EUROPEAN UROLOGY 60 (2011)

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1 EUROPEAN UROLOGY 60 (2011) available at journal homepage: Collaborative Review Neuro-urology Contemporary Management of Lower Urinary Tract Disease With Botulinum Toxin A: A Systematic Review of (OnabotulinumtoxinA) and Dysport (AbobotulinumtoxinA) Altaf Mangera a, *, Karl-Erik Andersson b, Apostolos Apostolidis c, Chris Chapple a, Prokar Dasgupta d, Antonella Giannantoni e, Stavros Gravas f, Stephan Madersbacher g a Sheffield Teaching Hospitals NHS Trust, Sheffield, UK; b Wake Forest University School of Medicine, Winston Salem, NC, USA; c Aristotle University of Thessaloniki, Thessaloniki, Greece; d Medical Research Council Centre for Transplantation, Urology Department, NIHR Biomedical Centre, King s College London, King s Health Partners, Guy s Hospital, London, UK; e Department of Urology and Andrology, University of Perugia, Perugia, Italy; f Department of Urology, University of Thessaly, Larissa, Greece; g Department of Urology and Andrology, Donauspital, Vienna, Austria Article info Article history: Accepted July 1, 2011 Published online ahead of print on July 13, 2011 Keywords: AbobotulinumtoxinA Bladder outflow obstruction Botulinum toxin Detrusor sphincter dyssynergia Dysport Idiopathic detrusor overactivity Neurogenic detrusor overactivity OnabotulinumtoxinA Painful bladder syndrome Abstract Context: The use of botulinum toxin A (BoNTA) in the treatment of lower urinary tract dysfunction has expanded in recent years and the off-licence usage list includes neurogenic detrusor overactivity (NDO), idiopathic detrusor overactivity (IDO), painful bladder syndrome (PBS), and lower urinary tract symptoms resulting from bladder outflow obstruction (BOO) or detrusor sphincter dyssynergia (DSD). There are two commonly used preparations of BoNTA: (onabotulinumtoxina) and Dysport (abobotulinumtoxina). Objective: To compare the reported outcomes of onabotulinumtoxina and abobotulinumtoxina in the treatment of NDO, IDO, PBS, DSD, and BOO for adults and children. Evidence acquisition: We performed a systematic review of the published literature on PubMed, Scopus, and Embase in the English language reporting on outcomes of both BoNTA preparations. Review articles and series with <10 cases were excluded. The articles were graded for level of evidence and conclusions drawn separately for data with higher-level evidence. Evidence synthesis: There is high-level evidence for the use of onabotulinumtoxina and abobotulinumtoxina in adults with NDO but only for abobotulinumtoxina in children with NDO. Only onabotulinumtoxina has level 1 evidence supporting its use in IDO, BOO, DSD, and PBS/interstitial cystitis. Conclusions: We identified good-quality studies that evaluated onabotulinumtoxina for all the indications described above in adults; such was not the case with abobotulinumtoxina. Although this does not imply that onabotulinumtoxina is more effective than abobotulinumtoxina, it should be a consideration when counselling patients on the use of botulinum toxin in urologic applications. The two preparations should not be used interchangeably, either in terms of predicting outcome or in determining doses to be used. # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Sheffield Teaching Hospitals NHS Trust, Sheffield, UK. H Floor, Royal Hallamshire Hospital, Glossop Rd, Sheffield, S10 2JF, UK. Tel address: mangeraaltaf@hotmail.com (A. Mangera). 1. Introduction In 1988, Dysktra et al. first published on the use of botulinum toxin A (BoNTA), injected into the external urinary sphincter, to treat detrusor sphincter dyssynergia (DSD) in patients with spinal cord injury [1]. This was followed by Schurch et al. using local injections of BoNTA to treat neurogenic detrusor overactivity (NDO) [2]. The applications list for lower urinary tract dysfunction (LUTD) has since increased to include idiopathic detrusor /$ see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 EUROPEAN UROLOGY 60 (2011) overactivity (IDO) [3], bladder outflow obstruction (BOO) [4], and painful bladder syndrome/interstitial cystitis (PBS/ IC) [5]. Botulinum toxin (BoNT) use for LUTD remains unlicensed. There are seven serotypes of the toxin, BoNTA to BoNTG, with the most commonly used being BoNTA. The toxins disrupt different parts of the soluble N-ethylmaleimidesensitive factor attachment protein receptor (SNARE) complex, with BoNTA acting against synaptosomal-associated protein molecular weight 25 kda (SNAP-25) [6]. Because SNAP-25 is necessary for fusion of neurotransmitter-filled vesicles with the plasma membrane and their release during exocytosis, its cleavage by BoNTA causes a highly specific neuromuscular blockade of vesicular acetylcholine release at somatic and autonomic presynaptic nerve terminals [6]. Previously, internalisation of the neurotoxic component of BoNTA has been achieved due to binding of the toxin to its specific receptor protein, synaptic vesicle protein 2 (SV2), in the presynaptic nerve terminals [6,7]. Both SNAP-25 and SV2 have been identified on nerve fibres in both the detrusor and suburothelium of human bladders [7,8]. The action of BoNTA is not permanent because neuronal death does not occur and eventually the toxin is inactivated and removed. BoNTA was the first licensed serotype in clinical use under the trade name (Allergan Pharmaceuticals, Irvine, CA, USA); however, other brands also exist, including Dysport (Ipsen Biopharm Ltd, Slough, UK), Xeomin (Merz Pharmaceuticals UK Ltd, Herts, UK), Prosigne (Lanzhou Biological Products, Lanzhou, China), and PurTox (Mentor Corporation, Madison, WI, USA). The different companies manufacturing BoNTA have different isolation, extraction, purification, and formulation processes, and therefore different fragments of BoNT are isolated. Although the BoNTA products are of the same serotype, their dose, efficacy, duration of effect, and safety profile are different enough for them not to be considered generic equivalents [9]. There are no randomised studies directly comparing the different agents for dose, efficacy, and safety for the different indications of use. Consequently, it can be problematic to assume a direct dose correlation. However, it was said 1 U of has been shown, in small studies, to be approximately similar in terms of efficacy to 3 5 U of Dysport [8,10,11], 1 U of Xeomin [12], and 1 U of Prosigne [13]. This simple linear relationship is disputed in terms of the biologics of measuring efficacy and safety for the different applications of BoNT use [14,15]. To our knowledge, there are no adequately powered studies or systematic reviews of the comparison of the efficacy of and Dysport. In addition, no