Comparative Outcomes of Onabotulinum Toxin A and Abobotulinum Toxin A in Neurogenic Detrusor Overactivity Management

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Intradetrusor Injections of Onabotulinum Toxin A (Botox

^W

) 300 or 200 U Versus Abobotulinum Toxin A (Dysport

^W

) 750 U in the Management of Neurogenic Detrusor Overactivity:

A Case Control Study

Benoit Peyronnet,

^1,2,3

* Evelyne Castel-Lacanal,

⁴

Mathieu Roumiguie,

³

Lucie Even,

³

Philippe Marque,

⁴

Michel Souli e,

³

Pascal Rischmann,

³

and Xavier Game

³

1Service d’Urologie, CHU Rennes, Rennes, France

2Equipe thematique INPHY CIC 1414 et INSERM UMR 991, CHU Rennes, Rennes, France

3Departement d’Urologie, Transplantation Renale et Andrologie, CHU Rangueil, Toulouse, France

4Service de Medecine Physique et Readaptation, CHU Rangueil, Toulouse, France

Aims: To compare the outcomes of the first intradetrusor injections of abobotulinum toxin 750 U and onabotulinum toxin 200 and 300 U in patients with neurogenic detrusor overactivity (NDO).Methods: A retrospective case-control study was conducted including 211 NDO patients treated in three consecutives eras with onabotulinum toxin 300 U (2004–2006; 80 patients), abobotulinum toxin 750 U (2007–2011; 78 patients) or onabotulinum toxin 200 U (2011–2014; 53 patients).

Urodynamic and clinical parameters were compared between groups. The primary endpoint was the rates of success defined as the combination of urgency, urinary incontinence, and detrusor overactivity resolution. Results: When comparing abobotulinum toxin to onabotulinum toxin any doses (200 or 300 U; n¼133), success rates were similar (65.4%

vs. 55.6%;P¼0.16). Patients treated with abobotulinum toxin 750 U had higher success rate (65.4% vs. 41.5%;P¼0.007) compared to those who received onabotulinum toxin 200 U. In contrast, there were similar success rates in abobotulinum toxin 750 U and onabotulinum toxin 300 U groups (65.4% vs. 65%;P¼0.91) but with a trend towards longer interval between the first and the second injection in the onabotulinum toxin 300 U group (12.4 vs. 9.3 months; P¼0.09).

Conclusions: Intradetrusor injections of abobotulinum toxin 750 U for NDO provided better outcomes than injections of onabotulinum toxin 200 U. Success rates of abobotulinum toxin 750 U and onabotulinum toxin 300 U were similar but interval between injections tended to be longer with onabotulinum toxin 300 U.Neurourol. Urodynam.

#2016 Wiley Periodicals, Inc.

Key words: abobotulinum toxin; botulinum toxin; detrusor overactivity; neurogenic bladder; onabotulinum toxin

INTRODUCTION

Intradetrusor injection of botulinum toxin is recommended as the second-line therapy in patients with neurogenic detrusor overactivity (NDO) when anticholinergic therapy is ineffective or poorly tolerated.¹Onabotulinumtoxin-A (BOTOX¹, Allergan, Inc., Irvine, CA) is the only botulinum toxin which use is supported by large multicenter randomized controlled trials^2–5 and is therefore the only one to be licensed in the US and Europe for the management of NDO.⁶However, the use of abobotulinumtoxin A (Dysport¹, Ipsen Biopharmaceuticals, Inc., Basking Ridge, NJ) for NDO is also supported by high level of evidence studies^7–10 and was used in several centers for intradetrusor injections.

During the past few years, several randomized controlled trials have aimed to compare these two different formulations of botulinum toxin A in the setting of cervical dystonia,¹¹ chronic anal fissure,¹² hyperhidrosis,¹³ or plastic surgery.¹⁴ However, in the management of NDO, even though prospective non comparative studies have assessed the safety and efficacy of intradetrusor injections of abobotulinum toxin,^7,15only one small sample case-control retrospective study has aimed to compare the results of these two toxins.¹⁶Moreover, the issue of the dose equivalence of the two toxins in the setting of intradetrusor injections has rarely been adressed and remained unsolved.¹⁷ The primary aim of the present study was to compare the outcomes of the first intradetrusor injections of abobotulinum toxin A 750 U and onabotulinum toxin A in NDO

patients. The secondary objective was to evaluate the dose equivalence between the two toxins.

