Adverse Events of Intravesical Botulinum Toxin A Injections for Idiopathic Detrusor Overactivity: Risk Factors and Influence on Treatment Outcome

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1 EUROPEAN UROLOGY 58 (2010) available at journal homepage: Incontinence Adverse Events of Intravesical Botulinum Toxin A Injections for Idiopathic Detrusor Overactivity: Risk Factors and Influence on Treatment Outcome Hann-Chorng Kuo a, *, Chun-Hou Liao b, Shiu-Dong Chung c a Department of Urology, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan b Department of Urology, Cardinal Tien Hospital and Fu-Jen Catholic University, Taipei, Taiwan c Department of Urology, Far Eastern Memorial Hospital, Taipei, Taiwan Article info Article history: Accepted September 6, 2010 Published online ahead of print on September 17, 2010 Keywords: Botulinum toxin Overactive bladder Adverse events Detrusor overactivity Abstract Background: Intravesical injection of botulinum toxin type A (BoNTA) provides effective treatment for detrusor overactivity and overactive bladder (OAB). However, the high rates of treatment-related adverse events (AEs) prevent its more widespread use. Objective: To investigate the risk factors of increasing AEs after BoNTA injection for idiopathic detrusor overactivity (IDO). Design, setting, and participants: This study included a total of 217 patients receiving their first intravesical BoNTA injection for refractory IDO in a tertiary university hospital from 2004 to Measurements: AE incidence was analyzed according to gender, age, comorbidities, prostate condition in men, OAB subtype, BoNTA dose, injection site, and baseline urodynamic parameters. Successful outcome was determined based on patient perception of improvement of bladder condition at 3 mo. Results and limitations: Successful outcomes were reported by 144 (66.3%) patients. By multivariable analysis, male gender ( p = 0.013) and baseline postvoid residual (PVR) 100 ml ( p = 0.003) were independent predictors of acute urinary retention (AUR). Baseline PVR 100 ml ( p = 0.007) and receiving >100 U BoNTA ( p = 0.029) were predictors of straining to void. The incidence of large PVR after treatment was associated with comorbidity ( p = 0.011). Urinary tract infection occurred more frequently in women ( p = 0.003) and in men with retaining prostate ( p = 0.008). No AUR developed after bladder base/trigonal injection. Nevertheless, the occurrence of AUR or large PVR did not affect therapeutic outcome. This study is limited by nonconsecutive enrollment of patients. Conclusions: Male gender, baseline PVR 100 ml, comorbidity, and BoNTA dose >100 U are risk factors for increasing incidence of AEs after intravesical BoNTA injection for IDO. # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, Buddhist Tzu Chi General Hospital, 707, Section 3, Chung Yang Road, Hualien, Taiwan. Tel ext. 2117; Fax: address: hck@tzuchi.com.tw (H.-C. Kuo) /$ see back matter # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 920 EUROPEAN UROLOGY 58 (2010) Introduction 2. Patients and methods Intravesical injection of botulinum toxin type A (BoNTA) has emerged as a novel treatment for patients with overactive bladder (OAB) or idiopathic detrusor overactivity (IDO) refractory to antimuscarinic therapy [1,2]. The success rate of BoNTA treatment for OAB has been reported to range from 50 80% in patients with or without detrusor overactivity (DO) [3 5]. For treatment of OAB or DO, the dose of BoNTA has decreased from 300 U to 100 U of Botox (Allergan, Irvine, CA, USA), and similar therapeutic effects are observed at this dose [5 8]. However, the incidence of reported treatment-related adverse events (AEs) remains high [8,9]. Recent studies demonstrated significant dose-dependent improvements in urinary symptoms and urodynamic parameters in patients with OAB [10,12 14]. However, the incidence of AEs is also associated with increasing dose of BoNTA [8,14]. The main AEs associated with BoNTA injection are acute urinary retention (AUR), large postvoid residual (PVR), difficulty in