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Keywords:

  • intravesical botulinum toxin;
  • overactive bladder;
  • detrusor overactivity;
  • OnabotulinumtoxinA

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

What's known on the subject? and What does the study add?

  • It is known that intravesical botulinum toxin (BT) is an effective treatment for overactive bladder, especially in the patients with neurogenic detrusor overactivity. Several studies have shown that diagnostic and health-related quality of life parameters improve after intravesical BT treatment.
  • The present study has the merit of reporting a ‘real-life’ experience in a large teaching hospital in the UK National Health Service. As opposed to controlled trials, this retrospective study based largely on patient choice, shows that most patients fail to persist with intravesical BT treatment, mainly due to tolerability issues.

Objectives

  • To assess the long-term compliance with repeated injections of intravesical botulinum toxin (BT) in a ‘real-life’ mixed population of patients with idiopathic detrusor overactivity and neurogenic detrusor overactivity.
  • To identify the reasons why patients discontinued BT therapy and to explore the outcomes of those patients who did discontinue treatment.

Patients and Methods

  • Retrospective evaluation of the case notes of a series of patients who had received intravesical BT treatment at a large UK teaching hospital.
  • No antibiotic prophylaxis was given for the procedure.

Results

  • Over a period of 7 years, 268 patients were initiated on intravesical BT treatment for overactive bladder (OAB) at our institution, with 137 followed up for ≥36 months, with 80 patients having ≥60 months follow-up after their first injection.
  • Almost two-thirds of patients (61.3%) had discontinued intravesical BT therapy at 36 months, with a 63.8% discontinuation rate at 60 months.
  • The main reasons for discontinuation were tolerability issues, mainly urinary tract infections and the need for clean intermittent self-catheterisation. Primary and secondary losses of efficacy were of secondary importance.
  • Most of the patients that discontinued have remained under urology care and now receive alternative methods of treatment.

Conclusions

  • Intravesical BT therapy is an effective short-term treatment for OAB.
  • With time, two-thirds of patients discontinued treatment usually because of the tolerability issues associated with treatment.

Abbreviations
BT

botulinum toxin

CISC

clean intermittent self-catheterisation

HRQL

health-related quality of life

OAB

overactive bladder

PVR

postvoid residual urine volume

RCT

randomised controlled trial

UDS

urodynamic studies

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

Intravesical botulinum toxin (BT) was first used in the urological tract in 1988 to treat detrusor sphincter dyssynergia [1]. Since then, it has been used to treat various urological conditions, e.g. idiopathic and neurogenic detrusor over-activity (IDO and NDO), BOO and painful bladder syndrome, in both children and adults [2]. Although the use of BT is not currently licensed in the UK for use in the urological tract (at the time of writing), it has found its way in to the arsenal of many urological surgeons dealing with lower urinary tract dysfunction. The USA Food and Drug Administration has recently approved its use for urinary incontinence in patients with neurological conditions. The efficacy and side-effect profile of intravesical BT have been shown in several randomised placebo-controlled trials (RCTs) [3-11], some of which have shown the efficacy and durability of intravesical BT treatment over a period, mainly in patients with NDO [12-15]. However, little is known about the long-term patient tolerability to and acceptance of repeated intravesical BT therapy.

Antimuscarinics and conservative management options (lifestyle modifications, bladder retraining) are the first-line treatment for overactive bladder (OAB). If antimuscarinic therapy fails or if the patients have significant side-effects from its use, BT is one of the second-line treatment options. It is administered via intravesical injections using a cystoscope under local or general anaesthesia. Efficacy of the BT diminishes with time, so that patients require repeated injections every 5–9 months.

The aim of the present study was to evaluate the use of intravesical BT as a long-term option for patients with IDO and NDO, who had failed conservative measures, including antimuscarinics. The primary objective of the present study was to assess the long-term compliance of patients with repeated injections of intravesical BT. Secondary aims were to identify the reasons why patients discontinued BT therapy and to explore the outcomes of those patients who did discontinue treatment.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

We identified 268 patients who had received intravesical BT, after its introduction into the Department of Urology of our hospital in 2004, for the treatment of refractory detrusor overactivity. Of these patients, 118 had <3 years of follow-up and 13 had inadequate records. Thus, 137 patients with ≥36 months follow-up were available for evaluation. All patients were resistant to or intolerant of oral antimuscarinic therapy and detrusor overactivity had been confirmed by urodynamic studies (UDS) in all patients. Most of the patients had urinary incontinence. Various anticholinergic therapies had been used, at doses up to the maximum recommended level. Patients with evidence of BOO on UDS according to ICS normogram were not offered BT treatment. Patients were fully consented to the use of onabotulinumtoxinA including the side-effects associated with the treatment. The possibility of having to perform clean intermittent self-catheterisation (CISC) after the procedure was explained to the patient before the treatment.

