Medicamenteuze behandeling ouderen
Uitgangsvraag
Wat is de waarde van medicamenteuze behandeling bij ouderen met UI in de tweede- en derdelijnszorg?
Aanbeveling
Kies bij het behandelen van ouderen met UI zoveel mogelijk voor niet-farmacologische behandelingen alvorens antimuscarinica voor te schrijven.
Overweeg bij ouderen met UI antimuscarinica voor te schrijven indien conservatieve behandelingen onvoldoende effectief zijn, waarbij aandacht voor ontwikkelen van bijwerkingen zoals droge mond en obstipatie, en cognitieve achteruitgang. Wees u er van bewust dat er op groepsniveau geen effectiviteit van antimuscarina is gevonden. Staak de behandeling indien er na 6 weken geen verbetering van klachten optreedt.
Wees terughoudend met het voorschrijven van antimuscarinica bij kwetsbare oudere patiënten die at risk zijn voor cognitieve disfunctie of die reeds medicatie gebruiken met hoge anticholinerge load.
De keuze van het antimuscarinicum maakt geen relevant verschil betreffende kans op anticholinerge bijwerkingen, mogelijk met uitzondering van oxybutynine in negatieve zin.
Overweeg mirabegron als alternatief voor antimuscarinica. Monitor bijwerkingen, met name hypertensie.
Overwegingen
Voor- en nadelen van de interventie en de kwaliteit van het bewijs
In de literatuuranalyse werd onderzocht wat de waarde is van medicamenteuze behandeling bij ouderen met UI in de tweede- en derdelijnszorg. De effectiviteit en veiligheid van behandeling met antimuscarinica of mirabegron/vibegron werden onderzocht.
Antimuscarinica versus placebo
1. Darifenacine of fesoterodine versus placebo
Voor de vergelijking tussen darifenacine en placebo en fesoterodine en placebo werd de bewijskracht voor de cruciale uitkomstmaat kwaliteit van leven beoordeeld als laag vanwege beperkingen in de studiepopulatie, methodologische beperkingen en populatiegrootte. Er werd geen bewijs gevonden voor de cruciale uitkomstmaat verbetering van aandrang urine-incontinentie klachten. Dit leidt tot een zeer lage overall bewijskracht. Dit betekent dat andere studies kunnen leiden tot nieuwe inzichten. Het gebruik van darifenacine bij ouderen met UI leidt mogelijk tot meer bijwerkingen zoals een droge mond en obstipatie. Het gebruik van fesoterodine bij ouderen met UI leidt mogelijk tot meer bijwerkingen zoals een droge mond en obstipatie, maar mogelijk geen verschil in cognitief functioneren in vergelijking met placebo. Er kunnen op basis van alleen de literatuur geen sterke aanbevelingen geformuleerd worden over de waarde van darifenacine of fesoterodine bij ouderen met UI in de tweede- en derdelijnszorg.
2. Oxybutynine versus placebo
Voor de vergelijking tussen oxybutynine en placebo werd de bewijskracht voor de cruciale uitkomstmaat verbetering van aandrang urine-incontinentie klachten beoordeeld als laag vanwege beperkingen in de studiepopulatie. Er werd geen bewijs gevonden voor de cruciale uitkomstmaat kwaliteit van leven. Dit leidt tot een zeer lage overall bewijskracht. Dit betekent dat andere studies kunnen leiden tot nieuwe inzichten. Er kunnen op basis van alleen de literatuur geen sterke aanbevelingen geformuleerd worden over de waarde van oxybutynine bij ouderen met UI in de tweede- en derdelijnszorg.
3. Solifenacine versus placebo
Voor de vergelijking tussen solifenacine en placebo werd er geen bewijs gevonden voor de cruciale uitkomstmaten verbetering van aandrang urine-incontinentie klachten en kwaliteit van leven. Dit betekent dat andere studies kunnen leiden tot nieuwe inzichten. Er kunnen op basis van alleen de literatuur geen sterke aanbevelingen geformuleerd worden over de waarde van solifenacine bij ouderen met UI in de tweede- en derdelijnszorg.
4. Tolterodine versus placebo
Voor de vergelijking tussen tolterodine en placebo werd de bewijskracht voor de cruciale uitkomstmaat verbetering van urine-incontinentie klachten beoordeeld als gemiddeld vanwege beperkingen in de studiepopulatie. Er werd geen bewijs gevonden voor de cruciale uitkomstmaat kwaliteit van leven. Dit leidt tot een zeer lage overall bewijskracht. Dit betekent dat andere studies kunnen leiden tot nieuwe inzichten. Het gebruik van tolterodine bij ouderen met UI leidt waarschijnlijk tot meer bijwerkingen zoals een droge mond. Er kunnen op basis van alleen de literatuur geen sterke aanbevelingen geformuleerd worden over de waarde van tolterodine bij ouderen met UI in de tweede- en derdelijnszorg.
Mirabegron versus placebo of antimuscarinica
1. Mirabegron of vibegron versus placebo
Voor de vergelijking tussen mirabegron en placebo werd de bewijskracht voor de cruciale uitkomstmaat verbetering van urine incontinentie klachten beoordeeld als laag vanwege methodologische beperkingen en de populatiegrootte. Er werd geen bewijs gevonden voor de cruciale uitkomstmaat kwaliteit van leven. Voor de vergelijking tussen vibegron en placebo werd geen bewijs gevonden voor de cruciale uitkomstmaten verbetering van urine incontinentie klachten en kwaliteit van leven. Dit leidt tot een zeer lage overall bewijskracht. Dit betekent dat andere studies kunnen leiden tot nieuwe inzichten. Er kunnen op basis van alleen de literatuur geen sterke aanbevelingen geformuleerd worden over de waarde van mirabegron of vibegron bij ouderen met UI in de tweede- en derdelijnszorg. Extra aandacht dient besteed te worden aan het feit dat voornoemde studies bekende bijwerkingen van antimuscarinica als uitgangspunt namen, bijwerkingen waarop sympathicomimetica inderdaad veelal beter scoorden. Daar stonden wel andere bijwerkingen, typisch voor sympathicomimetica, tegenover. Men denke hierbij vooral aan verhoging van de bloeddruk en tachycardie.
2. Vibegron versus tolterodine en mirabegron versus solifenacine
Voor de vergelijking tussen vibegron en tolterodine werd er geen bewijs gevonden voor de cruciale uitkomstmaten verbetering van urine incontinentie klachten en kwaliteit van leven. Ditzelfde geldt voor de vergelijking tussen mirabegron en solifenacine. Dit betekent dat andere studies kunnen leiden tot nieuwe inzichten. Het gebruik van vibegron bij ouderen met UI leidt mogelijk tot minder bijwerkingen zoals een droge mond vergeleken met tolterodine. Er kunnen op basis van alleen de literatuur geen sterke aanbevelingen geformuleerd worden over de waarde van vibegron vergeleken met tolterodine, of over de waarde van mirabegron vergeleken met solifenacine bij ouderen met UI in de tweede- en derdelijnszorg.
Er zijn twee beperkende factoren bij deze analyse. Er zijn weinig studies naar kwetsbare ouderen gedaan, ten eerste omdat onderzoek doen in deze patiënten groep niet eenvoudig is vanwege hun kwetsbaarheid en ten tweede omdat er geen consensus is om cognitieve achteruitgang eenduidig te meten, De MocA (Montreal Cognitive Assessment) en MMSE (Mini Mental State Exam) zijn veelgebruikte instrumenten voor het in kaart brengen van cognitieve achteruitgang. Voor deze instrumenten wordt geadviseerd een daling van 3 respectievelijk 4 punten aan te houden, aangezien deze verschillen niet te verklaren zijn vanuit meetfouten (Feeney, 2016). Voor beoordeling van de literatuur heeft de werkgroep deze waarden aangehouden.
Op basis van de huidige literatuur is de evidentie betreffende de werkzaamheid van de antimuscarinica op de cruciale uitkomstmaten aandrang urine-incontinentie en kwaliteit van leven van lage tot zeer lage kwaliteit. Voor een deel van de studies geldt dat de kwaliteit matig is, waarbij het niet mogelijk is via het GRADE systeem om tot duidelijke conclusies te komen. Antimuscarinica geven daarbij wel significant meer bijwerkingen, zoals droge mond en obstipatie, wat volgens de werkgroep een reden kan zijn tot staken van deze middelen. In de geselecteerde literatuur wordt in de onderzochte studiepopulaties geen cognitieve achteruitgang beschreven bij het gebruik van de verschillende antimuscarinica. Gezien het werkingsmechanisme is echter wel de verwachting dat de anticholinerge bijwerkingen inclusief cognitieve achteruitgang vaker zullen voorkomen wanneer er een verminderde cholinerge functie is, zoals bij kwetsbare ouderen. Derhalve adviseert de werkgroep om terughoudend te zijn met antimuscarinica bij deze kwetsbare groep.
De literatuur laat wat betreft de sympathicomimetica mirabegron en – het nu nog niet in Nederland beschikbare- vibegron ook geen duidelijk positief effect zien op de uitkomstmaten urine-incontinentie en kwaliteit van leven. Wel lijkt vooral vibegron minder bijwerkingen zoals droge mond te laten zien dan bijvoorbeeld tolterodine.
Gezien de positieve significante effecten van niet-farmacologische interventies, zoals blaastraining (vanzelfsprekend zonder de betreffende medicamenteuze bijwerkingen), zijn dit de eerst aangewezen behandelopties, ook bij oudere patiënten. Op basis van deze literatuur search zou behandeling met anticholinergica en sympathicomimetica niet als eerste keuze worden geadviseerd bij ouderen. De huidige module beschrijft de plaats van farmacotherapeutische interventies bij ouderen met aandrang urine-incontinentie. Voor meer informatie over de conservatieve behandeling, zie de module ‘Conservatieve behandeling UI bij ouderen’.
