Journal Article Page
European UrologyVolume 62, issue 3, pages e49-e68, September 2012
Female Urology - Incontinence
Botulinum Toxin A Versus Placebo for Refractory Detrusor Overactivity in Women: A Randomised Blinded Placebo-Controlled Trial of 240 Women (the RELAX Study)
Accepted 28 December 2011, Published online 5 January 2012, pages 507 - 514
Emerging data suggest botulinum toxin is an effective treatment for detrusor overactivity (DO), but large studies confirming efficacy and safety are lacking.
Study the efficacy and safety of onabotulinumtoxinA (onaBoNTA) for the treatment of DO.
Design, setting, and participants
A double-blind placebo-controlled randomised trial in eight UK urogynaecology centres was conducted between 2006 and 2009. A total of 240 women with refractory DO were randomised to active or placebo treatment and followed up for 6 mo.
Treatment consisted of 200 IU onaBoNTA or placebo injected into the bladder wall (20 sites; 10 IU per site in 1 ml saline).
Primary outcome was voiding frequency per 24 h at 6 mo. Secondary outcomes included urgency and incontinence episodes and quality-of-life data. Intention-to-treat analysis was used with imputation of missing data.
Results and limitations
A total of 122 women received onaBoNTA and 118 received the placebo. Median (interquartile range) voiding frequency was lower after onaBoNTA compared with placebo (8.3 [6.83–10.0] vs 9.67 [8.37–11.67]; difference: 1.34; 95% confidence interval [CI], 1.00–2.33; p = 0.0001). Similar differences were seen in urgency episodes (3.83 [1.17–6.67] vs 6.33 [4.0–8.67]; difference: 2.50; 95% CI, 1.33–3.33; p < 0.0001) and leakage episodes (1.67 [0–5.33] vs 6.0 [1.33–8.33]; difference: 4.33; 95% CI, 3.33–5.67; p < 0.0001). Continence was more common after botulinum toxin type A (BoNTA; 31% vs 12%; odds ratio [OR]: 3.12; 95% CI, 1.49–6.52; p = 0.002). Urinary tract infection (UTI; 31% vs 11%; OR: 3.68; 95% CI, 1.72–8.25; p = 0.0003) and voiding difficulty requiring self-catheterisation (16% vs 4%; OR: 4.87; 95% CI, 1.52–20.33; p = 0.003) were more common after onaBoNTA.
This randomised controlled trial of BoNTA for refractory DO, the largest to date, confirms efficacy and safety of the compound. UTI (31%) and self-catheterisation (16%) are common. A third of women achieved continence.
The study received ethical committee approval from the Scottish Multicentre Research Ethics Committee (reference: 04/MRE10/67). The trial has a EudraCT number (2004-002981-39), a clinical trial authorisation from the UK Medicines and Healthcare Regulatory Agency, and it was registered on Current Controlled Trials (ISRCTN26091555) on May 26, 2005.
Detrusor overactivity (DO) is characterised by spontaneous contractions of the detrusor muscle during bladder filling, causing symptoms of urgency, frequency, nocturia, and incontinence (overactive bladder [OAB]) . Treatments include behavioural therapy  or anticholinergic drugs (including oxybutynin , tolterodine , and solifenacin ) that have moderate efficacy but troublesome side effects including dry mouth, constipation, and blurred vision . These are responsible for frequent discontinuation of treatment . Botulinum toxin type A (BoNTA) has been rapidly adopted as a treatment for DO and OAB. Although it is now widely available, the evidence in support is still only moderate.
BoNTA was first used to treat neurogenic DO  and . In 2005, we developed this study protocol to demonstrate efficacy at least comparable with modern anticholinergic drugs when there were no published randomised controlled trials (RCTs) of BoNTA in idiopathic DO. Some RCTs subsequently were published, and these are considered later. A 2009 expert consensus statement advocated caution in the use of BoNTA in idiopathic DO and recommended larger placebo-controlled studies . Our study contributes to that recommendation.
The trial was approved by the Scottish Multicentre Research Ethics Committee (04/MRE10/67), registered on Current Controlled Trials (ISRCTN26091555), May 26, 2005, and participants were recruited between July 2006 and November 2009 from eight UK hospitals.
Participants were women with OAB symptoms and DO on urodynamics within 2 yr of recruitment , deemed to be refractory to treatment: 8 wk of treatment with any anticholinergic drug and one or more of the following: improvement rated “a little better” or worse on the Patient Global Impression of Improvement (PGI-I) scale , verbal report of unacceptable improvement, treatment stopped because of side effects, and patients previously treatment with no benefit.
