Urinary Incontinence,Overactive Bladder,and Other Lower Urinary Tract Symptoms: A Longitudinal Population-Based Survey in Men Aged 45–103 Years

Background

Lower urinary tract symptoms (LUTS) such as urinary incontinence (UI) and overactive bladder (OAB) are highly prevalent conditions, but there are few studies describing progression and remission of LUTS in men, especially over the long term.

Objective

To describe the prevalence of UI, OAB, and LUTS using current International Continence Society definitions in the same men studied longitudinally over time.

Design

Prospective, population-based, longitudinal study.

Setting and participants

In 1992, 10 458 men aged 45–99 yr, resident in the city of Gothenburg, were selected at random from the Population Register.

Measurements

The men received a postal questionnaire about the presence of LUTS, as well as questions on social, medical, health-related quality of life (HRQoL), and demographic data. Responders in 1992 were reassessed 11 yr later in 2003 using a similar questionnaire.

Results and limitations

In 2003, 4072 of the 7763 men who responded in 1992 were still available in the Population Register and 3257 men (80%) aged 56–103 yr, responded. Prevalence of UI and OAB had increased (p < 0.01) in the same men assessed in 1992 (4.5% and 15.6%, respectively) and 2003 (10.5% and 44.4%, respectively). The prevalence of nocturia, urgency, slow stream, hesitancy, incomplete emptying, postmicturition dribble, and the number of daytime micturitions had also increased (p < 0.01). Only a minority reported regression of symptoms. Men with UI or OAB reported a poorer (p < 0.001) HRQoL compared with men without UI or OAB.

Conclusions

There was a marked increase in the prevalence of UI, OAB, and other LUTS in the same men assessed longitudinally over this 11-yr period. UI and OAB had a negative influence on HRQoL, and men who developed UI or OAB had a greater deterioration in HRQoL than men who had no change in their UI/OAB status over time.     

Prevalence,Severity, and Symptom Bother of Lower Urinary Tract Symptoms among Men in the EPIC Study: Impact of Overactive Bladder

Background

Lower urinary tract symptoms (LUTS) are prevalent among men.

Objective

To describe the prevalence, severity, and symptom bother of LUTS in all men and men with overactive bladder (OAB) symptoms in the EPIC study.

Design, setting, and participants

A secondary analysis of data from EPIC, a multinational population-based survey of 19 165 adults, was performed. Current International Continence Society definitions were used for individual LUTS and OAB; OAB cases were defined as men reporting urgency.

Measurements

Participants were asked about the presence of individual LUTS and associated symptom bother. LUTS severity was measured using the International Prostate Symptom Score (IPSS).

Results and limitations

There was substantial overlap of storage, voiding, and postmicturition symptoms among all men (n = 7210) and in men with OAB symptoms (n = 502); men with OAB symptoms were more likely to experience multiple LUTS subtypes. Among both populations, nocturia was the most commonly reported symptom, except for urgency (the hallmark symptom) among men with OAB symptoms; terminal dribble and sensation of incomplete emptying were the most common voiding and postmicturition symptoms. The prevalence of all LUTS increased with age among the general population; only storage LUTS increased with age among men with OAB symptoms. Number of LUTS and mean IPSS increased with age in both populations but were higher among men with OAB symptoms at all ages; the proportion reporting moderate–severe LUTS was higher than the general population (30% vs 6%). The proportion of men with OAB symptoms reporting symptom bother increased with urgency severity and severity and number of LUTS. LUTS severity may have been underestimated by the IPSS, which does not assess incontinence.

Conclusions

Men with LUTS commonly experience coexisting storage, voiding, and postmicturition symptoms, emphasizing the need for comprehensive urologic assessments. Men with OAB symptoms reported more LUTS and greater severity than the general population. Symptom bother was related to number of LUTS and urgency severity.     

Urinary Incontinence in French Women: Prevalence,Risk Factors,and Impact on Quality of Life

Background

The lack of epidemiologic data on the prevalence of female urinary incontinence (UI) attending general practitioners (GPs) in France led us to conduct a cross-sectional study in our country.

Objectives

To determine the prevalence of UI and to assess its impact on the quality of life (QoL).

Design, setting, and participants

This cross-sectional study of women aged >18 yr was conducted by attending GPs between June 2007 and July 2007.

Measurements

The main outcome measures were urinary symptoms, functional impairment, International Consultation on Incontinence Questionnaire–Short Form score, and medical care seeking.

