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European UrologyVolume 62, issue 3, pages e49-e68, September 2012
Female Urology - Incontinence
Treatment of Overactive Bladder with Botulinum Toxin: Are There More Challenges to Deal With?
Published online 31 May 2012, pages 515 - 517
Refers to article:
Botulinum Toxin A Versus Placebo for Refractory Detrusor Overactivity in Women: A Randomised Blinded Placebo-Controlled Trial of 240 Women (the RELAX Study)
Accepted 28 December 2011
September 2012 (Vol. 62, Issue 3, pages 507 - 514)
Bladder wall injections with botulinum neurotoxin type A (BoNTA) have emerged as an official second-line treatment for intractable incontinence due to neurogenic detrusor overactivity (DO), but it remains an unlicensed treatment for intractable urinary symptoms associated with idiopathic detrusor overactivity (IDO)/overactive bladder (OAB) despite increasing acceptance and use under local institution approvals worldwide. Although the efficacy of BoNTA intradetrusor injections in patients with OAB/IDO has been established in several randomized controlled and open-label studies, mainly using the onabotulinumtoxinA (Botox) format , the risk–benefit ratio of the treatment remains a major issue. Analysis of clinical and urodynamic results of a single large dose-ranging trial identified a plateau of efficacy at doses of onabotulinumtoxinA >150 U  and ; the 100-U dose was the minimum dose to achieve a durable efficacy. Respective data on the abobotulinumtoxinA (Dysport) format derive from small noncontrolled studies and cannot be considered definitive. In addition, safety concerns associated largely with the risk of increased postvoid residuals (PVRs) and/or the need for clean intermittent catheterizations (CICs) following treatment have yet to be addressed. The specific effect of using (or having to use) CICs on quality of life (QoL) and well-being of patients with IDO, surprisingly, has been little studied. In most reports it has been masked under the vast overall improvement in patients’ QoL related to the reduction in urgency and associated incontinence . However, other studies have suggested patients’ reservations regarding the treatment and its side effects ; only about half the women with OAB, independent of the response to first-line therapy with anticholinergics, considered intradetrusor BoNTA an acceptable treatment for their symptoms when taking into account both outcomes and possible complications. CIC-related issues were the second most common cause for treatment discontinuation when repeat injection data were analyzed .
1. Can we predict the “expected” adverse events of the treatment?
To date, robust predictors of increased PVR and/or the need for posttreatment CIC in a nonobstructed anatomically or functionally patient have not been identified. Urodynamic parameters associated with detrusor contractility—lower maximum flow rate, isovolumetric pressure in women, and bladder contractility index in men—have been proposed as predictors of posttreatment CIC . In addition, data from the literature are inconclusive and confusing. Using the same dose of 200 U of onabotulinumtoxinA in IDO patients, three placebo-controlled trials reported a wide range of posttreatment CICs (16%, 37%, and 42%, respectively) , , and , despite using apparently similar injection techniques. The dose-ranging study of five onabotulinumtoxinA doses in IDO patients by Dmochowski et al. identified a dose-dependent increase in PVRs ≥200 ml up to the 200-U dose, although the rate of posttreatment CICs was dose dependent up to the 150-U dose . De novo CIC was started in 21% of the patients who received the 200-U dose in this study. The lack of standardization of what may be considered an elevated PVR value could be largely responsible for such discrepancy in reported CIC rates. Commonly, values between 100 and 200 ml are the cut-off levels above which CICs are considered in most BoNTA studies. These are arbitrary values, some if which may have been applied simply as an extension of neurogenic patient practices. They have been dissociated from patients’ percentage of functional bladder capacity, and only a few researchers have tried to evaluate usually the lower PVR values (≥100 ml) in association with patients’ persisting symptoms , , and . Significant variations in practices and lack of consensus among physicians even from the same country add to the confusion and cannot be helpful during a consultation on intradetrusor BoNTA, potentially affecting patients’ decision to accept the treatment, should it receive approval for use in IDO/OAB refractory to anticholinergics.