In de Europese richtlijn (EAU) female non-neurogenic lower urinary tract symptoms (F-LUTS), herzien in 2022, wordt medicatie gebruik bij oudere patiënten met aandrang urine incontinentie ook separaat geanalyseerd en beschreven. Hierbij dient te worden opgemerkt dat de EAU-richtlijn een andere systematiek voor het beoordelen van literatuur hanteert en naast de resultaten van reviews en RCTs ook studies met een andersoortige designs in de literatuur searches betrekt. Hierdoor kunnen de uitkomsten soms afwijken van de in de uw voorliggend richtlijn gebruikte systematiek. Samengevat wordt in de EAU-richtlijn gesteld dat:
- Antimuscarinica even effectief zijn bij ouderen, vergeleken met jongere patiënten;
- In cohortstudies gezien werd dat Oxybutinine mogelijk de cognitieve functie kan verslechteren bij oudere patiënten;
-Solifenacine, darifenacine en fesoterodine geen cognitieve dysfunctie veroorzaken in korte termijn studies;
- De impact van medicatie met anticholinergische effecten cumulatief is en vergroot bij langduriger exposure bij ouderen;
- Mirabegron effectief en veilig is bij ouderen boven de 65 jaar, waarbij een gunstiger bijwerkingenprofiel wordt gezien ten opzichte van antimuscarinica. Onbehandelde hypertensie is wel een contra-indicatie voor deze medicatie. Daarbij is verder van belang dat mirabegron een matige CYP-2D6 remmer is, wat van invloed kan zijn op de omzetting van medicatie die via dit enzym worden afgebroken. Mirabegron zelf wordt gemetaboliseerd door CYP3A4, wat bij gelijktijdig gebruik van sterke CYP3A4 remmers een dosisaanpassing vraagt. Zeker bij ouderen met polyfarmacie is het van belang om deze aspecten mee te nemen bij een eventuele start van Mirabegron.
In de praktijk ziet de werkgroep ook verbetering bij specifieke patiëntengroepen die onvoldoende effect ervaren van de conservatieve maatregelen, of niet in aanmerking komen voor meer invasieve behandelingen. Het valt dan te overwegen om in het kader van 'shared decision making' de optie voor behandeling met deze medicatie te bespreken, waarbij men alert dient te zijn op eventuele bijwerkingen, zoals droge mond en obstipatie.
Terughoudendheid bij kwetsbare ouderen lijkt hierbij geïndiceerd gezien kans op anticholinerge bijwerkingen. Mirabegron wordt in de internationale EAU richtlijn wel geadviseerd bij ouderen, maar hierbij wordt aangeraden om bloeddruk te controleren indien er gelijktijdig gebruik is van antihypertensiva, in ieder geval een keer in de eerste weken na start van het gebruik. Daarnaast wordt er in de samenvatting van de literatuur geen eenduidig positief effect op aandrang urine incontinentie beschreven, aangezien er nog onvoldoende studies zijn verricht naar dit onderwerp. Het is belangrijk om effect van de medicatie op de eindpunten aandrang urine-incontinentie en kwaliteit van leven te evalueren indien bovenstaande medicatie wordt gestart. Daarbij zal ook aandacht moeten zijn voor eventuele bijwerkingen.
Kwaliteit van leven is een belangrijke uitkomstmaat, maar wordt regelmatig niet meegenomen in de studies; wellicht kan dit in toekomstig onderzoek meer worden meegenomen, aangezien dit een zeer belangrijke maat is voor de patiënten.
Waarden en voorkeuren van patiënten (en evt. hun verzorgers)
De tolerantie van antimuscarinica en mirabegron is onderzocht in o.a. de PREFER studie (Staskin, 2018) waarbij patiënten met aandrang urine incontinentie mirabegron met tolterodine in een cross-over design als monotherapie gedurende 3 maanden gebruikten. De ‘medication tolerability score’ en klinische verbetering was meer uitgesproken in de mirabegron groep dan bij de tolterodine groep en meer uitgesproken bij vrouwen, patiënten ouder dan 65 jaar en patiënten zonder incontinentie bij start van de studie. In de richtlijn van de EAU wordt het volgende beschreven over waarden en voorkeur voor patiënten; 1) naleving aan antimuscarinische behandeling is laag en verminderd over tijd door gebrek aan effect, bijwerkingen en kosten, 2) de meeste patiënten stoppen de antimuscarinische medicijnen in de 1e 3 maanden. Hierbij wil de werkgroep aanraden de anticholinerge effecten bij kwetsbare ouderen in ogenschouw te nemen. Bespreek vooraf met de patiënt de uit de literatuur bekende (mogelijke) bijwerkingen van de medicatie en beslis samen met de patiënt tot starten van medicatie, met inachtname het geslacht, de leeftijd en de medicatie-tolerantie-score.
Kosten (middelenbeslag)
De prijs van antimuscarinica/sympathicomimetica varieert per dag tussen de € 0,24 (solifenacine 10mg/oxybutinine 5 mg) en de € 0,90 (fesoterodine 4mg/mirabegron 50mg). Op jaarbasis kan dit evenwel een behoorlijke impact geven op het eigen risico (www.farmacotherapeutischkompas.nl)). De prijs van het nog in Nederland toe te laten vibregon is nog niet bekend.
Aanvaardbaarheid, haalbaarheid en implementatie
Gezien de brede beschikbaarheid van de medicatie, ziet de werkgroep geen problemen voor haalbaarheid en implementatie van de geformuleerde aanbevelingen. In de dagelijkse praktijk wordt deze medicatie al voorgeschreven.
Rationale van de aanbeveling: weging van argumenten voor en tegen de interventies
Voor de werking van mirabegon in zijn algemeenheid en de relatie hiervan met de EAU richtlijn verwijst de werkgroep naar de module ‘Bèta-3 receptor agonist’. Specifiek voor de kwetsbare oudere beschrijft de werkgroep het onderstaande.
Geen van de antimuscarinica of sympathicomimetica is superieur ten opzichte van een ander ten aanzien van het genezen of verbeteren van aandrang urine incontinentie. De zorgen rondom bijwerkingen aangaande de cognitie kan bij de keuze tussen antimucarinica en sympathicomimetica een rol spelen. De meeste patiënten stoppen met het gebruik van antimuscarinica in de eerste 3 maanden. Dit hoge aantal kan worden verklaard door een ervaren gebrek aan effectiviteit, bijwerkingen en kosten van het geneesmiddel. De werking van antimuscarinica is maximaal na 4 weken. Bij mirabegron is de tijd tot maximaal effect langer, namelijk rond de 6 weken. Het is belangrijk om een individuele keuze te maken in samenspraak met de patient. Daarbij zal rekening gehouden moeten worden met de kans op cholinerge bijwerkingen bij kwetsbare ouderen door start van antimuscarinica. Tevens zal de kans op cardiovasculaire bijwerkingen door mirabegron, naast klinisch relevante interacties met andere medicatie bij polyfarmacie meegenomen moeten worden. Raadzaam is het recept voor maximaal 6 weken voor te schrijven met het oog op duurzaamheid en na 6 weken de behandeling te evalueren ten aan zien van effect en bijwerkingen, met instructie om eerder contact op te nemen bij hinderlijke bijwerkingen. Bloeddrukcontrole is noodzakelijk bij gebruik van mirabegron bij patiënten die antihypertensiva gebruiken. Wees bovendien alert op relevante interacties op CYP-enzymniveau indien er sprake is van polyfarmacie.
Onderbouwing
Achtergrond
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 2e / 3de 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.
Conclusies
Antimuscarinic treatment versus placebo
1. Darifenacin versus placebo
1.1. Improvement of urine incontinence complaints (critical)
No GRADE |
It was not possible to draw conclusions or grade the level of evidence for improvements from urine incontinence complaints in the comparison darifenacin and placebo, due to the absence of data. |
1.2. Quality of life (critical)
Low GRADE |
The evidence suggests that darifenacin results in little to no difference in quality of life when compared with placebo in elderly with urine incontinence.
Source: Chapple, 2007 |
1.3. Adverse event (important)
1.3.1. Adverse event: dry mouth
Low GRADE |
The evidence suggests darifenacin increases the adverse event dry mouth when compared with placebo in elderly with urine incontinence.
Source: Chapple, 2007 |
1.3.2. Adverse event: obstipation
Low GRADE |
The evidence suggests darifenacin increases the adverse event obstipation when compared with placebo in elderly with urine incontinence.
Source: Chapple, 2007 |
1.3.3. Adverse event: cognitive decline
No GRADE |
No evidence was found regarding the effect of darifenacin on the adverse event cognitive decline when compared with placebo in elderly with urine incontinence. |
2. Fesoterodine versus placebo
2.1. Improvement of urine incontinence complaints (critical)
No GRADE |
It was not possible to draw conclusions or grade the level of evidence for improvements from urine incontinence complaints in the comparison fesoterodine and placebo, due to the absence of data. |
2.2. Quality of life (critical)
Low GRADE |
The evidence suggests fesoterodine result in little to no difference in quality of life when compared with placebo in elderly with urine incontinence.
Source: Dubeau, 2014 |
2.3. Adverse event (important)
2.3.1. Adverse event: dry mouth
Low GRADE |
The evidence suggests fesoterodine increases the adverse event dry mouth when compared with placebo in elderly with urine incontinence.