PATIENTS AND METHODS

Study Design

Data of all consecutive patients who underwent a first intradetrusor injection of botulinum toxin A for NDO at a single-institution between 2004 and 2014 were retrospectively collected. In our department, onabotulinum toxin 300 U was the only first-line botulinum toxin used to treat NDO from 2004 to 2006. From 2006 to 2011, abobotulinum toxin 750 U was used as the only first-line botulinum toxin (second era). From 2011, as onabotulinum-toxin A became licensed in US and

Dr. Hashim Hashim led the peer-review process as the Associate Editor responsible for the paper.

Potential conflicts of interest: Dr. Game reports personal fees from Allergan, personal fees from Ipsen, outside the submitted work; Dr. guillotreau reports personal fees from Allergan, outside the submitted work; Dr. castel-lacanal reports personal fees from Allergan, outside the submitted work; Other authors have nothing to disclose.

Correspondence to: Benoit Peyronnet, Service d’Urologie, Hopital Pontchaillou 2 rue Henri Le Guilloux, 35000 Rennes, France. E-mail: [email protected] Received 24 December 2015; Accepted 13 March 2016

Published online in Wiley Online Library (wileyonlinelibrary.com).

DOI 10.1002/nau.23009

#2016 Wiley Periodicals, Inc.

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Europe, we decided to use it as the first-line botulinum toxin at the labelled dosage of 200 U (third era: 2011–2014).

Patients underwent botulinum toxin injection only if they were able and willing to do clean intermittent self-catheterization (CISC), had not received therapeutic botulinum toxin (for any indication) in the previous 3 months, had no history of myasthenia or coagulation disorders.

The results of the first injection were evaluated at 6 weeks and categorized as success or failure. The success was defined as the combination of urgency, urinary incontinence, and detrusor overactivity resolution.

Other outcomes of interest included complications graded according to the Clavien classification,¹⁸ changes in urodynamic parameters and mean time between the first and the second injection. A new injection was performed at the time of NDO symptoms recurrence. Patients were asked to progressively decrease anticholinergics from the 2nd week until the 4th week after the injections, until the complete stoppage of the drugs.

Intradetrusor Injections

Urinalysis was done 7 days before injection and appropriate antibiotics prescribed in case of preoperative bacteriuria. The injections were performed in the operating theatre under local anaesthesia (30 ml of 1% lidocaine solution diluted in 100 ml of 1,4% NaHC03 instilled into the bladder) using a rigid cystoscope. We used either 200 U of onabotulinumtoxin diluted in 30 ml of injectable saline and injected in 30 sites (1 ml6.67 U in each site) or 300 U of onabotulinum toxin diluted in 30 ml of injectable saline and injected in 30 sites (1 ml10 U in each site) or 750 U of abobotulinumtoxin dissolved in 20 ml of saline and injected in 20 sites (1 ml75 U per site). The intradetrusor injections of toxin were distributed over the bladder wall sparing the trigone. Cardiac and respiratory functions were monitored during the procedure. Procedures were carried out as a day case, the patients being discharged home in the evening.

Pre- and Post-Treatment Evaluation

Patients filled in a 3-day bladder diary, performed a urine analysis and had urodynamic testing before and 6 weeks after each injection. Urodynamics were carried out according to the ICS and manufacturer recommendations (Laborie¹, Mississauga, Ontario, Canada).^19,20All patients had undergone renal and bladder ultrasound and a 24 hr creatinine clearance measurement in the previous 6 months. Low compliance bladder was defined as compliance<20 ml/cm H2O.

Statistical Analysis

Perioperative parameters were compared between groups.