BoNT preparations are licensed for use for any urologic application; therefore, it is essential that patients are informed of the correct evidence and risks prior to being given a specific BoNT preparation. New terminology has been approved for the different BoNTA preparations, and is called onabotulinumtoxina, Dysport is called abobotulinumtoxina, and Xeomin is called incobotulinumtoxina. The changes to the established drug names, enforced by the US Food and Drug Administration (FDA), were made to reinforce individual potencies, to prevent drug errors, and to prevent interchangeability of Table 1 Characteristics of and Dysport Proprietary name Dysport Drug name OnabotulinumtoxinA AbobotulinumtoxinA Molecular size 900 kd >300 kd Protein content Albumin Hemagglutinin Stabilisation Vacuum drying Lyophilisation Storage pre/ postreconstitution 2 8 8C/refrigerate 24 h 2 8 8C/refrigerate 4 h products (Table 1). Prosigne has been described in only one study [13], and no studies using incobotulinumtoxina or PurTox for urologic applications exist. The objectives of the systematic review were (1) to assess in parallel the efficacy of onabotulinumtoxina and abobotulinumtoxina for the treatment of NDO, IDO, and DSD in adults and children and for BOO and PBS/IC in adults and (2) to document the reported details on the administration and adverse events of onabotulinumtoxina and abobotulinumtoxina. 2. Evidence acquisition 2.1. Literature search In accordance with the PRISMA guidelines [16], a systematic literature review was performed to identify articles published between 1985 and December 2010 on the use of intravesical BoNT injections for the treatment of LUTD. We performed a search of the PubMed, Scopus, and Embase databases utilising the MeSH term botulinum toxin a or the search terms botulinum toxin, botulinum neurotoxin,, onabotulinumtoxina, Dysport, abobotulinumtoxina, Xeomin, incobotulinumtoxina, Prosigne, PurTox, and BoNT combined with the search terms neurogenic detrusor overactivity, idiopathic detrusor overactivity, overactive bladder, (urge)ncy, (urge)ncy incontinence, sensory bladder, interstitial cystitis, painful bladder, bladder outflow obstruction, detrusor sphincter dyssynergia, benign prostatic hyperplasia/ enlargement, adverse events, and LUTS. Where possible, language and article-type limits were applied to exclude non-english articles, review articles, and editorials or letters. References of articles were screened to identify any missed articles. Because numerous studies are ongoing, we searched the abstracts of the 2011 annual meeting of the European Association of Urology to identify level 1 data awaiting publication. These studies are presented in the supplementary tables but are not included in the analysis because they are still awaiting peer review Inclusion and exclusion criteria Two independent reviewers (AM and CRC) reviewed each title and abstract and, if unclear, the full article excluding nonhuman studies, articles with 10 cases (except when recording adverse events), and articles with <4 wk followup. In addition, because this review is intended to evaluate the available clinical evidence on onabotulinumtoxina and abobotulinumtoxina, articles not differentiating the individual outcomes of these two preparations were

3 786 EUROPEAN UROLOGY 60 (2011) excluded. Articles were further separated into categories shown in Figure 1. All articles were reviewed for primary and secondary outcomes, injection protocols, and adverse events by one author (AM) in an Excel spreadsheet. When outcomes of a BoNT injection were reported at more than one time point, the reported outcomes closest to 4 wk of follow-up were used. This threshold was chosen because BoNT has been shown to have peak efficacy commencing at this time point and subsequent parameters have not been found to be significantly different up to 6 mo. If more than one treatment of BoNT was given, the outcomes of the first treatment were used. However, it has been shown that successive BoNT injections have not affected outcomes significantly up to eight consecutive injections [17,18] Assessment of results Data were compiled into high-level data (level 1 and 2) and lower-level data (level 3). The levels of evidence chosen were those applied by the European Association of Urology [19]. Level 1 studies included randomised controlled studies, and level 2 included well-designed quasi-experimental studies. Level 3 studies included nonexperimental, comparative, and correlation studies. Paediatric studies were evaluated separately. The most commonly reported outcome parameters, administration details, and adverse events from [(Fig._1)TD$FIG] all of the studies were summarised and presented, giving due preference to high-level studies Statistical analysis Where possible, the individual study data were converted in to a percentage change format so that they would be comparable between studies. This is done by subtracting the baseline (pretreatment) value from the posttreatment value and dividing by the baseline value by 100. The mean and the standard error of the mean were calculated for each parameter for the studies reporting on onabotulinumtoxina and abobotulinumtoxina at different doses. High-level studies were presented separately to all of the studies by dose and also by combining all doses for each preparation. Conclusion statements were provided from the collected literature regarding the strength of the available evidence for both preparations of BoNTA. 3. Evidence synthesis 3.1. Botulinum toxin A for neurogenic detrusor overactivity A total of 43 articles met the inclusion criteria. All of the commonly reported parameters are included in Supplementary Table 1. Three studies were level 1 evidence, two Ar cles a er excluding duplicates, non-english ar cles, and reviews/editorials NDO IDO DSD BOO PBS/IC Adverse (n = 88) (n = 57) (n = 24) (n = 20) (n = 13) events Ar cles a er exclusions applied by reviewers described in sec on 2.2 (n = 11) NDO IDO DSD BOO PBS/IC (n = 43) (n = 30) (n = 10) (n = 10) (n = 9) NDO NDO IDO IDO DSD DSD Dysport Adult Paeds Adult Paeds Adult Paeds (n = 9) (n = 1) (n = 9) (n = 37)* (n = 7)* (n = 28) (n = 8) Dysport Dysport Unreported Dysport Unreported Dysport Unreported (n = 28)** (n = 10)** (n = 3) (n = 26) (n = 7) (n = 1) Fig. 1 The flow and distribution of articles following the inclusion and exclusion criteria. NDO = neurogenic detrusor overactivity; IDO = idiopathic detrusor overactivity; DSD = detrusor sphincter dyssynergia; BOO = bladder outlet obstruction; PBS/IC = painful bladder syndrome/interstitial cystitis; Paeds = paediatric patients. *One article deals with both children and adults. **One article deals with both preparations.

