What Is the Most Effective Treatment for Nocturia Or Nocturnal Incontinence in Adult Women?

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Review

What Is the Most Effective Treatment for Nocturia or Nocturnal

Incontinence in Adult Women?

a, b c d

Dina Bedretdinova *, David Ambu¨hl , Muhammad Imran Omar , Vasileios Sakalis ,

e f g h

Nikesh Thiruchelvam , Marc Schneider , Arjun Nambiar , Ruud Bosch

a b c

INSERM CESP U1018, Villejuif, France; Department of Urology, University Hospital Bern, Inselspital Anna Seiler-Haus, Bern, Switzerland; European

Association of Urology Guidelines Office, Arnhem, The Netherlands; Department of Urology, General Hospital of Thessaloniki Agios Pavlos, Thessaloniki,

e f

Greece; Department of Urology, Cambridge University Hospitals NHS Trust, Cambridge, UK; Department of Urology, University Hospital Bern, Inselspital

g h

Anna Seiler-Haus, Bern, Switzerland; Department of Urology, Freeman Hospital, Newcastle-upon-Tyne, UK; Department of Urology, University Medical

Centre Utrecht, Utrecht, The Netherlands

Article info Abstract

Article history: Context: Nocturia is a prevalent symptom with varied aetiology and no consensus on

treatment options.

Accepted January 28, 2020

Objective: We systematically reviewed evidence comparing the beneﬁts and harms of various

treatment options for nocturia or nocturnal incontinence in women.

Associate Editor:

Evidence acquisition: Literature search was performed using Embase, Medline, and Cochrane

Malte Rieken

databases (from 1 January 1946 to 26 September 2017), following the methods detailed in the

Cochrane Handbook. The protocol was registered with PROSPERO. Certainty of evidence was

assessed with the Grading of Recommendations Assessment, Development and Evaluation Keywords:

(GRADE) approach.

Antimuscarinics Evidence synthesis: The literature search identiﬁed 3573 citations, of which 11 full-text articles

Desmopressin were included. Three studies on desmopressin and four on antimuscarinics provided evidence of

Nocturia improving nocturia symptoms. Four studies onbehavioural treatment providedlimited evidence

and controversial results. One study on oestrogen did not prove the beneﬁt of any mode of

Systematic review

administration, and onesmall studyon functional magnetic stimulationprovided some evidence

Treatment of effectiveness in nocturia. One randomised controlled trial (RCT; 141 participants) reported a

Women statistically signiﬁcant difference between the desmopressin and placebo groups (desmopressin

patients experienced 0.75 [95% conﬁdence interval {CI} 0.47–1.03] nocturia episodes less

than those experience by the placebo group; certainty of evidence = low). The only RCT on

antimuscarinics in women with nocturia reported that oxybutynin reduced the number of

nocturia episodes by 0.3 (95% CI –0.02 to 0.62) versus placebo. In one RCT comparing tolterodine

with the combination of tolterodine with behavioural therapy, there was signiﬁcant change from

baseline nocturnal incontinence episodes in both groups.

Conclusions: There is some evidence that desmopressin and antimuscarinics are effective

treatment options for nocturia; however, there is very limited evidence for other treatment

options. The ﬁndings should be interpreted with caution as there were some methodological

ﬂaws in the included studies, particularly outcome heterogeneity.

Patient summary: This review identiﬁed several medical treatments for nocturia in women,

such as desmopressin and antimuscarinics, which appear to improve the severity of the

condition.

* Corresponding author. 82, rue du General Leclerc, 94276 Le Kremlin-Bicetre Cedex, France.

Tel. +33(0)1 45 21 24 37, Mob: +33(0)6 72 16 25 70, Fax: +33(0)1 45 21 20 75.

E-mail address: [email protected] (D. Bedretdinova).

https://doi.org/10.1016/j.euf.2020.01.012

Please cite this article in press as: Bedretdinova D, et al. What Is the Most Effective Treatment for Nocturia or Nocturnal

Incontinence in Adult Women?. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.01.012

EUF-869; No. of Pages 11

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1. Introduction nocturia or nocturnal incontinence in terms of improving

symptom severity and quality of life in adult women.

Nocturia is defined by the International Continence Society

(ICS) as “waking to pass urine during the main sleep period”.

2. Evidence acquisition

Nocturnal incontinence is a complaint of intermittent

incontinence that occurs during the main period of sleep

This SR was undertaken under the auspices of the EAU. We

after the age of 3–5 yr at which bladder control usually

followed the Preferred Reporting Items for Systematic

occurs [1]. Nocturnal polyuria (NP) is defined as passing

Reviews and Meta-analysis (PRISMA) guidance and the

large volumes of urine during the main sleep period that

Cochrane Handbook for SRs of interventions [14,15]. The

should be quantified using a bladder diary [2]; some of the

protocol was registered at PROSPERO (CRD42017058997).

definitions propose thresholds such as nocturnal urine

The databases searched were the Embase, OVID Medline

> –

volume 20 33% of total 24-h urinary volume. Epub Ahead of Print, In-Process & Other Non-Indexed Citations,

