Comparative assessment of onabotulinumtoxinA and mirabegron for overactive bladder: an indirect treatment comparison.

CONTEXT: OnabotulinumtoxinA and mirabegron have recently gained marketing authorisation to treat symptoms of overactive bladder (OAB). OBJECTIVE: To evaluate the relative efficacy of mirabegron and onabotulinumtoxinA in patients with idiopathic OAB. DESIGN: Network meta-analysis. DATA SOURCES: A search of 9 electronic databases, review documents, guidelines and websites. METHODS: Randomised trials comparing any licensed dose of onabotulinumtoxinA or mirabegron with each other, anticholinergic drugs or placebo were eligible (19 randomised trials were identified). 1 reviewer extracted data from the studies and a second reviewer checked the data. Candidate trials were assessed for similarity and networks were developed for each outcome. Bayesian network meta-analysis was conducted using both fixed-effects and random-effects models. When there were differences in mean baseline values between mirabegron and onabotulinumtoxinA trials they were adjusted for using network meta-regression (NMR). RESULTS: No studies directly comparing onabotulinumtoxinA to mirabegron were identified. A network was created for each of the 7 outcomes, with 3-9 studies included in each individual network. The trials included in the networks were broadly similar. Patients in the onabotulinumtoxinA trials had more urinary incontinence and urgency episodes at baseline than patients in the mirabegron trials and these differences were adjusted for using NMR. Both onabotulinumtoxinA and mirabegron were more efficacious than placebo at reducing the frequency of urinary incontinence, urgency, urination and nocturia. OnabotulinumtoxinA was more efficacious than mirabegron (50 and 25 mg) in completely resolving daily episodes of urinary incontinence and urgency and in reducing the frequency of urinary incontinence, urgency and urination. NMR supported the results of the network meta-analysis. CONCLUSIONS: In the absence of head-to-head trials comparing onabotulinumtoxinA to mirabegron, this indirect comparison indicates that onabotulinumtoxinA may be superior to mirabegron in improving symptoms of urinary incontinence, urgency and urinary frequency in patients with idiopathic OAB.

OnabotulinumtoxinA in the treatment of overactive bladder: a cost-effectiveness analysis versus best supportive care in England and Wales.

The cost-effectiveness of onabotulinumtoxinA (BOTOX(®)) 100 U + best supportive care (BSC) was compared with BSC alone in the management of idiopathic overactive bladder in adult patients who are not adequately managed with anticholinergics. BSC included incontinence pads and, for a proportion of patients, anticholinergics and/or occasional clean intermittent catheterisation. A five-state Markov model was used to estimate total costs and outcomes over a 10-year period. The cohort was based on data from two placebo-controlled trials and a long-term extension study of onabotulinumtoxinA. After discontinuation of initial treatment, a proportion of patients progressed to downstream sacral nerve stimulation (SNS). Cost and resource use was estimated from a National Health Service perspective in England and Wales using relevant reference sources for 2012 or 2013. Results showed that onabotulinumtoxinA was associated with lower costs and greater health benefits than BSC in the base case, with probabilistic sensitivity analysis indicating an 89 % probability that the incremental cost-effectiveness ratio would fall below £20,000. OnabotulinumtoxinA remained dominant over BSC in all but two scenarios tested; it was also economically dominant when compared directly with SNS therapy. In conclusion, onabotulinumtoxinA appears to be a cost-effective treatment for overactive bladder compared with BSC alone.

The impact of lower urinary tract symptoms on health-related quality of life among patients with multiple sclerosis.