4 EUROPEAN UROLOGY 60 (2011) for onabotulinumtoxina and one abobotulinumtoxina. Three were level 2 evidence in adults: One reported outcomes for onabotulinumtoxina, one reported outcomes for abobotulinumtoxina, and one reported outcomes for both preparations. For children, we found no level 1 evidence and two level 2 studies, both for abobotulinumtoxina; the remainder were level 3. Seven parameters were identified as commonly reported: return of continence in 54%, daily leak in 20%, daily catheterisation in 20%, mean cystometric capacity (MCC) in 95%, reflex volume (RV) in 46%, mean detrusor pressure (MDP) in 61%, mean voiding pressure (MVP) in 27%, and patient satisfaction/quality of life (QoL) in 24%. The urodynamic parameters were recorded in accordance with International Continence Society guidelines. It must be noted, however, that RV was not recorded in patients in whom detrusor overactivity was cured; therefore, the observations recorded will be biased. Patient satisfaction/ QoL was measured with nine different tools Botulinum toxin A for neurogenic detrusor overactivity in adults Ehren et al. have compared abobotulinumtoxina 500 U with placebo and found it to significantly reduce the need for anticholinergic medication (primary outcome). There were also significant improvements in urodynamic parameters and days without leakage compared with placebo [20]. The other study using this preparation (level 2) randomised patients to either 500 U or 750 U [21]. The authors found a trend towards greater improvement with 750 U that was not significant. Grosse et al. utilised onabotulinumtoxina and abobotulinumtoxina in one level 2 study [22]. The authors presented the differences in the changes of parameters among 500 U, 750 U, and 1000 U of abobotulinumtoxina and a combination of doses for onabotulinumtoxina (but mostly 300 U). They reported a significant difference only in continence volume (the volume reported by a patient in a bladder diary when they felt securely continent) between the two preparations. None of the other studies assessing onabotulinumtoxina have presented this parameter, so we were unable to present this in our review. The authors also found 9 of 22 nonresponders in the abobotulinumtoxina group and 7 of 22 nonresponders in the onabotulinumtoxina group. Similarly, onabotulinumtoxina 200 U and 300 U has been shown to lead to significant improvements in parameters compared to placebo (level 1) [23,24]. In addition, improvements in symptomatic and urodynamic parameters have been shown to be superior to intravesical resiniferatoxin by Giannantoni et al. [25]. Abdel-Meguid et al. reported improved continence rates and reductions in incontinence episodes in patients with spinal cord injury receiving 100 U of the 300 U of onabotulinumtoxina into the trigone compared with 300 U in the detrusor alone, which did not significantly affect MCC, MDP, and QoL outcomes [26]. The largest study to date (still in abstract form) of 275 NDO patients has reported similar improvements with U of onabotulinumtoxina [27]. There is high-level evidence advocating the use of both preparations of BoNTA. OnabotulinumtoxinA was given to 1068 patients in 28 studies, and abobotulinumtoxina was Table 2 Outcomes of all studies of onabotulinumtoxina and abobotulinumtoxina for the treatment of neurogenic detrusor overactivity in adults MDP, RV, MCC, Daily catheterisation, Daily leak, Return of continence, % (SEM) No. of studies; No. of patients All studies Levels of evidence OnabotulinumtoxinA, 200 U 1 and 2 1; OnabotulinumtoxinA, 300 U 1 and 2 3; (12) 65(10) 13 (11) 67 (9) 49 (28) 42 OnabotulinumtoxinA, all doses 1 and 2 4; 114 * 63.5 (7) S59 (5) S16 (7) 62 (10) 48 (13) AbobotulinumtoxinA, 500 U 1 and 2 3; (21) 53 (45) 74 AbobotulinumtoxinA, 750 U 1 and 2 2; (57) 94 (33) AbobotulinumtoxinA, 1000 U 1 and 2 1; AbobotulinumtoxinA, all doses 1 and 2 3; (9) 46 (19) 44 (18) OnabotulinumtoxinA, 200 U All 2; (11) 65 (27) OnabotulinumtoxinA, 300 U All 23; (7) 76 (5) 21 (5) 90 (17) 71 (12) 50 (5) OnabotulinumtoxinA, all doses All 28; 1068 * 71 (6) S73 (5) S21 (4) 87 (14) 68 (9) S51 (4) AbobotulinumtoxinA, 500 U All 7; (1) 56 (9) 64 (28) 40 (17) AbobotulinumtoxinA, 750 U All 3; (35) 94 (33) 52 AbobotulinumtoxinA, 1000 U All 4; (11) 70 (15) 87 (10) 53 (4) AbobotulinumtoxinA, all doses All 10; 491 * 66 (5) 64 (8) 79 (14) S46 (8) MCC = mean cystometric capacity; MDP = mean detrusor pressure; RV = reflex volume; SEM = standard error of the mean. Includes studies reporting combined outcomes of different doses that could not be included in individual dose outcomes for each preparation. *

5 788 EUROPEAN UROLOGY 60 (2011) Table 3 Outcomes of all studies of onabotulinumtoxina and abobotulinumtoxina for the treatment of neurogenic detrusor overactivity in children All studies No. of studies; No. of patients Return of continence, % (SEM) Daily leak, MCC, RV, MDP, OnabotulinumtoxinA, all 2; (11) 98 (14) 36.5 (5) AbobotulinumtoxinA, all 2; (3) 48 (7) 48 (10) MCC = mean cystometric capacity; MDP = mean detrusor pressure; RV = reflex volume; SEM = standard error of the mean. given to 491 patients in 10 studies (Table 2). The duration of efficacy could not be compared easily between studies because this parameter relied on the study protocol. A total of 14 studies reported the time interval between injections; the range for onabotulinumtoxina was 6 16 mo, and the range for abobotulinumtoxina was 5 12 mo. Only seven studies reported on patients who failed to respond to BoNT; the range for onabotulinumtoxina was 6 25%, and the range for abobotulinumtoxina was 10 32% Botulinum toxin A for neurogenic detrusor overactivity in children Seven studies reported on the effects of BoNTA in NDO in children. The majority of patients had meningomyelocele. Two studies were level 2, and five studies were level 3; two administered onabotulinumtoxina, two administered abobotulinumtoxina, and three did not report the preparation (Table 3). There is only level 2 evidence for abobotulinumtoxina in children with