Complications of Synthetic Midurethral Slings: Is There a Relevant Discrepancy Between Observational Data and Clinical Trials?

CONTEXT: The complications of synthetic midurethral slings (MUSs) in women with stress urinary incontinence (SUI) have become a globally debated issue. OBJECTIVE: To systematically review the short- and long-term complications of mesh slings reported in observational data compared with clinical trial data, to determine whether the complication rates from clinical trials reflects "real-world" observational data. EVIDENCE ACQUISITION: PubMed and Cochrane Library were searched. Methods as detailed in Preferred Reporting Items for Systematic Reviews and Meta-analyses and Cochrane Handbook for Systematic Reviews of Interventions were followed. EVIDENCE SYNTHESIS: Thirty registries/databases including 709 335 MUS procedures (1-22 yr of follow-up) were identified. MUS procedures were associated with intraoperative bladder perforation in 0.86-3.6%, urethral perforation in 0-0.1%, vascular injury in 0.04-0.1%, voiding lower urinary tract symptoms (LUTS) in 1.47-3.5%, vaginal exposure in 0.2-1.9%, and reoperation in up to 9% of cases. Forty-three randomised clinical trials were identified, including 6284 women who underwent MUS procedures and 2177 women who underwent other interventions (1-10 yr of follow-up). MUS procedures were associated with urinary tract perforation in 2.58%, vaginal injury in 1.43%, de novo voiding LUTS in 4.37%, de novo storage LUTS in 5.41%, mesh extrusion/exposure (vaginal/urinary tract) in 2.54%, dyspareunia in 2.26%, pain (pelvic/suprapubic/perineal) in 2.83%, and reoperation for complications required in 1.82% of cases. Meta-analyses of the randomised controlled trials revealed that retropubic MUSs were associated with more events of urinary tract perforation (risk ratio [RR] 9.81, 95% confidence interval [CI] 5.05-19.04, high certainty of evidence [COE]) and voiding LUTS (RR 1.57, 95% CI 1.19-2.07, high COE) than transobturator MUSs. MUSs were associated with more events of pain than mini-slings (RR 1.72, 95% CI 1.04-2.87, moderate COE). CONCLUSIONS: Short- and long-term data on complications of polypropylene mesh used for female SUI are fairly comparable when using outcome data from well-designed clinical trials or from less structured prospective or retrospective registries. Comparisons have to be made with caution since the two systems of data collection are inherently incomparable. This knowledge should be incorporated in the discussion on how to implement polypropylene mesh for female stress incontinence. PATIENT SUMMARY: In order to know whether mesh tapes used for treating stress incontinence work well and are safe, high-quality information is important. It appears that well-designed clinical studies give similar results to large registration databases. These data should be interpreted with caution in view of the different ways the information was collected. These results will help physicians and patients understand the risks of mesh tapes.

Functional and radioligand binding characterization of the α1L-adrenoceptor subtype of the human vas deferens.

Alpha1 -adrenoceptor antagonists can cause ejaculatory dysfunction as an adverse effect. Contractions of the human vas deferens are mediated via α1A -adrenoceptors, and this study investigated whether the low affinity state of this receptor (α1L -adrenoceptor) is involved in mediating contractions of this tissue. The potency of agonists and the affinity of receptor subtype selective antagonists were determined in functional experiments and in [(3) H]tamsulosin binding experiments to identify the α1 -adrenoceptor subtype population present in the human vas deferens. The α1A -adrenoceptor selective agonist A61603 was a full agonist and was 250-fold more potent than noradrenaline. Prazosin antagonized contractile responses to phenylephrine with a low affinity (pKd = 8.6). Only high concentrations of RS17053 antagonized responses to phenylephrine and yielded a relatively low affinity estimate of 7.0. BMY7378 (α1D -adrenoceptor selective) gave a low affinity estimate (pKd = 6.7), whilst tamsulosin (α1A - and α1D -adrenoceptor selective) had a high affinity (pKd = 9.9). [(3) H]Tamsulosin bound to human vas deferens membranes with a high affinity (pKd = 10.0). Prazosin, RS17053 and BMY7378 competed with [(3) H]tamsulosin with low affinities for a single population of binding sites (pKd values of 8.5, 7.2 and 6.3, respectively). These functional and radioligand binding data indicate that the human vas deferens possesses a homogeneous population of α1 -adrenoceptors which have the pharmacological properties of the putative α1L -adrenoceptor, the same functional receptor previously identified in the human prostate.