After stopping oral medication (no specified washout period), women completed a 3-d urinary diary data during the following 2 wk: at least eight voids and two “moderate” or “severe” urgency episodes per 24 h  were required. Incontinence was not an entry criterion. Women with urodynamic stress incontinence , neurologic disease, voiding dysfunction, or contraindications to onabotulinumtoxinA (onaBoNTA; BOTOX, Allergan, USA) were excluded.
Randomisation was on a 1:1 basis using computer-generated block randomisation with random block size of 4–10. Drugs were packaged by a third-party company in consecutively numbered identical drug packs. Telephone confirmation of pack number to the trial office was required before administration to ensure packs were used in order. Treatment was undertaken in a surgical suite in every case, under local or general anaesthesia. Drugs were reconstituted in the preparation room out of sight of the treating surgeon (active drug vials and placebo vials were not identical). Women received 200 IU of onaBoNTA or placebo (vacuum-dried 0.9% sodium chloride) diluted in 20 ml of normal saline (10 IU/ml), injected in 20 sites, sparing the trigone . Antibiotic prophylaxis was not required, but two centres administered intraoperative antibiotics.
2.1. Data collection
Women were reviewed at 6 wk and 3 mo (by post) and at 6 mo by a research nurse blinded to allocated treatment. Outcome data were urinary voiding frequency, incontinence episode frequency, and urgency episode frequency (moderate or severe on the Indevus Urgency Severity Scale [IUSS])  from a 3-d voiding diary; International Consultation on Incontinence Questionnaire short form (ICIQ-SF) score ; Incontinence Quality of Life (IQOL) questionnaire score ; complications; need for additional treatment during follow-up; and time to return of troublesome symptoms. We predefined a window for valid data: 6 wk (−2 wk to +2 wk), 3 mo (−2 wk to +4 wk), and 6 mo (−2 wk to +8 wk).
Ethical approval of the study required allowing women to receive additional anticholinergic treatment for persistent refractory symptoms during follow-up.
2.2. Statistical analysis
Primary outcome was urinary voiding frequency per 24 h at 6 mo. Sample size calculations were taken from data comparing solifenacin versus placebo . To detect a difference in outcome of the same magnitude or greater (ie, 1.29 voids per 24 h) at the 5% statistical significance level and with 80% power, a minimum total sample size of 220 patients was required. We recruited 240 patients to allow for a 10% dropout rate. Data were analysed on an intention-to-treat basis. Analysis of continuous outcomes was undertaken using t tests or nonparametric methods; investigation into the potential impact of imbalances at baseline used multiple linear regression techniques. For categorical outcomes the groups were compared using chi-square tests or the Fisher exact test. Times to patient-reported recurrence of symptoms were displayed using Kaplan-Meier curves and analysed using a log-rank test and Cox proportional hazards regression model.
A total of 415 women were screened, and 240 were enrolled and treated (Fig. 1). At enrolment, 100 women (41.6%) were taking no medication due to side effects or previously failed therapy. A total of 122 women were randomised to onaBoNTA and 118 women to placebo. All were treated as allocated. Groups were similar at baseline (Table 1). Median voiding frequency was lower after onaBoNTA compared with placebo (8.33 vs 9.67; p = 0.0001) (Table 2; Fig. 2a). We tested whether any baseline covariates modified the primary outcome, but the only associated factor was baseline leakage severity: For each additional voiding episode at baseline, there was an additional 0.37 (95% confidence interval [CI], 0.17–0.58; p < 0.001) reduction in voiding frequency.
(n = 122)
(n = 118)
|Age, yr (range)||60.7 (50.8–67.8)||58.2 (51.5–69.2)|
|Body mass index >30||49 (40.2)||50 (43.5)|
|White||118 (96.7)||109 (93.9)|
|Other||4 (3.3)||7 (6.2)|
|Smoking||30 (24.6)||24 (20.5)|
|0||10 (8.2)||6 (5.1)|
|1+||112 (92.8)||111 (94.9)|
|Previous continence surgery||44 (36.1)||46 (39)|
|Voiding frequency per 24 h||10.3 (9.3–12.7)||10.7 (9.3–13.3)|
|Incontinence episodes per 24 h||6.2 (3.7–8.3)||6.2 (3.0–8.7)|
|Urgency episodes per 24 h†||8.0 (5.7–10.3)||7.7 (6.0–9.7)|
|Urgency severity score (IUSS)||2.1 (1.7–2.4)||2.1 (1.7–2.3)|
|Maximum voided volume||350 (275–450)||300 (250–420)|
|Mean voided volume||165.8 (122.0–203.7)||164.4 (121.8–198.0)|
|Continent||6 (4.9)||8 (6.8)|
|ICIQ score||17.0 (14.0–19.0)||16.0 (13.0–18.0)|
|I-QOL score||24.4 (11.4–38.6)||23.3 (12.5–34.1)|
|Treated with flexible cystocope||43 (35.2)||44 (37.3)|
|Treated under local anaesthesia||58 (47.5)||60 (50.8)|
* Data are displayed as medians (interquartile range) or number (%).