Means and standard deviations were reported for continuous variables, and proportions for nominal variables. Comparisons between abobotulinum toxin and onabotulinum toxin 200 U groups and abobotulinum toxin and onabotulinum toxin 300 U were performed using the x² test or Fisher’s exact test for discrete variables, and Student’st-test or Mann–Whitney test for continuous variables as appropriate. Comparisons between the three groups (abobotulinum toxin, onabotulinum toxin 200 U, onabotulinum toxin 300 U) were performed using analysis of variance (ANOVA) for continuous variables andx² test for nominal variables. Nominal variables before and after injections were compared using the Mc Nemar test and the paired studentt-test was used to compare continuous variables across time. A sensitivity analysis was performed by matching

patients who underwent abobotulinum toxin, onabotulinum toxin 200 U, or onabotulinum toxin 300 U intradetrusor injections in a 1:1:1 fashion according to age, gender, and condition causing NDO. Statistical analyses were performed using JMP v.10.0 software (SAS Institute Inc., Cary, NC). All tests were two-sided with a level ofP<0.05 considered statistically significant.

RESULTS

Patients’ Characteristics

Two-hundred and eleven patients were included for analysis with respectively 78 in the abobotulinum group and 133 in the onabotulinum groups (Botox¹ 300 U: n¼80; Botox¹200 U:

n¼53). The patients’ characteristics are summarized in Table I.

There were more male patients in the onabotulinum 300 U group compared to the onabotulinum 200 U group and to the abobotulinum group (61.3% vs. 43.4% vs. 43.6%; P¼0.04).

Neurological conditions were similar between the three groups (multiple sclerosis [MS]: 39.2% vs. 30.2% vs. 30.8%; spinal cord injury [SCI]: 48.1% vs. 41.5% vs. 46.1%; others: 12.7% vs. 28.3%

vs. 23.1%; P¼0.16). In the multiple sclerosis subpopulation, Expended Disability Status Scale (EDSS) was significantly lower in the Botox¹200 U group compared to the abobotulinum toxin group (4.6 vs. 6.1;P¼0.02). The rates of low compliance bladder were similar between the three groups (11.3 % vs. 15.1 % vs. 5.1

%;P¼0.15).

Onabotulinum Toxin Versus Abobotulinum Toxin When comparing abobotulinum toxin to onabotulinum toxin any doses (Botox¹200 or 300 U; n¼133), success rates were similar (65.4% vs. 55.6%;P¼0.16; see Table II). There were no statistically significant differences between both group in terms of interval between the first and the second injection (9.3 vs. 11 months;P¼0.17), urinary incontinence resolution (78.2%

vs. 74.6%;P¼0.45), detrusor overactivity resolution (67.9% vs.

66.2%;P¼0.79), or complications (7.5% vs. 3.9%;P¼0.38). At week 6, maximum cystometric capacity (MCC), volume at first desire to void and maximum detrusor pressure (MDP) were significantly improved in both groups compared to baseline with similar changes observed in the two groups. The odds- ratio for complete success was 1.5 for abobotulinum toxin versus onabotulinum toxin (IC 95%: 0.8–2.7).

Onabotulinum Toxin 200 U Versus Abobotulinum Toxin 750 U Patients treated with abobotulinum toxin 750 U had higher success rate (65.4% vs. 41.5%;P¼0.007; see Table III) and more frequent urinary incontinence resolution (78.2% vs. 60.4%;

P¼0.03; see Fig. 1) compared to those who received onabotulinum toxin 200 U. There were no statistically significant differences between both groups in terms of detrusor overactivity resolution (67.9% vs. 58.4%; P¼0.27) and complications (3.9% vs. 13.2%;

P¼0.09). At week 6, urodynamic parameters (MCC, MDP, volume at first desire to void) improved signifcantly compared to baseline with comparable changes of MDP and MCC observed in the two groups. Increase in volume of first desire to void tended to be greater in the abobotulinum toxin 750 U (108.5 vs. 54.3;P¼0.09).

Mean interval between the first and the second injection were similar in onabotulinum toxin 200 U and abobotulinum toxin 750 U groups (9.1 vs. 9.3 months; P¼0.89). The odds-ratio for complete success was 2.7 for abobotulinum toxin versus onabotulinum toxin (IC 95%: 1.3–5.3).