Injection Techniques

Our institution uses OnabotulinumtoxinA, which is a 900 kD albumin protein, sold under the trade name OnabotulinumtoxinA by Allergan Pharmaceuticals, Irvine, CA, USA. As per the manufacturer's recommendation, the OnabotulinumtoxinA was reconstituted with 0.9% normal saline to a dosage of 10 units/mL. At the beginning of the study period, general anaesthesia was used to administer the treatment but with time, most patients changed to having their injections under local anaesthesia using a flexible cystoscope in a day-case setting. Thereafter, cystoscopy under general anaesthesia was reserved for patients who did not tolerate the local anaesthetic procedure or who expressed a wish to have the procedure under general anaesthesia. The OnabotulinumtoxinA was injected intra-detrusor muscle supra-trigonally in aliquots of 1 mL, delivering 10 units at each injection site. Antibiotic prophylaxis was not routinely given.

At the beginning of the study, patients with IDO were injected with a dose of 200 units of OnabotulinumtoxinA, and patients with NDO were injected with a dose of 300 units of OnabotulinumtoxinA. This was consistent with the reported literature at the time [16]. We subsequently reduced the administered dose (initially to 200 units for all and latterly to 100 units) as published evidence became available [17]. This has been done in an attempt to maximise efficacy and minimise side-effects. Therefore, the initial cohort of patients had 30 injections into their bladder wall, which were gradually decreased to 10 injection sites by the end of the study period. On the day of the procedure, patients were discharged once they had voided spontaneously with a postvoid residual urine volume (PVR) of <150 mL. Although OnabotulinumtoxinA is yet to be licensed in the UK for its use in the management of detrusor overactivity, the Leeds Teaching Hospitals Use of Medicine Committee approved its use for this purpose in 2004.

Follow-up

All patients were followed up on at least two occasions after the initial injection. There was an initial clinic review 2–4 weeks after treatment and a second review after 8–12 weeks. Assessment was by patient history, bladder diary and ultrasonographic measurement of the PVR. Structured health-related quality of life (HRQL) questionnaires were not routinely used. However, the data obtained from the outpatient setting was reproducible, as this study reflects the practice of a single urologist. Some of the patients went on to have UDS after treatment if they had persistent symptoms. If the patient had urinary retention, symptomatic difficulties secondary to poor bladder emptying or large PVRs (>150 mL), then CISC was instituted.

At each of the follow-up visits, patients had the choice to maintain their current regimen of treatment or move to an alternative mode of treatment. If the patient and the clinician judged the treatment to be successful, (i.e. effective in improving or resolving the symptoms with nil or minor tolerability issues), the patient was booked for repeat treatments with an average treatment interval of 8 months. If the treatment was deemed unsuccessful, then either further investigation of the cause of the problem was organised (usually by UDS) or the patient was offered other therapeutic options. Rarely, patients were offered a second treatment if the first treatment had failed but subsequent UDS confirmed detrusor overactivity.

Subsequent follow-up was on an individualised basis. They were not seen routinely in the Outpatient Department between treatments but they did have access to a urology nurse specialist in cases of emergency and could request a clinic appointment if they wished. We found that the duration of response varied among patients and we attempted to adjust the frequency of re-injection to the needs of the individual. In practice, this meant that most patients received injections every 5–9 months. There was no minimum pre-fixed time in between treatments, although no patient had repeat injections within 3 months of the previous treatment.

Outcome Measure

The primary outcome measure was whether the patient continued or discontinued the use of BT therapy. Information was obtained from patients' notes and the electronic patient records. Data on treatment efficacy and side-effects of the treatment were collected. If the patients stopped the intravesical BT regimen the reasons for stopping and subsequent alternative management plans were identified.

Statistics

Statistical analysis was done using SPSS Version 19.0.0, Copyright 2010, IBM Company on the following groups of patients:

  1. Group of patients still on treatment vs group of patients who have stopped treatment.
  2. Group of patients with ≥5-years follow-up vs group of patients with ≥3-years follow-up.

Categorical variables were compared using the Pearson's chi-square Test and means were compared using 0020 the Independent samples t-test. A P < 0.05 was considered to indicate statistical significance.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

Discontinuation of BT Therapy

In all, 137 patients had ≥3-years follow-up, with 80 patients (58.4%) having ≥5-years follow-up. Of the whole cohort of 137 patients, 84 patients (61.3%) had stopped BT therapy with the remaining 53 (38.7%) still on the treatment. In the cohort of patients with ≥5-years follow-up, 51 patients (63.8%) had stopped BT therapy. Most patients received repeat BT injections with an average treatment interval of 8 months.

