possible to pool the results.

3.2  Quality of life (critical)

Not reported.

3.3   Adverse events (important)

3.3.1 Dry mouth

Ouslander (1995) reported that 22 of the 52 patients (42%) who received oxybutynin had a dry mouth as compared to 19 of the 54 patients (35%) who received placebo (RR=1.20, 95%CI 0.74 to 1.95). This difference is not clinically relevant.

Szonyi (1995) reported that 93% of the patients who received oxybutynin had a dry mouth as compared to 85% of the patients who received placebo. However, since the number of patients is not reported, no GRADE assessment could be performed.

3.3.2 Obstipation

Ouslander (1995) reported that 16 of the 53 patients (30%) who received oxybutynin had constipation as compared to 13 of the 52 patients (25%) who received placebo (RR=0.83, 95%CI 0.48 to 1.42). This difference is not clinically relevant.

Szonyi (1995) reported that 50% of the patients who received oxybutynin had constipation as compared to 45% of the patients who received placebo. However, since the number of patients is not reported, no GRADE assessment could be performed.

3.3.3 Cognitive decline

Not reported.

4. Solifenacin versus placebo

4.1 Improvement of urine incontinence complaints (critical)

Kosilov (2015) reported the average number of episodes of incontinence. Patients who received solifenacin had a change of 2.2 episodes from baseline to 6 weeks, as compared to 0.2 episodes for patients treated with placebo. Since no standard deviations have been reported, no GRADE assessment can be performed.

4.2 Quality of life (critical)

Not reported.

4.3 Adverse events (important)

4.3.1 Dry mouth

Kosilov (2015) reported that 5 of the 52 patients (9.6%) who received solifenacin had a dry mouth as compared to 2 of the 59 patients (3.4%) who were treated with placebo (RR=2.84, 95%CI 0.57 to 14.01). This difference is clinically relevant favouring placebo.

4.3.2. Obstipation

Not reported.

4.3.3. Cognitive decline

Kosilov (2015) reported that cognitive impairment occurred in 1 of the 59 patients (1.7%) that received placebo and did not occur in patients who received solifenacin (RR=0.38, 95%CI 0.02 to 9.07). This difference is clinically relevant favouring solifenacin.

5. Tolterodine versus placebo

5.1 Improvement of urine incontinence complaints (critical)

Zinner (2002) reported the mean reduction in incontinence episodes per week. At baseline, mean frequency of incontinence episodes over both groups was 23. Patients who received tolterodine (n= 214) had a mean reduction of 11.5 (SD 18.2) episodes, as compared to a reduction of 6.3 (SD 15) episodes for patients treated with placebo (n= 223). This resulted in a SMD of -0.31 (95% CI -0.50 to -0.12), which is not clinically relevant.

5.2 Quality of life (critical)

Not reported.

5.3 Adverse events (important)

5.3.1 Dry mouth

Zinner (2002) reported that 52 of the 214 patients (24.3%) who received tolterodine had a dry mouth as compared to 16 of the 223 patients (7.2%) who were treated with placebo (RR=3.39, 95%CI 2.00 to 5.74). This difference is clinically relevant favouring placebo.

5.3.2. Obstipation

Zinner (2002) reported that 13 of the 214 patients (6.1%) who received tolterodine had constipation as compared to 10 of the 223 patients (4.5%) who were treated with placebo (RR=1.35, 95%CI 0.61 to 3.02). This difference is clinically relevant favouring placebo.

5.3.3. Cognitive decline

Not reported.

Level of evidence of the literature

According to GRADE, the level of evidence starts at high because it was based on RCTs.

1.     Darifenacin versus placebo

1.1.Improvement of urine incontinence complaints (critical)

The level of evidence regarding the outcome measure improvement of urine incontinence complaints could not be assessed with GRADE.

1.2.Quality of life (critical)

The level of evidence regarding the outcome measure quality of life was downgraded by two levels to low because the optimal information size has not been reached and the upper limit of the 95% confidence interval crossed the line of a clinically relevant effect (-2, imprecision).

1.3.Adverse events (important)

1.3.1.     Adverse event: dry mouth

The level of evidence regarding the adverse event dry mouth was downgraded by two levels to low because the upper limit of the 95% confidence interval was >3 times higher than the point estimate (-2, imprecision).