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Onabotulinum Toxin 300 U Versus Abobotulinum Toxin 750 U There were similar success rates in abobotulinum toxin 750 U and onabotulinum toxin 300 U groups (65.4% vs. 65%;

P¼0.91; see Table IV). The odds-ratio for complete success was 0.98 for abobotulinum toxin versus onabotulinum toxin (IC 95%: 0.51–1.89). Urinary incontinence and detrusor overactivity resolution rates were comparable between

TABLE II. Outcomes of Onabotulinum Toxin Versus Abobotulinum Toxin Intradetrusor Injections

Onabotulinum toxin N¼133

Abobotulinum toxin N¼78 P-value

Success rate 74 (55.6%) 51 (65.4%) 0.16

Urinary incontinence resolution

97 (74.6%) 61 (78.2%) 0.45 Detrusor overactivity

resolution

88 (66.2%) 53 (67.9%) 0.79

Complications 10 (7.5%) 3 (3.9%) 0.38

UTI 8 1

Fatigue 1 1

Gross hematuria 1 1

Mean volume at first desire to void (ml)

Baseline 172.4 (12.3) 207.5 (17.5) 0.11

6 weeks after injection 270.4(18.1) 316(23.3) 0.15

Change þ98 (17.4) þ108.5 (20.5) 0.65

Mean maximum cystometric capacity (cm H2O)

Baseline 288.5 (14.4) 266 (19.5) 0.35

6 weeks after injections 418.1(15.5) 410.9(20.2) 0.78 Change þ129.6 (17.6) þ144.9 (24.1) 0.77 Mean maximum detrusor

pressure (cm H₂O)

Baseline 47.7 (3) 41.8 (3.5) 0.22

6 weeks after injection 23.1(2.1) 23.1(2.2) 0.98

Change 24.6 (3.4) 18.7 (3.9) 0.27

UTI, urinary tract infection.

Significant change from baseline (P<0.05).

TABLE III. Outcomes of Onabotulinum Toxin 200 U Versus Abobotulinum Toxin 750 U Intradetrusor Injections

Onabotulinum toxin 200 U N¼53

Success rate 22 (41.5%) 51 (65.4%) 0.007

32 (60.4%) 61 (78.2%) 0.03 Detrusor overactivity

resolution

31 (58.4%) 53 (67.9%) 0.27

Complications 7 (13.2%) 3 (3.9%)

UTI 6 1

Fatigue 1 1 0.09

Gross Hematuria 0 1

Baseline 132.5 (20.1) 207.5 (17.5) 0.005

6 weeks after injection 186.8(17.7) 316(23.3) <0.001

Change þ54.3 (24.9) þ108.5 (20.5) 0.09

Mean maximum cystometric capacity (cm H2O)

Baseline 255 (23.5) 266 (19.5) 0.72

pressure (cm H₂O)

Baseline 47.7 (5.3) 41.8 (3.5) 0.36

Change 25.6 (5.5) 18.7 (3.9) 0.25

TABLE I. Patients’ Characteristics

Onabotulinum toxin 200 U, N¼53

Onabotulinum toxin 300 U, N¼80

Abobotulinum toxin 750 U,

N¼78 P-value

Mean age (years) 45.5 (2) 43.5 (1.7) 45.3 (1.7) 0.69

Gender

Male 23 (43.4%) 49 (61.3%) 34 (43.6%) 0.04

Female 30 (56.6%) 31 (38.8%) 44 (56.4%)

Mean duration from neurological disease onset (years)

11.6 (1.6) 12.2 (1.3) 13.4 (1.2) 0.64

Neurological conditions 0.16

Spinal cord injury 22 (41.5%) 38 (48.1%) 38 (46.1%)

Multiple sclerosis 16 (30.2%) 31 (39.2%) 24 (30.8%)

Others 15 (28.3%) 11 (12.7%) 18 (23.1%)

Myelomeningocele 6 (11.3%) 2 (2.5%) 7 (9%)

Myelitis 3 (5.7%) 5 (6.2%) 4 (5.1%)

Meningo-encephalopathy 6 (11.3%) 2 (2.5%) 4 (5.1%)

