Antimuscarinica en mirabegron
Uitgangsvraag
Wat is de rol van medicamenteuze behandeling bij kinderen met functionele urine-incontinentie?
Aanbeveling
Start antimuscarinica bij onvoldoende effect van urotherapie bij kinderen met functionele urine-incontinentie ten gevolge van een overactieve blaas. Oxybutynine is eerste keus.
Overweeg switch naar een competitieve anti cholinerge receptorantagonist als Tolterodine of Solifenacine bij onvoldoende effect of bijwerkingen van Oxybutynine.
Overweeg switch naar add-on of monotherapie mirabegron indien antimuscarinica onvoldoende werken. Terughoudendheid geboden bij stadium 2 Hypertensie of bekende QTc verlenging.
Overwegingen
Voor- en nadelen van de interventie en de kwaliteit van het bewijs
In de literatuuranalyse werd onderzocht wat de rol is van medicamenteuze behandeling bij kinderen met functionele urine-incontinentie. Er werden drie RCT’s gevonden. Twee RCT’s (Newgreen, 2016; Soliman, 2021) vergeleken het effect van solifenacine met placebo bij kinderen met een overactieve blaas. Daarnaast vergeleek Soliman (2021) ook het effect van mirabegron met placebo en mirabegron met solifenacine. De studie van Nijman (2005) vergeleek tolterodine met placebo bij kinderen met symptomen van urge-incontinentie die wijzen op overactiviteit van de detrusor. De bewijskracht voor de cruciale uitkomstmaat ‘effect van behandeling’ werd voor alle interventies beoordeeld als zeer laag vanwege methodologische beperkingen en het kleine aantal deelnemers. Voor de andere belangrijke uitkomstmaat ‘complicaties’ was de bewijskracht ook zeer laag vanwege methodologische beperkingen, het kleine aantal deelnemers en het lage aantal events waardoor er grote spreiding gezien wordt in de richting van het effect. De overall bewijskracht is daarom zeer laag. Er kunnen op basis van literatuur alleen geen sterke aanbevelingen worden geformuleerd over de rol van medicamenteuze behandeling bij kinderen met functionele urine-incontinentie.
Antimuscarinica hebben een aanvullende rol bij kinderen met incontinentie voor urine op basis van een overactieve blaas, als urotherapie alleen, onvoldoende effect heeft. Het meest voorgeschreven anticholinergicum bij kinderen is oxybutynine. In de literatuursearch voor deze module kwam helaas geen vergelijkende RCT naar voren over effectiviteit en bijwerkingen. Oxybutynine is officieel geregistreerd voor kinderen vanaf 6 jaar. Voor doseringen wordt verwezen naar het Kinderformularium. Oxybutynine extended release is niet verkrijgbaar in Nederland. Indien oxybutynine onvoldoende werkzaam is of bijwerkingen geeft kan een competitieve cholinerge receptorantagonist met selectiviteit voor de blaas als solifenacine of tolterodine overwogen worden. Solifenacine is geregistreerd voor kinderen vanaf 2 jaar. Tolterodine is niet officieel geregistreerd maar is wel veilig gebleken voor kinderen. Voor doseringen wordt verwezen naar het Kinderformularium.
Zowel solifenacine (Newgreen, 2016; Soliman, 2021) als tolterodine (Nijman, 2005) hebben in de gevonden RCT’s een positief effect op de afname van het aantal mictiemomenten per 24 uur, het aantal episodes van functionele urine-incontinentie overdag en een toename van het MVV zonder ernstige bijwerkingen, t.o.v. placebo.
In prospectieve / cross over studies die tolterodine vergelijken met oxybutynine (Bolduc, 2003; Kilic, 2006) en een systematic review van Mehdi 2013 lijkt tolterodine even effectief met veel minder bijwerkingen dan oxybutynine. De bewijskracht hiervan is echter zeer laag.
Mirabegron is een selectieve B3 receptor agonist welke het glad spierweefsel van de blaas relaxeert. Mirabegron heeft een positief (ad-on) effect bij volwassenen met overactieve blaas maar is nog niet voor kinderen geregistreerd in Nederland. De dosering is 25 of 50 mg. De EAU richtlijn non-neurogenic LUTS bij volwassen vrouwen claimt dat beta3 sympathicomimetica effectiever zijn dan placebo en vergelijkbaar met anti-muscarinica als het gaat om het effect op symptomen van overactieve blaas en periodes van functionele urine-incontinentie. Er zijn minder bijwerkingen, vergelijkbaar met placebo. Geadviseerd wordt in deze richtlijn, B3 agonisten voor volwassen vrouwen, als alternatief of add on naast anticholinergica te gebruiken als monotherapie ineffectief is gebleken en urotherapie niet het gewenste effect heeft bereikt.
Er wordt in een RCT bij kinderen een positief effect gezien van mirabegron op het MVV, de mictiefrequentie overdag en het aantal episodes van functionele urine-incontinentie t.o.v. placebo, vergelijkbaar met solifenacine (Soliman, 2021). In een systematic review en meta-analyse van 8 (prospectieve en retrospectieve) studies (Kim, 2021) en in een meta-analyse van 2 prospectieve en 1 retrospective studie (Nasution, 2021) wordt daarnaast een veelbelovend , effectief en veilig resultaat gezien bij kinderen met overactieve blaas. Zowel als monotherapie als ad-on naast een anticholinergicum.
Er start binnenkort in Nederland een dubbelblinde gerandomiseerde klinische multicentre trial waar propyverine hydrochloride vergeleken wordt met placebo bij kinderen met overactieve blaas. Gezien het effect bij volwassenen en gebruik in het buitenland is dit mogelijk een potentieel middel voor de toekomst.
Waarden en voorkeuren van patiënten (en evt. hun verzorgers)
Bij het voorschrijven van medicatie dienen belang en mogelijkheden ten aanzien van therapietrouw, de belasting van dagelijkse medicatie inname en het bijwerkingsprofiel met ouders en patiënt besproken te worden. Voor het algemene bijwerkingenprofiel van zowel oxybutynine als tolterodin, solifenacine en mirabegron wordt verwezen naar het kinderformularium. Bij gebruik van oxybutynine worden anticholinerge bijwerkingen gezien met het risico op beperkte compliance (droge mond tot 80% en obstipatie 30%, wazig zien 18%, en invloed op gedrag tot 15%) . Het bijwerkingenspectrum van de beide competitieve anticholinerge receptorantagonisten tolterodine en solifenacine is vergelijkbaar met dat van oxybutynine. De frequentie waarin de bijwerkingen optreden is in meerdere studies echter duidelijk lager gebleken.
Bij solifenacine zijn in de verschillende studies obstipatie (5,5%-11,4%), droge mond (2,7-10%) en gedragsveranderingen (1,4-2,9%) beschreven. Tolterodine geeft vooral gastro-intestinale bijwerkingen 25% en HP 10% met weinig droge mond en obstipatie (<4%)
Mirabegron gaf als monotherapie minder van al deze bijwerkingen dan solifenacine (<5%) (soliman 2021) Hoofdpijn (3%‒5.9%), obstipatie (3.5%‒5.7%), rhinitis/ nasopharyngitis (1.7%‒5.8%) en wazig zien (1.7%‒2.9%) worden beschreven. Voor cardiovasculaire problemen door mirabegron zijn weinig aanwijzingen. Zowel Blais (2016) en Morin (2016) rapporteerden normale ECG/QTc intervallen, een minimale verhoging van de systolische bloeddruk (5 mmHg) en een minimale verhoging van de hartfrequentie in rust (5 BPM). Mirabegron lijkt veilig te kunnen worden gegeven aan kinderen met minder bijwerkingen dan solifenacine of oxybutinine. Terughoudendheid is mogelijk gewenst bij kinderen met stadium 2 Hypertensie of bekende QTc verlenging.
De doseringsfrequentie van de antimuscarinica kan bij de keuze ook een rol spelen, zowel het geven van een 1 of 2dd dosering die mogelijk de therapietrouw kan bevorderen, als juist de mogelijkheid tot gefaseerd afbouwen met een 3 dd dosering als bij oxybutynine.
Kosten (middelenbeslag)
Er zijn geen kosteneffectiviteitsstudies verricht naar het gebruik van antimuscarinica of mirabegron. De kosten van de verschillende middelen, inclusief mirabegron, zijn vergelijkbaar. Gebruik van medicamenteuze behandeling kost 50 cent tot 1 euro per dag.
Betmiga 25 mg retard tablet kost momenteel nog 4,00 euro per stuk.
Aanvaardbaarheid, haalbaarheid en implementatie
Implementatie: geen problemen verwacht
Betmiga is in de dosering die gangbaar is voor kinderen (25 mg; Franco-Buenaventura, 2024) niet zomaar verkrijgbaar in Nederland en kan alleen via de internationale apotheek in Venlo vanuit Belgie geimporteerd worden welke dan niet vergoed wordt.
In de klinische praktijk wordt daarom vaak 50 mg om de dag voorgeschreven.
De fabrikant heeft aangegeven voornemens te zijn het product voor kinderen, 25mg, medio 2026 op de Nederlandse markt beschikbaar te willen hebben.
Aanbevelingen
Concluderend kan voor patiënten met functionele urine-incontinentie op basis van een overactieve blaas , het starten van antimuscarinica worden overwogen als urotherapie alleen onvoldoende is gebleken. Oxybutynine blijft daarin eerste keus. Ondanks de zeer lage bewijskracht voor het effect van overige antimuscarinica als tolterodine en solifenacine, wordt wel een positief effect gezien. Er zijn geen ernstige bijwerkingen beschreven en minder dan met oxybutynine. Voor mirabegron als monotherapie of add on is nog weinig bewijs. De eerste resultaten bij kinderen zijn hoopvol en de bijwerkingen lijken gering. Mogelijk is Propyverine hydrochloride nog een middel in de toekomst.
Onderbouwing
Achtergrond
Urotherapy is the first choice of treatment for children with functional urinary incontinence.
Antimuscarinics can be considered for those with an overactive bladder in whom urotherapy alone is insufficient. Various drugs are used, sometimes for a long period, as monotherapy or in combination when monotherapy fails. There is varying effect and no clarity about which drug or combination of drugs gives the best results. Little is known about the optimal combinations, dosages or durations of therapy. As a result, there is a lot of practice variation. The individual drugs regularly cause side effects with a negative effect on compliance. Mirabegron is a relatively new beta-3-adrenergic agonist, which gives relaxation of the smooth muscle of the bladder without anticholinergic side effects. Combination therapy with anticholinergic drugs may work. It is used in adults with overactive bladder for more than a decade now but little is yet known about its effect and side effects in children.
Conclusies / Summary of Findings
PICO 1: Solifenacin versus placebo
- Effect of treatment
|
Very low GRADE |
The evidence is very uncertain about the effect of solifenacin on effect of treatment when compared with placebo in children with functional urinary incontinence.
Source: Newgreen, 2016; Soliman, 2021 |
- Complications
|
Very low GRADE |
The evidence is very uncertain about the effect of solifenacin on the complications constipation, dry mouth, influence on behavior and headache when compared with placebo in children with functional urinary incontinence.
Source: Newgreen, 2016; Soliman, 2021 |
PICO 2: Mirabegron versus placebo
- Effect of treatment
|
Very low GRADE |
The evidence is very uncertain about the effect of mirabegron on effect of treatment when compared with placebo in children with functional urinary incontinence.