urination, and urinary tract infection (UTI), which occurred in approximately 20 43% of patients [1,2,8,10,11]. Large PVR after BoNTA injection was clinically relevant and clean intermittent catheterization (CIC) was necessary [4,8,11]. In a recent report, complete continence after 200 U Botox injection was 51% at 4 wk [15]. Although patients without complete continence may experience improvement in urgency incontinence, they might not be satisfied with the treatment outcome due to these bothersome AEs. In urologic practice, elderly patients may have comorbidities with OAB. Although detrusor BoNTA injection for refractory OAB in elderly patients was safe [16], the high rate of AEs deserves special attention before this treatment is recommended to this group. This study aimed to analyze the risk factors associated with the increasing incidence of AEs after intravesical BoNTA injection. A total of 217 patients who received intravesical BoNTA injection for refractory IDO for the first time were enrolled in this study. These patients had participated in previous prospective clinical trials and a new prospective trial at the authors hospital from 2004 to The inclusion criteria were urodynamic DO with or without urinary incontinence refractory to previous antimuscarinics for >3 mo. Exclusion criteria were UTI, bladder outlet obstruction (BOO), neurogenic bladder, abnormal liver function, serum creatinine level elevated to twice the normal limit, or having a PVR >150 ml at the time of enrollment. All the studies were approved by the institutional review board and ethics committee of the hospital. The patients were randomly assigned to receive different doses of BoNTA intravesical injections at different sites, including 100, 150, or 200 U Botox via detrusor or suburothelial injection in the bladder body and the bladder base, including trigonal injections based on the study designs of different clinical trials [1,4,8,12]. The comorbidities of patients were recorded at baseline, including diabetes mellitus, chronic kidney disease, congestive heart failure, and chronic obstructive pulmonary disease. They were obtained from the medical records of the study patients and are the most frequently observed conditions in elderly patients. The conditions of male patients retaining prostate without BOO or those who have previously undergone transurethral resection of the prostate (TURP) and patients with OAB-dry or OAB-wet were also recorded. Videourodynamic study (VUDS) was routinely performed at baseline for diagnosis of DO and detection of BOO. The cystometric bladder capacity (CBC), voiding detrusor pressure, maximum flow rate (Q max ), and PVR were recorded. The VUDS was performed and terminology was defined according to the recommendation of the International Continence Society [17]. VUDS was repeated at 3 and 6 mo after intravesical BoNTA injection. During the follow-up period, the patients were requested to visit regularly until they could void with a PVR <50 ml. Uroflowmetry for Q max, voided volume, and PVR were measured at each visit. The total bladder capacity was calculated by summation of the voided volume and PVR. The voiding efficiency (VE) was calculated as the percentage of voided volume of the total bladder capacity. All patients were closely monitored at 1 2 wk, 1 mo, 3 mo, and every month thereafter until the response to BoNTA had disappeared. The Table 1 Characteristics of study patients Demographics Characteristics Patients, n (%) Gender Men 112 (51.6) Women 105 (48.4) Age, yr (44.7) < (55.3) Comorbidity Diabetes mellitus 46 (21.2) Chronic kidney disease 8 (3.7) Congestive heart failure 15 (6.9) Chronic obstructive pulmonary disease 15 (6.9) OAB subtype OAB-dry 33 (15.2) OAB-wet 184 (84.8) BPH condition Previous TURP 57 (50.9) Retaining prostate (non-turp) 55 (49.1) Botox dose, U (78.3) (6.0) (15.7) Injection site Suburothelial 110 (50.9) (91: 100 U; 13: 150 U; U) Detrusor 63 (29.0) (35: 100 U, 28: 200 U) Bladder base/trigone 44 (20.3) (all: 100 U) OAB = overactive bladder; BPH = benign prostatic hyperplasia.

