Botulinum toxin type A for the treatment of non-neurogenic overactive bladder: does using onabotulinumtoxinA (Botox®) or abobotulinumtoxinA (Dysport®) make a difference?

Authors


Correspondence: Pravisha Ravindra, Nottingham Urology Centre, Nottingham University Hospitals NHS Trust, City Hospital Campus, Hucknall Road, Nottingham, NG5 1PB, UK.

e-mail: pravisharavindra@doctors.org.uk

Abstract

Objective

  • To compare the clinical effects of two different commercially available botulinum toxin type A products, onabotulinumtoxinA (Botox®; Allergan Inc., Irvine, CA, USA) and abobotulinumtoxinA (Dysport®; Ipsen Ltd, Slough, UK), on non-neurogenic overactive bladder (OAB).

Patients and Methods

  • We included 207 patients, who underwent treatment with botulinum toxin type A for non-neurogenic OAB from January 2009 to June 2012 at our institution, in a prospective database that recorded details of their presentation, treatment and outcomes.
  • In December 2009, our institution switched from using onabotulinumtoxinA to using abobotulinumtoxinA.

Results

  • Results from the onabotulinumtoxinA cohort (n = 101) and the abobotulinumtoxinA cohort (n = 106) were compared.
  • Similar reductions in daytime frequency, nocturia and incontinence episodes were observed after treatment, with no difference in duration of effect.
  • The abobotulinumtoxinA cohort had almost twice the rate of symptomatic urinary retention (23 vs 42%) requiring intermittent self-catheterisation (ISC).

Conclusions

  • AbobotulinumtoxinA use was complicated by a significantly higher risk of requiring ISC.
  • The study suggests that these two toxins are not interchangeable at the doses used.
Abbreviations
OAB

overactive bladder

UI

urinary incontinence

ISC

intermittent self-catheterisation

DOA

detrusor overactivity

ICIQ

International Consultation on Incontinence Modular Questionnaire

PVR

post-void residual urine volume

Introduction

Botulinum toxin type A has been used to treat overactive bladder (OAB), either of neurogenic or idiopathic origin, for over a decade with successful outcomes [1-6]. Reports have largely included patients treated with onabotulinumtoxinA (Botox®; Allergan Inc., Irvine, CA, USA). The use of abobotulinumtoxinA (Dysport®, Ipsen, Dijon, France) is less well studied, although this preparation is in clinical use [7]. No comparative studies of the two preparations in the treatment of idiopathic OAB have been reported [8], although two studies comparing the two formulations in neurogenic OAB found no differences [9, 10]. Although both are type A toxins, they are derived from different bacterial strains and are manufactured differently. An abobotulinumtoxinA to onabotulinumtoxinA dose conversion of 2.5:1 has been suggested but this has not been validated in urological applications [10]. A Cochrane review of randomised controlled trials comparing formulations of botulinum toxin type A in different kinds of dystonia concluded that a 3:1 ratio (abobotulinumtoxinA: onabotulinumtoxinA) appeared to be closer to the true equivalence; however the incidence of side effects was still higher for abobotulinumtoxinA, proposing equivalence was not applicable for all parameters [11]. Studies performed subsequently have demonstrated conversions of 2:1, 2.5:1 and 3:1 suggesting the true conversion ratio may lie between 2 and 3:1 [12-14]. The product characteristics of onabotulinumtoxinA and abobotulinumtoxinA are shown in Table 1 [15].

Table 1. Comparison of product characteristics of onabotulinumtoxinA and abobotulinumtoxinA
 OnabotulinumtoxinAAbobotulinumtoxinA
  1. Adapted from study by Albanese [15].
Brand nameBotox®Dysport®
ManufacturerAllergan Inc.Ipsen
SerotypeAA
Specific activity, U/ng2040
Packaging, U/vial50, 100 and 200300 and 500
Constituents and excipientsHaemagglutininHaemagglutinin
Human albumin 0.05%Human albumin 20%
SaccharoseLactose
Sodium chloride 
pH7.47.4
Complex size, kDa900900
PreparationVacuum driedLyophilised
Storage of packaged product−5 °C or 2–8 °C2–8 °C
Storage once reconstituted2–8 °C for 24 h2–8 °C for several h

