Some text in this chapter has been reproduced with permission from Abdel-Fattah et al.1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text.
In 2016, the UK government’s National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) programme funded the Female Urgency, Trial of Urodynamics as Routine Evaluation (FUTURE) project. This report describes the research. FUTURE was a superiority randomised controlled trial (RCT) evaluating the clinical and cost-effectiveness of invasive urodynamics in the management of refractory overactive bladder (OAB) symptoms in women.
Female urinary incontinence (UI), defined as the experience of involuntary urinary leakage,2 is a highly prevalent condition of varying aetiology amongst women of all ages, and has a significant impact on women’s lives.3
Types of urinary incontinence
Urinary incontinence can be characterised according to the incontinence symptoms. OAB is the symptom complex of urinary urgency (sudden desire to void that is difficult to defer) and is often associated with urgency urinary incontinence (UUI).4 UUI is characterised by the involuntary loss of urine associated with feelings of urgency. Stress urinary incontinence (SUI) is characterised by the involuntary loss of urine associated with exertion, effort, sneezing or coughing. Mixed urinary incontinence (MUI) is identified by the presence of involuntary urine loss in association with symptoms of both SUI and UUI.2
Epidemiology of incontinence in women
The prevalence estimates of UI in the literature vary widely primarily due to the varying definition of UI used in these studies.5 The Epidemiology of Incontinence in the County of Nord-Trøndelag (EPINCONT) survey uses the standard definition for UI (as above), and estimated an overall prevalence of UI in women of 30%, broadly increasing with age.6
The Leicestershire Medical Research Council (MRC) Incontinence Study showed a 21% overall prevalence of UI in women aged ≥ 40 years in the UK; UUI and MUI represented 11% and 36% of these women, respectively.7 The Epidemiology of Lower Urinary Tract Symptoms (EpiLUTS) study reported a similar UUI prevalence rate of 13.3% for men and 30.3% for women in the USA.8 In 2016, Komeso reported a large epidemiological study showing that the prevalence of UI increases with age; this was most apparent for UUI and MUI: the odds of occurrence of UUI were two- and ninefold increased in the 7th and 10th decades, compared with the 6th decade [odds ratio (OR) 2.18 (95% confidence interval (CI) 1.50 to 3.15) and OR 9.19 (95% CI 5.56 to 15.20)], respectively.9 The prevalence of MUI also significantly increased in the 8th to 10th decades (both p ≤ 0.005) but, interestingly, the prevalence of SUI did not seem to increase with age in this study. Estimation models predict that the worldwide number of adults aged ≥ 20 years with UUI or MUI was 103 million in 2008, with a projected increase to 127 million in 2018.10 We can therefore conclude that the prevalence of OAB/MUI is likely to increase in the years to come, especially given the ageing population in the UK. The EPINCONT data estimate an annual incidence and remission rate of 1.7% and 3.1%, respectively.11 A similar study reported annual incidence and remission rates of 1.3% and 2.1%, respectively.12
The burden of incontinence
Urinary incontinence significantly impacts both the patient and society as it brings significant personal, sexual and economic burdens.
