The Effects of Age, Gender, and Postvoid Residual Volume on Catheterization Rates After Treatment with OnabotulinumtoxinA for Overactive Bladder

Take Home Message In this pooled analysis, most men and women receiving onabotulinumtoxinA 100 U for overactive bladder with urinary incontinence did not require clean intermittent catheterization (CIC). These findings indicate that in the absence of urinary retention, CIC may not be necessary in most patients receiving onabotulinumtoxinA.


Introduction
Overactive bladder (OAB) symptoms are reportedly more common among women (43%) than men (27%) in the USA [1] and can occur with urinary incontinence (UI), which has been associated with quality of life (QoL) impairments, anxiety, and depression [1][2][3].OAB with UI is often managed initially with an anticholinergic (antimuscarinic) agent; however, many patients discontinue treatment owing to an inadequate response or systemic side effects [4,5].b3 adrenoreceptor agonists may be used, but patients with OAB who experience lack of efficacy may need other treatment modalities [5].
In randomized placebo-controlled trials, onabotulinum-toxinA has demonstrated significant improvements in UI, urgency, frequency, and QoL in patients with idiopathic OAB inadequately managed with an anticholinergic agent [6][7][8][9].In these trials, transient increases in postvoid residual urine volume (PVR) were reported following onabotulinum-toxinA treatment, sometimes requiring clean intermittent catheterization (CIC; $6.5%) [6][7][8][9].In real-world clinical practice, the possibility of greater PVR requiring catheterization may be a concern when treating OAB in patients with lower bladder contractility, who are often older [10], and may influence a physician's decision to offer onabotulinum-toxinA treatment.However, whether patient age affects CIC incidence and outcomes following onabotulinumtoxinA treatment requires further characterization.An objective of this pooled analysis of four randomized trials was to evaluate the safety of onabotulinumtoxinA in women and men with OAB across age groups during the 12 wk after the first onabotulinumtoxinA treatment.We also assessed the impact of maximum PVR (PVR max ) after onabotulinum-toxinA use on CIC initiation and rates of spontaneous and nonspontaneous voiding in women and men as a function of age.

Study design
This was a pooled post hoc analysis of four randomized, double-blind, placebo-controlled trials of onabotulinumtoxinA 100 U versus placebo (NCT00910845, NCT00910520, NCT01767519, and NCT01945489) conducted in North America and Europe that have previously been described [6][7][8][9].In brief, patients were randomized 1:1 to receive onabo-tulinumtoxinA 100 U or matched placebo in the first treatment cycle, followed by a 12-wk open-label treatment cycle during which all patients could receive retreatment with onabotulinumtoxinA 100 U. Pro-tocols were approved by an ethics committee or institutional review board at each site.The study conduct was aligned with Good Clinical Practice principles and all patients provided written informed consent.

Patient population
Adults with idiopathic OAB, at least three urgency UI episodes (UIEs)

Statistical analysis
Data for patients receiving their first treatment with onabotulinum-toxinA for OAB were analyzed and summarized descriptively.Demographics and baseline characteristics were analyzed in the pooled intent-to-treat population (all randomized patients).Patients were stratified by age (<40, 40-49, 50-59, 60-69, 70-79, and !80 yr) and PVR max (0-200, 201-350, and >350 ml).Safety was analyzed in the pooled safety population (all patients who took at least one dose of study treatment).
The software program used for the analyses was SAS v9.4 (SAS Institute, Cary, NC, USA).

Patient demographics and baseline characteristics
Among 1504 patients with OAB in the intent-to-treat population, 87.7% were women and 88.8% were White, and the mean age was 60.5 yr (Table 1).The mean OAB duration was 6.7 yr, the daily average number of UIEs was 5.4, and the daily average number of urgency UIEs was 4.9.
Baseline characteristics for men and women were generally well balanced, with a few exceptions (Table 1).There was a higher proportion of women than men in the 50-59-yr, 70-79-yr, and !80-yr age groups (Table 1).The mean OAB duration, daily average number of UIEs, and daily average number of urgency UIEs were higher for women than for men (Table 1).
Baseline PVR was not notably higher for patients who started CIC after onabotulinumtoxinA treatment (34.0 ml) than for the overall population (including those who did not perform CIC; 21.3 ml).

3.6.
Incidence of spontaneous versus nonspontaneous voiding in the CIC cohort stratified by PVR max Overall, 0.1% (2/1504) of patients were unable to void spontaneously; both were women who started CIC (Supplementary Fig. 2), representing 0.2% (2/1319) of the female population.One patient was 75 yr old with PVR max of 250 ml; the other was 76 yr old with PVR max of 700 ml.All male patients were able to void spontaneously following treatment with onabotulinumtoxinA.

Functional bladder capacity and PVR ratio stratified by patient characteristics
Across all age groups, baseline PVR was low.Average baseline functional bladder capacity ranged from 294 to 476 ml, with considerable variability (Table 2).The mean PVR ratio was highest at week 2, regardless of age or the need to ini-tiate CIC, and was higher at all time points for male than for female patients (Supplementary Figs.3-6).