1.3.2.     Adverse event: obstipation

The level of evidence regarding the adverse event obstipation was downgraded by two levels to low because of the low number of events and the 95% confidence interval crossed the line of no (clinically relevant) effect (-2, imprecision).

1.3.3.     Adverse event: cognitive decline

The level of evidence regarding the adverse event cognitive decline could not be assessed with GRADE. 

2.     Fesoterodine versus placebo

2.1.Improvement of urine incontinence complaints (critical)

The level of evidence regarding the outcome measure improvement of urine incontinence complaints could not be assessed with GRADE.

2.2.Quality of life (critical)

The level of evidence regarding the outcome measure quality of life was downgraded by two levels to low because of study limitations regarding allocation concealment and substantial loss to follow up (-1, risk of bias) and the optimal information size has not been reached (-1, imprecision).

2.3.Adverse events (important)

2.3.1.     Adverse event: dry mouth

The level of evidence regarding the adverse event dry mouth was downgraded by two levels to low because of study limitations regarding allocation concealment and substantial loss to follow up (-1, risk of bias) and the optimal information size has not been reached (-1, imprecision).

2.3.2.     Adverse event: obstipation

The level of evidence regarding the adverse event obstipation was downgraded by two levels to low because of study limitations regarding allocation concealment and substantial loss to follow up (-1, risk of bias) and the optimal information size has not been reached (-1, imprecision).

2.3.3.     Adverse event: cognitive decline

The level of evidence regarding the adverse event cognitive decline was downgraded by two levels to low because of study limitations regarding allocation concealment and substantial loss to follow up (-1, risk of bias) and the optimal information size has not been reached (-1, imprecision).

3.     Oxybutynin versus placebo

3.1.Improvement of urine incontinence complaints (critical)

The level of evidence regarding the outcome measure improvement of urine incontinence complaints was downgraded by two levels to low because the optimal information size has not been reached and the lower limit of the 95% confidence interval crossed the line of a clinically relevant effect (-2, imprecision).

3.2.Quality of life (critical)

The level of evidence regarding the outcome measure quality of life could not be assessed with GRADE.

3.3.Adverse events (important)

3.3.1.     Adverse event: dry mouth

The level of evidence regarding the adverse event dry mouth was downgraded by three levels to very low because the study population consisted of severely cognitive impaired patients (-1, indirectness) and the 95% confidence interval crossed both lines of no (clinically relevant) effect (-2, imprecision).

3.3.2.     Adverse event: obstipation

The level of evidence regarding the adverse event obstipation was downgraded by three levels to very low because the study population consisted of severely cognitive impaired patients (-1, indirectness) and the 95% confidence interval crossed both lines of no (clinically relevant) effect (-2, imprecision).

3.3.3.     Adverse event: cognitive decline

The level of evidence regarding the adverse event cognitive decline could not be assessed with GRADE.

4. Solifenacin versus placebo

4.3. Adverse events (important)

4.3.1     Adverse event: dry mouth

The level of evidence regarding the adverse event dry mouth was downgraded by three levels to very low because of study limitations regarding blinding and selective outcome reporting (-1, risk of bias) and the 95% confidence interval crossed both lines of no (clinically relevant) effect (-2, imprecision).

4.3.3     Adverse event: cognitive decline

The level of evidence regarding the adverse event cognitive decline was downgraded by three levels to very low because of study limitations regarding blinding and selective outcome reporting (-1, risk of bias) and the 95% confidence interval crossed both lines of no (clinically relevant) effect (-2, imprecision).

4.1.Improvement of urine incontinence complaints (critical); 4.2. Quality of life (critical); 4.3.2. Adverse event: obstipation (important)

The level of evidence regarding the outcome measures improvement of urine incontinence complaints, quality of life, and obstipation could not be assessed with GRADE.

5. Tolterodine versus placebo

5.1.Improvement of urine incontinence complaints (critical)

The level of evidence regarding the outcome measure improvement of urine incontinence complaints was downgraded by one level to moderate because the optimal information size has not been reached (-1, imprecision).

5.2.Quality of life (critical)

The level of evidence regarding the outcome measure quality of life could not be assessed with GRADE.

