Reports

Immunosuppression in Heart Transplant Patients at High Risk for Poor Outcomes
Antibiotic Stewardship and the Role of Broad-spectrum Agents

The Challenge of Urgency: Recent Advances in Recognizing and Treating Overactive Bladder

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 - 104th Annual Meeting of the American Urological Association

Chicago, Illinois / April 25-30, 2009

Anticholinergics, though effective for treatment of overactive bladder (OAB), often prove difficult for patients to tolerate, with dry mouth being the most common and one of the most bothersome side effects. The estimated incidence of dry mouth ranges as high as 90% in studies of patients taking anticholinergics for OAB (Haab F, Castro-Díaz D. Int J Clin Pract 2005;59(8):931-7).

VECTOR Study

Among studies reported here during the scientific sessions, VECTOR (Vesicare in Comparison to Oxybutynin for Overactive Bladder Patients) was notable for its focus on safety. According to Dr. Sender Herschorn, Chair, Division of Urology, University of Toronto, Ontario, who reported the findings at a late-breaking session on behalf of investigators at 12 Canadian sites, “The fact that some patients discontinue treatment for OAB because of intolerable side effects counters our best efforts to encourage them to seek treatment which could improve their quality of life. It is important for medical professionals, as well as the patients themselves, to be aware of treatment options to optimize the management of OAB.”

The frequency and severity of anticholinergic side effects arise from the nonspecific binding properties of some agents. Older medications competitively bind the M1, M2 and M3 muscarinic receptors, which have distribution in various organ systems. In contrast, newer agents have greater receptor specificity, particularly for the M3 receptors, which predominate in the bladder.

Solifenacin succinate binds preferentially to M3 receptors, Dr. Herschorn noted. In clinical trials of solifenacin, the frequency of dry mouth ranged between 10% and 30%, and most cases were mild or moderate in severity. The proportion of patients who discontinued treatment because of drug-related adverse effects ranged between 4% and 7% (Cardozo et al. Int Urogynecol J Pelvic Floor Dysfunct 2006; 17(5):512-9, Haab et al. Eur Urol 2005;47(3):376-84).

The relative tolerability of solifenacin and oxybutynin immediate-release (IR) had not been assessed in a randomized clinical trial, providing the rationale for the VECTOR trial. The study involved 132 patients who had at least a three-month history of OAB symptoms, including urgency with or without incontinence, frequency and nocturia. The patients reported more than one urge episode within a 24-hour period and eight or more micturition episodes per day.

The patients were randomized in double-blind fashion to daily therapy with solifenacin or to oxybutynin IR and follow-up lasted for eight weeks. The primary end point was the proportion of patients who reported dry mouth during the study following direct questioning at each follow-up visit. If reported, dry mouth was rated as mild, moderate or severe.

The results showed that treatment with solifenacin reduced the incidence of dry mouth by almost 50% compared with oxybutynin IR. Dr. Herschorn observed that dry mouth was reported in 35% of patients receiving solifenacin vs. 83% of the oxybutynin IR group (P<0.0001). Among patients reporting dry mouth, the condition was significantly milder in the solifenacin group, he noted. Dry mouth was mild in 75% of solifenacin-treated patients and moderate in 13%. In contrast, 30% of oxybutynin IR patients reported mild dry mouth, 42% had moderate symptoms and 28% had severe dry mouth (P<0.001). Significantly fewer solifenacin patients withdrew from the study because of dry mouth compared to oxybutynin IR (3% vs. 19%, P=0.0032). Although the rates of dry mouth for solifenacin and oxybutynin IR were higher in VECTOR than previously reported in other studies, these rates are not unexpected given the direct questioning approach used for collecting adverse events (AEs) in this study.

AEs were frequent in both groups, but significantly less common in the solifenacin group (P=0.003). AEs were also significantly less severe with solifenacin (P=0.009) and associated with significantly fewer treatment-related AEs (P=0.0093).

Dr. Herschorn told delegates, “Overall, solifenacin was associated with a superior tolerability profile compared to oxybutynin IR. Patients treated with solifenacin had significantly fewer episodes of dry mouth, significantly lower severity of dry mouth, significantly fewer withdrawals due to dry mouth and significantly fewer overall adverse events.”

The trial lacked the statistical power to demonstrate a difference in efficacy, he added. However, available data suggested the two agents demonstrated comparable effectiveness for reducing OAB symptoms and improving patient-reported outcomes.

Urgency: Key to Treatment Success

Prompt diagnosis and early treatment of OAB have been complicated by an incomplete understanding of the underlying pathophysiology of urgency, the hallmark symptom of the condition, Dr. David Staskin, Tufts University, Boston, Massachusetts, told delegates. Recent advances in the science of OAB have provided insights into the origin of the condition, the selection of appropriate therapies and the development of new pharmacologic agents.

The driving force of OAB is urgency, concurred Dr. Alan Wein, University of Pennsylvania, Philadelphia. It drives behavioural adaptation, including fluid restriction, toilet mapping, intentionally increased voiding frequency and restriction of activities; however, successful treatment of urgency results in improvement in all or most of the other symptoms associated with OAB. “Urgency is the most bothersome symptom,” he stated. “Quality-of-life gains come from controlling urgency, above those from reducing incontinence.”

The status of urgency as the “premier symptom” of OAB has given rise to an extensive search for the optimal definition and characterization of the symptom and for the optimal approach to evaluate the success of therapy. Urgency has proven difficult to measure, to convey to patients and to assess after initiation of therapy. The challenge of urgency has led to development of multiple tools to aid clinicians in defining, describing, grading and rating. All of the efforts, however, lead back to the focus on a single symptom. “Since improvement in overall symptoms and quality of life are the primary goals of treatment of a nonmalignant condition such as OAB, have we ‘experts’ gone overboard in trying to quantitate a single symptom?” Dr. Wein asked. “Is measurement of one symptom better than assessment of ‘the whole’?”

Given all the issues surrounding urgency, Dr. Wein suggested that an overall evaluation, such as the Patient Global Impression of Improvement or the Patient Perception of Bladder Condition, might be the most relevant approach to assessing OAB patients. In the assessment of response to treatment for OAB, various metrics or scales for urgency have been developed, noted Dr. Staskin, several of which have shown potential in clinical trials. These include Warning Time (before an episode of urgency), Urgency Perception Score, the Indevus Urgency Severity Scale, the OAB Symptom Composite Score, the Patient Perception of Intensity of Urgency Scale and the Treatment Benefit Scale.

Dr. Staskin singled out an increase in warning time as an example of a meaningful outcome to patients with OAB. However, he noted that other validated metrics for urgency have proven useful for assessment response to treatment. “Patients treated with active drug showed a highly significant reduction in urgency severity, incidence and bother, alongside that in micturition frequency, incontinence and urge incontinence,” he observed. “Associated with this, patients perceived a significant reduction in the severity of their OAB problems.”

We Appreciate Your Feedback

Please take 30 seconds to help us better understand your educational needs.