The efficacy of botulinum neurotoxin type A intradetrusor injections to treat refractory nonneurogenic overactive bladder (OAB) with or without idiopathic detrusor overactivity has been shown in many case series,1 and these results have been confirmed by two randomized, placebo-controlled trials.2,3 Among the adverse events of botulinum neurotoxin type A intradetrusor injections, increased postvoid residual (PVR) with the potential need for clean intermittent self-catheterization is the most significant potential problem. A recent randomized, placebo-controlled trial using 200 units of botulinum neurotoxin type A (Botox, Allergan, Inc., Irvine, CA) was stopped prematurely because of high PVR and urinary tract infection rates, with 43% of patients requiring clean intermittent self-catheterization, all in the botulinum neurotoxin type A group.3 Similarly high clean intermittent self-catheterization rates of 38%2 and 50%4 had been reported previously. Thus, the key question is whether the need for clean intermittent self-catheterization after botulinum neurotoxin type A treatment impairs quality of life.
Although indwelling urethral and suprapubic catheters were used traditionally, clean intermittent self-catheterization initially reported by Lapides et al5 has revolutionized the modern management of voiding dysfunction, because urologic complications are decreased and quality of life may be improved.6 Indeed, clean intermittent self-catheterization is effectively used in women with urinary retention after incontinence surgery, radical hysterectomy, and radical rectal surgery as well as in those with an underlying neurologic disease. Thus, we hypothesize that the need for clean intermittent self-catheterization after botulinum neurotoxin type A injections is outweighed by the efficacy of this treatment, so that clean intermittent self-catheterization is no burden for patients with refractory OAB.
The aim of this study was to assess the short-term effect of clean intermittent self-catheterization on quality of life after first intradetrusor injections of 200 units of botulinum neurotoxin type A in women with refractory idiopathic detrusor overactivity.
PATIENTS AND METHODS
A consecutive series of 70 women with refractory idiopathic detrusor overactivity underwent botulinum neurotoxin type A intradetrusor injections in a prospective, nonrandomized, open label, single-center study between October 2002 and August 2008. The study inclusion criteria were refractory OAB, defined as failure to respond to behavioral treatment (lifestyle modifications and bladder training), pharmacotherapy with more than one antimuscarinic for at least 3 months, and urodynamically proven detrusor overactivity in nonpregnant and nonlactating women aged at least 18 years without neurologic disease, with no oral anticoagulant or antiplatelet treatment, and willingness to perform clean intermittent self-catheterization after botulinum neurotoxin type A treatment if necessary. Five patients (7%) (aged 37, 45, 50, 60, and 62 years) lost to follow-up were excluded. Thus, a total of 65 women had analyzable data.
Urodynamic studies were performed according to “Good Urodynamic Practices.”7 Urinary tract infections were treated before botulinum neurotoxin type A injections according to the antibiotic sensitivity pattern. We discussed with all patients that after botulinum neurotoxin type A injections, clean intermittent self-catheterization may become necessary for several months and that willingness to do so is a prerequisite for this therapy. All patients provided written informed consent before treatment. This study had the approval of the local ethics committee (Joint University College London/University College London Hospitals Committees on the Ethics of Human Research). All methods, definitions, and units conform to the standards recommended by the International Continence Society.8
Intradetrusor botulinum neurotoxin type A injections were performed in an out-patient setting using the previously described minimally invasive technique.9 After intraurethral instillation of 20 mL 2% lignocaine gel (Instillagel, Farco-Pharma GmbH, Köln, Germany) and exposure for 2 to 5 minutes, a 27-G 4-mm-long needle (Olympus MAJ-656, KeyMed, Milton Keynes, UK) was passed through the sheath (Olympus NM-101C-0427) of the 2-mm-diameter working channel of a flexible cystoscope (Olympus), and 200 units of botulinum neurotoxin type A (Botox) at 1:10 dilution with 0.9% saline were injected at 20 different sites in the detrusor, sparing the trigone. The bladder was emptied after the procedure and patients were discharged without an indwelling catheter on 100 mg trimethoprim twice daily for 3 days.
As an indicator of quality of life we assessed short-term lower urinary tract symptom distress and effect on daily activities using two validated condition-specific questionnaires, Urogenital Distress Inventory 6 (UDI-6)10 and Incontinence Impact Questionnaire 7 (IIQ-7),10 before and 4 weeks after botulinum neurotoxin type A injections. Responses to UDI-6 and IIQ-7 were scored from 0 to 100 according to standard scoring,10 with higher scores indicating more bother or effect, respectively. An assessment of PVR and urine analysis was carried out 2 weeks after injections. Because there are no generally accepted criteria for initiating clean intermittent self-catheterization, PVR more than 100 mL with lower urinary tract symptoms was taken as the indication for clean intermittent self-catheterization. Urinary tract infections were treated according to antibiotic sensitivity, but patients were not routinely prescribed prophylactic antibiotics if they were performing clean intermittent self-catheterization.
