A systematic review of interventions for the treatment for nocturia or nocturnal incontinence in terms of improving symptom severity and quality of life in adult women

Bedretdinova D1, Ambuehl D2, Omar M3, Sakalis V4, Thiruchelvam N5, Schneider M2, Nambiar A6, Bosch R7

Research Type

Basic Science / Translational

Abstract Category

Nocturia

Abstract 40
Nocturia
Scientific Podium Short Oral Session 4
Wednesday 4th September 2019
12:07 - 12:15
Hall K
Female Nocturia Incontinence
1.INSERM CESP U1018, Villejuif, France, 2.Department of Urology, University Hospital Bern, Inselspital Anna Seiler-Haus, Bern, Switzerland, 3.European Association of Urology Guidelines Office, NL, 4.Department of Urology, Salisbury District Hospital, Salisbury, UK, 5.Department of Urology, Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom, 6.Department of Urology, Freeman Hospital, Newcastle-upon-Tyne, UK, 7.University Medical Center Utrecht, NL
Presenter
M

Muhammad Imran Omar

Links

Abstract

Hypothesis / aims of study
Nocturia is defined by the International Continence Society (ICS) as “the complaint that the individual has to wake at night one or more times for voiding” [1]. Nocturnal incontinence is a complaint of intermittent incontinence that occurs during main period of sleep after the age of 3-5 at which bladder control usually occurs. Nocturnal polyuria (NP) is defined as passing large volumes of urine during the main sleep period that should be quantified using a bladder diary [1]. The threshold of NP is usually considered as nocturnal urine volume greater than 20% to 33% of total 24-hour urinary volume (dependent on age).
Although these are prevalent symptoms, there is no consensus about treatment options. We aimed to systematically review the available evidence comparing the benefits and harms of different treatment options for nocturia or nocturnal incontinence in terms of improving symptom severity and quality of life in women.
Study design, materials and methods
Literature search was performed using Embase, Medline, Cochrane databases (from January 1, 1946 to September 26, 2017). We followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidance and the Cochrane Handbook for Systematic Reviews of Interventions [2, 3]. The protocol was registered at PROSPERO (CRD42017058997). The certainty of evidence was assessed with Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We searched for comparative studies of any treatment options of nocturia or nocturnal incontinence in adult women.
Results
The literature search identified 3573 citations, and 195 were selected for full-text screening (Figure 1). After screening of full texts, 11 (10 randomised controlled studies and 1 non-randomised comparative study) studies about treatment of nocturia in women were included. We could not identify any study specifically focusing on the treatment of nocturnal incontinence. 3 RCTs on desmopressin and 3 RCTs and 1 non-RCT on antimuscarinics provided evidence of improving nocturia symptoms. 4 RCTs on behavioural treatment provided limited evidence and contradicting results. 1 RCT on oestrogens didn’t show the benefit of any mode of administration, and one RCT on functional magnetic stimulation provided some evidence about its effectiveness in nocturia.  Results from one RCT showed statistically significant difference as patients using desmopressin experienced 0.75 fewer (95% CI 0.47-1.03) nocturia episodes than those using placebo; participants = 141; certainty of evidence = low).
We could not combine three RCTs on desmopressin versus placebo in the meta-analysis as they used different doses and mode of administration of the drug, although we include here the forest plot that shows the main findings (Figure 2).
In only RCT on antimuscarinics in women with nocturia comparing oxybutynin and placebo we found that drug reduced number of nocturia episodes by 0.3 (95%CI -0.02 to 0.62) but due to small sample size it did not reach statistical significance. We did not identify any study recruiting women with nocturnal incontinence, however,  we identified one RCT comparing tolterodine to combination of tolterodine with behavioural therapy nocturnal incontinence episodes were reported and though there was no statistically significant difference between groups, there was significant change from baseline in both groups. Random sequence generation was judged to be high in 2 and unclear in 4 studies. Allocation concealment was judged unclear in 4 studies. This was considered while assessing the overall certainty of evidence. As a result, the majority of outcomes were either rated as “low” or “very low” when assessing the certainty using the GRADE approach.
Interpretation of results
The result of this systematic review confirm that desmopressin and antimuscarinics are effective treatment options for nocturia in women.  The effectiveness of treatments, such as behavioural treatment, hormonal therapy, functional magnetic stimulation, was contradictory across studies. Many of the studies had methodological flaws and provided conflicting results when evaluating the same treatment. Therefore, the findings of this SR should be interpreted with caution.
Whilst 3 reported RCTs on desmopressin showed that it is more effective than placebo in women in terms of decreasing number of episodes of nocturia there are two main issues to consider. First, the necessity of screening for hyponatremia at baseline, as it is a contraindication for antidiuretic therapy. The second issue we observed in the largest identified RCT is a dose-titration phase study before the full trial. This increases the likelihood of a positive outcome, since non-responders were excluded at this stage. 
Antimuscarinics showed benefit in OAB-related nocturia but most studies were with a mixed population. We found only one RCT comparing antimuscarinic monotherapy versus placebo in women, other studies reported comparison of antimuscarinics to combination therapy without a placebo group. We suggest to consider subcategorizing OAB-related nocturia in trials with OAB medications to show benefit.
That logically leads us to the hypothesis that although nocturia is common symptom among identified studies, the underlying pathophysiological mechanisms can be different in every patient; hence, if the causes of nocturia can be identified then nocturia should be treated with a cause-specific approach, for example in case of sleep apnoea, cardiovascular diseases, diabetes mellitus. The question of subcategories of nocturia should be discussed by professional communities, as the use of questionnaires (especially in epidemiological studies) mix all those heterogeneous patients in one population, and conclusions derived from those articles should be regarded with caution.
Furthermore, the issue of objective markers for nocturia, such as voiding diaries, versus subjective patient perception (questionnaires) might have an impact on the results.
Concluding message
There is some evidence that desmopressin and antimuscarinics are effective treatment options for nocturia in women, however there is very limited evidence for other treatment options. However, the findings should be interpreted with caution as there were some methodological flaws in the included articles, and many studies were judged to be either at high or unclear risk of bias for many domains. We have not found any studies regarding the treatment of nocturnal incontinence in adult women.
Figure 1 Figure 1. PRISMA flow diagram
Figure 2 Figure 2. Forest plot of three studies comparing desmopressin to placebo
References
  1. Hashim, H., et al., International Continence Society (ICS) report on the terminology for nocturia and nocturnal lower urinary tract function. Neurourol Urodyn, 2019.
  2. Knoll, T., et al., Key Steps in Conducting Systematic Reviews for Underpinning Clinical Practice Guidelines: Methodology of the European Association of Urology. Eur Urol, 2018. 73(2): p. 290-300.
  3. Moher, D., et al., Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med, 2009. 6(7): p. e1000097.
Disclosures
<span class="text-strong">Funding</span> European Association of Urology Guidelines Office Board <span class="text-strong">Clinical Trial</span> No <span class="text-strong">Subjects</span> Human <span class="text-strong">Ethics not Req'd</span> it is a systematic review <span class="text-strong">Helsinki</span> Yes <span class="text-strong">Informed Consent</span> Yes