† Defined as severity of moderate or severe from the urgency severity score in the urinary diary.
IUSS = Indevus Urgency Severity Scale; ICIQ = International Consultation on Incontinence Questionnaire; I-QOL = Incontinence Quality of Life (questionnaire).
|Treatment group (n = 100)||Placebo group (n = 99)||Difference/OR and 95% CI||p value|
|Voiding frequency per 24 h||8.33 (6.83–10.00)||9.67 (8.37–11.67)||1.34 (1.00–2.33)||0.0001|
|Incontinence episodes per 24 h||1.67 (0.00–5.33)||6.00 (1.33–8.33)||4.33 (3.33–5.67)||<0.0001|
|Urgency episodes per 24 h||3.83 (1.17–6.67)||6.33 (4.00–8.67)||2.50 (1.33–3.33)||<0.0001|
|Urgency severity score (IUSS)||1.50 (1.00–2.00)||1.90 (1.50–2.30)||0.40 (0.20–0.60)||0.0006|
|Continent||31 (31.3)||12 (12.0)||3.12 (1.49–6.52)†||0.002|
|ICIQ score||10.00 (4.00–15.00)||15.00 (11.00–18.00)||5.00 (3.00–7.00)||<0.0001|
|IQOL score||55.11 (23.30–78.41)||27.27 (18.18–46.59)||−27.84 (−31.82 to −12.50)||<0.0001|
* Data are displayed as medians and interquartile ranges (IQR), with p values calculated using the Mann-Whitney U test. The difference between medians is displayed with 95% confidence intervals.
† For continence the OR with 95% CI is displayed.
OR = odds ratio; CI = confidence interval; IUSS = Indevus Urgency Severity Scale; ICIQ = International Consultation on Incontinence Questionnaire; IQOL = Incontinence Quality of Life (questionnaire).
This analysis includes only those women who returned a minimum of 2 d of valid data “in window.” Only 23 of 199 women (11.6%) returned data >2 wk each side of the 6-mo date.
Inclusion of “out of window” data did not affect the results (data not shown).
Analysis of primary outcome data only in women who had not received additional treatment demonstrated the same effect between the onaBoNTA group (8.00 [6.67–10.00]) and the placebo group (9.33 [8.33–11.33]); difference: 1.33 (0.67–2.33); p = 0.0001. Analyses of secondary outcome data in this subset were not done.
Other 6-mo outcome data are shown in Table 2 and Figure 2b–2d. There were large changes in urgency episodes (3.83 vs 6.33; p < 0.0001) and leakage episodes (1.67 vs 6.00; p = 0.0001) after onaBoNTA, with no significant change after placebo. No covariates were associated with modifying effects on the secondary outcomes. Almost a third of onaBoNTA women (31.3% vs 12.0%; odds ratio [OR]: 3.12; 95% CI, 1.49–6.52; p = 0.002) were continent. IUSS and both ICIQ and IQOL scores were also significantly improved compared with placebo, but neither QOL scale score was restored to normal (0 for ICIQ; 100 for IQOL). Outcome data at 6 wk and 3 mo mirrored the primary outcomes (Table 3; Fig. 2a–2d).
