Combination treatment with mirabegron and solifenacin in patients with overactive bladder: exploratory responder analyses of efficacy and evaluation of patient-reported outcomes from a randomized, double-blind, factorial, dose-ranging, Phase II study (SYMPHONY).

PURPOSE: This large dose-ranging study explored the benefits of different combinations of mirabegron and solifenacin on health-related quality of life (HRQoL), based on patient-reported outcomes (PROs), and patients ('responders') achieving clinically meaningful improvements in efficacy and HRQoL. METHODS: SYMPHONY (NCT01340027) was a Phase II, placebo- and monotherapy-controlled, dose-ranging, 12-week trial. Adult patients with overactive bladder (OAB) for ≥3 months were randomized to 1 of 12 groups: 6 combination (solifenacin 2.5/5/10 mg + mirabegron 25/50 mg), 5 monotherapy (solifenacin 2.5/5/10 mg, or mirabegron 25/50 mg), or placebo. Change from baseline to end of treatment was assessed, versus placebo and solifenacin 5 mg in: PROs (OAB-q [Symptom Bother/total HRQoL] and Patient Perception of Bladder Condition score), and responders achieving minimally important differences (MIDs) in PROs and predetermined clinically meaningful improvements in efficacy (e.g. <8 micturitions/24 h). Changes in PROs and responders were analysed using an ANCOVA model and logistic regression, respectively. RESULTS: The Full Analysis Set included 1278 patients. Combination therapy of solifenacin 5/10 mg + mirabegron 25/50 mg significantly improved PROs versus solifenacin 5 mg and placebo, and significantly more responders achieved MIDs in PROs and efficacy. Micturition frequency normalization was approximately twofold greater with 10 + 25 mg (OR 2.06 [95 % CI 1.11, 3.84; p = 0.023]) and 5 + 50 mg (OR 1.91 [95 % CI 1.14, 3.21; p = 0.015]) versus solifenacin 5 mg. CONCLUSION: Combining mirabegron 25/50 mg and solifenacin 5/10 mg improves objective and subjective efficacy outcomes compared with placebo or solifenacin 5 mg.

Clinical safety, tolerability and efficacy of combination tolterodine/pilocarpine in patients with overactive bladder.

AIMS: The purpose of this study was to assess the safety, tolerability and impact on overactive bladder (OAB) symptoms of a novel combination of tolterodine immediate-release (IR) 2 mg and delayed-release pilocarpine 9 mg in patients with OAB. METHODS: Eligible patients with OAB were randomised to each of three treatments [tolterodine/pilocarpine (2/9 mg), tolterodine IR 2 mg or placebo] twice daily for 4 weeks in a double-blind, crossover fashion. At the end of the 12-week, double-blind treatment period, patients could enter an open-label extension during which they were re-randomised to either tolterodine/pilocarpine (3/13.5 mg) twice daily or tolterodine extended-release 4 mg once daily for 12 weeks. RESULTS: A total of 138 patients were randomised to double-blind medication. Both tolterodine/pilocarpine (2/9) and tolterodine IR 2 mg significantly reduced incontinence episodes and daily micturitions (p < 0.001 vs. placebo), with similar reductions in symptoms observed between active treatment groups. Tolterodine/pilocarpine (2/9) was associated with consistently lower Visual Analogue Scale (VAS) scores for all dry mouth parameters compared with tolterodine alone. Salivary flow over a 3 h period remained fairly constant after tolterodine/pilocarpine (2/9) administration, similar to placebo, but decreased markedly after administration of tolterodine alone. In the extension study, patients receiving tolterodine/pilocarpine (3/13.5) reported comparable dry mouth VAS scores to tolterodine extended-release alone without additional side effects or loss of efficacy. The combination was well tolerated, and the adverse effects observed were consistent with the known safety profiles of tolterodine and pilocarpine. CONCLUSIONS: A combination of tolterodine/pilocarpine (2/9) effectively reduced the incidence of dry mouth compared with tolterodine IR alone while maintaining treatment efficacy in OAB.