Results and limitations

Overall, 241 GPs enrolled 2183 women seen during 1 d. The prevalence of UI was 26.8% (n = 584) and increased with age, body mass index (BMI), and number of children delivered (p < 0.0001). Among women with UI, 496 were included in a cross-sectional survey: 45.2% (n = 224) had stress UI, 42.1% (n = 209) had mixed UI, and 10.9% (n = 53) had urge UI, while 2% (n = 10) had UI of indeterminate type. Overall, 288 of 496 women (51.8%) stated that UI had a negative impact on their QoL; this effect remained mostly mild or moderate, and only 197 of 496 women (39.7%) had asked for medical help. Longer duration of symptoms, higher frequency of comorbid urinary symptoms, and altered QoL were most frequent among women with mixed UI (p < 0.001). Misclassification may have occurred because the diagnosis of UI was based on self-reported data rather than on clinical or urodynamic examinations.

Conclusions

UI symptoms were found in almost one in four women attending GPs. Clinical and functional UI impairment were associated with age, BMI, and parity. UI caused distress to women, but only those who were severely affected sought help. The results emphasize the need for policy development for UI prevention and management in France.     

Genetic influences are important for most but not all lower urinary tract symptoms: a population-based survey in a cohort of adult Swedish twins

Background

The relative importance of genetic and environmental factors for the occurrence of lower urinary tract symptoms (LUTS) is poorly understood.

Objective

To (1) estimate the prevalence of urinary incontinence (UI), overactive bladder (OAB), and other LUTS and (2) to assess the heritability of these symptoms.

Design, setting, and participants

Cross-sectional survey of LUTS in a national population-based cohort of Swedish twins 20–46 yr of age (n = 42 582) from the Swedish Twin Registry.

Measurements

Prevalence rates were determined and heritability of LUTS (in female twins) was assessed using indicators of twin similarity.

Results and limitations

A total of 25 364 twins completed the questionnaire (response rate: 59.6%). LUTS were more common in women (UI: 7%; OAB: 9%; nocturia: 61%; micturition frequency: 18%) than in men (UI: 1%; OAB: 5%; nocturia: 40%; micturition frequency: 11%), and prevalence increased with age. The strongest genetic effects were observed for UI, frequency, and nocturia. The lowest estimate for genetic effects was observed for OAB where environmental effects dominated, and more specifically shared family environment accounted for a third or more of the total variation. For stress UI, a fifth of the total variation in susceptibility to the disorder could be attributed to shared environment. Nonshared environmental effects were seen in the range of 45–65% for the various LUTS. The prevalence of LUTS was low in the men, and there were too few male cases to compute measures of similarity or heritability estimates.

Conclusions

This study provides robust evidence of a genetic influence for susceptibility to UI, frequency, and nocturia in women. In contrast, shared environmental factors seem more important for the predisposition to develop OAB, which may reflect familial patterns such as learning from parental behaviours.     

OnabotulinumtoxinA 100 U Significantly Improves All Idiopathic Overactive Bladder Symptoms and Quality of Life in Patients with Overactive Bladder and Urinary Incontinence: A Randomised,Double-Blind,Placebo-Controlled Trial

Background

Overactive bladder (OAB) syndrome with urinary incontinence (UI) is prevalent in the population and impairs health-related quality of life (HRQOL).

Objective

To assess the impact on efficacy, safety, and HRQOL of onabotulinumtoxinA (BOTOX^®, Allergan, Inc.) treatment in patients with OAB with UI.

Design, setting, and participants

This pivotal, multicentre, double-blind, randomised, placebo-controlled, phase 3 study enrolled patients with idiopathic OAB with ≥3 urgency UI episodes over 3 d and ≥8 micturitions per day who were inadequately managed by anticholinergics.

Intervention

OnabotulinumtoxinA at a 100 U dose (n = 277) or placebo (n = 271), administered as 20 intradetrusor injections of 0.5 ml.

Outcome measurements and statistical analysis

Co–primary end points were change from baseline in the number of UI episodes per day and proportion of patients reporting positive treatment response on the treatment benefit scale (TBS) at week 12. Additional end points included other OAB symptoms (episodes of urinary urgency incontinence, micturition, urgency, and nocturia) and HRQOL (Incontinence Quality of Life [I-QOL], King's Health Questionnaire [KHQ]). Safety assessments included adverse events (AEs), postvoid residual (PVR) urine volume, and initiation of clean intermittent catheterisation (CIC).

Results and limitations

OnabotulinumtoxinA significantly decreased UI episodes per day at week 12 (−2.95 for onabotulinumtoxinA versus −1.03 for placebo; p < 0.001). Reductions from baseline in all other OAB symptoms were also significantly greater following onabotulinumtoxinA compared with placebo (p ≤ 0.01). Patients perceived a significant improvement in their condition, as measured by patients with a positive treatment response on the TBS (62.8% for onabotulinumtoxinA versus 26.8% for placebo; p < 0.001). Clinically meaningful improvements from baseline in all I-QOL and KHQ multi-item domains (p < 0.001 versus placebo) indicated positive impact on HRQOL. AEs were mainly localised to the urinary tract. Mean PVR was higher in the onabotulinumtoxinA group (46.9 ml versus 10.1 ml at week 2; p < 0.001); 6.9% of onabotulinumtoxinA patients versus 0.7% of placebo patients initiated CIC.