AIMS: Lower urinary tract symptoms are commonly experienced among patients with multiple sclerosis (MS), however, their impact on health-related quality of life (HRQOL) has not been well characterized. Herein the incremental impact of lower urinary tract symptoms on HRQOL among patients with MS has been evaluated. METHODS: A cross-sectional online survey was administered to US residents with a self-reported MS diagnosis. Data pertaining to demographics, disease history, urinary symptoms, and HRQOL, including the Short Form 36, version 2 (SF-36v2), were collected. Patients were stratified into four urinary symptom groups: no/minimal urinary symptoms, urinary urgency (UU), urinary urgency incontinence (UUI), and other lower urinary tract symptoms. Multiple linear regression models evaluated the impact of these symptoms. RESULTS: Out of the 1,052 respondents, mean age was 47.8 ± 10.6 years; mean time since MS diagnosis was 8.5 ± 7.8 years. UUI and UU subgroups showed the greatest adjusted HRQOL decrement compared with the no/minimal urinary symptoms group, scoring 2.8 (SE ± 0.7, UUI) and 3.5 (SE ± 0.8, UU) points lower on SF-36v2 Physical Component Summary, respectively, and 3.7 (SE ± 1.0, UUI) and 5.0 (SE ± 1.2, UU) points lower on SF-36v2 Mental Component Summary (P < 0.001 for all), respectively. CONCLUSIONS: Both UU and UUI symptoms contribute to a decrement in HRQOL among patients with MS.

Patient-reported goal achievement following onabotulinumtoxinA treatment in patients with neurogenic detrusor overactivity.

AIMS: To identify the self-reported treatment goals of patients with urinary incontinence (UI) due to neurogenic detrusor overactivity (NDO), determine whether patients achieved their goals following onabotulinumtoxinA treatment, and assess impact of neurogenic disease (multiple sclerosis or spinal cord injury) and/or clean intermittent catheterization (CIC) on goal achievement. METHODS: Data from two Phase III studies of onabotulinumtoxinA 200U (n = 227) or placebo (n = 241) in NDO patients (≥14 UI episodes/week; inadequately managed by anticholinergics) were pooled for analysis. At baseline, patients listed their top two qualitative treatment goals, which were distributed into eight subcategories. Six weeks post-treatment, patients rated whether they achieved their goals (5-point Likert scale). The frequency distribution of goals, the proportion of patients who achieved their goals, and goal achievement by etiology and use/non-use of CIC were assessed. RESULTS: At baseline, the most common goals were "be dry" (37.9%), "reduce other urinary symptoms" (26.4%), and "improve quality of life/sleep/emotions" (21.4%). Significantly higher proportions of onabotulinumtoxinA-treated patients achieved their overall goals versus placebo (62.0% vs. 17.2%; P < 0.001). OnabotulinumtoxinA treatment resulted in higher goal achievement in all goal categories, regardless of etiology. CIC use did not negatively impact patients' overall goal achievement; significantly higher proportions of onabotulinumtoxinA-treated patients versus placebo achieved their goals regardless of baseline catheterization use or de novo CIC during the first 6 weeks of the study. CONCLUSIONS: The majority of patients with UI due to NDO achieved their self-determined treatment goals following onabotulinumtoxinA 200U therapy, regardless of etiology or CIC use. Neurourol. Urodynam. 35:595-600, 2016. © 2015 The Authors. Neurourology and Urodynamics, published by Wiley Periodicals, Inc.

Impact of onabotulinumtoxinA on quality of life and practical aspects of daily living: A pooled analysis of two randomized controlled trials.