Nocturia is a prevalent symptom in men and women of all

Ovid MEDLINE(R) Daily and Ovid MEDLINE(R), EBM

age groups. This paper will focus on women only. According to

Reviews—Cochrane Central Register of Controlled Trials, and

Bosch and Weiss [3], one in five or six younger people consis-

EBM Reviews—Cochrane Database of Systematic Reviews from

tently wake to void at least twice each night. Up to 60% of older

1946 to September 2017. Studies were limited to full-text

people void two or more times nightly [3]. Age is one of the

articles published in English, French, Spanish, Russian, and

most important risk factors. There is some controversial evi-

German language. The complete search strategy is provided

dence about gender as a risk factor. There is some evidence in the Supplementary material (Literature search strategy). The

about the association with metabolic syndrome, obesity, dia-

detailed PICO search strategy is shown in Table 1.

betes, cardiac disease, other conditions and ethnicity (African-

American race) [4,5].Althoughnocturiaisnotalife-threatening

2.1. Data collection and analysis

condition itself, there is a risk of increased mortality in some

patients due to hip fractures caused by risk of falls when getting

The study selection process is described in Fig. 1 [15]. All

up to urinate [6]. Economic burden of nocturia is important,

stages of selection were done with Covidence (www.

frequently leading to repeated consultations, diagnostic pro- covidence.org).

cedures, medications, and therapies, with costs adding up with

Two review authors (D.B. and D.A.) independently assessed

every patient. Sleep disturbance/bother and impact on quality

the risk of bias (RoB), using the Cochrane RoB assessment tool

of life are the most important reasons for consultation [7].

for randomised controlled trials (RCTs) [16]. RoB in non-RCT

Concerning the optimal treatment of nocturia in women,

was evaluated with an extra item to assess the risk of

there is no consensus due to the multifactorial pathophysiol-

confounding [17,18]. Study authors were contacted to provide

ogy (common symptom in different diseases).Theunderlying

missing information. Any disagreements were resolved by

causes may be urological, for example, lower urinary tract

discussion or by consulting a third review author (I.O.).

symptoms and neurogenic voiding dysfunction, or nonuro-

Meta-analysis, funnel plot interpretation, or assessment

logical, such as chronic heart failure and sleep apnoea, or

of heterogeneity and sensitivity analyses was planned, but

hormonal in origin [8]. The optimal treatment was investi-

was not feasible due to paucity of data. Furthermore, the

gated previously, but evidence was limited [9–13]. Currently

studies used different dosages and modes of administration

available treatments include antidiuretics and antimuscari-

of drugs. Quantitative synthesis was not undertaken for

nics. Desmopressin is an antidiuretic, working at the level of

nonrandomised studies. Instead, we used the narrative

the renal collecting duct, binding to the V2 receptors present

synthesis [14,19] approach to summarise the results.

inthedistal collectingtubules.Itisthoughttoworkinpatients

The Grading of Recommendations Assessment,

with NP by decreasing diuresis. Muscarinic receptor

Development and Evaluation (GRADE) approach was used

antagonists or antimuscarinics, such as darifenacin, fesoter-

for assessing the certainty of evidence. The following out-

odine, oxybutynin, propiverine, solifenacin, tolterodine, and

comes were selected for the “summary of findings” table:

trospium chloride, block the activity of muscarinic acetylcho-

line receptor. Some of them are more specific to the M3 1

receptor, which is most prevalent in detrusor muscle; some Number/frequency of nocturia episodes

are less specific and act on all receptor subtypes (M1, M2, and 2 NPI (NP Index; nocturnal urine volume/24-h urine

M3), leading to more side effects. volume [%])

There is no consensus on which treatment option is most 3 Nocturnal urinary volume

effective in women with nocturia or nocturnal inconti- 4 Nocturnal urinary incontinence episodes

nence. Furthermore, since the topic is not covered in the

recent European Association of Urology (EAU) guidelines, 3. Evidence synthesis

the Urinary Incontinence Panel conducted a systematic

review (SR) on female nocturia and female nocturnal 3.1. Description of the included studies

incontinence to enable recommendations in a future

version of the guidelines. In this study, we systematically A total of 3573 references were identified for screening and

reviewed evidence for the most effective treatment of 281 were selected for full-text screening. The authors of

Please cite this article in press as: Bedretdinova D, et al. What Is the Most Effective Treatment for Nocturia or Nocturnal

Incontinence in Adult Women?. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.01.012

EUF-869; No. of Pages 11

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Table 1 – PICO search strategy.