Outcome measures were changes in quality of life as assessed by UDI-6 and IIQ-7 before and 4 weeks after first botulinum neurotoxin type A intradetrusor injections and the need for clean intermittent self-catheterization due to botulinum neurotoxin type A treatment.
For a calculated sample size of 54 patients (ie, 27 in each group), the study was designed to have 95% power (β=0.05) for the unpaired t test to detect a difference of 25 in the UDI-6 and IIQ-7 quality-of-life score (this difference was estimated to be clinically relevant) between women performing clean intermittent self-catheterization and those who did not after botulinum neurotoxin type A injections at a two-tailed significance level of 5% (α=0.05), assuming a standard deviation (SD) of 25.
Data distribution was tested by Q-Q plots. Normally distributed data were presented as mean and SD, skewed data as median and interquartile range (IQR). Comparing related/unrelated samples, the paired/unpaired t test was used for normally distributed data and the Wilcoxon signed rank test/Mann-Whitney U test for skewed data, respectively. Urinary tract infection rates 2 weeks after botulinum neurotoxin type A treatment between women later performing clean intermittent self-catheterization and those who did not were compared applying the Fisher exact test. A P<.05 was considered significant. Statistical analysis was performed using SPSS 16.0 (SPSS Inc., Chicago, IL).
The mean age of the 65 women was 51 years (SD±15 years, range 19–79 years). Before botulinum neurotoxin type A injections, all women voided spontaneously. Two weeks after botulinum neurotoxin type A intradetrusor injections, 28 (43%) of 65 women required catheterization, and all managed clean intermittent self-catheterization. None needed an indwelling catheter, and all instructed in clean intermittent self-catheterization performed it also at the 4 weeks outcome time point.
Baseline characteristics of women performing clean intermittent self-catheterization and of those who did not after botulinum neurotoxin type A treatment are shown in Table 1. There were no statistically significant differences between the two groups (Table 1).
Four weeks after botulinum neurotoxin type A injections, there was a significant improvement in quality of life in both groups (Fig. 1 A and B): The mean UDI-6 and IIQ-7 scores reduced from 61 (95% confidence interval [CI] 55–67) to 33 (95% CI 25–41; P<.001) and 62 (95% CI 53–71) to 30 (95% CI 20–40; P<.001) in women performing clean intermittent self-catheterization and from 60 (95% CI 54–66) to 28 (95% CI 21–35; P<.001) and 64 (95% CI 56–72) to 25 (95% CI 17–33; P<.001) in those who did not, respectively. Comparison of UDI-6 and IIQ-7 scores in patients performing clean intermittent self-catheterization and in those who did not revealed no significant differences before and after botulinum neurotoxin type A treatment (Fig. 1). In addition, the single UDI-6 and IIQ-7 items were similar in both groups before (Table 2) and after (Table 3) botulinum neurotoxin type A injections.
Two weeks after botulinum neurotoxin type A injections, antibiotic treatment for lower urinary tract infection was required in 12 (18%) of the 65 women. Urinary tract infections were significantly (P=.02) more frequent in women later performing clean intermittent self-catheterization (9 of 28, 32%) than in those who did not (3 of 37, 8%).
The present study assessed the short-term effect of clean intermittent self-catheterization on quality of life after botulinum neurotoxin type A intradetrusor injections for treating women with refractory idiopathic detrusor overactivity. We found the same significant improvement in quality of life after botulinum neurotoxin type A injections in women who did and did not need to perform clean intermittent self-catheterization. Importantly, all our patients were informed of the potential need for clean intermittent self-catheterization, and willingness to do so was an inclusion criterion. Thus, our results indicate that clean intermittent self-catheterization after botulinum neurotoxin type A intradetrusor injections does not impair quality of life in appropriately informed and selected women in the short-term.