NDO. OnabotulinumtoxinA was administered at 12 U/kg and abobotulinumtoxina was administered at U/kg. It must be noted that the FDA is investigating a number of deaths related to BoNT administration in children with cerebral palsy who were injected for muscle spasticity in the legs [28]. Because the investigation is ongoing, there are no formal details to date on the preparations and the doses of BoNT under investigation. The FDA has stated that the deaths were due to higher doses of Myobloc or onabotulinumtoxina doses of U/kg [29]. symptomatic, urodynamic, and QoL parameters. Dmochowski et al. have compared a range of doses of onabotulinumtoxina [33]. The authors reported change in incontinence episodes from baseline but did not show the original baseline values; therefore, these results could not be included in the analysis. Tincello et al. have reported (in abstract form) the largest randomised controlled study of onabotulinumtoxina to date, in 227 patients, utilising 200 U and found significant improvements in symptoms and QoL parameters over placebo [34]. One hundred units were found to confer similar improvements with the Kings Health Questionnaire as well as incontinence episodes with higher doses but with a lower rate of retention of urine (18% vs 25%). When considering all data, 26 studies reported on 1150 patients receiving onabotulinumtoxina and 2 studies reported on 41 patients receiving abobotulinumtoxina (Supplementary Table 2) Botulinum toxin A for idiopathic detrusor overactivity in children Two studies described the use of BoNTA in children with IDO (Supplementary Table 2). One used onabotulinumtoxina, and the other did not document the preparation. Hoebke et al. used 100-U intradetrusor injections sparing the trigone. Of 15 patients in the study, 3 were deemed not to have responded. The reported improvements in urodynamic parameters are comparable to adult studies. Again, one must emphasise caution when using BoNT in children Botulinum toxin A for idiopathic detrusor overactivity Thirty studies were included for the indication of IDO; 28 included adults and 2 included children. Four level 1 studies and two level 2 studies investigated onabotulinumtoxina, and we could find no level 1 or 2 evidence for abobotulinumtoxina. There is no high-level evidence for BoNTA in children with IDO Botulinum toxin A for idiopathic detrusor overactivity in adults In total, 416 patients were reported in high-level studies as receiving onabotulinumtoxina (Table 4). Four randomised placebo-controlled studies have demonstrated significant improvements in adults with IDO [30 33]. Brubaker et al. used 200 U and found that 60% of patients improved their global impression index for a median duration of effect of 373 d [30]. Flynn et al. and Sahai et al. used 200/300 U and 200 U, respectively, and found improvements in 3.3. Botulinum toxin A for bladder outlet obstruction Nine studies investigated BoNTA use in BOO. Of these, one was level 1, two were level 2, and the remainder were level 3 (Supplementary Table 3). Only one level 3 study investigated abobotulinumtoxina. The onabotulinumtoxina dose used was between 100 U and 300 U, but up to 600 U have been described in split doses. The dose of abobotulinumtoxina was U. Marberger et al. randomised 380 patients to receive placebo or onabotulinumtoxina (100 U, 200 U, or 300 U) administered to both lateral lobes. There was no significant difference in the decrease of International Prostate Symptom Score or in adverse events, up to 72 wk, for the different doses of onabotulinumtoxina compared with placebo [35]. This abstract report showed a high placebo response; however, improvements from baseline were significant, thus the 100-U dose may be sufficient. All studies injected BoNTA transperineally into both lobes of the prostate except Silva

6 EUROPEAN UROLOGY 60 (2011) Table 4 Outcomes of all studies of onabotulinumtoxina and abobotulinumtoxina for the treatment of idiopathic detrusor overactivity in adults IIQ-7, UDI-6, MDP, MCC, Return of continence, % (SEM) Daily UI, Daily urgency episodes, Daily frequency, No. of studies; No. of patients All studies Levels of evidence OnabotulinumtoxinA, all doses 1 and 2 6; 416 S37 (6) S48 (11) S67 (5) 41 (13) S43 (5) S67 (0.2) OnabotulinumtoxinA, 100 U All 6; (5) 37 (7) (0.2) 41 (8) OnabotulinumtoxinA, 200 U All 15; (4) 62 (8) 73 (8) 57 (7) 80 (9) 43 (4) 51 (3) 67 (2) OnabotulinumtoxinA, all doses All 26; 1150 * S35 (5) S53 (7) S68 (6) 57 (6) 58 (8) S39 (5) S39 (5) S53 (7) AbobotulinumtoxinA, 500 U All 2; (15) (14) 26 IIQ-7 = Incontinence Impact Questionnaire 7 Items; MCC = mean cystometric capacity; MDP = mean detrusor pressure; RV = reflex volume; SEM = standard error of the mean; UDI-6 = Urogenital Distress Inventory 6 Items; UI = urgency incontinence. Includes studies reporting combined outcomes of different doses that could not be included in individual dose outcomes for each preparation. * et al, who injected transrectally into the transition zone [36 38]. The only level 1 study, by Maria et al, showed a 54% improvement in American Urological Association (AUA) symptom score from baseline compared with no change for placebo [4]. One level 2 study compared onabotulinumtoxina with an a-antagonist and a 5a-reductase inhibitor, and the other study compared onabotulinumtoxina with and without an a-antagonist (Supplementary Table 3) [39,40]. Reductions in prostate volume and prostate-specific antigen are variable. Maria et al. [4] and Nikoobakht et al. [41] have respectively reported large reductions of 55% and 43% for onabotulinumtoxina and 34% and 32% for abobotulinumtoxina; however, other studies have shown lesser reductions. The combined outcomes of the all of the studies are shown in Table Botulinum toxin A for detrusor sphincter dyssynergia Eight studies investigated BoNTA in DSD in adults (Supplementary Table 4). Of these, two were level 1, both studying onabotulinumtoxina, and the rest were level 3. Only one study investigated abobotulinumtoxina, and another used either abobotulinumtoxina