P Population Inclusion criteria:

Adult women (18 yr old) categorised within the following symptom groups:

Nocturia as the primary presentation (ie, nocturia as the predominant bothersome symptom)

Nocturia as a secondary component of LUTS, that is, LUTS including nocturia

Nocturnal incontinence as a secondary component of incontinence

Nocturnal polyuria (following International Continence Society deﬁnition, or as deﬁned by trialist)

Exclusion criteria:

Neurourology patients such as patients with spinal cord injury, multiple sclerosis, myelomeningocele and nerve tube defects,

Parkinson’s disease, and Alzheimer’s disease (according to EAU guidelines [13])

Children

I Intervention Medical treatment (we included all published doses and schedules): anticholinergic drug, mirabegron, desmopressin, diuretics

(all types), sleep promoting agents (eg, hypnotics—diazepam, nitrazepam), oestrogen (topical or hormone replacement therapy),

treatment for pain (eg, sodium hyaluronate bladder instillations), phytotherapy (eg, herbal treatment)

Surgical treatment: botulinum toxin type A, neuromodulation (sacral nerve stimulation, etc.), neurostimulation (eg, parasacral

transcutaneous electrical neural stimulation), surgery to relieve bladder outlet obstruction in women

Lifestyle modiﬁcation (eg, moderating ﬂuid intake at night, leg elevation, avoiding caffeine, etc.)

Any other treatment (eg, acupuncture, continuous positive airway pressure machine, etc.), compression stockings,

psychotherapy, hypnotherapy

C Comparator Placebo

No treatment

Other experimental treatment as listed above under intervention

O Outcomes No core outcome set for nocturia was found in the COMET database

The primary beneﬁt outcome was

Improvement in symptom severity/number of voids for nocturia (outcome measure as deﬁned by trialist).

The primary harm outcomes were:

Adverse events of treatment (ad hoc listing of events, eg, dry eyes, blurring of vision, constipation, etc.) and events leading to

potential harm (eg, hyponatraemia, voiding difﬁculties)

Any other outcomes judged relevant by the review author team.

Secondary outcomes:

Night-time incontinence episodes

Quality of life (measured by validated questionnaire, such as IPSS, ICIQ-SF, at any time point)

Sleep quality (measured by validated questionnaire, at any time point)

Global improvement scales (not speciﬁc to incontinence, pain, or sexual function; measured by validated questionnaire

[SF-Qualiveen], at any time point)

Healthcare resource use (QALY)

Bladder function (measured by validated questionnaire or by urodynamic or by voiding diary, at any time point)

Sexual function (measured by validated questionnaire, at any time point)

EAU = European Association of Urology; ICIQ-SF = Incontinence Questionnaire Urinary Incontinence Short Form; IPSS = International Prostate Symptom Score;

LUTS = lower urinary tract symptoms; QALY = quality-adjusted life-year.

41 articles with mixed population had been contacted to get Lose et al [21] used desmopressin in doses of 0.1, 0.2, and

separate female data, but after 12 months and with two 0.4 mg orally at bedtime after a dose-titration period in

reminders, data were received from only one study; hence, participants who responded to the dose-titration phase. Of

it was decided to exclude these articles. The characteristics the 80 withdrawals after the dose-titration phase, only eight

of 11 included studies are reported in the Supplementary patients lacked a pharmacological response. The authors

material (Forest plots). randomised 144 women to desmopressin (N = 72) or

placebo (N = 72), and after a follow-up of 3 wk, a benefit

3.1.1. RoB in included studies of desmopressin was seen for all measured outcomes for

The domains of RoB for the 11 included studies are summarised nocturia (Table 2). There was a difference in the number of

in Fig. 2. All except one study showed high RoB in at least one of nocturnal voids in favour of desmopressin, as well as for

the seven domains that apply to RCTs as well as non-RCTs. nocturnal diuresis.

Yamaguchi et al [22] reported results of different doses

3.2. Desmopressin of desmopressin separately for men and women (aged

55–75 yr). A total of 58 women in five groups (12 in

m m m

This is a synthetic analogue of the hormone vasopressin. It is placebo, 12 in 10 g, 11 in 25 g, 11 in 50 g, and

most often used for the management of nocturia due to 12 in 100 g groups) were followed for 4 wk. The authors

NP. We found three trials specifically conducted in women observed a dose-response relationship. In the gender

[20–22], but more additional data could be extracted from comparison, they found that female patients were more

mixed populations [9–11,13]. sensitive to desmopressin, so they propose to minimise

In the oldest study, by Hilton and Stanton in 1982 [20], the risk of hyponatraemia in women by using lower doses.

there were statistically significant differences in the main There were statistically significant differences in the

nocturia outcomes. Further studies in a mixed population change in nocturnal urinary volumes in the following

supported that finding [9–11,13]. comparisons in favour of the higher desmopressin

Please cite this article in press as: Bedretdinova D, et al. What Is the Most Effective Treatment for Nocturia or Nocturnal

Incontinence in Adult Women?. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.01.012

EUF-869; No. of Pages 11

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t Rec ords identified through database Additional records identified through

c searching other sources

f n n

i ( =3573) ( =0) t n e

d I

Rec ords after duplicates removed

(n =3475) g n i n e

c Records screened

(D.B., D.A., V.S.)