Discussion
In this pooled analysis of four randomized clinical trials of onabotulinumtoxinA 100 U for the treatment of OAB with UI [6][7][8][9], the incidence of CIC was low overall, particularly for women and younger patients, and especially for those with PVR max 200 ml, consistent with prior findings [11].
There was no apparent relationship between baseline PVR and CIC initiation, and few patients met the clinical criterion for urinary retention, with only 0.1% of patients unable to spontaneously void following onabotulinumtoxinA treatment.These findings support past conclusions that CIC may not be necessary in most patients treated with onabo-tulinumtoxinA, as clinical urinary retention is rare and most patients did not develop significantly elevated PVR.These data provide additional context for clinicians regarding elevated PVR following onabotulinumtoxinA treatment.CIC rates were low, especially in the younger age groups (<50 yr), with the highest rates observed in the 70-79-yr group for women and the 50-79-yr group for men.These findings are consistent with research showing significant increases in PVR and decreases in contractility after the age of 50 yr in women [12], suggesting that the risk of needing CIC after treatment increases with age.In this study, CIC was used primarily by patients with PVR max !350 ml according to the study protocols [6][7][8][9].
Most patients receiving onabotulinumtoxinA could void spontaneously, and very few met the International Continence Society (ICS) clinical criterion for urinary retention (inability to pass urine despite persistent effort) [13].Complete inability to void was rare and observed in only 2/1319 women, both of whom were aged >70 yr with PVR max >200 ml; none of the men were unable to spontaneously void after onabotulinumtoxinA treatment.
In both males and females, the PVR ratio after onabo-tulinumtoxinA was highest at week 2 and declined thereafter.This observation is consistent with the change in PVR observed over time in the current analysis and coincides with the onset of treatment efficacy in clinical trials [6,7,9].OnabotulinumtoxinA 100 U was well tolerated in women and men in all age groups, with no unexpected safety signals.The TEAE profile was consistent with previous publications and generally limited to local urologic events.
The CIC incidence observed in the current analysis (women 6%, men 10%) is higher than in recent real-world reports (ranging from 1.6% to 2.7%) [14,15].This discrepancy between clinical trials and real-world studies probably reflects the close monitoring and specific criteria for initiating CIC use in the clinical trials and suggests that a different standard for CIC initiation is being applied in clinical practice.Furthermore, changes in real-world practice since the completion of these trials may have contributed to differences in CIC rates.
When deciding whether to initiate CIC, PVR should be interpreted in the context of other clinical characteristics.For example, in patients with PVR max in the range 201-350 ml, functional bladder capacity and symptoms should be considered, as some patients with large functional bladder capacity may remain asymptomatic despite elevated PVR, and some asymptomatic patients may not require CIC [16,17].It is important also to consider that functional bladder capacity can vary, for example, according to behavioral stressors and external stimulants [18,19].
In this analysis, a few patients with a PVR max !350 ml, including one older patient (!80 yr), did not start CIC.In practice, the impact of factors such as low vision and dexterity issues on CIC initiation should be considered in the older patient population.Although younger patients may be more able to perform CIC, evaluation of their functional    a Urinary tract infection was defined as a positive urine culture result with a bacteriuria count of >10 5 cfu/ml and leukocyturia of >5 cells per high-power field, regardless of the patient's symptoms.b Urinary retention was defined as PVR ≥200 ml requiring CIC.CIC was initiated if PVR was ≥350 ml regardless of symptoms, or ≥200 to <350 ml with associated symptoms that, in the investigator's opinion, required CIC.bladder capacity and PVR may help in establishing if CIC is actually necessary.
This analysis provides valuable data for men, who are often under-represented in the literature on OAB.The proportion of male patients starting CIC was low across the age groups, particularly in the group with PVR max <200 ml, and no male patients aged <40 yr or !80 yr started CIC.However, the small male population in this study limits the interpretability of these findings.
This pooled analysis was conducted post hoc.The PVR max categories are somewhat arbitrary and may not be aligned with any specific clinical practice.Few patients started CIC in some age and PVR max groups, limiting the interpretability of the associated findings, and caution is advised when interpreting CIC duration by age and sex owing to small sample sizes in certain groups.PVR max ranges used in these analyses may not be relevant for all patients, as functional capacity varies among individuals.The estimated functional capacity was calculated as a proxy given the limitations of the data available, and this analysis did not consider exogenous factors that may have affected this parameter.
Future studies evaluating the influence of patient characteristics such as diabetes mellitus or other comorbidities on CIC incidence may build on this work in furthering our understanding of any increase in the risk of PVR elevation after treatment in specific populations [20].In addition, multivariable analysis of age, baseline PVR, and minimum/maximum PVR (a measure of best and worst contractility) as independent variables may provide insight into the combined role of age and PVR in predicting the need for CIC.

Conclusions
In this pooled analysis of onabotulinumtoxinA 100 U treatment for OAB with UI, mean PVR at baseline increased with age and was similar for the overall population and for patients who started CIC.Most women and men did not develop markedly raised PVR necessitating CIC.The mean PVR ratio was highest at week 2, inability to spontaneously void after onabotulinumtoxinA treatment was extremely rare, and few patients had urinary retention according to the ICS criteria.These data on CIC incidence after onabo-tulinumtoxinA treatment according to patient characteristics may facilitate more individually tailored counseling on the risk of developing elevated PVR requiring CIC.
These data were presented in part at ICS 2022, Vienna, Austria and TOXINS 2022, New Orleans, LA, USA.
functional capacity (baseline PVR + baseline volume voided per micturition); NA = not applicable; PVR = postvoid residual urine volume; SD = standard deviation.a Data missing for 1 patient.

Table 1 -
Patient demographics and baseline characteristics in the pooled intent-to-treat population of all randomized patients

Table 2 -
Baseline PVR and EFC by age category

Table 3 -
Safety and tolerability in the pooled safety population for patients with data available at week 12