or onabotulinumtoxina but did not report separate outcomes. All studies utilised a dose of 100 U of onabotulinumtoxina except one, in which U were used. The dose of abobotulinumtoxina used was 150 U. The changes in reported parameters are shown in Table 6. Gallien et al. reported significant improvements in postvoid residual urine volume (PVRU), voiding volume, and MDP compared with placebo [42]. De Seze et al. showed significant improvements using onabotulinumtoxina compared with 0.5% lidocaine Botulinum toxin A for detrusor sphincter dyssynergia in children Only two studies could be included for the use of BoNTA in children; however, neither disclosed the preparation used. Consequently, we were unable to report outcomes for onabotulinumtoxina and abobotulinumtoxina in this category Botulinum toxin A for painful bladder syndrome/interstitial cystitis All the nine articles reporting the use of BoNTA for PBS/IC utilised onabotulinumtoxina (Supplementary Table 5). Of these, one was level 1 and two were level 2. The level 1 study reported on QoL outcomes utilising the Chronic Prostatitis Symptom Index (female modification; CPSI-F) and AUA indices as well as graded chronic pain and perceived stress scales and the visual analogue scale (VAS); outcomes were not found to be significantly different from placebo [43]. One of the level 2 studies compared onabotulinumtoxina 100 U or 200 U with hydrodistension versus hydrodistension alone [44]. The authors found a significant decrease in symptom indices, bladder diary, and urodynamic parameters at 3 mo more often with onabotulinumtoxina than with hydrodistension alone. The other

7 790 EUROPEAN UROLOGY 60 (2011) Table 5 Outcomes of all studies of onabotulinumtoxina and abobotulinumtoxina for the treatment of bladder outlet obstruction Evidence Levels of evidence No. of studies; No. of patients IPSS, Q max, Prostate volume, PSA, PVRU, QoL, OnabotulinumtoxinA 1 and 2 3; (8) 32 (17) 21 (11) 15 (9) 26 (14) 35 (6) OnabotulinumtoxinA All 9; (5) 41 (9) 19 (5) 13 (5) 36 (9) 39 (4) AbobotulinumtoxinA All 1; IPSS = International Prostate Symptom Score; PSA = prostate-specific antigen; PVRU = postvoid residual urine volume; Q max = maximum flow rate; QoL = quality of life; SEM = standard error of the mean. Table 6 Outcomes of all studies of onabotulinumtoxina and abobotulinumtoxina for the treatment of detrusor sphincter dyssynergia Evidence Levels of evidence No. of studies; No. of patients PVRU, MUP, MVP, OnabotulinumtoxinA 1 2; (23) 23 (6) 9 (12) OnabotulinumtoxinA All 7; (8) 30 (7) 26 (8) AbobotulinumtoxinA All 1; MUP = Maximum urethral pressure; MVP = maximum detrusor pressure during voiding cystometry; PVRU = postvoid residual urine volume; SEM = standard error of the mean. Table 7 Outcomes of all studies of onabotulinumtoxina for the treatment of painful bladder syndrome/interstitial cystitis Evidence Levels of evidence No. of studies; No. of patients Daytime frequency, Nocturia, MCC, VAS, OnabotulinumtoxinA 1 and 2 3; (5) 58 (13) 44 (18) 47 (8) OnabotulinumtoxinA All 9; (3) 70 (6) 60 (18) 44 (6) MCC = mean cystometric capacity; SEM = standard error of the mean; VAS = visual analogue scale. study showed better improvements in frequency, nocturia, and global IC score with 300 U of onabotulinumtoxina compared with instillations of bacillus Calmette-Guérin. In Table 7, we have combined all data describing only onabotulinumtoxina injections Administration: technique, site, and volume of injection Administration in neurogenic detrusor overactivity The number and volume of injections varied among the 43 studies. OnabotulinumtoxinA was given at injection sites, with 30 being the most common, at a volume of 3 30 ml, with 30 ml being the most common. AbobotulinumtoxinA was given at injection sites, with 30 being the most common, at a volume of 5 30 ml, with 30 ml being the most common. Unfortunately, subanalysis of volume and injection site number is beyond the scope of this review; however, these variables may have some effect on outcomes. All studies but four [26,45 47] reported injections into the detrusor muscle sparing the trigone. Trigonal injections may possibly improve daily incontinence and lead to better continence rates than detrusor injections alone; however, the urodynamic parameters in these studies were affected to a lesser extent Administration in idiopathic detrusor overactivity The number of injection sites using onabotulinumtoxina varied from 3 to 40, with 20 being the most common, and sites were injected with abobotulinumtoxina. The total injection volume varied from 20 ml to 30 ml for abobotulinumtoxina and from 3 ml to 30 ml with onabotulinumtoxina, with 20 ml being the most common. Both the abobotulinumtoxina studies used intradetrusor injections sparing the trigone; however, an abstract reported by Manecksha et al. has shown greater reductions in Overactive Bladder Symptom Score lasting for a longer period of time with trigonal injections compared with detrusor injections alone utilising 500 U of abobotulinumtoxina [48]. Of the onabotulinumtoxina studies, two included the trigone, one compared trigonal and nontrigonal injections [49], and another used suburothelial and bladder base injections [50,51]. Kuo described improvements in symptoms with detrusor, suburothelial, or bladder base injections, but MCC was not increased in the bladder base injection group [50]. Moreover, there were no cases of ureteric reflux. Lucioni et al. compared trigonal and nontrigonal injections and found no significant difference in symptomatic improvements [49] Administration in bladder outlet obstruction All studies except three injected BoNTA into the prostatic lobes via the transperineal route. In contrast, Silva et al. and Reddy et al. used a transrectal approach injecting into the transition zone [36 38,52]. OnabotulinumtoxinA was delivered in 4 9 ml, most commonly 4 ml. AbobotulinumtoxinA was given in 4 ml. There is no standard administration method at present, and this issue needs to be addressed in future trials.