Strumpell-lorrain sd 1 (1.9%) 1 (1.2%) 1 (1.3%)

Multiple system atrophy 0 1 (1.2%) 1 (1.3%)

Stroke 0 0 1 (1.3%)

AIS

A 13 (61.9%) 17 (65.4%) 15 (51.8%) 0.20

B 4 (19%) 2 (7.7%) 3 (10.3%)

C 1 (4.8%) 5 (19.2%) 3 (10.3%)

D 3 (14.3%) 2 (7.7%) 4 (13.8%)

E 0 0 4 (13.8%)

EDSS 6.1 (0.4) 5.5 (0.4) 4.6 (0.4) 0.06

sd, syndrome; AIS, ASIA impairment scale; EDSS, expended disability status scale.

Statistically significant.

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both groups (78.2% vs. 85%, P¼0.32 and 67.9% vs. 71.3%, P¼0 .65, respectively). There were no statistically significant differences between the two groups in terms of complications rates (3.9% vs. 3.8%; P¼0.97). At week 6, urodynamic parameters (MCC, MDP, volume at first desire to void) improved signifcantly compared to baseline with comparable changes observed in the onabotulinum toxin 300 U and abobtulinum toxin 750 U groups. There was a trend towards longer interval between the first and the second injection in the onabotulinum toxin 300 U group compared to the abobotulinum 750 U group (12.4 vs. 9.3 months;P¼0.09).

Match-Paired Analysis

Thirty-nine patients in each group fitted the above- mentioned match-pairing criteria (i.e., age, gender, neurological condition). The patients’ characteristics of these subgroups are shown in Supplementary Table SI. This match-paired analysis was restricted to patient with spinal cord injury, multiple sclerosis, spina bifida, or myelitis.

Match-paired comparisons of onabotulinum toxin 200 U and abobotulinum toxin 750 are shown in Supplementary Table SII.

Success rate remained higher in patients who received abobotulinum toxin 750 U compared to those treated with onabotulinum toxin (71.8% vs. 35.9%;P¼0.001) with a higher rate of urinary incontinence resolution (76.9% vs. 59%;P¼0.03).

Mean intervals between the first and the second injection were similar in onabotulinum toxin 200 U and abobotulinum toxin 750 U groups (8.4 vs. 8.9 months;P¼0.72).

Match-paired comparisons of onabotulinum toxin 300 U and abobotulinum toxin 750 are shown in Supplementary Table SIII. Success rate tended to be higher in patients treated with onabotulinum toxin 300 U than in patients who underwent abobotulinum toxin 750 U injections (87.2% vs. 71.8%;

P¼0.09) with a higher rate of urinary incontinence resolution (94.9% vs. 76.9%;P¼0.02). Mean interval between the first and the second injection was longer in onabotulinum toxin 300 U group but it did not reach statistical significance (10.2 vs. 8.9 months;P¼0.39).

DISCUSSION

The efficacy of abobotulinum toxin and onabotulinum toxin in the treatment of NDO has been proven in randomized controlled trials.^2–5,8In the present study, we found similar outcomes between abobotulinum toxin and onabotulinum toxin when analysis was conducted regardless of the doses used. When the analyis was performed in subgroup according to the doses of onabotulinum toxin used (Botox¹200 or 300 U), abobotulinum toxin 750 U provided better outcomes than onabotulinum toxin 200 U in NDO patients but urodynamic and clinical results of intradetrusor injections of onabotulinum toxin 300 U and abobotulinum toxin 750 U were similar despite a tendency towards longer interval between the first and the second injection in the onabotulinum toxin 300 U group.

