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Five-Year Followup Results of a Prospective, Multicenter Study of Patients with Overactive Bladder Treated with Sacral Neuromodulation
Author's Accepted Manuscript Five Year Follow-up Results of a Prospective, Multicenter Study in Overactive Bladder Subjects Treated with Sacral Neuromodulation Steven Siegel , Karen Noblett , Jeffrey Mangel , Jason Bennett , Tomas L. Griebling , Suzette E. Sutherland , Erin T. Bird , Craig Comiter , Daniel Culkin , Samuel Zylstra , Fangyu Kan , Kellie Chase Berg PII: DOI: Reference:
S0022-5347(17)77099-1 10.1016/j.juro.2017.07.010 JURO 14849
To appear in: The Journal of Urology Accepted Date: 2 July 2017 Please cite this article as: Siegel S, Noblett K, Mangel J, Bennett J, Griebling TL, Sutherland SE, Bird ET, Comiter C, Culkin D, Zylstra S, Kan F, Berg KC, Five Year Follow-up Results of a Prospective, Multicenter Study in Overactive Bladder Subjects Treated with Sacral Neuromodulation, The Journal of Urology® (2017), doi: 10.1016/j.juro.2017.07.010. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.
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Five Year Follow-up Results of a Prospective, Multicenter Study in Overactive Bladder Subjects Treated with Sacral Neuromodulation
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Corresponding Author: Steven Siegel, MD Metro Urology, Woodbury, MN [email protected] Phone: 651-999-6800 Fax: 651-999-6830
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1. Metro Urology, Woodbury, MN 2. University of California, Riverside, CA 3. MetroHealth Medical Center, Cleveland, OH 4. Female Pelvic Medicine, Grand Rapids, MI 5. University of Kansas, Kansas City, KS 6. University of Washington, Seattle, WA 7. Scott and White Healthcare, Temple, TX 8. Stanford University, Stanford, CA 9. University of Oklahoma HSC, Oklahoma City, OK 10. Milford Regional Medical Center, Whitinsville, MA 11. Medtronic, Minneapolis, MN
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Steven Siegel1, Karen Noblett2, Jeffrey Mangel3, Jason Bennett4, Tomas L. Griebling5, Suzette E. Sutherland6, Erin T. Bird7, Craig Comiter8, Daniel Culkin9, Samuel Zylstra10, Fangyu Kan11, Kellie Chase Berg11
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Running Title: 5 Year Results of Sacral Neuromodulation for OAB ClinicalTrials.gov identifier: InSite for Overactive Bladder, NCT00547378
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Conflicts of Interest: Medtronic sponsored this study in full. Manuscript Word count: 2501 Keywords: overactive bladder, sacral neuromodulation, urinary incontinence, urgency frequency, quality of life
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Abstract Objective: To evaluate therapeutic success rate, changes in quality of life (QOL) and safety with sacral neuromodulation (SNM) at 5 years after InterStim™ implant. Subjects with bothersome
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symptoms of overactive bladder (OAB) including urinary urge incontinence (UI) and/or urgencyfrequency (UF), who had failed at least 1 anticholinergic medication and had at least 1 medication untried were included.
Methods: Therapeutic success was defined as a UI or UF response: ≥ 50% improvement in
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average leaks or voids/day or a return to normal voiding (<8 voids/day). QOL was evaluated using the International Consultation on Incontinence Modular Questionnaire (ICIQ-OABqol). Safety was evaluated through adverse events (AE).
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Results: Of the 340 subjects who completed test stimulation, 272 were implanted; 91% were female and mean age was 57 years. At baseline, UI subjects had 3.1±2.7 leaks/day (n=202); UF subjects had 12.6±4.5 voids/day (n=189). The 5 year therapeutic success rate was 67% (95% CI: 60%-74%) using the modified completers analysis and 82% (95% CI: 76-88%) using the completers analysis. UI subjects had a mean reduction from baseline of 2.0 ± 2.2 leaks/day; UF
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subjects had a mean reduction of 5.4 ± 4.3 voids/day (both p<0.0001, completers analysis). Subjects showed improvement in all measures of ICIQ-OABqol (p<0.0001). The most common device-related AEs were undesirable change in stimulation (60/272, 22%), implant site pain (40/272, 15%), and therapeutic product ineffective (36/272, 13%).
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Conclusions: This multicenter study shows that SNM has sustained efficacy and QOL
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improvements and an acceptable safety profile through 5 years in OAB subjects.