The effect of mirabegron on patient-related outcomes in patients with overactive bladder: the results of post hoc correlation and responder analyses using pooled data from three randomized Phase III trials.

PURPOSE: To understand how improvements in the symptoms of overactive bladder (OAB) seen with the ß3-adrenoceptor agonist mirabegron 50 mg, correlate with patient experience as measured by validated and standard patient-reported outcomes (PROs), and to identify whether there is overall directional consistency in the responsiveness of PROs to treatment effect. METHODS: In a post hoc analysis of pooled data from three randomized, double-blind, placebo-controlled, 12-week Phase III trials of mirabegron 50 mg once daily, responder rates for incontinence frequency (≥50 % reduction in incontinence episodes/24 h from baseline to final visit), micturition frequency (≤8 micturitions/24 h at final visit), and PROs [minimally important differences in patient perception of bladder condition (PPBC) and subsets of the overactive bladder questionnaire (OAB-q) measuring total health-related quality of life (HRQoL), and symptom bother] were evaluated individually and in combination. RESULTS: Mirabegron 50 mg demonstrated greater improvement from baseline to final visit than placebo for each of the responder analyses, whether for individual objective and subjective outcomes or combinations thereof. These improvements versus placebo were statistically significant for all double and triple responder analyses and for all single responder analyses except PPBC. PRO measurements showed directional consistency and significant correlations, and there were also significant correlations between objective and subjective measures of efficacy. CONCLUSIONS: The improvements in objective measures seen with mirabegron 50 mg translate into a meaningful clinical benefit as evident by the directional consistency seen in HRQoL measures of benefit.

Tissue engineered buccal mucosa for urethroplasty: progress and future directions.

PURPOSE: Autologous buccal mucosa is commonly utilized in the surgical treatment of urethral strictures. Extensive strictures require a larger quantity of tissue, which may lead to donor site morbidity. This review assesses progress in producing tissue engineered buccal mucosa as an alternative graft material. RESULTS: Few clinical studies have introduced cells onto biological or synthetic scaffolds and implanted resulting constructs in patients. The available studies show that buccal mucosa cells on acellular human dermis or on collagen matrix lead to good acute stage tissue integration. Urothelial cells on a synthetic substrate also perform well. However while some patients do well many years post-grafting, others develop stricture recurrence. Acellular biomaterials used to treat long urethral defects in animals commonly lead to fibrosis. CONCLUSIONS: Tissue engineered buccal mucosa shows promise as a substitute for native tissue. The fibrosis which occurs months post-implantation may reflect the underlying disease process recurring in these patients.

Safety and tolerability of the ß3 -adrenoceptor agonist mirabegron, for the treatment of overactive bladder: results of a prospective pooled analysis of three 12-week randomised Phase III trials and of a 1-year randomised Phase III trial.

AIMS: To evaluate the safety and tolerability of the ß3 -adrenoceptor agonist, mirabegron, in patients with overactive bladder (OAB). METHODS: Tolerability and safety data from three 12-week, randomised, placebo-controlled, double-blind, Phase III trials (Studies 046, 047 and 074) were pooled by treatment group. The three studies were of a similar design, although the assessed doses of mirabegron [25, 50 or 100 mg once daily (qd)] varied, and tolterodine extended release (ER) 4 mg was included as an active-control arm in Study 046 only. Tolerability and safety data from a 1-year, randomised, double-blind, Phase III trial (Study 049) are also presented. Safety variables included the incidence and severity of treatment-emergent adverse events (TEAEs), vital signs and electrocardiogram data. RESULTS: Mirabegron (25, 50 or 100 mg qd) was safe and well-tolerated in patients with OAB over 12-week (n = 2736) and 1-year (n = 1632) periods. The incidence of TEAEs and treatment discontinuations as a result of TEAEs was low; the majority were mild in severity and few were serious. Hypertension, nasopharyngitis and urinary tract infection were the most common TEAEs with mirabegron. The mirabegron tolerability profile was similar to that seen with placebo and tolterodine ER 4 mg, except for dry mouth, which occurred, on average, five times less frequently with mirabegron than tolterodine ER 4 mg. In the pooled 12-week analysis, mirabegron 50 mg was associated with placebo-adjusted mean increases of 0.4-0.6 mmHg in blood pressure and approximately one beat per minute in pulse rate, both reversible upon treatment discontinuation. The incidence of Major Adverse Cardiovascular Events as adjudicated by an independent cardiovascular committee was low and similar across treatment groups. CONCLUSION: The favourable tolerability profile of mirabegron in patients with OAB may allow improved treatment compliance compared with antimuscarinics, with important implications for patient outcomes.

