- Email: [email protected]
Botulinum Toxin A—When is a Unit Not a Unit?
414
LETTERS TO THE EDITOR/ERRATA
rendered dry, who then exhibited a deterioration in upper tract status, made us realize that perhaps a less strict definition of dryness (as accepted by Snodgrass) is safer for these children. This safety pop-off valve prevents long-term upper tract damage in children with a neuropathic bladder. However, one must not lose sight of the indication for surgery in these individuals, which is to render them dry. Almost dry does not constitute true success. Therefore, we think that the question asked in the title remains unanswered, and we expectantly await the results from the series of Snodgrass et al2 and other such studies. 1. Churchill BM, Gilmour RF, Khoury AE and McLorie GA: Biological response of bladders rendered continent by insertion of artificial sphincter. J Urol 1987; 138: 1116. 2. Snodgrass WT, Elmore J and Adams R: Bladder neck sling and appendicovesicostomy without augmentation for neurogenic incontinence in children. J Urol 2007; 177: 1510. 3. Khoury AE, Dave S, Peralta-Del Valle MH, Braga LH, Lorenzo AJ and Bagli D: Severe bladder trabeculation obviates the need for bladder outlet procedures during augmentation cystoplasty in incontinent patients with neurogenic bladder. BJU Int 2008; 101: 223.
Botulinum Toxin A— When is a Unit Not a Unit? To the Editor: As a consultant pediatric surgeon, I have treated several children and young adults suffering from neuropathic bladder with intravesical injections of botulinum toxin A (BTX-A). Numerous studies have been published on the use of this product in various clinical settings in the adult and pediatric populations, many in The Journal of Urology®, which is a leading publication in the field.1–5 However, I wish to draw attention to a shortcoming in the way the use of this product is reported. There are 2 commercially available BTX-A preparations. However, these preparations are not bioequivalent and the unit designations are not interchangeable. Indeed, to this day there are no international units to measure the potency of botulinum toxin-A. The methods used for performing the potency assay are specific to each product. The most commonly available product, Botox®, is packaged as vials containing 100 Allergan units of toxin, with 1 unit corresponding to the calculated median intraperitoneal lethal dose in mice. The other form, Dysport®, is available in vials of 500 Speywood units, with 1 unit corresponding to the median intraperitoneal lethal dose in mice, although these must be different mice, since the accepted conversion rate is 3 Dysport units for 1 Botox unit. Although Dysport is not currently available in the United States, it is used by many European teams.
Reporting can lead to confusion since, even if most authors refer to the actual product used in the materials and methods section of the full text version of the article, this information does not appear in the abstract.1–5 Some authors remark in their conclusions on a specific efficacious dose of BTX-A without specifying the product to which they are referring.3 Others refer to international units, which to this day do not exist.4,5 The lack of equivalence between both measuring systems is not sufficiently specified or known, thus risking errors in prescription, especially with regard to the pediatric population. Until there is a homogenization of the unit of measure of BTX-A it is our duty to ensure that there is as much clarity as possible when referring to this potentially dangerous product. Respectfully, Luke Harper Division of Pediatric Surgery CHU Pellegrin Bordeaux, France 1. Giannantoni A, Porena M, Costantini E, Zucchi A, Mearini L and Mearini E: Botulinum A toxin intravesical injection in patients with painful bladder syndrome: 1-year followup. J Urol 2008; 179: 1031. 2. Neel KF, Soliman S, Salem M, Seida M, Al-Hazmi H and Khatab A: Botulinum-A toxin: solo treatment for neuropathic noncompliant bladder. J Urol 2007; 178: 2593. 3. Kuo HC: Comparison of effectiveness of detrusor, suburothelial and bladder base injections of botulinum toxin A for idiopathic detrusor overactivity. J Urol 2007; 178: 1359. 4. Radojicic ZI, Perovic SV and Milic NM: Is it reasonable to treat refractory voiding dysfunction in children with botulinum-A toxin? J Urol 2006; 176: 332. 5. Kajbafzadeh AM, Moosavi S, Tajik P, Arshadi H, Payabvash S, Salmasi AH et al: Intravesical injection of botulinum toxin type A: management of neuropathic bladder and bowel dysfunction in children with myelomeningocele. Urology 2006; 68: 1091.