5.3.Adverse events (important)

5.3.1.     Adverse event: dry mouth

The level of evidence regarding the adverse event dry mouth was downgraded by one level to moderate because the optimal information size has not been achieved (-1, imprecision).

5.3.2.     Adverse event: obstipation

The level of evidence regarding the adverse event obstipation was downgraded by three levels to very low because of the low number of events and the 95% confidence interval crossed both lines of no (clinically relevant) effect (-2, imprecision).

5.3.3.     Adverse event: cognitive decline

The level of evidence regarding the adverse event cognitive decline could not be assessed with GRADE.

2. Mirabegron versus placebo or antimuscarinic treatment

Description of studies

1. Mirabegron versus placebo

Griebling (2020) performed a pre-planned analysis of a phase 4 placebo-controlled study (PILLAR) to assess differences in cognitive function between mirabegron and placebo for treatment of wet overactive bladder (OAB) in patients aged ≥65 years. Community-dwelling patients with an age of 65 years or older with wet OAB (≥1 incontinence episode and ≥3 urgency episodes during the 3-day diary, plus an average of ≥8 micturitions/24 h) were included. There were no specific exclusion criteria regarding cognitive status, but subjects needed to be able to complete the micturition diaries and questionnaires. In total, 445 subjects received mirabegron and 442 subjects received placebo. Subjects were initially treated with 25 mg/day and could enhance the dose to 50 mg/day after week 4/8. The treatment duration was 12 weeks. Groups were similar at baseline. The outcome of interest was the Montreal Cognitive Assessment (MoCA) test score and adverse events.

Kosilov (2015) performed a randomized controlled trial to assess the effectiveness and safety of mirabegron and solifenacin for managing heavy symptoms of overactive bladder. Patients with severe symptoms of overactive bladder (the frequency of episodes of incontinence (EI) ³3/day) with an age over 65 years were included. Exclusion criteria were chronic active diseases including hypertension and intolerance to antimuscarinics and agonists of b3-adrenoreceptors. Sixty-three patients were treated with mirabegron (50 mg/day), 52 patients were treated with solifenacin (10 mg/day), and 65 patients were treated with placebo for 6 weeks. Comparisons between these different treatments were conducted. Outcomes of interest were the frequency of episodes of incontinence and adverse events.

Wagg (2020) performed a double-blind, randomised, placebo-controlled trial to study the efficacy, safety and tolerability of mirabegron in patients ³65 years. Community-dwelling patients aged ³65 years with one or more incontinence episodes, three or more urgency episodes, and an average of eight or more micturition episodes per day based on a 3 day micturition diary were included. Besides, subjects needed to be mental capable to complete the study or consent procedures. Exclusion criteria were nursing home residence, bladder outlet obstruction, predominant stress incontinence, postvoid residual volume >150 ml, neurogenic detrusor overactivity, acute urinary tract infection, recent initiation of conservative/invasive therapy for OAB, permanent or intermittent catheterisation, severe renal or hepatic impairment, or uncontrolled hypertension. In total, 445 subjects received mirabegron and 443 subjects received a placebo for 3 months. Patients started with an initial dose of 25 mg/day mirabegron or matched placebo and the dose could be increased to 50 mg/day after 4 or 8 weeks. Outcomes of interest were urgency incontinence episodes/24 hours and adverse events.

2. Vibegron versus placebo

Varano (2021) performed a subpopulation analysis from the phase 3 double-blind controlled EMPOWUR trial to determine the efficacy and safety of vibegron in patients aged ³65 and ³75 years. Adults with a history of OAB for at least 3 months before the screening visit and met prespecified criteria for wet or dry OAB were included. Exclusion criteria were:

History of 24-h urine volume > 3000 mL in the past 6 months

Lower urinary tract pathology (e.g., bladder outlet obstruction) that could account for OAB symptoms

History of stress urinary incontinence surgery within 6 months of screening

Intradetrusor injection of botulinum toxin within 9 months of screening, or electrostimulation within 28 days of screening

Diabetes insipidus

Uncontrolled hyperglycemia (fasting blood glucose > 150 mg/dL or 8.33 mmol/L and/or non-fasting blood glucose > 200 mg/dL or 11.1 mmol/L or, if in the opinion of the investigator, was uncontrolled)

Current history or evidence of stage ≥ 2 pelvic organ prolapse or use of pessary for the treatment of pelvic organ prolapse

History of neurodegenerative diseases (e.g., multiple sclerosis, Parkinson disease) that could affect the lower urinary tract or its nerve supply.