Source: Dubeau, 2014; Wagg, 2013 |
2.3.2. Adverse event: obstipation
Low GRADE |
The evidence suggests fesoterodine increases the adverse event obstipation when compared with placebo in elderly with urine incontinence.
Source: Dubeau, 2014; Wagg, 2013 |
2.3.3. Adverse event: cognitive decline
Low GRADE |
The evidence suggests fesoterodine results in little to no difference in cognitive decline when compared with placebo in elderly with urine incontinence.
Source: Dubeau, 2014; Wagg, 2013 |
3. Oxybutynin versus placebo
3.1. Improvement of urine incontinence complaints (critical)
Low GRADE |
The evidence suggests oxybutynin results in little to no difference in improvement of urine incontinence complaints when compared with placebo in elderly with urine incontinence.
Source: Ouslander, 1995 |
3.2. Quality of life (critical)
No GRADE |
No evidence was found regarding the effect of oxybutynin on quality of life when compared with placebo in elderly with urine incontinence. |
3.3. Adverse events (important)
3.3.1. Adverse event: dry mouth
Very low GRADE |
The evidence is very uncertain about the effect of oxybutynin on the adverse event dry mouth when compared with placebo in elderly with urine incontinence.
Source: Ouslander, 1995; Szonyi, 1995 |
3.3.2. Adverse event: obstipation
Very low GRADE |
The evidence is very uncertain about the effect of oxybutynin on the adverse event obstipation when compared with placebo in elderly with urine incontinence.
Source: Ouslander, 1995; Szonyi, 1995 |
3.3.3. Adverse event: cognitive decline
No GRADE |
No evidence was found regarding the effect of oxybutynin on the adverse event cognitive decline when compared with placebo in elderly with urine incontinence. |
4. Solifenacin versus placebo
4.1. Improvement of urine incontinence complaints (critical)
No GRADE |
It was not possible to draw conclusions or grade the level of evidence for improvements from urine incontinence complaints in the comparison solifenacin and placebo, due to the absence of data. |
4.2. Quality of life (critical)
No GRADE |
No evidence was found regarding the effect of solifenacin on the quality of life when compared with placebo in elderly with urine incontinence. |
4.3. Adverse events (important)
4.3.1. Adverse event: dry mouth
Very low GRADE |
The evidence is very uncertain about the effect of solifenacin on the adverse event dry mouth when compared with placebo in elderly with urine incontinence.
Source: Kosilov, 2015 |
4.3.2. Adverse event: obstipation
No GRADE |
No evidence was found regarding the effect of solifenacin on the adverse event obstipation when compared with placebo in elderly with urine incontinence. |
4.3.3. Adverse event: cognitive decline
Very low GRADE |
The evidence is very uncertain about the effect of solifenacin on the adverse event cognitive decline when compared with placebo in elderly with urine incontinence.
Source: Kosilov, 2015 |
5. Tolterodine versus placebo
5.1. Improvement of urine incontinence complaints (critical)
Moderate GRADE |
Tolterodine likely results in little to no difference in the improvement of urine incontinence complaints when compared with placebo in elderly with urine incontinence.
Source: Zinner, 2002 |
5.2. Quality of life (critical)
No GRADE |
No evidence was found regarding the effect of tolterodine on the quality of life when compared with placebo in elderly with urine incontinence. |
5.3. Adverse events (important)
5.3.1. Adverse event: dry mouth
Moderate GRADE |
Tolterodine likely increases the adverse event dry mouth when compared with placebo in elderly with urine incontinence.
Source: Zinner, 2002 |
5.3.2. Adverse event: obstipation
Very low GRADE |
The evidence is very uncertain about the effect of tolterodine on the adverse event obstipation when compared with placebo in elderly with urine incontinence.
Source: Zinner, 2002 |
5.3.3. Adverse event: cognitive decline
No GRADE |
No evidence was found regarding the effect of tolterodine on the adverse event cognitive decline when compared with placebo in elderly with urine incontinence. |
2. Mirabegron versus placebo or antimuscarinic treatment
1. Mirabegron versus placebo
1.1. Improvement of urine incontinence complaints (critical)
Very low GRADE |
The evidence is very uncertain about the effect of mirabegron on improvement of urine incontinence complaints when compared with placebo in elderly with urine incontinence.
Source: Wagg, 2020, Kosilov, 2015 |
1.2. Quality of life (critical)
No GRADE |
No evidence was found regarding the effect of mirabegron on quality of life when compared with placebo in elderly with urine incontinence. |
1.3. Adverse events (important)
1.3.1. Adverse event: dry mouth
Very low GRADE |
The evidence is very uncertain about the effect of mirabegron on the adverse event dry mouth when compared with placebo in elderly with urine incontinence.
Source: Griebling, 2020; Kosilov, 2015 |
1.3.2. Adverse event: obstipation
Very low GRADE |
The evidence is very uncertain about the effect of mirabegron on the adverse event obstipation when compared with placebo in elderly with urine incontinence.
Source: Griebling, 2020 |
1.3.3. Adverse event: cognitive decline
Very low GRADE |
The evidence is very uncertain about the effect of mirabegron on the adverse event cognitive decline when compared with placebo in elderly with urine incontinence.
Source: Griebling, 2020; Kosilov, 2015; Wagg, 2020 |
2. Vibegron versus placebo
2.1. Improvement of urine incontinence complaints (critical)
No GRADE |
It was not possible to draw conclusions or grade the level of evidence for improvements from urine incontinence complaints in the comparison vibegron and placebo, due to the absence of data. |
2.2. Quality of life (critical)
No GRADE |
No evidence was found regarding the effect of vibegron on quality of life when compared with placebo in elderly with urine incontinence. |
2.3. Adverse events (important)
2.3.1. Adverse event: dry mouth
Very low GRADE |
The evidence is very uncertain about the effect of vibegron on the adverse event dry mouth when compared with placebo in elderly with urine incontinence.
Source: Varano, 2021; Yoshida, 2021 |
2.3.2. Adverse event: obstipation
Very low GRADE |
The evidence is very uncertain about the effect of vibegron on the adverse event obstipation when compared with placebo in elderly with urine incontinence.
Source: Yoshida, 2021 |
2.3.3. Adverse event: cognitive decline
No GRADE |
No evidence was found regarding the effect of vibegron on the adverse events cognitive decline when compared with placebo in elderly with urine incontinence. |
3. Vibegron versus tolterodine
3.1. Improvement of urine incontinence complaints (critical)
No GRADE |
It was not possible to draw conclusions or grade the level of evidence for improvements from urine incontinence complaints in the comparison vibegron and tolterodine, due to the absence of data. |
3.2. Quality of life (critical)
No GRADE |
No evidence was found regarding the effect of vibegron on quality of life when compared with tolterodine in elderly with urine incontinence. |
3.3. Adverse events (important)
3.3.1. Adverse event: dry mouth
Low GRADE |
The evidence suggests that vibegron results in a reduction in the adverse event dry mouth when compared with tolterodine in elderly with urine incontinence.
Source: Varano, 2021 |
3.3.2. Adverse event: obstipation; 3.3.3. Adverse event: cognitive decline
No GRADE |
No evidence was found regarding the effect of vibegron on the adverse events obstipation or cognitive decline when compared with tolterodine in elderly with urine incontinence. |
4. Mirabegron versus solifenacin
4.1. Improvement of urine incontinence complaints (critical)
No GRADE |
It was not possible to draw conclusions or grade the level of evidence for improvements from urine incontinence complaints in the comparison mirabegron and solifenacin, due to the absence of data. |
4.2. Quality of life (critical)
No GRADE |
No evidence was found regarding the effect of mirabegron on quality of life when compared with solifenacin in elderly with urine incontinence. |
4.3. Adverse events (important)
4.3.1. Adverse event: dry mouth
Very low GRADE |
The evidence is very uncertain about the effect of mirabegron on the adverse event dry mouth when compared with solifenacin in elderly with urine incontinence.
Source: Kosilov, 2015 |
4.3.2. Adverse event: obstipation
No GRADE |
No evidence was found regarding the effect of mirabegron on the adverse event obstipation when compared with solifenacin in elderly with urine incontinence. |
4.3.3. Adverse event: cognitive decline
Very low GRADE |
The evidence is very uncertain about the effect of mirabegron on the adverse event cognitive decline when compared with solifenacin in elderly with urine incontinence.
Source: Kosilov, 2015 |
Samenvatting literatuur
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.
- 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).
Zoeken en selecteren
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 10th 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.
Referenties
- 1 - Dubeau CE, Kraus SR, Griebling TL, Newman DK, Wyman JF, Johnson TM 2nd, Ouslander JG, Sun F, Gong J, Bavendam T. Effect of fesoterodine in vulnerable elderly subjects with urgency incontinence: a double-blind, placebo controlled trial. J Urol. 2014 Feb;191(2):395-404. doi: 10.1016/j.juro.2013.08.027. Epub 2013 Aug 21. PMID: 23973522.
- 2 - Griebling TL, Campbell NL, Mangel J, Staskin D, Herschorn S, Elsouda D, Schermer CR. Effect of mirabegron on cognitive function in elderly patients with overactive bladder: MoCA results from a phase 4 randomized, placebo-controlled study (PILLAR). BMC Geriatr. 2020 Mar 18;20(1):109. doi: 10.1186/s12877-020-1474-7. PMID: 32183741; PMCID: PMC7079371.
