BACKGROUND Serelaxin, a recombinant form of human relaxin-2, is in development for treating acute heart failure (AHF) and a Phase II study in Japanese AHF patients was conducted. METHODS AND RESULTS A randomized, double-blind, placebo-controlled study of serelaxin at 10 and 30 µg·kg(-1)·day(-1)continuous intravenous infusion for up to 48 h, added to standard care for Japanese AHF patients. Primary endpoints were adverse events (AEs) through Day 5, serious AEs (SAEs) through Day 14, and serelaxin pharmacokinetics. Secondary endpoints included changes in systolic blood pressure (SBP) and cardiorenal biomarkers. A total of 46 patients received the study drug and were followed for 60 days. The observed AE profile was comparable between the groups, with no AEs of concern. Dose-dependent increase in the serum concentration of serelaxin was observed across the 2 dose rates of serelaxin. A greater reduction in SBP was observed with serelaxin 30 µg·kg(-1)·day(-1)vs. placebo (-7.7 [-16.4, 1.0] mmHg). A greater reduction in NT-proBNP was noted with serelaxin (-50.8% and -54.9% for 10 and 30 µg·kg(-1)·day(-1), respectively at Day 2). CONCLUSIONS Serelaxin was well tolerated in this study with Japanese AHF patients, with no AEs of concern and favorable beneficial trends on efficacy. These findings support further evaluation of serelaxin 30 µg·kg(-1)·day(-1)in this patient population.

PURPOSE:This study assessed the benefit of adding behavioural modification to darifenacin treatment for overactive bladder (OAB).MATERIALS AND METHODS:The ABLE trial was a randomised, open-label, parallel-group, multicentre study of 12 weeks of darifenacin treatment [with voluntary up-titration from 7.5 mg once daily (qd) to 15 mg qd at week 2] alone or in combination with a Behavioural Modification Programme (BMP) for men and women with dry or wet OAB. Efficacy was assessed as the change in the number (per day) of micturitions (primary variable), urge urinary incontinence (UUI) episodes, urgency episodes, pads used and nocturnal voids. Health-related quality of life (HRQoL) was also evaluated. Tolerability and safety assessments included adverse events and the number of discontinuations.RESULTS:Of 592 patients screened, 395 were randomised, 190 to darifenacin alone and 205 to darifenacin + BMP. At baseline, the majority of subjects were dry (mean 2.8 and three UUI episodes per day in the darifenacin and darifenacin + BMP groups respectively). At study end, darifenacin alone and darifenacin + BMP both produced significant reductions from baseline in median numbers of micturitions, UUI episodes, urgency episodes and nocturnal voids (all p < 0.05), but not in the number of pads used. HRQoL also improved. There were no significant differences between treatment groups in efficacy or HRQoL variables.CONCLUSIONS:Darifenacin treatment provides a degree of normalisation of micturition variables and improvement in HRQoL that cannot be further enhanced by behavioural therapy of the type used in this study. Whether behavioural modification would add benefit over darifenacin treatment in patients with more pronounced incontinence problems remains to be determined.

INTRODUCTION AND OBJECTIVE:Patient perception of overactive bladder (OAB) treatment outcomes can be a useful indicator of benefit and may help drive persistence on treatment, which is known to be poor in OAB. It remains unclear whether OAB patients dissatisfied with one antimuscarinic can achieve satisfaction with another and supporting data are limited. This study investigated patient-reported outcomes and clinical parameters during darifenacin treatment in OAB patients who expressed dissatisfaction with prior extended-release (ER) oxybutynin or tolterodine therapy (administered for >or= 1 week within the past year). METHODS:This open-label study was conducted in darifenacin-naïve OAB patients. Patients received 7.5 mg darifenacin once daily with the possibility of up-titrating to 15 mg after 2 weeks, for up to 12 weeks. Efficacy parameters included the Patient's Perception of Bladder Condition (PPBC), patient satisfaction with treatment, micturition frequency and number of urgency and urge urinary incontinence (UUI) episodes. Adverse events (AEs) were also recorded. RESULTS:In total, 497 patients were treated (84.1% women). Darifenacin treatment resulted in statistically significant improvements in PPBC scores, micturition frequency, urgency and UUI episodes from baseline at 12 weeks. The improvements were similar for patients previously treated with oxybutynin ER or tolterodine ER. More than 85% of patients expressed satisfaction with darifenacin. As noted in other studies, the most common AEs were dry mouth and constipation, but these infrequently resulted in treatment discontinuation, which was low overall. CONCLUSIONS:In this study, PPBC score and OAB symptoms were significantly improved, and satisfaction was high during treatment with darifenacin (7.5/15 mg) in patients who were dissatisfied with the previous antimuscarinic treatment.