|6-wk outcomes||Treatment group||Placebo group||p value|
|n = 97||n = 98|
|Voiding frequency per 24 h||8.00 (6.33–10.00)||9.67 (8.37–11.67)||<0.0001|
|Incontinence episodes per 24 h||0.33 (0.00–4.00)||5.33 (1.67–7.00)||<0.0001|
|Urgency episodes per 24 h||2.67 (0.00–6.33)||6.17 (4.00–9.00)||<0.0001|
|Urgency severity score (IUSS)||1.30 (0.7–1.90)||1.90 (1.40–2.20)||<0.0001|
|Continent, n (%)||43 (41.8)||13 (13.1)||<0.0001|
|ICIQ score||7.00 (1.00–14.00)||14.00 (1.00–18.00)||<0.0001|
|IQoL score||55.68 (22.72–85.23)||30.68 (17.05–51.14)||0.0001|
|3-mo outcomes||n = 86||n = 86|
|Voiding frequency per 24 h||8.00 (6.30–10.00)||9.67 (8.00–11.00)||<0.0001|
|Incontinence episodes per 24 h||1.00 (0.00–6.00)||5.33 (2.00–8.33)||<0.0001|
|Urgency episodes per 24 h||3.00 (0.67 –6.33)||7.00 (3.67–8.67)||<0.0001|
|Urgency severity score (IUSS)||1.30 (0.80–2.00)||1.90 (1.40–2.30)||0.0001|
|Continent, n (%)||36 (35.0)||12 (12.0)||<0.0001|
|ICIQ score||8.00 (3.00–14.00)||15.00 (9.00–17.00)||<0.0001|
|IQOL score||64.77 (27.27–90.91)||25.00 (14.77–44.32)||<0.0001|
IUSS = Indevus Urgency Severity Scale; ICIQ = International Consultation on Incontinence Questionnaire; I-QOL = Incontinence Quality of Life (questionnaire).
The p values in this table are from secondary analyses and should be interpreted with due caution.
Figure 3 displays the time to patient-reported recurrence of symptoms. A total of 30 women (24.6%) after onaBoNTA and 71 women (60.2%) after placebo reported no change in symptoms (difference: 35.6%; 95% CI, 23.1–48.1; p < 0.0001). The placebo group had a considerably greater rate of recurrence (hazard ratio: 0.43; 95% CI, 0.31–0.57; p < 0.0001).
Urinary tract infection (UTI) was reported at least once by a third of women in the onaBoNTA group, and by 1 in 10 women in the placebo group (OR at 6 mo: 3.68; 95% CI, 1.72–8.25; p = 0.0003) (Table 4). Voiding difficulty requiring intermittent self-catheterisation (ISC) was reported by 16% of women in the onaBoNTA group and by 4% of the placebo group (OR at 6 mo: 4.87; 95% CI, 1.52–20.33; p = 0.003).
|Adverse events||At 6 wk||At 6 mo|
(n = 118)
(n = 113)
(n = 116)
(n = 110)
|Urinary tract infection, n (%)||35 (30)||10 (9)||4.34
|0.0001||36 (31)||12 (11)||3.68
|Voiding difficulty, n (%)||19 (16)||5 (4)||4.1
|0.004||10 (9)||1 (1)||10.28
|ISC, n (%)||16 (14)||5 (4)||3.39
|0.02||18 (16)||4 (4)||4.87
|Use of additional treatment, n (%)||8 (7)||22 (20)||0.30
|0.006||16 (14)*||35 (32)||0.34
* Three patients in the active group had received two different drugs.
OR = odds ratio; CI = confidence interval; ISC = intermittent self-catheterisation.
Reported events since discharge at each follow-up visit; urinary tract infection was reported by the patient (microbiological confirmation was not required).
Routine ultrasound screening for retention was not part of the study protocol. Voiding difficulty was diagnosed, and ISC commenced on the basis of symptoms (voiding difficulty and/or incomplete emptying) and confirmed by ultrasound and/or catheterisation. Threshold volume for ISC was 100 ml (three centres) or 150 ml (four centres).
Immediate adverse events or reactions were uncommon: 21 women after onaBoNTA (17%) and 22 after placebo (19%) required oral analgesia before discharge. During follow-up there were three drug-related serious adverse reactions. Two patients reported generalised muscle weakness severe enough to interfere with daily activities (one in each allocation arm), and one patient who received onaBoNTA suffered a bronchopneumonia within 3 wk of injection. One patient developed clot retention immediately after treatment, and her discharge was delayed by 48 h.
We have demonstrated highly significant effects on urinary symptoms among women with DO after treatment with 200 IU of onaBoNTA. This study represents the largest placebo-controlled trial studying onaBoNTA completed to date, provides conclusive evidence of the efficacy and safety of BoNTA for idiopathic DO in women, and gives reliable estimates of improvement in voiding frequency, urgency and incontinence episodes, and continence rate after 6 wk to 6 mo. The magnitude of these clinical effects in comparison with data from modern oral anticholinergic drugs should be emphasised. Published drug studies show reductions in frequency, urgency, and leakage of up to two episodes per day , , and . The patients in this study reported symptom improvements far in excess of this figure, despite, at the primary outcome assessment, a third of women in the placebo group receiving anticholinergic medication.
