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Predictors of Poor Response and Adverse Events Following Botulinum Toxin-A for Refractory Idiopathic Overactive Bladder
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Predictors of Poor Response and Adverse Events Following Botulinum Toxin A for Refractory Idiopathic Overactive Bladder (OAB) Mohammad Abrar , Luke Stroman , Sachin Malde , Eskinder Solomon , Arun Sahai PII: DOI: Reference:
S0090-4295(19)30880-5 https://doi.org/10.1016/j.urology.2019.08.054 URL 21812
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Urology
Received date: Revised date: Accepted date:
5 June 2019 28 August 2019 29 August 2019
Please cite this article as: Mohammad Abrar , Luke Stroman , Sachin Malde , Eskinder Solomon , Arun Sahai , Predictors of Poor Response and Adverse Events Following Botulinum Toxin A for Refractory Idiopathic Overactive Bladder (OAB), Urology (2019), doi: https://doi.org/10.1016/j.urology.2019.08.054
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Predictors of Poor Response and Adverse Events Following Botulinum Toxin A for Refractory Idiopathic Overactive Bladder (OAB)
Mohammad Abrar1, Luke Stroman1, Sachin Malde1, Eskinder Solomon1, Arun Sahai1 1
Department of Urology, Guy’s and St Thomas’ NHS Foundation Trust, Guy’s Hospital,
London, UK
Original Article Address for Correspondance: Arun Sahai Consultant Urological Surgeon & Honorary Senior Lecturer Department of Urology, Guy’s Hospital, London, SE1 9RT Email: [email protected] Telephone: 07956394943
COI: SM – Medtronic ES – Laborie, Medtronic AS – Medtronic, Allergan, Ferring, Astellas
Word Count Excluding Abstract: 2400 Abstract Word Count: 249 Total Word Count: 2649
Keywords: Botulinum Toxin A, Overactive Bladder, detrusor overactivity
Abstract Objectives: To ascertain whether a poor response and adverse events (voiding dysfunction and urinary tract infection) were predictable for first time botulinum toxinA (BTX-A) injections in a patient cohort of refractory idiopathic overactive bladder (OAB) with detrusor overactivity (DO).
Methods: Patients who received BTX-A injections for the first time between the dates of March 2004 to August 2017 were analysed in this single center study. Urogenital Distress Inventory short form (UDI-6) questionnaires were collected both pre- injection and post- injection prospectively. A poor response was defined as a decrease of less than 16.7 on the UDI-6 questionnaire. Additional information was gathered from patient records in a retrospective fashion. Predictors of poor response, voiding dysfunction and UTI were analysed with multivariate logistic regression analysis.
Results: 74 patients were analysed. The only predictor of poor response was male gender (OR,5.45; 95% CI 1.83-16.47; p=0.002). Lower maximum urinary flow rates (OR,0.91; 95% CI, 0.83-0.99; p=0.023), male gender (OR,5.14; 95% CI 1.41-18.72; p=0.013) and hysterectomy in females (OR,4.55; 95% CI, 1.09-18.87;p=0.038) were predictors of clean intermittent self catheterisation (CISC). There was an increased risk of UTIs in patients who performed CISC (OR,5.26; 95% CI 1.38-20.0;pvalue=0.015).
Conclusions: Male gender was associated with a poor response to BTX-A injections and increased risk of CISC. Lower maximum urinary flow rates and women with hysterectomies were at increased risk of requiring CISC post- injection. Performing CISC was associated with increased risk of UTI. These factors could be helpful when counselling or selecting patients.
Abbreviations MCC- Maximum Cystometric Capacity MDP- Maximum Detrusor Pressure (on cystometric filling) RDV- Reflex Detrusor Volume BC- Bladder Compliance PVR- Post-void Residual Volume Qmax- Maximum Urinary Flow Rate PdetQmax- Detrusor Pressure at Qmax PIP1- Projected Isovolumetric Pressure (Qmax + PdetQmax) BCI- Bladder Contractility Index (5 Qmax + PdetQmax) SD- Standard Deviation OR- Odds Ratio CI- Confidence Interval
Introduction Intradetrusor Botulinum Toxin- A (BTX-A) injections have long been established as an effective and safe treatment for refractory idiopathic OAB after other medications such as antimuscarinics or beta- 3 adrenergic receptor agonists have failed or not been tolerated. BTX-A injections have been given a grade A recommendation for both neurogenic and idiopathic refractory OAB by an expert European panel (1) and appear in all urinary incontinence guidelines as the standard of care in this setting. The success rate of BTX-A varies between 60-80% (2). However, it is associated with adverse events: the two main ones being voiding dysfunction, necessitating clean intermittent self- catherisation (CISC) and urinary tract infections (UTIs). The reported rate of CISC varies between 6-45% and the UTI rate also varies between 045% (3). UTI rates are unexpectedly high and difficult to explain based on current knowledge. The variability of the CISC rate may in part be explained by differing study criteria for instigating CISC, typically based on post- void residual volume (PVR) and / or symptoms. Currently, there is no uniform policy on when CISC should be instigated. The primary objective of this study was to identify any factors which can be used to predict poor response to BTX-A injections in a cohort with refractory idiopathic OAB. The secondary objectives were to identify any factors which can be used to predict adverse events in the same cohort and whether or not there is a link between adverse events and poor response. The adverse events assessed specifically were voiding dysfunction necessitating CISC and UTIs.
Materials and Methods Patients who underwent BTX-A injections for the first time between the dates of March 2004 to August 2017 to treat symptoms of refractory idiopathic OAB with DO were analysed. This study was registered at our centre as an audit and has Department of Research and Development approval ID 8237. Inclusion criteria included all adults patients (18 and over) who had received BTX-A injections for the first time at our institution in addition to the following criteria: a diagnosis of idiopathic OAB, patients refractory to anticholinergic therapy for 6 or more weeks due to poor efficacy or tolerability, proven detrusor DO on urodynamics with or without
incontinence, willing and able to perform CISC and completed UDI-6 questionnaires pre and post injection. Four patients had previous prostatic surgery (x2 transurethral resection of the prostate, x2 radical prostatectomy). Seven patients had prior urinary incontinence surgery (x4 colposuspension, x1 TVT, x1 colposuspension and TVT). The exclusion criteria were: neurogenic bladder, bladder pain syndrome / interstitial cystitis, bladder outlet obstruction as diagnosed on urodynamics, previous bladder BTX-A injections, active UTI.
All patients had a clear urine dipstick on the day of injections. BTX-A injections were performed in a standardised way using a non-trigonal injection technique under local anaesthesia. BTX-A was administered at 10 U / mL / injection site. Patients were administered with oral ciprofloxacin 30 minutes before the injection and were given 3 days further treatment.
The information collected included: patient demographic factors (age at injection and gender); medical history (history of recurrent UTIs, diabetic status, previous incontinence
surgery,
previous
hysterectomy,
previous
prolapse
surgery,
menopausal status, previous prostate surgeries (TURP, HoLEP or RP) and baseline urodynamic data. Urodynamic data collected was post-void residual (PVR), maximum cystometric capacity (MCC), maximum detrusor pressure (MDP), reflex detrusor volume (RDV), Pressure at maximum flow rate (PdetQmax), maximum flow rate (Qmax) and bladder compliance (BC). Projected isovolumetric pressure (PIP1) is a calculated parameter thought to better represent detrusor contraction strength in females and so PIP1 was analysed within the female cohort. PIP1 is calculated as Qmax + PdetQmax. Bladder contractility index (BCI) is thought to better represent detrusor contraction in males and so BCI was analysed within the male cohort. BCI is calculated as 5 Qmax + PdetQmax (4).