(n = 3475)

Rec ords excluded

(n =3193)

Full-text articles assessed for

t eli gibility (D.B., D.A., V.S.) i

i n

( =281) n b Full-text articles excluded, with reasons ( =270)

l • 33 Not relevant study design

• 31 Conference abstract

Stud ies included in • 67 Not relevant outcomes

qualitati ve synthesis • 22 Language

(n =11)

• 68 Not relevant patient population

• 15 Inconclusive data

• 7 Not relevant comparator

Studies included in • 6 Paediatric population

quantitative synthesis (meta-

Included y

analysis) • 8 Double record

( =0) • 5 Not relevant intervention

• 4 Letter to editor/reply

• 2 Not relevant setting

• 2 Clinical trial entry

Fig. 1 – PRISMA flow diagram. PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-analysis.

dose: 10 versus 25 mg and 10 versus 100 mg. In addition, 3.3. Antimuscarinics

there were differences in the NP Index in following

comparisons in favour of desmopressin over placebo or We found four RCTs studying antimuscarinics such as

in favour of the higher desmopressin dose: placebo versus oxybutynin 2.5 mg/d [24] and tolterodine 4 mg/d [23,25,26].

25 mg, placebo versus 100 mg, 10 versus 25 mg, and Johnson et al [24] reported the results of a secondary

–

10 versus 100 mg (Table 3). analysis from a prospective RCT. In 131 women (aged 55 92

Unfortunately, we could not combine the above three yr) with nocturia followed up for 8 wk, they found that

studies in a meta-analysis because of different dosages 46 women on 2.5 mg once a day immediate release, with the

and modes of administration. However, we generated a possibility of self-titrating oxybutynin, had fewer nocturia

forest plot combining the main findings cited above for episodes than the 38 in the placebo group but more epi-

comparisons of desmopressin versus placebo (Fig. 3). sodes than the 47 patients in the behavioural treatment

Desmopressin can safely be combined with antimuscari- group. There was no statistically significant difference in

nics with a significant benefit in women with NP, as shown nocturia episodes between the oxybutynin and placebo

by Rovner et al [23] in a post hoc analysis of an RCT groups, but there was one in favour of behavioural

comparing 3-mo once-daily combination (desmopressin treatment.

25 mg/tolterodine 4 mg; n = 49) with monotherapy (tolter- Three selected studies on tolterodine in a female

odine 4 mg/placebo; n = 57). population did not include a placebo group but compared

Please cite this article in press as: Bedretdinova D, et al. What Is the Most Effective Treatment for Nocturia or Nocturnal

Incontinence in Adult Women?. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.01.012

EUF-869; No. of Pages 11

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Fig. 2 – Risk of bias summary according to the judgement of the review authors on each risk of bias item for each study included: (A) for RCT studies,

(B) for NRS. Key: red “-” is for high risk of bias, yellow “?” is for unclear risk of bias, and green “+” is for low risk of bias. NRS = nonrandomised study;

RCT = randomised controlled trial.

Table 2 – Summary of findings; desmopressin versus placebo.

Desmopressin compared with placebo for nocturia or nocturnal incontinence in terms of improving symptom severity and quality of life in adult

women?

Patient or population: nocturia or nocturnal incontinence in terms of improving symptom severity and quality of life in women?

Setting: outpatient department (multicentre study)

Intervention: Desmopressin

Comparison: Placebo

Outcomes Anticipated absolute effects (95% CI) Relative effect No. of participants Certainty of the Comments

Risk with placebo Risk with desmopressin (95% CI) (studies) evidence (GRADE)

^^ b

No. of nocturnal The mean no. of The mean no. of nocturnal – 141 (1 RCT) ⨁⨁xx Low

voids—3 wk nocturnal voids—3 voids—3 wk in the

wk was 0 intervention group was

0.75 lower (1.03 lower to

0.47 lower)

CI = conﬁdence interval; GRADE = Grading of Recommendations Assessment, Development and Evaluation; RCT = randomised controlled trial.

GRADE Working Group grades of evidence: high certainty—we are very conﬁdent that the true effect lies close to that of the estimate of the effect; moderate

certainty—we are moderately conﬁdent in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is

substantially different; low certainty—our conﬁdence in the effect estimate is limited: the true effect may be substantially different from the estimate of the

effect; very low certainty—we have very little conﬁdence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention

(and its 95% CI).

Downgraded two levels due to the following reasons: random sequence generation was done by pharmaceutical company, outcome assessors were not blinded

and supported by a grant from pharmaceutical company, and "patients with no pharmacological response during dose titration were excluded before

randomisation".

Please cite this article in press as: Bedretdinova D, et al. What Is the Most Effective Treatment for Nocturia or Nocturnal

Incontinence in Adult Women?. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.01.012 6 EUF-869;

Please Table 3 – Key characteristics of included studies assessing outcomes.

Incontinence Authors Year Reference Group 1 Comparator Study No. of Age (Mean, Range) Follow-up Outcome Mean difference I 2 (%) Certainty of

cite

participants evidence No.

this Desmopressin of in

Hilton and 1982 [20] Desmopressin Placebo Single site, 25 56 (41-76) 6 weeks Nocturnal urine 124 ml lower, 95% CI 100 Low Pages

Adult article Stanton (DDAVP) 20 mg cross-over output (ml) 204.53 to 43.47 ml lower

Nocturnal urinary 0.67 times lower, 95% 100 Low Women?.

in frequency CI 1.44 lower to

press 0.10 higher Lose et al 2003 [21] Desmopressin (0.1, Placebo Multicentre, 141 57 (21–89) 3 wk Nocturnal urinary 0.75 lower, 95% CI 100 Low

