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- Patients and Methods
- Conflict of Interest
Intravesical botulinum toxin (BT) was first used in the urological tract in 1988 to treat detrusor sphincter dyssynergia . 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 . 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.
- Top of page
- Patients and Methods
- Conflict of Interest
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.  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.