The outcomes of each patient were recorded as either having a good response or bad response based on the Urogenital Distress Inventory Short Form (UDI-6) questionnaire which patients prospectively completed before their BTX-A injections and 4-6 weeks following injection at follow-up. This questionnaire consisted of six questions relating to lower urinary tract symptoms. Specifically, frequent urination, urine leakage related to urgency or physical activity, small amounts of urine leakage,
difficulty with emptying of the bladder, and pain in the lower abdominal, pelvic or genital area. Utomo et al. validated the UDI6 questionnaire and determined that the minimally important change (MIC) was a decrease of 16.7 which correlated with a clinical improvement in symptoms (5). Thus, for this study, a poor response was defined as a decrease of less than 16.7 on the UDI6 questionnaire at follow- up.
CISC was initiated in patients with a post-void residual (PVR) > 150ml who were symptomatic. The occurrence of UTIs within 6 months of injection was the other adverse event recorded which was defined as patients being symptomatic and requiring antibiotics as assessed at follow up, or those with positive urine dipstick or mid stream urine (MSU) cultures which was assessed retrospectively by assessing the electronic patient record.
Data regarding patient demographics, BTX-A dose, outcomes, UDI-6, CISC use were recorded prospectively. In addition to this electronic patient records were accessed in a retrospective fashion to collect data related to urodynamics, UTI and relevant medical history. UTI was assessed if there was a positive dipstick or MSU at clinic review or if there was documentation in the consultation that a clinician had prescribed antibiotics for UTI prior to that visit. Preliminary independent T-tests (if variable was continuous) or Pearson’s ChiSquare tests (if variable was categorical) were performed where appropriate. All factors found were then entered into univariate logistic regression models. Following this, any factors found significant at the 10% level on univariate logistic regression were then all entered into a multivariate logistic regression model in a forward stepwise fashion. Results were considered significant if p <0.05 for a variable with a two- tailed test.
Results Overall, 74 patients (24 males and 50 females) underwent injection of BTX-A for the first time with completed UDI-6 scores pre and post injection. The mean age was 52.8. Urodynamic data was only available for review in 55 patients (all 74 patients had DO and urodynamics as documented in the records and / or database but
unfortunately, we could not retrieve all the traces as most had been shipped off site for secure storage). The trust policy on the dosage of BTX-A varied in the time of the study meaning 21 patients were treated with 100 U and 53 were treated with 200 U. Patient characteristics and baseline urodynamic data can be seen in Table 1. Poor response to BTX-A was seen in 23 patients (31.9%). Mean UDI-6 scores were 58.64 and 19.16 for the responders’ group pre and post BTX-A, respectively. However, in the non-responders group UDI-6 scores were 58.53 at baseline and 55.31 post BTXA. Adverse outcomes such as symptomatic urinary retention of >150mls requiring CISC occurred in 32 (43.8%) and UTI in 25 (34.2%).
Univariate analysis suggested only older age (OR,1.05; 95% CI 1.01-1.09; p=0.027 and male gender (OR, 4.49; 95% CI 1.55-13.00; p=0.006) were associated with poor response (Table 2). However, multivariate logistic regression analysis (accounting for age, gender, dosage and the urodynamic parameters) suggested the only predictor of poor response was male gender (OR, 5.45; 95% CI 1.83- 16.47; p=0.002). Interestingly, lower dose of 100 U did not significantly predict a poorer response on univariate analysis (OR,2.66; CI= 0.92- 7.69; p=0.072).
Lower PIP1 in females was shown to be significant at predicting UTIs (OR, 0.93; 95% CI, 0.87-0.99; p=0.05) (Table 3). However, BCI did not significantly predict UTIs on univariate analysis (OR, 0.981; 95% CI 0.955 – 1.008; p=0.17). 53.1% of patients on CISC contracted a UTI compared to only 19.5% of patients who were not on CISC. The multivariate model shows people who were in the CISC group were at around 5 times increased odds to contract a UTI compared to patients who did not require CISC (OR,5.26; 95% CI, 1.38-20.0; p=0.015).
Male gender (OR,5.14, 95% CI, 1.41-18.72;p=0.013) (table 4) and lower maximum urinary flow rates (OR,0.91; 95% CI, 0.83-0.99;p=0.023) (table 4) were significant predictors of CISC. In females, hysterectomy was associated with an increased risk of CISC (OR,4.55; 95% CI, 1.09-18.87;p=0.038). Not enough women in this cohort had undergone prolapse surgery (n=2) and so univariate logistic regression analysis could not be done. On multivariate analysis, gender, Qmax and hysterectomies were found to be significant at the 5% level. This analysis showed that for every unit increase in Qmax, the odds of requiring CISC reduced by 9% and that males were
approximately at 5 times increased odds to need CISC compared with females. Females who had undergone hysterectomy were also shown to be at increased risk of CISC compared to women who had not.
It was found in this study cohort that voiding dysfunction necessitating CISC correlated with poor response on univariate analysis (OR,3.12; 95% CI, 1.128.7;p=0.031) but this association was not significant on multivariate analysis (table 2). There was also no association between post-operative UTI and response to BTXA on both univariate and multivariate analysis.
Discussion The only significant predictor of poor response was male gender. Hsiao et al found on multivariate analysis that females had 3.75 times increased odds of good response compared to males (OR,3.75; 95% CI, 1.40-10.06 ; p=0.009) (2). The reason why males could have a poorer response is not clear and whilst there is an abundance of literature on BTX-A injections in females with idiopathic OAB showing good efficacy, the literature on male patients is sparse. One possible explanation could be related to an increase in voiding dysfunction related to benign prostatic enlargement. A lower dosage in our study was not significantly associated with a poorer response (p= 0.072) on univariate analysis. This is similar to findings of Faure Walker et al who found in a male cohort, a higher dose of 200 U compared to 100 U did not correlate with a better response (6). A randomized control trial by Dmochowski et al., found that doses of 100 U and above offered better efficacy compared to 50 U but dosages of 100-300 U were comparable (7). A study by Denys et al. demonstrated no significant difference in urgency and incontinence episodes between the 100 U and 150 U groups at 3 months follow up. The study also demonstrated a dose of 50 U had no benefit as the results were not significantly different compared to a placebo injection.(8). Furthermore, other trials did not demonstrate an improvement in response at higher doses in keeping with our study findings (9) (10).
We found that a pre-operative lower Qmax was predictive of voiding dysfunction requiring CISC. This is an interesting finding as lower Qmax value could be a result
of poorer detrusor contractility. However, when looking at detrusor contractility measures such as PIP1 in females and BCI in males as well as PdetQmax, no correlation was found. A previous two center study utilizing 200 U, in concordance with this study suggested low Qmax could be predictive of CISC use but also suggested PIP1 < 50 and BCI < 120 maybe predictive unlike this cohort (4). Our study showed that pre-operative PVR is not correlated with CISC use. The literature is mixed in this regard, with some studies suggesting pre-operative PVR to be associated with increased CISC (3, 11) and others not (2, 4, 12). However, in most studies pre-operative PVR > 200mls was an exclusion criteria. Male gender was associated with 5 times increased odds of requiring CISC after BTX-A. Kuo et al found on multivariate analysis that males were at 9.2 times increased odds of going into acute urinary retention (AUR) compared to females (OR= 9.2, p=0.013). In our study females with a history of previous hysterectomy were at 4.55 times greater odds of needing CISC compared to females without on multivariate analysis. It has been suggested that voiding dysfunction after hysterectomy is associated with deafferentiation of the bladder wall or bladder neck with loss of sensation on filling cystometry which could lead to an increased bladder capacity and symptoms of detrusor underactivity (13, 14). In this study, diabetes mellitus did not affect CISC rates, however, another study has shown it to be a predictor of CISC, most likely as a result of autonomic neuropathy and subsequent detrusor underactivity (15).