Source: Soliman, 2021 |
- Complications
|
Very low GRADE |
The evidence is very uncertain about the effect of mirabegron on the complications constipation, dry mouth, and headache when compared with placebo in children with functional urinary incontinence.
Source: Soliman, 2021 |
|
No GRADE |
No evidence was found regarding the effect of mirabegron on the complication influence on behavior when compared with placebo in children with functional urinary incontinence. |
PICO 3: Tolterodine versus placebo
- Effect of treatment
|
Very low GRADE |
The evidence is very uncertain about the effect of tolterodine on effect of treatment when compared with placebo in children with functional urinary incontinence.
Source: Nijman, 2005 |
- Complications
|
Very low GRADE |
The evidence is very uncertain about the effect of tolterodine on the complications constipation, dry mouth, and headache when compared with placebo in children with functional urinary incontinence.
Source: Nijman, 2005 |
PICO 4: Mirabegron versus solifenacin
- Effect of treatment
|
Very low GRADE |
The evidence is very uncertain about the effect of mirabegron on effect of treatment when compared with solifenacin in children with functional urinary incontinence.
Source: Soliman, 2021 |
- Complications
|
Very low GRADE |
The evidence is very uncertain about the effect of mirabegron on the complications constipation, dry mouth, influence on behavior and headache when compared with solifenacin in children with functional urinary incontinence.
Source: Soliman, 2021 |
Samenvatting literatuur
Description of studies
Newgreen (2016) performed a phase 3 double-blind placebo controlled randomized controlled trial to assess the efficacy and safety of solifenacin in children with overactive bladder (OAB). Children between 5 and <12 years and adolescents between 12 and <18 years diagnosed with OAB and who had 4 or more episodes of daytime incontinence during a 7-day prebaseline diary period were included. Besides, the height and weight had to be within normal percentiles for age according to the Centers for Disease Control and Prevention growth charts and the Independent Ethics Committee/Institutional Review Board-approved written informed consent and assent, where applicable. Exclusion criteria were:
- Daily voiding frequency <5
- Extraordinary daytime urinary frequency (voiding frequency ≥1/h with a mean voided volume <50% of EBC and normal nocturnal bladder behaviour for age)
- Lower urinary tract pathologies other than OAB
- Any condition/treatment that could cause urinary symptoms or interfere with assessment of efficacy parameters e.g.
- monosymptomatic enuresis
- polyuria (>75 mL/kg/body weight/24 h)
- central or nephrogenic diabetes insipidus
- dysfunctional voiding
- congenital abnormalities affecting lower urinary tract function
- constipation (Rome III criteria)
- chronic UTI or >3 UTIs 2 months prior to screening
- catheterization within 2 weeks prior to screening
- haematuria ≥++ on dipstick test unless urological or kidney disease ruled out
- kidney or bladder stones
- partial/complete gastrointestinal obstruction, decreased gastrointestinal mortality (e.g., paralytic ileus), risk of gastric retention
- MVV (excluding morning volume) > EBC for age [(age+1)x30]mL or >390 mL
- PVR volume >20 mL
- Current UTI confirmed by urinalysis (>1x105 cfu/mL)
In total, 73 children and 22 adolescents received urotherapy and solifenacin while 75 children and 19 adolescents received only urotherapy (and placebo). It was not clear if groups were comparable at baseline. Outcomes of interest were efficacy and complications.
Nijman (2005) presented the results of two sequential randomized controlled trials to assess the efficacy and safety of tolterodine in children with symptoms of urinary urge incontinence suggestive of detrusor overactivity. Children between 5 and 10 years old with symptoms of urge incontinence suggestive of detrusor overactivity (defined as one diurnal incontinence episode or more per 24 hours for 5 or more days out of 7) were included. In the second study children had 6 or more voids per 24 hours at baseline. Exclusion criteria were treatment for detrusor overactivity within 14 days of randomization, monosymptomatic nocturnal enuresis, giggle incontinence, urinary tract infection, a history of urinary retention or a neuropathic bladder. Besides, children with a post-void residual volume of 20% or more of functional bladder capacity were excluded. In study 1, 235 children received tolterodine and 107 children received placebo. In study 2, 252 children received tolterodine and 117 patients received placebo. Groups were comparable at baseline. Outcomes of interest were efficacy and complications.
Soliman (2021) performed a prospective randomized controlled trial to assess the efficacy and safety of mirabegron as compared to solifenacin for children with newly diagnosed OAB.
Children between 5 and 14 years with persistent urgency, frequency with or without urgency urinary incontinence due to idiopathic OAB after at least 3 months of behavioral therapy were included. Exclusion criteria were children with active urinary tract infection, possible infravesical obstruction, neurogenic bladder, or abnormal serum creatinine. In total, 64 children received mirabegron (50 mg once daily), 65 children received solifenacin (5 mg) and 61 children received placebo. Groups were comparable at baseline. Outcomes of interest were efficacy and complications.
Results
PICO 1: Solifenacin versus placebo
1. Effect treatment
1.1. Mean voided volume/micturition (MVV)
Children
Newgreen (2016) reported that children who received urotherapy and solifenacin had a change in mean voided volume per micturition between baseline and end of treatment of 25.5 ml as compared to 13.4 ml for children who received urotherapy with placebo (p=0.046).
Adolescents
Newgreen (2016) reported that adolescents who received urotherapy and solifenacin had a change in mean voided volume per micturition between baseline and end of treatment of 2.3 ml as compared to 6.9 ml for children who received urotherapy with placebo.
5 to 14 years
Soliman (2021) reported that children who received solifenacin had a mean voided volume at last follow-up of 198.2 ml (SD=41.7) (change between initiation of treatment and follow-up of 92.5 ml) as compared to 109.6 ml (SD=29.5) for children who received placebo (change between initiation of treatment and follow-up of 5.5 ml) (MD=88.60, 95%CI 76.05 to 101.15).
1.2. Mean change in micturitions per 24 hours
Children
Newgreen (2016) reported that children who received urotherapy and solifenacin had a mean change in micturitions per 24 hours between baseline and end of treatment of -1.1 as compared to -0.8 for children who received urotherapy with placebo (p=0.303).
Adolescents
Newgreen (2016) reported that adolescents who received urotherapy and solifenacin had a mean change in micturitions per 24 hours between baseline and end of treatment of -0.4 as compared to -0.6 for children who received urotherapy with placebo.
5 to 14 years
Soliman (2021) reported the mean number of voidings per day at last follow-up. Children who received solifenacin had 4.2 (SD=0.7) voidings (change between initiation of treatment and follow-up of 3.5) as compared to 6.9 (SD=1.4) voidings for children who received placebo (change between initiation of treatment and follow-up of 1.0) (MD=-2.70, 95%CI -3.09 to -2.31).
1.3. Mean change in number of incontinence episodes per 24 hours
Children
Newgreen (2016) reported that children who received urotherapy and solifenacin had a mean change in the number of incontinence episodes per 24 hours between baseline and end of treatment of -1.1 as compared to -1.2 for children who received urotherapy with placebo (p=0.763).
Adolescents
Newgreen (2016) reported that adolescents who received urotherapy and solifenacin had a mean change in the number of incontinence episodes per 24 hours between baseline and end of treatment of -0.6 as compared to -0.7 for children who received urotherapy with placebo.
5 to 14 years
Soliman (2021) reported that children who received solifenacin had 1.1 (SD=1.0) incontinence episodes per day at last follow-up (change between initiation of treatment and follow-up of 1.8) as compared to 2.3 (SD=0.8) for children who received placebo (change between initiation of treatment and follow-up of 0.3) (MD=-1.20, 95%CI -1.52 to -0.88).
1.4 Mean number/24 hours of daytime incontinence episodes
Children
Newgreen (2016) reported an adjusted mean difference in the number of incontinence episodes per 24 hours between solifenacin and placebo of -0.1 (SE=0.2) between baseline and end of treatment in children with OAB (p=0.40).
1.5. Mean number/24 hours of daytime micturitions
Children
Newgreen (2016) reported an adjusted mean difference in the number of daytime micturitions per 24 hours between solifenacin and placebo of -0.1 (SE=0.3) between baseline and end of treatment in children with OAB (p=0.64).
1.6. Number/7 days incontinence-free days
Children
Newgreen (2016) reported an adjusted mean difference in the mean number of incontinence-free days per 7 days between solifenacin and placebo of -0.4 (SE=0.3) between baseline and end of treatment in children with OAB (p=0.56).
1.7. Post-void residual volume
Children
Newgreen (2016) reported that children who received urotherapy and solifenacin had a mean change in post-void residual volume between baseline and end of treatment of -1.0 ml (SD=6.5) as compared to 0.1 ml (SD=7.3) for children who received urotherapy with placebo (MD=-1.10, 95%CI -3.34 to 1.14).
Adolescents
Newgreen (2016) reported that adolescents who received urotherapy and solifenacin had a mean change in post-void residual volume between baseline and end of treatment of 1.0 ml (SD=9.9) as compared to -3.6 ml (SD=4.7) for children who received urotherapy with placebo (MD=4.60, 95%CI -0.05 to 9.25).
5 to 14 years
Soliman (2021) reported that children who received solifenacin had a post-void residual volume at last follow-up of 16.4 ml (SD=2.7) as compared to 16.2 ml (SD=3.1) (change from baseline to follow-up of 2.3 ml) for children who received placebo (change from baseline to follow-up of 2.3 ml) (MD=0.20, 95%CI -0.82 to 1.22).
1.8. Complete cure
Soliman (2021) reported complete cure defined as complete dryness based on objective voiding diaries. Twenty-two of the 65 children (33.8%) who received solifenacin had a complete cure as compared to 6 of the 61 children (9.8%) who received placebo (RR=3.44, 95%CI 1.50 to 7.91). This difference is clinically relevant favoring solifenacin.
2. Complications
2.1. Constipation
Children
Newgreen (2016) reported that 4 of the 73 children (5.5%) who received urotherapy and solifenacin had constipation as compared to 2 of the 73 children (2.7%) who received urotherapy and placebo (RR=2.00, 95%CI 0.38 to 10.58). This difference is clinically relevant favoring placebo.
Adolescents
Newgreen (2016) reported no cases of constipation in adolescents with OAB who either received solifenacin or placebo.
5 to 14 years
Soliman (2021) reported that 8 of the 70 children (11.4%) who received solifenacin had constipation as compared to 1 of the 69 children (1.4%) who received placebo (RR=7.89, 95%CI 1.01 to 61.38). This difference is clinically relevant favoring placebo.
2.2. Dry mouth
Children
Newgreen (2016) reported that 2 of the 73 children (2.7%) who received urotherapy and solifenacin had a dry mouth as compared to 1 of the 73 children (1.4%) who received urotherapy and placebo (RR=2.00, 95%CI 0.19 to 21.58). This difference is clinically relevant favoring placebo.
Adolescents
Newgreen (2016) reported that 1 of the 19 adolescents (5.3%) who received urotherapy and placebo had a dry mouth, while this did not occur in adolescents who received urotherapy and solifenacin (RR=0.29, 95%CI 0.01 to 6.72).
5 to 14 years
Soliman (2021) reported that 7 of the 70 children (10.0%) who received solifenacin had a dry mouth while this did not occur in children who received placebo (RR=14.79, 95%CI 0.86 to 254.04).
2.3. Influence on behavior
Children
Newgreen (2016) reported that 1 of the 73 children (1.4%) who received urotherapy and solifenacin had altered mood, while this did not occur in children who received urotherapy and placebo (RR=3.00, 95%CI 0.12 to 72.45).