Reply: I agree with Harper in the context of the responsible tone and intent of the letter. I believe this letter clearly indicates that botulinum toxin preparations between different providers are not bioequivalent or interchangeable. This point is clearly emphasized in the summary of product characteristics for all botulinum toxin products. This lack of interchangeability refers not only to dosing recommendations, but also to efficacy and safety data using any particular brand. Therefore, I believe caution needs to be applied when considering any form of dose conversion factor because it is more than just the dose—it is also the other aspects relating to penetration of the toxin at its target. Any form of dose conversion assumes similar levels of safety and efficacy across brands, which is clearly not proved at present. We are beholden as clinicians, considering the lack of randomized controlled data in this area, to consider the data for
LETTERS TO THE EDITOR/ERRATA
each brand, bearing in mind that any conclusions can be drawn only if an investigation is carried out using that brand from a clinical and regulatory perspective. Certainly the majority of data published to date in urology have used the Botox brand. Most published data are derived from experience in the adult population, not the pediatric population and, therefore, there is a paucity of data in pediatrics for all brands regarding dosage, efficacy and safety. Thus, it is important to recognize that reportedly efficacious and well tolerated doses in adults cannot safely be extrapolated to the pediatric setting, irrespective of the brand of botulinum toxin. I must congratulate Harper on bringing up this important point. Christopher Chapple Division of Urological Surgery Royal Hallamshire Hospital University of Sheffield Sheffield, United Kingdom
Re: Urodynamic Measures Do Not Predict Stress Continence Outcomes After Surgery for Stress Urinary Incontinence in Selected Women C. W. Nager, M. FitzGerald, S. R. Kraus, T. C. Chai, H. Zyczynski, L. Sirls, G. E. Lemack, L. K. Lloyd, H. J. Litman, A. M. Stoddard, J. Baker and W. Steers for the Urinary Incontinence Treatment Network J Urol 2008; 179: 1470 –1474.
To the Editor: The authors must be congratulated for their effort in performing such a trial to determine the prognostic value of preoperative urodynamics in patients with stress urinary incontinence. Although this study represents a hot and still controversial topic, misunderstanding as well as confusion due to this report must be avoided. Therefore, we would like to offer some comments and criticisms regarding their analysis. First, the authors limited their attention to Valsalva leak point pressure (VLPP) and the presence or absence of abnormal detrusor contraction. This approach represents a limitation, since other urodynamic parameters such as opening detrusor pressure (ODP), closing detrusor pressure (CDP), maximum flow rate, detrusor pressure at maximum flow rate and acceleration of flow rate (AFR)—which are important measures in the assessment of urinary
415
incontinence— have not been considered in the final analysis.1–3 The AFR, which reflects the speed of the detrusor contraction and opening of the bladder neck, has been shown to be an important parameter to study voiding in men and women.2,3 The evaluation of voiding pattern cannot be ignored preoperatively, since the development or persistence of voiding difficulties postoperatively will affect the surgical outcome. The ODP and CDP have also been demonstrated to be simple, useful and noninvasive preoperative parameters to predict outcomes and de novo detrusor overactivity (DO) after continence surgery.1 We found that women who were not cured after colposuspension had significantly lower preoperative ODP and CDP compared to women who were continent after surgery. Second, the assessment was limited to a 24hour pad test, 3-day bladder diary, stress test, self-reported questionnaire and re-treatment for stress urinary incontinence.4 It is not surprising that using such a definition of cure, the results obtained are contradictory to the data published in the literature.5– 8 Ideally, the outcomes assessment should follow the guidelines of the National Institutes of Health, which state that “the development of new symptoms as well as conditions (such as DO) must be considered in the assessment of surgical outcomes.”9,10 Since previous studies have revealed that women with postoperative DO have AFRs, ODPs and CDPs that are significantly higher preoperatively than those with a normal urodynamic test after colposuspension,1 we disagree with the conclusions that urodynamic measures do not predict the outcome of continence surgery. Third, the urodynamic protocol did not involve provocative maneuvers for DO.11 This omission explains why few women had DO compared to other series examining patients with mixed symptoms undergoing urodynamic evaluation.11,12 Thus, some women with urodynamic stress incontinence might have had missed underlying DO. This omission would explain the low cure rate for stress incontinence (53% vs 47%) and the low overall success rate (37% vs 28%) in the no DO and DO groups. This finding emphasizes the importance of performing good quality urodynamics with a range of provocative maneuvers.11 Finally, we believe that the title of the article is inappropriate. The authors only showed that VLPP and the presence of DO, when not using provocative maneuvers, do not predict the outcomes of continence surgery. Therefore, the conclusion that “the study addressed the possible prognostic value of urodynamic studies for success/failure outcome” is in-
LETTERS TO THE EDITOR/ERRATA
rendered dry, who then exhibited a deterioration in upper tract status, made us realize that perhaps a less strict definition of dryness (as accepted by Snodgrass) is safer for these children. This safety pop-off valve prevents long-term upper tract damage in children with a neuropathic bladder. However, one must not lose sight of the indication for surgery in these individuals, which is to render them dry. Almost dry does not constitute true success. Therefore, we think that the question asked in the title remains unanswered, and we expectantly await the results from the series of Snodgrass et al2 and other such studies. 1. Churchill BM, Gilmour RF, Khoury AE and McLorie GA: Biological response of bladders rendered continent by insertion of artificial sphincter. J Urol 1987; 138: 1116. 2. Snodgrass WT, Elmore J and Adams R: Bladder neck sling and appendicovesicostomy without augmentation for neurogenic incontinence in children. J Urol 2007; 177: 1510. 3. Khoury AE, Dave S, Peralta-Del Valle MH, Braga LH, Lorenzo AJ and Bagli D: Severe bladder trabeculation obviates the need for bladder outlet procedures during augmentation cystoplasty in incontinent patients with neurogenic bladder. BJU Int 2008; 101: 223.