Conclusions

OnabotulinumtoxinA 100 U was well tolerated and demonstrated significant and clinically relevant improvements in all OAB symptoms, patient-reported benefit, and HRQOL in patients inadequately managed by anticholinergics.

Trial registration

ClinicalTrials.gov: NCT00910520.     

Gender and Age Differences in the Perception of Bother and Health Care Seeking for Lower Urinary Tract Symptoms: Results from the Hospitalised and Outpatients’ Profile and Expectations Study

Background

Few comparisons have been made of health care seeking behaviour for lower urinary tract symptoms (LUTS) between men and women, as well as trends across age groups.

Objective

To investigate the bother from LUTS and effect on health care seeking in both men and women of different age groups and in comparison between the two genders.

Design, setting, and participants

A representative cross section of each of 13 clinics of a general academic hospital, with equal numbers of subjects recruited in each of six design cells that were defined by age (18–40, 41–60, 61–80 yr) and gender.

Intervention

A 2-h in-person interview, conducted by a trained psychologist/interviewer in a clinic office.

Measurements

Severity of LUTS was measured by the International Prostate Symptom Score (IPSS). Treatment seeking was measured by a single item. A bother question was modified to assess overall bother. Impact on quality of life (QoL) was measured by the IPSS QoL question.

Results and limitations

The final study sample comprised 415 patients. More women than men reported the presence of LUTS (85.5% vs 75.2%; p = 0.01). LUTS were more bothersome in women (25.4% of women vs 17.6% of men with bother “some” or “a lot”; p = 0.02). Severity of LUTS increased with age in both genders (men: p < 0.001; women: p = 0.03). Bother from LUTS increased as severity of symptoms increased in both genders (p < 0.001) but was associated with age only in men (p < 0.001). QoL showed similar results as bother. Although men and women had equal prevalence of treatment seeking (27.9% vs 23.7%; p = 0.40), men, but not women, were more likely to seek treatment as age (p < 0.01) and severity of LUTS (p < 0.001) increased. In multivariate logistic regressions, only bother from LUTS was associated with treatment seeking in women, compared with bother, age, and the presence of voiding symptoms in men.

Conclusions

In our hospital-based sample, differences in LUTS frequency, bother, and health care seeking profiles between men and women suggest a different perception and response to LUTS between the two genders.     

An Updated Systematic Review and Statistical Comparison of Standardised Mean Outcomes for the Use of Botulinum Toxin in the Management of Lower Urinary Tract Disorders

Context

Botulinum toxin A (BoNTA) has received regulatory approval for use in neurogenic detrusor overactivity (NDO) and overactive bladder (OAB), but it remains unlicensed in other lower urinary tract symptoms (LUTS) indications such as nonneurogenic LUTS in men with benign prostatic enlargement (LUTS/BPE), bladder pain syndrome (BPS), and detrusor sphincter dyssynergia (DSD).

Objective

To compare statistically the outcomes of high level of evidence (LE) studies with placebo using BoNTA for LUTS indications; NDO, OAB, LUTS/BPE, BPS and DSD.

Evidence acquisition

We conducted a systematic review of the published literature on PubMed, Scopus, and Embase reporting on BoNTA use in LUTS dysfunction. Statistical comparison was made between high LE studies with placebo and low LE studies.

Evidence synthesis

In adult NDO, there are significantly greater improvements with BoNTA in daily incontinence and catheterisation episodes (−63% and −18%, respectively; p < 0.01), and the urodynamic parameters of maximum cystometric capacity (MCC), reflex volume, and maximum detrusor pressure (MDP) (68%, 61%, and −42%, respectively; all p < 0.01). In OAB, BoNTA leads to significant improvements in bladder diary parameters such as daily frequency (−29%), daily urgency (−38%), and daily incontinence (−59%) (all p < 0.02). The urodynamic parameters of MCC and MDP improved by 58% (p = 0.04) and −29% (p = 0.002), respectively. The risk of urinary tract infection was significantly increased from placebo at 21% versus 7% (p < 0.001), respectively; the risk of intermittent self-catherisation increased from 0% to 12% (p < 0.001). Men with LUTS/BPE showed no significant improvements in International Prostate Symptom Score, maximum flow rate, or prostate volume. There were insufficient data for statistical analysis in DSD, BPS, and paediatric studies. Low LE studies were found to overestimate the effects of BoNTA in all indications, but differences from high LE studies were significant in only a few parameters.

Conclusions

BoNTA significantly improves all symptoms and urodynamic parameters in NDO and OAB. The effect of BoNTA in treating LUTS dysfunction appears to be overestimated in lower as opposed to higher LE studies.     