Adolescents
Newgreen (2016) reported no cases of altered mood in adolescents with OAB who either received solifenacin or placebo.
5 to 14 years
Soliman (2021) reported that 2 of the 70 children (2.9%) who received solifenacin had a change in behavior while this did not occur in children who received placebo (RR=4.93, 95%CI 0.24 to 100.85).
2.4. Headache
Children
Newgreen (2016) reported no cases of headache in children with OAB who either received solifenacin or placebo.
Adolescents
Newgreen (2016) reported that 1 of the 19 adolescents (5.3%) who received urotherapy and placebo had a headache, while this did not occur in adolescents who received urotherapy and solifenacin (RR=0.29, 95%CI 0.01 to 6.72).
5 to 14 years
Soliman (2021) reported that no headache occurred in children who either received solifenacin or placebo.
2.5. Other complications
The complications ‘dry eyes’, ‘palpitations’, ‘caries’, and ‘increased residue’ were not reported.
Level of evidence of the literature
According to GRADE, the level of evidence of randomized controlled trials start at high.
1. Effect of treatment
The level of evidence regarding the outcome measure mean voided volume/micturition was downgraded by three levels to very low because of methodological limitations with respect to blinding, uncertainties about the analysis of the effect, and concerns about the role of the sponsor (-1, risk of bias), heterogeneity between the studies (-1, inconsistency), and the optimal information size is not achieved (-1, imprecision).
The level of evidence regarding the outcome measure mean change in micturitions per 24 hours was downgraded by three levels to very low because of methodological limitations with respect to blinding, uncertainties about the analysis of the effect, and concerns about the role of the sponsor (-1, risk of bias), heterogeneity between the studies (-1, inconsistency), and the optimal information size is not achieved (-1, imprecision).
The level of evidence regarding the outcome measure mean change in incontinence episodes per 24 hours was downgraded by three levels to very low because of methodological limitations with respect to blinding, uncertainties about the analysis of the effect, and concerns about the role of the sponsor (-1, risk of bias), heterogeneity between the studies (-1, inconsistency), and the optimal information size is not achieved (-1, imprecision).
The level of evidence regarding the outcome measure mean number per 24 hours of daytime incontinence episodes was downgraded by three levels to very low because of uncertainties about the analysis of the effect and concerns about the role of the sponsor (-1, risk of bias) and the optimal information size was not achieved (-2, imprecision).
The level of evidence regarding the outcome measure daytime micturitions was downgraded by three levels to very low because of uncertainties about the analysis of the effect and concerns about the role of the sponsor (-1, risk of bias) and the optimal information size was not achieved (-2, imprecision).
The level of evidence regarding the outcome measure incontinence-free days was downgraded by three levels to very low because of uncertainties about the analysis of the effect and concerns about the role of the sponsor (-1, risk of bias) and the optimal information size was not achieved (-2, imprecision).
The level of evidence regarding the outcome measure post-void residual volume
was downgraded by three levels to very low because of methodological limitations with respect to blinding, uncertainties about the analysis of the effect, and concerns about the role of the sponsor (-1, risk of bias), heterogeneity between the studies
(-1, inconsistency), and the optimal information size is not achieved (-1, imprecision).
The level of evidence regarding the outcome measure complete cure was downgraded by three levels to very low because of concerns about blinding and missing data (-1, risk of bias) and the optimal information size is not achieved (-2, imprecision).
2. Complications
The level of evidence regarding the outcome measure constipation was downgraded by three levels to very low because of methodological limitations with respect to blinding and concerns about the role of the sponsor (-1, risk of bias), and the low number of events resulting in the 95% confidence interval crossing the lines of no (clinically relevant) effect (-2, imprecision).
The level of evidence regarding the outcome measure dry mouth was downgraded by three levels to very low because of methodological limitations with respect to blinding and concerns about the role of the sponsor (-1, risk of bias), and the low number of events resulting in the 95% confidence interval crossing the lines of no (clinically relevant) effect (-2, imprecision).
The level of evidence regarding the outcome measure influence on behavior was downgraded by three levels to very low because of methodological limitations with respect to blinding and concerns about the role of the sponsor (-1, risk of bias), and the low number of events resulting in the 95% confidence interval crossing the lines of no (clinically relevant) effect (-2, imprecision).
The level of evidence regarding the outcome measure headache was downgraded by three levels to very low because of methodological limitations with respect to blinding and concerns about the role of the sponsor (-1, risk of bias), and the low number of events resulting in the 95% confidence interval crossing the lines of no (clinically relevant) effect (-2, imprecision).
PICO 2: Mirabegron versus placebo
1. Effect treatment
1.1. Mean voided volume/micturition (MVV)
Soliman (2021) reported that children who received mirabegron had a mean voided volume at last follow-up of 206 ml (SD=39.3) (change between initiation of treatment and follow-up of 102.9 ml) as compared to 109.6 ml (SD=29.5) for children who received placebo (change between initiation of treatment and follow-up of 5.5 ml) (MD=96.40, 95%CI 84.25 to 108.55).
1.2. Mean change in micturitions per 24 hours
Soliman (2021) reported the mean number of voidings per day at last follow-up. Children who received mirabegron had 3.9 (SD=0.5) voidings (change between initiation of treatment and follow-up of 3.5) as compared to 6.9 (SD=1.4) voidings for children who received placebo (change between initiation of treatment and follow-up of 1.0) (MD=-3.00, 95%CI -3.37 to -2.63).
1.3. Mean change in number of incontinence episodes per 24 hours
Soliman (2021) reported that children who received mirabegron (n=64) had 0.9 (SD=0.8) incontinence episodes per day at last follow-up (change between initiation of treatment and follow-up of 1.8) as compared to 2.3 (SD=0.8) for children who received placebo (change between initiation of treatment and follow-up of 0.3) (MD=-1.40, 95%CI -1.68 to -1.12).
1.4. Post-void residual volume
Soliman (2021) reported that children who received mirabegron had a post-void residual volume at last follow-up of 16.1 ml (SD=2.8) as compared to 16.2 ml (SD=3.1) (change from baseline to follow-up of 2.3 ml) for children who received placebo (change from baseline to follow-up of 2.3 ml) (MD=-0.10, 95%CI -1.14 to 0.94).
1.5. Complete cure
Soliman (2021) reported complete cure defined as complete dryness based on objective voiding diaries. Twenty of the 64 children (31.3%) who received mirabegron had a complete cure as compared to 6 of the 61 children (9.8%) who received placebo (RR=3.18, 95%CI 1.37 to 7.38). This difference is clinically relevant favoring mirabegron.
2. Complications
2.1. Constipation
Soliman (2021) reported that 2 of the 71 children (2.8%) who received mirabegron had constipation as compared to 1 of the 69 children (1.4%) who received placebo (RR=1.94, 95%CI 0.18 to 20.95). This difference is clinically relevant favoring placebo.
2.2. Dry mouth
Soliman (2021) reported that 2 of the 71 children (2.8%) who received mirabegron had a dry mouth while this did not occur in children who received placebo (RR=4.86, 95%CI 0.24 to 99.46).
2.3. Influence on behavior
Soliman (2021) reported that no cases of altered mood occurred in children who either received mirabegron or placebo.
2.4. Headache
Soliman (2021) reported that 1 of the 71 children (1.4%) who received mirabegron had a headache, while this did not occur in children who received placebo (RR=2.92, 95%CI 0.12 to 70.39).
2.5. Other complications
The complications ‘dry eyes’, ‘palpitations’, ‘caries’, and ‘increased residue’ were not reported.
Level of evidence of the literature
According to GRADE, the level of evidence of randomized controlled trials start at high.
1. Effect of treatment
The level of evidence regarding the outcome measure mean voided volume/micturition was downgraded by three levels to very low because of concerns about blinding and missing data (-1, risk of bias) and the optimal information size is not achieved (-2, imprecision).
The level of evidence regarding the outcome measure mean change in micturitions per 24 hours was downgraded by three levels to very low because of concerns about blinding and missing data (-1, risk of bias) and the optimal information size is not achieved (-2, imprecision).
The level of evidence regarding the outcome measure mean change in incontinence episodes per 24 hours was downgraded by three levels to very low because of concerns about blinding and missing data (-1, risk of bias) and the optimal information size is not achieved (-2, imprecision).
The level of evidence regarding the outcome measure post-void residual volume
was downgraded by three levels to very low was downgraded by three levels to very low because of concerns about blinding and missing data (-1, risk of bias) and the optimal information size is not achieved (-2, imprecision).
The level of evidence regarding the outcome measure complete cure was downgraded by three levels to very low because of concerns about blinding and missing data (-1, risk of bias) and the optimal information size is not achieved (-2, imprecision).
2. Complications
The level of evidence regarding the outcome measure constipation was downgraded by three levels to very low because of concerns about blinding and missing data (-1, risk of bias) and the 95% confidence interval crossed the lines of no (clinically relevant) effect (-2, imprecision).
The level of evidence regarding the outcome measure dry mouth was downgraded by three levels to very low because of concerns about blinding and missing data (-1, risk of bias) and the 95% confidence interval crossed the lines of no (clinically relevant) effect (-2, imprecision).
The level of evidence regarding the outcome measure influence on behavior could not be assessed with GRADE as no events did occur.
The level of evidence regarding the outcome measure headache was downgraded by three levels to very low because of concerns about blinding and missing data (-1, risk of bias) and the 95% confidence interval crossed the lines of no (clinically relevant) effect (-2, imprecision).
PICO 3: Tolterodine versus placebo
1. Effect treatment
1.1. Mean voided volume/micturition (MVV)
Study 1: ³1 diurnal incontinence episode per 24 hours for ³5 days out of 7
Nijman (2005) reported that children who received tolterodine had a change in mean voided volume per micturition from baseline to end of treatment of 13.7 ml (SD=32.9) as compared to 5.8 ml (SD=27.8) for children who received placebo (MD=7.90, 95%CI 1.16 to 14.64).
Study 2: ³1 diurnal incontinence episode per 24 hours for ³5 days out of 7 & ³6 voids per 24 hours at baseline
Nijman (2005) reported that children with 6 or more voids per 24 hours at baseline who received tolterodine had a change in mean voided volume per micturition from baseline to end of treatment of 18.7 ml (SD=40.1) as compared to 9.6 ml (SD=27.4) for children who received placebo (MD=9.10, 95%CI 2.09 to 16.11).
1.2. Mean change in voids per 24 hours
Study 1: ³1 diurnal incontinence episode per 24 hours for ³5 days out of 7
Nijman (2005) reported that children who received tolterodine had a mean change in voids per 24 hours from baseline to end of treatment of -0.7 (SD=1.9) as compared to -0.5 (SD=1.7) for children who received placebo (MD=-0.20, 95%CI
-0.60 to 0.20).
Study 2: ³1 diurnal incontinence episode per 24 hours for ³5 days out of 7 & ³6 voids per 24 hours at baseline
Nijman (2005) reported that children with 6 or more voids per 24 hours at baseline who received tolterodine had a mean change in voids per 24 hours from baseline to end of treatment of -1.4 (SD=2.3) as compared to -1.5 (SD=2.1) for children who received placebo (MD=0.10, 95%CI -0.37 to 0.57).
1.3. Mean change in number of incontinence episodes per week
Study 1: ³1 diurnal incontinence episode per 24 hours for ³5 days out of 7
Nijman (2005) reported that children who received tolterodine had a mean change in diurnal urge incontinence episodes per week from baseline to end of treatment of -5.3 (SD=7.6) as compared to -3.8 (SD=6.1) for children who received placebo (MD=
-1.50, 95%CI -3.01 to 0.01).