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INTRODUCTION Overactive bladder (OAB) is a common chronic condition which negatively impacts quality of life (QOL) of 10-30% of the population.1 Symptom control over long time periods is
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usually needed for satisfactory management. While treatments such as behavioral therapies, biofeedback, physical therapy, and oral medications are typically offered as first and second line remedies, a substantial proportion of patients continue to experience enough bother to seek further therapeutic options.2 Advanced treatment options including sacral neuromodulation (SNM), percutaneous tibial nerve modulation (PTNM) and intradetrusor onabotulinum toxin
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(BoNT) injection have been incorporated into treatment guidelines.2,3 Scarce data exist regarding the long-term efficacy for PTNM and BoNT beyond three years.4,5 While several
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papers have documented long term efficacy for SNM,6–10 most were single center, retrospective studies that either lacked rigorous analysis or were limited due to incomplete follow-up. The InSite study reflects current standard practices including minimally invasive techniques, routine use of fluoroscopy, and exclusive use of staged implantation of the tined lead. The InSite trial was designed to be implemented in two phases. Phase one was a
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prospective, multicenter, randomized trial comparing SNM to standard medical therapy at 6months.11 It provided level one evidence for the objective and subjective superiority of SNM over standard medical therapy among OAB patients who had previously had insufficient relief after trialing a median of 2 anticholinergic medications. The second phase was a prospective
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evaluation of safety and efficacy of SNM over 5 years. The primary objective of this portion of the study satisfied the FDA post-approval requirements to evaluate the tined lead. Results for
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subjects followed through 1 and 3 years have been previously reported.12,13 This manuscript represents the completion of the InSite trial at 5 years, including all subjects from both phases.
METHODS
Enrollment criteria and design were published previously.11–13 Subjects had a primary
diagnosis of OAB as demonstrated on a 3-day voiding diary with > 8 voids/day (urgency frequency, UF) and/or > 2 involuntary leaking episodes in 72 hours (urinary incontinence, UI). Subjects experienced previous treatment failure with at least one anticholinergic medication 3
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and had at least 1 medication untried. Institutional Review Boards approved the protocol and informed consent forms were signed prior to participation. All subjects underwent a staged implant procedure with the InterStim System (neurostimulator models 3023/3058, lead models
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3093/3889; Medtronic, Minneapolis, MN). Test stimulation success was defined as improvement from baseline: ≥50% improvement in average voids/day or a return to normal voiding (< 8 voids/day) for subjects with UF and 50% improvement in average leaks/day for subjects with UI. After completion of test stimulation, those who met success criteria were
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implanted with the neurostimulator.
Subjects returned for visits post-implant at 3 months, 6 months, 12 months, and yearly thereafter to 5 years. Electronic voiding diaries were used which allowed collection of real time
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OAB data. QOL was assessed using the validated International Consultation on Incontinence Modular Questionnaire (ICIQ)-OABqol which evaluated total health related QOL and 4 subscales (Concern, Coping, Sleep, and Social).14 Responses to the “interference” question on the OABqol measured how much urinary symptoms interfere with everyday activities. Other patient reported outcome tools used included the Male/Female Lower Urinary Track Symptoms-Sex
(VAS) for pelvic pain.
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(MLUTSsex15 and FLUTSsex16), Beck Depression Inventory II (BDI-II)17 and Visual Analog Scale
The primary safety objective was to demonstrate that the upper bound of the 95% confidence interval (CI) for the cumulative 5-year rate of adverse events (AE) related to the
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tined lead that required surgery was <33%. Device-related AEs were defined as those related to the implant procedure, therapy, device or implant site. A Clinical Events Committee reviewed
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and adjudicated all AEs.
Statistical Analyses
Various outcome measures were evaluated to determine 5-year efficacy of SNM,
including success rates (OAB, UI and UF subgroups) and absolute change (UI and UF) in leaking and voiding frequency from baseline and trends in these measures over time. Two analyses for success rate at 5 years were conducted. The first was a modified completers analysis evaluating all subjects who received a full system implant and had a baseline and 5-year evaluation, or 4
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withdrew early due to a device-related AE, or lack of efficacy resulting in explant. These early withdrawal subjects had their missing data imputed to their baseline assessment and were considered failures. Implanted subjects who withdrew for reasons unrelated to the device were
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excluded from the primary efficacy analysis. The second (sensitivity) analysis was a completers analysis and included all implanted subjects with diary data at baseline and 5 years. Descriptive statistics were reported and p-values for paired comparison between baseline and visits
through 5 years for leaking and voiding episodes/day were presented using a Wilcoxon signed-
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rank test. To assess the trend of efficacy over time, outcomes were evaluated for subjects with data available at baseline and each follow-up.
To assess QOL, data were analyzed as changes from baseline to follow-up visits. No
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data were imputed for missing values and descriptive statistics were reported. Withintreatment comparisons were made using a Wilcoxon signed-rank test. All subjects with device implant and the required outcome data at both baseline and follow-up visits were included. Published scoring criteria were followed for ICIQ-OABqol.14 “Overall, how much do your urinary symptoms interfere with your everyday life?” on the OABqol was measured on a scale from 0-
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10. A lower score was indicative of less OAB symptom interference. Based on the difference between scores at follow-up visits and baseline, percentages of subjects are reported in each category as follows: worsened: ≥2, no change: -1 to 1, improved: -4 to -2, and greatly improved: ≤ -5.