The only factors found to be statistically significant at predicting UTIs on multivariate analysis were CISC and projected isovolumetric pressure (PIP1) in females. A lower PIP1 was shown to increase the risk of UTIs. The bladder contractility index (BCI) in males showed no association with UTI on univariate or multivariate analysis. Poor contractility causing a large PVR after BTX-A injections have been linked to UTIs (3, 16). However, PVR was not associated with UTIs independently in this cohort.
This study demonstrated that the need for CISC increases the risk of UTIs on both univariate and multivariate models. Patients who required CISC were at 5.26 times increased odds of contracting a UTI compared to patients who did not require CISC on multivariate analysis. This could demonstrate that instrumentation is a significant risk factor for contracting UTIs post-botox injections. CISC use was associated with an increased poor response rate on univariate analysis but this association was not
significant on multivariate analysis. Another study also reported that the majority of patients preferred better control of their OAB symptoms and needing to selfcatheterise compared to their pre-treatment state post BTX-A injections (17). Kuo et al., found UTIs to correlate with poor response, but this was not found in our study (3).
The study was limited by its lack of full urodynamics set and small sample size. Furthermore the cohort assessed non-consecutive patients as not all patients who had received BTX-A injections had completed UDI-6 pre and post-operatively. The UDI6 questionnaire has been given a Grade A recommendation (in terms of validity, reliability and responsiveness to change) by the International Consultation on Incontinence. It has been found to correlate accurately with symptom bother and overall bother is one of the recommended questionnaires to use by the European Association of Urology when doing a diagnostic work- up (18). However, whilst the UDI6 questionnaire contains questions pertaining to OAB, it also includes questions related to stress incontinence which are not relevant. Using just subset questions of the questionnaire would not be possible as individually they have not been validated. Finally there is no agreed consenus on how to define a poor response to treatment. Larger prospective studies, ideally with uniform criteria for defining poor response are required.
Conclusions This study has demonstrated that male gender is a potential predictor of poor response to BTX-A injections as well as the need for CISC. It has also demonstrated that lower Qmax is a potential risk factor for voiding dysfunction necessitating CISC, as is hysterectomies for females. Lower PIP1 in females and CISC are correlated with an increased risk of UTIs. Adverse events (UTI, CISC) have not been shown to correlate with poor response. This information is useful for clinicians in terms of patient selection but also when counselling patients for the procedure.
References 1. Apostolidis A, Dasgupta P, Denys P, Elneil S, Fowler CJ, Giannantoni A, et al. Recommendations on the Use of Botulinum Toxin in the Treatment of Lower Urinary Tract Disorders and Pelvic Floor Dysfunctions: A European Consensus Report. Eur Urol. 2009;55(1):100-20. 2. Hsiao SM, Lin HH, Kuo HC. Factors Associated with Therapeutic Efficacy of Intravesical OnabotulinumtoxinA Injection for Overactive Bladder Syndrome. PLoS One. 2016;11(1):e0147137. 3. Kuo HC, Liao CH, Chung SD. Adverse events of intravesical botulinum toxin a injections for idiopathic detrusor overactivity: risk factors and influence on treatment outcome. Eur Urol. 2010;58(6):919-26. 4. Sahai A, Sangster P, Kalsi V, Khan MS, Fowler CJ, Dasgupta P. Assessment of urodynamic and detrusor contractility variables in patients with overactive bladder syndrome treated with botulinum toxin-A: is incomplete bladder emptying predictable? BJU Int. 2009;103(5):630-4. 5. Utomo E, Korfage IJ, Wildhagen MF, Steensma AB, Bangma CH, Blok BFM. Validation of the urogenital distress inventory (UDI‐6) and incontinence impact questionnaire (IIQ‐7) in a Dutch population. NeurourolUrodyn. 2015;34(1):24-31. 6. Faure Walker NA, Syed O, Malde S, Taylor C, Sahai A. Onabotulinum toxin A Injections in Men With Refractory Idiopathic Detrusor Overactivity. Urology. 2019;123:242-6. 7. Dmochowski R, Chapple C, Nitti VW, Chancellor M, Everaert K, Thompson C, et al. Efficacy and Safety of OnabotulinumtoxinA for Idiopathic Overactive Bladder: A Double-Blind, Placebo Controlled, Randomized, Dose Ranging Trial. J Urol. 2010;184(6):2416-22. 8. Denys P, Le Normand L, Ghout I, Costa P, Chartier-Kastler E, Grise P, et al. Efficacy and Safety of Low Doses of OnabotulinumtoxinA for the Treatment of Refractory Idiopathic Overactive Bladder: A Multicentre, Double-Blind, Randomised, Placebo-Controlled Dose-Ranging Study. Eur Urol.61(3):520-9. 9. Rovner E, Kennelly M, Schulte-Baukloh H, Zhou J, Haag-Molkenteller C, Dasgupta P. Urodynamic results and clinical outcomes with intradetrusor injections of onabotulinumtoxinA in a randomized, placebo-controlled dose-finding study in idiopathic overactive bladder. Neurourol Urodyn. 2011;30(4):556-62. 10. Cohen BL, Barboglio P, Rodriguez D, Gousse AE. Preliminary results of a dose‐finding study for botulinum toxin‐A in patients with idiopathic overactive bladder: 100 versus 150 units. Neurourol Urodyn. 2009;28(3):205-8. 11. Osborn DJ, Kaufman MR, Mock S, Guan MJ, Dmochowski RR, Reynolds WS. Urinary Retention Rates after Intravesical OnabotulinumtoxinA Injection for Idiopathic Overactive Bladder in Clinical Practice and Predictors of this Outcome. Neurourol Urodyn. 2015;34(7):675-8. 12. Liao CH, Kuo HC. Increased risk of large post-void residual urine and decreased long-term success rate after intravesical onabotulinumtoxinA injection for refractory idiopathic detrusor overactivity. J Urol. 2013;189(5):1804-10. 13. Geller EJ. Prevention and management of postoperative urinary retention after urogynecologic surgery. Int J Womens Health. 62014. p. 829-38. 14. Everaert K, Muynck MD, Rimbaut S, Weyers S. Urinary retention after hysterectomy for benign disease: extended diagnostic evaluation and treatment with sacral nerve stimulation. BJU Int. 2003;91(6):497-501.
