The Effects of Antimuscarinic Treatments in Overactive Bladder: A Systematic Review and Meta-Analysis

Abstract

Objectives:

To evaluate the tolerability, safety and efficacy of antimuscarinic drugs used to treat overactive bladder and to identify any differences between individual antimuscarinics.

Methods:

Medline, Embase, CCTR and Cinahl databases were searched for published RCTs including an antimuscarinic agent from 1966 to August 2004. Data from included trials were extracted and meta-analysed where possible.

Results:

Fifty-six trials were included. The antimuscarinics were found to be safe and efficacious. All antimuscarinics apart from oxybutynin IR were found to be well tolerated. Dry mouth was the most commonly reported adverse event and no drug was associated with an increase in any serious adverse event. There were significant differences between the antimuscarinics in rates of withdrawal and rates and range of adverse events and efficacy outcomes.

Conclusions:

The antimuscarinics have different tolerability and safety profiles, which are clinically significant.

Introduction

Overactive bladder (OAB), otherwise known as the urgency frequency syndrome, is a symptom complex defined by the International Continence Society (ICS) as ‘urgency, with or without urge incontinence, usually with frequency and nocturia’ [1]. This is distinct from the urodynamic diagnosis of detrusor overactivity (DO), which refers to an involuntary rise in detrusor pressure during filling of the bladder in a laboratory situation in a conscious co-operative patient [1].

Non-surgical treatment is the mainstay of therapy for OAB and available options include bladder training, biofeedback, medication, and a combination of these options. The principal pharmacological treatment utilised to improve the symptoms of OAB is based on muscarinic receptor antagonism (antimuscarinics). To date no proof of concept studies for other oral pharmaco-therapeutic mechanisms have shown any significant efficacy. The mode of action of antimuscarinics, traditionally considered to be on muscarinic receptors lying within the detrusor muscle, has become increasingly controversial. At licensed doses, antimuscarinic treatments do not inhibit the normal voiding phase of the micturition cycle, whilst they do alter bladder sensation during filling as evidenced by an improvement in filling symptoms (urgency, frequency, nocturia and incontinence) and bladder capacity. This has led to a recent hypothesis suggesting that antimuscarinic treatments may act via other mechanisms related to the afferent as opposed to the efferent system.

This systematic review was carried out to assess the safety, tolerability and efficacy of antimuscarinic treatments for OAB and DO. Further objectives of the review were to: (1) consider the effects of antimuscarinics on outcomes such as quality of life (QoL), which are important to patients and (2) assess whether there are differences between individual antimuscarinic drugs that are currently being used to treat OAB. These objectives were included to address criticism of a previous Cochrane review of pharmacological therapies for OAB [2].

The Cochrane review was criticised because the cover statement and conclusions do not appear to reflect the results of the review [3], [4], [5]. In particular, the outcome measures reported by Herbison and colleagues were ‘not necessarily the most pertinent outcomes to patients with OAB’ [6]. Although important factors such as QoL were mentioned in the review, these were not explored further in any detail. To address this criticism, we have analysed all reported QoL data in included trials and carried out meta-analyses of these data where possible. These analyses are described in detail in a separate publication [42].

In addition, the Cochrane review did not attempt to differentiate between individual antimuscarinic drugs. The authors chose to ‘lump’ the drugs together and evaluate the effects of the class, rather than to ‘split’ the drugs and assess any variation in effect between drugs. Due to the heterogeneity evident in the meta-analyses of some outcomes such as withdrawals and adverse events it was suggested that the drugs might have different profiles, yet potential differences were not explored further. In addition, a number of active controlled trials that have attempted to differentiate between OAB treatments have been published, but these were not evaluated by Herbison and colleagues [2]. In order to assess whether there are differences between individual antimuscarinic drugs, our methodology was distinctly different from that employed in the Cochrane review. We included active controlled trials in addition to placebo controlled trials and reviewed individual antimuscarinic drugs compared with either placebo or active controls. Our meta-analyses adopted a ‘splitting’ approach in order to assess any variation in effect between drugs.