A reappraisal of storage and voiding dysfunction.

Lower urinary tract symptoms are common in women. They may be more broadly classified into storage and voiding disorders. Recent literature has focussed on the management of voiding dysfunction and the spectrum of symptoms presented by women with such disorders. Symptoms of voiding dysfunction and storage symptoms may coexist, making diagnosis and management even more challenging. The purpose of this paper is to review the literature regarding the definition and management of voiding dysfunction with and without associated storage symptoms.

Oxybutynin topical and transdermal formulations: an update.

Oxybutynin, an antimuscarinic agent, is well established for the treatment of overactive bladder (OAB) and is the gold standard for the treatment of severe neurogenic bladder. Although oral oxybutynin is effective in relieving the urinary symptoms of OAB, medication adherence is low at least in part because of substantial anticholinergic adverse effects. The poor anticholinergic tolerability has been attributed to high circulating levels of N-desethyloxybutynin (DEO), a pharmacologically active product of presystemic metabolism of oral oxybutynin in the liver and gastrointestinal tract. Transdermal formulations of oxybutynin avoid first-pass metabolism and thereby produce lower DEO plasma concentrations. Oxybutynin chloride topical gel (OTG) (Gelnique(R), Watson Pharmaceuticals, Corona, CA, USA), a new gel-based transdermal formulation of oxybutynin, was approved by the U.S. Food and Drug Administration in January 2009. Results of a placebo-controlled U.S. phase III study demonstrated that OTG is efficacious in relieving symptoms of OAB and is associated with a low incidence of anticholinergic adverse events. Patients may find that OTG, with its excellent efficacy, convenient once-daily application and outstanding tolerability profile, is a valuable alternative to oral antimuscarinic agents for the treatment of OAB.

Trospium chloride has no effect on memory testing and is assay undetectable in the central nervous system of older patients with overactive bladder.

BACKGROUND: Muscarinic receptors in the brain play an important role in cognitive function, especially memory, and there is growing awareness that specific antimuscarinic drugs for overactive bladder (OAB) may have adverse central nervous system (CNS) effects. Selection of an antimuscarinic OAB drug with reduced potential for CNS effects could be especially beneficial in the elderly people, in whom even the modest cognitive impairment may negatively affect independence. PURPOSE: The purpose of the study is to determine if trospium chloride is assay detectable in the CNS of older adults with OAB and to assess whether deterioration of memory occurs in these individuals. METHODS: Twelve cognitively intact older adults (>or=65-75 years old) with OAB were given extended-release trospium chloride 60 mg once daily over a 10-day period to achieve plasma steady-state levels. Standardised memory testing (Hopkins Verbal Learning Test-Revised and Brief Visuospatial Memory Test-Revised) was performed predose and postdose. Cerebrospinal spinal fluid (CSF) and plasma samples were drawn on day 10 and assayed for trospium chloride. Predose (day 0) and postdose (day 10) results on the memory tests were compared using a reliable change index to assess a meaningful change in learning or memory. RESULTS: Trospium chloride levels in all the CSF samples (n = 72) of all participants were assay undetectable (<40 pg/ml) on day 10 at steady-state peak plasma concentration concurrent with measureable peak plasma values (C(max) = 925 pg/ml). Repeat memory testing revealed no significant net drug effect on learning or recall. CONCLUSIONS: This is the first study to investigate for the presence of an OAB antimuscarinic in the human brain, performed by assaying for concentrations of trospium chloride and correlating with simultaneous clinical cognitive safety measures. The results of both pharmacological and neuropsychological testing support the hypothesis of a lack of detectable CNS penetration for the quaternary amine trospium chloride.

STEP: simplified treatment of the enlarged prostate.