15. Wang CC, Liao CH, Kuo HC. Diabetes mellitus does not affect the efficacy and safety of intravesical onabotulinumtoxina injection in patients with refractory detrusor overactivity. NeurourolUrodyn. 2014;33(8):1235-9. 16. Brubaker L, Richter HE, Visco A, Mahajan S, Nygaard I, Braun TM, et al. Refractory Idiopathic Urge Urinary Incontinence and Botulinum A Injection. The JUrol. 2008;180(1):217-22. 17. Sahai A, Khan MS, Le Gall N, Dasgupta P. Urodynamic assessment of poor responders after botulinum toxin-A treatment for overactive bladder. Urology. 2008;71(3):455-9. 18. Burkhard F, Lucas M, Berghmans L, Bosch J, Cruz F, Lemack G, et al. EAU guidelines on urinary incontinence. Arnhem, The Netherlands: European Association of Urology. 2018.
Table 1. Patient Characteristics
Gender
Age
Diabetic Status
Prostate Surgery (Males)
Incontinence Surgery (Females)
Hysterectomy (Females)
Prolapse Surgery (Females)
Menopausal status (Females)
History of UTIs
Dosage
Characteristic
Frequency (%)
Male
24 (32.4)
Female
50 (67.6)
Overall Mean
52.8
Male Mean
56.7
Female Mean
51.0
Non- diabetic
60 (85.7)
Diabetic
10 (14.3)
No previous surgery
17 (81.0)
Previous surgery
4 (19.0)
No previous surgery
41 (85.4)
Previous Surgery
7 (14.6)
No hysterectomy
36 (75)
Hysterectomy
12 (25)
No previous Surgery
46 (92)
Previous Surgery
2 (4)
Pre-menopausal
20 (40.0)
Post- menopausal
30 (60.0)
No History of UTIs
56 (80)
History of UTIs
14 (20)
100U
21 (28.4)
200U
53 (71.6)
Baseline Urodynamics MCC
MDP
PVR
RDV
Mean (SD)
202.1 (103.5)
Median (IQR)
188.0 (115)
Mean (SD)
75.0 (43.3)
Median (IQR)
74.0 (71)
Mean (SD)
27.6 (62.5)
Median (IQR)
0.0 (27.0)
Mean (SD)
129.3 (105.1)
Median (IQR)
101.0 (109.0)
Mean (SD)
40.2 (16.9)
Median (IQR)
35.0 (18.0)
Mean (SD)
17.1 (7.6)
Median (IQR)
16.0 (14.0)
Mean (SD)
54.4 (14.7)
Median (IQR)
54.5 (20.8)
Mean (SD)
124.4 (51.4)
Median (IQR)
101.5 (71.0)
Mean (SD)
79.9 (105.3)
Median (IQR)
38.8 (47.3)
PdetQmax
Qmax
PIP1 (females)
BCI (males)
BC
Table 2 Significant predictors of poor response (change in UDI6 < 16.7) after univariate and multivariate analysis.
Variable
Age
Gender (Male)
Dosage (100u)
Diabetic Status
History of UTIs Prostate Surgery (Males)
Univariate
Multivariate
logistic regression
Logistic regression
OR (95%
p-
CI)
value
1.05 (1.011.09) 4.49 (1.55 to 13.00) 2.66 (0.927.69) 2.22 (0.578.62) 0.29 (0.061.46) 0.70 (0.086.21)
0.027
0.006
0.072
0.249
0.135
n
70
72
OR (95% CI)
5.45 (1.8316.47)
72
68
68
pvalue -
0.002
-
-
-
-
-
-
-
-
21 0.749
Incontinence Surgery (Females) Hysterectomy (females)
1.55 (0.259.52) 2.33 (0.5310.31)
46 0.636
0.265
Prolapse Surgery
46
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
46 -
-
(Females) Menopausal Status (Females) Post- op UTI
Post- op CISC
MCC
MDP
PVR
RDV
PdetQmax
Qmax
PIP1 (females)
BCI (males)
BC
1.70 (0.387.58) 1.17 (0.413.37) 3.12 (1.12-
48 0.489
0.766 0.031
71
71
8.70) 1.00 (0.991.00) 1.01 (0.991.02) 1.00 (0.991.01) 1.00 (0.991.00) 1.01 (0.981.05) 0.96 (0.881.04) 0.99 (0.921.06) 1.00 (0.981.02) 1.00 (0.991.01)
0.471
0.401
0.787
0.391
0.555
0.332
0.714
0.890
0.877
53
53
63
52
52
53
32
20
51
Table 3 Significant predictors of UTI after univariate and multivariate analysis
Variable
logistic regression
logistic regression
1.00(0.971.04)
Gender (Male)
Dosage (100u)
Diabetic Status
History of UTIs Surgery
(Males) Incontinence Surgery (Females) Hysterectomy (females) Prolapse Surgery (Females) Menopausal Status (Females)
Multivariate
OR (95% CI)
Age
Prostate
Univariate
0.71 (0.252.04) 0.70 (0.232.09) 0.78 (0.183.32) 3.25 (0.9710.87) 0.61 (0.057.25) 1.39 (0.277.14) 1.01 (0.254.12) 2.44 (0.708.47) 4.67 (1.66-
CISC
p-
n
value 0.908
0.523
0.517
0.732
0.056
0.696
0.691
0.988
-
0.162 0.004
71
OR
p-
(95% CI)
value
-
-
-
-
-
-
5.26
0.015
73
73
69
69
21
47
47
47
49
73
13.16)
(1.3820.00)
MCC
MDP
1.001 (0.9951.006) 0.99 (0.971.00)
0.844
0.150
54
54
-
-
-
-
PVR
RDV
PdetQmax
Qmax
PIP1 (females)
BCI (males)
BC
1.004 (0.9961.012) 1.001 (0.9961.007) 0.97 (0.931.01) 0.93 (0.861.02) 0.93 (0.870.995) 0.98 (0.96 –
64
0.324
-
-
-
-
-
-
-
-
0.93
0.050
53
0.648
53
0.137
54
0.110
33 0.036
(0.871.00)
0.170
20
1.01) 1.00 (0.991.01)
-
-
-
-
52
0.878
Table 4 Significant predictors of CISC after univariate and multivariate analysis
Variable
Univariate
Multivariate
logistic regression
Logistic regression
OR (95% CI)
p-
n
value
Age
1.02(0.99- 1.06)
0.194
Gender
3.14 (1.14- 8.65)
0.027
71 73
(Male) Dosage (100u) Diabetic Status History of UTIs
OR (95% CI)
p-value
-
-
5.14 (1.41-
0.013
18.72) 0.71 (0.26- 2.02)
0.531
1.27 (0.33- 4.85)
0.728
2.70 (0.80- 9.17)
0.110
73 69
69
-
-
-
-
-
-
Prostate Surgery
21 0.10 (0.008- 1.28)
0.077
-
-
-
-
4.55 (1.09-
0.038
(Males) Incontinence Surgery
47 12.77 (0.54- 14.29)
0.223
4.55 (1.09- 18.87)
0.038
(Females) Hysterectomy
47
(females)
18.87)
Prolapse Surgery
47 -
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
0.91 (0.83-
0.023
(Females) Menopausal Status
49 3.25 (0.87- 12.20)
0.080
MCC
1.001 (0.995- 1.006)
0.835
MDP
0.995 (0.982- 1.008)
0.440
PVR
1.006 (0.997- 1.014)
0.213
RDV
1.001 (0.996- 1.006)
0.630
1.02 (0.99- 1.05)
0.265
0.90 (0.83-0.98)
0.013
(Females)
PdetQmax Qmax PIP1 (females) BCI (males) BC
54 54 64 53 53 54
0.99) 0.95 (0.90- 1.01)
0.106
0.99 (0.98 – 1.01)
0.531
1.003 (0.997- 1.008)
0.365
33 20 52
-
-
-
-
-
-
Predictors of Poor Response and Adverse Events Following Botulinum Toxin A for Refractory Idiopathic Overactive Bladder (OAB) Mohammad Abrar , Luke Stroman , Sachin Malde , Eskinder Solomon , Arun Sahai PII: DOI: Reference:
S0090-4295(19)30880-5 https://doi.org/10.1016/j.urology.2019.08.054 URL 21812
To appear in:
Urology
Received date: Revised date: Accepted date:
5 June 2019 28 August 2019 29 August 2019
Please cite this article as: Mohammad Abrar , Luke Stroman , Sachin Malde , Eskinder Solomon , Arun Sahai , Predictors of Poor Response and Adverse Events Following Botulinum Toxin A for Refractory Idiopathic Overactive Bladder (OAB), Urology (2019), doi: https://doi.org/10.1016/j.urology.2019.08.054
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
Predictors of Poor Response and Adverse Events Following Botulinum Toxin A for Refractory Idiopathic Overactive Bladder (OAB)
Mohammad Abrar1, Luke Stroman1, Sachin Malde1, Eskinder Solomon1, Arun Sahai1 1
Department of Urology, Guy’s and St Thomas’ NHS Foundation Trust, Guy’s Hospital,
London, UK
Original Article Address for Correspondance: Arun Sahai Consultant Urological Surgeon & Honorary Senior Lecturer Department of Urology, Guy’s Hospital, London, SE1 9RT Email: [email protected] Telephone: 07956394943
COI: SM – Medtronic ES – Laborie, Medtronic AS – Medtronic, Allergan, Ferring, Astellas
Word Count Excluding Abstract: 2400 Abstract Word Count: 249 Total Word Count: 2649
Keywords: Botulinum Toxin A, Overactive Bladder, detrusor overactivity
Abstract Objectives: To ascertain whether a poor response and adverse events (voiding dysfunction and urinary tract infection) were predictable for first time botulinum toxinA (BTX-A) injections in a patient cohort of refractory idiopathic overactive bladder (OAB) with detrusor overactivity (DO).