Personal impact
Urinary incontinence is an important source of personal embarrassment, and the stigma surrounding adult UI is a significant barrier to seeking appropriate healthcare support.13 The private and personal nature of UI can undoubtedly impact overall mental health. Indeed, studies have identified an increased psychological burden and increased likelihood of depression in UI sufferers.14–16 UI is second only to dementia as a reason for placing elderly women in residential or nursing homes.17
Overactive bladder and UUI have been shown to have a negative impact on a woman’s physical, social and psychological well-being, leading to low self-esteem, embarrassment and low productivity of working women. Women reported avoiding employment because of fear of embarrassing situations; 60% reported social isolation, avoiding leaving their home and 50% reported reduction or avoidance of sexual activity.7,12,18 Norton et al. reported that 50% of women were avoiding sexual activity due to fear of UI, while 25–50% of women had difficulty with orgasm or dyspareunia, leading to negative impact on personal relationships for some women.18
Personal and societal economic impact
Urinary incontinence has significant cost implications for the health resources in the UK, with an estimated total annual cost to the NHS of £301 million or 0.3% of the total NHS budget in 2009.19 Furthermore, UI can incur significant personal costs. Patient-purchased management devices, such as absorptive pads, can create significant economic burden, which was estimated at £230 million in the UK or £290 per woman per year at 2000 prices.20 One US study reported $750 per year in personal costs.21
A large multinational study estimated the health-related costs for management of OAB and UUI in 2005 at approximately €7.0 billion across six countries: Sweden, Canada, Spain, Germany, Italy and the UK.10
Pathophysiology of overactive bladder
The standardised definition of OAB according to the International Continence Society (ICS) is ‘urgency, with or without UUI, usually in the presence of frequency and nocturia, in the absence of any other pathology’.4 It is important to highlight that OAB is not synonymous with detrusor overactivity (DO) assessed via urodynamics although the prevalence of DO increases in those with UI from 44% to 69%. There is a good correlation between UUI (wet OAB) and DO on urodynamic investigations.22 It is important to understand that DO is a urodynamic diagnosis, and that the observation of involuntary contractions must be correlated with the patients’ symptoms during the urodynamic test and with their presenting symptoms. However, asymptomatic DO can also be diagnosed. Idiopathic DO is the most common type of DO when there is no defined cause such as inflammatory factors,23 or underlying neurogenic pathology.24
Clinical assessment of urinary incontinence in women
Norton et al. showed that 25% of women waited more than 5 years before seeking help because of embarrassment or fear of surgery.18 Data from National Institute for Health and Care Excellence (NICE) indicate that the standard benchmark rate for a referral to a UI service for women in the UK is 0.8% (800 per 100,000 adult female/year).25
There are several essential elements for the comprehensive clinical assessment (CCA) that can together form a platform for diagnosis for women with lower urinary tract symptoms (LUTS) and UI. CCA includes (1) history-taking using structured interviews, validated questionnaires for symptom severity and impact on health-related quality of life (HRQoL) and sexual function, (2) bladder diaries and (3) non-invasive tests such as cough stress test (CST), pad tests, uroflowmetry and bladder scan, urinalysis, and measurement of body mass index (BMI).
Structured interview and validated questionnaires
Initial patient interview is vital in cases of LUTS and UI. It can detect risk factors for various types of LUTS such as age, menopause, parity, previous pelvic floor surgery, chronic cough, chronic constipation, cardiac failure or neurological diseases. Moreover, the obstetric history and concomitant drug history (such as sedatives, diuretics or anticholinergics) are important for assessment of UI and planning future management. It is also important to classify the predominant or most bothersome type of UI to the patient (OAB/UUI vs. SUI). The interview can establish the severity of the condition, including the number of incontinence pads used and previous treatments tried. NICE guideline NG123 recommends: ‘At the initial clinical assessment, categorise the woman’s UI as SUI, MUI or UUI/OAB. Start initial treatment on this basis. In MUI, direct treatment towards the predominant symptom’.3
Such interviews can be performed with the aid of integrated validated questionnaires completed by the patients during or prior to the interview. This can help to explore all elements of LUTS, including the storage phase, voiding phase and UI.
Several validated questionnaires exist to assess the severity, type and HRQoL impact of UI. For instance, the International Consultation on Incontinence Questionnaire (ICIQ), with the full detailed ICIQ-FLUTS module, and the short form (SF), ICIQ-UI-SF, and the HRQoL questionnaire, ICIQ-LUTSQoL.26 Other tools include the urinary distress inventory-6,27 impact of incontinence questionnaire-7 (IIQ-7),28 and the King’s Health Questionnaire (KHQ).29 Sexual function can similarly be assessed using validated questionnaires. One widely used example is the SF of the pelvic organ prolapse / urinary incontinence sexual questionnaire 12 (PISQ-12).30 To represent sexually inactive patients, the International Urogynaecological Association (IUGA) developed the PISQ-IUGA revised (PISQ-IR).31
Examination
Following the patient interview, physical examination is essential to formulate the diagnosis. In addition to an abdominal examination, gynaecological examination can aid in detecting anatomical defects, possible pelvic masses, vaginal atrophy, urogenital fistulae, prolapse, as well as assessment of the pelvic floor during increased intra-abdominal pressure.32
The CST is a simple bedside test often performed during the examination with a comfortably full bladder, either in the lithotomy position or upright, where the patient is asked to cough or perform the Valsalva manoeuvre. Leakage of urine during the period of increased intra-abdominal pressure points towards a diagnosis of SUI.2 The mobility of the urethra can also be assessed visually at the same time.