Contemporary issues with pharmacotherapy for lower urinary tract symptoms.

Two articles appeared in the November 2012 edition of the journal evaluating aspects relating to the use of two important pharmacotherapeutic classes for lower urinary tract symptoms (LUTS) in real life clinical practice. LUTS is a non-specific term that encompasses urine storage, voiding and postmicturition symptoms. LUTS is a common bothersome problem affecting both men and women with a comparable prevalence in age-matched patients of both sexes that increases with ageing.

Urgency and pain in patients with overactive bladder and bladder pain syndrome. What are the differences?

BACKGROUND: The Overactive Bladder Syndrome (OAB) and the Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) are different urological conditions sharing 'urgency' as a common symptom. The aim of this review is to address our existing knowledge and establish how these symptoms are interrelated and to determine whether or not there is a common link between both symptoms complexes that help to distinguish one from the other. METHODS: Pubmed was used to obtain references for this non-systematic review aiming to discuss differences between OAB and BPS/IC. Guidelines of several professional associations and discussions based on expert opinion from the authors were implemented. RESULTS: Whilst in BPS the hallmark symptom is pain on bladder filling, urgency is the defining symptom of OAB. Whilst it is likely that the pain in BPS/IC arises from local inflammation in the bladder wall, the nature of urgency as a symptom, its origin, and the relationship between urgency and pain, as well as the different afferent mechanisms associated with the genesis of these sensory symptoms, remains unknown. Although the aetiology of both OAB and PBS/IC is unclear, the influence of environmental factors has been suggested. Both are chronic conditions with very variable symptom resolution and response to therapy. The relationship with voiding dysfunction, gynaecological causes of chronic pelvic pain or the possible alteration of the hypothalamic-pituitary-adrenal axis and psychological disorders has not been established. Inflammation has been suggested as the common link between OAB and BPS/IC. CONCLUSIONS: OAB and BPS/IC are different symptoms complexes that share urgency as a common symptom. None of them have a specific symptom although pain on bladder filling is the hallmark symptom in BPS/IC. Bladder pain with urgency should be a trigger for referral to the provider with appropriate knowledge and expertise in this disease state, whereas the management of OAB should be part of normal routine care in the community.

Phase II study on the efficacy and safety of the EP1 receptor antagonist ONO-8539 for nonneurogenic overactive bladder syndrome.

PURPOSE: We evaluated the efficacy, safety and tolerability of the EP1 receptor antagonist ONO-8539 in patients with overactive bladder syndrome. MATERIALS AND METHODS: This was a 12-week, randomized, double-blind, placebo controlled, parallel group, multicenter study with a 2-week single blind placebo run-in phase. The 435 patients were randomized to receive twice daily ONO-8539 (30, 100 or 300 mg), placebo or once daily tolterodine (4 mg). RESULTS: At the end of the 12-week treatment no statistically significant difference was found between ONO-8539 and placebo in the change from baseline in the number of micturitions per 24 hours. The primary end points for 30, 100 and 300 mg ONO-8539, and placebo were -1.02, -1.53, -1.31 and -1.40, respectively. There was no statistically significant difference between any ONO-8539 group and placebo in the change from baseline in the number of urgency or urinary urgency incontinence episodes per 24 hours, or the mean volume voided per micturition, which were secondary end points. Statistically significant differences for tolterodine vs placebo were observed in the change from baseline in the number of micturitions (p = 0.045), urgency episodes (p = 0.04) and mean volume voided per micturition (p <0.001). The incidence of adverse events was 54.1% in the placebo group, 43.0% to 54.0% in the ONO-8539 groups and 46.6% in the tolterodine group. The intensity of adverse events was similar among the treatment groups. Similar to other treatments, the most frequently reported adverse events after ONO-8539 were nasopharyngitis and diarrhea. CONCLUSIONS: The results of this study, which to our knowledge represents the first evaluation of ONO-8539 in patients with overactive bladder, suggest a minimal role for EP1 receptor antagonism in the management of overactive bladder syndrome.

The assessment of a novel electrical stimulation waveform recently introduced for the treatment of overactive bladder.