Materials and Methods

All patients who underwent intravesical botulinum toxin type A injections for idiopathic OAB between 17 January 2009 and 31 June 2012 at the Nottingham Urology Centre were included in the study. Patients had a clinical diagnosis of OAB syndrome, as defined by the ICS, with or without urinary incontinence (UI) [16]. Patients with neurogenic OAB were excluded. All had undergone conservative treatment with bladder retraining and pelvic floor exercises. Vaginal oestrogens were given where appropriate. All patients had failed to improve on at least two anticholinergic medications before being considered for botulinum toxin type A injections. Most, but not all, patients had evidence of detrusor overactivity (DOA) on urodynamic studies. A previous study showed that the presence of DOA on a urodynamic study did not influence the response to botulinum toxin type A treatment [17].

From January 2009 to December 2009, patients underwent treatment with onabotulinumtoxinA (Botox®) with a standard dose of 200U. From December 2009 to June 2012, departmental protocol was changed to using abobotulinumtoxinA (Dysport®) with a standard dose of 500U based on a suggested conversion ratio of 2.5:1 for the two toxins. In July 2011, after publication of data suggesting a lower optimum dose of botulinum toxin type A, the dose of abobotulinumtoxinA was reduced to 300U. The majority of patients underwent the procedure under local anaesthetic using flexible cystoscopy. All treatments took place on a day case basis and all received 20 1-mL equally spaced intra-detrusor injections. A non-trigone sparing approach was used, whereby 1/20 injections was administered to the trigone. There were no changes to the treatment protocol other than the change in toxin used and a single consultant surgeon performed all procedures. Patients were advised to stop their antimuscarinic treatment after the procedure. Patients who had been treated more than once with botulinum toxin type A were included in this study, but patients who were treated more than once during the study period only had their initial treatment included.

All patients were routinely reviewed at 2 weeks to assess for symptomatic urinary retention and then at 3 months to assess response. Intermittent self-catheterisation (ISC) was instituted only where post-void residual urine volumes (PVRs) of >150 mL were associated with symptoms of voiding dysfunction. Patients with an asymptomatic high PVR were not commenced on ISC.

Data on demographics, diagnosis, date and dose of treatment were prospectively recorded. Patients were asked to complete a bladder diary and the OAB and UI modules of the International Consultation on Incontinence Modular Questionnaire (ICIQ), the ICIQ-OAB and the ICIQ-UI. The principal endpoint was patient-reported global satisfaction with outcome (on the 5-point Likert scale), with secondary endpoints including changes from baseline bladder diary and questionnaire responses, subjective duration of clinical benefit, postoperative PVR and the incidence of postoperative retention requiring ISC.

Statistical analyses were performed using GraphPad Prism, version 5.0 for Microsoft Windows (GraphPad Software, San Diego, California, USA). When comparing categorical variables, P values were determined using the chi-squared test. When the sample sizes were too small, Fisher's exact test was used. The Kolmogorov–Smirnov test was used to assess normality of continuous data. The unpaired t-test was used to compare means of two groups of independent normally distributed data, while the Mann–Whitney test was used to compare medians of independent non-Gaussian data. In all cases, a P value of ≤0.05 was considered to indicate statistical significance.

Results

A total of 207 patients underwent treatment for idiopathic OAB with botulinum toxin type A treatment during the period concerned. The median (range) age was 62 (19–94) years. Of the 207 patients, 46 (22%) were men. In all, 101 patients received onabotulinumtoxinA and 106 received abobotulinumtoxinA. Principal endpoint data were available for 99% of patients from the onabotulinumtoxinA cohort (100 patients) and for 75% of patients from the abobotulinumtoxinA cohort (79 patients). There were no significant demographic differences between the two groups. A summary of patient demographics is shown in Table 2.