Overactive bladder (OAB), a chronic condition requiring long‐term management, is associated with substantial impact on health‐related quality of life (HRQoL). The short‐term benefits of antimuscarinic drug treatment are well known. Here we investigate the impact on HRQoL of long‐term treatment with the M3‐selective muscarinic receptor antagonist darifenacin over 2 years.

Background:  Antimuscarinic agents used in the treatment of overactive bladder (OAB) differ in their potential to impair cognitive function. It is hypothesised that low brain concentrations and relatively low selectivity for the M1 muscarinic receptor may reduce the potential for adverse central nervous system (CNS) effects with darifenacin, compared with other antimuscarinics, particularly oxybutynin.

Antimuscarinics, used commonly to treat overactive bladder, may differ in their potential to increase heart rate via effects on cardiac muscarinic M2receptors. This prospective, 3-way crossover, randomized, double-blind study assessed the heart rate effects of 7 days' exposure to a nonselective M2/M3receptor blocker (tolterodine; 4 mg/d), a highly selective M3receptor blocker (darifenacin; 15 mg/d), and placebo in 162 healthy participants ≥50 years. Heart rate was measured by 24-hour Holter monitoring. Tolterodine significantly increased heart rate versus darifenacin and heart rate versus placebo, while darifenacin did not affect heart rate versus placebo. The proportion of participants with an increase in mean heart rate per 24 hours of ≥5 beats per minute was higher with tolterodine than with darifenacin (P = .0004) or with placebo (P = .0114) but did not differ between darifenacin and placebo. The results show that antimuscarinics exert differential effects on heart rate depending on their muscarinic receptor profile. This should be considered when selecting a treatment.

Background: Antimuscarinic agents used in the treatment of overactive bladder (OAB) differ in their potential to impair cognitive function. It is hypothesised that low brain concentrations and relatively low selectivity for the M-1 muscarinic receptor may reduce the potential for adverse central nervous system (CNS) effects with darifenacin, compared with other antimuscarinics, particularly oxybutynin. Methods: Cognitive function studies evaluating darifenacin, oxybutynin, tolterodine, solifenacin and/or trospium were identified from publications databases (Medline, Biosis and Embase) and congress abstracts. Preclinical studies and randomised controlled trials in adults were reviewed. Results: Five randomised, double-blind, multiple-dose studies of cognitive function were identified. Oxybutynin was consistently associated with cognitive deficit (four studies), whereas darifenacin did not impair cognition (three studies). These findings were supported by data from sleep/attention and EEG studies. Tolterodine data were limited to one small study with each formulation. For solifenacin and trospium, there were no human studies evaluating memory, the cognitive function most vulnerable to CNS anticholinergics. Conclusions: There is compelling evidence of cognitive impairment with oxybutynin, whereas darifenacin stands out by demonstrating no impairment of memory or other cognitive functions in three randomised, controlled trials. This may be attributed to the differences in physicochemical properties, efflux mechanisms and relative M-1 muscarinic receptor sparing. The risk of CNS impairment is of particular concern for vulnerable populations such as the elderly (a substantial proportion of the OAB population), and CNS-compromised neurogenic bladder patients such as those with multiple sclerosis or Parkinson's disease.