Transdermal amplitude modulated signal (TAMS) is a novel electrical stimulus which has been recently introduced for the treatment of overactive bladder (OAB) syndrome. It has been suggested that it has advantages over conventional waveforms by providing more effective penetration of the skin to enhance the efficacy of therapy. As there is no literature which supports this, we performed this study to evaluate potential advantages of the TAMS signal for electrical stimulation of subcutaneous nerves as compared to conventional stimuli. The stimuli were applied on forearms of ten healthy volunteers and electrical parameters of stimuli and sensation measurements were recorded. None of the recorded electrical parameters showed significant differences (paired t-test p ≥ 0.250) between the TAMS and conventional waveforms. Similarly, the mean sensation recorded at motor threshold level and at 50% of maximal motor response level showed no differences (paired t-test p = 0.242 and p = 0.687 respectively). It is unlikely, based on the results of this study, that TAMS provides any enhancement of the efficacy of conventional stimuli. We would recommend that further studies are carried out to clearly demonstrate in man what, if any, advantages the TAMS waveform has over conventional stimulation before it is widely deployed into clinical practice.

Nocturia: current concepts and future perspectives.

Nocturia is a prevalent highly bothersome urinary symptom that may significantly detriment the health and well-being of sufferers. It is characterized by waking at night to void, each void preceded and followed by sleep, hence leading to fragmentation of sleep and day-time tiredness. This may result in reduced productivity in the workplace, which contributes to the significant burden to the wider society that nocturia incurs. Nocturia was traditionally viewed as one of the many urinary tract symptoms that occur due to lower urinary tract dysfunction. However, recently it has been recognized that due to its multi-factorial aetio-pathogenesis, nocturia should be viewed as distinct clinical condition in its own right. Careful assessment of the nocturic patient is essential so that treatment strategies are guided by the likely causes. Much research is currently being undertaken into the underlying causes and the optimal management approaches. This review will explore the contemporary status of research on nocturia with a focus on the current and newly available pharmacotherapies.

Guías EAU sobre incontinencia urinaria / EAU Guidelines on Urinary Incontinence

Contexto: Las primeras directrices sobre incontinencia de la European Association of Urology (EAU) se publicaron en 2001. Dichas directrices se han actualizado con regularidad en los últimos años. Objetivo: El objetivo de este artículo es ofrecer un resumen de la actualización de las directrices sobre incontinencia urinaria (IU) de la EAU realizada en 2009. Recogida de evidencias: El comité de trabajo de la EAU formó parte de la IV Consulta Internacional sobre Incontinencia (ICI) y, con permiso de la ICI, llevó a cabo la extracción de la información de relevancia. La metodología de la IV ICI consistió en una amplia revisión de la literatura por parte de expertos internacionales y en la creación de un nivel de consenso. Asimismo, el nivel de evidencia se calificó de acuerdo con un sistema Oxford modificado y los grados de recomendación se atribuyeron en consonancia. Resumen de evidencias: Está disponible una versión completa de las directrices de la EAU sobre incontinencia urinaria en formato impreso (ampliada y en formato reducido), así como en formato de CD-ROM, pudiendo solicitarse a la oficina de la EAU o en línea en la dirección (http://www.uroweb.org/guidelines/online-guidelines/). La amplitud e invasividad de la evaluación de la IU depende de la gravedad y/o complejidad de los síntomas y signos clínicos, y es diferente para varones, mujeres, personas mayores de salud delicada, niños y pacientes con neuropatías. En el nivel de tratamiento inicial se aplican pruebas básicas de diagnóstico para descartar enfermedades o problemas subyacentes, tales como infecciones del tracto urinario. El tratamiento suele ser conservador (intervenciones en los hábitos de vida, fisioterapia, terapia física, farmacoterapia) y es de naturaleza empírica. En el nivel de tratamiento especializado (cuando haya fracasado la terapia inicial, ante un diagnóstico incierto o si los síntomas y señales son complejos o graves) suele ser necesaria una evaluación más elaborada, incluyendo técnica de imagen, endoscopia y urodinámica. Entre las opciones de tratamiento se incluyen intervenciones invasivas y la cirugía. Conclusiones: Las opciones de tratamiento de la IU están creciendo en número con rapidez, y estas guías de la EAU proporcionan una gradación de las evidencias (orientada por la medicina basada en la evidencia), así como una escala de recomendaciones para que la valoración sea la adecuada y las opciones de tratamiento estén en consonancia, aplicándose así una perspectiva clínica (AU)