Study 2: ³1 diurnal incontinence episode per 24 hours for ³5 days out of 7 & ³6 voids per 24 hours at baseline
Nijman (2005) reported that children with 6 or more voids per 24 hours at baseline who received tolterodine had a mean change in diurnal urge incontinence episodes per week from baseline to end of treatment of -10.0 (SD=12.2) as compared to -8.8 (SD=11.1) for children who received placebo (MD=-1.20, 95%CI -3.71 to 1.31).
2. Complications
2.1. Constipation
Study 1: ³1 diurnal incontinence episode per 24 hours for ³5 days out of 7
Nijman (2005) reported that 4 of the 235 children (1.7%) who received tolterodine had constipation as compared to 1 of the 107 children (0.9%) who received placebo (RR=1.82, 95%CI 0.21 to 16.10). This difference is clinically relevant favoring placebo.
Study 2: ³1 diurnal incontinence episode per 24 hours for ³5 days out of 7 & ³6 voids per 24 hours at baseline
Nijman (2005) reported that 6 of the 251 children (2.4%) with 6 or more voids per 24 hours at baseline who received tolterodine had constipation as compared to 1 of the 117 children (0.9%) who received placebo (RR=2.80, 95%CI 0.34 to 22.97). This difference is clinically relevant favoring placebo.
2.2. Dry mouth
Study 1: ³1 diurnal incontinence episode per 24 hours for ³5 days out of 7
Nijman (2005) reported that 3 of the 235 children (1.3%) who received tolterodine had a dry mouth as compared to 3 of the 107 children (2.8%) who received placebo (RR=0.46, 95%CI 0.09 to 2.22). This difference is clinically relevant favoring tolterodine.
Study 2: ³1 diurnal incontinence episode per 24 hours for ³5 days out of 7 & ³6 voids per 24 hours at baseline
Nijman (2005) reported that 1 of the 251 children (0.4%) with 6 or more voids per 24 hours at baseline who received tolterodine had a dry mouth as compared to 1 of the 117 children (0.9%) who received placebo (RR=0.47, 95%CI 0.03 to 7.39). This difference is clinically relevant favoring tolterodine.
2.3. Headache
Study 1: ³1 diurnal incontinence episode per 24 hours for ³5 days out of 7
Nijman (2005) reported that 24 of the 235 children (10.2%) who received tolterodine had a headache as compared to 15 of the 107 children (14.0%) who received placebo (RR=0.73, 95%CI 0.40 to 1.33). This difference is clinically relevant favoring tolterodine.
Study 2: ³1 diurnal incontinence episode per 24 hours for ³5 days out of 7 & ³6 voids per 24 hours at baseline
Nijman (2005) reported that 11 of the 251 children (4.4%) with 6 or more voids per 24 hours at baseline who received tolterodine had a headache as compared to 2 of the 117 children (1.7%) who received placebo (RR=2.56, 95%CI 0.58 to 11.38). This difference is clinically relevant favoring placebo.
2.4. Other complications
The complications ‘dry eyes’, ‘influence on behavior’, ‘palpitations’, ‘caries’, and ‘increased residue’ were not reported.
Level of evidence of the literature
According to GRADE, the level of evidence of randomized controlled trials start at high.
1. Effect of treatment
The level of evidence regarding the outcome measure mean voided volume/micturition was downgraded by three levels to very low because of concerns about the role of the sponsor and allocation concealment (-1, risk of bias), heterogeneity in study groups (-1, inconsistency), and the optimal information size is not achieved (-1, imprecision).
The level of evidence regarding the outcome measure mean change in voids per 24 hours was downgraded by three levels to very low because of concerns about the role of the sponsor and allocation concealment (-1, risk of bias), heterogeneity in study groups (-1, inconsistency), and the optimal information size is not achieved (-1, imprecision).
The level of evidence regarding the outcome measure mean change in incontinence episodes per 24 hours was downgraded by three levels to very low because of concerns about the role of the sponsor and allocation concealment (-1, risk of bias), heterogeneity in study groups (-1, inconsistency), and the optimal information size is not achieved (-1, imprecision).
2. Complications
The level of evidence regarding the outcome measure constipation was downgraded by three levels to very low because of concerns about the role of the sponsor and allocation concealment (-1, risk of bias) and the 95% confidence interval crossed the lines of no (clinically relevant) effect (-2, imprecision).
The level of evidence regarding the outcome measure dry mouth was downgraded by three levels to very low because of concerns about the role of the sponsor and allocation concealment (-1, risk of bias) and the 95% confidence interval crossed the lines of no (clinically relevant) effect (-2, imprecision).
The level of evidence regarding the outcome measure headache was downgraded by three levels to very low because of concerns about the role of the sponsor and allocation concealment (-1, risk of bias) and the 95% confidence interval crossed the lines of no (clinically relevant) effect (-2, imprecision).
PICO 4: Mirabegron versus solifenacin
1. Effect treatment
1.1. Mean voided volume/micturition (MVV)
Soliman (2021) reported that children who received mirabegron had a mean voided volume at last follow-up of 206 ml (SD=39.3) (change between initiation of treatment and follow-up of 102.9 ml) as compared to 198.2 ml (SD=41.7) for children who received solifenacin (change between initiation of treatment and follow-up of 92.5 ml) (MD=7.80, 95%CI -6.18 to 21.78).
1.2. Mean change in micturitions per 24 hours
Soliman (2021) reported the mean number of voidings per day at last follow-up. Children who received mirabegron had 3.9 (SD=0.5) voidings (change between initiation of treatment and follow-up of 3.5) as compared to 4.2 (SD=0.7) voidings for children who received solifenacin (change between initiation of treatment and follow-up of 3.5) (MD=-0.30, 95%CI -0.51 to -0.09).
1.3. Mean change in number of incontinence episodes per 24 hours
Soliman (2021) reported that children who received mirabegron had 0.9 (SD=0.8) incontinence episodes per day at last follow-up (change between initiation of treatment and follow-up of 1.8) as compared to 1.1 (SD=1.0) for children who received solifenacin (change between initiation of treatment and follow-up of 1.8) (MD=-0.20, 95%CI -0.51 to 0.11).
1.4. Post-void residual volume
Soliman (2021) reported that children who received mirabegron had a post-void residual volume at last follow-up of 16.1 ml (SD=2.8) as compared to 16.4 ml (SD=2.7) (change from baseline to follow-up of 2.3 ml) for children who received solifenacin (change from baseline to follow-up of 2.3 ml) (MD=-0.30, 95%CI
-1.25 to 0.65).
1.5. Complete cure
Soliman (2021) reported complete cure defined as complete dryness based on objective voiding diaries. Twenty of the 64 children (31.3%) who received mirabegron had a complete cure as compared to 22 of the 65 children (33.8%) who received solifenacin (RR=0.92, 95%CI 0.56 to 1.52).
2. Complications
2.1. Constipation
Soliman (2021) reported that 2 of the 71 children (2.8%) who received mirabegron had constipation as compared to 8 of the 70 children (11.4%) who received solifenacin (RR=0.25, 95%CI 0.05 to 1.12). This difference is clinically relevant favoring mirabegron.
2.2. Dry mouth
Soliman (2021) reported that 2 of the 71 children (2.8%) who received mirabegron had a dry mouth as compared to 7 of the 70 children (10%) of the children who received solifenacin (RR=0.28, 95%CI 0.06 to 1.31). This difference is clinically relevant favoring mirabegron.
2.3. Influence on behavior
Soliman (2021) reported that 2 of the 70 children (2.9%) who received solifenacin had a change in behavior while this did not occur in children who received mirabegron (RR=0.20, 95%CI 0.01 to 4.04).
2.4. Headache
Soliman (2021) reported that 1 of the 71 children (1.4%) who received mirabegron had a headache while this did not occur in children who received solifenacin (RR=2.96, 95%CI 0.12 to 71.41).
2.5. Other complications
The complications ‘dry eyes’, ‘palpitations’, ‘caries’, and ‘increased residue’ were not reported.
Level of evidence of the literature
According to GRADE, the level of evidence of randomized controlled trials start at high.
1. Effect of treatment
The level of evidence regarding the outcome measure mean voided volume/micturition was downgraded by three levels to very low because of concerns about blinding and missing data (-1, risk of bias) and the optimal information size is not achieved (-2, imprecision).
The level of evidence regarding the outcome measure mean change in micturitions per 24 hours was downgraded by three levels to very low because of concerns about blinding and missing data (-1, risk of bias) and the optimal information size is not achieved (-2, imprecision).
The level of evidence regarding the outcome measure mean change in incontinence episodes per 24 hours was downgraded by three levels to very low because of concerns about blinding and missing data (-1, risk of bias) and the optimal information size is not achieved (-2, imprecision).
The level of evidence regarding the outcome measure post-void residual volume
was downgraded by three levels to very low was downgraded by three levels to very low because of concerns about blinding and missing data (-1, risk of bias) and the optimal information size is not achieved (-2, imprecision).
The level of evidence regarding the outcome measure complete cure was downgraded by three levels to very low because of concerns about blinding and missing data (-1, risk of bias) and the 95% confidence interval crossed the lines of no (clinically relevant) effect (-2, imprecision).
2. Complications
The level of evidence regarding the outcome measure constipation was downgraded by two levels to low because of concerns about blinding and missing data (-1, risk of bias) and the low number of events resulting in the 95% confidence interval crossing the lines of no (clinically relevant) effect (-2, imprecision).
The level of evidence regarding the outcome measure dry mouth was downgraded by three levels to very low because of concerns about blinding and missing data (-1, risk of bias) and the 95% confidence interval crossed the lines of no (clinically relevant) effect (-2, imprecision).
The level of evidence regarding the outcome measure influence on behavior was downgraded by three levels to very low because of concerns about blinding and missing data (-1, risk of bias) and the 95% confidence interval crossed the lines of no (clinically relevant) effect (-2, imprecision).
The level of evidence regarding the outcome measure headache was downgraded by three levels to very low because of concerns about blinding and missing data (-1, risk of bias) and the 95% confidence interval crossed the lines of no (clinically relevant) effect (-2, imprecision).
Zoeken en selecteren
A systematic review of the literature was performed to answer the following question:
What is the effectiveness of antimuscarinics and/or mirabegron in the treatment of children with functional urinary incontinence?
| P: | Children with functional urinary incontinence (OAB, dysfunctional voiding, voiding postponement, giggling incontinence, hypotonic bladder) |
| I: | Antimuscarinics (solifenacin, oxybutinin, tolterodine) and/or mirabegron |
| C: |
Placebo or (one of the other) antimuscarinics alone, and in combination with mirabegron |
| O: |
Effect of treatment (subjective improvement, objective improvement including improvement in uroflowmetry values with residue determination, degree of urinary incontinence, micturition frequency, frequency voiding charts/voiding diary, urgency complaints, quality of life, bladder volume), complications ((dry mouth, dry eyes, influence on behavior (drowsiness or aggression), constipation, palpitations, headache, caries, and increased residue)) |
Relevant outcome measures
The guideline development group considered effect of treatment as a critical outcome measure for decision making; and complications as an important outcome measure for decision making.