3 Fig. 1 The changes of bladder capacity, maximum flow rate (Q max ), postvoid residual (PVR), and voiding efficiency after botulinum toxin type A injection. Data are expressed as mean (standard deviation) and p values indicate the difference between data at baseline and each time point. EUROPEAN UROLOGY 58 (2010)

4 922 EUROPEAN UROLOGY 58 (2010) occurrence of urgency episodes and urgency incontinence were verified using a 3-d voiding diary at baseline and before each visit. All patients were requested to grade the treatment outcome at 3 mo (primary end point). The grading was done on the basis of changes in the patient s perception of bladder condition (PPBC) [18]. Mild improvement was considered if the patient improved by 1 point, moderate if the patient improved by 2 points, and marked if the patient became dry or improved by 3 points. Patients with moderate and marked improvement were considered as exhibiting a successful result. We also added a grade of worsening if the patient felt that the bladder condition deteriorated after Botox injection. Procedure-related AEs were recorded during the 6-mo follow-up period after BoNTA treatment. AEs included AUR (patients had severe difficulty in urination with PVR >350 ml and an indwelling catheter or CIC was necessary); gross hematuria and general weakness in the early stage; PVR >150 ml; straining to void (feeling difficulty urinating and needing abdominal straining to empty the bladder, which was not experienced prior to treatment); and UTI (symptomatic or asymptomatic with white blood cell count >10/high power field in urinalysis) during the follow-up period. The incidences of these AEs were analyzed according to the baseline urodynamic parameters and clinical demographics. Other nonspecific AEs that occurred after BoNTA were also recorded on the basis of the patients self-report and chart recording. The AEs were also graded according to the classification of surgical complications [19]. Univariable analyses using chi-square tests, and univariable and multivariable logistic regression analyses were performed to determine whether the factors were predictive of future risk of specific AEs. Multiple measurement analysis was used to compare the changes in the urodynamic parameters after BoNTA injections between subgroups. Mean and standard deviations (SD) were used for reported parametric continuous variables. A p value <0.05 was considered significant. [(Fig._2)TD$FIG] 3. Results A total of 217 patients aged yr (mean SD: ) were studied. The patient characteristics are listed in Table 1. There was no significant difference in the mean age among all subgroups. At 3 mo, 144 patients reported successful results (96 dry, 48 moderately improved; total 66.3%), 36 (16.6%) showed mild improvement, and 37 (21 no change, 16 getting worse; total 17.1%) reported treatment failure. Fig. 1 shows changes in the bladder capacity, Q max, PVR, and VE from baseline to 12 mo after BoNTA injection. The PVR and bladder capacity peaked and the VE decreased to the minimum value at 1 mo, and slowly returned to baseline levels in 9 mo. Urodynamic DO was absent in 127 (59%) patients at 3 mo and in 86 (40%) at 6 mo. Changes in these urodynamic parameters over time showed a similar trend across the subgroups ( p > 0.05) (Fig. 2). During the follow-up period, specific AEs occurred in 113 patients (52.1%) and nonspecific AEs in 36 (16.6%). Most of the AEs were grade 1; among the 21 grade 2 AEs, 11 (5%) were considered procedure related (febrile UTI in 9 patients, hematuria in 1, and AUR in 1). AUR occurred in 18 (8.3%) patients, large PVR (150 ml) in 103 (47.5%), and straining to void in 101 (46.5%). Gross hematuria occurred in 17 (7.8%) patients, UTI in 31 (14.3%), and general weakness in 6 (2.8%). Patients with AUR were treated with an indwelling Foley catheter for 3 7 d. Most of the patients could void without performing CIC. Among the 103 patients with PVR >150 ml, only 5 required CIC during Fig. 2 The changes of postvoid residual (PVR) and voiding efficiency at different time points after botulinum toxin type A injection in patients in different age and comorbidity subgroups. Data are expressed as mean plus or minus standard deviation shown in the tables below the curves. There is no significant difference in the trend between subgroups ( p values above curves).