- 3 - Kosilov K, Loparev S, Ivanovskaya M, Kosilova L. A randomized, controlled trial of effectiveness and safety of management of OAB symptoms in elderly men and women with standard-dosed combination of solifenacin and mirabegron. Arch Gerontol Geriatr. 2015 Sep-Oct;61(2):212-6. doi: 10.1016/j.archger.2015.06.006. Epub 2015 Jun 25. PMID: 26169181.
- 4 - Lackner TE, Wyman JF, McCarthy TC, Monigold M, Davey C. Efficacy of oral extended-release oxybutynin in cognitively impaired older nursing home residents with urge urinary incontinence: a randomized placebo-controlled trial. J Am Med Dir Assoc. 2011 Nov;12(9):639-47. doi: 10.1016/j.jamda.2010.05.003. Epub 2010 Oct 2. PMID: 21450183.
- 5 - Samuelsson E, Odeberg J, Stenzelius K, Molander U, Hammarstrm M, Franzen K, Andersson G, Midlv P. Effect of pharmacological treatment for urinary incontinence in the elderly and frail elderly: A systematic review. Geriatr Gerontol Int. 2015 May;15(5):521-34. doi: 10.1111/ggi.12451. Epub 2015 Feb 5. PMID: 25656412.
- 6 - Varano S, Staskin D, Frankel J, Shortino D, Jankowich R, Mudd PN Jr. Efficacy and Safety of Once-Daily Vibegron for Treatment of Overactive Bladder in Patients Aged ³65 and ³75 Years: Subpopulation Analysis from the EMPOWUR Randomized, International, Phase III Study. Drugs Aging. 2021 Feb;38(2):137-146. doi: 10.1007/s40266-020-00829-z. Epub 2021 Jan 20. PMID: 33469832; PMCID: PMC7882560.
- 7 - Wagg A, Khullar V, Marschall-Kehrel D, Michel MC, Oelke M, Darekar A, Bitoun CE, Weinstein D, Osterloh I. Flexible-dose fesoterodine in elderly adults with overactive bladder: results of the randomized, double-blind, placebo-controlled study of fesoterodine in an aging population trial. J Am Geriatr Soc. 2013 Feb;61(2):185-93. doi: 10.1111/jgs.12088. Epub 2013 Jan 25. PMID: 23350833.
- 8 - Wagg A, Staskin D, Engel E, Herschorn S, Kristy RM, Schermer CR. Efficacy, safety, and tolerability of mirabegron in patients aged ³65yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol. 2020 Feb;77(2):211-220. doi: 10.1016/j.eururo.2019.10.002. Epub 2019 Nov 13. PMID: 31733990.
- 9 - Yoshida M, Takeda M, Gotoh M, Yokoyama O, Kakizaki H, Takahashi S, Masumori N, Nagai S, Minemura K. Cardiovascular safety of vibegron, a new ?3-adrenoceptor agonist, in older patients with overactive bladder: Post-hoc analysis of a randomized, placebo-controlled, double-blind comparative phase 3 study. Neurourol Urodyn. 2021 Aug;40(6):1651-1660. doi: 10.1002/nau.24732. Epub 2021 Jun 17. PMID: 34139038; PMCID: PMC8362047.
Evidence tabellen
Research question: What is the effectivity and safety of antimuscarinic treatment or mirabegron in elderly patients with urine incontinence, compared to placebo or no treatment?
Antimuscarinic treatment versus placebo (Evidence table for systematic review)
Study reference |
Study characteristics |
Patient characteristics |
Intervention (I) |
Comparison / control (C)
|
Follow-up |
Outcome measures and effect size |
Comments |
Samuelsson, 2015
[individual study characteristics deduced from Samuelsson, 2015]
PS., study characteristics and results are extracted from the SR (unless stated otherwise) |
SR and meta-analysis of RCTs and prospective controlled observational studies
Literature search up to October 2013
A: Chapple, 2007 B: Ouslander, 1995 C: Szonyi, 1995 D: Zinner, 2002
Study design: A: RCT B: RCT C: RCT D: RCT
Setting and Country: A: USA, Poland, South Africa, Hungary, Sweden, UK, Germany B: USA C: UK D: Europe, USA, Canada, Australia, and New Zealand
Source of funding and conflicts of interest: A: sponsored by Novartis Pharmaceuticals B: Not reported C: sponsored by Smith&Nephew Pharmaceuticals Ltd D sponsored by Pharmacia
|
Inclusion criteria SR: - Patients aged 65 years or older with urinary incontinence (elderly) - Patients living in nursing homes (frail elderly) - At least 20 patients in the intervention group and 20 in the control group - Treatment with one or more drugs for urinary Incontinence as intervention - Treatment with placebo or other specified treatment as control - Urinary leakage, quality of life or adverse events as outcomes - The study design should be a randomized controlled study or observational cohort study. - Studies written in English
Exclusion criteria SR: - Outdated treatments
15 studies included
Important patient characteristics at baseline:
N, mean age A: 399 patients, 72 ± 5 years B: 150 patients, 85.6 ± 8.6 years C: 60 patients, 82 ± 6 years D: 437 patients, 74 ± 6 years
Sex: A: 77.4% women B: Not reported C: 95% women D: 74.4% women
Groups not comparable at baseline |
Describe intervention:
A: Darifenacin 7.5 mg daily (voluntary up-titration to 15 mg after 2 weeks) B: Oxybutynin 2.5-5 mg x 3 + prompted voiding C: Oxybutynin 2.5 mg twice daily and bladder training D: Tolterodine ER capsules 4 mg once daily
|
Describe control:
A: Placebo B: Placebo C: Placebo D: Placebo
|
End-point of follow-up:
A: 12 weeks B: 20 days C: 6 weeks D: 12 weeks
For how many participants were no complete outcome data available? (intervention/control) A: 22/16 B: 12/12 C: 8/5 D: 21/29
|
Urinary leakage Defined as urgency urinary incontinence episodes per week (12 weeks) A: I: 19.8–14.0
Defined as incontinence episodes per week Mean reduction D: I: 23.2-11.5
Defined as incontinence episodes/3 days (day 20) B: I: 6.8
Defined as change in incontinence episodes/day during first 14 days vs last 14 days C: I: IQR = 10-8 (difference 8)
Quality of life Defined as OABq (mean change at week 12) A: I: 22.9
Adverse events Any adverse event A: I: 149 (56.0%) B: RD = 0.02 (-0.01, 0.05) D: I: 116 (54.2%)
Dry mouth A: I: 59 (22.2%) B: I: 22 (42%) C: I: 93% D: I: 52 (24.3%)
Constipation A: I: 41 (15.4%) B: I: 16 (30%) C: I: 50% D: I: 13 (6.1%)
|
Risk of bias (high, some concerns or low): A: Low B: Some concerns C: Some concerns D: Low
Brief description of author’s conclusion Anticholinergics have a small, but significant, effect on urinary leakage in older adults with UUI. Treatment with drugs for UUI in the frail elderly is not evidence based.
Personal remarks on study quality, conclusions, and other issues (potentially) relevant to the research question
Level of evidence: A: High B: Moderate C: Moderate D: High
Sensitivity analyses None
Heterogeneity Due to clinical heterogeneity, random effects model was used. |
Antimuscarinic treatment versus placebo (evidence table for intervention studies)
Study reference |
Study characteristics |
Patient characteristics 2 |
Intervention (I) |
Comparison / control (C) 3
|
Follow-up |
Outcome measures and effect size 4 |
Comments |
Dubeau, 2014 |
Type of study: RCT
Setting and country: 108 United States sites
Funding and conflicts of interest: Supported by Pfizer. Authors have financial interest and/or other relationship with Pfizer or Astellas |
Inclusion criteria: - Men or women ³65 years old - Self-reported urgency urinary incontinence (UUI) symptoms for ³3 months - 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 - 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 - Capable of adequate mobility for independent toileting (could use cane or walker) - Independent completion of bladder diaries and study related questionnaires
Exclusion criteria: - Any condition contraindicating the use of fesoterodine - Clinically significant hepatic disease or liver enzymes >2 times the upper limit of normal - Clinically significant renal disease and/or estimated creatinine clearance <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) >200 ml - Predominant stress urinary incontinence - Recurrent urinary tract infection - Significant constipation - Mini-Mental State Examination (MMSE) score <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
N total at baseline: Intervention: 281 Control: 281
Important prognostic factors: Mean age (range) I: 74.8 (65 to 91) C: 75.3 (65 to 90)
Sex: I: 80% F C: 84% F
Groups comparable at baseline
|
Describe intervention (treatment/procedure/test): Fesoterodine once daily for 12 weeks. Initiated on 4 mg but could be increased to 8 mg at 4 weeks (and returned back to 4 mg any time but not increase again).
|
Describe control (treatment/procedure/test): Placebo once daily for 12 weeks. Sham dose escalation and de-escalation between 4 mg and 8 mg.
|
Length of follow-up: 12 weeks
Loss-to-follow-up: Intervention: 55 (20%) Reasons: adverse events, insufficient clinical response, withdrew consent, did not meet entrance criteria, had protocol violations, were lost to follow-up, and other reasons
Control: 61 (22%) Reasons: adverse events, insufficient clinical response, withdrew consent, did not meet entrance criteria, had protocol violations, were lost to follow-up, and other reasons
Incomplete outcome data: Not reported
|
Improvement UI complaints Defined as reduction in mean number of UUI episodes per 24 hours (UUS rating 5)
At 4 weeks: I: -2.36 C: -1.54 P<0.001
At 12 weeks: I: -2.84 C: -2.20 P=0.002
Quality of life Defined as health-related quality of life (HRQL)
At 4 weeks: I: 17.8 (SE=1.4) C: 12.0 (SE=1.4) P<0.05
At 12 weeks: I: 23.1 (SE=1.5) C: 17.6 (SE=1.5) P<0.05
Adverse events: Dry mouth I: 66 (23.5%) C: 17 (6.0%)
Obstipation: I: 31 (11.0%) C: 12 (4.3%)
Cognitive decline MMSE (Mini-Mental State Examination)
LS mean ± SE I: 0.15±0.12 C: 0.33±0.12 P=0.28
|
Author’s conclusion: Flexible dose fesoterodine significantly improved urgency urinary incontinence episodes and other outcomes vs placebo and was generally well tolerated.
