Introduction

The International Continence Society has defined overactive bladder (OAB) as a syndrome characterized by urgent urination, often accompanied by frequent urination and nocturia, with or without urgent urinary incontinence (UUI)1. Although OAB does not directly affect the life expectancy of patients, it often makes patients feel anxious, depressed, and helpless and has a negative impact on their quality of life.

In China, according to the first large-scale epidemiological survey released by the Chinese Urology Association in June 2010, the overall prevalence of OAB in people aged > 18 years was 5.2%, with an increase in the incidence rate with age. The prevalence of OAB was 11.3% in people aged > 40 years2. These figures are expected to increase further as the population ages and the demand for good quality of life increases. According to a survey in 2018, nearly one-fourth of Chinese people aged > 40 years had experienced symptoms of OAB3.

Sacral neuromodulation (SNM) has been widely used as a third-line treatment for OAB. Although China performed the first SNM implantation in 1999, the application of SNM remains limited. By 2020, the cumulative number of implants used was only a few hundred4. Imported stimulators (Medtronic, InterStim system, United States) for clinical use are expensive, increasing the financial burden on the medical care system and patients and limiting the application of this therapy in China.

In this context, the development of the novel SNM BetterStim system by Beijing PINS Medical Co., LTD. is aimed at reducing the costs of the treatment, such that it benefits more patients in need. At present, its efficacy and safety have been preliminarily confirmed, but the long-term clinical effect still needs to be observed. In addition, compared with the InterStim SNM system, the BetterStim SNM system equipment is more suitable for Chinese body size, and supports remote-programming function5,6.

This study aimed to compare the clinical effects of the InterStim and BetterStim systems in treating patients with OAB in order to identify the characteristics of each system, thereby helping clinicians and patients make more informed treatment choices.

Methods

Clinical data

The InterStim system data were obtained from the previously established Chinese SNM database. The research design and inclusion and exclusion criteria have been published in detail elsewhere4,7. The BetterStim system data were obtained from clinical trials completed in 2020. The primary criteria for inclusion were as follows: (1) age ≥ 16 years; (2) an established refractory OAB diagnosis; (3) normal upper urinary tract function; (4) bladder capacity > 100 mL; (5) willingness to undergo minor surgery; and (6) compliance with follow-up requirements. The main exclusion criteria were as follows: (1) multiple sclerosis, spinal cord injury, stroke, and other neurological diseases; (2) associated uncontrolled urinary tract infection, urinary tract obstruction, or urinary tract tumor; (3) participation in other clinical trials within 3 months of the present trial; and (4) other circumstances that the researcher considered inappropriate for participation in this trial. The stimulator parameters used in this study were all unified standards, that is, the frequency was 14 Hz, the pulse width was 210us, and the amplitude was slightly below the sensory threshold. This study only included patients who underwent stage II permanent implantation, and all the patients provided written informed consent to participate in the study. For participants that are minors, informed consent obtained from their parents and/or legal guardian.

The baseline period was defined as the period before the patients underwent stage I implantation. The experience period was defined as the period after stage I implantation and before stage II permanent implantation. Based on the different implanted systems, the patients were divided into the InterStim and BetterStim system groups. The degree of improvement in the different symptoms between baseline and the experience period and after permanent implantation (at the last follow-up) was compared. The differences in the degree of improvement in the different symptoms were compared between the two groups.

Evaluation of therapeutic effect

In this study, both subjective and objective indicators were used to evaluate patient response to treatment. Subjective indicators consisted of the scaled scores of patients in different treatment periods, including urgency perception scale (UPS) and OAB-related quality of life (OAB-qol) score8,9. Objective indicators reflected the voiding diary of patients 3–5 days before and on the follow-up day. Only the data most closely related to OAB symptoms (daily urination times, average urine volume, and daily urine leakage times) were included in the analysis.

The main outcome of this study was the difference in the improvement of symptoms and scores of patients with OAB between the BetterStim and InterStim systems, and the reasons for these differences were further analyzed. The secondary outcome was the incidence of adverse events associated with the different systems. All clinical data were collected after obtaining study approval from the Ethics Departments of Beijing Hospital (approval number: 2015BJYYEC-08-04). All procedures performed in this study were in accordance with the Declaration of Helsinki (as revised in 2013).

