Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 38th Annual Meeting of the International Continence Society

Cairo, Egypt / October 20-24, 2008

According to Prof. Linda Cardozo, King’s College Hospital, London, UK, urgency including urgency bother is the fundamental symptom of overactive bladder (OAB), driving all other OAB symptoms directly or indirectly. The double-blind SUNRISE (Solifenacin for Urgency of OAB in a Rising Dose Efficacy) trial evaluated the antimuscarinic solifenacin 5 mg or 10 mg once daily for 16 weeks in 641 patients with OAB using severe urgency with or without urgency incontinence as the primary efficacy variable. The agent demonstrated a highly significant reduction in urgency severity, incidence and bother (Int Urogynecol J 2006;17(Suppl 2):S88, Abstr 052).

SUNRISE Subgroup Analysis

An analysis of the study was carried out to determine if there was any difference in the efficacy of the antimuscarinic in improving urgency end points among subgroups. Urgency was assessed on a 5-point Patient Perception of Intensity of Urgency Scale (PPIUS), in which the primary variable was the change in number of episodes of PPIUS 3 and 4 (severe urgency and urge incontinence) per 24 hours. For urgency bother, a visual analogue scale (VAS) of 0 (no bother at all) to 100 (worst possible bother) was used to answer the question, “How much bother has urgency been for you in the past week?”

The analysis showed that solifenacin was effective in reducing episodes of severe urgency and urgency incontinence in a wide range of patient subgroups that comprised men and women, OAB wet and dry patients, and patients both younger and older than 65. The beneficial effects were more pronounced in patients over 65 and among those who were dry on study entry.

These findings supported and extended those from a similar subgroup analysis of the multinational comparison of the STAR (Solifenacin vs. Tolterodine) study, Prof. Cardozo noted. “They underline the flexibility of solifenacin, which enables us to meet the requirements of each individual patient more effectively.” In SUNRISE, solifenacin was found to be effective across all the subgroups studied in reducing episodes of severe urgency and urgency incontinence. According to VAS, urgency bother was reduced by 59% in the solifenacin-treated patients vs. 35% in the placebo-treated cohort. “Reduction of urgency bother is an important target for OAB treatment, and the ability of an antimuscarinic agent to reduce urgency bother may be an important indicator of its overall efficacy in OAB,” she observed, adding, “We are now planning a study to see if solifenacin reduces bladder wall thickness, a parameter which helps us differentiate between detrusor overactivity and other causes of urgency-frequency.”

Severe OAB Symptoms

As efficacy of antimuscarinic therapy in patients with severe OAB symptoms has not been adequately explored, Dr. James P. Capó, Internal Medicine Associates of Atlanta, Georgia, and colleagues carried out a post-hoc analysis of VENUS (Vesicare Efficacy and Safety in Patients with Urgency Study). He analyzed data from the 158 patients who had severe OAB symptoms defined as a baseline score of <u>></u>5 on the 6-point scale of the Patient Perception of Bladder Condition (PPBC). Their mean age was 57.2 years (34.2% <u>></u>65 years old) and most (85.4%) were female. The primary end point was the mean change from baseline to week 12 in urgency episodes/day. Secondary end points included mean changes in daily micturitions, incontinence episodes, nocturia episodes and nocturnal voids. Patient-reported outcomes such as symptom bother, health-related quality of life and warning time (WT) (the time between first sensation of urgency to voiding or incontinence) were also reported.

Nearly all (94.8%) solifenacin-treated patients with severe OAB symptoms (mean PPBC score of 5.2 at baseline) reported greater improvements than placebo recipients (68.8%). The mean number of urgency episodes/day among active treatment recipients fell from 7.88 at baseline to 3.33 (57.7%) vs. 38.8% (from 7.94 to 4.86) with placebo. Patients with severe OAB symptoms showed similar reductions in daily micturitions and incontinence episodes.

Likewise, in patients with severe OAB symptoms, the median WT improved by 23 seconds vs. 9 seconds for placebo. The Indevus Urgency Severity Scale (IUSS) dropped 50% from 2.4 at baseline (moderate to severe urgency) to 1.2 (mild to moderate), and Urgency Perception Scale (UPS) scores improved from 1.8 at baseline (not usually able to hold urine/able to hold if go to toilet immediately) to 2.2 (able to hold if go to toilet immediately). These results are consistent with the significant improvements observed in the overall VENUS population.