Antimuscarinics are the main drugs used to treat patients with (OAB). They have proven efficacy and are generally considered to be safe. However, interest has refocused on potential cardiovascular problems. Several long-term follow-up studies have suggested that an elevated heart rate (HR) increases the risk of cardiovascular disease, sudden death in patients with cardiovascular disorders and all-cause mortality. Since both OAB and cardiovascular disease increase with age, many OAB patients will have simultaneous cardiovascular disorders. Depending on their muscarinic receptor profile, antimuscarinics have the potential to increase heart rate which may be important when treating OAB patients. In the present study, the distribution of HRs prior to the initiation of treatment with antimuscarinics, and the prevalence of cardiovascular comorbidities in OAB patients were explored, utilizing large databases.

Background: Overactive bladder (OAB) increases in prevalence with advancing age. This study specifically investigated patients ! 65 years, evaluating the efficacy, tolerability, safety and quality of life (QoL) outcomes from darifenacin treatment.Methods: Patients (n = 400, mean age 72 years) with OAB were randomized (2:1) to receive 12 weeks of double-blind treatment with darifenacin (7.5 mg once daily for 2 weeks, then optional titration to 15 mg daily) or placebo (with sham titration). Efficacy, tolerability and safety were assessed from patient diary data, adverse events and discontinuations and QoL outcomes using specific questionnaires.Results: Mean urgency urinary incontinence episodes (UUIEs) decreased significantly from baseline to Week 12 with both darifenacin (-88.6%) and placebo (-77.9%; p > 0.05), with 70% and 58% patients responding with >= 50% reductions, respectively (p = 0.021). This was accompanied by significant differences between groups in reductions in micturition frequency (-25.3% with darifenacin vs. -18.5% placebo; p < 0.01). QoL assessments revealed significant improvements with darifenacin versus placebo at Week 12 in OAB-q, Patient Perception of Bladder Condition, and patient and physician assessments of treatment benefit (all p < 0.001). The most commonly reported adverse events were dry mouth and constipation.Conclusions: This study demonstrated that marked improvements in CAB symptoms can be achieved in patients >= 65 years, with significant treatment differences in responder rates, micturition frequency and QoL. Reduction in UUIEs may not be the optimal endpoint in this population, whereas OoL appears to be a sensitive and relevant patient-oriented measure of treatment effect.

Overactive bladder (OAB), a chronic condition, significantly impairs quality of life and impacts patients’ daily activities. The ABLE study evaluated whether addition of a Behavioral Modification Program (BMP) to darifenacin (DAR) treatment (tx) could reduce OAB symptoms more than DAR alone. The present analysis assessed the impact on health-related quality of life (HrQoL).

OBJECTIVES:To investigate the effects of darifenacin controlled-release (CR) and oxybutynin extended-release (ER) on cognitive function (particularly memory) in older subjects. METHODS:Healthy subjects (n=150) >/=60 years were randomised to darifenacin, oxybutynin ER or placebo in a multicentre, double-blind, double-dummy, parallel-group, 3-week study. Doses were administered according to US labels: oxybutynin ER 10mg once daily (od), increasing to 15mg od then 20mg od by week 3; darifenacin 7.5mg od in weeks 1 and 2, then 15mg od in week 3. The primary end point was accuracy on the Name-Face Association Test (delayed recall) at week 3. RESULTS:Results of the Name-Face Association Test at week 3 showed no significant difference between darifenacin and placebo on delayed recall (mean difference, -0.06, p=0.908). In contrast, oxybutynin ER resulted in memory impairment, with significantly lower scores than placebo and darifenacin (mean differences, -1.30, p=0.011 and -1.24, p=0.022, respectively) for delayed recall on the Name-Face Association Test at week 3. Additional tests of delayed recall indicated significant memory impairment with oxybutynin ER versus placebo at certain time points, whereas darifenacin was similar to placebo. No between-treatment differences were detected in self-rated memory, demonstrating that subjects were unaware of memory deterioration. CONCLUSIONS:While darifenacin had no significant effects on memory versus placebo, oxybutynin ER caused significant memory deterioration (magnitude of effect comparable to brain aging of 10 years). The results also demonstrate that subjects may not recognise/report memory deterioration.