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Safety through 5 years was evaluated by reported AEs. The primary safety objective of 5-year AEs related to the tined lead that required surgery is reported as the Kaplan-Meier
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estimate of the survival function at 5 years with the 95% CI based on Greenwood standard error. Descriptive statistics were used to report the most common device-related AEs and surgical intervention rates. All statistical tests were examined for significance at the 0.05 level. The software package SAS (version 9.2, SAS Institute, Cary, NC) was used for all analyses.
RESULTS Overall 340 subjects received test stimulation and 272 (80%) subjects were implanted with the InterStim System. Baseline demographics are listed in Table 1. 5
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Using the modified completers analysis (n=183/272), the overall OAB response rate demonstrating therapeutic success was 67% at 5 years. The UI response rate was 64% for subjects characterized with UI at baseline. These subjects had an average reduction of 1.7 ± 2.1
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leaks/day as compared to baseline (p<0.0001). Complete continence at 5 years was achieved in 38% of subjects. For subjects with UF, a therapeutic response rate of 57% was observed.
These subjects had an average reduction of 4.4 ± 4.4 voids per day from baseline (p<0.0001). Using the completers analysis with no imputation of missing data (n=150/272), the
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overall OAB response rate demonstrating therapeutic success at 5 years was 82% (Figure 1). The UI response rate was 76% for subjects characterized with UI at baseline. These subjects had an average reduction of 2.0 ± 2.2 leaks/day as compared to baseline (p<0.0001). Complete
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continence at 5 years was achieved in 45% of subjects. For subjects with UF, a therapeutic response rate of 71% was observed. The mean reduction in voids/day was 5.4 ± 4.3 (p<0.0001). Response rates and mean reductions in leaks and voids show sustained efficacy of SNM through 5 years.
Sustained QOL improvements were reported from baseline to 5 years in all ICIQ-OABqol
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domains (all statistically significant with p<0.0001, Figure 2). At 5 years, 84% of subjects reported improved or greatly improved urinary symptom interference score (Figure 3). The impact on sexual function was evaluated using the MLUTSsex and FLUTSsex questionnaires. There was significant improvement from baseline to 5 years for females (p<0.0001, n=155) but
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no significant change for males was found which may be due to the small sample size (n=8). Depression, as measured by the BDI-II, significantly improved from baseline to 5 years
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(p<0.0001, n=168). The Visual Analog Scale (VAS) for pelvic pain was also significantly improved from baseline to 5 years (p<0.0001, n=166). Based on the 140 subjects who reached the 5-year visit and had programming data
available, 60.7% of the subjects were programmed to an amplitude less than 2 volts; the majority had a pulse width of 210 µsec; 63.6% had rate programmed to 14 hz and 67.9% were on continuous stimulation. The 5-year cumulative rate of AEs related to the tined lead that required surgery after full system implant was 22.4% (95% CI: 16.6%-27.7%), which fulfills the primary safety 6
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objective. There were no unanticipated adverse device effects. For subjects with a fully implanted system, undesirable change in stimulation was the most common AE occurring in 22% (60/272) of subjects, followed by implant site pain in 15% (40/272), and therapeutic
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product ineffective in 13% (36/272). All other device-related AEs occurring on or after implant were reported in less than 6% of subjects. One event was classified as serious: implant site erosion, which was resolved.
Surgical interventions including revision, replacement or permanent explant of any
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device component were also reported. A subject could experience multiple types of surgical interventions and an intervention could be due to multiple reasons such as AE, patient request, lack/loss of efficacy, or battery replacement. Eighty-four subjects (30.9%) had a surgical
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intervention due to an AE and 91 subjects (33.5%) had a surgical intervention due to battery replacement. In all 272 implanted subjects, the permanent explant rate was 19.1% (95% CI: 14.1%-23.9%) at 5 years. The top reason reported by investigators for permanent explant was due to an AE (11.0%, 30/272), most often for therapeutic product not effective (2.6%, 7/272). Other reasons include subject need for MRI, lack/loss of efficacy, and subject withdrew
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consent. A total of 8.5% (23/272) of permanent explants were associated with a lack or loss of efficacy. Ninety-one subjects (33.5%) had surgical interventions due to lack/loss of efficacy
DISCUSSION
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after full system implant.