Methods: Patients who received BTX-A injections for the first time between the dates of March 2004 to August 2017 were analysed in this single center study. Urogenital Distress Inventory short form (UDI-6) questionnaires were collected both pre- injection and post- injection prospectively. A poor response was defined as a decrease of less than 16.7 on the UDI-6 questionnaire. Additional information was gathered from patient records in a retrospective fashion. Predictors of poor response, voiding dysfunction and UTI were analysed with multivariate logistic regression analysis.
Results: 74 patients were analysed. The only predictor of poor response was male gender (OR,5.45; 95% CI 1.83-16.47; p=0.002). Lower maximum urinary flow rates (OR,0.91; 95% CI, 0.83-0.99; p=0.023), male gender (OR,5.14; 95% CI 1.41-18.72; p=0.013) and hysterectomy in females (OR,4.55; 95% CI, 1.09-18.87;p=0.038) were predictors of clean intermittent self catheterisation (CISC). There was an increased risk of UTIs in patients who performed CISC (OR,5.26; 95% CI 1.38-20.0;pvalue=0.015).
Conclusions: Male gender was associated with a poor response to BTX-A injections and increased risk of CISC. Lower maximum urinary flow rates and women with hysterectomies were at increased risk of requiring CISC post- injection. Performing CISC was associated with increased risk of UTI. These factors could be helpful when counselling or selecting patients.
Abbreviations MCC- Maximum Cystometric Capacity MDP- Maximum Detrusor Pressure (on cystometric filling) RDV- Reflex Detrusor Volume BC- Bladder Compliance PVR- Post-void Residual Volume Qmax- Maximum Urinary Flow Rate PdetQmax- Detrusor Pressure at Qmax PIP1- Projected Isovolumetric Pressure (Qmax + PdetQmax) BCI- Bladder Contractility Index (5 Qmax + PdetQmax) SD- Standard Deviation OR- Odds Ratio CI- Confidence Interval
Introduction Intradetrusor Botulinum Toxin- A (BTX-A) injections have long been established as an effective and safe treatment for refractory idiopathic OAB after other medications such as antimuscarinics or beta- 3 adrenergic receptor agonists have failed or not been tolerated. BTX-A injections have been given a grade A recommendation for both neurogenic and idiopathic refractory OAB by an expert European panel (1) and appear in all urinary incontinence guidelines as the standard of care in this setting. The success rate of BTX-A varies between 60-80% (2). However, it is associated with adverse events: the two main ones being voiding dysfunction, necessitating clean intermittent self- catherisation (CISC) and urinary tract infections (UTIs). The reported rate of CISC varies between 6-45% and the UTI rate also varies between 045% (3). UTI rates are unexpectedly high and difficult to explain based on current knowledge. The variability of the CISC rate may in part be explained by differing study criteria for instigating CISC, typically based on post- void residual volume (PVR) and / or symptoms. Currently, there is no uniform policy on when CISC should be instigated. The primary objective of this study was to identify any factors which can be used to predict poor response to BTX-A injections in a cohort with refractory idiopathic OAB. The secondary objectives were to identify any factors which can be used to predict adverse events in the same cohort and whether or not there is a link between adverse events and poor response. The adverse events assessed specifically were voiding dysfunction necessitating CISC and UTIs.
Materials and Methods Patients who underwent BTX-A injections for the first time between the dates of March 2004 to August 2017 to treat symptoms of refractory idiopathic OAB with DO were analysed. This study was registered at our centre as an audit and has Department of Research and Development approval ID 8237. Inclusion criteria included all adults patients (18 and over) who had received BTX-A injections for the first time at our institution in addition to the following criteria: a diagnosis of idiopathic OAB, patients refractory to anticholinergic therapy for 6 or more weeks due to poor efficacy or tolerability, proven detrusor DO on urodynamics with or without
incontinence, willing and able to perform CISC and completed UDI-6 questionnaires pre and post injection. Four patients had previous prostatic surgery (x2 transurethral resection of the prostate, x2 radical prostatectomy). Seven patients had prior urinary incontinence surgery (x4 colposuspension, x1 TVT, x1 colposuspension and TVT). The exclusion criteria were: neurogenic bladder, bladder pain syndrome / interstitial cystitis, bladder outlet obstruction as diagnosed on urodynamics, previous bladder BTX-A injections, active UTI.
All patients had a clear urine dipstick on the day of injections. BTX-A injections were performed in a standardised way using a non-trigonal injection technique under local anaesthesia. BTX-A was administered at 10 U / mL / injection site. Patients were administered with oral ciprofloxacin 30 minutes before the injection and were given 3 days further treatment.
The information collected included: patient demographic factors (age at injection and gender); medical history (history of recurrent UTIs, diabetic status, previous incontinence
surgery,
previous
hysterectomy,
previous
prolapse
surgery,
menopausal status, previous prostate surgeries (TURP, HoLEP or RP) and baseline urodynamic data. Urodynamic data collected was post-void residual (PVR), maximum cystometric capacity (MCC), maximum detrusor pressure (MDP), reflex detrusor volume (RDV), Pressure at maximum flow rate (PdetQmax), maximum flow rate (Qmax) and bladder compliance (BC). Projected isovolumetric pressure (PIP1) is a calculated parameter thought to better represent detrusor contraction strength in females and so PIP1 was analysed within the female cohort. PIP1 is calculated as Qmax + PdetQmax. Bladder contractility index (BCI) is thought to better represent detrusor contraction in males and so BCI was analysed within the male cohort. BCI is calculated as 5 Qmax + PdetQmax (4).