In total, 647 participants aged ³65 were randomized to either placebo (n=228), vibegron 75 mg (n=247) or tolterodine extended release 4 mg (n=172). Besides, 183 participants aged ³75 years were randomized to either placebo (n=60), vibegron 75 mg (n=75) or tolterodine extended release 4 mg (n=48). Outcomes of interest were the number of urge urinary incontinence episodes and adverse events.

Yoshida (2021) performed a post-hoc subgroup analysis of a randomized, placebo-controlled, double-blind comparative phase 3 study to assess the safety and efficacy of vibegron in patients aged ³65 years. Patients with overactive bladder with ≥8 micturitions/day and either ≥1 urgency episodes/day or ≥1 urgency incontinence episodes/day were included. Exclusion criteria were urinary tract infection, bladder cancer, bladder calculus, interstitial cystitis, enlarged prostate, residual urinary volume >100 ml, and systolic blood pressure ≥ 160 mmHg, diastolic blood pressure ≥ 100 mmHg, or pulse rate ≥110 bpm. Subjects ³65 years were randomized to vibegron 50 mg (n=131), vibegron 100 mg (n=130) or placebo (n=131) for 12 weeks. The outcomes of interest were the change in urgency urinary incontinence and adverse events.

3. Vibegron versus tolterodine

In the study of Varano (2021), the efficacy and safety of vibegron was also compared with tolterodine. The description of this study can be found under “Vibegron versus placebo”. 

4. Mirabegron versus solifenacin

In the study of Kosilov (2015), the effectiveness and safety of mirabegron was also compared with solifenacin. The description of this study can be found under “Mirabegron versus placebo”. 

Results

1. Mirabegron versus placebo

1.1. Improvement of urine incontinence complaints (critical)

Kosilov (2015) reported the average number of episodes of incontinence. Patients who received mirabegron had a change of 2.3 episodes from baseline to 6 weeks, as compared to 0.2 episodes for patients treated with placebo. Since no standard deviations have been reported, no GRADE assessment can be performed.

Wagg (2020) reported the mean number of incontinence episodes per 24 hours. Patients who received mirabegron (n= 445) had an adjusted mean change of -2.0 episodes (SE=0.1) from baseline to 12 weeks, as compared to -1.5 episodes (SE=0.1) for patients receiving placebo (n= 443), translating into a SMD of -0.24 (95% CI -0.37 to -0.11). This difference is not clinically relevant.

1.2 Quality of life (critical)

Not reported.

1.3. Adverse events (important)

1.3.1. Dry mouth

Griebling (2020) reported that 6 of the 445 patients (1.3%) who received mirabegron had a dry mouth as compared to 7 of the 442 patients (1.6%) who were treated with placebo (RR=0.85, 95%CI 0.29 to 2.51). This difference is not clinically relevant.

Kosilov (2015) reported that 1 of the 63 patients (1.6%) who received mirabegron had a dry mouth as compared to 2 of the 59 patients (3.4%) who were treated with placebo (RR=0.47, 95%CI 0.04 to 5.03). This difference is clinically relevant favouring mirabegron.

1.3.2. Obstipation

Griebling (2020) reported that 3 of the 445 patients (0.7%) who received mirabegron had constipation as compared to 4 of the 442 patients (0.9%) who were treated with placebo (RR=0.74, 95%CI 0.17 to 3.31). This difference is clinically relevant favouring mirabegron.

1.3.3. Cognitive decline

Griebling (2020) reported cognitive function with the Montreal Cognitive Assessment (MoCA). The MoCA consists of 30-items and higher scores indicates better cognitive function. A MoCA score <26 indicates impaired cognitive function. For patients treated with mirabegron, the mean MoCA score was 26.9 (SE=0.1) after 12 weeks as compared to a mean MoCA score of 27.0 (SE=0.1) for patients receiving placebo. This difference is not clinically relevant. An impaired cognitive function at 12 weeks was reported in 104 of the 425 patients (24.5%) receiving mirabegron as compared to 106 of the 411 patients (25.8%) receiving placebo (RR=0.95, 95%CI 0.75 to 1.20). This difference is not clinically relevant.