Assessment tools
Frequency/volume charts or bladder diaries can help provide clinical information on urinary symptoms and habits, and symptom severity.2 Three-day bladder diaries offer reduced patient burden33 and correlate well with UI episodes measured over 4 subsequent days (correlation coefficient = 0.887).34 NICE recommends a 3-day bladder diary in the initial assessment of women with UI.3
Bladder scans are helpful non-invasive bedside tests to assess the post-void residual (PVR) urine volumes for women with UI and are recommended by NICE as part of the CCA.3
Integrating all the above elements of a CCA can form a platform for diagnosis of women with LUTS and UI. However, the bladder has been traditionally described as an unreliable witness. Several authors in the past believed the real pathophysiology for LUTS might be difficult to interpret based on symptoms alone. This sentiment is primarily due to the frequent lack of agreement between the clinical diagnosis and diagnosis based on invasive investigations (i.e. urodynamics). Interestingly, the current literature lacks any robust evidence to show that treatments of UI based on urodynamic findings are associated with better outcomes compared to those based on CCA alone.35
Urodynamic assessment of urinary incontinence in women
Urodynamic assessment is a combination of non-invasive measures (uroflowmetry) and invasive measures (cystometry).
The role of urodynamic testing in uncomplicated UI is debatable, with several trials suggesting no benefit over office-based, non-invasive, preoperative assessment.36–38 However, urodynamic assessment may be beneficial where the clinical features are unclear.39
At the time of the study design, in women with OAB/UUI and after failure of conservative and medical treatment, NICE recommended ‘urodynamic’ investigation to confirm the diagnosis of DO in women with urgency-predominant UI.25 NICE recommends uroflowmetry and multichannel filling and voiding cystometry.
Uroflowmetry
Uroflowmetry is a non-invasive method to measure urinary flow rate, and the total volume of voided urine. The primary measurements for female patients are the maximum and average flow rates (Q-max and Q-avg, respectively), the voiding pattern, the PVR and the voided volumes.40 Such measurements aid in assessing patients with potential voiding dysfunction.41
Invasive urodynamic tests (multichannel filling cystometry and voiding pressure flow)
The test involves the insertion of one or two small catheters less than size 8 Fr into the bladder and another one into the vagina or the rectum (the latter is preferrable). The rationale for urodynamics is to reproduce the women’s symptoms and to identify the underlying pathology. The bladder is slowly filled with saline, and the bladder pressure is measured. At the same time, abdominal pressure is measured, since the bladder is an abdominal organ. The difference between these pressures is calculated throughout the test by a computer and plotted as the ‘detrusor pressure’, which indicates whether the bladder is contracting and generating pressure. The patient is asked to report her sensations related to bladder filling. Key abnormal observations that might be seen during the filling cystometry include bladder contractions (referred to as DO), steady climbing detrusor pressure (low compliance) and urinary leakage when there is a rise in abdominal pressure (USI). When the patient experiences a strong desire to pass urine, she is said to have reached functional cystometric capacity, and permission to pass urine is given. This is the start of the pressure flow study, which looks at voiding function. Key abnormal observations that might be seen during the pressure flow study include a slow flow rate despite high detrusor pressure, which may indicate bladder outlet obstruction. Alternatively, slow flow may be due to weak bladder contraction, referred to as detrusor underactivity.
During bladder filling, DO is particularly relevant to the current study; these are uninhibited bladder contractions, which hinder effective urine storage, and are frequently associated with urgency and/or UUI. Urodynamic stress incontinence (USI) may also be seen, and if USI and DO incontinence (DOI) are both present, the woman is diagnosed with urodynamic MUI. Urodynamics can also identify other pathologies, for example bladder outflow obstruction or detrusor underactivity during voiding, which may influence the choice of therapy.