0.2, 0.4 mg orally at multinational, frequency 1.03 lower to

Eur as: bedtime after dose- double-blind 0.47 lower

E Bedretdinova titration period) RCT Urol

Nocturnal diuresis 0.62 ml/min lower, 95% 100 Low R

O (ml/min) CI 0.76 lower to Focus

0.48 lower E

Desmopressin Multicentre 21 NA (55–75) 4 wk Change on 206.02 ml higher, 95% 100 Low A

Yamaguchi et al 2013 [22] Desmopressin N

m m g 25 g double-blind nocturnal urinary CI 11.27 higher to (2020), 10 U

RCT volume (ml) 400.77 higher R D,

Desmopressin 23 4 wk MD 143.26 ml higher, 100 Low O

Desmopressin L et

mg 100 mg 95% CI 20.52 higher to O 10

G https://doi.org/10.1016/j.euf.2020.01.012 al.

266 higher Y

m F

What Placebo Desmopressin 25 g 20 Change in NPI MD 7.75 higher, 95% CI 100 Low

(nocturnal urine 1.41 higher to C

volume/24-h urine 14.09 higher S

volume [%]) X

X the m 22 MD 6.78 higher, 95% CI 100 Low

Placebo Desmopressin 100 X

g 1.02 higher to (

Most 2

12.54 higher 0

Desmopressin 25 mg21 8.54 higher, 95% CI 100 Low 1

Desmopressin 9

m )

g Effective 10 2.66 higher to X

14.42 higher X

Desmopressin Desmopressin 23 7.57 higher, 95% CI 100 Low X

–

10mg 100 mg 2.31 higher to X

Treatment 12.83 higher X Antimuscarinics Johnson et al 2005 [24] 2.5 mg once a day Placebo Single-site 84 68 (55–92) 8 wk Number of nocturia MD 0.30 lower, 95% CI 100 High immediate release, secondary episodes 0.62 lower to with possibility of analysis from 0.02 higher

for self-titration prospective

RCT Nocturia Behavioural 2.5 mg once a day 93 Number of nocturia 0.30 lower, 95% CI 100 High treatment immediate release episodes 0.59 lower to oxybutynin 0.01 lower

or FitzGerald et al 2008 [25] Tolterodine tartrate Tolterodine 4 mg + Multicentre 271 Only per group, 8 wk Number of nocturia 0.26 higher, 95% CI 100 Moderate

extended-release behavioural RCT mean (SD): 55.8 episodes reported 0.00–0.52 higher Nocturnal capsules 4 mg treatment (14.2) as change from alone 58.0 (13.5) baseline EUF-869;

Please Table 3 (Continued )

Incontinence Authors Year Reference Group 1 Comparator Study No. of Age (Mean, Range) Follow-up Outcome Mean difference I (%) Certainty of

evidence cite participants

No. 218 Number of 0.06 higher, 95% CI 100 Moderate

this

nocturnal 0.08 lower to in

Pages

incontinence 0.20 higher

Adult article episodes Rovner et al 2018 [23] Desmopressin Tolterodine 4 mg Multicentre 97 55 (24–84) 3 mo Mean number of 0.34 lower, 95% CI 100 Moderate

11 m

Women?. g + tolterodine RCT nocturnal voids 0.80 lower to 25 in 4mg 0.12 higher

press Yuan and He 2011 [26] Tolterodine 4 mg + Tolterodine 4 mg Well-designed 407 Only per group, 4 wk Number of MD 1.20 lower, 95% CI 100 Very low estazolam 1 mg large mean (SD): 56.5 nocturnal voids 1.28 lower to 1.12 lower

comparative (9.2) Eur as: study 57 (8.9)

E Bedretdinova Urol

Oestrogens U

Lose and Englev 2000 [27] Oestradiol- Oestriol vaginal RCT 251 66 (47–87) 24 wk Number of women RR 0.94, 95% CI 0.74– 100 Low R

Focus

releasing vaginal pessary reporting nocturia 1.19 P

ring A

Behavioural treatment

(2020), ﬁ U

Aslan et al 2008 [30] Bladder training + Control Single-site RCT 50 Only per group, 6 mo Nocturia Signi cant decrease in Very low R D,

Kegel exercises mean (SD): 78.88 complaints the treatment group O

L et

(4.80) compared with the O

G https://doi.org/10.1016/j.euf.2020.01.012 al.