OBJECTIVE: To evaluate the impact of onabotulinumtoxinA on individual domains of the quality of life questionnaires in a pooled analysis of two phase 3 trials in overactive bladder patients with urinary incontinence who were inadequately managed by ≥1 anticholinergic. METHODS: Patients received intradetrusor injections of onabotulinumtoxinA 100U (n = 557) or placebo (n = 548). The proportions of patients with a positive response (condition "greatly improved" or "improved") on the Treatment Benefit Scale, and changes in Incontinence Quality of Life scores and King's Health Questionnaire domain scores were analyzed in the overall population and subgroups with clean intermittent catheterization use and urinary tract infection status during the first 12 weeks of treatment. Responses to individual King's Health Questionnaire items were also assessed. RESULTS: Significantly greater proportions of onabotulinumtoxinA-treated patients achieved positive Treatment Benefit Scale response versus placebo (61.8% vs. 28.0%; P < 0.001). OnabotulinumtoxinA showed significantly greater improvements versus placebo in Incontinence Quality of Life total (22.5 vs. 6.6), Incontinence Quality of Life subscale scores and all domains of the King's Health Questionnaire. Notably, a similar trend was observed regardless of clean intermittent catheterization/urinary tract infection status. Additionally, onabotulinumtoxinA resulted in significantly greater improvements than the placebo in practical aspects of patients daily lives, including pad use, need to change undergarments, sleep, relationship with partner and work life/daily activities. CONCLUSION: In overactive bladder patients with urinary incontinence, onabotulinu-mtoxinA 100U demonstrated significant improvements across the individual domains of the quality of life questionnaires, regardless of clean intermittent catheterization or urinary tract infection status, and provided a positive impact on practical aspects of patients' daily lives.

Psychometric properties of the incontinence utility index among patients with idiopathic overactive bladder: data from two multicenter, double-blind, randomized, Phase 3, placebo-controlled clinical trials.

BACKGROUND: Overactive bladder is a prevalent and burdensome condition. Generic utility measures may fail to reflect its full impact on patients' health status. The Incontinence Utility Index (IUI) is a community-based preference index derived from the Incontinence Quality of Life Questionnaire (I-QOL) developed to value health states related to urinary symptoms in patients with neurogenic detrusor overactivity. This study assessed the measurement properties of the IUI in patients with idiopathic overactive bladder (OAB). METHODS: Data were used from two clinical trials which recruited patients with OAB whose symptoms were inadequately managed with ≥ 1 anticholinergic medication. Psychometric evaluation included: Differential Item Functioning (DIF) analysis, concordance between I-QOL and IUI (Intraclass correlation coefficient [ICC], criterion and convergent validity according to relevant patient reported outcomes and clinical variables (Spearman's correlation coefficient, rho), responsiveness, and agreement between utility measures (ICC and Bland-Altman method). RESULTS: A total of 1,105 idiopathic OAB patients were included. Mean age (range) was 60.4 years (18-90), 87.8% (n = 970) were female. DIF was identified in 3 items, none of which are contained in the IUI. ICC (CI95%) was 0.944 (0.936-0.950). Statistically significant differences (p < 0.001) were found in IUI scores for patients improving according to the Treatment Benefit Scale (TBS). Moderate to strong correlations (rho > |0.6|) were found in the expected direction with daily incontinence, urgency episodes and disease-specific domains of King's Health Questionnaire (KHQ). Low to moderate correlations (rho:<|0.6|) were found with Short Form version 2 (SF-12v2) summary components. A large effect size was found for patients reporting improvement (0.98-1.21) or great improvement (1.87-2.56) in the TBS, as well as in patients responding to treatment (1.19-2.40). Across utility measures, directional trends were consistent with OAB symptom profile, however, a lack of agreement in absolute values was observed. CONCLUSIONS: The IUI presents good psychometric properties for valuing the impact of UI-related problems in idiopathic OAB patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00910845 and NCT00910520.

Lower urinary tract symptom prevalence and management among patients with multiple sclerosis.