Kosilov (2015) reported that cognitive impairment occurred in 1 of the 59 patients (1.7%) that received placebo and did not occur in patients who received mirabegron (RR=0.31, 95%CI 0.01 to 7.52). This difference is clinically relevant favouring mirabegron.

Wagg (2020) reported no statistically significant change in MoCA score from baseline to 12 weeks of treatment. An adjusted mean change of -0.2 points (SE=0.1) was found for patients treated with mirabegron (n= 445) as compared to -0.1 points (SE=0.1) for patients receiving placebo (n= 443), translating into a SMD of -0.05 (95% CI -0.18 to 0.08) This difference is not clinically relevant.

Due to heterogeneity in reporting of data, it was not possible to pool the results.

2. Vibegron versus placebo

2.1. Improvement of urine incontinence complaints (critical)

Varano (2021) reported the change in average daily number of urge urinary incontinence episodes for patients aged ³65 years and ³75 years from baseline to 12 weeks of treatment.

For patients ³65 years, the LS mean change was -2.0 episodes for patients receiving vibegron as compared to -1.2 episodes for patients receiving placebo at 12 weeks of treatment.

For patients ³75 years, the LS mean change was -2.0 episodes for patients receiving vibegron as compared to -0.4 episodes for patients receiving placebo at 12 weeks of treatment. Since no standard deviations have been reported, no GRADE assessment can be performed.

Yoshida (2021) reported the change in the number of urgency urinary incontinence episodes per 24 hours from baseline to week 12 for patients treated with 50 mg vibegron and patients receiving 100 mg vibegron. For patients receiving 50 mg vibegron, the LS mean change was
-0.36 (95%CI -0.66 to -0.06) episodes as compared with placebo. For patients receiving 100 mg vibegron, the LS mean change was -0.48 (95%CI -0.79 to -0.18) episodes as compared with placebo. Since no standard deviations have been reported, no GRADE assessment can be performed.

2.2. Quality of life (critical)

Not reported.

Adverse events (important)

2.3.1. Dry mouth

Varano (2021) reported that 9 of the 545 patients (1.7%) who received vibegron had a dry mouth as compared to 5 of the 540 patients (0.9%) who were treated with placebo (RR=1.78, 95%CI 0.60 to 5.29). This difference is clinically relevant favouring placebo.

Yoshida (2021) reported that 3 of the 261 patients (1.1%) who received vibegron had a dry mouth as compared to 2 of the 131 patients (1.5%) who were treated with placebo (RR=0.75, 95%CI 0.13 to 4.45). This difference is clinically relevant favouring vibegron.

2.3.2. Obstipation

Yoshida (2021) reported that 5 of the 261 patients (1.9%) who received vibegron had constipation, while no constipation was experienced by patients treated with placebo (RR=5.54, 95%CI 0.31 to 99.47). This difference is clinically relevant favouring placebo.

2.3.3. Cognitive decline

Not reported.

3. Vibegron versus tolterodine

3.1. Improvement of urine incontinence complaints (critical)

Varano (2021) reported the change in average daily number of urge urinary incontinence episodes for patients aged ³65 years and ³75 years from baseline to 12 weeks of treatment.

For patients ³65 years, the LS mean change was -2.0 episodes for patients receiving vibegron as compared to -1.8 episodes for patients receiving tolterodine at 12 weeks of treatment.

For patients ³75 years, the LS mean change was -2.0 episodes for patients receiving vibegron as compared to -2.0 episodes for patients receiving tolterodine at 12 weeks of treatment. Since no standard deviations have been reported, no GRADE assessment can be performed.

3.2. Quality of life (critical)

Not reported.

3.3. Adverse events (important)

3.3.1. Dry mouth

Varano (2021) reported that 9 of the 545 patients (1.7%) who received vibegron had a dry mouth as compared to 28 of the 430 patients (6.5%) who were treated with tolterodine (RR=0.25, 95%CI 0.12 to 0.53). This difference is clinically relevant favouring vibegron.