Table 1 shows the baseline demographics of the patients. We attempted to identify for those patients with 3-years follow-up, whether age, sex, aetiology (NDO vs IDO) and presence of incontinence predicted discontinuation from therapy by comparing the patients who stopped treatment and the patients who remained on treatment. Overall, there were few differences between those who stopped therapy and those who continued therapy. We did find that patients who were incontinent at baseline were more likely to stop treatment than those who were ‘dry’ before therapy (P = 0.008). We also found that that older patients (aged > 50 years) were more likely to stay on the treatment while younger patients were more likely to stop their treatment (P = 0.026). There was no statistical difference between the two groups of patients based on sex, age and aetiology (IDO vs NDO). Although not statistically significant, it should be noted that half of the patients with NDO remained on the intravesical BT whilst only a third of the patients with IDO did.

Table 1. Baseline demographics of patients who dropped out from BT therapy compared with those who continued with therapy at 3 years.
VariableTotal cohortPatients who stopped treatmentPatients still on treatmentP
N1378453 
Men, n (%)43 (31.4)30 (35.7)13 (24.5)0.165
Women, n (%)94 (68.6)54 (64.3)40 (75.5)
Mean (range) no. of procedures4.9 (1–16)2.4 (1–8)10.0 (4–16) 
Mean age, years57.358.958.50.863
Neuropathic, n3315180.320
Idiopathic, n1046935
Incontinent at baseline, n11375380.008
Not incontinent at baseline, n24915
Age ≥ 50 years, n10559460.026
Age < 50 years, n32257

Table 2 compares the basic baseline demographics of the patients started on intravesical BT therapy, with ≥3-years (Group A) and ≥5-years follow-up (Group B), with P-values comparing the groups. There was no statistically significant difference between the two groups of patients for sex, number of patients with just one procedure, mean time between procedures, number of patients who stopped the intravesical BT treatment, age, aetiology (IDO vs NDO), age group and associated incontinence.

Table 2. Baseline demographics of patients followed for 3 years and 5 years.
VariablePatients with ≥3-years follow-upPatients with ≥5-years follow-upP
N13780 
Men, n (%)43 (31.4)31 (38.8)0.270
Women, n (%)94 (68.6)49 (61.2)
Patients with only one procedure, n (%)33 (24.1)12 (15.0)0.111
Patients with more than one procedure, n (%)104 (75.9)68 (85.0)
Mean (range) time between procedures, months7.8 (3–48)8.2 (4–48)0.782
Patients who stopped treatment, n (%)84 (61.3)51 (63.8)0.721
Patients still on treatment, n (%)53 (38.7)29 (36.3)
Mean age, years58.759.80.876
Neuropathic, n33200.880
Idiopathic, n10460
Incontinent, n113680.370
Not incontinent, n2418
Age ≥ 50 years, n105630.720
Age < 50 years, n3217

The rate of discontinuation from BT therapy is shown in Fig. 1. At 36 months, 84 of the initial 137 patients (61.3%) had stopped their BT therapy regimen. In all, 33 patients of the initial cohort (24.1%) had only a single BT treatment. There appears to be a plateauing effect reached in the discontinuation rate from treatment from 3 years onwards, with the discontinuation rate at 5 years being 63.8%.

figure

Figure 1. Timeline of the proportion of patients still having intravesical onabotulinumtoxinA.

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The reasons for discontinuation were analysed in patients with ≥3-years follow-up and are shown in Fig. 2. Primary failure refers to patients who had a single intravesical BT treatment but who did not have any therapeutic benefit from it. Secondary failure refers to patients who got initial therapeutic relief from intravesical BT therapy but stopped after two or more treatments because of efficacy issues. Discontinuations secondary to tolerability issues refer to any reason that led to the patients stopping BT therapy other than efficacy issues. These included patients who were intolerant of having to perform CISC after the procedure and those who had significant complications (including complete urinary retention and recurrent UTIs), which in their view outweighed the benefits of the intravesical BT therapy.

figure

Figure 2. The reasons why patients discontinued the intravesical BT regime. PF, no improvement of symptoms after first treatment; SF, no improvement of symptoms after subsequent treatment; TI, inconvenience, complications and side-effects associated with the symptoms.