8 EUROPEAN UROLOGY 60 (2011) Administration in detrusor sphincter dyssynergia OnabotulinumtoxinA was given in a total volume of ml, most commonly 4 ml. This was administered either transurethrally (three studies) or transperineally (four studies) via one to eight injections. AbobotulinumtoxinA was given transurethrally at a volume of 4 ml via one injection into the external urethral sphincter Administration in painful bladder syndrome/interstitial cystitis All nine studies used suburothelial injections for the treatment of PBS/IC. Of these, four included the trigone and one injected around the bladder neck. The volume varied from 2 ml to 30 ml in injection sites. The method of administration clearly requires further study Adverse events Adverse events in neurogenic detrusor overactivity Reports of muscle weakness or hypoasthenia were first described by Wyndaele and Van Dromme [53] and by De Laet and Wyndaele [54]. Twohigh-levelstudiesreported on one patient each who developed hypoasthenia after receiving abobotulinumtoxina 750 U [21,22]. Grise et al. reported one case each of haematuria, pyelonephritis, and urgency [21]. Similarly Giannantoni et al. noted one case of hypoasthenia with 300 U of onabotulinumtoxina [25]. The rate of urinary tract infection (UTI) was reported at 21 32%, and rate of injection site pain reported was up to 10% [23]. The incidence of severe treatment-related adverse events in high-level studies is low in patients receiving both preparations of BoNTA. When analysing all studies, only a few have reported isolated cases of muscular weakness with onabotulinumtoxina; 2 of 26 studies reported a rate of 2 15% [55,56], and 6 of 10 studies reported a range of 2 12% with abobotulinumtoxina [17,22,56 59]. Of the 1025 patients who received onabotulinumtoxina, only 5 (0.005%) were reported to have developed muscular weakness compared with 13 of 491 (0.026%) who received abobotulinumtoxina. The majority of cases of hypoasthenia are transient and self-limiting, and we found no reports of adults requiring hospitalisation and intervention [60]. There are only a handful of reports in which muscular weakness led to significant disruption of patient QoL [53,61]. Schulte-Baukloh et al. have demonstrated formation of antibody to onabotulinumtoxina using a mouse diaphragm assay for onabotulinumtoxina in 8 of 25 patients with NDO; of these, 4 revealed a strong antibody reaction and 4 showed an equivocal reaction [62]. However, the correlation between the presence of antibodies and failure was not convincing. In contrast, using abobotulinumtoxina in children, Kajbazadeh et al. have shown, via an enzymelinked immunosorbent assay, an increase in antibody titres in most children 1 mo postinjection of BoNTA; however, pretreatment levels returned in 13 of 15 children [63]. In NDO patients, unchanged or less fibrosis and inflammation were found in the bladder wall postinjection of 300 U of onabotulinumtoxina [64 66]. The current consensus view is that antibody formation to BoNTA is not relevant in contemporary clinical practice Adverse events in idiopathic detrusor overactivity Bauer et al. have specifically looked at adverse events after injection of both 100 U and 200 U of onabotulinumtoxina and 500 U of abobotulinumtoxina by using a patient questionnaire [60]. Dry mouth occurred in the 42% of the 200-U onabotulinumtoxina group, 20% of the 100-U onabotulinumtoxina group, and 10% of the abobotulinumtoxina group. There was a 20% higher incidence of weakness, impaired vision, and dysphagia in the 200-U onabotulinumtoxina group. The weakness of this study is the reliance on a questionnaire that may have introduced suggestion bias that cannot be assessed due to the lack of a placebo arm. However, it was shown higher doses of the toxin led to higher rates of adverse events. Moreover, the muscular weakness was transient and mild, but the authors reported lower satisfaction in these patients. One study reported no significant differences in inflammation, fibrosis, and dysplasia in the bladder wall of patients with IDO who received onabotulinumtoxina [64]. From the high-level studies, the reported range for increased PVRU (>200 ml) was 27 43% [30 32], which was temporary and reported in one study to last a median of 62 d [30]. The rate of UTI ranged from 13% to 44% [30 32,67], and this was related to clean intermittent selfcatheterisation (CISC). Kuo compared suburothelial, detrusor, and bladder base injections and found the risk of urinary retention was 13%, 13%, and 0%, respectively, in the three groups [50]. The increase in PVRU was highest in the suburothelial injection group (47%), followed by the detrusor injection group (33%) and the bladder base injection group (13%). Dmochowski et al. have shown a variable rate of increased PVRU (>200 ml) with the various doses of onabotulinumtoxina (50 U, 9%; 100 U, 18%; 150 U, 28%; 200 U, 23%; and 300 U, 25%) compared with a placebo rate of 2% [33]. The two level 3 studies assessing abobotulinumtoxina have reported CISC rates of 19% and 35% [68,69]. Kessler et al. showed that 43% of patients required CISC after receiving 200 U of onabotulinumtoxina; however, this did not significantly affect scores on the Urogenital Distress Inventory 6 Items and Incontinence Impact Questionnaire 7 items [70] Adverse events in bladder outlet obstruction The randomised placebo controlled study by Maria et al. revealed no local or systemic complications after single or repeat injections of 200 U of onabotulinumtoxina [4]. Kuo and Liu reported gross haematuria in 14% and acute prostatitis in 2% that were treated conservatively and that settled within 3 d [39]. The only study using abobotulinumtoxina reported no local or systemic complications except haematuria in 3 of 72 patients (4%) [41]. There are no reports of BoNT adversely affecting sexual function, and International Index of Erectile Function scores have been shown not to be changed by the administration of 100 U, 200 U, and 300 U of onabotulinumtoxina [35].