Limitations: - Population less cognitively impaired than other vulnerable elderly individuals - MMSE not sufficiently sensitive to small short-term changes in cognition - Patients may underreport mild cognitive changes |
Kosilov, 2015 |
Type of study: RCT
Setting and country: Russia
Funding and conflicts of interest: Authors declared no conflicts of interest. Funding not reported.
|
Inclusion criteria: - Age >65 years - Severe symptoms of overactive bladder (the frequency of episodes of incontinence (EI) ³3/day)
Exclusion criteria: - Chronic active diseases including hypertension - Intolerance to antimuscarinics and agonists of b3-adrenoreceptors
N total at baseline: Intervention: 63 Control: 59
Important prognostic factors: Not reported
Unclear if groups were comparable at baseline
|
Describe intervention (treatment/procedure/test): Solifenacin 10 mg/day |
Describe control (treatment/procedure/test): Placebo |
Length of follow-up: 6 weeks
Loss-to-follow-up: N=7 (2.9%) in total population because of intolerable side-effects
Incomplete outcome data: Not reported |
Number of episodes of incontinence I: 2.2 (5.5 3.3) C: 0.2 (4.3 4.1)
Adverse events Dry mouth: I: 5 (9.6%) C: 2 (3.4%)
Cognitive impairment: I: 0 C: 1 (1.7%)
|
Author’s conclusion Taking any of these drugs separately for the treatment of severe malfunction of lower urinary tracts in elderly people may turn out to be insufficient for effective symptom management
Limitations: - No direct comparison |
Lackner, 2011 |
Type of study: RCT
Setting and country: 12 skilled nursing homes in the Twin Cities, Minnesota (US)
Funding and conflicts of interest: Supported by a research grant from Ortho-McNeil Pharmaceuticals |
Inclusion criteria: - Female nursing home residents with an age ³ 65 years - Urge urinary incontinence - Mild to severe cognitive impairment (participants did not have delirium or a diagnosis of dementia with Lewy bodies) - Ambulatory - Able to communicate - Post void residual urine (PVR) volume <150 mL - Remain incontinent following a 2-day prompted voiding program conducted by investigators
Exclusion criteria: - Males - Unstable or severe medical condition that precluded the use of oxybutynin - Terminal illness - Use antimuscarinic, bisphosphonate, or acetylcholinesterase inhibitors during the month before or during treatment
N total at baseline: Intervention: 26 Control: 24
Important prognostic factors: Mean age ± SD I: 89.2 ± 5.2 C: 88.0 ± 7.1
Groups comparable at baseline
|
Describe intervention (treatment/procedure/test): Oxybutynin 5 mg/day |
Describe control (treatment/procedure/test): Placebo |
Length of follow-up: 4 weeks
Loss-to-follow-up: Intervention: 1 (3.8%) Reasons: excessive post void residual urine volume
Control: 2 (8.3%) Reasons: death and decline in medical condition
Incomplete outcome data: Not reported |
Urinary incontinence episodes After 4 weeks (median (range)) I: 4 (0-11) C: 2.5 (0-14) P = 0.75
Median change from baseline I: 38% C: 53% P=0.97
|
Author’s conclusion: Extended-release oxybutynin 5 mg per day for 4 weeks in older cognitively impaired female nursing home residents did not significantly reduce urinary incontinence.
Limitations: - Insufficient power
|
Wagg, 2013 |
Type of study: RCT
Setting and country: 61 sites in Austria, Belgium, Denmark, Finland, Germany, Israel, Italy, Norway, Portugal, Slovakia, Spain, Sweden, Switzerland, Turkey, and the United Kingdom
Funding and conflicts of interest: Funded by Pfizer. Conflicts of interest with pharmaceutical companies (Pfizer/Astellas). Sponsor involved in design and conduct of study.
|
Inclusion criteria: - Men and women aged ³65 years with OAB symptoms for ³3 months, a mean of ³8 micturitions and ³3 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 Mini-Mental State Examination (MMSE) score of ³20 - Need to be able to complete micturition diaries and study-related questionnaires - Adhere to study procedures.
Exclusion criteria: - 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
N total at baseline: Intervention: 392 Control: 393
Important prognostic factors: Mean age ± SD I: 72.6 ± 5.8 C: 72.8 ± 5.7
Sex (female) I: 213 (54%) C: 205 (52%)
Groups comparable at baseline
|
Describe intervention (treatment/procedure/test): Fesoterodine once daily for 12 weeks. Initiated on 4 mg but could be increased to 8 mg at 4 weeks and 8 weeks (and could return back to 4 mg at week 8).
|
Describe control (treatment/procedure/test): Placebo once daily for 12 weeks. Sham dose escalation and de-escalation.
|
Length of follow-up: 12 weeks
Loss-to-follow-up: Intervention: 78 (20%) Reasons: adverse events, insufficient clinical response, no longer willing to participate
Control: 52 (13%) Reasons: adverse events, insufficient clinical response, no longer willing to participate
Incomplete outcome data: Not reported |
UUI episodes Median change/24h at week 12 I: -1.0 C: -0.7 P = 0.73
Median number of UUI episodes per 24 hours (for those with UUI>0 at baseline) decreased from 1.3 to 0.0 in the fesoterodine group and from 1.7 to 0.0 in the placebo group.
HRQL LS Mean (±SE) Change From Baseline at Week 12 I: 11.6 C: 7.1 P<0.05
Adverse events Dry mouth I: 133 (33.9%) C: 21 (5.3%)
Obstipation I: 35 (8.9%) C: 10 (2.5%)
Cognitive decline MMSE score (change from baseline to week 12) I: 0.24±1.76 C: 0.23±1.82
Mean MMSE scores at week 12 I: 28.4 (range 20–30) C: 28.3 (range 19–30)
|
Author’s conclusion: Fesoterodine was associated with significantly greater improvements in most diary variables and participant-reported outcomes than placebo and was generally well tolerated in older people
Limitations:
Other remarks: Subgroup 65–75 and >75 |
Mirabegron/vibegron versus placebo or antimuscarinic treatment (evidence table for intervention studies)
Study reference |
Study characteristics |
Patient characteristics 2 |
Intervention (I) |
Comparison / control (C) 3
|
Follow-up |
Outcome measures and effect size 4 |
Comments |
Griebling, 2020 |
Type of study: Pre-planned analysis of phase 4 placebo-controlled study (PILLAR).
Setting and country: Multicentre study in US and Canada.
Funding and conflicts of interest: Funded by Astellas and authors are employees of Astellas. |
Inclusion criteria: Community-dwelling patients aged ≥65 years with wet overactive bladder (OAB) (≥1 incontinence episode and ≥3 urgency episodes during the 3-day diary, plus an average of ≥8 micturitions/24 h.
Exclusion criteria: Patients needed to be able to complete the micturition diaries and questionnaires.
N total at baseline: Intervention: 445 Control: 442
Important prognostic factors: Mean age ± SD I: 71.7 ± 5.5 C: 71.9 ± 6.0
Sex: I: 71.2% F C: 71.9% F
Groups comparable at baseline
|
Describe intervention (treatment/procedure/test): Mirabegron Initial 25 mg/day and optional to enhance to 50 mg/day after week 4/8
|
Describe control (treatment/procedure/test): Placebo |
Length of follow-up: 12 weeks
Loss-to-follow-up: Not reported
Incomplete outcome data: The number of patients missing scores were 29 for placebo and 18 for the mirabegron total group.
|
Cognitive decline Defined by MoCA test (mean (SE)) I: 26.9 (0.1) C: 27.0 (0.1)
Impaired cognitive function at 12 weeks: I: 24.5% (104/425) C: 25.8% (106/411)
Adverse events Dry mouth: I: 6 (1.3%) C: 7 (1.6%) |
Author’s conclusion: Treatment with mirabegron for 12 weeks did not contribute to drug-related cognitive side effects in patients aged ≥65 years, as measured by the MoCA. Furthermore, the pattern of change in cognition over time in an older OAB trial population does not appear to differ from that of subjects receiving placebo.