This study began recruiting when no RCT data were available. Four studies have reported during the lifetime of this trial. The first RCT randomised 34 patients (men and women) to receive 200 U onaBoNTA or placebo in a study powered to detect a 50-ml difference in maximum bladder capacity . Significant increases in bladder capacity with parallel improvements in OAB symptoms were seen, with those treated with onaBoNTA maintaining symptomatic improvements for 6 mo. Brubaker et al.  planned to randomise 210 women using time to failure as the primary outcome based on the PGI-I scale . This trial was terminated prematurely after recruitment of 43 women because of a high rate (12 of 28 women) of increased residual urine volumes on ultrasound in the active arm. Two-thirds of the 28 women receiving active drug reported “slight improvement” or better, but because the primary outcome was a single-symptom scale response, it is difficult to make detailed comparisons. A third small study reported data from 15 women receiving 200 or 300 U with 50% reduction in incontinence episodes, 12% improvement in frequency, and 24% improvement in nocturia at 6 wk . These data agree with our own that urgency and incontinence symptoms appear more responsive to treatment than frequency.
The only published study of similar size to our own was a dose-ranging study funded by Allergan . Patients (men and women) were randomised into five groups to receive placebo or onaBoNTA in five different doses (50, 100, 150, 200, or 300 U). A total of 272 patients completed the study (≤50 patients in each group), and the primary outcome was reduction in urgency incontinence episode frequency per week. Although all doses of onaBoNTA were superior to placebo, there was no clear dose response for the primary outcome. A secondary analysis to determine cumulative efficacy on urgency incontinence episodes showed a dose-response effect that tailed off above 150 U. There was a distinct dose response when the proportions of patients with no incontinence during follow-up were compared. Detailed comparisons between these published studies and our own are hampered by differences in outcome measures used, whether diary data were compared daily or weekly, and the fact that two studies recruited both men and women.
Our study is not without weaknesses. Due to the size of the study population we wished to recruit, and the time required to complete this, some of the findings may be less relevant. Most significantly, 200 U was the standard dose being administered in the United Kingdom when the study began, and many centres still offer this, but on the basis of the dose-ranging study cited earlier , Allergan is now pursuing a product licence for 150 U of onaBoNTA for idiopathic DO. Furthermore, there are differences in administration with variations in the number of injection sites and the dose of onaBoNTA given at each site. However, our study still provides a robust data set on a large group of patients to provide additional important information on the risks of voiding difficulty and other complications.
There is no internationally accepted definition of refractory idiopathic DO, and so our definition was an arbitrary one. However, the patients recruited certainly represent the most severe cases, and our analysis showed that only the primary outcome was influenced by baseline symptom severity, so it can be concluded that the effect of onaBoNTA may be of similar magnitude on the symptoms of urgency and incontinence, irrespective of how a refractory patient is defined.
Some may criticise the decision to include only women with proven DO, rather than those with OAB symptoms alone, but this was also a decision made when no evidence existed, and we believed it was important to make this distinction. It is another consequence of the long lifetime of this study that many clinicians are now treating patients with OAB symptoms alone, although it must be stressed that RCT evidence supporting this decision has only recently become available .
We acknowledge that we did not insist on confirming urinary retention or urinary tract infection by formal ultrasound estimation of bladder volume or by collecting data on urine culture within the protocol. This was done for pragmatic reasons, but the follow-up visits were conducted by experienced staff, all of whom were supervising the teaching of ISC for affected women. Thus we are confident that these figures are accurate and reliable, particularly because the proportions concur with data from the smaller RCTs published. The previous RCTs all used antibiotic prophylaxis , , and  but found UTI no less often than we did, suggesting it is the effect of onaBoNTA on residual volume or the need for ISC that predisposes to infection, rather than the procedure itself.
This large placebo-controlled study confirms 200 U onaBoNTA as an effective and safe treatment for refractory DO in women. Urgency and incontinence improve more than frequency. The magnitude of improvement is considerably larger than that after anticholinergic medication. Within 6 mo of treatment, the risk of voiding difficulty requiring ISC is almost 1 in 6 and the risk of UTI is 1 in 3.
Author contributions: Douglas G. Tincello had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Tincello, Kenyon, Abrams, Slack, Taylor.