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Tolerability issues were the major problem in the present cohort of patients, with 47 of the 84 patients (55.9%) discontinuing the treatment regimen as a consequence. The other 37 patients (44.1%) who discontinued treatment did so because it did not provide them with symptomatic relief. In all, 23 patients (16.8% of the initial cohort) never had any relief of their symptoms with the intravesical OnabotulinumtoxinA, while the other 14 (11.7%) had a secondary failure of efficacy. Of the 37 patients who stopped their treatment owing to lack of efficacy, 16 (43.2%) of those also reported concurrent tolerability issues.

Table 3 shows the tolerability issues associated with patients who declined to have further injections of intravesical BT. Most of the problems arose secondary to high PVRs. In all, 37 patients (58.7%) were advised to perform CISC after treatment, with five of those patients already performing CISC before the procedure. Six patients failed to learn or perform CISC adequately. In all, 23 patients (36.5%) stopped BT therapy owing to difficulties with UTIs. Those patients who did have UTIs were managed by various methods including: intermittent antibiotics for symptomatic infections, long-term low-dose antibiotics or prophylaxis at the time of injection. Patients who stopped BT therapy because of UTIs did so despite therapeutic benefit from the treatment. Three (4.8%) patients stopped their treatment citing worsening symptoms as the reason to stop. There was no difference between the two groups of patients (IDO or NDO) and the incidence of the tolerability issues.

Table 3. Tolerability issues associated with onabotulinumtoxinA treatment.
Tolerability issuesNumber of patients (%)
Worsening symptoms3 (4.8)
High PVRs: 
Need for CISC31 (49.2)
Recurrent UTIs23 (36.5)
Unable to perform CISC6 (9.5)
Total63

Table 4 shows the outcome of patients who stopped intravesical BT therapy. In all, 46 of these 84 patients (54.8%) were still under urological follow-up 36 months after their first BT treatment. In all, 21 of these patients had adopted an alternative mode of therapy for their OAB symptoms; 10 patients (21.7%) went on to have sacral neuromodulation, and six (13.4%) went on to have major surgical operations (ileocystoplasty or ileal conduit diversion) to treat their refractory OAB symptoms. The rest (54.4%) went back to conservative management of their symptoms. In all, 38 of the 84 patients (45.2%) who stopped intravesical BT therapy were not under urological follow-up 36 months after their first intravesical BT treatment. A significant proportion (52.6%) of this cohort of patients was lost to follow-up. All the other patients (47.4%) were discharged from urology care on conservative management for their OAB symptoms (lifestyle modifications with or without anticholinergics).

Table 4. Outcome of patients who have stopped onabotulinumtoxinA treatment.
OutcomeNumber of patients who stopped intravesical onabotulinumtoxinA treatment n = 84
Primary failure (n = 23)Secondary failure (n = 14)Tolerability issue (n = 47)
Still under urology care (n = 46), n14 10 22 
SNS627
Conservative management6613
Major surgery222
Not under urology care (n = 38), n9 4 25 
SNS000
Conservative management6210
Major surgery000
Lost to follow-up3215

Figure 3 shows the treatments algorithm of patients in the present study. The initial starting dose of OnabotulinumtoxinA was 300 units, although subsequently decreased to 200 units in patients with IDO in 2006 as clinical evidence became available. None of the patients in this cohort was treated with <200 units of OnabotulinumtoxinA. Patients with primary or secondary failures were re-investigated with UDS. If detrusor overactivity was confirmed despite the treatment with OnabotulinumtoxinA, a higher dose was offered to the patient, in an attempt to improve efficacy. In the present series, no patient with secondary failure received a lower dose than their first treatment dose.

figure

Figure 3. Treatment algorithm in our cohort of patients.

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Overall, of all the 84 patients who stopped their BT therapy, 43 patients (51.1%) went back to a management plan based upon lifestyle changes and anticholinergics. Patients who went back to conservative management were restarted on a similar treatment regimen as before the start of their intravesical BT treatment.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

The present study shows that by 3 years, almost two-thirds of patients who had been initiated on intravesical BT therapy for refractory OAB had discontinued treatment and most of those patients stopped treatment as a consequence of tolerability issues. The overall discontinuation rate at 5 years was about the same as at 3 years.

Although there are several publications relating to the efficacy and safety of intravesical BT in the treatment of resistant OAB, most of the published series are short term and deal with short-term efficacy and tolerability issues. The present series has the merit of reporting the outcome of therapy in a ‘real world’ situation. Although there were not the strict criteria that determine entry to clinical trials, the process for identifying, assessing, treating and following patients with resistant OAB were consistent in the present study, as the methods section of this paper describes. The duration of follow-up is longer than other reported studies and identifies a discontinuation rate that is discordant with other studies, and it is interesting that most patients stopped therapy because of tolerability issues. To the best of our knowledge, this is the first study that specifically reports on patient-reported tolerability issues on a cohort of patients with ≥3-years follow-up.