We propose a simple and practical approach to the identification, evaluation and treatment of lower urinary tract symptoms (LUTS) resulting from an enlarging and obstructive prostate. The proposed Simplified Treatment for Enlarged Prostate (STEP) plan is a logical guide to patient management by the primary care provider (PCP). Symptoms of enlarged prostate (EP) are common and may frequently progress into a condition with profound adverse effects on quality of life. Despite the high prevalence, EP is underdiagnosed and undertreated. This situation may result from patient- and provider-related issues. Assessment of symptoms of EP should be initiated with a discussion of LUTS. Evaluation includes a focused history, physical examination and selected laboratory tests. Certain factors put the symptomatic patient at risk for disease progression; however, not all factors can be readily evaluated in the PCP setting. The serum prostate-specific antigen (PSA) level acts both as an indicator of prostatic size and a screening tool for prostatic cancer, and thereby provides an important tool for PCPs. The STEP plan is a logical guide to patient management. Step 1, watchful waiting, is appropriate in patients with symptoms that are not bothersome. If symptoms cause bother, the initiation of an alpha-blocker (AB) in step 2, provides relatively rapid symptom improvement. Patients with bothersome symptoms and a PSA > or = 1.5 ng/ml are at risk for progression and consideration should be given to combination treatment with an AB and a 5alpha-reductase inhibitor (step 3). Patients with refractory symptoms should be referred to a urologist (step 4). Identification, evaluation and management of EP are within the domain of the primary care setting. The STEP approach provides a simple and practical framework for PCPs to manage most men with symptoms of EP.

Urinary urgency - translating the evidence base into daily clinical practice.

AIM: To consider the currently available knowledge and understanding of the symptom of urgency. MATERIALS & METHODS: Each faculty member reviewed the literature base of a different aspect of urgency and along with their personal clinical experience provided a base of evidence for discussion. RESULTS: This overview summarises relevant published literature and the current clinical experience of the authors. DISCUSSION: Whilst the mechanisms producing the sensation of urgency are still not fully understood and we are working within a definition that may complicate measurement and treatment, our pressing need is to effectively manage our patients for whom the practical nature of urgency can be all too apparent. CONCLUSION: Health care professionals have an important role to play today in helping to alleviate the widespread problem of urgency and its consequences.

Trospium chloride once-daily extended release is effective and well tolerated for the treatment of overactive bladder syndrome: an integrated analysis of two randomised, phase III trials.

BACKGROUND: Trospium chloride is an antimuscarinic agent with a hydrophilic polar quaternary amine structure that is minimally metabolised by hepatic cytochrome P450 and is actively excreted in the urine, each of which confers a potential benefit with regard to efficacy and tolerability. PURPOSE: We analysed pooled data from two identically designed phase III trials of a once-daily, extended-release (XR) formulation of trospium chloride (trospium XR 60-mg capsules) in subjects with overactive bladder syndrome (OAB). METHODS: Adults with OAB of > or = 6 months' duration with urinary urgency, frequency and > or = 1 urge urinary incontinence (UUI) episode/day were enrolled in these multicentre, parallel-group, double-blind trials. Participants were randomised (1 : 1) to receive trospium XR 60 mg or placebo for 12 weeks. Primary efficacy variables were changes in urinary frequency and the number of UUI episodes/day. Adverse events (AEs) were recorded throughout. RESULTS: In total, 1165 subjects were randomised (trospium XR, 578; placebo, 587). At baseline, subjects averaged 12.8 toilet voids/day and 4.1 UUI episodes/day. Compared with placebo, subjects treated with trospium XR had significantly greater reductions from baseline in the mean number of toilet voids/day (-1.9 vs. -2.7; p < 0.001) and UUI episodes/day (-1.8 vs. -2.4; p < 0.001) at week 12. The most frequent AEs considered possibly related to study treatment were dry mouth (trospium XR, 10.7%; placebo, 3.7%) and constipation (trospium XR, 8.5%; placebo, 1.5%). Notably, rates of central nervous system (CNS) AEs were lower with trospium XR vs. placebo (dizziness: 0.2% vs. 1.0%; headache: 1.4% vs. 2.4%). CONCLUSIONS: Treatment with trospium XR resulted in statistically significant improvements in both of the dual primary and all of the secondary outcome variables. Trospium XR demonstrated favourable rates of AEs, particularly CNS AEs (numerically lower than with placebo) and dry mouth (lower than previously reported with trospium immediate-release, although not compared in a head-to-head study).

