Several publications endorse the effectiveness of botulinum toxin A (BTX-A) bladder injection in patients complaining of refractory overactive bladder (OAB). However, most studies have been conducted exclusively, or mainly, in female patients. Differences in pathophysiological mechanisms and even in the voiding physiology itself make therapeutic effects, as well as adverse events of BTX-A injection in men, an issue of special interest. We sought to systematically review the literature on the use of BTX-A injections in the bladder to treat idiopathic OAB in men.

A systematic review was performed to identify clinical trials on efficacy and safety of BTX-A injections in the detrusor for treatment in males with idiopathic OAB published from inception to October 2020. Letters were sent by e-mail to all corresponding authors (n=49) of studies that did not discriminate outcomes for male population or did not discriminate outcomes for idiopathic OAB (when there were both neurogenic and idiopathic OAB) initially in May 2020, and then again in November 2020 and in April 2021. Quality assessment was performed using the Cochrane Collaboration’s tool for assessing risk of bias and study characteristics were extracted by two reviewers independently. A meta-analysis was planned but was not possible due to the heterogeneity of the reported outcomes, which were reported differently and at different time points by the different studies.   A qualitative narrative synthesis of the available information is thus presented. Pooling of data was only possible for adverse events.

After screening 75 abstracts, twelve comparative trials were included in the qualitative synthesis, of which six were conducted exclusively in men (mean age: 66,7 years).  (Figure 1) There were only two randomized trials, and the rest were comparative cohort studies. Total number of participants in each study ranged from 28 to 146. Follow-up ranged from three to 69 months. Four studies included patients who have previously undergone transurethral resection of the prostate (TURP) or radical prostatectomy. Six studies excluded patients with OAB believed to be due to an underlying obstructive condition or bladder outlet obstruction (BOO). Onabotulinumtoxin was used exclusively in ten out of twelve studies, and the dosage ranged from 100 to 300 units. Therapeutic response to intravesical BTX-A injection was assessed differently across the studies, which used quality of life symptom questionnaires and voiding diary parameters. Improvement with statistical significance was observed in the Treatment Benefit Scale (TBS) (major improvement: 29.5%; improvement: 32.9%), UDI-6 (mean: -4.2 points and mean: -4,9 points), IIQ-7 (mean: -6.6 points), PGI (mean: 2.7 points), OABSS (mean: -3.87 points), Quality of Life Score (mean: 40.7%) and VAS-QoL (mean: -5,7 cm). 
A small randomized, placebo-controlled study, which included 28 patients, assessed the effects of BTX-A in men who underwent TURP to treat benign prostatic enlargement and persisted with bothersome OAB symptoms 3 months postoperatively. Patients receiving onabotulinumtoxin A demonstrated significantly improved quality of life scores at 180 and 270 days after treatment (p = 0.02 and 0.03, respectively) as well as significantly lower International Consultation on Incontinence Questionnaire (ICIQ) score (p < 0.05). Baseline urinary frequency was 10.5 versus post treatment 11.0 voids/day (p = 0.47). Frequency episodes improved from 11 episodes per day to eight episodes per day in the treatment arm. The placebo arm did not have a decrease in frequency episodes. This response was durable up to 90 days, although this was not statistically significant. IPSS, PVR, and urgency were unchanged postoperatively in both groups. 
Only two studies reported urodynamics separately for men before and after intravesical injection of BTX-A in. In the first study, after three weeks of the injection of 100 units of BTX-A, there was an increase in post-void residual volume (from 41 ± 80 mL to 134 ± 140 mL), reduction in the prevalence of detrusor overactivity (DO) (from 100% to 69%), a decrease in the maximum detrusor pressure during detrusor contractions (from 57 ± 33 cmH2O to 52 ± 48 cmH2O) and increased cystometric capacity (from 216 ± 92 cmH2O to 255 ± 112 cmH2O). Pressure-flow studies showed a decrease in the bladder contraction index (BCI) (from 105 ± 32 to 90 ± 31), reduction in maximum urinary flow (from 17 ± 7 mL/sec to 13 ± 7 mL/sec) and in the efficiency of bladder emptying (from 88 ± 18% to 76 ± 26%), all with statistical significance in comparison with the baseline parameters. The second study compared urodynamics data from baseline to three months postoperatively. Maximum detrusor pressure reduced after botulinum toxin injection (from 96.3 ± 67.6 to 43.4 ± 17.9 cmH2O) as well as the leak volume (from 198.0 ± 178.7 to 42.8 ± 70.8 mL) both with statistical significance. 
Pooling of outcome data was only possible for adverse events reported after BTX-A by seven studies which showed urinary tract infection (UTI), urinary retention (UR), increased post-void residual volume (PVR), de novo intermittent catheterization (IC), and hematuria rates of 29,8%, 20.0%, 37.3%, 28.3% and 12,4%, respectively. (Table 1)

There is limited evidence on the risk-benefit profile of BTX-A in male patients. This systematic review identified only two small randomized clinical trials (RCTs) and ten observational studies, mostly retrospective case series, including less than 1000 men in total. Due to several limitations, such as the marked heterogeneity both in inclusion criteria, as well as in BTX-A dosages and in the different outcome measures adopted to assess therapeutic response, only adverse event rates could be pooled.  	 In general, marked improvements in storage symptoms were reported after treatment, which reflected in better quality of life and could be confirmed by objective parameters of bladder diary records. Among the different botulinum toxins, onabotulinumtoxin was the most used, with wide dose variation, ranging from 100 to 300 units. OAB symptom improvement has been reported by most studies through validated questionnaires and bladder diaries. Urodynamics was used to assess such outcomes in two of the included studies, and clearly demonstrated improvements of cystometric parameters after BTX-A bladder injections. On the other hand, reduction in both maximum urinary flow, as well as in BCI, impaired bladder emptying efficiency and the overall safety profile was only moderately satisfactory, with a pooled rate of adverse events roughly ranging from 20% to 30% for UTI, UR and for de novo intermittent catheterization. Our systematic review initially identified 75 studies, which had included male patients. Only twelve of them fulfilled the inclusion criteria for the qualitative synthesis. This might be seen as a gap in the medical literature, since the risk-benefit profile of BTX-A could be distinct across genders.

Limited information regarding the efficacy and safety of BTX-A bladder injection for male idiopathic OAB from relatively low evidence is available. Further research is needed to better understand the risk-benefit profile of BTX-A in the male population.