OAB is a common, chronic condition that significantly impacts QOL. Therefore, it is
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important for a successful therapy to achieve substantial and sustained symptom relief. This prospective study demonstrates sustained efficacy and safety of SNM in OAB subjects after 5 years of treatment. The therapeutic success rate was 82% at 5 years and 85% at 1 year,13 which strongly demonstrates the long-term durability for SNM patients in clinical practice. The 60 month dry rate for the 118 UI patients was 45%, which is considerably higher than the dry rates at 6 months reported in the recent Rosetta trial comparing SNM to BoNT 200 units; 2% (N=174 patients) vs 20% (N= 190 patients), respectively.18 Speculations why include differences in analysis methods, the high rate of experience among InSite study implanters, predominant use 7
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of the 3889 lead vs the 3093 lead (extended number one electrode, now discontinued) that was exclusively used in the Rosetta trial, and the opportunity in InSite to adjust for sub-optimal responses via reprogramming or lead revision. The mean reduction in leaks and voids/day were
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2.0 and 5.4 at 60 months in the current study vs 3.3 and not reported in Rosetta at 6 months.18 The differences could be due to purposeful selection of patients with more severe UI in Rosetta (baseline mean of 5.4 leaks/day) and excluding those with UF only, in order to justify the BoNT treatment arm dose used. A sub-analysis of InSite patients showed that SNM was effective in
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treating both severe and less severe UI and UF at 12 and 24 months follow-up.19
Improvements in QOL, sexual function in female subjects, and pelvic pain measures were also sustained over 5 years. The rate of device-related AEs and surgical intervention
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remains significantly lower than previously published studies using older techniques and devices,20 but must be acknowledged as a consideration when evaluating candidates for this therapy. Investigators were required to report all device-related undesirable changes experienced in subjects regardless of the clinical significance. In addition, the Clinical Events Committee had a rigorous process for AE adjudication. The fact that one-third of the device-
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related AEs occurred within the first 12 months of implant may suggest that further refinements of lead placement technique or patient selection could result in improvements in safety profile.2120 During the long follow-up of 5 years, more subjects chose to replace their device rather than have it permanently explanted. Most AEs were minor and could be treated
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with non-invasive measures. Over time, it is expected that all the subjects who have been successfully managed will need device replacements to maintain benefit due to the nature of
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treatment and the underlying chronic condition. Most surgical interventions were performed to allow for continuation of the therapy. Of all implanted subjects, less than 20% underwent permanent explant for various reasons including AEs, patient request, or lack/loss of efficacy. Few studies have published outcome data or continuation rates of other advanced OAB
treatments beyond 36 months. In the multicenter STEP study,5 50 out of 60 subjects were enrolled and outcomes for PTNM were documented for a total of 29 (58%) subjects at 36 months. Although only a small number of subjects were included, PTNM showed safety with sustained improvements after 3 years. In a single-center study measuring long-term outcome of 8
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of BoNT for the treatment of OAB, 137 out of 268 subjects were followed for ≥36 months.4 In that study, 61.3% had discontinued therapy by 36 months, which included initial therapy failures. The main reasons for discontinuation from the study were tolerability issues including
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the need for intermittent catheterization and urinary tract infections. Initial costs are predictably lower for PTNM and BoNT versus SNM. To be more cost effective, it is necessary for SNM to provide long-term benefit. Previous studies have shown SNM becomes more cost effective compared to BoNT after 3-5 years, indicating SNM may be
technological advances including longer lasting batteries.
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comparatively cost saving in the long term.22, 23 This advantage could be magnified with
The strengths of the InSite study include the large number of subjects with protocol-
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mandated follow-up, and the rigorous modified completer analysis including subjects withdrawn for lack of benefit or device-related complications as failures. Additionally, the private practice and academic centers contributing subjects reflect real-world experience with the therapy, and thus the results are more generalizable. Limitations include the homogeneous population, with a minority of male subjects, which could detract from generalizability.
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Furthermore, centers could follow individual protocols regarding perioperative antibiotics, lead choice, and procedure techniques. Although this approximates what is occurring in general practice with SNM therapy, this lack of standardization along with the potential impact on infection rates, device-related complications, and ultimate therapy success or failure rates may
CONCLUSION
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have impacted overall study results.
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InterStim therapy provides a durable treatment effect from implant to 60 months.
Statistically significant treatment effects from baseline to 60 months were shown in both the cardinal symptoms of OAB (leaks and/or voids) and in QOL. In addition, the InSite study shows a safety profile for InterStim therapy that indicates low rates of serious device-related AEs and types of device-related AEs that are consistent with product labeling and published literature.
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Reference List
6.
7. 8.
9.
10.
11.
12.
13.
14. 15.
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5.
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4.
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3.
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2.