Botulinum Toxin A— When is a Unit Not a Unit? To the Editor: As a consultant pediatric surgeon, I have treated several children and young adults suffering from neuropathic bladder with intravesical injections of botulinum toxin A (BTX-A). Numerous studies have been published on the use of this product in various clinical settings in the adult and pediatric populations, many in The Journal of Urology®, which is a leading publication in the field.1–5 However, I wish to draw attention to a shortcoming in the way the use of this product is reported. There are 2 commercially available BTX-A preparations. However, these preparations are not bioequivalent and the unit designations are not interchangeable. Indeed, to this day there are no international units to measure the potency of botulinum toxin-A. The methods used for performing the potency assay are specific to each product. The most commonly available product, Botox®, is packaged as vials containing 100 Allergan units of toxin, with 1 unit corresponding to the calculated median intraperitoneal lethal dose in mice. The other form, Dysport®, is available in vials of 500 Speywood units, with 1 unit corresponding to the median intraperitoneal lethal dose in mice, although these must be different mice, since the accepted conversion rate is 3 Dysport units for 1 Botox unit. Although Dysport is not currently available in the United States, it is used by many European teams.
Reporting can lead to confusion since, even if most authors refer to the actual product used in the materials and methods section of the full text version of the article, this information does not appear in the abstract.1–5 Some authors remark in their conclusions on a specific efficacious dose of BTX-A without specifying the product to which they are referring.3 Others refer to international units, which to this day do not exist.4,5 The lack of equivalence between both measuring systems is not sufficiently specified or known, thus risking errors in prescription, especially with regard to the pediatric population. Until there is a homogenization of the unit of measure of BTX-A it is our duty to ensure that there is as much clarity as possible when referring to this potentially dangerous product. Respectfully, Luke Harper Division of Pediatric Surgery CHU Pellegrin Bordeaux, France 1. Giannantoni A, Porena M, Costantini E, Zucchi A, Mearini L and Mearini E: Botulinum A toxin intravesical injection in patients with painful bladder syndrome: 1-year followup. J Urol 2008; 179: 1031. 2. Neel KF, Soliman S, Salem M, Seida M, Al-Hazmi H and Khatab A: Botulinum-A toxin: solo treatment for neuropathic noncompliant bladder. J Urol 2007; 178: 2593. 3. Kuo HC: Comparison of effectiveness of detrusor, suburothelial and bladder base injections of botulinum toxin A for idiopathic detrusor overactivity. J Urol 2007; 178: 1359. 4. Radojicic ZI, Perovic SV and Milic NM: Is it reasonable to treat refractory voiding dysfunction in children with botulinum-A toxin? J Urol 2006; 176: 332. 5. Kajbafzadeh AM, Moosavi S, Tajik P, Arshadi H, Payabvash S, Salmasi AH et al: Intravesical injection of botulinum toxin type A: management of neuropathic bladder and bowel dysfunction in children with myelomeningocele. Urology 2006; 68: 1091.