Dynamic Progression of Overactive Bladder and Urinary Incontinence Symptoms: A Systematic Review

Context

Overactive bladder (OAB) and urinary incontinence (UI) are worldwide public health problems. Longitudinal epidemiologic studies that assess the natural history of OAB and UI are valuable in making accurate prognoses, determining causes and consequences, and predicting resource utilization.

Objective

Our aim was to assess whether the severity of OAB and UI symptoms progress dynamically over time, with the secondary aim of assessing factors that may be associated with symptom progression and regression.

Evidence acquisition

A systematic review of English articles published between January 1, 1990, and September 20, 2009, was conducted using PubMed and Embase. Search terms included longitudinal, natural history, overactive bladder, incontinence, progression, remission, and regression. Eligibility was assessed by Dr. Irwin with editorial assistance. Studies were required to be longitudinal and population based; meeting abstracts and conference proceedings were excluded. Results were assessed qualitatively.

Evidence synthesis

Overall, the 7 longitudinal studies of OAB and 14 longitudinal studies of UI reviewed reported an increase in the incidence and remission/regression of both OAB and UI symptoms over time that varied across studies (eg, OAB incidence, 3.7–8.8%; UI incidence, 0.8–19%). The studies provide evidence for a dynamic progression of OAB and UI symptoms (eg, among women with OAB without urge urinary incontinence [UUI], 28% reported OAB with UUI 16 yr later) and also show that although symptom severity progresses dynamically, for many individuals symptoms also persist over long time periods.

Conclusions

The results support the hypothesis that OAB and UI symptom severity progress dynamically and are also sustained over time. However, the variations in symptom definitions and methods used across studies prevent statistical determinations of overall incidence rates. The recognition of OAB and UI as progressive conditions allows for a shift from the current treatment paradigm of symptom control alone to one of symptom management.     

Prevalence of overactive bladder, urinary incontinence, and lower urinary tract symptoms: results of Korean EPIC study

Objective

Despite growing interest in overactive bladder (OAB), urinary incontinence (UI), and lower urinary tract symptoms (LUTS), there is no epidemiologic study on the prevalence in general population of Korea. This survey was aimed at estimating the prevalence of OAB, UI, and other LUTS among Korean men and women.

Methods

Population-based cross-sectional telephone survey was conducted between May and September 2006 using questionnaire regarding demographics and the prevalence. A geographically stratified random sample of men and women aged????18?years were selected. Current International Continence Society definitions were used for individual LUTS and OAB.

Results

Of a total of 9,067 individuals contacted, 2,000 (888 men, 1,112 women) agreed to participate. Overall prevalence of LUTS was 61.4% (53.7% of men, 68.9% of women) and the prevalence increased with age. Storage LUTS was more prevalent than voiding or post-micturition LUTS in both men (storage; 44.6%, voiding; 28.5%, post-micturition; 15.9%) and women (storage; 64.4%, voiding; 25.9%, post-micturition; 13.9%). Nocturia was the most frequently reported symptom (36.6% of men, 48.2% of women). Overall prevalence of OAB was 12.2% (10.0% of men, 14.3% of women). UI was reported by 2.9% of men and 28.4% of women. The most prevalent type was other UI in men and stress urinary incontinence in women.

Conclusions

Lower urinary tract symptoms and OAB are prevalent among Korean men and women and the prevalence increases with age. Storage LUTS is more prevalent than voiding or post-micturition LUTS and nocturia is the most common symptom.     

The Effect of Benign Lower Urinary Tract Symptoms on Subsequent Prostate Cancer Testing and Diagnosis

Background

Lower urinary tract symptoms (LUTS) are common and have been associated with the subsequent diagnosis of prostate cancer (PCa) in population cohorts.

Objective

To determine whether the association between LUTS and PCa is due to the intensity of PCa testing after LUTS diagnosis.

Design, setting, and participants

We prospectively followed a representative, population-based cohort of 1922 men, aged 40–79 yr, from 1990 until 2010 with interviews, questionnaires, and abstracting of medical records for prostate outcomes. Men were excluded if they had a previous prostate biopsy or PCa diagnosis. Self-reported LUTS was defined as an American Urological Association symptom index score >7 (n = 621). Men treated for LUTS (n = 168) were identified from review of medical records and/or self report. Median follow-up was 11.8 yr (interquartile range: 10.7–12.3).

Outcome measurements and statistical analysis

Associations between self-reported LUTS, or treatment for LUTS, and risk of subsequent prostate biopsy and PCa were estimated using Cox proportional hazard models.