Baseline incontinence severity is predictive of the percentage of patients continent after receiving once-daily trospium chloride extended release.

OBJECTIVE: It has been assumed that a patient's underlying baseline overactive bladder (OAB) incontinence severity is predictive of the resulting efficacy of pharmacological treatment. The objective of this study was to stratify and analyse the effects of baseline incontinence disease severity on the treatment outcome of the percentage of patients continent (PPC) during treatment with once-daily trospium chloride 60 mg extended release (XR). METHODS: A post hoc analysis was conducted on pooled data from two 12-week, randomised, double-blind phase III studies in the USA in which 1165 patients with baseline urgency, and an average of >or= 1 urge urinary incontinence (UUI) episode/day and >or= 10 toilet voids/day on a 3-day bladder diary, received once-daily trospium chloride 60 mg XR (n = 578) or placebo (n = 587). Patients were stratified by the mean number of UUIs/day (1.0, > 1.0-2.0, > 2.0-5.0 or > 5.0) at baseline. The efficacy parameter that was analysed was complete continence (defined as no UUIs on a 3-day bladder diary collected at week 12 of treatment). RESULTS: Baseline UUI levels were inversely correlated with the week 12 PPC (p < 0.0001). Post-treatment PPCs were higher with trospium chloride XR vs. placebo at all degrees of severity. Complete continence was achieved in 75% of trospium chloride XR recipients with 1.0 UUI/day at baseline and 48% of those with > 1.0-2.0 UUIs/day at baseline. CONCLUSIONS: These findings support the assumption that baseline incontinence severity affects the likelihood of achieving continence from OAB therapy, and that patients with less severe OAB (e.g. 1 UUI/day) can expect higher 'dry rates' following treatment (e.g. up to 75%) than those with more severe OAB. This information can provide a useful tool for the physician and patient in establishing expectations during therapy.

Effects of oxybutynin transdermal system on health-related quality of life and safety in men with overactive bladder and prostate conditions.

AIMS: Overactive bladder (OAB) is common in men and may exist concomitantly with benign prostatic hyperplasia (BPH) and obstruction. We present a subanalysis of results from men with OAB in a 6-month, open-label study of treatment with the oxybutynin transdermal system (OXY-TDS). Broad entry criteria were incorporated to yield a clinically representative population. METHODS: All participants received OXY-TDS 3.9 mg/day. Effectiveness was assessed by changes in scores on validated questionnaires, which included the single-item Patient Perception of Bladder Condition (PPBC), the King's Health Questionnaire (KHQ) and the Beck Depression Inventory-II (BDI-II). RESULTS: The proportion of men (n=369; mean age=69.6 years) who reported that their bladder condition caused moderate, severe or many severe problems (PPBC>or=4) improved from 77.3% at baseline to 38.1-53.6% in subsequent months. Mean KHQ scores decreased significantly (p12 (associated with a diagnosis of depression) decreased from 23.9% to 17.9% (p=0.0055). Men with a history of 'prostate problems' or use of 'BPH medication' (32.2%) had KHQ domain changes that were similar (p>or=0.1016) to those of other men. Most men (76.2%) reported no treatment-related adverse events; two men (0.5%) experienced symptoms of mild urinary retention, but neither required catheterisation. CONCLUSIONS: Oxybutynin transdermal system treatment of men with OAB was effective and well tolerated, regardless of history of prostate condition.

A practical guide to the evaluation and treatment of male lower urinary tract symptoms in the primary care setting.