To our knowledge, only one study has aimed to compare intradetrusor injection of abobotulinum toxin and onabotulinum toxin in the setting of NDO. In this series, Grosse et al compared 28 cases treated with abobotulinum toxin (500, 750, or 1000 U) to 28 matched controls who received onabotulinum toxin (mostly 300 U). They found no difference in clinical and urodynamic outcomes between the two toxins, but, besides the small sample size, their findings were partly flawed by the comparisons of various doses of the two drugs.¹⁶

In two prospectives open-label studies published in 2006 and 2010, Ruffion et al. and Grise et al. reported that the optimum dose abobotulinum toxin may be 750 U as 1000 U exposed to major complications (one general muscle weakness with asthenia)⁷ and 500 U tended to provide poorer outcomes.¹⁵ Hence, the use of a unique dose of 750 U of abobotulinum toxin is a point of strength of our study. Interestingly, although the three randomized controlled trials published to date reported no clinically significant additional benefit was observed with a dose of 300 U compared to a dose of 200 U,^2–5 we found a tendency towards lower efficacy of abobotulinum toxin 750 U compared to onabotulinum toxin 300 U but better outcomes for abobotulinum toxin 750 U compared to onabotulinum toxin 200 U suggesting significant difference between the doses of Fig. 1. Outcomes in onabotulinum toxin 200 U, onabotulinum toxin 300 U,

and abobotulinum toxin 750 U groups.Statistically significant.

TABLE IV. Outcomes of Onabotulinum Toxin 300 U Versus Abobotulinum Toxin 750 U Intradetrusor Injections

Onabotulinum toxin 300 U N¼80

Success rate 52 (65%) 51 (65.4%) 0.91

68 (85%) 61 (78.2%) 0.32

Detrusor overactivity resolution

57 (71.3%) 53 (67.9%) 0.65

Complications 3 (3.8%) 3 (3.9%) 0.97

UTI 2 1

Fatigue 0 1

Gross hematuria 1 1

Baseline 1091.8 (15.4) 207.5 (17.5) 0.51

6 weeks after injection 313.3(17.7) 316(23.3) 0.94 Change þ121.5 (23.1) þ108.5 (20.5) 0.87 Mean maximum

cystometric capacity (cm H2O)

Baseline 308.9 (19.1) 266 (19.5) 0.10

pressure (cm H₂O)

Baseline 47.7 (3.6) 41.8 (3.5) 0.26

Change 24.1 (4.5) 18.7 (3.9) 0.37

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200 and 300 U of onabotulinum toxin. Several hypoteses can be made to explain these findings. Firstly, the primary endpoint chosen in randomized controlled trials was the reduction in number of urinary incontinence episodes per week,^2–5which could be considered more accurate but maybe less clinically relevant than the composite nominal endpoint used in our study. Moreover, the primary aim of these randomized trials was to compare onabotulinum toxin to placebo and it could be assumed that they were not powered to detect differences, presumably slighter, between the doses of 200 and 300 U.

Finally, the population in the phase three trials was highly selected (SCI T1 level or lower and MS clinically stable with EDSS6.5) while any types of neurological conditions, regardless of its severity, were included in the present report (e.g., myelomeningocele).

The issue of dose equivalence between abobotulinum and onabotulinum toxins remains controversial. The relative potency measured by the number of units per nanogram is twofold lower for onabotulinum toxin (20 U/ng) than for abobotulinum toxin (40 U/ng).²¹However, in several studies estimating the potency ratio between onabotulinum toxin and abobotulinum toxin, dose-equivalence ratios ranging from 1:1 to 6:1 (abobotulinum toxin: onabotulinum toxin) have been advocated.11–14,22,23

To date, two studies aimed to assess dose-equivalence between the toxins in the field of intradetrusor injections for NDO.^17,24 Using a rat model, Behr-Roussel et al. found a conversion ratio of 1:1.33 for minimal effective dose between abobotulinum toxin and onabotulinum toxin (10 vs. 7.5 U).¹⁷In a more recent study, Oliveira et al. compared the relative potency of abobotulinum toxin and onabotulinum toxin by evaluating the expression of cleaved synaptosomal associated protein of 25 kDa (cSNAP- 25) in the bladder wall of mice injected with on of the two brands.²⁴Their results suggested a conversion ratio of 1:1.6 between onabotulinum toxin and abobotulinum toxin.²⁴Our findings are in favor of a higher dose-equivalence ratios around 2.5:1 (abobotulinum toxin: onabotulinum toxin) or even slightly higher.