BACKGROUND: This study was conducted to assess self-reported prevalence and management of lower urinary tract symptoms (LUTS), along with drivers of treatment seeking, among patients with multiple sclerosis (MS). METHODS: An online, cross-sectional survey was administered to US-residing participants with self-reported MS to assess presence of LUTS, including urinary incontinence (UI). Participants experiencing LUTS were asked additional questions related to management and current therapies. Multivariate logistic regression identified drivers of treatment-seeking behavior. RESULTS: A total of 1052 participants completed the survey; 1047 were included in the analysis. Nine hundred sixty-six participants (92%) reported at least one LUTS, the most common being post-micturition dribble (64.9%), urinary urgency (61.7%), and a feeling of incomplete emptying (60.7%). Eight hundred twenty-six (79%) reported having some type of UI. Of those with any type of LUTS, 70% (n = 680) had previously discussed urinary symptoms with a health-care provider (HCP), while only 32% (n = 311) had seen an HCP in the past year. Logistic regression found urgency (odds ratio [OR] 1.20 [95% confidence interval (CI), 1.00-1.44]), intermittent urine stream (OR 1.40 [95% CI, 1.15-1.69]), and urgency UI (OR 1.78 [95% CI, 1.22-2.60]) to be significant predictors of seeking treatment. Of those who had discussed LUTS with an HCP, 480 (70.6%) were currently receiving at least one LUTS treatment; the most common treatments were reducing fluid intake, pelvic exercises, oral anticholinergic medications, and avoiding certain foods/alcohol. CONCLUSIONS: LUTS are commonly experienced among people with MS but are largely untreated. Proper LUTS assessment and work-up is warranted in MS patients.

Development of the Incontinence Utility Index: estimating population-based utilities associated with urinary problems from the Incontinence Quality of Life Questionnaire and Neurogenic Module.

BACKGROUND: Generic utility instruments may not fully capture the impact and consequences of urinary problems. Condition-specific preference-based measures, developed from previously validated disease-specific patient-reported outcomes instruments, may add relevant information for economic evaluations. The aim of this study was to develop a condition-specific preference-based measure, the Incontinence Utility Index (IUI), for valuing health states associated with urinary problems. METHODS: A two-step process was implemented. First, an abbreviated health state classification system was developed from the Incontinence Quality of Life Questionnaire (I-QOL) and Neurogenic Module by applying Rasch modelling, classical psychometrical testing and expert criteria to data from two pivotal trials comprised of neurogenic detrusor overactivity (NDO) patients. Criterion, convergent validity and concordance with the original instrument was assessed in the abbreviated version. Then, a multi-attribute utility function (MAUF) was estimated from a representative sample of the UK non-institutionalized adult general population. Visual analogue and time-trade off (TTO) evaluations were applied in the elicitation process. Predictive validity of the MAUF was tested comparing estimated and direct utility scores. RESULTS: The abbreviated health state classification system generated from the NDO sample contained 5 attributes with 3 levels of response and had adequate psychometrical properties: significant differences in scores according to the reduction in the frequency of urinary incontinence episodes [UIE] (p < 0.001); Spearman correlation coefficient with number of daily UIE = -0.43; p < 0.01 and Intraclass Correlation Coefficient (ICC, 95% CI) with the original version = 0.90 (0.89-0.91; p < 0.001). Next, 442 participants were interviewed (398 cases were valid, generating 2,388 TTO evaluations) to estimate the social preferences for derived health states. Mean age was 44.75 years (interquartile range 33.5-55.5) and 60.1% were female. An overall algorithm for the IUI was estimated and transformed onto a dead = 0.00 and full health = 1.00 scale. Model fits were acceptable (R-squared = 0.923 and 0.978). Predictive validity was adequate: ICC (95% CI) = 0.928 (0.648-0.985) and Mean of Absolute Differences = 0.038. CONCLUSIONS: The newly developed IUI is a preference-based measure for urinary problems related to NDO that provides general population-based utility scores with adequate predictive validity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00461292, NCT00311376.

Impact of urinary incontinence on healthcare resource utilization, health-related quality of life and productivity in patients with overactive bladder.