Coyne KS, Sexton CC, Thompson CL, et al. The prevalence of lower urinary tract symptoms (LUTS) in the USA, the UK andSweden: results from the Epidemiology of LUTS (EpiLUTS) study. BJU Int. 2009;104(3):352-360. doi:10.1111/j.1464-410X.2009.08427.x. Gormley EA, Lightner DJ, Faraday M, Vasavada SP. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline amendment. J Urol. 2015;193(5):15721580. doi:10.1016/j.juro.2015.01.087. Osman NI, Chapple CR. The management of overactive bladder syndrome: A review of the European Association of Urology Guidelines. Clin Pract. 2013;10(5):593-606. doi:10.2217/cpr.13.48. Mohee A, Khan A, Harris N, Eardley I. Long-term outcome of the use of intravesical botulinum toxin for thetreatment of overactive bladder (OAB). BJU International. 2013;111(1):106-113. doi:doi:10.1111/j.1464-410X.2012.11282.x. Peters KM, Carrico DJ, Wooldridge LS, Miller CJ, MacDiarmid SA. Percutaneous tibial nerve stimulation for the long-term treatment of overactive bladder: 3-year results of the STEP study. J Urol. 2013;189(6):2194-2201. doi:10.1016/j.juro.2012.11.175. Groenendijk PM, Lycklama A Nijeholt AAB, Ouwerkerk TJ, van den Hombergh U. Five-Year Follow-up After Sacral Neuromodulation: Single Center Experience. Neuromodulation. 2007;10(4):363-368. doi:10.1111/j.1525-1403.2007.00122.x . Peeters K, Sahai A, De Ridder D, Van Der Aa F. Long-term follow-up of sacral neuromodulation for lower urinary tract dysfunction. BJU Int. 2014;113(5):789-794. doi:10.1111/bju.12571. Marinkovic SP, Gillen LM, Marinkovic CM. Neuromodulation for Overactive Bladder Symptoms in Women Utilizing Either Motor or Sensory/Motor Provocation with a Minimum Nine-Year FollowUp. Neuromodulation. 2015;18(6):517-521. doi:10.1111/ner.12291. Kessler TM, Buchser E, Meyer S, et al. Sacral Neuromodulation for Refractory Lower Urinary Tract Dysfunction: Results of a Nationwide Registry in Switzerland. Eur Urol. 2007;51(5):13571363. doi:10.1016/j.eururo.2006.11.011. Sutherland SE, Lavers A, Carlson A, Holtz C, Kesha J, Siegel SW. Sacral nerve stimulation for voiding dysfunction: One institution’s 11-year experience. Neurourol Urodyn. 2007;26(1):19-28. doi:10.1002/nau.20345. Siegel S, Noblett K, Mangel J, et al. Results of a prospective, randomized, multicenter study evaluating sacral neuromodulation with InterStim therapy compared to standard medical therapy at 6-months in subjects with mild symptoms of overactive bladder. Neurourol Urodyn. 2015;34(3):224-230. doi:10.1002/nau.22544. Siegel S, Noblett K, Mangel J, et al. Three-year Follow-up Results of a Prospective, Multicenter Study in Overactive Bladder Subjects Treated With Sacral Neuromodulation. Urology. 2016;94:57-63. doi:10.1016/j.urology.2016.04.024. Noblett K, Siegel S, Mangel J, et al. Results of a prospective, multicenter study evaluating quality of life, safety, and efficacy of sacral neuromodulation at twelve months in subjects with symptoms of overactive bladder. Neurourol Urodyn. 2016;35(2):246-251. doi:10.1002/nau.22707. Coyne K, Revicki D, Hunt T, et al. Psychometric validation of an overactive bladder symptom and health-related quality of life questionnaire: the OAB-q. Qual Life Res. 2002;11(6):563-574. Frankel SJ, Donovan JL, Peters TI, et al. Sexual dysfunction in men with lower urinary tract symptoms. J Clin Epidemiol. 1998;51(8):677-685. https://libcontent.medtronic.com:2908/pubmed/9743316.
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1.
10
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21.
22.
23.
RI PT
SC
20.
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19.
TE D
18.
EP
17.
Jackson S, Donovan J, Brookes S, Eckford S, Swithinbank L, Abrams P. The Bristol Female Lower Urinary Tract Symptoms questionnaire: development and psychometric testing. Br J Urol. 1996;77(6):805-812. https://libcontent.medtronic.com:2908/pubmed/8705212. Beck AT, Steer RA, Brown GK. Manual for the Beck Depression Inventory II. San Antonio, TX: The Psychological Corporation; 1996. Amundsen CL, Richter HE, Menefee SA, et al. OnabotulinumtoxinA vs Sacral Neuromodulation on Refractory Urgency Urinary Incontinence in Women: A Randomized Clinical Trial. JAMA. 2016;316(13):1366-1374. doi:10.1001/jama.2016.14617. Noblett K, Berg KC, Kan F, Siegel S. Baseline Symptom Severity and Therapeutic Success in a Large Prospective Trial of Sacral Neuromodulation Therapy For Overactive Bladder Patients. FPMRS. In press. Van Kerrebroeck PEV, van Voskuilen AC, Heesakkers JPFA, et al. Results of sacral neuromodulation therapy for urinary voiding dysfunction: outcomes of a prospective, worldwide clinical study. J Urol. 2007;178(5):2029-2034. doi:10.1016/j.juro.2007.07.032. Noblett K, Benson K, Kreder K. Detailed analysis of adverse events and surgical interventions in a large prospective trial of sacral neuromodulation therapy for overactive bladder patients. Neurourol Urodyn. August 2016. doi:10.1002/nau.23076. Bertapelle MP, Vottero M, Del Popolo G, et al. Sacral neuromodulation and Botulinum toxin A for refractory idiopathic overactive bladder: a cost-utility analysis in the perspective of Italian Healthcare System. World J Urol. September 2014. doi:10.1007/s00345-014-1401-7. Hassouna MM, Sadri H. Economic evaluation of sacral neuromodulation in overactive bladder: A Canadian perspective. Can Urol Assoc J. 2015;9(7-8):242-247. doi:10.5489/cuaj.2711.