Conservative and non-surgical management of overactive bladder
Lifestyle modifications
Weight loss in high-BMI individuals has been shown to reduce the severity of UI symptoms.42,43 NICE recommends weight loss if BMI is more than 30, modification of fluid intake to avoid excessive or low fluid intake and a trial of caffeine reduction.
Other lifestyle modifications include smoking cessation and reduction of high-intensity exercise, although evidence is less clear for such modifications.32
Pelvic floor strengthening
Pelvic floor exercises
Pelvic floor muscle training (PFMT) is widely used to treat UI and focuses on strengthening the pelvic floor muscles (PFM) through exercises. A 2018 Cochrane review found that PFMT significantly improves female UI symptoms [risk ratio (RR) 6.33 (95% CI 3.88 to 10.33); 3 trials, 242 women; moderate-quality evidence].44
Biofeedback
Pelvic floor muscle training can be combined with patient biofeedback to relay information regarding PFM contraction back to the patient. This is thought to help maintain awareness of PFM function during exercises, for example through vaginal pressure measurements.45 However, a recent RCT (n = 600) suggests that biofeedback provides no benefit over regular PFMT [mean difference in ICIQ-UI-SF at 24 months −0.09 (95% CI −0.92 to 0.75); p = 0.84].46
Behavioural therapy
NG123 recommends a minimum of 6 weeks bladder retraining as first-line treatment for women with OAB/UUI.3
Pharmacological treatment
In clinical practice, anticholinergic or antimuscarinic medications are usually considered as first-line treatment in women with OAB and UUI alongside bladder retraining and PFMT. There are several types of anticholinergic drugs used in clinical practice, predominantly oral medications (oxybutynin, tolterodine, solifenacin, darifenacin, trospium, fesoteoridne and propiverine). Common side effects include constipation, dry eyes and dry mouth. The long-term effect of using anticholinergic drugs on cognitive function is unknown. There are concerns about the long-term use of anticholinergic drugs and the impact on the cognitive function especially in elderly patients with multiple morbidity as anticholinergic load burden can be highest in them.47
Standard clinical practice based on NICE recommendations is that women with OAB/UUI are started on one of the above medications as part of the conservative management plan, after a full review of physical and mental status and comorbidities, as well other medications that the patient may be taking, with special consideration of the anticholinergic load. NICE recommends review of treatment outcome in 4–6 weeks and to try an alternative anticholinergic medication if ineffective or poorly tolerated. Transdermal oxybutynin can be an option in women with intolerance to oral medications.
Mirabegron and vibegron are another class of oral medication that can be used in women with OAB/UUI. They are beta-3 adrenergic agonists and facilitate urine storage, hence are used in medical treatment of OAB/UUI if anticholinergic medications are not tolerated or contraindicated. In clinical practice, clinicians would recommend a trial of a minimum of two or three types of pharmacological treatment before proceeding to invasive treatments.
National Institute for Health and Care Excellence Guideline NG123 recommends initial conservative treatment, which includes lifestyle modifications, bladder training and PFMT and pharmacological therapy (anticholinergics and/or beta-3 agonist).3 However, these measures are unsuccessful for approximately 25–40% of women. These women are then considered to have refractory OAB.48 For these women, and at the time of the study design, NICE recommended ‘urodynamic’ investigation to confirm the diagnosis of DO, before proceeding to invasive treatments such as a botulinum toxin injection A (BoNT-A) or sacral neuromodulation (SNM).25
Invasive treatments for refractory overactive bladder
National Institute for Health and Care Excellence recommend injection of BoNT-A into the bladder wall or SNM as the treatments for women with refractory OAB following failure of conservative and medical treatment and a confirmation of urodynamic diagnosis of DO.25
Botulinum toxin injection treatment
This is the injection of BoNT-A into the bladder wall during cystoscopy (rigid or flexible), under general or more commonly local anaesthesia. The treatment, if successful, is usually repeated every 6–12 months.