2. Increased postvoid residuals: clinical repercussions
Maximum efficacy of the treatment is thought to be reached at 4–6 wk, a time point established for primary outcome assessments in all randomized controlled trials (RCTs). However, both randomized and open-label studies have suggested a clinically significant early effect of BoNTA within the first 2 wk after treatment  and . Considering the high reported rates of posttreatment CICs  and  and the current lack of predicting factors for increased PVR and the need for CIC posttreatment where even the very low 50-U dose was found to be associated with a 9% retention rate  and , a first review of the patients at 6 wk after treatment could be considered a stretch . Safety alternatives to protect patients who might have gone into partial retention early after treatment need to be in place. Such cases might have been considered as “nonresponders” or be complicated by a urinary tract infection (UTI), both conditions masked as persisting lower urinary tract symptoms (LUTS). Treating physicians and/or centers may need to establish a more rigorous follow-up within the first 2 wk after treatment to increase efficacy and protect patients—and the treatment—from the most common and treatable complications.
3. Predictors of efficacy
As yet, no predictors of efficacy have been identified in prospectively designed studies. Younger age and higher filling detrusor pressures in patients with OAB-wet, originally recognized as predictors of efficacy in a univariate analysis of the results of a small RCT, were not confirmed in multivariate models . Poor bladder compliance confirmed either urodynamically or by the presence of bladder wall fibrosis was proposed as a predictor of poor response to treatment . Although research of predicting factors seems to be heavily based on urodynamic parameters so far, the role of urodynamics as a prerequisite for the treatment has been questioned. In a post hoc analysis, the presence of DO in patients with refractory OAB symptoms was not found to be a predicting factor in the efficacy of BoNTA . Smaller studies have also recruited nonurodynamically defined OAB patients with consistent results  and . Whether bladder diaries and validated QoL questionnaires can be used as primary recruitment tools as opposed to the traditional urodynamic assessment for the use of BoNTA in idiopathic OAB should be addressed via specifically designed research.
4. Does patient gender have an effect on the efficacy and safety of the treatment?
To date, no study has compared efficacy between the two genders. Several publications reported on the effect of treatment in women with IDO/OAB , , , and  as opposed to a paucity of respective literature in men. Although the incidence of OAB is equal between men and women, most studies using BoNTA for (non-neurogenic) OAB have recruited primarily female patients, apparently due to the higher rates of OAB-wet in women, and they have not stratified results by gender because they were not designed accordingly. Interestingly, a retrospective analysis suggested that male gender is a risk factor for post-BoNTA retention, whereas women were found to be more prone to UTIs .
5. Other clinical issues
When the effect of the toxin starts wearing off, it is common practice to restart anticholinergics in patients who had discontinued their use , but published data to confirm prolongation of the toxin's efficacy with additional anticholinergic therapy or conversely a rejuvenation of the previously inadequate efficacy of oral anticholinergics in non-neurogenic OAB patients do not exist. Neurogenic DO data suggest no additional benefit in those using anticholinergics since baseline .
More surprisingly, considering the widespread use of the treatment, little long-term data are available. Dropout rates recorded in a single study, with results of another real-time study pending, were as high as 37% after only two injections, with efficacy and complication issues rated as the top two problems . For those continuing with the treatment, the few available reports suggest that sustained efficacy can be promised  and .
An ongoing debate about the need for antibiotic prophylaxis following BoNTA bladder injections remains unresolved. An increased risk of LUTS bacterial colonization and/or symptomatic UTIs has been consistently demonstrated by RCTs , , , and . It appears to be dose dependent , associated with increased PVR , and may be independent of the use of antibiotics , although this needs to be proven in a prospective trial. Because UTIs appear to be related to the lower success rate , prevention or timely diagnosis and treatment may be important in preserving efficacy of the treatment.
In summary, although approval is now sought for the use of BoNTA in intractable IDO/OAB, a number of clinical challenges regarding both the maximization of efficacy and the minimization of adverse events are pending and require further research. While the cost effectiveness of BoNTA versus other treatments for refractory OAB still cannot be supported conclusively , discussion has been raised and trials are designed to address the possibility of using BoNTA as first-line treatment for intractable incontinence , , and . Results will certainly be of interest.
Conflicts of interest
Apostolos Apostolidis is an investigator for Allergan, Pfizer, Astellas, Pharmaserve Lilly, and GSK. He is a consultant for Allergan and Astellas, has received honoraria from Pfizer, Astellas, and Allergan, and has received research grants from Pfizer and Astellas.
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2nd Department of Urology, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road, Nea Efkarpia, 56403 Thessaloniki, Greece
© 2012 European Association of Urology, Published by Elsevier B.V.
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