Results and limitations

Fifty-five percent of eligible men enrolled in the study. Men treated for LUTS were more likely to undergo a prostate biopsy (hazard ratio [HR]: 2.4; 95% confidence interval [CI], 1.7–3.3). Men younger than 65 yr who were treated for LUTS were more likely to be diagnosed with PCa (HR: 2.3, 95% CI, 1.5–3.5), while men aged >65 yr were not (HR: 0.89, 95% CI, 0.35–1.9). Men with self-reported LUTS were not more likely to be biopsied or diagnosed with PCa. Neither definition of LUTS was associated with subsequent intermediate- to high-risk cancer. The study is limited by lack of histologic or prostate-specific antigen level data for the cohort.

Conclusions

These results indicate that a possible cause of the association between LUTS and PCa is increased diagnostic intensity among men whose LUTS come to the attention of physicians. Increased symptoms themselves were not associated with intensity of testing or diagnosis.     

Lower urinary tract symptoms: lack of change in prevalence and help‐seeking behaviour in two population‐based surveys of women in 1991 and 2007

OBJECTIVES

To test the hypothesis that the overt prevalence and help‐seeking pattern for lower urinary tract symptoms (LUTS) might have changed over time, by comparing the prevalence of urinary incontinence (UI), overactive bladder (OAB) and other LUTS (principally storage symptoms) and help‐seeking pattern in two equivalent groups of women 16 years apart.

SUBJECTS AND METHODS

We compared two cross‐sectional studies; population‐based random samples of women aged ≥20 years in the central district of Gothenburg in 1991 (2911) and 2007 (3158) were asked to complete similar self‐administered postal questionnaires regarding UI and other LUTS.

RESULTS

The mean (sd , range) age of the two groups was 48.1 (20.4, 20–98 ) years in 1991 and 46.2 (20.0, 20–101) years in 2007, respectively. When comparing the two study populations there were no significant differences in the reported prevalence of UI, OAB or nocturia (defined as two or more voids per night) over time. Nocturia according to the International Continence Society definition was significantly more prevalent in 2007 than 1991, as was daytime voiding frequency of eight or more times a day. OAB dry (i.e. with no incontinence) was more common in 1991, while OAB wet (i.e. with incontinence) was more prevalent in 2007. Of the women in 1991 and 2007, 6% and 7%, respectively, had sought help from the healthcare system due to UI. Significantly more women in 2007 than in 1991 stated that the presence of UI limited their social life (29% vs 13%, P < 0.001).

CONCLUSION

LUTS are common in women and the prevalence rates of UI and OAB have not changed during the last 16 years. Many women still do not seek help from the healthcare system, and the help‐seeking pattern has remained unchanged, despite effective treatment currently being offered.     

TVT-O for the Treatment of Pure Urodynamic Stress Incontinence: Efficacy,Adverse Effects,and Prognostic Factors at 5-Year Follow-up

Background

Inside-out tension-free vaginal transobturator tape (TVT-O) is currently one of the most effective and popular procedures for the surgical treatment of female stress urinary incontinence (SUI), but data reporting long-term outcomes are scarce.

Objective

To evaluate the efficacy and safety of TVT-O 5-yr implantation for management of pure SUI in women.

Design, setting, and participants

A prospective observational study was conducted in four tertiary reference centers. Consecutive women presenting with urodynamically proven, pure SUI treated by TVT-O were included. Patients with mixed incontinence and/or anatomic evidence of pelvic organ prolapse were excluded.

Intervention

TVT-O implantation without any associated procedure.

Outcome measurements and statistical analysis

Data regarding subjective outcomes (International Consultation on Incontinence-Short Form [ICIQ-SF], Patient Global Impression of Improvement, patient satisfaction scores), objective cure (stress test) rates, and adverse events were collected during follow-up. Multivariable analyses were performed to investigate outcomes.

Results and limitations

Of the 191 women included, 21 (11.0%) had previously undergone a failed anti-incontinence surgical procedure. Six (3.1%) patients were lost to follow-up. The 5-yr subjective and objective cure rates were 90.3% and 90.8%, respectively. De novo overactive bladder (OAB) was reported by 24.3% of patients at 5-yr follow-up. Median ICIQ-SF score significantly improved from 17 (interquartile range [IQR]:16–17) preoperatively to 0 (IQR: 0–2) (p < 0.0001).Failure of a previous anti-incontinence procedure was the only independent predictor of subjective recurrence of SUI (hazard ratio [HR]: 4.4; p = 0.009) or objective (HR: 3.7; p = 0.02). No predictive factor of de novo OAB was identified.

Conclusions

TVT-O implantation is a highly effective option for the treatment of women with pure SUI, showing a very high cure rate and a low incidence of complications after 5-yr follow-up.     

A Multicenter,Double-blind,Randomized, Placebo-controlled Trial of the β3-Adrenoceptor Agonist Solabegron for Overactive Bladder

Background

β-Adrenoceptor agonists are effective in animal models of bladder dysfunction, and the human bladder primarily expresses the β3 receptor subtype.