OBJECTIVE: To evaluate the impact of urinary incontinence (UI) on healthcare resource utilization (HRU), health-related quality of life (HRQoL) and productivity measures in patients with overactive bladder (OAB). PATIENTS AND METHODS: This retrospective, cross-sectional study used data from the Adelphi OAB/UI Disease Specific Programme, a multinational survey of patient- and physician-reported data, fielded between November 2010 and February 2011. The primary patient groups of interest were those with OAB, both with and without UI. Health-related quality of life and productivity measures were derived from the EuroQoL-5D, the Incontinence Quality of Life questionnaire, the Overactive Bladder Questionnaire, and the Work Productivity and Activity Impairment Questionnaire. Measures of HRU included OAB-related surgeries, OAB-related hospitalizations, incontinence pads, anticholinergic use and physician visits. Multivariate linear regression models and literature-based minimal clinically important differences were used to assess statistically significant and clinically meaningful differences in HRQoL and productivity measures between patients with OAB with UI and those without UI. RESULTS: A total of 1 730 patients were identified, with a mean age of 60.7 years, and 77.0% of them were women, 84.2% were non-Hispanic whites, and 71% were incontinent. Bivariate analyses showed that HRU was significantly higher among patients with OAB with UI than among those without UI in all categories except for the number of OAB-related physician visits. In both bivariate and multivariate analyses, incontinent patients presented with clinically and statistically significantly lower HRQoL and productivity measures with respect to all study endpoints, except for percentage of work time missed due to their OAB/UI. CONCLUSIONS: Urinary incontinence was associated with significantly higher HRU and lower HRQoL and productivity in this population of patients with OAB from five different countries. In addition to clinical considerations, the economic and humanistic impact of UI should be taken into account when evaluating treatment options for patients with OAB.

Systematic review of the epidemiology of urinary incontinence and detrusor overactivity among patients with neurogenic overactive bladder.

BACKGROUND: The prevalence and incidence of neurogenic overactive bladder (nOAB) are poorly defined. This systematic literature review identified nOAB epidemiological data and estimated the incidence and prevalence of urinary incontinence (UI) and detrusor overactivity (DO) in patients with multiple sclerosis (MS), spinal cord injury (SCI), Parkinson's disease (PD), stroke and spina bifida. An initial search of MEDLINE, Embase, PubMed, and the Cochrane library was supplemented by an internet search for grey literature and manual searching of the bibliographies of retrieved articles. Additional study selection identified comparable studies for statistical analysis. A descriptive statistical analysis, single-arm meta-analysis and stratified analysis were conducted using predefined criteria. SUMMARY: Initial selection identified 189 articles containing prevalence data. Secondary selection for statistical analysis identified 39 and 52 articles with prevalence of UI and DO, respectively. Random-effect meta-analysis found the prevalence of UI was 50.9% in patients with MS, 52.3% with SCI, 33.1% with PD and 23.6% with stroke. Spina bifida was excluded due to insufficient data. The prevalence of DO may be biased and artificially elevated because it can only be measured with urodynamic investigations. KEY MESSAGES: A substantial proportion of patients with neurological conditions develop UI that may be attributable to nOAB.

Psychometric performance of the incontinence quality-of-life questionnaire among patients with overactive bladder and urinary incontinence.

BACKGROUND: The Incontinence Quality-of-Life Instrument (I-QOL) is a condition-specific questionnaire that assesses the health-related QOL impact of urinary incontinence, but it has not been validated in patients with overactive bladder (OAB) who have been inadequately managed by anticholinergic therapy. OBJECTIVE: This study assessed the reliability and validity of the I-QOL among patients with OAB with urinary incontinence. METHODS: I-QOL scores were analyzed from a Phase II study that compared the efficacy and tolerability of onabotulinumtoxinA and placebo. Conceptual framework was confirmed via confirmatory factor analysis. Reliability was assessed using Cronbach's alpha and intraclass correlation coefficients (ICCs). Validity was tested by comparing I-QOL scores to tertiles of urinary symptom severity. Effect size statistics estimated the ability of the I-QOL to detect change. Responder analysis with cumulative distribution function was plotted to show differentiation between treatment groups with respect to I-QOL scores. RESULTS: Comparative fit indices ranged from 0.87 to 0.99 on the confirmatory factor analysis. I-QOL scores showed high internal consistency (0.86 ≤ Cronbach's α ≤ 0.93), good test-retest reliability (0.68 ≤ ICC ≤ 0.84), and good differentiation between tertiles of increasing urinary symptom severity (all, P ≤ 0.002). Significant differences in I-QOL change scores were noted between responders and nonresponders across all responder definitions (all, P < 0.001) and corresponded with large effect sizes among responders to treatment (1.34 ≤ effect size ≤ 2.82). CONCLUSION: This study demonstrated that OAB with urinary incontinence affects health-related QOL and that the I-QOL reliably and validly measures these impacts.