The outcomes of each patient were recorded as either having a good response or bad response based on the Urogenital Distress Inventory Short Form (UDI-6) questionnaire which patients prospectively completed before their BTX-A injections and 4-6 weeks following injection at follow-up. This questionnaire consisted of six questions relating to lower urinary tract symptoms. Specifically, frequent urination, urine leakage related to urgency or physical activity, small amounts of urine leakage,
difficulty with emptying of the bladder, and pain in the lower abdominal, pelvic or genital area. Utomo et al. validated the UDI6 questionnaire and determined that the minimally important change (MIC) was a decrease of 16.7 which correlated with a clinical improvement in symptoms (5). Thus, for this study, a poor response was defined as a decrease of less than 16.7 on the UDI6 questionnaire at follow- up.
CISC was initiated in patients with a post-void residual (PVR) > 150ml who were symptomatic. The occurrence of UTIs within 6 months of injection was the other adverse event recorded which was defined as patients being symptomatic and requiring antibiotics as assessed at follow up, or those with positive urine dipstick or mid stream urine (MSU) cultures which was assessed retrospectively by assessing the electronic patient record.
Data regarding patient demographics, BTX-A dose, outcomes, UDI-6, CISC use were recorded prospectively. In addition to this electronic patient records were accessed in a retrospective fashion to collect data related to urodynamics, UTI and relevant medical history. UTI was assessed if there was a positive dipstick or MSU at clinic review or if there was documentation in the consultation that a clinician had prescribed antibiotics for UTI prior to that visit. Preliminary independent T-tests (if variable was continuous) or Pearson’s ChiSquare tests (if variable was categorical) were performed where appropriate. All factors found were then entered into univariate logistic regression models. Following this, any factors found significant at the 10% level on univariate logistic regression were then all entered into a multivariate logistic regression model in a forward stepwise fashion. Results were considered significant if p <0.05 for a variable with a two- tailed test.
Results Overall, 74 patients (24 males and 50 females) underwent injection of BTX-A for the first time with completed UDI-6 scores pre and post injection. The mean age was 52.8. Urodynamic data was only available for review in 55 patients (all 74 patients had DO and urodynamics as documented in the records and / or database but
unfortunately, we could not retrieve all the traces as most had been shipped off site for secure storage). The trust policy on the dosage of BTX-A varied in the time of the study meaning 21 patients were treated with 100 U and 53 were treated with 200 U. Patient characteristics and baseline urodynamic data can be seen in Table 1. Poor response to BTX-A was seen in 23 patients (31.9%). Mean UDI-6 scores were 58.64 and 19.16 for the responders’ group pre and post BTX-A, respectively. However, in the non-responders group UDI-6 scores were 58.53 at baseline and 55.31 post BTXA. Adverse outcomes such as symptomatic urinary retention of >150mls requiring CISC occurred in 32 (43.8%) and UTI in 25 (34.2%).
Univariate analysis suggested only older age (OR,1.05; 95% CI 1.01-1.09; p=0.027 and male gender (OR, 4.49; 95% CI 1.55-13.00; p=0.006) were associated with poor response (Table 2). However, multivariate logistic regression analysis (accounting for age, gender, dosage and the urodynamic parameters) suggested the only predictor of poor response was male gender (OR, 5.45; 95% CI 1.83- 16.47; p=0.002). Interestingly, lower dose of 100 U did not significantly predict a poorer response on univariate analysis (OR,2.66; CI= 0.92- 7.69; p=0.072).
Lower PIP1 in females was shown to be significant at predicting UTIs (OR, 0.93; 95% CI, 0.87-0.99; p=0.05) (Table 3). However, BCI did not significantly predict UTIs on univariate analysis (OR, 0.981; 95% CI 0.955 – 1.008; p=0.17). 53.1% of patients on CISC contracted a UTI compared to only 19.5% of patients who were not on CISC. The multivariate model shows people who were in the CISC group were at around 5 times increased odds to contract a UTI compared to patients who did not require CISC (OR,5.26; 95% CI, 1.38-20.0; p=0.015).
Male gender (OR,5.14, 95% CI, 1.41-18.72;p=0.013) (table 4) and lower maximum urinary flow rates (OR,0.91; 95% CI, 0.83-0.99;p=0.023) (table 4) were significant predictors of CISC. In females, hysterectomy was associated with an increased risk of CISC (OR,4.55; 95% CI, 1.09-18.87;p=0.038). Not enough women in this cohort had undergone prolapse surgery (n=2) and so univariate logistic regression analysis could not be done. On multivariate analysis, gender, Qmax and hysterectomies were found to be significant at the 5% level. This analysis showed that for every unit increase in Qmax, the odds of requiring CISC reduced by 9% and that males were
approximately at 5 times increased odds to need CISC compared with females. Females who had undergone hysterectomy were also shown to be at increased risk of CISC compared to women who had not.
It was found in this study cohort that voiding dysfunction necessitating CISC correlated with poor response on univariate analysis (OR,3.12; 95% CI, 1.128.7;p=0.031) but this association was not significant on multivariate analysis (table 2). There was also no association between post-operative UTI and response to BTXA on both univariate and multivariate analysis.
Discussion The only significant predictor of poor response was male gender. Hsiao et al found on multivariate analysis that females had 3.75 times increased odds of good response compared to males (OR,3.75; 95% CI, 1.40-10.06 ; p=0.009) (2). The reason why males could have a poorer response is not clear and whilst there is an abundance of literature on BTX-A injections in females with idiopathic OAB showing good efficacy, the literature on male patients is sparse. One possible explanation could be related to an increase in voiding dysfunction related to benign prostatic enlargement. A lower dosage in our study was not significantly associated with a poorer response (p= 0.072) on univariate analysis. This is similar to findings of Faure Walker et al who found in a male cohort, a higher dose of 200 U compared to 100 U did not correlate with a better response (6). A randomized control trial by Dmochowski et al., found that doses of 100 U and above offered better efficacy compared to 50 U but dosages of 100-300 U were comparable (7). A study by Denys et al. demonstrated no significant difference in urgency and incontinence episodes between the 100 U and 150 U groups at 3 months follow up. The study also demonstrated a dose of 50 U had no benefit as the results were not significantly different compared to a placebo injection.(8). Furthermore, other trials did not demonstrate an improvement in response at higher doses in keeping with our study findings (9) (10).
We found that a pre-operative lower Qmax was predictive of voiding dysfunction requiring CISC. This is an interesting finding as lower Qmax value could be a result
of poorer detrusor contractility. However, when looking at detrusor contractility measures such as PIP1 in females and BCI in males as well as PdetQmax, no correlation was found. A previous two center study utilizing 200 U, in concordance with this study suggested low Qmax could be predictive of CISC use but also suggested PIP1 < 50 and BCI < 120 maybe predictive unlike this cohort (4). Our study showed that pre-operative PVR is not correlated with CISC use. The literature is mixed in this regard, with some studies suggesting pre-operative PVR to be associated with increased CISC (3, 11) and others not (2, 4, 12). However, in most studies pre-operative PVR > 200mls was an exclusion criteria. Male gender was associated with 5 times increased odds of requiring CISC after BTX-A. Kuo et al found on multivariate analysis that males were at 9.2 times increased odds of going into acute urinary retention (AUR) compared to females (OR= 9.2, p=0.013). In our study females with a history of previous hysterectomy were at 4.55 times greater odds of needing CISC compared to females without on multivariate analysis. It has been suggested that voiding dysfunction after hysterectomy is associated with deafferentiation of the bladder wall or bladder neck with loss of sensation on filling cystometry which could lead to an increased bladder capacity and symptoms of detrusor underactivity (13, 14). In this study, diabetes mellitus did not affect CISC rates, however, another study has shown it to be a predictor of CISC, most likely as a result of autonomic neuropathy and subsequent detrusor underactivity (15).