Published data confirm several tolerability issues with intravesical BT therapy including: UTIs, urinary retention, the need for CISC and high PVRs. Contemporary RCTs report an incidence of UTIs of 1.3–64% [18-20], the need for CISC of 1.3–42.2% and high PVRs of 28.6–53.7% [18-20]. The present data are comparable with these results, with the incidence of UTI being 16.8%, the need for CISC being 22.6% and significant PVRs being present in 22.6%. In the present cohort of patients, we speculate that if antibiotics prophylaxis was used primarily, the UTIs rate might have been lower. This in turn might have led to increased confidence in the therapy and improved compliance with the regimen. Moreover, a greater proportion of patients with NDO remain on the treatment compared with those in the IDO group, possibly explained by the fact they were already performing CISC before treatment and therefore, the need for CISC after treatment was not deemed unacceptable.

It is interesting to speculate why patients with tolerability issues discontinued later rather than earlier in the present study. We wonder whether this was a HRQL issue, in that the patients initially enjoyed the improved symptomatic relief from the BT therapy after switching from conservative management and noticed a significant improvement in their urinary symptoms and in their HRQL. However, as they became used to the treatment, the inconvenience of having repeated treatments and having to deal with the side-effects of treatment came to have a greater impact on their HRQL. This hypothesis is supported by the number of patients who ultimately returned to their initial treatment (lifestyle changes and anticholinergics). We think that the conservative management regime was deemed more acceptable to the patients after ‘experiencing’ the intravesical BT regime. The patients did not perceive conservative management as being more effective than intravesical BT treatment; they just seemed to find it more acceptable.

The efficacy of therapy in the present study is largely consistent with published data, which has documented efficacy in placebo-controlled RCTs including patients with IDO and NDO. The present initial efficacy rate was 83.2% with only 16.8% of patients receiving a single treatment. A proportion of patients had a subsequent failure to respond (11.8% of the original cohort). Rovner et al. [21] reported that 42.9–70.2% of patients had persisting urinary incontinence 12 weeks after BT injection therapy and other contemporary RCTs report a 27.8–41.1% primary failure rate [19, 20]. Secondary failure has been reported previously, although others show no loss of efficacy, or even improved efficacy with repeated injection [13, 22]. Again, it is interesting to speculate why a drug that is initially effective may subsequently become ineffective and there are several possible reasons for this apparent secondary failure. First, it may be that the treatment really had lost its efficacy having initially shown efficacy. Second, it may be that there was a technical issue with the subsequent BT injections that resulted in lesser efficacy. Third, it might be that the benefits, which the patient initially identified, were relative to the degree of disability before treatment and that with time, there may have been more measured assessment of the benefits offered by BT compared with other therapies. This latter explanation is supported by the fact that almost half the patients that discontinued BT treatment returned to behavioural therapy and anti-cholinergics, despite such approaches having ‘failed’ initially.

The present study has a few limitations. Firstly, although OnabotulinumtoxinA was unlicensed for use in the treatment of LUTS for the study period, it was felt that the body of evidence at the time was sufficient to treat patients. Patients were properly counselled about the unlicensed nature of the treatment. Secondly, it is a ‘real-life’ study and data was collected retrospectively from patients' notes. Success was patient-reported rather than assessed by any specific urological tool or questionnaire. The patients were under the care of a single surgeon, in a single centre and the setting may therefore not be generalisable to other units. However, this single centre set-up provided a centralised and standardised follow-up for all the patients. There are other technical issues that might have biased the results, namely the lack of antibiotic prophylaxis, the initial use of general anaesthesia and the relatively high doses used in the early years of the study. Furthermore, CISC was instituted in patients with a post-micturition residual of 150 mL, in an attempt to minimise the development of UTIs and long-term kidney damage. However, it may be that many patients were unnecessarily started on CISC, increasing the incidence of tolerability issues and discontinuation rate in the present patient group.

This said, it is the first long-term study reporting efficacy, tolerability and compliance with treatment and as such, needs to be repeated in other populations and in other centres. If such a discontinuation rate is confirmed more generally, then it may be that measures can be instituted to minimise discontinuation, including such measures as appropriate patient support.

In conclusion, the present series from a University Hospital in the UK confirms the utility of intravesical BT therapy as a method of treatment for patients with resistant OAB. In the long-term only one-third of patients continued with therapy, with discontinuation largely being a consequence of tolerability issues.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References
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