Statistical analysis

Data analysis was performed using SPSS statistical software (version 22.0, SPSS Inc., Chicago, IL, USA). Repeated measures analysis of variance and Mauchly’s sphericity test were used for analysis of data derived from the same system. Any data that failed to pass the test of sphericity were corrected by Greenhouse–Geisser and/or Huynh–Feldt correction methods. An independent sample t-test was used to compare data derived from the different systems. The chi-square test was used for intergroup comparisons of qualitative data. Statistical significance was set at P < 0.05.

Ethics declarations

All clinical data were collected after approval of the study by the Ethics Departments of Beijing Hospital (approval number: 2015BJYYEC-08-04). All the patients provided written informed consent to participate in the study. The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the Declaration of Helsinki (as revised in 2013).

Results

A total of 113 patients with OAB were included in the study. There were 43 and 70 patients in the InterStim and BetterStim system groups, respectively. Baseline information for both groups is shown in Table 1. The proportion of male patients was 34.9% (15/43) in the InterStim system group and 28.6% (20/70) in the BetterStim system group (P > 0.05). The follow-up time was 21.63 ± 12.53 months for the InterStim system group and 33.33 ± 15.59 months for the BetterStim system group (P < 0.001). The baseline data were comparable between the two groups, excluding the longer follow-up time in the BetterStim system group.

Table 1 Baseline information.
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Significant improvements were noted in daily urination times, average volume, and daily urine leakage time in both groups at different periods, and no significant differences were noted between the groups in these three variables at baseline (Table 2). It is noteworthy that significantly higher daily urination times were observed during the experience period and at the last follow-up in the BetterStim system group compared to the InterStim group. Significant between-group differences in the daily urine leakage time were observed only during the experience period, and these values were higher in the InterStim system group.

Table 2 Objective indicator data.
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Patients with OAB using the different systems were satisfied with the improvements obtained in the subjective indicators (Table 3). Specifically, UPS and OAB-qol scores significantly improved over the treatment period in both groups. Regarding between-group differences, UPS and OAB-qol scores were significantly lower in the BetterStim system group at baseline, but these differences were not maintained at the last follow-up.

Table 3 Subjective indicator data.
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At the last follow-up, 14 patients experienced device-related adverse events. Of these, four patients were in the InterStim system group, with two cases of recurrent symptoms, one case of disconnection between 0 and 3 o’clock, and one case of drowsiness. With repeated programmed adjustments and avoidance of the faulty circuit, all the patients were able to maintain curative efficacy without surgical intervention. Device-related adverse events occurred in 10 patients in the BetterStim system group, including undesirable changes in stimulation in 10 patients, efficacy fluctuations in eight patients, and pain at the implant site in five patients. A total of eight patients removed the device due to adverse events after stage II permanent implantation, including four cases of unsatisfactory or ineffective treatment effect, one case of discomfort at the implantation site, one case of wire breakage, one case of capsular exudate, and one case requiring cystectomy. There was no significant difference in the incidence of complications between the two groups (P = 0.435).

Discussion

To the best of our knowledge, this study is the first to compare the differences in the clinical outcomes of two SNM systems (InterStim and BetterStim systems) in the treatment of OAB. This comparison provides reference for clinicians in clinical treatment selection.

As an advanced, innovative, and minimally invasive treatment method, SNM has been recommended by several professional international society guidelines for the treatment of refractory lower urinary tract dysfunction diseases, including OAB and UUI, and is used worldwide10. The budget spent by the United States on UUI in 2020 exceeded 80 billion dollars11. Specifically, for each patient with OAB, the cost is approximately $11,134 per year, which represents a considerable socio-economic burden12. As a developing country with a population of 1.44 billion, there are more patients with OAB in China than in any other country. Unfortunately, compared with China’s average annual income of 60,000 yuan, the imported SNM, which costs as much as 130,000 yuan, is undoubtedly a “luxury” treatment and has not yet been included in China’s latest medical insurance catalog (2020 edition). On this basis, a domestic stimulator was developed and successfully completed a clinical trial in 20205,6.