Reply: I agree with Harper in the context of the responsible tone and intent of the letter. I believe this letter clearly indicates that botulinum toxin preparations between different providers are not bioequivalent or interchangeable. This point is clearly emphasized in the summary of product characteristics for all botulinum toxin products. This lack of interchangeability refers not only to dosing recommendations, but also to efficacy and safety data using any particular brand. Therefore, I believe caution needs to be applied when considering any form of dose conversion factor because it is more than just the dose—it is also the other aspects relating to penetration of the toxin at its target. Any form of dose conversion assumes similar levels of safety and efficacy across brands, which is clearly not proved at present. We are beholden as clinicians, considering the lack of randomized controlled data in this area, to consider the data for
LETTERS TO THE EDITOR/ERRATA
each brand, bearing in mind that any conclusions can be drawn only if an investigation is carried out using that brand from a clinical and regulatory perspective. Certainly the majority of data published to date in urology have used the Botox brand. Most published data are derived from experience in the adult population, not the pediatric population and, therefore, there is a paucity of data in pediatrics for all brands regarding dosage, efficacy and safety. Thus, it is important to recognize that reportedly efficacious and well tolerated doses in adults cannot safely be extrapolated to the pediatric setting, irrespective of the brand of botulinum toxin. I must congratulate Harper on bringing up this important point. Christopher Chapple Division of Urological Surgery Royal Hallamshire Hospital University of Sheffield Sheffield, United Kingdom
Re: Urodynamic Measures Do Not Predict Stress Continence Outcomes After Surgery for Stress Urinary Incontinence in Selected Women C. W. Nager, M. FitzGerald, S. R. Kraus, T. C. Chai, H. Zyczynski, L. Sirls, G. E. Lemack, L. K. Lloyd, H. J. Litman, A. M. Stoddard, J. Baker and W. Steers for the Urinary Incontinence Treatment Network J Urol 2008; 179: 1470 –1474.
To the Editor: The authors must be congratulated for their effort in performing such a trial to determine the prognostic value of preoperative urodynamics in patients with stress urinary incontinence. Although this study represents a hot and still controversial topic, misunderstanding as well as confusion due to this report must be avoided. Therefore, we would like to offer some comments and criticisms regarding their analysis. First, the authors limited their attention to Valsalva leak point pressure (VLPP) and the presence or absence of abnormal detrusor contraction. This approach represents a limitation, since other urodynamic parameters such as opening detrusor pressure (ODP), closing detrusor pressure (CDP), maximum flow rate, detrusor pressure at maximum flow rate and acceleration of flow rate (AFR)—which are important measures in the assessment of urinary
415
incontinence— have not been considered in the final analysis.1–3 The AFR, which reflects the speed of the detrusor contraction and opening of the bladder neck, has been shown to be an important parameter to study voiding in men and women.2,3 The evaluation of voiding pattern cannot be ignored preoperatively, since the development or persistence of voiding difficulties postoperatively will affect the surgical outcome. The ODP and CDP have also been demonstrated to be simple, useful and noninvasive preoperative parameters to predict outcomes and de novo detrusor overactivity (DO) after continence surgery.1 We found that women who were not cured after colposuspension had significantly lower preoperative ODP and CDP compared to women who were continent after surgery. Second, the assessment was limited to a 24hour pad test, 3-day bladder diary, stress test, self-reported questionnaire and re-treatment for stress urinary incontinence.4 It is not surprising that using such a definition of cure, the results obtained are contradictory to the data published in the literature.5– 8 Ideally, the outcomes assessment should follow the guidelines of the National Institutes of Health, which state that “the development of new symptoms as well as conditions (such as DO) must be considered in the assessment of surgical outcomes.”9,10 Since previous studies have revealed that women with postoperative DO have AFRs, ODPs and CDPs that are significantly higher preoperatively than those with a normal urodynamic test after colposuspension,1 we disagree with the conclusions that urodynamic measures do not predict the outcome of continence surgery. Third, the urodynamic protocol did not involve provocative maneuvers for DO.11 This omission explains why few women had DO compared to other series examining patients with mixed symptoms undergoing urodynamic evaluation.11,12 Thus, some women with urodynamic stress incontinence might have had missed underlying DO. This omission would explain the low cure rate for stress incontinence (53% vs 47%) and the low overall success rate (37% vs 28%) in the no DO and DO groups. This finding emphasizes the importance of performing good quality urodynamics with a range of provocative maneuvers.11 Finally, we believe that the title of the article is inappropriate. The authors only showed that VLPP and the presence of DO, when not using provocative maneuvers, do not predict the outcomes of continence surgery. Therefore, the conclusion that “the study addressed the possible prognostic value of urodynamic studies for success/failure outcome” is in-