9 792 EUROPEAN UROLOGY 60 (2011) Adverse events in detrusor sphincter dyssynergia De Seze et al. reported good tolerance of onabotulinumtoxina, and only one of five patients reported transient worsening of preexisting stress incontinence [71]. Gallien et al. reported urinary leakage in 5% and 4% of the placebo and onabotulinumtoxina groups, respectively [42]. UTIsoccurredin29%and36%oftheplaceboand onabotulinumtoxina groups, respectively. In addition, one patient in the onabotulinumtoxina group reported faecal incontinence. The only study investigating abobotulinumtoxina showed that 2 of 17 patients developed de novo stress incontinence and 3 had exacerbation of preexisting incontinence [72]. There have also been reports of generalised muscle weakness following urethral injections [54]. Three of the five patients injected by Dysktra and Sidi developed temporary upper limb weakness [73] Adverse events in painful bladder syndrome/interstitial cystitis Gottsch et al. injected 50 U of onabotulinumtoxina in to the bladder neck and found no systemic or local complications [43]. In contrast, Kuo and Chancellor reported 2 of 15 patients with haematuria, 7 with dysuria, and 5 with large PVRU after receiving 200 U of onabotulinumtoxina [44]. It must also be noted that patients received hydrodistension with onabotulinumtoxina, but the incidence of haematuria and large PVRU was 0%, and 4% developed dysuria after hydrodistension alone. 4. Conclusions We have produced the most comprehensive review of the BoNTA literature for five urologic applications to date. Unlike the majority of previous reviews published for BoNT treatments, we have summarised separate reported outcomes for the two common preparations at the various doses for which they have been used. Unfortunately, in the urologic arena, there are no head-to-head comparative studies of the two preparations. Therefore, we were unable to directly assess the two preparations due to a lack of standardised data, a deficiency in high-quality data, and the risk of methodological error in comparing data with a big discrepancy in the number of reports. In this comparative review, we found that of the two common preparations of BoNT, onabotulinumtoxina has been studied more widely than abobotulinumtoxina in five urologic applications. In 79 healthy volunteers, Wohlfarth et al. suggested bioequivalence of 1.57 U of abobotulinumtoxina and 1 U of onabotulinumtoxina in striated muscle (95% confidence interval, U) [74]. Therefore, the dose-equivalence ratio of 3:1 was within the statistical error limits. Sampaio et al. applied Cochrane criteria to head-to-head studies investigating dose-equivalence ratios for both formulations in patients with single focal dystonia [75]. At a dose ratio of 3:1, abobotulinumtoxina had a stronger clinical effect, a longer duration of effect, and an increased risk of side effects than onabotulinumtoxina. This and another review suggest that a dose-equivalence ratio of <3:1 is probably more suitable [75,76]. However, it must be borne in mind that these studies are in striated muscle. The knowledge of BoNT pharmacokinetics in smooth muscle is even more limited and cannot be extrapolated from skeletal muscle to urologic practice. The BoNTA dose-efficacy curve is a classic parabola, and as the top of the curve is reached, further efficacy is not gained [14,27,33]. The excess toxin, however, may diffuse away from the site of application, increasing the risk of side effects [27,33]. The best approach is summarised in the principle of as much as needed, but as little as possible. This approach maximises therapeutic efficacy, reduces the risk of side effects and antibody formation, and minimises treatment-related costs. Therefore, it can be seen why it is essential that both preparations are studied fully at different doses and that their outcomes not be combined. From our systematic review on the use of BoNTA for LUTD, we found onabotulinumtoxina was more comprehensively evaluated than abobotulinumtoxina. We have determined the presence of high-level data to support the use of onabotulinumtoxina in the five urologic disorders reviewed. AbobotulinumtoxinA, however, has been described only in three high-level studies in NDO. A direct randomised double-blind comparative study of the two preparations at their most efficacious dose is clearly required. However, even with onabotulinumtoxina, doseranging studies are being reported only at present and suggest 200 U for NDO and 100 U for IDO [27,33]. We have produced summary statements (Appendix) of our findings of the literature regarding onabotulinumtoxina and abobotulinumtoxina in the five applications we investigated to give the reader clear take home messages. Author contributions: Altaf Mangera had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Mangera, Chapple, Apostolidis, Dasgupta, Giannantoni, Gravas, Madersbacher, Andersson. Acquisition of data: Mangera, Chapple. Analysis and interpretation of data: Mangera, Chapple, Apostolidis, Dasgupta, Giannantoni, Gravas, Madersbacher, Andersson. Drafting of the manuscript: Mangera, Chapple. Critical revision of the manuscript for important intellectual content: Chapple, Apostolidis, Dasgupta, Giannantoni, Gravas, Madersbacher, Andersson. Statistical analysis: Mangera, Chapple. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Andersson. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Drs. Chapple and Giannantoni are consultants and scientific advisors to Allergan. Dr. Apostolidis is an