AIMS: Lower urinary tract symptoms (LUTS) are common in both men and women, and are among the most prevalent patient complaints heard by primary care physicians (PCPs). This article aims to provide PCPs with a logical algorithm for the assessment and initiation of treatment for LUTS in the male patient. RESULTS: Management of LUTS involves a focused history and physical, as well as the assessment of bother. In patients for whom treatment is warranted, a series of decisions regarding therapy should be considered. Male patients commonly suffer from storage and/or voiding symptoms. Treatment of male LUTS is commonly begun with agents that are aimed at remedying the outlet symptoms of benign prostatic hyperplasia (BPH). When this intervention is ineffective or when refractory symptoms persist, consideration should be given to treating the storage symptoms characteristic of overactive bladder (OAB). DISCUSSION: This article is intended to provide the PCP with a logical guide to the treatment of male LUTS. Benign prostatic hyperplasia and OAB predominate among the causes of these symptoms, and the PCP should be comfortable treating each. Recent data detailing the safety of the use of these treatments in the male patient are reviewed and incorporated into the algorithm. CONCLUSION: Primary care physicians are in a unique position to successfully identify and treat male patients with LUTS. With this paper, they now have a tool to approach treatment logically and practically.

In vivo comparison of suburethral sling materials.

In vivo tissue responses were compared for three commercially available polypropylene suburethral slings that differ markedly in fabric structure and in size of resulting interstices and pores. All three elicited the same basic inflammatory response; however, individual fabric structures produced distinct differences in tissue formation within each mesh. The presence of numerous, closely spaced, small diameter filaments prevented formation of extensive fibrous connective tissue within two slings (ObTape and IVS Tunneller mesh). The much larger diameter monofilament and open knit structure of the Monarc sling permitted the most extensive fibrous tissue integration. These differences may be of interest to physicians considering clinical use.

Prospective randomized controlled trial of extended-release oxybutynin chloride and tolterodine tartrate in the treatment of overactive bladder: results of the OBJECT Study.

OBJECTIVE: To compare the efficacy and tolerability of extended-release oxybutynin chloride and tolterodine tartrate at 12 weeks in participants with overactive bladder. SUBJECTS AND METHODS: The OBJECT (Overactive Bladder: Judging Effective Control and Treatment) study was a prospective, randomized, double-blind, parallel-group study conducted between March and October 2000 at 37 US study sites. Participants who had between 7 and 50 episodes of urge incontinence per week and 10 or more voids in 24 hours received extended-release oxybutynin, 10 mg/d, or tolterodine, 2 mg twice daily. The outcome measures were the number of episodes of urge incontinence, total incontinence, and micturition frequency at 12 weeks adjusted for baseline. RESULTS: A total of 315 women and 63 men were randomized and treated, and 332 participants (276 women, 56 men) completed the study. At the end of the study, extended-release oxybutynin was significantly more effective than tolterodine in each of the main outcome measures: weekly urge incontinence (P=.03), total incontinence (P=.02), and micturition frequency episodes (P=.02) adjusted for baseline. Both drugs improved symptoms of overactive bladder significantly from baseline to the end of the study as assessed by the 3 main outcome measures (P<.001). Dry mouth, the most common adverse event, was reported by 28.1% and 33.2% of participants taking extended-release oxybutynin and tolterodine, respectively (P=.32). Rates of central nervous system and other adverse events were low and similar in both groups. CONCLUSIONS: Extended-release oxybutynin was more effective than tolterodine as measured by end-of-study urge incontinence, total incontinence, and micturition frequency episodes. Both groups had similar rates of dry mouth and other adverse events.

Hydronephrosis and renal deterioration in the elderly due to abnormalities of the lower urinary tract and ureterovesical junction.

The geriatric population presents a unique challenge to the health care provider. The incidence of common lower urinary tract disorders, such as benign prostatic hypertrophy (BPH), prostate cancer and incontinence increase dramatically with aging. In their more severe forms, these disorders may predispose to hydronephrosis and ultimately to renal deterioration. This review of lower urinary tract and ureterovesical junction (UVJ) physiology and pathophysiology, will focus on: (1) anatomic UVJ obstruction from prostate cancer, or severe bladder hypertrophy, (2) functional obstruction from compression or stretching of the UVJ during bladder distention from urinary retention, and (3) bladder decompensation in the female. We will present a diagnostic and treatment algorithm and discuss future trends in the geriatric population. Clearly, the geriatric health care provider always must consider the lower urinary tract when confronted with acute renal deterioration, because prompt diagnosis and treatment of significant, lower-urinary-tract disease can maximize recovery of renal function.