Objective

To evaluate the efficacy and tolerability of the highly selective and potent β3-adrenoceptor agonist solabegron in a clinical proof-of-concept study in incontinent women with overactive bladder (OAB).

Design, setting, and participants

This was a randomized, double-blind trial in adult women with OAB (one or more 24-h incontinence episodes and eight or more average 24-h micturitions).

Interventions

Solabegron 50 mg (n = 88), solabegron 125 mg (n = 85), or placebo (n = 85)—all twice daily—were administered.

Outcome measurements and statistical analysis

The primary efficacy end point was percentage change from baseline to week 8 in the number of incontinence episodes over 24 h. Secondary end points included actual change and percentage change from baseline to week 4 and week 8 in micturitions per 24 h, urgency episodes per 24 h, and volume voided per micturition. Adverse events (AEs) were assessed, as well.

Results and limitations

Solabegron 125 mg produced a statistically significant difference in percent change from baseline to week 8 in incontinence episodes over 24 h when compared with placebo (p = 0.025). Solabegron 125 mg treatment also showed statistically significant reductions from baseline to weeks 4 and 8 in micturitions over 24 h and a statistically significant increase from baseline to week 8 in urine volume voided. Solabegron was well tolerated, with a similar incidence of AEs in each treatment group. There were no significant treatment differences for mean changes from baseline to week 8 in systolic blood pressure (BP), diastolic BP, mean arterial pressure (MAP), or heart rate during the 24-h ambulatory measurement.

Conclusions

Solabegron significantly reduced the symptoms of OAB in women with moderate to severe OAB. Solabegron was safe, well tolerated, and did not demonstrate significant differences in AEs as compared to placebo. β3-Adrenoceptor agonists may represent a new therapeutic approach for treating OAB symptoms.     

In the Human Urothelium and Suburothelium,Intradetrusor Botulinum Neurotoxin Type A Does Not Induce Apoptosis: Preliminary Results

Background

Intradetrusor injections of botulinum neurotoxin type A (BoNTA) are emerging as the preferred second-line treatment for neurogenic and idiopathic overactive bladder (OAB). In animal experiments, intradetrusor BoNTA injections have been shown to cause apoptosis in the bladder urothelium and suburothelium but not the detrusor.

Objective

To investigate BoNTA-induced apoptosis in patients with refractory neurogenic OAB.

Design, setting, and participants

Twelve refractory OAB patients with neurogenic detrusor overactivity resulting from multiple sclerosis (MS) and seven controls were included prospectively.

Measurements

The number of apoptotic cells before and 4 wk after first intradetrusor BoNTA (300 U of BOTOX [Allergan, Irvine, CA, USA]) injections were estimated using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) staining.

Results and limitations

Comparison of TUNEL-positive cells (yes vs no) in the bladder urothelium and suburothelium revealed no significant differences in OAB patients before (4 of 12, 33%) versus after (3 of 12, 25%) BoNTA treatment (p = 0.99). In addition, no significant differences (p = 0.99) were found in OAB patients versus controls. Because our findings are based on first intradetrusor BoNTA injections only, it is unclear whether the results could be extrapolated to repeat injections.

Conclusions

In contrast to preliminary animal experiments, first intradetrusor BoNTA injections for treating refractory neurogenic OAB—a highly effective treatment—did not induce apoptosis in the bladder urothelium and suburothelium.     

Solifenacin Plus Tamsulosin Combination Treatment in Men With Lower Urinary Tract Symptoms and Bladder Outlet Obstruction: A Randomized Controlled Trial

Background

Alpha blockers are prescribed to manage lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Antimuscarinics are prescribed to treat overactive bladder (OAB).

Objective

To investigate the safety of a combination of solifenacin (SOLI) and tamsulosin oral controlled absorption system (TOCAS) in men with LUTS and bladder outlet obstruction (BOO).

Design, setting, and participants

Randomized, double-blind, parallel-group, placebo-controlled study in men aged >45 yr with LUTS and BOO for ≥3 mo, total International Prostate Symptom Score (IPSS) ≥8, BOO index ≥20, maximum urinary flow rate (Q_max) ≤12 ml/s, and voided volume ≥120 ml.

Interventions

Once-daily coadministration of TOCAS 0.4 mg plus SOLI 6 mg, TOCAS 0.4 mg plus SOLI 9 mg, or placebo for 12 wk.

Outcome measurements and statistical analysis

Primary (safety) measurements: Q_max and detrusor pressure at Q_max (P_detQ_max). Other safety assessments included postvoid residual (PVR) volume. Secondary end points included bladder contractile index (BCI) score and percent bladder voiding efficiency (BVE). An analysis of covariance model compared each TOCAS plus SOLI combination with placebo.