In women with refractory OAB and associated DO on urodynamics, Brubaker et al. showed that approximately 60% of the women who received BoNT-A had a positive clinical response based on the Patient Global Impression of Improvement scale (PGI-I).49 Secondary analyses performed in two RCTs of BoNT-A versus placebo suggested that successful treatment outcomes did not appear to be related to the preoperative urodynamic diagnosis of DO.50,51 Chapple et al. (2013), in a double-blind, placebo-controlled RCT, showed that BoNT-A significantly improves all symptoms of refractory OAB and HRQoL; there was no impact of the preoperative diagnosis of DO on the treatment outcomes.51 Similarly, Rovner et al. (2011) in a placebo-controlled RCT showed that 57% of the patients were satisfied with their treatment (compared to 19% placebo) at 3 months following BoNT-A treatment, irrespective of the presence of DO on urodynamics.50 BoNT-A is now licensed in the UK for the treatment of refractory OAB/UUI symptoms without the need for preoperative urodynamics.
In a recent observational study embedded within the Bladder Ultrasound Study (BUS), 666 women with non-refractory OAB underwent urodynamics; the results suggested that clinicians and patients appeared to be guided in part by the urodynamic diagnosis in selecting treatment options.52 Several confounding influences were identified, such as natural fluctuation of disease state, regression to the mean and Hawthorne effects. The economic modelling within the BUS study suggested that urodynamics can be a cost-effective diagnostic strategy for women with predominant symptoms of OAB.52 However, this was based on fewer women undergoing invasive treatment in the urodynamics group rather than achieving better outcomes. The authors reported significant cost savings in the urodynamics group associated with a small reduction in clinical effectiveness. It is important to highlight that the BUS study assessed a different cohort of women with significantly milder OAB symptoms and therefore the results could not be generalised to women with refractory OAB.52
Sacral neuromodulation
The principle of SNM is that electrical stimulation of the sacral reflex pathway will inhibit the reflex behaviour of the bladder.53 SNM is a two-stage procedure; stage one is a test phase using either a temporary or permanent lead, connected to an external stimulator, while the second stage involves the placement of a subcutaneous implantable pulse generator (IPG; permanent battery implant). If a patient reports at least 50% improvement of the refractory OAB symptoms during the test phase, as recorded in the bladder diaries, they are offered the permanent implant. SNM has a unique advantage, as patient outcomes are assessed before a commitment is made to the full implant.
Three RCTs comparing SNM to placebo showed that 52% of patients were dry at 18 months and a further 24% reported at least 50% reduction in leakage episodes; at 3 years, 46% were dry and 13% improved.53–55 In one RCT, patients with urgency and increased frequency showed improvements in several short form-36 (SF-36) domains in the active treatment group (n = 51; 90% women) at 6 months’ follow-up.55 NICE concluded that following SNM, up to two-thirds of patients achieve continence or substantial improvement in symptoms, with the beneficial effects lasting for up to 3–5 years after implantation.25 Around one-third of patients may require re-operation, most often due to pain at the implant site, infection, or the need for adjustment and modification of the lead. Urodynamic investigation is considered a standard practice prior to SNM treatment. However, one recent observational study reported that pre-operative diagnosis of DO was not a prerequisite selection criterion for SNM.56
Sequence of treatment in women with refractory overactive bladder
The best sequence of interventions for women with refractory OAB is not known.
In 2013, NICE CG171 included a health economic evaluation which suggested that, in the short term, BoNT-A was a cost-effective intervention both in comparison with no active treatment and also in comparison with SNM.25 On the balance of evidence, NICE justified the recommendation to offer BoNT-A as first intervention to women with refractory OAB and DO. They recommended SNM for women who are unable to catheterise or have a cultural or ethical objection to catheterisation, or those with persistent symptoms following BoNT-A treatment.