The working group defined the outcome measures as follows:
- Effect treatment:
- Subjective improvement
- Objective improvement: improvement of uroflowmetry values with residual determination, degree of urinary incontinence (according to the ICCS criteria), micturition frequency, frequency voiding charts/voiding diary, urgency complaints, quality of life, bladder volume
- Complications: dry mouth, dry eyes, influence on behavior (drowsiness or aggression), constipation, palpitations, headache, caries, and increased residue
The working group defined the following minimal clinically (patient) important differences:
- Effect of treatment:
- Dichotomous (dry versus non-dry): 15% difference
- Continuous: 0.5 SD or -0.5 < SMD > 0.5
- Complications: 25% difference (RR < 0.8 or > 1.25)
Search and select (Methods)
The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms from 2000 until 12th of September, 2023. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 574 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), randomized controlled trial, or observational studies comparing
- Children with functional urinary incontinence between 5 and 18 years;
- Full-text English language publication; and
- Studies according to PICO.
Thirteen studies were initially selected based on title and abstract screening. After reading the full text, ten studies were excluded (see the table with reasons for exclusion under the tab Methods), and three studies were included.
Results
Three studies 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.
Referenties
- 1 - Blais AS, Nadeau G, Moore K, Genois L, Bolduc S. Prospective Pilot Study of Mirabegron in Pediatric Patients with Overactive Bladder. Eur Urol. 2016 Jul;70(1):9-13. doi: 10.1016/j.eururo.2016.02.007. Epub 2016 Feb 11. PMID: 26876327.
- 2 - Bolduc S, Upadhyay J, Payton J, Bägli DJ, McLorie GA, Khoury AE, Farhat W. The use of tolterodine in children after oxybutynin failure. BJU Int. 2003 Mar;91(4):398-401. doi: 10.1046/j.1464-410x.2003.04085.x. PMID: 12603422.
- 3 - Franco-Buenaventura D, García-Perdomo HA. Safety and effectiveness of mirabegron for children and adolescents with refractory idiopathic overactive bladder for improving urinary symptoms: a systematic review. Cent European J Urol. 2024;77(2):206-212. doi: 10.5173/ceju.2023.237. Epub 2024 Feb 25. PMID: 39345308; PMCID: PMC11428357.
- 4 - Kilic N, Balkan E, Akgoz S, Sen N, Dogruyol H. Comparison of the effectiveness and side-effects of tolterodine and oxybutynin in children with detrusor instability. Int J Urol. 2006 Feb;13(2):105-8. doi: 10.1111/j.1442-2042.2006.01240.x. PMID: 16563131.
- 5 - Kim JK, De Jesus MJ, Lee MJ, Dos Santos J, Dy JS, Ming JM, Rickard M, Lorenzo AJ, Chua ME. β3-Adrenoceptor Agonist for the Treatment of Bladder Dysfunction in Children: A Systematic Review and Meta-Analysis. J Urol. 2022 Mar;207(3):524-533. doi: 10.1097/JU.0000000000002361. Epub 2021 Dec 1. PMID: 34850638.
- 6 - Medhi B, Mittal N, Bansal D, Prakash A, Sarangi SC, Nirthi B. Comparison of tolterodine with standard treatment in pediatric patients with non-neurogenic dysfunctional voiding/over active bladder: a systematic review. Indian J Physiol Pharmacol. 2013 Oct-Dec;57(4):343-53. PMID: 24968572.
- 7 - Morin F, Blais AS, Nadeau G, Moore K, Genois L, Bolduc S. Dual Therapy for Refractory Overactive Bladder in Children: A Prospective Open-Label Study. J Urol. 2017 Apr;197(4):1158-1163. doi: 10.1016/j.juro.2016.11.101. Epub 2016 Nov 30. PMID: 27914999.
- 8 - Nasution R, Husein A, Adhyatma KP. Efficacy and safety of mirabegron in pediatric population: A systematic review. International Journal of Surgery Open. 2021;37: 100412.
- 9 - Newgreen D, Bosman B, Hollestein-Havelaar A, Dahler E, Besuyen R, Sawyer W, Bolduc S, Rittig S. Solifenacin in Children and Adolescents with Overactive Bladder: Results of a Phase 3 Randomised Clinical Trial. Eur Urol. 2017 Mar;71(3):483-490. doi: 10.1016/j.eururo.2016.08.061. Epub 2016 Sep 28. PMID: 27687820.
- 10 - Nijman RJ, Borgstein NG, Ellsworth P, Djurhuus JC. Tolterodine treatment for children with symptoms of urinary urge incontinence suggestive of detrusor overactivity: results from 2 randomized, placebo controlled trials. J Urol. 2005 Apr;173(4):1334-9. doi: 10.1097/01.ju.0000152322.17542.63. PMID: 15758796.
- 11 - Soliman MG, El-Abd S, El-Gamal OM, Raheem AA, Abou-Ramadan AR, El-Abd AS. Mirabegron versus Solifenacin in Children with Overactive Bladder: Prospective Randomized Single-Blind Controlled Trial. Urol Int. 2021;105(11-12):1011-1017. doi: 10.1159/000515992. Epub 2021 May 19. PMID: 34010843.
Evidence tabellen
Research question: What is the effectiveness of antimuscarinics or mirabegron in the treatment of children with urinary incontinence?
|
Study reference |
Study characteristics |
Patient characteristics 2 |
Intervention (I) |
Comparison / control (C) 3
|
Follow-up |
Outcome measures and effect size 4 |
Comments |
|
Newgreen, 2016 |
Type of study: Phase 3 randomised clinical trial
Setting and country: 16 countries worldwide
Funding and conflicts of interest: Astellas Pharma funded the study and played a role in study design and conduct; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. The authors received a fee or are employees at Astellas.
|
Inclusion criteria:
Exclusion criteria:
- polyuria (>75 mL/kg/body weight/24 h) - central or nephrogenic diabetes insipidus - dysfunctional voiding - congenital abnormalities affecting lower urinary tract function - constipation (Rome III criteria) - chronic UTI or >3 UTIs 2 months prior to screening - catheterization within 2 weeks prior to screening - haematuria ≥++ on dipstick test unless urological or kidney disease ruled out - kidney or bladder stones - partial/complete gastrointestinal obstruction, decreased gastrointestinal mortality (e.g., paralytic ileus), risk of gastric retention
N total at baseline: Intervention: 73 children & 22 adolescents Control: 75 children & 19 adolescents
Important prognostic factors2: Children: Age ± SD: I: 7.6 ± 1.6 C: 7.4 ± 1.6
Adolescents: Age ± SD: I: 14.2 ± 1.8 C: 14.4 ± 1.9
Children Sex: I: 39.7% M C: 52.1% M
Adolescents Sex: I: 22.7% M C: 15.8% M
Unclear if groups were comparable at baseline.
|
Urotherapy plus solifenacin
“Starting dose was based on the weight of the child at screening to deliver steady-state plasma drug exposure similar to that of the 5-mg tablet dose in adults (paediatric equivalent dose 5 mg). It could be titrated up or down every 3 weeks up to a maximum of three times (week 9) to a final dose of PED 2.5, PED 5, PED 7.5 or PED 10 (equivalent to 2.5, 5.0, 7.5 or 10.0 mg, respectively, in adults)” |
Urotherapy with placebo |
Length of follow-up: 12 weeks of treatment
Loss-to-follow-up: Children Intervention: 8 (11.0%) Reasons: adverse events, withdrawal by subject or other
Control: 9 (12%) Reasons: adverse event, lost to follow-up, withdrawal by subject, protocol violation or other
Adolescents Intervention: 5 (22.7%) Reasons: adverse events, withdrawal by subject, protocol violation, or other
Control: 3 (15.8%) Reasons: adverse event or withdrawal by subject
Incomplete outcome data: Not reported
|
Mean voided volume/micturition (MVV) (change from baseline to end of treatment) Children I: 25.5 ml C: 13.4 ml p=0.046
Adolescents I: 2.3 ml C: 6.9 ml
Mean change in micturitions/24 hours Children I: -1.1 C: -0.8 p=0.303
Adolescents I: -0.4 C: -0.6
Mean change in number of incontinence episodes/24 hours Children I: -1.1 C: -1.2 p=0.763 Adolescents I: -0.6 C: -0.7
Mean number/24 hours of daytime incontinence episodes Adjusted mean difference =
Mean number/24 hours of daytime micturitions Adjusted mean difference =
Number/7 days incontinence-free days Adjusted mean difference = -0.4 (SE=0.3), p=0.56
Post-void residual volume (change from baseline) Children I: -1.0 ml (SD=6.5) C: 0.1 ml (SD=7.3)
Adolescents I: 1.0 ml (SD=9.9) C: -3.6 ml (SD=4.7)
Constipation Children I: 4/73 (5.5%) C: 2/73 (2.7%)
Adolescents I: 0 C: 0
Dry mouth Children I: 2/73 (2.7%) C: 1/73 (1.4%)
Adolescents I: 0 C: 1/19 (5.3%)
Altered mood Children I: 1/73 (1.4%) C: 0
Adolescents I: 0 C: 0
Headache Children I: 0 C: 0
Adolescents I: 0 C: 1/19 (5.3%)
|
Author’s conclusion “In this 12-wk study, a once-daily oral suspension of solifenacin in children aged 5–<12 yr with overactive bladder was superior to placebo in increasing mean volume voided/micturition. Solifenacin was well tolerated, with a low incidence of dry mouth and constipation”.
Limitations - For adolescents, it was not possible to draw firm efficacy conclusions because of the low numbers recruited - Influence of sponsor |
|
Nijman, 2005 |
Type of study Two RCTs
Setting and country: The Netherlands
Funding and conflicts of interest Financial interest and/or other relationship with pharmaceutical companies.
|
Inclusion criteria: - Children between 5 and 10 years old with symptoms of urge incontinence suggestive of detrusor overactivity (defined as one diurnal incontinence episode or more per 24 hours for 5 or more days out of 7) - In the second study children had 6 or more voids per 24 hours at baseline.
Exclusion criteria: - Treatment for detrusor overactivity within 14 days of randomization - Monosymptomatic nocturnal enuresis - Giggle incontinence - Urinary tract infection - History of urinary retention - Neuropathic bladder - Post-void residual volume of 20% or more of functional bladder capacity
N total at baseline: Study 1 I: 235 C: 107
Study 2 I: 252 C: 117
Important prognostic factors2: Age ± SD: Study 1: I: 8 ± 1.5 C: 8 ± 1.6 Study 2: I: 7 ± 1.5 C: 7 ± 1.5
Sex (%M) Study 1: I: 54% C: 55% Study 2: I: 51% C: 56%
Groups were comparable at baseline
|
Tolterodine 2 mg daily |
Placebo |
Length of follow-up: 12 weeks
Loss-to-follow-up: Study 1: Intervention: 23 (9.8%) Reasons: adverse event, lost to follow-up, protocol violation, withdrew consent
Control: 17 (15.9%) Reasons: adverse events, lost to follow-up, protocol violation, withdrew consent
Study 2: Intervention: 17 (6.7%) Reasons: adverse event, lack of efficacy, lost to follow-up, protocol violation, withdrew consent
Control: 8 (6.8%) Reasons: adverse events, lack of efficacy, protocol violation, withdrew consent
Incomplete outcome data: Not reported
|
Diurnal urge incontinence episodes per week (mean change from baseline to week 12) Study 1 I: -5.3 (SD=7.6) C: -3.8 (SD=6.1)
Study 2 I: -10.0 (SD=12.2) C: -8.8 (SD=11.1)
Voids per 24 hours Study 1 I: -0.7 (SD=1.9) C: -0.5 (SD=1.7)
Study 2 I: -1.4 (SD=2.3) C: -1.5 (SD=2.1)
Voided volume per micturition Study 1 I: 13.7 ml (SD=32.9) C: 5.8 ml (SD=27.8)
Study 2 I: 18.7 ml (SD=40.1) C: 9.6 ml (SD=27.4)
Headache Study 1 I: 24/235 (10%) C: 15/107 (14%)
Study 2 I: 11/251 (4%) C: 2/117 (2%)
Dry mouth Study 1 I: 3/235 (1%) C: 3/107 (3%)
Study 2 I: 1/251 (0.4%) C: 1/117 (1%)
Constipation Study 1 I: 4/235 (2%) C: 1/107 (1%)
Study 2 I: 6/251 (2%) C: 1/117 (1%)
|
Author’s conclusion “Analysis of the primary efficacy outcome did not reveal a statistically significant effect of treatment. However, secondary analyses demonstrated that tolterodine was well tolerated among 5 to 10-year-old children with diurnal incontinence”.