Maximal flow rate, projected isovolumetric pressure, and bladder contractility index have been suggested as predictors of incomplete bladder empting.11 However, there are no generally accepted criteria for initiating clean intermittent self-catheterization after botulinum neurotoxin type A injections. The reported clean intermittent self-catheterization rates vary widely and seem to depend on the cause of OAB, injected dose, injection technique, definition of significant PVR, and presence of lower urinary tract symptoms. In patients with neurogenic detrusor overactivity secondary to multiple sclerosis,12 we found the clean intermittent self-catheterization rate was almost 100% using 300 units of botulinum neurotoxin type A. In this group of patients, however, it seems likely that the neural mechanism for voiding is affected by the underlying neurologic disease. Injecting the same dose in idiopathic detrusor overactivity patients, a de novo catheterization rate of 50% was reported.4 With a smaller dose of 200 units of botulinum neurotoxin type A, two placebo-controlled trials in idiopathic detrusor overactivity patients found clean intermittent self-catheterization was needed in 38% and 43%, respectively.2,3 This is in line with our findings, where 43% of our patients were introduced to clean intermittent self-catheterization after botulinum neurotoxin type A injections. In contrast, a clean intermittent self-catheterization rate of only 3–4% was observed by Schmid et al (Schmid DM, Roy-Guggenbuehl SG, Werner MW, Perruchini DP, Sulser TS, Schurch B. The Zurich experiences including 6 year results of 200 cases treated with botulinum-A toxin injections into the detrusor muscle for overactive bladder refractory to anticholinergics [meeting abstract 568]. Eur Urol suppl 2008;7:212).13 using 100 units of botulinum neurotoxin type A in patients with refractory OAB. The reasons for these marked discrepancies are unclear, although differences in the study inclusion criteria, in the doses of botulinum neurotoxin type A, and in the indication for clean intermittent self-catheterization may be of significance. Importantly, it remains to be established which dose of botulinum neurotoxin type A has the best effect with lowest clean intermittent self-catheterization rate, and an ongoing, although sponsored, randomized, placebo-controlled, dose–response study (NCT00168454) may answer these question.
In a nonrandomized prospective study by Gamé and colleagues,14 botulinum neurotoxin type A intradetrusor injections for treating patients with neurogenic detrusor overactivity significantly decreased the incidence of urinary tract infections, and in this study all patients performed clean intermittent self-catheterization already before botulinum neurotoxin type A treatment. In contrast, in two placebo-controlled, randomized studies of treating idiopathic detrusor overactivity patients with botulinum neurotoxin type A intradetrusor injections, increased urinary tract infection rates of 75%3 and 100%2 were found in those performing clean intermittent self-catheterization. In the present study, urinary tract infections during follow-up were not routinely assessed, and the effect of clean intermittent self-catheterization on urinary tract infections could therefore not be evaluated. However, 2 weeks after botulinum neurotoxin type A injections (ie, before initiation of clean intermittent self-catheterization), urinary tract infections were significantly more frequent in women who later performed clean intermittent self-catheterization compared with those who did not, probably due to their persistent higher PVR.
Since there is a lack of high level-of-evidence data in the literature, PVR more than 100 mL with lower urinary tract symptoms was taken as the indication for clean intermittent self-catheterization in the present study based on our favorable clinical experience with neurologic patients. Remarkably, the need to perform clean intermittent self-catheterization had no effect on our patients’ quality of life after botulinum neurotoxin type A injections. This is at least partially explained by the fact that we stipulated that a willingness to perform clean intermittent self-catheterization if necessary, was a study inclusion criterion. Indeed, meeting patients’ expectations is related to increased satisfaction15,16 and patients’ satisfaction is an important indicator of the quality of care.17 This also underlies the significance of the informed consent procedure before botulinum neurotoxin type A treatment.
Our findings are in line with a recent questionnaire study reporting that most patients perceive clean intermittent self-catheterization as an easy and painless procedure that does not interfere with daily activities.6 In a nonselected population-based study in Norway,18 most patients were able to perform clean intermittent self-catheterization, even those with high disability scores. They considered clean intermittent self-catheterization an advantage, and they were not averse to the procedure, which they found easy to perform. Clean intermittent self-catheterization has been shown to be a safe and valuable technique for children,19 older people,20 and even for multiple sclerosis patients with cognitive dysfunction.21
We are aware of limitations of our study. There are no validated clean intermittent self-catheterization-specific quality-of-life instruments available so far, and the quality-of-life questionnaires used, although validated, are not clean intermittent self-catheterization–specific. Our study was neither randomized nor placebo controlled, but it was prospective and representative of everyday clinical experience. In addition, it was adequately powered and sized to detect differences between the two groups investigated. Quality-of-life assessment was performed 4 weeks posttreatment, but not serially, and this may have biased the results. However, it was the same in both the clean intermittent self-catheterization patients and those not performing clean intermittent self-catheterization, so that it should not be relevant for comparison of the two groups. The length of time for which patients performed clean intermittent self-catheterization and the long-term effect of clean intermittent self-catheterization on quality of life was not assessed in the present study, but it is part of an ongoing evaluation. Because our findings are derived from female patients only, it is unclear whether the results could be extrapolated to men.
In conclusion, intradetrusor botulinum neurotoxin type A injections for refractory idiopathic detrusor overactivity in women significantly improved quality of life. This effect was similar in both women performing clean intermittent self-catheterization and those who did not, indicating that clean intermittent self-catheterization after botulinum neurotoxin type A treatment did not impair quality of life in appropriately informed and selected women. Our recommendation therefore is that all patients should be informed of the potential need for clean intermittent self-catheterization after botulinum neurotoxin type A injections, and a willingness to do so should be a prerequisite for this still unlicensed off-label treatment.
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