5 EUROPEAN UROLOGY 58 (2010) Table 2 Univariable analyses data of adverse event incidence according to patient demographics Patients, n Success rate, AUR, PVR >150 ml, Straining to void, Hematuria, UTI, General weakness, Female (66) 2 (2) 48 (45) 45 (43) 6 (6) 23 (22) 5 (5) Male (67) 16 (14) 55 (49) 56 (50) 11 (10) 8 (7) 1(1) p value Age, yr < (68) 5 (4) 50 (42) 53 (43) 10 (8) 20 (17) 3 (3) (65) 13 (13) 53 (55) 48 (49) 7 (7) 11 (11) 3 (3) p value Medical disease No (70) 8 (6) 52 (39) 57 (43) 9 (7) 20 (16) 0 (0) Yes (61) 10 (12) 51 (61) 44 (52) 8 (10) 11 (13) 6 (7) p value OAB-dry (79) 3 (9) 10 (30) 13 (39) 6 (18) 5 (15) 1 (3) OAB-wet (64) 15 (8) 93 (51) 88 (48) 11 (6) 26 (14) 5 (3) p value Men No TURP (60) 10 (18) 26 (47) 27 (49) 9 (16) 7 (13) 1 (2) TURP (74) 8 (14) 29 (51) 29 (51) 2 (4) 1 (2) 0 (0) p value BoNTA, U (65) 12 (8) 79 (47) 73 (43) 17 (10) 27 (16) 6 (4) > (72) 6 (13) 24 (51) 28 (60) 0 (0) 4 (9) 0 (0) p value SI (64) 12 (11) 59 (54) 56 (51) 7 (6) 13 (12) 2 (2) Trigone (68) 0 (0) 21 (48) 19 (43) 6 (14) 6 (14) 3 (7) Detrusor (70) 6 (10) 23 (37) 26 (41) 4 (6) 12 (18) 1 (2) p value AUR = acute urinary retention; PVR = postvoid residual; UTI = urinary tract infection; OAB = overactive bladder; TURP = transurethral resection of the prostate; BoNTA = botulinum toxin type A; SI = suburothelial injection. Table 3 Univariable analyses data of adverse event incidence according to baseline urodynamic variables Patients, n Success rate, AUR, Large PVR, Straining to void, Hematuria, UTI, General weakness, Bladder capacity, ml < (66) 8 (8) 48 (46) 59 (53) 9 (9) 17 (16) 3 (3) (66) 10 (9) 55 (52) 52 (47) 8 (7) 14 (13) 3 (3) p value Qmax <10 ml/s (72) 10 (12) 42 (49) 40 (47) 4 (5) 8 (9) 3 (3) Qmax 10 ml/s (62) 8 (6) 61 (47) 61 (47) 13 (10) 23 (17) 3 (2) p value PVR <100 ml (69) 9 (5) 81 (45) 77 (42) 15 (8) 25 (14) 3 (2) PVR 100 ml (56) 9 (23) 22 (61) 24 (67) 2 (6) 6 (17) 3 (8) p value VE <70% (64) 6 (17) 20 (56) 21 (58) 1 (3) 6 (17) 3 (8) 70% (67) 12 (7) 83 (46) 80 (44) 16 (9) 25 (14) 3 (2) p value Male Pdet <40 cm H 2 O (62) 7 (13) 26 (47) 26 (47) 3 (5) 3 (5) 0 (0) Pdet 40 cm H 2 O (72) 8 (14) 29 (51) 29 (51) 7 (12) 5 (9) 1 (2) p value Female Pdet <20 cm H 2 O (67) 0 (0) 23 (40) 23 (40) 3 (5) 14 (25) 2 (4) Pdet 20 cm H 2 O (65) 3 (6) 25 (52) 23 (48) 4 (8) 9 (19) 3 (6) p value DO Phasic (69) 9 (7) 60 (46) 59 (46) 6 (5) 21 (16) 3 (2) Terminal (62) 9 (10) 43 (49) 42 (49) 11 (13) 10 (11) 3 (4) p value AUR = acute urinary retention; PVR = postvoid residual; VE = voiding efficiency; UTI = urinary tract infection; Qmax = maximum flow rate; Pdet = voiding detrusor pressure; DO = detrusor overactivity.