Limitations - Short study duration - Results to not apply to all elderly individuals with OAB |
Kosilov, 2015 |
Type of study: RCT
Setting and country: Russia
Funding and conflicts of interest: Authors declared no conflicts of interest. Funding not reported.
|
Inclusion criteria: - Age >65 years - Severe symptoms of overactive bladder (the frequency of episodes of incontinence (EI) ³3/day)
Exclusion criteria: - Chronic active diseases including hypertension - Intolerance to antimuscarinics and agonists of b3-adrenoreceptors
N total at baseline: Intervention: 63 Control: 59
Important prognostic factors: Not reported
Unclear if groups were comparable at baseline
|
Describe intervention (treatment/procedure/test): Mirabegron 50 mg/day |
Describe control (treatment/procedure/test): Placebo |
Length of follow-up: 6 weeks
Loss-to-follow-up: N=7 (2.9%) in total population because of intolerable side-effects
Incomplete outcome data: Not reported |
Number of episodes of incontinence I: 2.3 (5.2 to 2.9) C: 0.2 (4.3 to 4.1)
Adverse events Dry mouth: I: 1 (1.6%) C: 2 (3.4%)
Cognitive impairment: I: 0 C: 1 (1.7%) |
Author’s conclusion Taking any of these drugs separately for the treatment of severe malfunction of lower urinary tracts in elderly people may turn out to be insufficient for effective symptom management
Limitations: - No direct comparison |
Kosilov, 2015 |
Type of study: RCT
Setting and country: Russia
Funding and conflicts of interest: Authors declared no conflicts of interest. Funding not reported.
|
Inclusion criteria: - Age >65 years - Severe symptoms of overactive bladder (the frequency of episodes of incontinence (EI) ³3/day)
Exclusion criteria: - Chronic active diseases including hypertension - Intolerance to antimuscarinics and agonists of b3-adrenoreceptors
N total at baseline: Intervention: 63 Control: 52
Important prognostic factors: Not reported
Unclear if groups were comparable at baseline
|
Describe intervention (treatment/procedure/test): Mirabegron 50 mg/day |
Describe control (treatment/procedure/test): Solifenacin 10 mg/day |
Length of follow-up: 6 weeks
Loss-to-follow-up: N=7 (2.9%) in total population because of intolerable side-effects
Incomplete outcome data: Not reported |
Number of episodes of incontinence I: 2.3 (5.2 to 2.9) C: 2.2 (5.5 to 3.3)
Adverse events Dry mouth: I: 1 (1.6%) C: 5 (9.6%)
|
Author’s conclusion Taking any of these drugs separately for the treatment of severe malfunction of lower urinary tracts in elderly people may turn out to be insufficient for effective symptom management
Limitations: - No direct comparison |
Varano, 2021 |
Type of study: Subpopulation analysis from RCT
Setting and country: 199 study sites in the USA, Canada, Poland, Hungary, Latvia, and Lithuania
Funding and conflicts of interest: This study and medical writing and editorial support for the preparation of this manuscript were funded by Urovant Sciences (Irvine, CA). Conflicts of interests with pharmaceutical companies (Astellas/Pfizer).
|
Inclusion criteria: Adults with a history of OAB for at least 3 months before the screening visit and met prespecified criteria for wet or dry OAB
Exclusion criteria: - 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.
N total at baseline: Intervention: 322 (FAS n=317) Control: 288 (FAS n=277)
Important prognostic factors: Number of patients with mean age ³65 and sex (based on FAS) I: 242 (76.0%); 204 (84%) females C: 220 (79.4%); 178 (81%) females
Number of patients with mean age ³75 and sex (based on FAS) I: 75 (23.3%); 59 (79%) females C: 57 (20.6.0%); 43 (75%) females
Groups comparable at baseline
|
Describe intervention (treatment/procedure/test): Vibegron 75 mg/day |
Describe control (treatment/procedure/test): Placebo |
Length of follow-up: 12 weeks
Loss-to-follow-up: Intervention: 21 (6.5%) Reasons: withdrew consent and adverse events
Control: 26 (9.0%) Reasons: withdrew consent, lack of efficacy, adverse event, and withdrawn by sponsor
Incomplete outcome data: Not reported |
UUI episodes Mean daily number of UUI episodes at 12 weeks Least squares ³65 years after 12 weeks I: -2.0 C: -1.2 P <0.001 Least squares ³75 years after 12 weeks I: -2.0 C: -0.4 P<0.0001 for patients ³75
Adverse events Dry mouth I: 9 (1.7%) C: 5 (0.9%) |
Author’s conclusion: In this subpopulation analysis of patients with OAB aged ≥ 65 and ≥ 75 years from the EMPOWUR study, once-daily vibegron 75 mg showed rapid onset and robust efficacy versus placebo and was generally safe and well tolerated.
Limitations: Underpowered - Mostly female patients |
Varano, 2021 |
Type of study: Subpopulation analysis from RCT
Setting and country: See above
Funding and conflicts of interest: See above
|
Inclusion criteria: See above
Exclusion criteria: See above
N total at baseline: Intervention: 322 (FAS n=317) Control: 220 (FAS n=213)
Important prognostic factors: Number of patients with mean age ³65 and sex (based on FAS) I: 242 (76.0%); 204 (84%) females C: 166 (77.9%); 132 (80%) females
Number of patients with mean age ³75 and sex (based on FAS) I: 75 (23.3%); 59 (79%) females C: 47 (22.1%); 35 (75%) females
Groups comparable at baseline
|
Describe intervention (treatment/procedure/test): Vibegron 75 mg/day |
Describe control (treatment/procedure/test): Tolterodine 4 mg extended release |
Length of follow-up: 12 weeks
Loss-to-follow-up: Intervention: 21 (6.5%) Reasons: withdrew consent and adverse events
Control: 26 (11.8%) Reasons: adverse event, withdrew consent, withdrawn by principal investigator, lack of efficacy, protocol deviation, death
Incomplete outcome data: Not reported |
UUI episodes Mean daily number of UUI episodes at 12 weeks Least squares ³65 years after 12 weeks I: -2.0 C: -1.8 Least squares ³75 years after 12 weeks I: -2.0 C: -2.0
Adverse events Dry mouth: I: 9 (1.7%) C: 28 (6.5%)
|
Author’s conclusion: See above
Limitations: See above |
Wagg, 2020 |
Type of study: RCT
Setting and country: 103 sites in the USA and Canada
Funding and conflicts of interest: Funded by Astellas. Conflicts of interest with pharmaceutical companies.
|
Inclusion criteria: - 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 - Mental capable to complete the study or consent procedures
Exclusion criteria: 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
N total at baseline: Intervention: 445 Control: 443
Important prognostic factors: Mean age ± SD I: 71.7 ± 5.5 C: 71.9 ± 6.0
Sex (female) I: 317 (71%) C: 324 (73%)
Groups comparable at baseline
|
Describe intervention (treatment/procedure/test): Mirabegron Initial dose of 25 mg/day After week 4 or 8, the dose could be increased to 50 mg/day |
Describe control (treatment/procedure/test): Matched placebo |
Length of follow-up: 12 weeks
Loss-to-follow-up: Intervention: 36 (8.1%) Reasons: adverse events, lack of efficacy, protocol violation, withdrawal by patient or study terminated by sponsor
Control: 42 (9.5%) Reasons: adverse events, lack of efficacy, protocol violation, or withdrawal by patient
Incomplete outcome data: Intervention: 4 (1%) Control: 4 (1%)
|
Number of incontinence episodes/24 h Difference [SE]: –0.6 [0.1] 95% CI –0.8 to –0.3
Urgency incontinence episodes Difference [SE]: –0.56 [0.14] 95% CI –0.83 to –0.29
Montreal Cognitive Assessment There was no statistically significant change in MoCA score from baseline to end of treatment, with adjusted mean (standard error) changes of -0.1 (0.1) points for placebo and -0.2 (0.1) for mirabegron. |
Author’s conclusion Mirabegron efficacy, safety, and tolerability over 12 wk were confirmed in patients aged ³65 years with OAB and incontinence
Limitations: - Study was not designed to detect a difference between individual mirabegron doses and placebo, because patients were not randomly allocated to individual doses - Patients remaining on 25 mg had different baseline demographic and disease characteristics from those electing to increase their dose to 50 mg mirabegron at week 4 or 8 |
Yoshida, 2021 |
Type of study: Post-hoc analysis of RCT
Setting and country: 109 sites in Japan
Funding and conflicts of interest: Funding by Kyorin and Kissei Pharmaceutical. Conflicts of interests with pharmaceutical companies (Kyorin/Astellas/Pfizer).
|
Inclusion criteria: Patients with overactive bladder with ≥8 micturitions/day and either ≥1 urgency episodes/day or ≥1 urgency incontinence episodes/day
Exclusion criteria: - Urinary tract infection - Bladder calculus - Interstitial cystitis - Enlarged prostate - Residual urinary volume >100 ml - Systolic blood pressure ≥ 160 mmHg, diastolic blood pressure ≥ 100 mmHg, or pulse rate ≥110 bpm
N total at baseline: Intervention: 261 (I1=131 with 50 mg; I2=130 with 100 mg) Control: 131
Important prognostic factors: Age (mean ± SD) I1: 70.9 ± 4.4 I2: 71.2 ± 4.6 C: 71.7 ± 4.8
Sex (number of females) I1: 123 (93.9%) I2: 117 (90.0%) C: 118 (90.1%)
Groups probably comparable at baseline
|
Describe intervention (treatment/procedure/test): 1: Vibegron 50 mg/day 2: Vibegron 100 mg/day
|
Describe control (treatment/procedure/test): Placebo |
Length of follow-up: 12 weeks
Loss-to-follow-up: Not reported
Incomplete outcome data: Missing data for systolic/diastolic blood pressure I1: n=5 (3.8%) I2: n=7 (5.4%) C: n=8 (6.1%) |
UUI episodes/24h Difference from placebo on LS mean change I1: -0.36 (95% CI -0.66 to -0.06) I2: -0.48 (95% CI -0.79 to -0.18)
Adverse events Dry mouth: I: 3 (1.1%) C: 2 (1.5%)
|
Author’s conclusion: Vibegron exerts its efficacy on OAB symptoms with minimal influence on cardiovascular parameters in both patients aged ≥65 and <65 years, suggesting that vibegron may be useful in OAB treatment regardless of age.