Treatment-emergent adverse events were mostly mild or moderate and resulted in few discontinuations (severe subgroup 4.5%, all VENUS participants 6.5%), investigators observed.

Persistent OAB in BPH: Combination Therapy

Elderly men with benign prostatic hyperplasia (BPH) taking a1-adrenoceptor antagonists for lower urinary tract symptoms (LUTS) often develop OAB. Combining the anticholinergic solifenacin with the a1-adrenoceptor antagonist tamsulosin appears to be a rational choice.

Thus, Dr. Hidehiro Kakizaki, Department of Urology, Asahikawa Medical College, Japan, and colleagues explored the short-term (four weeks) efficacy and safety of tamsulosin 0.2 mg/day alone in 26 men aged 73.3±27.8 years who had both BPH and OAB symptoms after a1-adrenoceptor antagonist treatment (group 1) with the same tamsulosin dose added to low-dose (2.5 mg) solifenacin in 25 similarly affected men aged 75.1±16.4 years (group 2).

In group 2, the total International Prostate Symptom Score (IPSS), IPSS storage symptom score and the quality-of-life score all significantly improved vs. group 1. Scores for nocturia, urgency and urgency incontinence also improved in group 2, but in group 1, only the urgency score improved.

IPSS voiding symptom score did not change significantly; neither maximum flow rate nor post-void residual urine changed significantly in either group. No significant side effects in either group were reported. Findings confirmed short-term efficacy and safety of the combination therapy, authors concluded.

SCOPE: Cognitive Impairment

The potential to cause cognitive impairment has been documented with the anticholinergic oxybutynin because of its high affinity to M1 receptors. In the elderly or other vulnerable groups with an already high anticholinergic load, this may be of particular concern. Acting preferentially on M3 receptors in the bladder wall, solifenacin has a relatively low affinity for the M1 receptors.

SCOPE (Solifenacin Cognitive Function Pilot Exploratory Study) assessed cognitive impairment in 12 healthy men and women aged >65 years between solifenacin, oxybutynin and placebo.

Patients in the randomized, double-blind, three-period, six-treatment sequence, crossover study received a single dose of solifenacin 10 mg in one period, oxybutynin 10 mg in another and placebo in a third period, with 14-day washouts in between.

Led by Prof. Keith A. Wesnes, Cognitive Drug Research Ltd., Goring-on-Thames, UK, the study used the sensitive Cognitive Drug Research computerized system to assess aspects of learning, memory, information processing, alertness and self-rated contentment and calm.

There was no evidence to suggest that solifenacin impaired cognition or self-ratings of mood and alertness, or had any statistically significant deterioration in any of the five cognitive function tests or subjects’ self-ratings of alertness and mood compared with placebo. By contrast, oxybutynin was consistently associated with impaired attention, working and episodic memory, speed of memory and self-rated alertness.

All domains of cognition expected to be impaired by compounds having this mode of action were assessed. Oxybutynin was used as a positive control to demonstrate the success of the study design and to validate the assessment procedures. The impaired cognitive function and alertness found with oxybutynin validated the study and was consistent with previous findings.

Adverse cognitive effects with oxybutynin tended to peak at two hours’ post-dose, corresponding with its T-_max, whereas with solifenacin, there was no clear indication of cognitive impairment at any time point. “It shows that elderly people taking solifenacin for OAB would be less likely to experience declines in cognitive function and reductions in alertness than they would if they took oxybutynin for this condition,” Prof. Wesnes remarked.

These findings suggest that solifenacin may be valuable for use in elderly patients with OAB where management of total anticholinergic load is a concern, authors concluded.

Summary

Urgency including bother appears to drive all other OAB symptoms directly or indirectly. Findings confirm that the antimuscarinic solifenacin is effective in reducing these symptoms, even in severe OAB, and can be administered safely with an a1-adrenoceptor antagonist. The low affinity of this antimuscarinic for the M1 receptor makes cognitive impairment unlikely in the elderly and in routine clinical practice.