This analysis confirmed the effective and stable performance of both systems. The improvements in voiding diaries and subjective scores observed in both group patients are comparable to those previously reported in patients using other types of SNM devices13. Comparing the two systems directly, we found that there were slight differences concerning improvements in daily urination and urine leakage times. Specifically, although no significant difference was observed between the two groups at baseline, daily urination times were significantly higher in the BetterStim system group than the InterStim group during the experience period and at the last follow-up. Differences in daily leakage times were noted only in the experience period, with significantly higher daily leakage times in the InterStim system group than the BetterStim group.

These findings appear contradictory; however, a more refined classification method for OAB, namely dry and wet OAB, is required. UUI is a common symptom of OAB. According to the current definition of OAB by the International Continence Society, all patients with UUI have OAB, but not all patients with OAB have UUI1. In fact, up to 40–50% of women and 80% of men with OAB do not have UUI; this condition is termed dry OAB14,15. Conversely, OAB associated with UUI is referred to as wet OAB. Data from this study suggest that the InterStim system is more responsive during the experience period and may be more beneficial for patients with dry OAB. At the same time, data analysis demonstrated better efficacy of the InterStim system at the last follow-up. However, in this study, the follow-up time was longer in the BetterStim system group; therefore, it was not possible to conclude that the InterStim system had better efficacy in the mid-term. For patients with wet OAB, the BetterStim system showed better performance during the experience period, thereby possibly increasing the conversion rates. However, the above conclusions are based on the interpretation and analysis of the data included in this study based on clinical experience, and further studies are needed to verify and evaluate the preliminary conclusions of this study.

The differences in subjective scores between the different systems were analyzed, with significant differences in the UPS and OAB-qol scores observed at baseline. Specifically, patients in the InterStim system group had a stronger sense of urgency, and there was a greater impact on the OAB-qol of patients in the BetterStim system group. These differences disappeared at the last follow-up visit. In our view, the main reason for this finding is financial. The InterStim system is available for installation at the patient’s own expense, whereas the BetterStim system is available after screening as part of a clinical trial at no cost to the patient. Therefore, it is understandable that patients who chose self-paid InterStim implants reported greater subjective urgency, whereas baseline data in the BetterStim patients showed a greater impact on OAB-qol. We speculate that the effect of clinical trial recruitment led to a lower OAB- qol score in the BetterStim group during screening. In addition, for patients in clinical trials, there is a dedicated resident who is responsible for regular follow-up via telephone and adjustment of the stimulation parameters according to the needs of patients during each follow-up visit5. Overall, participants in clinical trials received more attention than patients undergoing routine clinical care, which may have led to a greater improvement in OAB-qol scores in the BetterStim system group.

The reported complication rates vary widely among studies, systems, and devices. In a randomized controlled trial of the InterStim system, during the 12-month follow-up, Noblett et al. found that approximately 30% (82/272) of patients showed device-related adverse events, although in most cases, surgical intervention was not required16. This incidence was significantly higher than the incidence of complications noted in the InterStim system group in our study. We postulate that the reason for this disparity is that the sample size of the InterStim system group in this study was small. Additional studies with larger sample sizes are required to assess the validity of these results. During the 2-year follow-up of a new rechargeable SNM device (Axonics System), only 16% (13/51) of the patients had adverse reactions17. This ratio is similar to the complication rate of the BetterStim system group in this study, and both are clinical trials, suggesting that adequate patient education and management may play a positive role in reducing the incidence of adverse events.

This study has several limitations. First, although more than 110 patients with OAB undergoing SNM were included in this study, the sample size may have been insufficient. The test efficiency was reduced after grouping according to the different systems, which may have affected the accuracy of our conclusions. Second, relatively few research indicators were used in this study. Since we used patients from two different datasets, only the corresponding indicators were included in this study. Third, the details of the mechanisms underlying these findings have not been clarified. The working principle of the two systems is the same, with electrical pulses applied to specific sacral nerves; however, the analysis shows that the clinical effects are slightly different.

The use of SNMs in China is increasing every year; therefore, it is necessary to carefully evaluate this therapy. To the best of our knowledge, this study is the first to compare the clinical outcomes of two different SNM systems used in the treatment of OAB. This study demonstrated that the InterStim system was more effective during the experience period and may bring greater benefit to patients with dry OAB. However, for patients with wet OAB, the BetterStim system performed better during the experience period and may help to further increase the conversion rates. Further studies are required to confirm is one system is more efficient for one subtype of OAB to improve the choice of treatment based on individualized characteristics.