Results and limitations

Both active treatment groups were noninferior to placebo at end of treatment (EOT) for P_detQ_max and Q_max. Mean change from baseline PVR was significantly higher at all time points for TOCAS 0.4 mg plus SOLI 6 mg, and at weeks 2, 12, and EOT for TOCAS 0.4 mg plus SOLI 9 mg versus placebo. Both treatment groups were similar to placebo for BCI and BVE. Urinary retention was seen in only one patient receiving TOCAS 0.4 mg plus SOLI 6 mg. Limitations of the study were that prostate size and prostate-specific antigen level were not measured.

Conclusions

TOCAS 0.4 mg plus SOLI 6 mg or 9 mg was noninferior to placebo at EOT for P_detQ_max and Q_max in men with LUTS and BOO, and there was no clinical or statistical evidence of increased risk of urinary retention.     

Developing and Validating the International Consultation on Incontinence Questionnaire Bladder Diary

Background

Despite the common use of urinary diaries to assess lower urinary tract symptoms (LUTS), a standardised validated diary does not exist.

Objective

To develop a validated urinary diary, using the psychometric validation protocol used in previous International Consultation on Incontinence Questionnaire (ICIQ) modules.

Design, setting, and participants

We invited 400 consecutive patients attending the urology department for assessment of LUTS to complete a urinary diary (developed and validated for content in a previous study), and the ICIQ Male or Female LUTS questionnaire.

Outcome measurements and statistical analysis

To establish construct validity, the urinary diary was compared with known theories from published literature; to establish criterion validity, the diary was compared with questionnaire responses and/or urodynamic observations. Optimal diary duration was tested by comparing the 4-d diary against shorter durations. Patients completed a second diary after 2–3 wk for test-retest analysis, and a subset receiving sacral nerve stimulation completed the diary before and after treatment for analysis of responsiveness. A variety of statistical tests were used for different stages of the study.

Results and limitations

The urinary diaries and ICIQ LUTS questionnaires were completed by 264 patients. Construct validity was established for two of three tested hypotheses. Criterion testing showed good agreement between questionnaire and diary recordings of nocturia (κ = 0.653; p < 0.001; 92.2%) and incontinence (κ = 0.351; p < 0.001; 64.5%), whereas good agreement (κ = 0.378; p < 0.001; 69.2%) was observed between urodynamically proven incontinence and diary reports (n = 104). Diary recordings of urgency showed weak agreement with questionnaire responses (κ = −0.215; p < 0.001; 36%) and urodynamic observations (κ = −0.105; p = 0.256; 43.7%). The 3-d diary explained at least 94% of the total variance of the 4-d diary. A second diary for test-retest analysis was returned by 59 patients, demonstrating fair to excellent agreement (Spearman correlations: 0.49–0.88). Pre- and post-treatment analysis, on pilot testing, showed that the diary is responsive to change.

Conclusions

Using the ICIQ psychometric validation methodology, a bladder diary was developed for the assessment of LUTS and shown to be valid, reliable, and responsive to change. The 3-d diary has been accepted as the ICIQ bladder diary.

Patient summary

In this study, patients and clinicians developed and tested a diary in which patients can record their urinary symptoms. The resulting 3-d diary is called the ICIQ bladder diary and is available for adult men and women with urinary symptoms.     

Efficacy and Safety of Solifenacin Plus Tamsulosin OCAS in Men with Voiding and Storage Lower Urinary Tract Symptoms: Results from a Phase 2, Dose-finding Study (SATURN)

Background

Storage symptoms are often undertreated in men with lower urinary tract symptoms (LUTS).

Objective

To evaluate the combination of an antimuscarinic (solifenacin) with an α-blocker (tamsulosin) versus tamsulosin alone in the treatment of men with LUTS.

Design, setting, and participants

A double-blind, 12-wk, phase 2 study in 937 men with LUTS (≥3 mo, total International Prostate Symptom Score [IPSS] ≥13, and maximum urinary flow rate 4.0–15.0 ml/s).

Intervention

Eight treatment groups: tamsulosin oral controlled absorption system (OCAS) 0.4 mg; solifenacin 3, 6, or 9 mg; solifenacin 3, 6 or 9 mg plus tamsulosin OCAS 0.4 mg; or placebo.

Outcome measurements and statistical analysis

The primary efficacy end point was change from baseline in total IPSS. Secondary end points included micturition diary and quality-of-life (QoL) parameters. Post hoc subgroup analyses were performed by severity of baseline storage symptoms, with statistical comparisons presented only for tamsulosin OCAS alone versus combination therapy, due to the small sample size of the solifenacin monotherapy and placebo subgroups.

