**3. Discussion**

The AUA guidelines suggest intra-detrusor injection with OnabotulinumtoxinA (evidence grade B), SNM (evidence grade C), or PTNS (evidence grade C) as the third-line treatment modalities for adult OAB [3]. In the absence of a direct head to head comparison of the three treatment modalities for adult OAB symptoms, the present detailed systemic review and network meta-analysis is the first review to combine all updated evidence and compares the efficacy of any dose of OnabotulinumtoxinA, sacral neuromodulation and PTNS. The compared outcomes included voiding frequency/day, urinary incontinence episodes/day, and ≥50% reduction in symptoms. Pairwise meta-analysis revealed that all three modalities were more efficacious than a placebo with regard to the outcomes of interests, including urinary frequency, incontinence, and achieving ≥50% of symptoms improvement. SNM achieved the greatest reduction in urinary incontinence episodes and voiding frequency/day. OnabotulinumtoxinA was associated with the highest risk of urine retention and UTI episodes in the follow-up period. As none of the included studies used a unified or standard questionnaire to evaluate the QoL, the results regarding QoL were not pooled for the meta-analysis. We suggested that International Continence Society or International Urogynecology Association should unify the QoL questionnaire based on evidence and experts' opinion for a better evaluation of post treatment result.

The cost of the treatment and the insurance payment system may influence the patient's preference for a specific therapy. A cost analysis was performed to assess the economic effectiveness of each treatment. Based on a literature review, SNM was considered to be the most expensive treatment compared with a OnabotulinumtoxinA injection and PTNS in the short term [25–27]. However, in a model of middle- and long-term treatment, the cost-effectiveness of SNM was comparable with OnabotulinumtoxinA [25,28]. There was no comparison between OnabotulinumtoxinA and PTNS. Martinson et al. constructed the Markov model to simulate the cost-effectiveness of PTNS and they concluded that PTNS was the least costly therapy compared with OnabotulinumtoxinA and SNM [26]. However, different regional health insurance and health care payment systems could affect the simulation result and lead to different outcomes. A local cost-effectiveness analysis is more valuable for urologists.

The current study primarily compared short-term efficacy at 12 weeks follow-up and data comparing long-term efficacy is lacking. Amundsen et al. conducted a randomized control trial with a 6 years follow-up, which confirmed the middle- to long-term efficacy, QoL and satisfaction with treatment for OnabotulinumtoxinA injection and SNM [24]. However, there has been no previous report on the long-term efficacy of PTNS. The present study did not compare long-term adherence between treatment modalities.

The major drawbacks for management with antimuscarinics lie in the low rates of adherence to the medication [29,30]. Adherence at 12 months was 39% for mirabegron vs. 14–35% for antimuscarinics [29]. The effects of OnabotulinumtoxinA persist for 6–9 months and the effect can be extended with repeated injections [31]. Long-term adherence to OnabotulinumtoxinA injections is less discussed. Patient preference is an important factor, especially when comprehensive data is not available to assist in the decision-making progress. No significant difference in patient satisfaction was reported between SNM and OnabotulinumtoxinA in the ROSETTA trials [23,24] or studies by Hoag et al. [32]. Since all three of the investigated third line treatments are effective, health care providers should carefully discuss the pros and cons of each treatment with the patient and determine the appropriate strategy based on each individual situation.

The adverse effects of an OnabotulinumtoxinA injection include hematuria, bacteriuria, UTIs, urine retention, and increased post-void residual urine [33]. The rate of post-therapeutic complications, including urine retention that needed clean intermittent catheterization and UTIs, were compared between treatments. Intravesical injection with OnabotulinumtoxinA lead to a significantly higher rate of CIC and UTIs. Nevertheless, the higher rate of CIC was not consistent among the included trials and the literature review, therefore this conclusion could be controversial. Side effects associated with SNM included pain at the stimulator and lead sites, lead migration, infection, and the requirement for surgical revision [21–24,32]. A screen test before implantation and two-stage implantation could increase the success rate [34]. The revision rate varied from 3–32% and the removal rate varied from 8.6–13% [24,35]. With improvements in battery longevity and better localization of lead placement, these revision and removal rates could be reduced. The only side effects of PTNS were local adverse events, including minor bleeding spots and temporary pain [4].

There were several limitations to the current network meta-analysis study. First, the variable qualities and publication biases of the included studies may compromise the results of the network meta-analysis. There was considerable heterogeneity across the study designs, including participants, scheduled follow-ups, questionnaires, evaluated parameters, OnabotulinumtoxinA dose, and SNM and PTNS protocols. The U.S Food and Drug Administration approved intra-detrusor injection of OnabotulinumtoxinA is 100 U [3], while the included ROSETTA trial used 200 U [23,24]. Different protocols were also used for PTNS. Second, the variable or ambiguous and potentially post-hoc definitions for the outcome parameters used in each study made it difficult to unify and compare the treatment results between the studies. However, because of the heterogeneity of enrolled patients, existing of high-risk bias and lacking long-term outcomes comparison, more high-quality studies are necessary to clarify this benefit and risk of the current available 3rd line therapy for overactive bladder symptoms. A strength of the current study was that it collected 17 randomized controlled trials published in English over three decades and used network meta-analysis to compare the three existing therapeutic options.

#### **4. Conclusions**

The results revealed that all three modalities were efficacious in managing adult OAB syndrome, and all were better than a placebo on the specific symptoms reported to be the outcome of the study. This review shows that at 12 weeks follow-up, SNM yielded the greatest reduction in urinary incontinence episodes and urinary frequency/day. OnabotulinumtoxinA resulted in a higher incidence of complications, including urinary tract infection and urinary retention.

As there is a lack of head to head comparison studies among SNM, PTNS, and OnabotulinumtoxinA for the treatment of adult OAB symptoms, the current network meta-analysis represents the best available evidence for the comparison of these three treatment modalities.