10 EUROPEAN UROLOGY 60 (2011) investigator and a consultant for Allergan. Dr. Dasgupta is an investigator and advisor to Allergan. Drs. Mangera, Gravas and Madersbacher have no conflicts of interest. Funding/Support and role of the sponsor: Dr. Mangera acknowledges the Urology Foundation and the Robert Luff Foundation for a 2-yr research fellowship grant. Appendix A. Conclusion statements Neurogenic detrusor overactivity (NDO) High-level data show the benefits of both onabotulinumtoxina and abobotulinumtoxina in the treatment of NDO in adults. When considering all studies, onabotulinumtoxina is better studied than abobotulinumtoxina. Only abobotulinumtoxina has high-level data supporting its use in children with NDO, but abobotulinumtoxina cannot be recommended for routine clinical use at present. Idiopathic detrusor overactivity (IDO) High-level data support the use of onabotulinumtoxina for IDO in adults. OnabotulinumtoxinA is much better investigated than abobotulinumtoxina when considering all studies. Only onabotulinumtoxina has been reported in one level 3 study showing clinical improvements in children with IDO, but onabotulinumtoxina cannot be recommended for routine clinical use at present. Bladder outlet obstruction (BOO) Only onabotulinumtoxina has been described in highlevel studies in adults with BOO. When considering all studies, onabotulinumtoxina is better studied than abobotulinumtoxina, although the literature is still poor in this area. The largest blinded randomised study conducted to date does not confirm the significant efficacy shown in earlier studies. Detrusor sphincter dyssynergia (DSD) Only onabotulinumtoxina has level 1 evidence supporting its use in adults with DSD. When considering all studies, onabotulinumtoxina is better studied than abobotulinumtoxina, although the literature is still poor in this area. We were unable to include any studies that investigated onabotulinumtoxina or abobotulinumtoxina in children with DSD. Painful bladder syndrome/interstitial cystitis (PBS/IC) Only onabotulinumtoxina has been used in patients with PBS/IC in both high- and low-level studies, but the literature is still poor in this area. Appendix B. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi: /j.eururo References [1] Dykstra DD, Sidi AA, Scott AB, Pagel JM, Goldish GD. Effects of botulinum A toxin on detrusor-sphincter dyssynergia in spinal cord injury patients. J Urol 1988;139: [2] Schurch B, Schmid DM, Stohrer M. Treatment of neurogenic incontinence with botulinum toxin A. N Engl J Med 2000;342:665. [3] Kuo HC. Urodynamic evidence of effectiveness of botulinum A toxin injection in treatment of detrusor overactivity refractory to anticholinergic agents. Urology 2004;63: [4] Maria G, Brisinda G, Civello IM, Bentivoglio AR, Sganga G, Albanese A. Relief by botulinum toxin of voiding dysfunction due to benign prostatic hyperplasia: results of a randomized, placebo-controlled study. Urology 2003;62: [5] Smith CP, Radziszewski P, Borkowski A, Somogyi GT, Boone TB, Chancellor MB. Botulinum toxin a has antinociceptive effects in treating interstitial cystitis. Urology 2004;64: [6] Montecucco C, Molgo J. Botulinal neurotoxins: revival of an old killer. Curr Opin Pharmacol 2005;5: [7] Coelho A, Dinis P, Pinto R, et al. Distribution of the high-affinity binding site and intracellular target of botulinum toxin type A in the human bladder. Eur Urol 2010;57: [8] Harper M, Fowler CJ, Dasgupta P. Botulinum toxin and its applications in the lower urinary tract. BJU Int 2004;93: [9] Leippold T, Reitz A, Schurch B. Botulinum toxin as a new therapy option for voiding disorders: current state of the art. Eur Urol 2003; 44: [10] Grosse J, Kramer G, Stöhrer M. Success of repeat detrusor injections of botulinum a toxin in patients with severe neurogenic detrusor overactivity and incontinence. Eur Urol 2005;47: [11] Maria G, Cadeddu F, Brisinda D, Brandara F, Brisinda G. Management of bladder, prostatic and pelvic floor disorders with botulinum neurotoxin. Curr Med Chem 2005;12: [12] Dressler D. Comparing and Xeomin for axillar hyperhidrosis. J Neural Transm 2010;117: [13] Gomes CM, de Castro Filho JE, Rejowski RF, et al. Experience with different botulinum toxins for the treatment of refractory neurogenic detrusor overactivity. Int Braz J Urol 2010;36: [14] Wenzel R, Jones D, Borrego JA. Comparing two botulinum toxin type A formulations using manufacturers product summaries. J Clin Pharm Ther 2007;32: [15] Wenzel RG. Pharmacology of botulinum neurotoxin serotype A. Am J Health Syst Pharm 2004;61:S5 10. [16] Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535. [17] Del Popolo G, Filocamo MT, Li Marzi V, et al. Neurogenic detrusor overactivity treated with english botulinum toxin A: 8-year experience of one single centre. Eur Urol 2008;53: [18] Sahai A, Dowson C, Khan MS, Dasgupta P. Repeated injections of botulinum toxin-a for idiopathic detrusor overactivity. Urology 2010;75: [19] Apostolidis A, Dasgupta P, Denys P, et al. Recommendations on the use of botulinum toxin in the treatment of lower urinary tract disorders and pelvic floor dysfunctions: a European consensus report. Eur Urol 2009;55: [20] Ehren I, Volz D, Farrelly E, et al. Efficacy and impact of botulinum toxin A on quality of life in patients with neurogenic detrusor