3.3.2. Obstipation

Not reported.

3.3.3. Cognitive decline

Not reported.

4. Mirabegron versus solifenacin

4.1 Improvement of urine incontinence complaints (critical)

Kosilov (2015) reported the average number of episodes of incontinence. Patients who received mirabegron had a change of 2.3 episodes from baseline to 6 weeks, as compared to 2.3 episodes for patients treated with solifenacin. Since no standard deviations have been reported, no GRADE assessment can be performed.

4.2 Quality of life (critical)

Not reported.

4.3 Adverse events (important)

4.3.1. Dry mouth

Kosilov (2015) reported that 1 of the 63 patients (1.6%) who received mirabegron had a dry mouth as compared to 5 of the 52 patients (9.6%) who were treated with solifenacin (RR=0.17, 95%CI 0.02 to 1.37). This difference was clinically relevant favouring mirabegron.

4.3.2. Obstipation

Not reported.

4.3.3. Cognitive decline

Kosilov (2015) reported no cognitive impairments for patients receiving mirabegron or solifenacin.

Level of evidence of the literature

According to GRADE, the level of evidence start at high because it was based on RCTs.

1. Mirabegron versus placebo

1.1. Improvement of urine incontinence complaints (critical)

The level of evidence regarding the outcome measure improvement of urine incontinence complaints was downgraded by two levels to low because of study limitations regarding allocation concealment and substantial loss to follow up (-1, risk of bias), discrepancy of results between Wagg (2020) and Kosilov (2015) (-1, inconsistency) and the optimal information size has not been reached (-1, imprecision). 

1.2. Quality of life (critical)

The level of evidence regarding the outcome measure quality of life could not be assessed with GRADE.

1.3. Adverse events (important)

1.3.1. Adverse event: dry mouth

The level of evidence regarding the adverse event dry mouth was downgraded by three levels to very low because of study limitations regarding allocation concealment and substantial loss to follow up (-1, risk of bias), and the 95% confidence interval crossed both lines of no (clinically relevant) effect (-2, imprecision).

1.3.2. Adverse event: obstipation

The level of evidence regarding the adverse event obstipation was downgraded by three levels to very low because of study limitations regarding allocation concealment (-1, risk of bias), and the 95% confidence interval crossed both lines of no (clinically relevant) effect (-2, imprecision).

1.3.3. Adverse event: cognitive decline

The level of evidence regarding the adverse event cognitive decline was downgraded by three levels to very low because of study limitations regarding allocation concealment and substantial loss to follow up (-1, risk of bias), difference in the direction of the effect (-1, inconsistency), and the 95% confidence interval crossed both lines of no (clinically relevant) effect (-1, imprecision).

2. Vibegron versus placebo

2.1. Improvement of urine incontinence complaints (critical)

The level of evidence regarding the outcome measure improvement of urine incontinence complaints could not be assessed with GRADE.

2.2. Quality of life (critical)

The level of evidence regarding the outcome measure quality of life could not be assessed with GRADE.

2.3. Adverse events (important)

2.3.1. Adverse event: dry mouth

The level of evidence regarding the adverse event dry mouth was downgraded by three levels to very low because of study limitations regarding allocation concealment and substantial loss to follow up (-1, risk of bias), difference in the direction of the effect (-1, inconsistency), and the 95% confidence interval crossed both lines of no (clinically relevant) effect (-1, imprecision).

2.3.2. Adverse event: obstipation

The level of evidence regarding the adverse event obstipation was downgraded by three levels to very low because of study limitations regarding blinding (-1, risk of bias), and the upper limit of the 95% confidence interval was >3 times higher than the point estimate (-2, imprecision).

2.3.3. Adverse event: cognitive decline

The level of evidence regarding the adverse event cognitive decline could not be assessed with GRADE.

3. Vibegron versus tolterodine 

3.1. Improvement of urine incontinence complaints (critical)

The level of evidence regarding the outcome measure improvement of urine incontinence complaints could not be assessed with GRADE.

3.2. Quality of life (critical)

The level of evidence regarding the outcome measure quality of life could not be assessed with GRADE.