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Table 1. Baseline demographics Demographic
Total (n=272)
Gender 248 (91%)
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Female Male
24 (9%)
Race
243 (89%)
Black
19 (7%)
Asian/White
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White
1 (<1%)
American Indian or Alaska Native
Native Hawaiian or Other Pacific Islander Other
2 (<1%)
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American Indian or Alaska Native/White
1 (<1%)
1 (<1%) 5 (2%)
Primary Pre-study Diagnosis
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Urge Incontinence Urgency-Frequency Interstitial Cystitis
157 (58%) 110 (40%) 5 (2%)
OAB Qualification per Diary*
UI only
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UF only
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Both
Age at implant
Years since diagnosis
128 (47%) 74 (27%) 61 (22%) 57.0 ± 14.2 8.3 ± 9.9
OAB medications tried prior to implant† 1
60 (22%)
2
84 (31%)
3
56 (21%)
4-7
67 (25%)
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Baseline leaks/day‡
3.1 ± 2.7 (n=202) 1.7 ± 2.2 (n=202)
Urgency of leaks§
3.0 ± 0.8 (n=202)
Baseline voids/day‡
12.6 ± 4.5 (n=189)
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Pads replaced/day
Void volume/void (ml)¶
159.1 ± 87.1 (n=154)
Urgency of voids§
3.0 ± 0.5 (n=189)
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* Baseline qualification not available for 9 subjects. † Five subjects did not have medication use prior to implant (either a protocol deviation or a contraindication for OAB medication.) ‡ Leaks and voids include only those subjects who qualified for UI (leaks) or UF (voids) at baseline. A subject could qualify for both. § Urgency of each leak and void was rated on the following scale: 1=no urgency, 2=mild, 3=moderate, 4=severe. ¶Void volume was only summarized for subjects reporting volume on at least 50% of their voids.
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Figure 1. OAB therapeutic success rate over time
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Completers analyses included subjects with diary data at baseline and follow-up visits. N’s are the number of subjects included in the analysis at each visit. Panel A: OAB response was defined as either ≥50% improvement in leaks/day for UI subjects or ≥50% improvement in voids/day or a return to normal voiding frequency (<8 voids/day) for UF subjects.
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Panels B: UI response was defined as ≥50% improvement in leaks/day. Panel C: UF response was defined as ≥50% improvement in voids/day or a return to normal voiding frequency (<8
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voids/day).
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Figure 2. OABqol – Improvement from baseline over time
Baseline= 33.8 (Concern); 37.0 (Coping); 37.6 (Sleep); 62.8 (Social); 41.4 (HRQL).
HRQL total and all four subscales (Concern, Coping, Sleep, Social) showed greater improvement at follow-up visits
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compared to baseline (all p<0.0001). Error bars are 95% confidence intervals. MID=Minimally Important Difference. The MID is the smallest score change that is perceived beneficial to patients and is often used to determine whether changes in scores are considered clinically significant. been suggested to be 10 points.
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N’s are the numbers of subjects included in the analysis at each visit.
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The MID for the OABqol subscales has
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Figure 3. Urinary Symptom Interference
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OABqol – “Overall, how much do your urinary symptoms interfere with your everyday life?”
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N’s are the numbers of subjects included in the analysis at each visit.
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Frequently used abbreviations: OAB – overactive bladder UI – urinary incontinence
AE – adverse event QOL – quality of life
SNM - sacral neuromodulation PTNM - percutaneous tibial nerve modulation
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BoNT - intradetrusor onabotulinum toxin
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UF – urgency frequency
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ICIQ-OABqol - International Consultation on Incontinence Modular Questionnaire
S0022-5347(17)77099-1 10.1016/j.juro.2017.07.010 JURO 14849
To appear in: The Journal of Urology Accepted Date: 2 July 2017 Please cite this article as: Siegel S, Noblett K, Mangel J, Bennett J, Griebling TL, Sutherland SE, Bird ET, Comiter C, Culkin D, Zylstra S, Kan F, Berg KC, Five Year Follow-up Results of a Prospective, Multicenter Study in Overactive Bladder Subjects Treated with Sacral Neuromodulation, The Journal of Urology® (2017), doi: 10.1016/j.juro.2017.07.010. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.
