Systematic Review And Meta-Analysis Of Randomized Controlled Trials With Antimuscarinic Drugs For Overactive Bladder

Main Category: Urology / Nephrology
Article Date: 25 Aug 2008 - 0:00 PDT

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UroToday.com - Overactive bladder (OAB) is a highly prevalent condition with enormous related costs per year. Several antimuscarinic drugs are on the market, with some drugs such as oxybutynin, tolterodine, propiverine, or trospium available both in immediate-release (IR) and extended-release (ER) formulations. Moreover, oxybutynin is available also as sustained-delivery patch for transdermal administration.

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, formulations 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.

A systematic review of the literature was performed in August 2007 using Medline, Embase, and Web of Science. Efficacy (micturitions/24 Hrs, volume voided per micturition, urgency urinary incontinence episodes/24 hrs, incontinence episodes/24 Hrs.) and safety (mainly, adverse event, and withdrawal rates) end-points were evaluated in the RCTs assessing the role of anticholinergic drugs in non-neurogenic OAB.

The data of our systematic review and meta-analysis showed that tolterodine IR had a more favorable profile of adverse events than oxybutynin IR, while the controlled-release formulations of the 2 drugs had similar efficacy and safety. In all the comparisons among IR and ER formulations, ER formulations showed some kind of advantages, either in terms of efficacy or safety. With regards to solifenacin, a single RCT demonstrated the non-inferiority of solifenacin compared to tolterodine ER, while our meta-analysis showed similar rates of adverse events, with the exception of constipation that was more common in the solifenacin arm. A single trial is currently available on fesoterodine, suggesting that the new drug might be more efficacious than tolterodine ER. With regards to the routes of administration, a transdermal route did not seem to provide any significant advantage compared to oral intake, considering higher rate of localized application side effects and withdrawal due to adverse events.

The overall quality of the randomized controlled trials available in the field of overactive bladder was good. However, almost all the trials evaluated short-term therapy (mostly 12 weeks). Moreover, almost all the studies provided efficacy data derived from bladder diaries. A more suitable evaluation should also include subjective outcomes - such as the so-called patient-reported outcomes - lacking in most of the studies. Besides, virtually all the evidence derived from pharmaceutical company-sponsored trials reflected the needs of the companies for registrational studies - rather than addressing the questions more relevant to the clinical practice.

Considering these limitations, providing clear recommendations for the every-day clinical practice was not easy. With regard to the selection of the first drug to use in naïve patients, the physician might prescribe oxybutynin ER, tolterodine ER 4 mg or solifenacin 5/10 mg. Similarly, darifenacin 15 mg and fesoterodine 4 mg might be considered as valuable options, although further evaluation is needed and RCTs are ongoing. In case of insufficient clinical efficacy, the choice of the second-line drug therapy really cannot be based on solid pieces of evidence due to the lack of randomized trials. Making assumptions from the available data, in case of lack of efficacy of the first-line ER drug, fesoterodine 8 mg and solifenacin 10 mg might be a possible option, although an increased rate of adverse events has to be expected. In case of failure of the first line ER drug due to adverse events such as dry mouth, the transdermal formulation might provide some advantages compared to the oral one. Should the patient experience constipation, shifting from solifenacin to tolterodine ER might be useful. Alternatively, those patients taking IR formulations of anticholinergic drugs, without successful results, might be offered dose titration - providing the patients have not experienced significantly adverse events. Ultimately, ER formulations might be the preferred choice.

Written by Giacomo Novara, MD, FEBU, as part of Beyond the Abstract on UroToday.com

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