Modeling dose-response relationships of the effects of fesoterodine in patients with overactive bladder

<p>Abstract</p> <p>Background</p> <p>Fesoterodine is an antimuscarinic for the treatment of overactive bladder, a syndrome of urgency, with or without urgency urinary incontinence (UUI), usually with increased daytime frequency and nocturia. Our objective was to develop predictive models to describe the dose response of fesoterodine.</p> <p>Methods</p> <p>Data from subjects enrolled in double-blind, placebo-controlled phase II and III trials were used for developing longitudinal dose-response models.</p> <p>Results</p> <p>The models predicted that clinically significant and near-maximum treatment effects would be seen within 3 to 4 weeks after treatment initiation. For a typical patient with 11 micturitions per 24 hours at baseline, predicted change was -1.2, -1.7, and -2.2 micturitions for placebo and fesoterodine 4 mg and 8 mg, respectively. For a typical patient with 2 UUI episodes per 24 hours at baseline, predicted change was -1.05, -1.26, and -1.43 UUI episodes for placebo and fesoterodine 4 mg and 8 mg, respectively. Increase in mean voided volume was estimated at 9.7 mL for placebo, with an additional 14.2 mL and 28.4 mL for fesoterodine 4 mg and 8 mg, respectively.</p> <p>Conclusions</p> <p>A consistent dose response for fesoterodine was demonstrated for bladder diary endpoints in subjects with overactive bladder, a result that supports the greater efficacy seen with fesoterodine 8 mg in post hoc analyses of clinical trial data. The dose-response models can be used to predict outcomes for doses not studied or for patient subgroups underrepresented in clinical trials.</p> <p>Trial Registration</p> <p>The phase III trials used in this analysis have been registered at ClinicalTrials.gov (NCT00220363 and NCT00138723).</p

Anterior colporrhaphy does not induce bladder outlet obstruction

We aimed to evaluate if anterior colporrhaphy causes incomplete voiding due to bladder outlet obstruction. Women scheduled for anterior colporrhaphy were asked to undergo multichannel urodynamic investigation before surgery and the first postoperative day. Bladder outlet obstruction was assessed using the Blaivas-Groutz voiding nomogram. Maximum flow rate, detrusor pressure and residual volume were compared between pre- and postoperative measurements and between women with and without an abnormal post-void residual volume (PVR; volume exceeding 150 ml). Seventeen women participated. One woman who was unobstructed before surgery was obstructed after surgery. Overall, detrusor pressure and maximum flow rate before and after surgery did not differ. After surgery, six women had an abnormal PVR, one was unable to void, four were mildly obstructed and one moderately obstructed. Urodynamic investigation the first day after anterior colporrhaphy did not show that anterior colporrhaphy induces bladder outlet obstruction. The explanation for postoperative urinary retention can therefore also lie in non-anatomical causes such as postoperative pain and psychological factor

Re-examining the effect of door-to-balloon delay on STEMI outcomes in the context of unmeasured confounders: a retrospective cohort study

Literature studying the door-to-balloon time-outcome relation in coronary intervention is limited by the potential of residual biases from unobserved confounders. This study re-examines the time-outcome relation with further consideration of the unobserved factors and reports the population average effect. Adults with ST-elevation myocardial infarction admitted to one of the six registry participating hospitals in Australia were included in this study. The exposure variable was patient-level door-to-balloon time. Primary outcomes assessed included in-hospital and 30 days mortality. 4343 patients fulfilled the study criteria. 38.0% (1651) experienced a door-to-balloon delay of >90 minutes. The absolute risk differences for in-hospital and 30-day deaths between the two exposure subgroups with balanced covariates were 2.81 (95% CI 1.04, 4.58) and 3.37 (95% CI 1.49, 5.26) per 100 population. When unmeasured factors were taken into consideration, the risk difference were 20.7 (95% CI −2.6, 44.0) and 22.6 (95% CI −1.7, 47.0) per 100 population. Despite further adjustment of the observed and unobserved factors, this study suggests a directionally consistent linkage between longer door-to-balloon delay and higher risk of adverse outcomes at the population level. Greater uncertainties were observed when unmeasured factors were taken into consideration

Basic mechanisms of urgency: roles and benefits of pharmacotherapy

Introduction Since urgency is key to the overactive bladder syndrome, we have reviewed the mechanisms underlying how bladder filling and urgency are sensed, what causes urgency and how this relates to medical therapy. Materials and methods Review of published literature. Results As urgency can only be assessed in cognitively intact humans, mechanistic studies of urgency often rely on proxy or surrogate parameters, such as detrusor overactivity, but these may not necessarily be reliable. There is an increasing evidence base to suggest that the sensation of ‘urgency’ differs from the normal physiological urge to void upon bladder filling. While the relative roles of alterations in afferent processes, central nervous processing, efferent mechanisms and in intrinsic bladder smooth muscle function remain unclear, and not necessarily mutually exclusive, several lines of evidence support an important role for the latter. Conclusions A better understanding of urgency and its causes may help to develop more effective treatments for voiding dysfunction