79.44 (5.32) control group between Y

the 8-wk and 6-mo F What

evaluations C

Lo et al 2003 [28] Pelvic ﬂoor Pelvic ﬂoor exercise + Prospective 24 Only per group, 4 wk Number of nocturia MD 0.54 lower, 95% CI 100 Very low U

exercise interferential therapy blinded single- mean (SD): 52.1 episodes 1.3 lower to X

X the

(transcutaneous site RCT (17.5) 0.22 higher; X

( electrical nerve 55.1 (15.1) participants = 24

Most 2

stimulation) 0

– Johnson et al 2005 [24] Behavioural Placebo Single-site 84 68 (55 92) 8 wk Number of nocturia MD 0.60 lower, 95% CI 100 Moderate 9

)

Effective treatment secondary episodes 0.88 lower to X

analysis from 0.32 lower X

prospective –

Behavioural 2.5 mg once a day RCT 0.30 lower, 95% CI 100 Moderate X

Treatment treatment immediate-release 0.59 lower to X

oxybutynin 0.01 lower FitzGerald et al 2008 [25] Tolterodine tartrate Tolterodine 4 mg + Multicentre 271 Only per group, 8 wk Number of nocturia 0.26 higher, 95% CI 100 Low extended-release behavioural RCT mean (SD): 55.8 episodes 0.00 to 0.52 higher

capsules 4 mg treatment (14.2) for alone 58.0 (13.5)

Nocturia 218 Number of MD 0.06 higher, 95% CI 100 Low nocturnal 0.08 lower to incontinence 0.20 higher episodes

or Functional magnetic stimulation

Nocturnal But et al 2005 [29] Functional Placebo Single-centre 39 54 (28–70) 2 mo Nocturia episodes From 2.6 to 1.4, magnetic RCT p = 0.0007 stimulation

CI = conﬁdence interval; MD = mean difference; NA = not available; NPI = Nocturnal Polyuria Index; RCT = randomised controlled trial; RR = relative risk; SD = standard deviation. 7

EUF-869; No. of Pages 11

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Fig. 3 – Forest plot combining the main findings cited above for comparisons of desmopressin versus placebo. CI = confidence interval; IV = inverse

variance; SD = standard deviation.

tolterodine monotherapy with some type of combination ring and oestriol vaginal pessary in 251 women (follow-up =

treatment. All three studies showed a significant change 24 wk). The authors estimated the subjective score of

from baseline. Various other studies in mixed populations urgency, frequency, nocturia, dysuria, stress, and urge

[9–11,13] showed comparable results. incontinence. There was no difference between the treat-

FitzGerald et al [25] followed up 305 women for 8 wk ment groups in the number of women reporting nocturia,

in two groups, with tolterodine tartrate extended-release though they reported significant change from baseline in

capsules 4 mg alone or in combination with behavioural both treatment arms (for nocturia, 51% and 54% responded

training. The authors observed small (in absolute numbers to treatment, respectively).

of episodes) but statistically significant differences

(p < 0.001) in mean nocturia frequency and nocturnal 3.5. Behavioural treatment

incontinence frequency as compared with baseline in both

groups, but no difference between study treatment groups. Analysing studies on behavioural treatment, we found more

Rovner et al [23] performed an RCT in 97 women heterogeneity in the results. While the studies by Johnson

randomised to a 3-mo once-daily combination (desmopres- et al [24], Aslan [30], and Lo et al [28] were favourable for

sin 25 mg/tolterodine 4 mg; n = 49) or monotherapy (tolter- behavioural treatment, FitzGerald et al [25] did not show a

odine 4 mg/placebo; n = 57). The significant changes in the benefit of the addition of behavioural therapy to drug

mean number of nocturnal voids from baseline were treatment. The heterogeneous character of behavioural

comparable between groups. In a post hoc analysis in sub- therapy itself can explain these results, while the treatment

groups with/without NP, the authors probed the benefit of also differed from site to site.

–

combination therapy, and there was no difference in the Aslan [30] studied 50 women aged 70 89 yr, who were

reduction of the mean number of nocturnal voids. randomised to the treatment group (bladder training and

The study by Yuan and He [26] was not an RCT, but a well- Kegel exercises) or the control group, in equal proportion.

designed large comparative study. They followed Follow-up at a single site in Turkey was for 6 mo. There was

407 women with overactive bladder (OAB) and nocturia a significant decrease of the nocturia complaints in the

for 4 wk. The patients were given tolterodine 2 mg twice a treatment group compared with the control group between

day as monotherapy in one group, and tolterodine 2 mg the 8-wk and 6-mo evaluations (p 0.05, reported binary;

twice a day combined with estazolam 1 mg at night in the certainty of evidence = very low).

other group for 4 wk. There were significant changes from Lo et al [28] conducted an RCT in only 24 women

baseline in both groups for the main outcomes, such as the (aged 20yr),12in eachgroup.Agroup withpelvicfloorexercise

number of nocturia episodes. The tested combination was compared with a group receiving interferential therapy

included an agent to promote sleep (estazolam); the (transcutaneous electrical nerve stimulation) in addition to

combination showed a significant benefit for women with pelvic floor exercise. The treatment was given three times a

OAB and nocturia compared with monotherapy: there were week for 4 wk. The authors did not reach planned recruitment

differences in the number of nocturia episodes per night, due to limitation of resources, and there was no difference in the

urgency episodes in 24 h, urgency incontinence episodes in number of nocturia episodes as indicated in their results.

24 h, and voided volume per micturition. Although they did not find significant changes between the

groups (probably because of small number of participants),

3.4. Oestrogen the differences before and after treatment were statistically

significant in both groups.