The only factors found to be statistically significant at predicting UTIs on multivariate analysis were CISC and projected isovolumetric pressure (PIP1) in females. A lower PIP1 was shown to increase the risk of UTIs. The bladder contractility index (BCI) in males showed no association with UTI on univariate or multivariate analysis. Poor contractility causing a large PVR after BTX-A injections have been linked to UTIs (3, 16). However, PVR was not associated with UTIs independently in this cohort.
This study demonstrated that the need for CISC increases the risk of UTIs on both univariate and multivariate models. Patients who required CISC were at 5.26 times increased odds of contracting a UTI compared to patients who did not require CISC on multivariate analysis. This could demonstrate that instrumentation is a significant risk factor for contracting UTIs post-botox injections. CISC use was associated with an increased poor response rate on univariate analysis but this association was not
significant on multivariate analysis. Another study also reported that the majority of patients preferred better control of their OAB symptoms and needing to selfcatheterise compared to their pre-treatment state post BTX-A injections (17). Kuo et al., found UTIs to correlate with poor response, but this was not found in our study (3).
The study was limited by its lack of full urodynamics set and small sample size. Furthermore the cohort assessed non-consecutive patients as not all patients who had received BTX-A injections had completed UDI-6 pre and post-operatively. The UDI6 questionnaire has been given a Grade A recommendation (in terms of validity, reliability and responsiveness to change) by the International Consultation on Incontinence. It has been found to correlate accurately with symptom bother and overall bother is one of the recommended questionnaires to use by the European Association of Urology when doing a diagnostic work- up (18). However, whilst the UDI6 questionnaire contains questions pertaining to OAB, it also includes questions related to stress incontinence which are not relevant. Using just subset questions of the questionnaire would not be possible as individually they have not been validated. Finally there is no agreed consenus on how to define a poor response to treatment. Larger prospective studies, ideally with uniform criteria for defining poor response are required.
Conclusions This study has demonstrated that male gender is a potential predictor of poor response to BTX-A injections as well as the need for CISC. It has also demonstrated that lower Qmax is a potential risk factor for voiding dysfunction necessitating CISC, as is hysterectomies for females. Lower PIP1 in females and CISC are correlated with an increased risk of UTIs. Adverse events (UTI, CISC) have not been shown to correlate with poor response. This information is useful for clinicians in terms of patient selection but also when counselling patients for the procedure.
References 1. Apostolidis A, Dasgupta P, Denys P, Elneil S, Fowler CJ, Giannantoni A, et al. Recommendations on the Use of Botulinum Toxin in the Treatment of Lower Urinary Tract Disorders and Pelvic Floor Dysfunctions: A European Consensus Report. Eur Urol. 2009;55(1):100-20. 2. Hsiao SM, Lin HH, Kuo HC. Factors Associated with Therapeutic Efficacy of Intravesical OnabotulinumtoxinA Injection for Overactive Bladder Syndrome. PLoS One. 2016;11(1):e0147137. 3. Kuo HC, Liao CH, Chung SD. Adverse events of intravesical botulinum toxin a injections for idiopathic detrusor overactivity: risk factors and influence on treatment outcome. Eur Urol. 2010;58(6):919-26. 4. Sahai A, Sangster P, Kalsi V, Khan MS, Fowler CJ, Dasgupta P. Assessment of urodynamic and detrusor contractility variables in patients with overactive bladder syndrome treated with botulinum toxin-A: is incomplete bladder emptying predictable? BJU Int. 2009;103(5):630-4. 5. Utomo E, Korfage IJ, Wildhagen MF, Steensma AB, Bangma CH, Blok BFM. Validation of the urogenital distress inventory (UDI‐6) and incontinence impact questionnaire (IIQ‐7) in a Dutch population. NeurourolUrodyn. 2015;34(1):24-31. 6. Faure Walker NA, Syed O, Malde S, Taylor C, Sahai A. Onabotulinum toxin A Injections in Men With Refractory Idiopathic Detrusor Overactivity. Urology. 2019;123:242-6. 7. Dmochowski R, Chapple C, Nitti VW, Chancellor M, Everaert K, Thompson C, et al. Efficacy and Safety of OnabotulinumtoxinA for Idiopathic Overactive Bladder: A Double-Blind, Placebo Controlled, Randomized, Dose Ranging Trial. J Urol. 2010;184(6):2416-22. 8. Denys P, Le Normand L, Ghout I, Costa P, Chartier-Kastler E, Grise P, et al. Efficacy and Safety of Low Doses of OnabotulinumtoxinA for the Treatment of Refractory Idiopathic Overactive Bladder: A Multicentre, Double-Blind, Randomised, Placebo-Controlled Dose-Ranging Study. Eur Urol.61(3):520-9. 9. Rovner E, Kennelly M, Schulte-Baukloh H, Zhou J, Haag-Molkenteller C, Dasgupta P. Urodynamic results and clinical outcomes with intradetrusor injections of onabotulinumtoxinA in a randomized, placebo-controlled dose-finding study in idiopathic overactive bladder. Neurourol Urodyn. 2011;30(4):556-62. 10. Cohen BL, Barboglio P, Rodriguez D, Gousse AE. Preliminary results of a dose‐finding study for botulinum toxin‐A in patients with idiopathic overactive bladder: 100 versus 150 units. Neurourol Urodyn. 2009;28(3):205-8. 11. Osborn DJ, Kaufman MR, Mock S, Guan MJ, Dmochowski RR, Reynolds WS. Urinary Retention Rates after Intravesical OnabotulinumtoxinA Injection for Idiopathic Overactive Bladder in Clinical Practice and Predictors of this Outcome. Neurourol Urodyn. 2015;34(7):675-8. 12. Liao CH, Kuo HC. Increased risk of large post-void residual urine and decreased long-term success rate after intravesical onabotulinumtoxinA injection for refractory idiopathic detrusor overactivity. J Urol. 2013;189(5):1804-10. 13. Geller EJ. Prevention and management of postoperative urinary retention after urogynecologic surgery. Int J Womens Health. 62014. p. 829-38. 14. Everaert K, Muynck MD, Rimbaut S, Weyers S. Urinary retention after hysterectomy for benign disease: extended diagnostic evaluation and treatment with sacral nerve stimulation. BJU Int. 2003;91(6):497-501.
15. Wang CC, Liao CH, Kuo HC. Diabetes mellitus does not affect the efficacy and safety of intravesical onabotulinumtoxina injection in patients with refractory detrusor overactivity. NeurourolUrodyn. 2014;33(8):1235-9. 16. Brubaker L, Richter HE, Visco A, Mahajan S, Nygaard I, Braun TM, et al. Refractory Idiopathic Urge Urinary Incontinence and Botulinum A Injection. The JUrol. 2008;180(1):217-22. 17. Sahai A, Khan MS, Le Gall N, Dasgupta P. Urodynamic assessment of poor responders after botulinum toxin-A treatment for overactive bladder. Urology. 2008;71(3):455-9. 18. Burkhard F, Lucas M, Berghmans L, Bosch J, Cruz F, Lemack G, et al. EAU guidelines on urinary incontinence. Arnhem, The Netherlands: European Association of Urology. 2018.