Table 2. Demographic data of patients receiving either AbobotulinumtoxinA or OnabotulinumtoxinA
 OnabotulinumtoxinAAbobotulinumtoxinA
No. of patients101106
Median age (range), years64 (27–90)61 (19–94)
Male patients (%)18 (18)28 (26)
Female patients (%)83 (82)78 (74)

Bladder diary data were available for 113 patients (47 from the onabotulinumtoxinA group and 66 from the abobotulinumtoxinA group). There were no significant preoperative differences between the two groups in terms of median number of voids during the day, night or episodes of incontinence over a 24-h period (Mann–Whitney U-Test, P = nonsignificant). Improvements were seen in all variables postoperatively, but there were no significant differences between the abobotulinumtoxinA and onabotulinumtoxinA cohorts (Table 3).

Table 3. Comparison of pre- and postoperative bladder diaries of patients who received either abobotulinumtoxinA or onabotulinumtoxinA
 Pre-procedurePost-procedureChangePOnabotulinumtoxinA vs abobotulinumtoxinA
Median daily voids     
OnabotulinumtoxinA106−4<0.001

−4 vs −4

nonsignificant

AbobotulinumtoxinA95−4<0.001
Median no. of night voids     
OnabotulinumtoxinA31−2<0.001

−2 vs −1

nonsignificant

AbobotulinumtoxinA21−1<0.001
Median no. of incontinence episodes     
OnabotulinumtoxinA30−3<0.001

−3 vs −3.5

nonsignificant

AbobotulinumtoxinA3.50−3.5<0.001

Pre- and postoperative ICIQ scores for the domains of OAB and UI were available for 82 patients (31 from the onabotulinumtoxinA group and 51 from the abobotulinumtoxinA group). The median ICIQ-OAB score fell from 10 preoperatively to 3.5 postoperatively, while the median ICIQ-UI score fell from 16 preoperatively to 4 postoperatively (Mann–Whitney U-Test, P < 0.001). There were no significant differences in postoperative improvements in ICIQ scores between patients receiving onabotulinumtoxinA and those receiving abobotulinumtoxinA.

Of 179 patients, 152 (85%) reported a global improvement in their symptoms after treatment with botulinum toxin type A. Out of 100 patients, 81 (81%) who received onabotulinumtoxinA and 71 out of 79 (90%) patients who received abobotulinumtoxinA reported that their symptoms were ‘better’ or ‘much better’. This difference was not significant (Fisher's exact test, P = 0.140).

There was no significant difference in the duration of effect of the two toxins used (unpaired t-test, P = 0.827). Patients in the onabotulinumtoxinA cohort reported an effect lasting a mean of 10.65 months (95% CI 9.52–11.78), while patients in the abobotulinumtoxinA cohort reported an effect lasting 10.87 months (95% CI 9.07–12.7).

Data on PVR were available for 103 out of 208 patients. Of these, 47 came from the onabotulinumtoxinA cohort and the remainder from the abobotulinumtoxinA cohort. Not all patients with a PVR >150 mL were commenced on ISC as some were asymptomatic, but all patients with a PVR >300 mL were symptomatic and therefore were commenced on ISC (Table 4).

Table 4. PVR in patients who received onabotulinumtoxinA or abobotulinumtoxinA and numbers who went on to commence ISC
PVR, mLOnabotulinumtoxinAAbobotulinumtoxinA
No. of patientsNo. commenced on ISC%No. of patientsNo. commenced on ISC%
0–150311333515
151–250745710770
>25099100131185

Data on ISC rates were available for 179 out of 208 patients and only these patients were analysed. Overall, 56 of 180 patients (31%) required ISC after botulinum toxin type A injection. Two patients had already been performing ISC before the treatment (for chronic retention and for multiple urethral strictures) and they were excluded from the analysis. Of the 100 patients who received onabotulinumtoxinA, 23 (23%) required ISC after their treatment. Of the 79 patients who received abobotulinumtoxinA, 33 (42%) required ISC. Patients who received abobotulinumtoxinA had a significantly higher chance of having to perform ISC than those who had received onabotulinumtoxinA (Fisher's exact test, P = 0.009).

Rates of ISC in patients who had received two different doses of abobotulinumtoxinA were compared. Twenty-six out of 80 patients received a 300U dose, while 49 out of 80 patients received a 500U dose. Four patients received other doses. The ISC rates in the 300U and 500U groups, however, were 46 and 37%, respectively. The difference between ISC rates in the two groups was not significant (Fisher's exact test, P = 0.620).