Results and limitations

Combination therapy was associated with significant improvements in micturition frequency and voided volume versus tamsulosin OCAS alone in the total study population; improvements in total IPSS were not significant. Statistically significant improvements in urgency episodes, micturition frequency, total urgency score, voided volume, IPSS storage subscore, IPSS-QoL index, and Patient Perception of Bladder Condition were observed in a subpopulation of men with two or more urgency episodes per 24 h (Patient Perception of Intensity of Urgency Scale grade 3 or 4) and eight or more micturitions per 24 h at baseline (storage symptoms subgroup) with combination therapy versus tamsulosin OCAS alone (p ≤ 0.05 for the dose–response slope, all variables). Combination therapy was well tolerated, and adverse events were consistent with the safety profiles of both compounds.

Conclusions

Solifenacin plus tamsulosin OCAS did not significantly improve IPSS in the total study population but offered significant efficacy and QoL benefits over tamsulosin OCAS monotherapy in men with both voiding and storage symptoms at baseline. Combination therapy was well tolerated.

ClinicalTrials.gov identifier

NCT00510406     

Systematic Review and Meta-analysis of Candidate Gene Association Studies of Lower Urinary Tract Symptoms in Men

Context

Although family studies have shown that male lower urinary tract symptoms (LUTS) are highly heritable, no systematic review exists of genetic polymorphisms tested for association with LUTS.

Objective

To systematically review and meta-analyze studies assessing candidate polymorphisms/genes tested for an association with LUTS, and to assess the strength, consistency, and potential for bias among pooled associations.

Evidence acquisition

A systematic search of the PubMed and HuGE databases as well as abstracts of major urologic meetings was performed through to January 2013. Case-control studies reporting genetic associations in men with LUTS were included. Reviewers independently and in duplicate screened titles, abstracts, and full texts to determine eligibility, abstracted data, and assessed the credibility of pooled associations according to the interim Venice criteria. Authors were contacted for clarifications if needed. Meta-analyses were performed for variants assessed in more than two studies.

Evidence synthesis

We identified 74 eligible studies containing data on 70 different genes. A total of 35 meta-analyses were performed with statistical significance in five (ACE, ELAC2, GSTM1, TERT, and VDR). The heterogeneity was high in three of these meta-analyses. The rs731236 variant of the vitamin D receptor had a protective effect for LUTS (odds ratio: 0.64; 95% confidence interval, 0.49–0.83) with moderate heterogeneity (I² = 27.2%). No evidence for publication bias was identified. Limitations include wide-ranging phenotype definitions for LUTS and limited power in most meta-analyses to detect smaller effect sizes.

Conclusions

Few putative genetic risk variants have been reliably replicated across populations. We found consistent evidence of a reduced risk of LUTS associated with the common rs731236 variant of the vitamin D receptor gene in our meta-analyses.

Patient summary

Combining the results from all previous studies of genetic variants that may cause urinary symptoms in men, we found significant variants in five genes. Only one, a variant of the vitamin D receptor, was consistently protective across different populations.     

A Randomized Double-blind Placebo-controlled Phase 2 Dose-ranging Study of OnabotulinumtoxinA in Men with Benign Prostatic Hyperplasia

Background

Botulinum toxin treatment has been investigated as a minimally invasive alternative to oral medications in men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (LUTS/BPH).

Objective

To explore the efficacy of onabotulinumtoxinA 100 U, 200 U, and 300 U versus placebo in men with LUTS/BPH in a phase 2 dose-ranging study.

Design, setting, and participants

A multicenter double-blind randomized, placebo-controlled 72-wk study enrolled men ≥50 yr of age with LUTS/BPH, International Prostate Symptom Score (IPSS) ≥12, total prostate volume (TPV) 30–100 ml, and maximum flow rate (Q_max) 5–15 ml/s.

Intervention

Single transperineal (n = 63) or transrectal (n = 311) administration of placebo (n = 94) or onabotulinumtoxinA 100 U (n = 95), 200 U (n = 94), or 300 U (n = 97) into the prostate transition zone.

Outcome measurements and statistical analysis

The primary efficacy end point was a change from baseline in IPSS at week 12. Secondary end points were Q_max, TPV, and transition zone volume (TZV). Analysis of covariance and the Cochran-Mantel-Haenszel method assessed the efficacy and proportion of IPSS responders. Adverse events (AEs) were assessed.

Results and limitations

Significant improvements from baseline in IPSS, Q_max, TPV, and TZV were observed for all groups, including placebo, at week 12 (p < 0.001), with no significant differences between onabotulinumtoxinA and placebo. However, in an exploratory post hoc analysis, a significant reduction in IPSS versus placebo was observed with onabotulinumtoxinA 200 U in prior α-blocker users (n = 180) at week 12. AEs were comparable across all groups.

Conclusions

Reductions in LUTS/BPH symptoms were seen in all groups, including placebo, with no significant between-group differences owing to a large placebo effect from the injectable therapy. The findings from the post hoc analysis in men previously treated with α-blockers will be further explored in an appropriately designed study.

Trial registration

http://www.Clinical Trials.gov; NCT00284518.