Limitations: |
|
Soliman, 2021 |
Type of study: Prospective RCT
Setting and country: Egypt
Funding and conflicts of interest: The authors did not receive any funding. The authors have no conflicts of interest to disclose. |
Inclusion criteria: Children between 5 and 14 years with persistent urgency, frequency with or without urgency urinary incontinence due to idiopathic OAB after at least 3 months of behavioral therapy
Exclusion criteria: Children with active urinary tract infection, possible infravesical obstruction, neurogenic bladder, or abnormal serum creatinine.
N total at baseline: Intervention 1: 71 Intervention 2: 70 Control: 69
Important prognostic factors2: Age ± SD: I1: 9.4±1.8 years I2: 9.2±1.9 years C: 9±1.6 years
Sex: I1: 42.2% M I2: 46.2% M C: 45.9% M
Groups were comparable at baseline
|
Mirabegron: 50 mg once daily
Solifenacin: 5 mg
|
Placebo
|
Length of follow-up: 3 months
Loss-to-follow-up: Intervention: 7 (9.9%) Reasons: lost to follow-up and adverse events
Intervention: 5 (7.1%) Reasons: lost to follow-up and adverse events
Control: 8 (11.6%) Reasons: lost to follow-up and adverse events
Incomplete outcome data: Not reported
|
Incontinence episodes per day at last follow-up I1: 0.9 (SD=0.8) I2: 1.1 (SD=1) C: 2.3 (SD=0.8)
Mean number of voidings per day at last follow-up I1: 3.9 (SD=0.5) I2: 4.2 (SD=0.7) C: 6.9 (SD=1.4)
Mean voided volume at last follow-up I1: 206 ml (SD=39.3) I2: 198.2 ml (SD=41.7) C: 109.6 ml (SD=29.5)
Post-void residual volume at last follow-up I1: 16.1 ml (SD=2.8) I2: 16.4 ml (SD=2.7) C: 16.2 ml (SD=3.1)
Complete cure (defined as complete dryness) I1: 20/64 (31.3%) I2: 22/65 (33.8%) C: 6/61 (9.8%)
Dry mouth I1: 2/71 (2.8%) I2: 7/70 (10%) C: 0
Constipation: I1: 2/71 (2.8%) I2: 8/70 (11.4%) C: 1/69 (1.4%)
Change in behaviour I1: 0 I2: 2/70 (2.9%) C: 0
Headache I1: 1/71 (1.4%) I2: 0 C: 0
|
Author’s conclusion: “Both mirabegron and solifenacin have comparable efficacy regarding the control of OAB symptoms in the newly diagnosed children, but mirabegron seems to have less side effects”.
Limitations - Short duration of follow-up - Checked the adverse events from history taking |
Risk of bias table for interventions studies (cohort studies based on risk of bias tool by the CLARITY Group at McMaster University)
Research question: What is the effectiveness of antimuscarinics or mirabegron in the treatment of children with urinary incontinence?
|
Study reference
(first author, publication year) |
Was the allocation sequence adequately generated?
Definitely yes Probably yes Probably no Definitely no |
Was the allocation adequately concealed?
Definitely yes Probably yes Probably no Definitely no |
Blinding: Was knowledge of the allocated interventions adequately prevented?
Were patients blinded?
Were healthcare providers blinded?
Were data collectors blinded?
Were outcome assessors blinded?
Were data analysts blinded?
Definitely yes Probably yes Probably no Definitely no |
Was loss to follow-up (missing outcome data) infrequent?
Definitely yes Probably yes Probably no Definitely no |
Are reports of the study free of selective outcome reporting?
Definitely yes Probably yes Probably no Definitely no |
Was the study apparently free of other problems that could put it at a risk of bias?
Definitely yes Probably yes Probably no Definitely no |
Overall risk of bias If applicable/necessary, per outcome measure
LOW Some concerns HIGH
|
|
Newgreen, 2016 |
Probably yes;
Reason: Randomised in 1:1 ratio stratified by country.
|
Definitely yes;
Reason: Matching placebo formulation was used. |
Probably yes;
Reason: Double-blinded trial. |
Probably no;
Reason: Lost to follow-up was frequent, especially in adolescents group, but similar for both groups.
|
Probably yes;
Reason: All relevant outcomes were reported. |
Probably no;
Reason: Pharmaceutical company funded the study and played a role in study design and conduct.
|
Some concerns |
|
Nijman, 2005 |
Probably yes;
Reason: Centrally randomized at a 2:1 ratio.
|
No information |
Probably yes;
Reason: Double-blinded study. |
Probably no;
Reason: Lost to follow-up was frequent but similar for both groups. |
Probably yes;
Reason: All relevant outcomes were reported. |
Probably no;
Reason: Financial interest and/or other relationship with pharmaceutical company.
|
Some concerns |
|
Soliman, 2021 |
Definitely yes;
Reason: Randomly assigned using predefined randomization sequence created by a computer random number generator.
|
No information |
Probably no;
Reason: Single-blind study |
Probably no;
Reason: Lost to follow-up was frequent but similar for all groups. |
Probably yes;
Reason: All relevant outcomes were reported. |
Probably yes;
Reason: No other problems noted. |
Some concerns |
Table of excluded studies
|
Reference |
Reason for exclusion |
|
Athanasiou S, Pitsouni E, Grigoriadis T, Zacharakis D, Salvatore S, Serati M. Mirabegron in female patients with overactive bladder syndrome: What's new? A systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2020 Aug;251:73-82. doi: 10.1016/j.ejogrb.2020.05.018. Epub 2020 May 15. PMID: 32480182. |
Wrong population: no children |
|
Ayan S, Topsakal K, Gokce G, Gultekin EY. Efficacy of combined anticholinergic treatment and behavioral modification as a first line treatment for nonneurogenic and nonanatomical voiding dysfunction in children: a randomized controlled trial. J Urol. 2007 Jun;177(6):2325-8; discussion 2328-9. doi: 10.1016/j.juro.2007.02.001. PMID: 17509350. |
Wrong population: also children with nocturnal enuresis |
|
Kim JK, De Jesus MJ, Lee MJ, Dos Santos J, Dy JS, Ming JM, Rickard M, Lorenzo AJ, Chua ME. β3-Adrenoceptor Agonist for the Treatment of Bladder Dysfunction in Children: A Systematic Review and Meta-Analysis. J Urol. 2022 Mar;207(3):524-533. doi: 10.1097/JU.0000000000002361. Epub 2021 Dec 1. PMID: 34850638. |
Wrong comparison: baseline versus post-treatment; all cohort studies |
|
Medhi B, Mittal N, Bansal D, Prakash A, Sarangi SC, Nirthi B. Comparison of tolterodine with standard treatment in pediatric patients with non-neurogenic dysfunctional voiding/over active bladder: a systematic review. Indian J Physiol Pharmacol. 2013 Oct-Dec;57(4):343-53. PMID: 24968572. |
Only one suitable RCT |
|
Nasution R, Husein A, Adhyatma KP. Efficacy and safety of mirabegron in pediatric population: A systematic review. International Journal of Surgery Open. 2021;37: 100412. |
Wrong comparison: baseline versus post-treatment; all cohort studies |
|
Newgreen D, Bosman B, Hollestein-Havelaar A, Dahler E, Besuyen R, Snijder R, Sawyer W, Rittig S, Bolduc S. Long-Term Safety and Efficacy of Solifenacin in Children and Adolescents with Overactive Bladder. J Urol. 2017 Oct;198(4):928-936. doi: 10.1016/j.juro.2017.05.038. Epub 2017 May 12. PMID: 28506854. |
Wrong design: open-label extension. All children received solifenacin |
|
Nijman RJ, Borgstein NG, Ellsworth P, Siggaard C. Long-term tolerability of tolterodine extended release in children 5-11 years of age: results from a 12-month, open-label study. Eur Urol. 2007 Nov;52(5):1511-6. doi: 10.1016/j.eururo.2007.05.002. Epub 2007 May 11. PMID: 17574729. |
Wrong design: open-label extension. All children received tolterodine |
|
Noh JW, Lee B, Kim JH. Efficacy and safety of anticholinergics for children or adolescents with idiopathic overactive bladder: systematic review and meta-analysis. Int Urol Nephrol. 2019 Sep;51(9):1459-1471. doi: 10.1007/s11255-019-02209-y. Epub 2019 Jun 26. PMID: 31243632. |
Included only three suitable RCTs, which were also included in the search |
|
Qiu S, Bi S, Lin T, Wu Z, Jiang Q, Geng J, Liu L, Bao Y, Tu X, He M, Yang L, Wei Q. Comparative assessment of efficacy and safety of different treatment for de novo overactive bladder children: A systematic review and network meta-analysis. Asian J Urol. 2019 Oct;6(4):330-338. doi: 10.1016/j.ajur.2019.04.001. Epub 2019 Apr 13. PMID: 31768318; PMCID: PMC6872791. |
Only one suitable RCT |
|
Raman G, Tunnicliffe D, Lai E, Bennett T, Caldwell P. Safety and tolerability of solifenacin in children and adolescents with overactive bladder- a systematic review. J Pediatr Urol. 2023 Feb;19(1):19.e1-19.e13. doi: 10.1016/j.jpurol.2022.09.014. Epub 2022 Oct 1. PMID: 36336627. |
Only two RCTs, which were also included in the search |
Verantwoording
Beoordelingsdatum en geldigheid
Laatst beoordeeld : 17-07-2025
Algemene gegevens
De ontwikkeling/herziening van deze richtlijnmodule werd ondersteund door het Kennisinstituut van de Federatie Medisch Specialisten (www.demedischspecialist.nl/kennisinstituut) en werd gefinancierd uit de Kwaliteitsgelden Medisch Specialisten (SKMS). De financier heeft geen enkele invloed gehad op de inhoud van de richtlijnmodule.
Belangrijkste wijzigingen t.o.v. vorige versie: Er zijn veertien modules herzien/ontwikkeld:
- Anamnese
- Registratielijsten
- Uroflowmetrie en residubepaling
- Urineonderzoek (urine-incontinentie)
- Urethrocystoscopie
- Echo urinewegen
- Urodynamisch onderzoek
- Urotherapie
- Kinderbekkenfysiotherapie
- Antimuscarinica en mirabegron
- Botuline toxine A
- Methylfenidaat
- Neuromodulatie
- Organisatie van zorg
Samenstelling werkgroep
Voor het ontwikkelen van de richtlijnmodule is in 2022 een multidisciplinaire werkgroep ingesteld, bestaande uit vertegenwoordigers van alle relevante specialismen (zie hiervoor de Samenstelling van de werkgroep) die betrokken zijn bij de zorg voor kinderen met functionele urine-incontinentie.