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Five Year Follow-up Results of a Prospective, Multicenter Study in Overactive Bladder Subjects Treated with Sacral Neuromodulation
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Corresponding Author: Steven Siegel, MD Metro Urology, Woodbury, MN [email protected] Phone: 651-999-6800 Fax: 651-999-6830
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1. Metro Urology, Woodbury, MN 2. University of California, Riverside, CA 3. MetroHealth Medical Center, Cleveland, OH 4. Female Pelvic Medicine, Grand Rapids, MI 5. University of Kansas, Kansas City, KS 6. University of Washington, Seattle, WA 7. Scott and White Healthcare, Temple, TX 8. Stanford University, Stanford, CA 9. University of Oklahoma HSC, Oklahoma City, OK 10. Milford Regional Medical Center, Whitinsville, MA 11. Medtronic, Minneapolis, MN
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Steven Siegel1, Karen Noblett2, Jeffrey Mangel3, Jason Bennett4, Tomas L. Griebling5, Suzette E. Sutherland6, Erin T. Bird7, Craig Comiter8, Daniel Culkin9, Samuel Zylstra10, Fangyu Kan11, Kellie Chase Berg11
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Running Title: 5 Year Results of Sacral Neuromodulation for OAB ClinicalTrials.gov identifier: InSite for Overactive Bladder, NCT00547378
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Conflicts of Interest: Medtronic sponsored this study in full. Manuscript Word count: 2501 Keywords: overactive bladder, sacral neuromodulation, urinary incontinence, urgency frequency, quality of life
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Abstract Objective: To evaluate therapeutic success rate, changes in quality of life (QOL) and safety with sacral neuromodulation (SNM) at 5 years after InterStim™ implant. Subjects with bothersome
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symptoms of overactive bladder (OAB) including urinary urge incontinence (UI) and/or urgencyfrequency (UF), who had failed at least 1 anticholinergic medication and had at least 1 medication untried were included.
Methods: Therapeutic success was defined as a UI or UF response: ≥ 50% improvement in
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average leaks or voids/day or a return to normal voiding (<8 voids/day). QOL was evaluated using the International Consultation on Incontinence Modular Questionnaire (ICIQ-OABqol). Safety was evaluated through adverse events (AE).
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Results: Of the 340 subjects who completed test stimulation, 272 were implanted; 91% were female and mean age was 57 years. At baseline, UI subjects had 3.1±2.7 leaks/day (n=202); UF subjects had 12.6±4.5 voids/day (n=189). The 5 year therapeutic success rate was 67% (95% CI: 60%-74%) using the modified completers analysis and 82% (95% CI: 76-88%) using the completers analysis. UI subjects had a mean reduction from baseline of 2.0 ± 2.2 leaks/day; UF
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subjects had a mean reduction of 5.4 ± 4.3 voids/day (both p<0.0001, completers analysis). Subjects showed improvement in all measures of ICIQ-OABqol (p<0.0001). The most common device-related AEs were undesirable change in stimulation (60/272, 22%), implant site pain (40/272, 15%), and therapeutic product ineffective (36/272, 13%).
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Conclusions: This multicenter study shows that SNM has sustained efficacy and QOL
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improvements and an acceptable safety profile through 5 years in OAB subjects.
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INTRODUCTION Overactive bladder (OAB) is a common chronic condition which negatively impacts quality of life (QOL) of 10-30% of the population.1 Symptom control over long time periods is
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usually needed for satisfactory management. While treatments such as behavioral therapies, biofeedback, physical therapy, and oral medications are typically offered as first and second line remedies, a substantial proportion of patients continue to experience enough bother to seek further therapeutic options.2 Advanced treatment options including sacral neuromodulation (SNM), percutaneous tibial nerve modulation (PTNM) and intradetrusor onabotulinum toxin
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(BoNT) injection have been incorporated into treatment guidelines.2,3 Scarce data exist regarding the long-term efficacy for PTNM and BoNT beyond three years.4,5 While several
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papers have documented long term efficacy for SNM,6–10 most were single center, retrospective studies that either lacked rigorous analysis or were limited due to incomplete follow-up. The InSite study reflects current standard practices including minimally invasive techniques, routine use of fluoroscopy, and exclusive use of staged implantation of the tined lead. The InSite trial was designed to be implemented in two phases. Phase one was a
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prospective, multicenter, randomized trial comparing SNM to standard medical therapy at 6months.11 It provided level one evidence for the objective and subjective superiority of SNM over standard medical therapy among OAB patients who had previously had insufficient relief after trialing a median of 2 anticholinergic medications. The second phase was a prospective
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evaluation of safety and efficacy of SNM over 5 years. The primary objective of this portion of the study satisfied the FDA post-approval requirements to evaluate the tined lead. Results for
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subjects followed through 1 and 3 years have been previously reported.12,13 This manuscript represents the completion of the InSite trial at 5 years, including all subjects from both phases.