Another important point of the present study is that safety and tolerability were similar between the three groups with only two cases of fatigue (1 in the abobotulinum toxin 750 U and one in the onabotulinum toxin 200 U).

This is in accordance with datas from randomized controlled trials.^2–10

The present study has several limitations, mostly inherent to its non-randomized retrospective design. It was a single- center series which could have flawed our results. The definition of success in our study combining urinary continence resolution, lack of detrusor overactivity and of frequency, was more demanding than evaluations based on a single parameter but we believe that our criterion is closer to the goals of NDO treatment in clinical practice as it has recently been suggested in a survey involving French speaking experts in neurourology.²⁵Furthermore, our assesse- ment of return of continence could be called into question as it has been showed to be overestimated in nonrandomized trials.¹⁰ The injection techniques were not comparable between the three groups (different dilution and number of injection sites), which could be regarded as a drawback despite the fact that the impact of the number of injections sites on outcomes of botulinum toxin intradetrusor injections has been called into question in recent literature.^26,27Finally it should be stressed that, at this time, the use of abobotulinum toxin A in NDO is not approved in US and Europe which could limit the impact of our results on current daily practice.

CONCLUSION

Intradetrusor injections of either onabotulinum toxin 300 U or abobotulinum toxin 750 U provided comparable success rates in the management of NDO but interval between injections tended to be longer with onabotulinum toxin 750 U and there was a trend towards a higher success rate in this group in match-paired analysis. In contrast, abobotulinum toxin 750 U appeared more effective than onabotulinum toxin 200 U in these patients. Tolerability was similar in the three groups and no major complication was observed. Hence dose equivalence ratio around 2.5:1 (abobotulinum toxin:

onabotulinum toxin) or slightly higher could be advocated.

Larger series and further prospective randomized controlled trials are needed to confirm these findings.

REFERENCES

1. Nambiar A, Lucas M. Chapter 4: Guidelines for the diagnosis and treatment of overactive bladder (OAB) and neurogenic detrusor overactivity (NDO).

Neurourol Urodyn 2014;33:21–25.

2. Schurch B, de Seze M, Denys P, et al. Botulinum toxin type a is a safe and effective treatment for neurogenic urinary incontinence: Results of a single treatment, randomized, placebo controlled 6-month study. J Urol 2005;174:

196–200.

3. Herschorn S, Gajewski J, Ethans K, et al. Efficacy of botulinum toxin A injection for neurogenic detrusor overactivity and urinary incontinence:

A randomized, double-blind trial. J Urol 2011;185:2229–35.

4. Ginsberg D, Gousse A, Keppenne V, et al. Phase 3 efficacy and tolerability study of onabotulinumtoxinA for urinary incontinence from neurogenic detrusor overactivity. J Urol 2012;187:2131–9.

5. Cruz F, Herschorn S, Aliotta P, et al. Efficacy and safety of onabotulinumtoxin A in patients with urinary incontinence due to neurogenic detrusor overactivity: A randomised, double-blind, placebo-controlled trial. Eur Urol 2011;60:742–50.

6. Cruz F, Nitti V. Chapter 5: Clinical data in neurogenic detrusor overactivity (NDO) and overactive bladder (OAB). Neurourol Urodyn 2014;33:S26–31.

7. Ruffion A, Capelle O, Paparel P, et al. What is the optimum dose of type A botulinum toxin for treating neurogenic bladder overactivity? BJU Int 2006;97:1030–4.

8. Ehren I, Volz D, Farrelly E, et al. Efficacy and impact of botulinum toxin A on quality of life in patients with neurogenic detrusor overactivity: A randomised, placebo-controlled, double-blind study. Scand J Urol Nephrol 2007;41:335–40.

9. Manecksha RP, Cullen IM, Ahmad S, et al. Prospective randomised controlled trial comparing trigone-sparing versus trigone-including intradetrusor injection of abobotulinumtoxinA for refractory idiopathic detrusor overactivity. Eur Urol 2012;61:928–35.

10. Mangera A, Andersson KE, Apostolidis A, et al. Contemporary management of lower urinary tract disease with botulinum toxin A: A systematic review of botox (onabotulinumtoxinA) and dysport (abobotulinumtoxinA). Eur Urol 2011;60:784–95.