Table 1. Patient Characteristics
Gender
Age
Diabetic Status
Prostate Surgery (Males)
Incontinence Surgery (Females)
Hysterectomy (Females)
Prolapse Surgery (Females)
Menopausal status (Females)
History of UTIs
Dosage
Characteristic
Frequency (%)
Male
24 (32.4)
Female
50 (67.6)
Overall Mean
52.8
Male Mean
56.7
Female Mean
51.0
Non- diabetic
60 (85.7)
Diabetic
10 (14.3)
No previous surgery
17 (81.0)
Previous surgery
4 (19.0)
No previous surgery
41 (85.4)
Previous Surgery
7 (14.6)
No hysterectomy
36 (75)
Hysterectomy
12 (25)
No previous Surgery
46 (92)
Previous Surgery
2 (4)
Pre-menopausal
20 (40.0)
Post- menopausal
30 (60.0)
No History of UTIs
56 (80)
History of UTIs
14 (20)
100U
21 (28.4)
200U
53 (71.6)
Baseline Urodynamics MCC
MDP
PVR
RDV
Mean (SD)
202.1 (103.5)
Median (IQR)
188.0 (115)
Mean (SD)
75.0 (43.3)
Median (IQR)
74.0 (71)
Mean (SD)
27.6 (62.5)
Median (IQR)
0.0 (27.0)
Mean (SD)
129.3 (105.1)
Median (IQR)
101.0 (109.0)
Mean (SD)
40.2 (16.9)
Median (IQR)
35.0 (18.0)
Mean (SD)
17.1 (7.6)
Median (IQR)
16.0 (14.0)
Mean (SD)
54.4 (14.7)
Median (IQR)
54.5 (20.8)
Mean (SD)
124.4 (51.4)
Median (IQR)
101.5 (71.0)
Mean (SD)
79.9 (105.3)
Median (IQR)
38.8 (47.3)
PdetQmax
Qmax
PIP1 (females)
BCI (males)
BC
Table 2 Significant predictors of poor response (change in UDI6 < 16.7) after univariate and multivariate analysis.
Variable
Age
Gender (Male)
Dosage (100u)
Diabetic Status
History of UTIs Prostate Surgery (Males)
Univariate
Multivariate
logistic regression
Logistic regression
OR (95%
p-
CI)
value
1.05 (1.011.09) 4.49 (1.55 to 13.00) 2.66 (0.927.69) 2.22 (0.578.62) 0.29 (0.061.46) 0.70 (0.086.21)
0.027
0.006
0.072
0.249
0.135
n
70
72
OR (95% CI)
5.45 (1.8316.47)
72
68
68
pvalue -
0.002
-
-
-
-
-
-
-
-
21 0.749
Incontinence Surgery (Females) Hysterectomy (females)
1.55 (0.259.52) 2.33 (0.5310.31)
46 0.636
0.265
Prolapse Surgery
46
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
46 -
-
(Females) Menopausal Status (Females) Post- op UTI
Post- op CISC
MCC
MDP
PVR
RDV
PdetQmax
Qmax
PIP1 (females)
BCI (males)
BC
1.70 (0.387.58) 1.17 (0.413.37) 3.12 (1.12-
48 0.489
0.766 0.031
71
71
8.70) 1.00 (0.991.00) 1.01 (0.991.02) 1.00 (0.991.01) 1.00 (0.991.00) 1.01 (0.981.05) 0.96 (0.881.04) 0.99 (0.921.06) 1.00 (0.981.02) 1.00 (0.991.01)
0.471
0.401
0.787
0.391
0.555
0.332
0.714
0.890
0.877
53
53
63
52
52
53
32
20
51
Table 3 Significant predictors of UTI after univariate and multivariate analysis
Variable
logistic regression
logistic regression
1.00(0.971.04)
Gender (Male)
Dosage (100u)
Diabetic Status
History of UTIs Surgery
(Males) Incontinence Surgery (Females) Hysterectomy (females) Prolapse Surgery (Females) Menopausal Status (Females)
Multivariate
OR (95% CI)
Age
Prostate
Univariate
0.71 (0.252.04) 0.70 (0.232.09) 0.78 (0.183.32) 3.25 (0.9710.87) 0.61 (0.057.25) 1.39 (0.277.14) 1.01 (0.254.12) 2.44 (0.708.47) 4.67 (1.66-
CISC
p-
n
value 0.908
0.523
0.517
0.732
0.056
0.696
0.691
0.988
-
0.162 0.004
71
OR
p-
(95% CI)
value
-
-
-
-
-
-
5.26
0.015
73
73
69
69
21
47
47
47
49
73
13.16)
(1.3820.00)
MCC
MDP
1.001 (0.9951.006) 0.99 (0.971.00)
0.844
0.150
54
54
-
-
-
-
PVR
RDV
PdetQmax
Qmax
PIP1 (females)
BCI (males)
BC
1.004 (0.9961.012) 1.001 (0.9961.007) 0.97 (0.931.01) 0.93 (0.861.02) 0.93 (0.870.995) 0.98 (0.96 –
64
0.324
-
-
-
-
-
-
-
-
0.93
0.050
53
0.648
53
0.137
54
0.110
33 0.036
(0.871.00)
0.170
20
1.01) 1.00 (0.991.01)
-
-
-
-
52
0.878
Table 4 Significant predictors of CISC after univariate and multivariate analysis
Variable
Univariate
Multivariate
logistic regression
Logistic regression
OR (95% CI)
p-
n
value
Age
1.02(0.99- 1.06)
0.194
Gender
3.14 (1.14- 8.65)
0.027
71 73
(Male) Dosage (100u) Diabetic Status History of UTIs
OR (95% CI)
p-value
-
-
5.14 (1.41-
0.013
18.72) 0.71 (0.26- 2.02)
0.531
1.27 (0.33- 4.85)
0.728
2.70 (0.80- 9.17)
0.110
73 69
69
-
-
-
-
-
-
Prostate Surgery
21 0.10 (0.008- 1.28)
0.077
-
-
-
-
4.55 (1.09-
0.038
(Males) Incontinence Surgery
47 12.77 (0.54- 14.29)
0.223
4.55 (1.09- 18.87)
0.038
(Females) Hysterectomy
47
(females)
18.87)
Prolapse Surgery
47 -
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
0.91 (0.83-
0.023
(Females) Menopausal Status
49 3.25 (0.87- 12.20)
0.080
MCC
1.001 (0.995- 1.006)
0.835
MDP
0.995 (0.982- 1.008)
0.440
PVR
1.006 (0.997- 1.014)
0.213
RDV
1.001 (0.996- 1.006)
0.630
1.02 (0.99- 1.05)
0.265
0.90 (0.83-0.98)
0.013
(Females)
PdetQmax Qmax PIP1 (females) BCI (males) BC
54 54 64 53 53 54
0.99) 0.95 (0.90- 1.01)
0.106
0.99 (0.98 – 1.01)
0.531
1.003 (0.997- 1.008)
0.365
33 20 52
-
-
-
-
-
-