Interestingly, evidence from one recent study highlighted that 61% of women receiving BoNT-A discontinued their treatment at 3 years while 64% discontinued at 5 years.57 Most recently, Marcelissen et al. showed that only 30% of patients initiated on BoNT-A treatment were still on treatment at a minimum follow-up of 5 years; most patients who discontinued treatment (98%) did so after the after the first or second injection.58 In an economic model comparing SNM with BoNT-A over a 5-year period with a societal perspective, Leong et al. reported a greater gain in quality-adjusted life-year (QALYs) and a greater associated cost saving when patients were initiated on SNM treatment.59 As the QALY gain from BoNT-A injection was lower due to the loss of effect with re-injections over time, SNM was demonstrated to become cost-effective after 5 years compared with BoNT-A, with an incremental cost-effectiveness ratio (ICER) of 27,991 euros, which is within the accepted NICE threshold of £20,000–£30,000.
Accordingly, practice in the UK can vary and usually relies on the treatment options available within units. The brief survey of the potential collaborating sites for the FUTURE trial, at the time of the trial design, suggests a considerable number of units and surgeons offer BoNT-A treatment for women with refractory OAB with and without urodynamic evidence of DO. In addition, in tertiary units with SNM readily available, surgeons tend to offer women with confirmed DO the choice between BoNT-A and the SNM test procedure after discussion by the local multidisciplinary team (MDT). Some surgeons indicated that they favour SNM in younger patients and/or those with associated voiding dysfunction or faecal incontinence.
In summary, the current evidence highlights the uncertainties and the timely need for a robust RCT to address this important research question which was prioritised by the NICE guideline CG171 research recommendations: ‘Further research is needed to answer the question of whether the use of invasive urodynamics, prior to initial or subsequent treatments, affects the outcomes and cost-effectiveness of interventions in women with UI or OAB’.25
Rationale for the Female Urgency, Trial of Urodynamics as Routine Evaluations trial
Research question
Does routine urodynamic investigation in addition to CCA improve participant-reported outcomes following treatment, compared to CCA only, in women with refractory OAB symptoms and is it cost-effective?
Rationale
National Institute for Health and Care Excellence recommends urodynamic investigation to confirm the diagnosis of DO in women with refractory OAB before proceeding to invasive treatment.25
Refractory OAB is defined as OAB symptoms that are refractory to conservative and medical treatment including bladder retraining and PFMT and a minimum of two types of pharmacological therapy (anticholinergics and/or beta-3 agonist).
For clinicians, urodynamics is traditionally considered to inform the counselling of women on the chances of success of subsequent treatments. However, in women with refractory OAB, urodynamics fails to show evidence of DO in up to 45%.60 The accuracy of urodynamics relies on well-calibrated equipment, the experience of investigators and their objective interpretation of a number of subjective parameters. Hence the standardisation of the test is difficult and is affected by the wide variation in staff practice and type of equipment used.61 These factors raise a valid debate on the clinical and cost-effectiveness of urodynamics and whether it actually improves the outcomes following subsequent treatments compared to treatment guided by CCA only.
From the patients’ perspective, many describe urodynamics as an invasive and embarrassing investigation, associated with an element of emotional distress.62,63 Urodynamics is also associated with a risk of discomfort and urinary tract infection (UTI).52 However, the majority of women find it acceptable if it will ultimately improve their outcomes post treatment.52,64–66
Unfortunately, the urodynamics test may not replicate the patients’ symptoms in their day-to-day lives, which questions the validity of the treatment options offered based on its results.
For policy-makers, inevitably urodynamics is costly to the NHS, including purchase of equipment and disposables, and the need for specialist staff. The urodynamics tariff was £256/patient at the time of the trial design. Policy-makers are faced with the current pressure on health resources in the UK; therefore, there is a pressing need to direct resources towards evidence-based interventions that are proven to positively improve treatment outcomes.
Urodynamics is a test that has been embedded in clinical practice without robust evidence of its clinical or cost-effectiveness.67 Robust evidence shows urodynamics to have no impact on participant-reported outcomes following conservative treatment of UI68 and for those undergoing surgical treatment for symptoms of pure SUI.37 Accordingly, NICE CG171 has prioritised research to assess the clinical and cost effectiveness of urodynamics in treatment of refractory OAB.25 The outcome of the FUTURE trial will inform patients, clinicians and policy-makers whether routine urodynamic investigation improves the treatment outcomes in women with refractory OAB and whether it is cost-effective.