11. Yun JY, Kim JW, Kim HT, et al. Dysport and Botox at a ratio of 2.5:1 units in cervical dystonia: A double-blind, randomized study. Mov Disord 2015;30:

206–13.

12. Brisinda G, Albanese A, Cadeddu F, et al. Botulinum neurotoxin to treat chronic anal fissure: Results of a randomized ‘‘Botox vs. Dysport’’ controlled trial. Aliment Pharmacol Ther 2004;19:695–701.

13. Talarico-Filho S, MendonSca Nascimento DOM, et al. A double-blind, randomized, comparative study of two type A botulinum toxins in the treatment of primary axillary hyperhidrosis. Dermatol Surg 2007;33:S44–50.

14. Do Nascimento Remigio AF, Salles AG, et al. Comparison of the efficacy of onabotulinumtoxinA and abobotulinumtoxinA at the 1: 3 conversion ratio for the treatment of asymmetry after long-term facial paralysis. Plast Reconstr Surg 2015;135:239–49.

15. Grise P, Ruffion A, Denys P, et al. Efficacy and tolerability of botulinum toxin type A in patients with neurogenic detrusor overactivity and without concomitant anticholinergic therapy: Comparison of two doses. Eur Urol 2010;58:759–66.

16. Grosse J, Kramer G, Jakse G. Comparing two types of botulinum-A toxin detrusor injections in patients with severe neurogenic detrusor overactivity:

A case-control study. BJU Int 2009;104:651–6.

17. Behr-Roussel D, Oger S, Pignol B, et al. Minimal effective dose of dysport and botox in a rat model of neurogenic detrusor overactivity. Eur Urol 2012;61:1054–61.

18. Dindo D, Demartines N, Clavien P-A. Classification of surgical complications:

A new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205–13.

(6)

19. Abrams P, Cardozo L, Khoury S, et al. Recommendations of the International Scientific Committee: Evaluation and treatment of urinary incontinence, Pelvic Organ Prolapse and Faecal Incontinence, 2013. Available at: http://

www.icud.info/PDFs/INCONTINENCE%202013.pdf

20. Rovner E. Chapter 6: Practical aspects of administration of onabotulinumtox- inA. Neurourol Urodyn 2014;33:S32–7.

21. Wohlfarth K, Kampe K, Bigalke H. Pharmacokinetic properties of different formulations of botulinum neurotoxin type A. Mov Disord 2004;19:S65–7.

22. Rosales RL, Bigalke H, Dressler D. Pharmacology of botulinum toxin:

Differences between type A preparations. Eur J Neurol 2006;13:2–10.

23. Wohlfarth K, Schwandt I, Wegner F, et al. Biological activity of two botulinum toxin type A complexes (Dysport and Botox) in volunteers: A double-blind, randomized, dose-ranging study. J Neurol 2008;255:1932–9.

24. Oliveira R, Coelho A, Charrua A, et al. Expression of cleaved SNAP-25 after bladder wall injection of onabotulinumtoxinA or abobotulinumtoxinA: A comparative study in the mice. Neurourol Urodyn 2015, in press.

25. Peyronnet B, Sanson S, Amarenco G, et al. Definition of botulinum toxin failure in neurogenic detrusor overactivity: Preliminary results of the

DETOX survey. Prog Urol 2015; pii: S1166-7087(15)00225-0. DOI: 10.1016, in press.

26. Denys P, Del Popolo G, Amarenco G, et al. Efficacy and safety of two administration modes of an intra-detrusor injection of 750 units dysport¹ (abobotulinumtoxinA) in patients suffering from refractory neurogenic detrusor overactivity (NDO): A randomised placebo-controlled phase IIa study. Neurourol Urodyn 2016, in press.

27. Liao CH, Chen SF, Kuo HC. Different number of intravesical onabotulinum- toxinA injections for patients with refractory detrusor overactivity do not affect treatment outcome: A prospective randomized comparative study.

Neurourol Urodyn 2015; DOI: 10.1002, in press.

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