Acquisition of data: Tincello, Slack, Mayne.
Analysis and interpretation of data: Tincello, Abrams, Kenyon, Slack.
Drafting of the manuscript: Tincello, Kenyon, Slack.
Critical revision of the manuscript for important intellectual content: Tincello, Kenyon, Abrams, Mayne, Toozs-Hobson, Taylor, Slack.
Statistical analysis: Abrams, Tincello.
Obtaining funding: Tincello, Kenyon, Abrams, Slack, Taylor.
Administrative, technical, or material support: None.
Other (specify): None.
Financial disclosures: Douglas G. Tincello certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Douglas G. Tincello receives consultancy fees and research grants from Ethicon. Christopher Mayne receives consultancy/honoraria for teaching from Ethicon, Pfizer, Astellas, and American Medical Systems, and he has received a research grant from AMS. Philip Toozs-Hobson receives honoraria for lectures and teaching from Astellas and Pfizer. Keith R. Abrams receives honoraria for consultancy from Roche, Amaris, Innovus, UBC, Novartis, and Pfizer. Sara Kenyon, Mark Slack, and David Taylor have nothing to declare.
Funding/Support and role of the sponsor: The University of Leicester and the University Hospitals of Leicester NHS Trust helped manage the data. The study was funded by grants from The Moulton Charitable Trust and Wellbeing of Women. The application was funded after external peer review and the study design, conduct, and analysis was entirely independent of the funders or Allergan. Study medication (active and placebo) were provided by Allergan free of charge. The study was sponsored by University Hospitals of Leicester NHS Trust. The sponsor remained independent of the design, conduct, and analysis of the study. Keith R. Abrams is partly supported by the UK National Institute for Health Research (NIHR) as a senior investigator (NI-SI-0508-10061).
Acknowledgement statement: The authors acknowledge all the women who took part in the study, the local investigators and nurses at each centre, and Kate Yarrow, who managed the trial and coordinated all trial procedures and processes.
A.1. Data monitoring committee
Zarko Alfirevic, University of Liverpool (chair); Anthony Smith, St. Mary's Hospital, Manchester; Andy Vail, Hope Hospital, Manchester.
A.2. Steering committee
Jim Thornton (chair); Emma Hawkins, Queen's Hospital, Romford; Adrian Wagg, University College Hospital, London; Douglas Tincello, University of Leicester (PI); Mark Slack, Addenbrooke's Hospital, Cambridge (nonvoting); Sara Kenyon, University of Leicester (nonvoting); Peggy Robertson (patient representative).
A.3. The RELAX study group
Aberdeen Royal Infirmary: Kevin Cooper, Saatchi Swami, Karen Richardson, Lorna MacLeod (10 patients); Addenbrooke's Hospital, Cambridge: Mark Slack, Rohna Kearney, Ashish Pradhan, Helen Johnstone, Rob Sherwin, Helen Bowyer, Angela Emerton (68 patients); Birmingham Women's Hospital: Philip Toozs-Hobson, Pallavi Latthe, Matthew Parsons, Claire Burton, Swati Jha, Richard Foon, Kal Perkins, Shanteela McCooty, Kim Powles, Sandra Ward (42 patients); Derriford Hospital, Plymouth: Bob Freeman, Esther McLarty, Paula Brockman, Lyn Cogley, Heidi Hollands (4 patients); Falkirk & District Royal Infirmary: Kate Patrick, James Tweedle, Michael Hehir, Kathleen Riddle (23 patients); Princess Anne Hospital Southampton: Ash Monga, Kathleen Vits (42 patients); University Hospitals of Leicester NHS Trust: Douglas Tincello, Christopher Mayne, Joanne Townsend, Gill Parker, Jeanette Punter (50 patients); Wolverhampton: Ayman El-Naqa, Nicky Harris, Hilary Hale (1 patient).
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a University of Leicester, Leicester, UK
b University Hospitals of Leicester, Leicester, UK
c School of Health and Population Sciences, University of Birmingham, Birmingham, UK
d Birmingham Women's Hospital, Birmingham, UK
e Addenbrookes’ Hospital, Cambridge, UK
Corresponding author. Reproductive Science Section, CSMM, RKCSB, University of Leicester, Leicester Royal Infirmary, PO Box 65, Leicester LE2 7LX, United Kingdom. Tel. +44 116 252 5813; Hospital Fax: +44 116 273 1620, University Fax: +44 116 252 5846.
© 2012 European Association of Urology, Published by Elsevier B.V.
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