Werkgroep
- Dr. L.L. (Liesbeth) de Wall, kinderuroloog, NVU
- Drs. M.M.C. (Marleen) van den Heijkant, kinderuroloog, NVU
- Drs. M. (Marleen) Trompetter, uroloog (met aantekening voor kinderen), NVU
- Drs. J. (Hans) van der Deure, kinderarts, NVK
- Dr. E. (Ester) de Kleijn, kinderarts, NVK
- Drs. L. (Lieke) Langendonck, kinderarts, NVK
- Dr. A.J. (Anka) Nieuwhof – Leppink, urotherapeut, NVCK
- S. (Saskia) Bruijn, MSc, verpleegkundig specialist kinderurologie, urotherapeut NVCK
- Drs. A.E.H. (Rianne) Stollenga, kinderfysiotherapeut, KNGF/NVFK
- Drs. A. (Astrid) Huijpen, bekkenfysiotherapeut, KNGF/NVFB
- Drs. F.E. (Femke) de Bok, jeugdarts KNMG en arts Maatschappij en Gezondheid in opleiding, AJN
- Drs. E.C. (Esen) Doganer, beleidsadviseur, Stichting Kind en Ziekenhuis
- Drs. A. (Anne) Swinkels, junior projectmanager en beleidsmedewerker Stichting Kind en Ziekenhuis (vervanger van Esen tijdens haar zwangerschapsverlof)
Klankbordgroep
- Drs. B.J.M. (Bernadette) Berendes- van Dijk, bekkenfysiotherapeut, Stichting Bekkenbodem4All
- Dr. H. (Hanny) Cobussen-Boekhorst, verpleegkundig specialist kinderurologie, V&VN
- Drs. V.A.C.T. (Vera) Janssen, verpleegkundig specialist kinderurologie, V&VN
- Drs. W.J.P. (Wies) van Aalst, kinderfysiotherapeut, KNGF/NVKF
Met ondersteuning van
- Drs. D.A.M. (Danique) Middelhuis, adviseur, Kennisinstituut van de Federatie Medisch Specialisten
- Dr. I.M. (Irina) Mostovaya, senior adviseur en teamleider, Kennisinstituut van de Federatie Medisch Specialisten
- Dr. J. M. (Janneke) Schultink, adviseur, Kennisinstituut van de Federatie Medisch Specialisten
- L.H.M. (Linda) Niesink-Boerboom, Medisch informatiespecialist, Kennisinstituut van Medisch Specialisten
Belangenverklaringen
De Code ter voorkoming van oneigenlijke beïnvloeding door belangenverstrengeling is gevolgd. Alle werkgroepleden hebben schriftelijk verklaard of zij in de laatste drie jaar directe financiële belangen (betrekking bij een commercieel bedrijf, persoonlijke financiële belangen, onderzoeksfinanciering) of indirecte belangen (persoonlijke relaties, reputatiemanagement) hebben gehad. Gedurende de ontwikkeling of herziening van een module worden wijzigingen in belangen aan de voorzitter doorgegeven. De belangenverklaring wordt opnieuw bevestigd tijdens de commentaarfase.
Een overzicht van de belangen van werkgroepleden en het oordeel over het omgaan met eventuele belangen vindt u in onderstaande tabel. De ondertekende belangenverklaringen zijn op te vragen bij het secretariaat van het Kennisinstituut van de Federatie Medisch Specialisten.
|
Werkgroep |
||||
|
Achternaam werkgroeplid |
Functie |
Nevenfuncties |
Gemelde belangen |
Ondernomen actie |
|
De Wall (voorzitter) |
Kinderuroloog Radboudumc Amalia kinderziekenhuis |
Geen |
ZonMw studie: SENS-U studie
Mijn promotie onderzoek bevat diverse artikelen aangaande het onderwerp. Ik kan niet inschatten of dit meer bekendheid zal krijgen door de herziening van de richtlijn. De SENS-U studie betreft een ZonMw gesubsidieerde studie naar de bijdrage van echografische monitoring van de blaas bij ongewild urine verlies. De resultaten van deze studie zullen naar verwachting eind 2024/ begin 2025 op zijn vroegst gepubliceerd worden. Dit zal geen invloed hebben op de huidige revisie. |
Geen restricties |
|
Van den Heijkant |
(kinder)uroloog in van Weel Bethesda Ziekenhuis |
Geen |
Geen |
Geen restricties |
|
Trompetter |
Uroloog Isala |
Commissiewerk binnen het ziekenhuis |
Participeert in de SENS-U studie. Geen persoonlijk belang. |
Geen restricties |
|
Van der Deure |
Kinderarts, Deventer Ziekenhuis |
Geen |
Geen |
Geen restricties |
|
De Kleijn |
Kinderarts (Albert Schweitzer Ziekenhuis) |
Voorzitter centrale Opleidingscommissie, (Albert Schweitzer Ziekenhuis) onbetaald Opleider kindergeneeskunde, (Albert Schweitzer Ziekenhuis) onbetaald |
Geen |
Geen restricties |
|
Langendonck |
Kinderarts in Langeland Ziekenhuis Zoetermeer |
Geen |
Geen |
Geen restricties |
|
Nieuwhof-Leppink |
Coordinator Urotherapie Wilhelmina kinderziekenhuis UMC Utrecht |
-International children's continence society: board member -European society pediatric urology research commissie lid beide zijn onbetaalde functies
Gedetacheerd van uit het UMCU voor 2 uur in de week bij hogeschool utrecht HU als coordinator Urotherapie cursus. |
Studie naar de SENSU als evt toegevoegde waarde in de behandeling van kinderen met incontinentie. |
Geen restricties |
|
Bruijn |
Verpleegkundig specialist kinderurologie / urotherapeut AmsterdamUMC/ Emma Kinderziekenhuis |
Geen |
Geen |
Geen restricties |
|
Stollenga |
Kinderfysiotherapeut en kinderbekkenfysiotherapeut bij Jan van Rijn Kinderfysiotherapie (betaald)
|
Penningmeester NVCK (onbetaald) Lid specialistenregistratie bij NVFK (betaald) |
Geen |
Geen restricties |
|
Huijpen |
Fysiotherapeut, Bekkenfysiotherapeut MSc, specialisatie in kinderen met problemen met de zindelijkheid Eigenaar praktijk Fysio Centrum Zaanland betaalde functie |
Werkzaam in eigen praktijk als algemeen- bekken- en kinderbekkenfysiotherapeut Leidinggevende taken (personeel en planning) Werkzaan in het Zaans Medisch Centrum in de kliniek en op de gezamenlijk poli in samenwerking met kinderarts, Urotherapeut, kinderpsycholoog, uroloog en gynaecoloog betaalde functie |
Onze fysiotherapie praktijk werkt zelfstandig en we hebben productie afspraken met het Zaans Medisch Centrum, er is geen direct verband met de richtlijn. |
Geen restricties |
|
De Bok |
Jeugdarts KNMG, arts Maatschappij en Gezondheid in opleiding, AJN |
Promotie-onderzoek naast specialistenopleiding (betaald, in dienstverband als aios bij SBOH) Bestuurslid regio-bestuur AJN Jeugdartsen Noord Nederland (onbetaald) |
Betreft mijn eigen promotie-onderzoek, het onderwerp is ongerelateerd aan dat van deze richtlijn en commissie |
Geen restricties |
|
Doganer |
Junior projectmanager/beleidsmedewerker bij Stichting Kind en ZIekenhuis |
Geen |
Geen |
Geen restricties |
|
Swinkels |
Junior Projectmanager en beleidsmedewerker Stichting Kind en Ziekenhuis |
Geen |
Geen |
Geen restricties |
|
Klankbordgroep |
||||
|
Achternaam klankbordgroeplid |
Functie |
Nevenfuncties |
Gemelde belangen |
Ondernomen actie |
|
Berendes – van Dijk |
Geen, gepensioneerd |
Geen |
Geen |
Geen restricties |
|
Cobussen – Boekhorst |
Verpleegkundig specialist kinderurologie en functionele urologie Amalia kinderziekenhuis, Radboudumc Postbus 9101 , 6500 HB Nijmegen huispost 723 |
Verzorgen van scholingen en presentaties (betaald of in werktijd) bij diverse groepen en verenigingen. -lid van Female LUTS werkgroep van de EAU
Lid project van Astellas voor eerste lijn over volwassenen met klachten van OAB. |
Lid van ICEF (International Clinical Education Forum) van Hollister inc. (stoma en katheter materiaal) = betaalde functie |
Geen restricties |
|
Janssen |
Verpleegkundig specialist (kinder)urologie (betaald) parttime, en functionele urologie radboud UMC Amalia Ziekenhuis |
Presentaties voor oa. V&vn urologie (betaald), webinair Gag spoelingen (betaald via goodlife) |
Lid CAB Hollister: adviescommissie stoma en katheter materiaal, betaald |
Geen restricties |
|
Van Aalst |
Kinderbekkenfysiotherapeut in Radboudumc |
Geen |
Geen |
Geen restricties |
Inbreng patiëntenperspectief
Er werd aandacht besteed aan het patiëntenperspectief door Stichting Bekkenbodem4All, Stichting Kind en Ziekenhuis, Patiëntenfederatie Nederland, Stichting Bedplassen en Vereniging Samenwerkende Ouder- en Patiëntenorganisaties uit te nodigen voor de schriftelijke knelpuntenanalyse en was Stichting Kind en Ziekenhuis afgevaardigd in de werkgroep. De verkregen input is meegenomen bij het opstellen van de uitgangsvragen, de keuze voor de uitkomstmaten en bij het opstellen van de overwegingen (zie per module ook “Waarden en voorkeuren van patiënten”). De conceptrichtlijn is tevens voor commentaar voorgelegd aan Stichting Bekkenbodem4All, Stichting Kind en Ziekenhuis, Patiëntenfederatie Nederland, Stichting Bedplassen en Vereniging Samenwerkende Ouder- en Patiëntenorganisaties en de eventueel aangeleverde commentaren zijn bekeken en verwerkt.
Kwalitatieve raming van mogelijke financiële gevolgen in het kader van de Wkkgz
Bij de richtlijnmodule is conform de Wet kwaliteit, klachten en geschillen zorg (Wkkgz) een kwalitatieve raming uitgevoerd om te beoordelen of de aanbevelingen mogelijk leiden tot substantiële financiële gevolgen. Bij het uitvoeren van deze beoordeling is de richtlijnmodule op verschillende domeinen getoetst (zie het stroomschema op de Richtlijnendatabase).
Module |
Uitkomst raming |
Toelichting |
|
Antimuscarinica en mirabegron
|
Geen financiële gevolgen |
Uit de toetsing volgt dat de aanbeveling(en) niet breed toepasbaar zijn (<5.000 patiënten) en zal daarom naar verwachting geen substantiële financiële gevolgen hebben voor de collectieve uitgaven. |
Werkwijze
AGREE
Deze richtlijnmodule is opgesteld conform de eisen vermeld in het rapport Medisch Specialistische Richtlijnen 3.0 van de adviescommissie Richtlijnen van de Raad Kwaliteit. Dit rapport is gebaseerd op het AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II; Brouwers, 2010).