6 924 EUROPEAN UROLOGY 58 (2010) Table 4 Univariable and multivariable logistic regression analyses for the risk of specific adverse events AUR PVR 150 ml Straining to void OR (95% CI) p value OR (95% CI) p value OR (95% CI) p value Univariable analyses Male 9.0 ( ) ( ) ( ) Age 75 yr 3.2 ( ) ( ) ( ) Comorbidity 2.1 ( ) ( ) ( ) OAB-wet 1.1 ( ) ( ) ( ) Botox >100 U 1.9 ( ) ( ) ( ) Baseline PVR 100 ml 4.9 ( ) ( ) ( ) Baseline VE <70% 2.8 ( ) ( ) ( ) Multivariable analyses Male 9.2 ( ) Age 75 yr 2.1 ( ) ( ) Comorbidity 2.2 ( ) OAB-wet 1.7 ( ) Botox >100 U 2.1 ( ) Baseline PVR 100 ml 9.9 ( ) ( ) Baseline VE <70% 2.1 ( ) CI = confidence interval; AUR = acute urinary retention; PVR = postvoid residual; OR = odds ratio; OAB = overactive bladder; VE = voiding efficiency. Table 5 Success rate between patient subgroups with and without adverse events Success, n = 144 (%) Failure, n = 73 (%) p value AUR 11 (61.1) 7 (38.9) No AUR 133 (66.8) 66 (33.2) Large PVR 150 ml 70 (68) 33 (32) Small PVR <150 ml 74 (64.9) 40 (35.1) Straining to void 68 (67.3) 33 (32.7) No straining to void 76 (65.5) 40 (34.5) Hematuria 7 (41.2) 10 (58.8) No Hematuria 137 (68.5) 63 (31.5) UTI 15 (48.4) 16 (51.6) No UTI 129 (69.4) 57 (30.6) Weakness 3 (50) 3 (50) No weakness 141 (66.8) 70 (33.2) AUR = acute urinary retention; PVR = postvoid residual. the first month. The success rate assessed at 3 mo showed no significant difference among all subgroups. Table 2 compares the incidence of AEs in the different demographic and clinical subgroups and Table 3 compares the difference in AE incidence according to different baseline urodynamic variables by univariable analysis. Table 4 lists the univariable and multivariable logistic regression analyses for the risk of specific AEs. Univariable analyses revealed that male gender ( p = 0.001), age 75 yr ( p = 0.014), baseline PVR 100 ml ( p = 0.001), and a baseline VE <70% ( p = 0.05) were predictors of AUR. Further, age 75 yr ( p = 0.039), comorbidity ( p = 0.001), and OAB-wet ( p = 0.024) were predictors of large PVR. Patients with baseline PVR 100 ml ( p = 0.007), or receiving Botox dose >100 U ( p = 0.043) had higher incidence of straining to void. Female patients ( p = 0.002) and male patients with retaining prostate ( p = 0.022) had higher risk of UTI. No AUR was noted after bladder base/trigonal BoNTA injection, which was significantly lower than after bladder body (detrusor and suburothelial) injection ( p = 0.014). Multivariable analyses revealed that male gender ( p = 0.013) and baseline PVR 100 ml ( p = 0.003) were independent predictors of AUR. Baseline PVR 100 ml ( p = 0.007) and receiving >100 U BoNTA injection ( p = 0.029) were predictors of straining to void. Presence of comorbidity ( p = 0.011) was associated with large PVR after BoNTA injection. Although AEs were inconvenient problems after BoNTA injection, the occurrence of AUR, large PVR, or straining to void did not correlate with treatment failure. However, UTI or hematuria after BoNTA treatment were associated with a lower success rate (Table 5). 4. Discussion In recent decades, intravesical botulinum neurotoxin (BTX) injection has been shown to be an effective therapeutic alternative for IDO refractory to antimuscarinics. Urinary urgency and episodes of incontinence were found to improve after BTX injection [20,21]. The maximum effect on significant increases in cystometric capacity was observed at 4 wk, but PVR also increased at 4 wk [10]. Large PVR is associated with subsequent UTI [11]. Injecting dose and injection sites have not affected therapeutic results in previous studies [1,4,8,12,22]. This study further confirmed this finding. Interestingly, the success rate of bladder base/trigonal injection was not inferior to that of detrusor or suburothelial injection. The bladder base/trigonal injection bears no risk of AUR and the incidence of AUR at this location is significantly lower than that of bladder body (detrusor and suburothelial) injections. Therefore, BoNTA injection at the bladder base/trigone may be a better choice in elderly patients who are at risk of developing AUR or large PVR. Although clinical trials provided evidence of the efficacy of BoNTA on IDO, the incidence of AEs after BoNTA injection