We found only one RCT investigating oestrogen for nocturia. The study of Johnson et al [24] was described above. The

Lose and Englev [27] compared oestradiol-releasing vaginal authors found that the group with behavioural training (four

Please cite this article in press as: Bedretdinova D, et al. What Is the Most Effective Treatment for Nocturia or Nocturnal

Incontinence in Adult Women?. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.01.012

EUF-869; No. of Pages 11

E U R O P E A N U R O L O G Y F O C U S X X X ( 2 0 1 9 ) X X X – X X X 9

visits, anorectal and pelvic muscle biofeedback, teaching certainty using the GRADE approach. Therefore, the findings

skills, and strategies for dealing with incontinence and of this SR should be interpreted with caution.

urgency) showed better results than the groups receiving Although three reported studies on desmopressin [20–22]

placebo. There was a difference in number of nocturia epi- showed that this drug is more effective than placebo in

sodes in favour of behavioural treatment and also in favour of women in terms of decreasing the number of nocturia

the behavioural treatment group over the oxybutynin group. episodes, there are two main issues to consider. First is a

FitzGerald et al [25] reported the number of nocturia necessity of screening for hyponatraemia at baseline, since

episodes and nocturnal incontinence episodes as a change this is a contraindication for antidiuretic therapy. A second

from baseline. The result of the change in the number of issue that we observed in the largest study identified is a

nocturia episodes from baseline appears to favour the tolter- dose-titration phase before the full trial. This increases the

odine plus behavioural therapy group; however, 95% likelihoodofapositiveoutcomebecausenonresponderswere

confidence interval touched the line of no difference. There excluded at this stage. Furthermore, we may suppose that

was also no difference in the change in the number of noc- desmopressin is more effective in patients with NP as the

turnal incontinence episodes.Incontrast tothe Johnsonet al’s predominant cause of nocturia, although we did not find

[24] study, FitzGerald et al [25], who added behavioural studies that had distinguished these patient subcategories.

therapy to tolterodine 4 mg, did not show a significant benefit Antimuscarinics showed some benefit in OAB-related

of behavioural treatment. The difference in outcome between nocturia. However, most studies in our search reported on

these two studies can be explained by difference in age a mixed but female-predominant (about 80%) population. For

(Johnson et al [24] studied older women, mean age 68 yr, this reason, we did not include these studies in the final SR.

and in FitzGerald et al’s [25] study, the mean age was 56 yr); We found only one study with comparison of antimuscarinics

also patients in the FitzGerald et al’s [25] study were less as monotherapy versus placebo in women only [24]. Other

symptomatic (1.7 voids/night vs 1.9 voids/night in Johnson studies [23,25,26] reported comparison of antimuscarinics

et al’s [24] study), and there were pharmacological with some form of combination therapy, but without a

differences between the drugs: immediate release of placebo group. We suggest considering subcategorising

oxybutynin and sustained release formulation of tolterodine. OAB-related nocturia in trials with OAB medications, to study

the possible benefit of antimuscarinics.

3.6. Functional magnetic stimulation The abovementioned studies show that the underlying

pathophysiological mechanisms of nocturia that may vary

We identified one small, single-centre RCT in which func- from patient to patient are often not well addressed when

tional magnetic stimulation (FMS) was compared with pla- recruiting patients to trials. Important aetiological factors to

cebo [29]. But and colleagues [29] recruited 39 women (aged consider are sleep apnoea, cardiovascular disease, and

28–70 yr), who were randomly assigned to the FMS group diabetes mellitus. Ideally, nocturia should be treated with

(N = 23) or placebo (16). They followed these patients for 2 mo a cause-specific strategy. The question of subcategories of

and reported a significant decrease in voiding frequency nocturia should be considered when designing new trials;

(from 9.0 to 6.7, p = 0.0002), nocturia (from 2.6 to 1.4, the use of questionnaires only to select patients tends to

p = 0.0007), and pad use (from 3.9 to 2.2, p = 0.007) in the lump these heterogeneous patient categories together.

treatment group compared with the placebo group. Therefore, conclusions derived from the studies in this SR

should be regarded with caution. Furthermore, the issue of

3.7. Results on nocturnal incontinence objective markers for nocturia, such as voiding diaries,

versus subjective patient perception (questionnaires) might

We have found only one study that reported on the number have an impact on the results. This issue could not be

of nocturnal incontinence episodes as change from baseline addressed further in this review because of lack of data.

[26]. There was no statistically significant difference in the

mean difference. 3.8.2. Recommendations for future research

Additional research is needed to examine other options for

3.8. Discussion the treatment of nocturia and nocturnal incontinence in

women. Many studies were undertaken in a mixed

3.8.1. Principal findings population, and we suggest that authors report their results

Our SR confirms that desmopressin and antimuscarinics are for men and women separately because the underlying

effective treatment options for nocturia in women, whereas pathophysiology varies significantly between the two

other options, such as behavioural treatment, hormonal genders. We also highly recommend classifying the under-

therapy, or FMS, are controversial. Many of the studies had lying symptomatology as nocturia or NP, using standard ICS

methodological flaws and provided conflicting results when definitions.