Discussion

The present study has confirmed that botulinum toxin type A is an effective treatment for idiopathic OAB with overall patient-reported symptomatic improvement in 85% of patients and significant reductions in voiding frequency and episodes of UI.

There were no differences in clinical efficacy endpoints between patients who received onabotulinumtoxinA and those who received abobotulinumtoxinA (voiding diary, ICIQ questionnaires, patient-reported global satisfaction and duration of action). Although there has been no previous work comparing these outcome measures in OAB, the results match studies that have compared the efficacy and tolerability of onabotulinumtoxinA and abobotulinumtoxinA in chronic anal fissure and in cervical dystonia, where the results were indistinguishable between the two cohorts [18, 19].

Symptomatic urinary retention requiring ISC is a well recognised side effect of botulinum toxin type A treatment for OAB [8]. In our study, the ISC rate was nearly 100% in those with a PVR >250 mL. A significant difference in the ISC rate in patients given onabotulinumtoxinA (23%) and those given abobotulinumtoxinA (42%), where a dose conversion ratio of 2.5:1 was used, has also been demonstrated. Previous studies, which have looked at the adverse effects of using botulinum toxin type A in OAB, have mainly used onabotulinumtoxinA and have typically reported rates of about 16% [1, 2]. The few studies that specifically used abobotulinumtoxinA have reported ISC rates varying between 8.9 and 36% [7, 20-22]. One recent randomised controlled trial using onabotulinumtoxinA reported an ISC rate of 43% and ultimately had to be stopped owing to high UTI and PVR rates [3]. This figure is very much an outlier with respect to the rest of the literature, however, coming from a study with small numbers of patients and ISC instituted in patients with a PVR >200 mL, irrespective of symptoms. Although it has been shown that ISC is not a burden for the patient and can improve quality of life in those with voiding dysfunction [23], a higher ISC rate increases the cost of treatment and confers a greater risk of UTI [24]. Furthermore, it has been shown that the need for ISC is a key reason for patients discontinuing intravesical botulinum toxin type A treatment [25]. If it is possible, therefore, to minimize the need for ISC without compromising efficacy by selecting a particular agent, important implications for clinicians using botulinum toxin type A for OAB treatment present themselves.

The present study has some limitations, particularly as it is a retrospective, non-randomised study from a single centre. Its findings do need to be interpreted cautiously, particularly with regard to the incomplete nature of some of the bladder diary, ICIQ, PVR and length of effect data. It should be noted that a minimum PVR of 150 mL associated with symptoms of voiding dysfunction was used before institution of ISC in the present study, but there has been some variability in the minimum PVR required before ISC was started in patients in other studies [7].

Further prospective research would be useful to confirm our findings. It has been demonstrated in the literature that those with a lower maximum flow rate, detrusor contractility (in women) and bladder contractility index (in men) were much more likely to require ISC; these and other predictors of retention after treatment could be further explored when comparing the two treatment formulations [26]. Although detailed urodynamic diagnosis data were not reported for this group of patients, it would be interesting to explore the correlation of the urodynamic diagnosis with post-treatment need for ISC.

The present study is the first of its kind to compare the use of the two different formulations of botulinum toxin type A most commonly used to treat OAB of non-neurogenic origin. It casts further doubt on the assumptions about abobotulinumtoxinA and onabotulinumtoxinA being interchangeable and having equivalent clinical effects. Further work is also necessary to see if the risk of ISC is dose-dependent, and if not, whether the molecular structure of either or the constituents of its formulation affects the ISC rate.

In conclusion, this study is the first to compare the clinical effects of onabotulinumtoxinA and abobotulinumtoxinA in the treatment of idiopathic OAB, although it was not designed prospectively to do so. The difference in ISC rates suggests that the effects of these toxins are not similar at the doses used, and that the two toxins are not interchangeable for this application.

Conflict of Interest

Richard Parkinson has acted as a paid consultant for Allergan. No funding was received for this study.

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