Elsevier

European Urology

Volume 54, Issue 4, October 2008, Pages 740-764
European Urology

Review – Neuro-urology
A Systematic Review and Meta-Analysis of Randomized Controlled Trials with Antimuscarinic Drugs for Overactive Bladder

https://doi.org/10.1016/j.eururo.2008.06.080Get rights and content

Abstract

Context

Anticholinergic drugs are commonly used in patients with overactive bladder (OAB) who do not achieve symptom relief and quality of life improvement with conservative management. Several drugs, with different doses, formulations, and routes of administration are currently available, making the choice quite difficult.

Objective

To evaluate efficacy and safety of different doses, formulations, and route of administration of the available anticholinergic drugs.

Evidence acquisition

A systematic review of the literature was performed in August 2007 using Medline, Embase, and Web of Science. Efficacy (micturitions per 24 h, volume voided per micturition, urgency urinary incontinence episodes per 24 h, incontinence episodes per 24 h) and safety (mainly, adverse events and withdrawal rates) end points were evaluated in the randomized control trials (RCTs) assessing the role of anticholinergic drugs in non-neurogenic OAB. Meta-analysis of RCTs was conducted using the Review Manager software 4.2 (Cochrane Collaboration).

Evidence synthesis

Our systematic search identified 50 RCTs and three pooled analyses. Tolterodine immediate release (IR) had a more favorable profile of adverse events than oxybutynin IR. Regarding different dosages of IR formulations, dose escalation might yield some limited improvements in the efficacy but at the cost of significant increase in the rate of adverse events. In the comparisons between IR and extended-release (ER) formulations, the latter showed some advantages, both in terms of efficacy and safety. With regard to the route of administration, use if a transdermal route of administration does not provide significant advantage over an oral one.

Conclusion

Many of the available RCTs have good methodological quality. ER formulations should be preferred to the IR ones. With regard to IR formulations, dose escalation might yield some improvements in the efficacy with significant increase in the AE. More clinical studies are needed to indicate which of the drugs should be used as first-, second-, or third-line treatment.

Introduction

Overactive bladder (OAB) is a highly prevalent condition [1], [2] with enormous related costs per year [3], [4]. First-line treatments for OAB include lifestyle modifications, behavioral therapy, pelvic floor muscle training, and bladder training. Antimuscarinic drugs are the first-line drug therapy, while other therapeutic options, such as botulinum toxin injection, neuromodulation, or surgical interventions are used in a smaller percentage of patients who are non-responders to drug therapies [5], [6].

Several antimuscarinic drugs are on the market, including oxybutynin, tolterodine, propiverine, trospium, the recently released solifenacin and darifenacin, and fesoterodine, which was the last one to receive the European Medicines Evaluation Agency (EMEA) marketing authorization in 2006. Moreover, some drugs such as oxybutynin, tolterodine, propiverine, or trospium are available both in immediate-release (IR) and extended-release (ER) formulations, while oxybutynin is also available in a sustained-delivery patch for transdermal administration [7]. Two meta-analyses evaluated the efficacy of the anticholinergic drugs in comparison to placebo, showing that the use of these drugs results in statistically significant improvements in symptoms and quality of life [8], [9]. To date, however, the clinical data available on the active comparisons of different drugs, formulations, and routes of administration are more limited. Specifically, a Cochrane meta-analysis based on a systematic review performed in January 2002 demonstrated that tolterodine was as effective as, but better tolerated than, oxybutynin; moreover, ER formulations of oxybutynin and/or tolterodine were shown to cause a lower risk of dry mouth compared to the IR formulations. Comparing head-to-head the ER formulations, xerostomia was less common in those patients receiving tolterodine [10]. In a more recent meta-analysis which mainly focused on placebo-controlled trials, Chapple et al reported some data on the trials of drugs which provided active drug controls. Solifenacin was shown to be more effective than tolterodine IR in terms of reduction of both urgency episodes and number of micturitions, while oxybutynin ER was shown to be more effective than tolterodine ER, in terms of reduction of incontinence episodes. Finally, oxybutynin IR 15 mg once daily, solifenacin 5 mg once daily, and solifenacin 10 mg once daily were more effective than tolterodine IR in increasing the volume voided per micturitions [8].

The purpose of the present systematic review and meta-analysis was to evaluate all the clinical data derived from randomized controlled trials in order to assess the efficacy and safety of different doses, formulations, and routes of administration of the currently available anticholinergic drugs, as well as head-to-head comparisons of different drugs.

Section snippets

Methods

The systematic review of the literature was performed in August 2007 using the Medical Literature Analysis and Retrieval System Online (U.S. National Library of Medicine's life science database; MEDLINE), the Excerpta Medica database (EMBASE), and Thomson-Reuters’ Web of Science. The MEDLINE search employed a complex search strategy, including both “MeSH” (Medical Subject Heading) and “free text” protocols. Specifically, the MeSH search was conducted by combining the following terms retrieved

Results

984 records were retrieved by searching MEDLINE: 910 records were retrieved from EMBASE, and 669 records were retrieved from Web of Science. The studies evaluating lower urinary tract storage symptoms in patients with bladder-outlet obstructions, papers evaluating neurogenic OAB or OAB in children, phase I studies, post-hoc analyses of RCTs, and duplicate publications were excluded. We finally identified 50 RCTs and three pooled analyses of RCTs for inclusion in this review (Fig. 1).

Discussion

Due to the large number of drugs available on the market, the selection of the most appropriate one for every single patient might be quite a complex task. The choice of the first drug to be used, the selection of the most appropriate dosage, formulation, and route of administration, the criteria for selection of a second anticholinergic drug in case of insufficient efficacy or intolerable adverse events, and, finally, costs are some of the most important issues that should be evaluated.

The

Conclusions

Many of the available RCTs in the field of muscarinic receptor antagonists for overactive bladder are of good methodological quality. ER formulations should be preferred to the IR formulations due to the more favorable profile of efficacy and adverse events. With regard to IR formulations, dose escalation might yield some improvements in the efficacy, but at the cost of a significant increase in the rate of adverse events. More clinical studies are needed to determine which of the available

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