Limitations: - Mostly female patients included - No elderly ³75 years |
FAS: full analysis set
Risk of bias table for intervention studies
Antimuscarinic treatment versus placebo
Study reference
(first author, publication year) |
Was the allocation sequence adequately generated?
|
Was the allocation adequately concealed?
|
Blinding: Was knowledge of the allocated interventions adequately prevented? Were patients/healthcare providers/data collectors/outcome assessors/data analysts blinded? |
Was loss to follow-up (missing outcome data) infrequent?
|
Are reports of the study free of selective outcome reporting?
|
Was the study apparently free of other problems that could put it at a risk of bias?
|
Overall risk of bias If applicable/necessary, per outcome measure
|
Dubeau, 2014 |
Probably yes;
Reason: Impala system (only for Pfizer-authorized users) was used for randomization. The randomization schedule was generated, secured, distributed and stored by Pfizer Global Clinical Data Services.
|
No information |
Probably yes;
Reason: Only mentioned that it was a double-blinded study, but not further elaborated. |
Probably no;
Reason: Loss to follow-up was frequent in intervention and control group. |
Probably yes;
Reason: Outcomes described in the protocol were also reported in the study. |
Probably yes;
Reason: No other problems noted. |
Some concerns |
Kosilov, 2015 |
Probably yes;
Reason: Simple probability sampling with randomization by the method of sequential numbers was used.
|
Probably yes;
Reason: Participants were not aware of pharmacological properties and names of the drugs. |
Probably no;
Reason: Participants were blinded, but no information about blinding of other study personnel. |
Probably yes;
Reason: Loss to follow-up was infrequent. |
Probably no;
Reason: One outcome measure was not reported in the methods section; the other outcomes were only mentioned in the analysis part.
|
Probably no;
Reason: No information about baseline characteristics of participants. |
Some concerns |
Lackner, 2011 |
Definitely yes;
Reason: Computer-generated randomization program was used by investigational pharmacy.
|
Probably yes;
Reason: Identical-appearing sham tablet used for placebo. |
Probably yes;
Reason: Participants and study personnel were blinded. |
Probably yes;
Reason: Loss to follow-up was infrequent in intervention and control group. |
Probably yes;
Reason: Secondary outcomes of previous study. |
Probably no;
Reason: Insufficient power. |
Some concerns |
Wagg, 2013 |
Probably yes;
Reason: Centralized system for randomization, but Pfizer Inc. generated and secured the randomization schedule.
|
Probably yes;
Reason: Study drug and placebo were identical in appearance. |
Probably yes;
Reason: Participants and investigators were blinded. |
Probably no;
Reason: Loss to follow-up was frequent in intervention and control group |
Probably yes;
Reason: Outcomes mentioned in the protocol were also reported in the article. |
Probably yes;
Reason: No other problems noted. |
Some concerns |
Mirabegron versus placebo or antimuscarinic treatment
Study reference
(first author, publication year) |
Was the allocation sequence adequately generated?
|
Was the allocation adequately concealed?
|
Blinding: Was knowledge of the allocated interventions adequately prevented? Were patients/healthcare providers/data collectors/outcome assessors/data analysts blinded? |
Was loss to follow-up (missing outcome data) infrequent?
|
Are reports of the study free of selective outcome reporting?
|
Was the study apparently free of other problems that could put it at a risk of bias?
|
Overall risk of bias If applicable/necessary, per outcome measure
|
Griebling, 2020 |
Probably yes;
Reason: Computer-generated randomisation schedule prepared by the sponsor.
|
No information |
Probably yes;
Reason: Patients, investigators, and the sponsor were blinded to treatment allocation. |
Probably yes;
Reason: No loss to follow-up. |
Probably yes;
Reason: All relevant outcomes were reported. |
Probably yes;
Reason: No other problems noted. |
Some concerns |
Kosilov, 2015 |
Probably yes;
Reason: Simple probability sampling with randomization by the method of sequential numbers was used. |
Probably yes;
Reason: Participants were not aware of pharmacological properties and names of the drugs. |
Probably no;
Reason: Participants were blinded, but no information about blinding of other study personnel. |
Probably yes;
Reason: Loss to follow-up was infrequent. |
Probably no;
Reason: One outcome measure was not reported in the methods section; the other outcomes were only mentioned in the analysis part.
|
Probably no;
Reason: No information about baseline characteristics of participants. |
Some concerns |
Varano, 2021 |
Probably yes;
Reason: Central, web based interactive response system. |
Probably yes;
Reason: Placebo capsules matching with intervention tablet. |
Probably yes;
Reason: Patients, investigators and sponsor were blinded.
|
Probably no;
Reason: Loss to follow-up was frequent in intervention and control group.
|
Probably yes;
Reason: All relevant outcomes were reported. |
Probably no;
Reason: Unpowered study. |
Some concerns
|
Wagg, 2020 |
Probably yes;
Reason: Computer-generated randomisation schedule prepared by the sponsor.
|
No information |
Probably yes;
Reason: Patients, investigators, and the sponsor were blinded to treatment allocation. |
Probably no;
Reason: Loss to follow-up was frequent in intervention and control group. |
Probably yes;
Reason: All relevant outcomes were reported. |
Probably yes;
Reason: No other problems noted. |
Some concerns |
Yoshida, 2021 |
No information |
No information |
Probably yes;
Reason: Only mentioned that it was a double-blinded study, but not further elaborated.
|
Probably yes;
Reason: Loss to follow-up was infrequent for intervention and control. |
Probably no;
Reason: All relevant outcomes were reported. |
Probably yes;
Reason: No other problems noted. |
HIGH |
Table of excluded studies
Reference |
Reason for exclusion |
Abreu-Mendes, 2021 |
No subgroup of elderly patients |
Cardozo, 2013 |
Wrong population: not specific elderly patients with dose escalation |
Cartwright, 2011 |
Wrong population: no elderly |
Castro-Diaz, 2015 |
Wrong study design: post-hoc analysis of three studies |
Chapple, 2013a |
Wrong population: no elderly |
Chapple, 2013b |
Wrong population: no elderly |
Chapple, 2013c |
Wrong population: no elderly |
Chapple, 2014a |
Wrong population: no elderly |
Chapple, 2014b |
Wrong population: no elderly |
Chapple, 2015 |
No meta-analysis, not only RCTs and older study |
Corcos, 2011 |
Wrong population: no elderly |
Dell’Utri, 2012 |
Wrong population: no elderly |
Dmochowski, 2010 |
Wrong population: no elderly |
Duong, 2021 |
No subgroup of elderly patients |
Goldfischer, 2015 |
Wrong population: no elderly |
Herschorn, 2010 |
Wrong population: no elderly |
Herschorn, 2013 |
Wrong population: no elderly |
Herschorn, 2017 |
Wrong population: no elderly |
Herschorn, 2018 |
Wrong population: no elderly |
Herschorn, 2020 |
Same registration number and outcomes as Wagg 2020 |
Huan, 2012 |
Wrong population: no elderly |
Inoue, 2019 |
Wrong population: no elderly |
Kaplan, 2011 |
Wrong population: no elderly |
Kaplan, 2014 |
Wrong population: no elderly |
Kessler, 2011 |
Wrong population: no elderly |
Khullar, 2011 |
Wrong population: no elderly |
Khullar, 2013 |
Wrong population: no elderly |
Khullar, 2016 |
Wrong population: no elderly |
Kobayashi, 2018 |
Wrong population: no elderly |
Kuo, 2015 |
Wrong population: no elderly |
Leone Roberti, 2012 |
Wrong population: no elderly |
Lozano-Ortega, 2020 |
Conflicts of interest |
Mahapatra, 2022 |
Wrong population: no elderly |
Meek, 2011 |
Wrong population: no elderly |
Micheson, 2019 |
Wrong population: no elderly |
Mueller, 2019 |
Subgroup analysis of Gratzke 2018, observational study |
Newman, 2010 |
Wrong population: no elderly |
Nitti, 2010 |
Wrong population: no elderly |
Nitti, 2013 |
Wrong population: no elderly |
Orešković, 2012 |
Wrong population: no elderly |
Paquette, 2011 |
No meta-analysis for elderly, older study |
Rana, 2016 |
Wrong population: no elderly |
Rangganata, 2020 |
Systematic review with only two suitable RCTs |
Robinson, 2018 |
Wrong population: no elderly |
Rosa, 2018 |
Wrong study design: narrative review |
Rossanese, 2015 |
Wrong population: no elderly |
Sand, 2012 |
Wrong population: no elderly |
Serels, 2010 |
Wrong population: no elderly |
Shin, 2019 |
Wrong population: no elderly |
Staskin, 2018 |
Wrong population: no elderly |
Staskin, 2020 |
Wrong population: no elderly |
Vecchioli Scaldazza, 2016 |
Wrong population: no elderly |
Vouri, 2017 |
Older systematic review only about adverse events |
Wagg, 2014 |
Not matching with PICO: no comparison between fesoterodine and placebo |
Wani, 2021 |
Wrong population: no elderly |
Yamaguchi, 2011 |
Wrong population: no elderly |
Yamaguchi, 2014 |
Wrong population: no elderly |
Yamaguchi, 2015 |
Wrong population: no elderly |
Yamaguchi, 2016 |
Wrong population: no elderly |
Yi, 2021 |
Wrong population: no elderly |
Yoshida, 2018 |
Wrong population: no elderly |
Verantwoording
Autorisatiedatum en geldigheid
Laatst beoordeeld : 11-04-2024
Laatst geautoriseerd : 11-04-2024
Geplande herbeoordeling : 11-04-2029
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.
Samenstelling werkgroep
Voor het ontwikkelen van de richtlijnmodule is in 2021 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 patiënten met urine-incontinentie in de 2e- en 3e-lijnszorg.