Context: The first European Association of Urology (EAU) guidelines on incontinence were published in 2001. These guidelines were periodically updated in past years. Objective: The aim of this paper is to present a summary of the 2009 update of the EAU guidelines on urinary incontinence (UI). Evidence acquisition: The EAU working panel was part of the 4th International Consultation on Incontinence (ICI) and, with permission of the ICI, extracted the relevant data. The methodology of the 4th ICI was a comprehensive literature review by international experts and consensus formation. In addition, level of evidence was rated according to a modified Oxford system and grades of recommendation were given accordingly. Evidence summary: A full version of the EAU guidelines on urinary incontinence is available as a printed document (extended and short form) and as a CD-ROM from the EAU office or online from the EAU Web site (http://www.uroweb.org/guidelines/online-guidelines/). The extent and invasiveness of assessment of UI depends on severity and/or complexity of symptoms and clinical signs and is different for men, women, frail older persons, children, and patients with neuropathy. At the level of initial management, basic diagnostic tests are applied to exclude an underlying disease or condition such as urinary tract infection. Treatment is mostly conservative (lifestyle interventions, physiotherapy, physical therapy, pharmacotherapy) and is of an empirical nature. At the level of specialised management (when primary therapy failed, diagnosis is unclear, or symptoms and/or signs are complex/severe), more elaborate assessment is generally required, including imaging, endoscopy, and urodynamics. Treatment options include invasive interventions and surgery. Conclusions: Treatment options for UI are rapidly expanding. These EAU guidelines provide ratings of the evidence (guided by evidence-based medicine) and graded recommendations for the appropriate assessment and according treatment options and put them into clinical perspective (AU)

[EAU Guidelines on Urinary Incontinence]. / Guías EAU sobre incontinencia urinaria.

CONTEXT: The first European Association of Urology (EAU) guidelines on incontinence were published in 2001. These guidelines were periodically updated in past years. OBJECTIVE: The aim of this paper is to present a summary of the 2009 update of the EAU guidelines on urinary incontinence (UI). EVIDENCE ACQUISITION: The EAU working panel was part of the 4th International Consultation on Incontinence (ICI) and, with permission of the ICI, extracted the relevant data. The methodology of the 4th ICI was a comprehensive literature review by international experts and consensus formation. In addition, level of evidence was rated according to a modified Oxford system and grades of recommendation were given accordingly. EVIDENCE SUMMARY: A full version of the EAU guidelines on urinary incontinence is available as a printed document (extended and short form) and as a CD-ROM from the EAU office or online from the EAU Web site (http://www.uroweb.org/guidelines/online-guidelines/). The extent and invasiveness of assessment of UI depends on severity and/or complexity of symptoms and clinical signs and is different for men, women, frail older persons, children, and patients with neuropathy. At the level of initial management, basic diagnostic tests are applied to exclude an underlying disease or condition such as urinary tract infection. Treatment is mostly conservative (lifestyle interventions, physiotherapy, physical therapy, pharmacotherapy) and is of an empirical nature. At the level of specialised management (when primary therapy failed, diagnosis is unclear, or symptoms and/or signs are complex/severe),more elaborate assessment is generally required, including imaging, endoscopy, and urodynamics. Treatment options include invasive interventions and surgery. CONCLUSIONS: Treatment options for UI are rapidly expanding. These EAU guidelines provide ratings of the evidence (guided by evidence-based medicine) and graded recommendations for the appropriate assessment and according treatment options and put them into clinical perspective.

Pelvic Organ Prolapse Quantification System (POP-Q) - a new era in pelvic prolapse staging.

The prolapse of one or several pelvic organs is a condition that has been known by medicine since its early days, and different therapeutic approaches have been proposed and accepted. But one of the main problems concerning the prolapse of pelvic organs is the need for a universal, clear and reliable staging method.Because the prolapse has been known and recognized as a disease for more than one hundred years, so are different systems proposed for its staging. But none has proved itself to respond to all the requirements of the medical community, so the vast majority were seen coming and going, failing to become the single most useful system for staging in pelvic organ prolapse (POP).The latest addition to the group of staging systems is the POP-Q system, which is becoming increasingly popular with specialists all over the world, because, although is not very simple as a concept, it helps defining the features of a prolapse at a level of completeness not reached by any other system to date. In this vision, the POP-Q system may reach the importance and recognition of the TNM system use in oncology.This paper briefly describes the POP-Q system, by comparison with other staging systems, analyzing its main features and the concept behind it.