evaluating the same treatment. RoB in random sequence We would like to emphasise the lack of long-term out-

generation was judged to be high in two and unclear in four comes and large studies in female patients. Some outcomes

studies. Allocation concealment was judged unclear in four are statistically significant, but it is unclear whether they

studies. This was considered while assessing the overall are clinically relevant. We recommend the professional

certainty of evidence. As a result, majority of the outcomes community to discuss and determine minimally important

were rated as either “low” or “very low” when assessing the difference (the smallest change in a treatment outcome that

Please cite this article in press as: Bedretdinova D, et al. What Is the Most Effective Treatment for Nocturia or Nocturnal

Incontinence in Adult Women?. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.01.012

EUF-869; No. of Pages 11

10 E U R O P E A N U R O L O G Y F O C U S X X X ( 2 0 1 9 ) X X X – X X X

an individual patient would identify as important and

4. Conclusions

which would indicate a change in the patient's

management) in the number of nocturia episodes per night. Nocturia is a common symptom that can be associated with

Furthermore, no core outcome set for nocturia can be found various diseases. Treatment choice should be made after

in the COMET database; therefore, we recommend its thorough clinical evaluation of all possible causes. RCT

development. evidence supports the use of desmopressin in the manage-

Many identified studies reported combination ment of nocturia associated with NP, with careful serum

treatments; this causes a problem of detecting what type sodium monitoring. RCT evidence also supports the use of

of treatment is primarily responsible for the outcome. antimuscarinic drugs for nocturia associated with symptoms

Therefore, we recommend designing trials with mono- of OAB. Behavioural treatments may be considered a

therapies for comparison. This issue is particularly noninvasive conservative measure for nocturia management,

relevant in case of behavioural treatment, usually but the evidence is of low quality, weak, and controversial.

combined with lifestyle changes: protocols are often Other treatment options cannot be recommended due to a

heterogeneous from site to site, which complicates lack of evidence or very low quality of evidence. We cannot

generalisation of the outcomes. provide any recommendations for the treatment of nocturnal

incontinence due to total absence of evidence.

3.8.3. Strength and limitations of the review

The main strength of this SR is that it is the first compre-

Author contributions

hensive literature search for all treatment options for : Dina Bedretdinova had full access to all the data in

the study and takes responsibility for the integrity of the data and the

nocturia in adult women, using a robust and transparent

accuracy of the data analysis.

methodological approach based on the Cochrane

Handbook. Study concept and design: Bedretdinova, Ambühl, Omar, Thiruchelvam,

Schneider, Nambiar, Bosch.

During full-text screening, we realised that the inclusion

Acquisition of data: Bedretdinova, Ambühl, Omar, Sakalis, Bosch.

of studies with nocturia as a secondary outcome led to a

Analysis and interpretation of data: Bedretdinova, Ambühl, Omar, Sakalis,

high level of heterogeneity among the studies and the Bosch.

impossibility of deriving conclusions from this selection.

Drafting of the manuscript: Bedretdinova, Omar.

We had to make an amendment in the protocol: after Critical revision of the manuscript for important intellectual content:

discussion in the EAU Urinary Incontinence Guidelines Thiruchelvam, Schneider, Nambiar, Bosch.

Panel, studies with nocturia as a secondary outcome were Statistical analysis: Bedretdinova, Ambühl, Omar.

Obtaining funding: None.

excluded because these did not focus on the treatment of

Administrative, technical, or material support: Omar, Bosch. nocturia patients.

Supervision: Bosch.

We did not include studies with mixed populations, even

Other: None.

if the female population was >80–90% of the total, because

randomisation was done in the whole population, leading to

imbalanced groups. During full-text screening, 60 articles

Financial disclosures: Dina Bedretdinova certiﬁes that all conﬂicts of

with mixed population were retrieved. In order to maximise

interest, including speciﬁc ﬁnancial interests and relationships and

the possibility of including as many female patients as afﬁliations relevant to the subject matter or materials discussed in the

possible in the review, the decision was made to contact manuscript (eg, employment/afﬁliation, grants or funding, consultan-

authors for separate female data. The first letters were sent cies, honoraria, stock ownership or options, expert testimony, royalties,

ﬁ

on 28 June 2018; unfortunately, only one author responded, or patents led, received, or pending), are the following: None.

and since we had decided to analyse this type of data

separately, we finally decided not to use the data of this

Funding/Support and role of the sponsor: None.

author in the review.

The major limitations of this review include significant Acknowledgements: The authors express their thanks to F.C. Burkhard

heterogeneity among the studies identified. Many of the for invaluable logistic support during the conception of the manuscript.

evaluated studies on desmopressin used a dose titration

phase, which may represent another source of bias.

While we identified only one study that reported

treatment of nocturnal incontinence in women, we could Appendix A. Supplementary data

not make any recommendations on this subject. There is no

consensus about definition of nocturnal incontinence; the Supplementary material related to this article can be

last ICS report on standardisation of terminology did not found, in the online version, at doi:https://doi.org/10.

include this term; instead, the term “enuresis” was 1016/j.euf.2020.01.012.

proposed (included in our search strategy as well). It may

be possible that patients with nocturia do not have

nocturnal incontinence because they wake up before

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Please cite this article in press as: Bedretdinova D, et al. What Is the Most Effective Treatment for Nocturia or Nocturnal

Incontinence in Adult Women?. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2020.01.012