Werkgroep
- Dhr. dr. M.R. (Michael) van Balken, uroloog, NVU (voorzitter)
- Dhr. dr. L.P.W. (Bart) Witte, uroloog, NVU
- Dhr. drs. M.A.C. (Martijn) Smits, uroloog, NVU
- Mevr. dr. M.K. (Marian) Engberts, urogynaecoloog, NVOG
- Mevr. dr. P. (Pieternel) Steures, urogynaecoloog, NVOG
- Mevr. drs. A.C. (Rianne) van der Meer, klinisch geriater, NVKG
- Mevr. C.W.L. (Tine) van den Bos, Bekkenbodem4All
Meelezers:
- Mevr. dr. T.A.M. (Doreth) Teunissen, huisarts, NHG
- Dhr. H.J. (Henk Jan) Mulder, urologie verpleegkundige, V&VN
- Mevr. drs. A. (Ana) Dos Santos, bekkenfysiotherapeut, NVFB
- Mevr. drs. C. (Corine) Adamse, bekkenfysiotherapeut, NVFB
- Dhr. dr. R.S. (Ramon) Dekker, internist, NIV
Met ondersteuning van:
- Mevr. dr. I.M. (Irina) Mostovaya, senior adviseur, Kennisinstituut van de Federatie Medisch Specialisten, Utrecht
- Mevr. drs. B. (Beatrix) Vogelaar, adviseur, Kennisinstituut van de Federatie Medisch Specialisten, Utrecht
- Mevr. drs. D.A.M. (Danique) Middelhuis, junior adviseur, Kennisinstituut van de Federatie Medisch Specialisten, Utrecht
- Mevr. drs. L. (Laura) van Wijngaarden, junior adviseur, Kennisinstituut van de Federatie Medisch Specialisten, Utrecht
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 |
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Achternaam werkgroeplid |
Hoofdfunctie |
Nevenwerkzaamheden |
Gemelde belangen |
Actie |
Van Balken (voorzitter) |
Uroloog, Rijnstate Ziekenhuis, Arnhem |
Bestuurslid NVU (vacatie)
Presentatie gehouden op de Post ICS IUGA congres in 2021 waarvoor vergoeding van Astellas |
Transparantieregister 2018:
Deelname als onderzoeker aan Renova-trial (OASIS). Bedrijf: Bluewind. Alleen tegemoetkoming onkosten te maken voor ziekenhuiskosten e.d.
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geen dienstverlening bedrijven tijdens Richtlijn- ontwikkeling
Extra kritisch commentaar gevraagd van onafhankelijke reviewers tijdens de commentaarfase
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Engberts |
Urogynaecoloog bij Isala |
Trainer Altis Sling Coloplast -> tegen vergoeding
Presentatie gehouden op de Post ICS IUGA congres in 2021 waarvoor vergoeding van Astellas |
Trainer bij Coloplast SIMS Altis tegen SUI om die reden bij herziening richtlijn UI NVOG met name medicatie bij OAB in combinatie/PTNS beoordeeld
Ik doe ook onderzoek naar Bulkamid & Altis sling maar hier is tot op heden nog geen vergoeding voor.
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Extra kritisch commentaar gevraagd van onafhankelijke reviewers tijdens de commentaarfase |
Witte |
Uroloog, Isala Klinieken, Zwolle, Nederland |
Secretaris Werkgroep Functionele en Reconstructieve Urologie van de Nederlandse Vereniging van Urologie, onbetaald.
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In 2018 heb ik een vergoeding gekregen als spreker in opdracht van Pierre Fabre.
In ons ziekenhuis lopen verschillende studies die extern gefinancierd worden. Van de OASIS studie is de inclusie net gesloten. Het gaat om een implanteerbaar device voor de behandeling van aandrangsincontinentie. Wij hebben 4 patiënten geïncludeerd. Follow up is 12 maanden. |
Geen actie |
Van den Bos |
Bekkenfysiotherapeut zzp bij paramedisch centrum AdFysio te De Lier 0.5 fte |
Voorzitter Bekkenbodem4All - vrijwilligers vergoeding
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Geen |
Geen actie |
Van der Meer |
Klinische geriater, Groene Hart Ziekenhuis Gouda, 0,7 fte
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Geen |
Geen |
Geen actie |
Smits |
Uroloog, Maastricht UMC+ |
Lid Werkgroep Functionele en Reconstructieve urologie NVU (-)
Presentatie gehouden op de Post ICS IUGA congres in 2021 waarvoor vergoeding van Astellas |
Diensteverlening honorarium Medtronic 2020 665euro = Deelname advisory board Medtronic
Deelname als onderzoeker aan:
Enkel support financiële support voor onkosten ziekenhuis
geen dienstverlening bedrijven tijdens Richtlijn- ontwikkeling |
Extra kritisch commentaar gevraagd van onafhankelijke reviewers tijdens de commentaarfase |
Steures |
Urogynaecoloog, Jeroen Bosch Ziekenhuis, ’s Hertogenbosch |
Lid van landerlijke werkgroep bekkenbodem
Lid commissie Actualisatie en revisie gynaecologische richtlijnmodules. Modules: urine-incontinentie |
Geen |
Geen actie |
Klankbordgroep |
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Achternaam klankbordgroeplid |
Hoofdfunctie |
Nevenwerkzaamheden |
Gemelde belangen |
Actie |
Teunissen |
Huisarts, zelfstandig 0,6 fte
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Geen |
Geen |
Geen |
Adamse |
Bekkenfysiotherapeut en Klinisch Epidemioloog, Antonius Ziekenhuis Sneek
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Commissielid Wetenschapscommissie NVFB
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Mogelijk positie bekkenfysiotherapie
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Geen |
Dekker |
Internist ouderengeneeskunde bij Ziekenhuis Rivierenland
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2021 – heden Commissielid NIV kerngroep Ouderengeneeskunde – Kwaliteit & Richtlijnen - onbetaald
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Geen |
Geen |
Dos Santos |
Geregistreerd bekkenfysiotherapeut MSc bij Pelvicentrum centrum voor bekkenfysiotherapie Leiden
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Lid van NVFB wetenschappelijke commissie vergoeding voor reiskosten en bijwonen vergaderingen
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Deelname aan het ontwikkelen kan ervoor zorgen dat collega gaan verwijzen naar mijn praktijk vanwege meer bekendheid.
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Geen |
Mulder |
Verpleegkundig specialist Martini Ziekenhuis Groningen
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Geen |
Geen |
Geen |
Inbreng patiëntenperspectief
Er werd aandacht besteed aan het patiëntenperspectief door afvaardiging van Stichting Bekkenbodem4All 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 en de eventueel aangeleverde commentaren zijn bekeken en verwerkt.
Kwalitatieve raming van mogelijke financiële gevolgen in het kader van de Wkkgz
Bij de richtlijn is conform de Wet kwaliteit, klachten en geschillen zorg (Wkkgz) een kwalitatieve raming uitgevoerd of de aanbevelingen mogelijk leiden tot substantiële financiële gevolgen. Bij het uitvoeren van deze beoordeling zijn richtlijnmodules op verschillende domeinen getoetst (zie het stroomschema op de Richtlijnendatabase).
Uit de kwalitatieve raming blijkt dat er waarschijnlijk geen substantiële financiële gevolgen zijn, zie onderstaande tabel.
Module |
Uitkomst raming |
Toelichting |
Module medicamenteuze behandeling ouderen |
Geen financiële gevolgen |
Hoewel uit de toetsing volgt dat de aanbeveling(en) breed toepasbaar zijn (>40.000 patiënten), volgt uit de toetsing dat [het overgrote deel (±90%) van de zorgaanbieders en zorgverleners al aan de norm voldoet OF het geen nieuwe manier van zorgverlening of andere organisatie van zorgverlening betreft, het geen toename in het aantal in te zetten voltijdsequivalenten aan zorgverleners betreft en het geen wijziging in het opleidingsniveau van zorgpersoneel betreft]. Er worden daarom geen financiële gevolgen verwacht. |
Werkwijze
AGREE
Deze richtlijnmodule is opgesteld conform de eisen vermeld in het rapport Medisch Specialistische Richtlijnen 2.0 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 patiënten met urine-incontinentie in de 2e en 3e lijnszorg. De werkgroep beoordeelde de aanbeveling(en) uit de eerdere richtlijnmodule (NVU, 2014) op noodzaak tot revisie. Tevens zijn er knelpunten aangedragen door de Nederlandse Vereniging voor Klinische Geriatrie (NVKG), Nederlandse Vereniging voor Obstetrie & Gynaecologie (NVOG), Nederlandse Vereniging voor Urologie (NVU), Bekkenbodem4All (B4A), Inspectie voor de Gezondheidszorg en Jeugd (IGJ), Nederlands Huisartsen Genootschap (NHG), Nederlandse Vereniging voor Bekkenfysiotherapie (NVFB (in afstemming met de Koninklijk Nederlands Genootschap voor Fysiotherapie (KNGF)), Nederlandse Vereniging van Ziekenhuizen (NVZ), Patiëntenfederatie, Verpleegkundigen & Verzorgenden Nederland (V&VN), Zorginstituut Nederland (ZiNL), Zelfstandige Klinieken Nederland (ZKN) en Zorgverzekeraars Nederland (ZN) via een schriftelijke knelpunteninventarisatie.
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 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 |
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Redelijk |
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Laag |
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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.
Implicaties van sterke en zwakke aanbevelingen voor verschillende richtlijngebruikers |
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Sterke aanbeveling |
Zwakke (conditionele) aanbeveling |
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. |
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. |
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.