Gore-Tex patch sling: 7 years later.

OBJECTIVES: To assess the long-term results of a transvaginal endoscopic Gore-Tex patch sling in women with genuine stress urinary incontinence due to urethral hypermobility and/or intrinsic sphincter deficiency, with or without coexistent urge incontinence. METHODS: Between December 1989 and June 1994, we performed a Gore-Tex patch sling procedure in 141 consecutive women. All patients had documented stress urinary incontinence on preoperative videourodynamic testing. We conducted outcomes analysis using the information from postoperative office visits, detailed chart reviews, patient questionnaires, and telephone surveys. RESULTS: A complete follow-up was available in 90 patients. The mean follow-up was 51 months (range 27 to 84). Their mean age was 54.2 years (range 32 to 86). Stress incontinence was completely cured in 80 (88.9%) of 90 patients. Pure stress incontinence persisted in 4 (4.4%) of 90 patients. Mixed incontinence occurred in 6 (6.7%) of 90 patients. Pure urge incontinence was experienced by 16 (17.8%) of 90 patients. Six patients required incision of the Gore-Tex patch for obstruction or retention; 3 remain continent. Five patients developed vaginal granulation tissue requiring Gore-Tex patch removal; 1 remains continent. There was no bladder or urethral erosion. CONCLUSIONS: The transvaginal Gore-Tex patch sling has provided durable efficacy with minimal morbidity for the treatment of stress urinary incontinence due to anatomic urethral hypermobility and/or intrinsic sphincter deficiency.

Effect of a urinary control insert on quality of life in incontinent women.

The aim of the study was to evaluate the efficacy, safety and effect on quality of life of the Reliance urinary control insert (Uromed Corp., Needham, MA) in women with genuine stress incontinence. Efficacy was evaluated at baseline and at the end of the 12-month study period by standardized pad-weight studies and by rating scales measuring acceptability, incontinence symptom improvement, ease of learning, comfort and time to habituation, recorded in diaries at monthly intervals in 63 women. The SF-36 Health Survey questionnaire was used to assess quality of life status at baseline without the device and after 12 months of device use. A significant decrease in urine loss at 12 months compared with baseline was shown by standardized pad-weight studies, with and without the device in situ. Urine loss was reduced by more than 80% in 91% of the 63 patients, and 79% were completely dry. Patient diaries showed significant improvement in control of leakage, comfort, and ease of device use during the study period. Short-term-36 Health Status data also indicated significant improvement in the physical functioning score at 12 months. Urinary tract infection and hematuria were the most common adverse effects. The Reliance urinary control insert is an efficacious and safe means of controlling genuine stress incontinence in women. The device was perceived as easy to use and comfortable for these 63 women, and resulted in improved quality of life.

A provocative maneuver to elicit cystometric instability: measuring instability at maximum infusion.

PURPOSE: We identify a provocative maneuver to enhance the sensitivity of cystometry in detecting detrusor instability when urge incontinence is suspected based on clinical history. MATERIALS AND METHODS: A total of 134 consecutive women with clinical urge incontinence underwent carbon dioxide cystometry between August 1995 and October 1996. The bladder was filled to maximal capacity with the patient supine. Six provocative maneuvers were performed consecutively to evoke detrusor instability, including lying supine, rising to a seated position, walking toward the bathroom, handwashing, coughing and sitting on the toilet with instructions not to void. Subjects were divided into 2 groups depending on the order of maneuvers. Sitting on the toilet was the last maneuver for group 1 (80 patients) and was in the middle of the sequence for group 2 (54). RESULTS: Sitting on the toilet evoked detrusor instability in 37.5% of group 1 and 53.8% of group 2. This maneuver with instructions not to void was the most provocative stimulus in eliciting detrusor instability with a detection rate of 68.4% for all subjects. CONCLUSIONS: Sitting on the toilet with the bladder at maximal capacity is the most provocative maneuver for detecting detrusor instability. The incidence of suspected detrusor instability is enhanced by using this test during routine cystometry.