7 EUROPEAN UROLOGY 58 (2010) remains high; incidence appears to have been underreported. Recent studies have reported that the total continence rate was approximately 50 60% [11,15], while Botox-treated patients had a nine-fold higher risk of elevated PVR volume compared with placebo-treated patients [23]. Patients who were not totally continent after BoNTA injection might not be satisfied with the treatment outcome if they had large PVR and required straining to void. The main AEs associated with intravesical BoNTA injection are large PVR and UTI [4,5,10 12,24,25]. The incidence of AEs in this study is in accordance with that reported previously. Except in 11 patients with grade 2 AE, the other AEs, such as hematuria, micturition pain, and general weakness, were grade-i complications that required no surgical intervention. Although large PVR, UTI, and urinary retention remain obstacles to the wide application of BoNTA for the treatment of refractory DO, there has been no reported factor to predict the occurrence of AEs after BoNTA injection. A lower Q max, lower projected isovolumetric pressure, and lower bladder contractility index have been reported as risk factors for incomplete emptying [26]. Another recent study revealed that Botox dose >150 U yielded higher PVR and need for CIC [14]. Therefore, patients at risk of AEs should be fully counseled on the possibility of urinary retention and trained in CIC before the procedure [27]. This study also found a higher rate of UTI in women after BoNTA injection, although fewer women had incidence of AUR. Women are prone to develop UTIs if they have large PVR [11]. After BoNTA injection, half of the women in this study had to void by abdominal straining and had large PVR, both of which are risk factors for UTI in women. The correlation of UTI with a lower success rate could be due to increased bladder inflammation and exacerbated storage symptoms due to prolonged or recurrent UTI attacks in patients with large PVR. It is important to give prophylactic antibiotics in patients who experience large PVR after BoNTA injection. Regarding the changes in the urodynamic parameters after BoNTA injection, we found that the PVR and bladder capacity returned gradually after the first month; this phenomenon was compatible with the return of urodynamic DO at 6 mo. Although BoNTA remained therapeutically effective in some patients up to 1 yr, the effect might disappear with time. Repeat injections are necessary to maintain continence, and patients should be informed about what to expect after each treatment, particularly the AEs to look for. Treatment of IDO is not like that for neurogenic DO (NDO). A good therapeutic result for NDO is dryness, and patients can accept the need of CIC [28,29]. However, patients with OAB need to be dry and able to void spontaneously without CIC after BoNTA injection. In fact, there is a discrepancy between objective improvement and the subjective success rate. Patients might not consider the therapeutic outcome satisfactory because of bothersome AEs or UTI, although the bladder capacity is increased. The limitations of this study are (1) nonconsecutive enrollment of patients and (2) the patient number in the subgroups receiving different Botox doses and via different injection sites are not comparable. 5. Conclusions Male gender, baseline PVR 100 ml, comorbidity, and BoNTA dose >100 U are risk factors for increasing incidence of AEs after intravesical BoNTA injection for IDO. Author contributions: Hann-Chorng Kuo 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: Kuo. Acquisition of data: Kuo. Analysis and interpretation of data: Liao. Drafting of the manuscript: Kuo. Critical revision of the manuscript for important intellectual content: Chung. Statistical analysis: Chung. Obtaining funding: Kuo. Administrative, technical, or material support: Kuo. Supervision: None. Other (specify): None. Financial disclosures: I certify 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: None. Funding/Support and role of the sponsor: None. References [1] Kuo HC. Urodynamic evidence of effectiveness of botulinum A toxin injection in treatment of detrusor overactivity refractory to anticholinergic agents. 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