3.3. Adverse events (important)

3.3.1. Adverse event: dry mouth

The level of evidence regarding the adverse event dry mouth was downgraded by two levels to low because of study limitations regarding substantial loss to follow up (-1, risk of bias) and the optimal information size has not been reached (-1, imprecision).

3.3.2. Adverse event: obstipation

The level of evidence regarding the adverse event obstipation could not be assessed with GRADE.

3.3.3. Adverse event: cognitive decline

The level of evidence regarding the adverse event cognitive decline could not be assessed with GRADE.

4. Mirabegron versus solifenacin

4.1. Improvement of urine incontinence complaints (critical)

The level of evidence regarding the outcome measure improvement of urine incontinence complaints could not be assessed with GRADE.

4.2. Quality of life (critical)

The level of evidence regarding the outcome measure quality of life could not be assessed with GRADE.

4.3. Adverse events (important)

4.3.1. Adverse event: dry mouth

The level of evidence regarding the adverse event dry mouth was downgraded by three levels to very low because of study limitations regarding blinding (-1, risk of bias) and the 95% confidence interval crossed both lines of no (clinically relevant) effect (-2, imprecision).

4.3.2. Adverse event: obstipation

The level of evidence regarding the adverse event obstipation could not be assessed with GRADE.

4.3.3. Adverse event: cognitive decline

The level of evidence regarding the adverse event cognitive decline was downgraded by three levels to very low because of study limitations regarding blinding (-1, risk of bias) and the optimal information size has not been reached (-2, imprecision).

A systematic review of the literature was performed to answer the following question:

What is the effectivity and safety of antimuscarinic treatment or mirabegron/vibegron in elderly patients with urine incontinence, compared to placebo or no treatment?

P: Elderly with urine incontinence

I1: Antimuscarinic treatment

I2: Mirabegron

C1: Placebo, no treatment

C2: Placebo, no treatment or antimuscarinic treatment

O: reduced urge urine incontinence episodes, quality of life, adverse events/complications (in particular cognitive decline)

Relevant outcome measures

The guideline development group considered improvement/cure of urge urine incontinence episodes and quality of life as critical outcome measures for decision making; and adverse events/complications as important outcome measures for decision making.

A priori, the working group defined adverse events as dry mouth, obstipation, and cognitive decline. Quality of life data was extracted when a validated questionnaire was used. For other outcomes, the working group did not define the outcome measures listed above but used the definitions used in the studies.

The working group defined the following minimal clinically (patient) important differences:

• Cognitive functioning:
  • Montreal Cognitive Assessment (MoCA, 0-30): ≥ 4 points (Feeney, 2016)
• Improvement/cure of overactive bladder complaints:
  • Urinary Distress Inventory (UDI-6): ≥ 8 points difference between groups (Barber, 2009)

In all other cases, the working group defined a 25% difference for dichotomous outcomes (RR < 0.8 or > 1.25), and 0.5 SD or -0.5 < SMD > 0.5 for continuous outcomes as a minimal clinically (patient) important difference.

Search and select (Methods)

The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms from 2010 until 10^th May 2022. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 450 hits. Studies were selected based on the following criteria:

• Systematic review (searched in at least two databases, and detailed search strategy, risk of bias assessment and results of individual studies available) or randomized controlled trial comparing antimuscarinic treatment with placebo or no treatment, or comparing mirabegron with placebo, no treatment or antimuscarinic treatment;
• Elderly patients with urine incontinence;
• Full-text English language publication;
• Studies including ≥ 20 (ten in each study arm) patients; and
• Studies according to PICO.

Seventy studies were initially selected based on title and abstract screening. After reading the full text, 61 studies were excluded (see the table with reasons for exclusion under the tab Methods), and nine studies were included (Dubeau, 2014; Griebling 2020; Kosilov, 2015; Lackner, 2011; Samuelsson, 2015; Varano, 2021; Wagg, 2013; Wagg, 2020; Yoshida, 2021). In case measurements of dispersion were not reported but could be derived from reported mean differences, an estimated SMD was developed using Revman version 5.4.1.

Results

One systematic review and eight RCTs were included in the analysis of the literature. Important study characteristics and results are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias tables.