Knelpuntenanalyse en uitgangsvragen
Tijdens de voorbereidende fase inventariseerde de werkgroep de knelpunten in de zorg voor kinderen met functionele urine-incontinentie. De werkgroep beoordeelde de aanbeveling(en) uit de eerdere richtlijnmodule (NVU, 2008) op noodzaak tot revisie. Tevens zijn er knelpunten aangedragen door Stichting Bekkenbodem4All, Koninklijk Nederlands Genootschap voor Fysiotherapie (KNGF) en AJN Jeugdartsen Nederland via een schriftelijke knelpuntenanalyse. Op basis van de uitkomsten van de knelpuntenanalyse zijn door de werkgroep concept-uitgangsvragen opgesteld en definitief vastgesteld.
Uitkomstmaten
Na het opstellen van de zoekvraag behorende bij de uitgangsvraag inventariseerde de werkgroep welke uitkomstmaten voor de patiënt relevant zijn, waarbij zowel naar gewenste als ongewenste effecten werd gekeken. Hierbij werd een maximum van acht uitkomstmaten gehanteerd. De werkgroep waardeerde deze uitkomstmaten volgens hun relatieve belang bij de besluitvorming rondom aanbevelingen, als cruciaal (kritiek voor de besluitvorming), belangrijk (maar niet cruciaal) en onbelangrijk. Tevens definieerde de werkgroep tenminste voor de cruciale uitkomstmaten welke verschillen zij klinisch (patiënt) relevant vonden.
Methode literatuursamenvatting
Een uitgebreide beschrijving van de strategie voor zoeken en selecteren van literatuur is te vinden onder ‘Zoeken en selecteren’ onder het kopje ‘Onderbouwing’. Indien mogelijk werd de data uit verschillende studies gepoold in een random-effects model. Review Manager 5.4 werd gebruikt voor de statistische analyses. De beoordeling van de kracht van het wetenschappelijke bewijs wordt hieronder toegelicht.
Beoordelen van de kracht van het wetenschappelijke bewijs
De kracht van het wetenschappelijke bewijs werd bepaald volgens de GRADE-methode. GRADE staat voor ‘Grading Recommendations Assessment, Development and Evaluation’ (zie http://www.gradeworkinggroup.org/). De basisprincipes van de GRADE-methodiek zijn: het benoemen en prioriteren van de klinisch (patiënt) relevante uitkomstmaten, een systematische review per uitkomstmaat, en een beoordeling van de bewijskracht per uitkomstmaat op basis van de acht GRADE-domeinen (domeinen voor downgraden: risk of bias, inconsistentie, indirectheid, imprecisie, en publicatiebias; domeinen voor upgraden: dosis-effect relatie, groot effect, en residuele plausibele confounding).
GRADE onderscheidt vier gradaties voor de kwaliteit van het wetenschappelijk bewijs: hoog, redelijk, laag en zeer laag. Deze gradaties verwijzen naar de mate van zekerheid die er bestaat over de literatuurconclusie, in het bijzonder de mate van zekerheid dat de literatuurconclusie de aanbeveling adequaat ondersteunt (Schünemann, 2013; Hultcrantz, 2017).
|
GRADE |
Definitie |
|
Hoog |
|
|
Redelijk |
|
|
Laag |
|
|
Zeer laag |
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Bij het beoordelen (graderen) van de kracht van het wetenschappelijk bewijs in richtlijnen volgens de GRADE-methodiek spelen grenzen voor klinische besluitvorming een belangrijke rol (Hultcrantz, 2017). Dit zijn de grenzen die bij overschrijding aanleiding zouden geven tot een aanpassing van de aanbeveling. Om de grenzen voor klinische besluitvorming te bepalen moeten alle relevante uitkomstmaten en overwegingen worden meegewogen. De grenzen voor klinische besluitvorming zijn daarmee niet één op één vergelijkbaar met het minimaal klinisch relevant verschil (Minimal Clinically Important Difference, MCID). Met name in situaties waarin een interventie geen belangrijke nadelen heeft en de kosten relatief laag zijn, kan de grens voor klinische besluitvorming met betrekking tot de effectiviteit van de interventie bij een lagere waarde (dichter bij het nuleffect) liggen dan de MCID (Hultcrantz, 2017).
Overwegingen (van bewijs naar aanbeveling)
Om te komen tot een aanbeveling zijn naast (de kwaliteit van) het wetenschappelijke bewijs ook andere aspecten belangrijk en worden meegewogen, zoals aanvullende argumenten uit bijvoorbeeld de biomechanica of fysiologie, waarden en voorkeuren van patiënten, kosten (middelenbeslag), aanvaardbaarheid, haalbaarheid en implementatie. Deze aspecten zijn systematisch vermeld en beoordeeld (gewogen) onder het kopje ‘Overwegingen’ en kunnen (mede) gebaseerd zijn op expert opinion. Hierbij is gebruik gemaakt van een gestructureerd format gebaseerd op het evidence-to-decision framework van de internationale GRADE Working Group (Alonso-Coello, 2016a; Alonso-Coello 2016b). Dit evidence-to-decision framework is een integraal onderdeel van de GRADE methodiek.
Formuleren van aanbevelingen
De aanbevelingen geven antwoord op de uitgangsvraag en zijn gebaseerd op het beschikbare wetenschappelijke bewijs en de belangrijkste overwegingen, en een weging van de gunstige en ongunstige effecten van de relevante interventies. De kracht van het wetenschappelijk bewijs en het gewicht dat door de werkgroep wordt toegekend aan de overwegingen, bepalen samen de sterkte van de aanbeveling. Conform de GRADE-methodiek sluit een lage bewijskracht van conclusies in de systematische literatuuranalyse een sterke aanbeveling niet a priori uit, en zijn bij een hoge bewijskracht ook zwakke aanbevelingen mogelijk (Agoritsas, 2017; Neumann, 2016). De sterkte van de aanbeveling wordt altijd bepaald door weging van alle relevante argumenten tezamen. De werkgroep heeft bij elke aanbeveling opgenomen hoe zij tot de richting en sterkte van de aanbeveling zijn gekomen.
In de GRADE-methodiek wordt onderscheid gemaakt tussen sterke en zwakke (of conditionele) aanbevelingen. De sterkte van een aanbeveling verwijst naar de mate van zekerheid dat de voordelen van de interventie opwegen tegen de nadelen (of vice versa), gezien over het hele spectrum van patiënten waarvoor de aanbeveling is bedoeld. De sterkte van een aanbeveling heeft duidelijke implicaties voor patiënten, behandelaars en beleidsmakers (zie onderstaande tabel). Een aanbeveling is geen dictaat, zelfs een sterke aanbeveling gebaseerd op bewijs van hoge kwaliteit (GRADE gradering HOOG) zal niet altijd van toepassing zijn, onder alle mogelijke omstandigheden en voor elke individuele patiënt.
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Implicaties van sterke en zwakke aanbevelingen voor verschillende richtlijngebruikers |
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Sterke aanbeveling |
Zwakke (conditionele) aanbeveling |
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Voor patiënten |
De meeste patiënten zouden de aanbevolen interventie of aanpak kiezen en slechts een klein aantal niet. |
Een aanzienlijk deel van de patiënten zouden de aanbevolen interventie of aanpak kiezen, maar veel patiënten ook niet. |
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Voor behandelaars |
De meeste patiënten zouden de aanbevolen interventie of aanpak moeten ontvangen. |
Er zijn meerdere geschikte interventies of aanpakken. De patiënt moet worden ondersteund bij de keuze voor de interventie of aanpak die het beste aansluit bij zijn of haar waarden en voorkeuren. |
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Voor beleidsmakers |
De aanbevolen interventie of aanpak kan worden gezien als standaardbeleid. |
Beleidsbepaling vereist uitvoerige discussie met betrokkenheid van veel stakeholders. Er is een grotere kans op lokale beleidsverschillen. |
Organisatie van zorg
In de knelpuntenanalyse en bij de ontwikkeling van de richtlijnmodule is expliciet aandacht geweest voor de organisatie van zorg: alle aspecten die randvoorwaardelijk zijn voor het verlenen van zorg (zoals coördinatie, communicatie, (financiële) middelen, mankracht en infrastructuur). Randvoorwaarden die relevant zijn voor het beantwoorden van deze specifieke uitgangsvraag zijn genoemd bij de overwegingen. Meer algemene, overkoepelende, of bijkomende aspecten van de organisatie van zorg worden behandeld in de module Organisatie van zorg.
Commentaar- en autorisatiefase
De conceptrichtlijnmodule werd aan de betrokken (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd ter commentaar. De commentaren werden verzameld en besproken met de werkgroep. Naar aanleiding van de commentaren werd de conceptrichtlijnmodule aangepast en definitief vastgesteld door de werkgroep. De definitieve richtlijnmodule werd aan de deelnemende (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd voor autorisatie en door hen geautoriseerd dan wel geaccordeerd.
Literatuur
Agoritsas T, Merglen A, Heen AF, Kristiansen A, Neumann I, Brito JP, Brignardello-Petersen R, Alexander PE, Rind DM, Vandvik PO, Guyatt GH. UpToDate adherence to GRADE criteria for strong recommendations: an analytical survey. BMJ Open. 2017 Nov 16;7(11):e018593. doi: 10.1136/bmjopen-2017-018593. PubMed PMID: 29150475; PubMed Central PMCID: PMC5701989.
Alonso-Coello P, Schünemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Rada G, Rosenbaum S, Morelli A, Guyatt GH, Oxman AD; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. 2016 Jun 28;353:i2016. doi: 10.1136/bmj.i2016. PubMed PMID: 27353417.
Alonso-Coello P, Oxman AD, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Vandvik PO, Meerpohl J, Guyatt GH, Schünemann HJ; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines. BMJ. 2016 Jun 30;353:i2089. doi: 10.1136/bmj.i2089. PubMed PMID: 27365494.
Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, Fervers B, Graham ID, Grimshaw J, Hanna SE, Littlejohns P, Makarski J, Zitzelsberger L; AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010 Dec 14;182(18):E839-42. doi: 10.1503/cmaj.090449. Epub 2010 Jul 5. Review. PubMed PMID: 20603348; PubMed Central PMCID: PMC3001530.
Hultcrantz M, Rind D, Akl EA, Treweek S, Mustafa RA, Iorio A, Alper BS, Meerpohl JJ, Murad MH, Ansari MT, Katikireddi SV, Östlund P, Tranæus S, Christensen R, Gartlehner G, Brozek J, Izcovich A, Schünemann H, Guyatt G. The GRADE Working Group clarifies the construct of certainty of evidence. J Clin Epidemiol. 2017 Jul;87:4-13. doi: 10.1016/j.jclinepi.2017.05.006. Epub 2017 May 18. PubMed PMID: 28529184; PubMed Central PMCID: PMC6542664.
Medisch Specialistische Richtlijnen 2.0 (2012). Adviescommissie Richtlijnen van de Raad Kwalitieit. http://richtlijnendatabase.nl/over_deze_site/over_richtlijnontwikkeling.html
Neumann I, Santesso N, Akl EA, Rind DM, Vandvik PO, Alonso-Coello P, Agoritsas T, Mustafa RA, Alexander PE, Schünemann H, Guyatt GH. A guide for health professionals to interpret and use recommendations in guidelines developed with the GRADE approach. J Clin Epidemiol. 2016 Apr;72:45-55. doi: 10.1016/j.jclinepi.2015.11.017. Epub 2016 Jan 6. Review. PubMed PMID: 26772609.
Schünemann H, Brożek J, Guyatt G, et al. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available from http://gdt.guidelinedevelopment.org/central_prod/_design/client/handbook/handbook.html.
Zoekverantwoording
Zoekacties zijn opvraagbaar. Neem hiervoor contact op met de Richtlijnendatabase.