Mapping EQ-5D utility scores from the Incontinence Quality of Life Questionnaire among patients with neurogenic and idiopathic overactive bladder.

OBJECTIVES: To provide a mapping algorithm for estimating EuroQol five-dimensional (EQ-5D) questionnaire index scores from the Incontinence-specific Quality of Life questionnaire (I-QOL) based on nationally representative samples of patients with idiopathic or neurogenic overactive bladder (OAB) using EQ-5D questionnaire preference valuations based on both the UK and US general populations. METHODS: Analyses were conducted for 2505 patients from the Adelphi Overactive Bladder Disease Specific Programme, a cross-sectional study of patients with idiopathic or neurogenic OAB, undertaken in the United States and Europe in 2010. A range of statistical modeling techniques was used. Tenfold cross-validation techniques were used to calculate mean absolute error (MAE) and root mean squared error (RMSE) goodness-of-fit statistics. Various predictor lists, together with a method combining stepwise selection with multivariable fractional polynomial techniques to allow nonlinear relationships to feature, were pursued. RESULTS: Choice of predictors was consistent for both the UK and US EQ-5D questionnaire tariffs. For idiopathic, the best model included the I-QOL total score and age (both modeled nonlinearly.) For neurogenic, the best model was the I-QOL social embarrassment domain score modeled linearly only. Best-fit results were better in the idiopathic (n = 2351; MAE = 0.10; RMSE = 0.14) than in the neurogenic sample (n = 254; MAE = 0.17; RMSE = 0.22). CONCLUSIONS: This research provides algorithms for mapping EQ-5D questionnaire index scores from the I-QOL, allowing calculation of appropriate preference-based health-related quality-of-life scores for use in cost-effectiveness analyses when only I-QOL data are available. The strongest results were for idiopathic patients, but those for neurogenic are consistent with those of other published mapping studies.

Health-related quality of life and economic impact of urinary incontinence due to detrusor overactivity associated with a neurologic condition: a systematic review.

BACKGROUND: Patients with neurologic diseases often have neurogenic detrusor overactivity (NDO), which can result in a loss of voluntary bladder control and uncontrollable urinary incontinence (UI).The impact of UI due to NDO on patients' lives has not been well studied. The objective of this review was to assess the health-related quality of life (HRQoL) and economic burden in patients with urgency UI due to NDO in select countries in North America, the European Union, Asia, and Australia. METHODS: Systematic literature searches and reviews of articles published in English (January 2000 to February 2011) were conducted using MEDLINE®, EMBASE®, and the Cochrane Library. Studies assessing the impact of UI on HRQoL of patients with an underlying neurologic condition of interest (i.e., multiple sclerosis, spinal cord injury, Parkinson's disease, stroke, or spina bifida) were included. Economic studies in urgency UI also were included. RESULTS: Of 876 citations generated in the initial search, a total of 27 articles were deemed relevant: 16 articles presented HRQoL data and 11 articles presented information on the economic burden of UI. Humanistic studies used a range of HRQoL instruments to measure HRQoL burden, and the economic studies included different cost components to quantify the economic burden, making meaningful comparisons challenging. Despite this heterogeneity, the literature suggests that HRQoL in patients with UI due to NDO is worse than patients with UI in general or those with the same underlying neurologic condition without UI. In addition, urgency UI also results in substantial economic costs. CONCLUSIONS: Incontinent patients with underlying neurologic conditions have impaired HRQoL as well as substantial economic burden attributable to UI due to NDO. There is a need for urgency UI treatments that improve HRQoL of these patients and alleviate the economic burden of this condition.