METHODS
Enrollment criteria and design were published previously.11–13 Subjects had a primary
diagnosis of OAB as demonstrated on a 3-day voiding diary with > 8 voids/day (urgency frequency, UF) and/or > 2 involuntary leaking episodes in 72 hours (urinary incontinence, UI). Subjects experienced previous treatment failure with at least one anticholinergic medication 3
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and had at least 1 medication untried. Institutional Review Boards approved the protocol and informed consent forms were signed prior to participation. All subjects underwent a staged implant procedure with the InterStim System (neurostimulator models 3023/3058, lead models
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3093/3889; Medtronic, Minneapolis, MN). Test stimulation success was defined as improvement from baseline: ≥50% improvement in average voids/day or a return to normal voiding (< 8 voids/day) for subjects with UF and 50% improvement in average leaks/day for subjects with UI. After completion of test stimulation, those who met success criteria were
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implanted with the neurostimulator.
Subjects returned for visits post-implant at 3 months, 6 months, 12 months, and yearly thereafter to 5 years. Electronic voiding diaries were used which allowed collection of real time
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OAB data. QOL was assessed using the validated International Consultation on Incontinence Modular Questionnaire (ICIQ)-OABqol which evaluated total health related QOL and 4 subscales (Concern, Coping, Sleep, and Social).14 Responses to the “interference” question on the OABqol measured how much urinary symptoms interfere with everyday activities. Other patient reported outcome tools used included the Male/Female Lower Urinary Track Symptoms-Sex
(VAS) for pelvic pain.
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(MLUTSsex15 and FLUTSsex16), Beck Depression Inventory II (BDI-II)17 and Visual Analog Scale
The primary safety objective was to demonstrate that the upper bound of the 95% confidence interval (CI) for the cumulative 5-year rate of adverse events (AE) related to the
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tined lead that required surgery was <33%. Device-related AEs were defined as those related to the implant procedure, therapy, device or implant site. A Clinical Events Committee reviewed
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and adjudicated all AEs.
Statistical Analyses
Various outcome measures were evaluated to determine 5-year efficacy of SNM,
including success rates (OAB, UI and UF subgroups) and absolute change (UI and UF) in leaking and voiding frequency from baseline and trends in these measures over time. Two analyses for success rate at 5 years were conducted. The first was a modified completers analysis evaluating all subjects who received a full system implant and had a baseline and 5-year evaluation, or 4
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withdrew early due to a device-related AE, or lack of efficacy resulting in explant. These early withdrawal subjects had their missing data imputed to their baseline assessment and were considered failures. Implanted subjects who withdrew for reasons unrelated to the device were
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excluded from the primary efficacy analysis. The second (sensitivity) analysis was a completers analysis and included all implanted subjects with diary data at baseline and 5 years. Descriptive statistics were reported and p-values for paired comparison between baseline and visits
through 5 years for leaking and voiding episodes/day were presented using a Wilcoxon signed-
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rank test. To assess the trend of efficacy over time, outcomes were evaluated for subjects with data available at baseline and each follow-up.
To assess QOL, data were analyzed as changes from baseline to follow-up visits. No
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data were imputed for missing values and descriptive statistics were reported. Withintreatment comparisons were made using a Wilcoxon signed-rank test. All subjects with device implant and the required outcome data at both baseline and follow-up visits were included. Published scoring criteria were followed for ICIQ-OABqol.14 “Overall, how much do your urinary symptoms interfere with your everyday life?” on the OABqol was measured on a scale from 0-
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10. A lower score was indicative of less OAB symptom interference. Based on the difference between scores at follow-up visits and baseline, percentages of subjects are reported in each category as follows: worsened: ≥2, no change: -1 to 1, improved: -4 to -2, and greatly improved: ≤ -5.
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Safety through 5 years was evaluated by reported AEs. The primary safety objective of 5-year AEs related to the tined lead that required surgery is reported as the Kaplan-Meier
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estimate of the survival function at 5 years with the 95% CI based on Greenwood standard error. Descriptive statistics were used to report the most common device-related AEs and surgical intervention rates. All statistical tests were examined for significance at the 0.05 level. The software package SAS (version 9.2, SAS Institute, Cary, NC) was used for all analyses.
RESULTS Overall 340 subjects received test stimulation and 272 (80%) subjects were implanted with the InterStim System. Baseline demographics are listed in Table 1. 5
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Using the modified completers analysis (n=183/272), the overall OAB response rate demonstrating therapeutic success was 67% at 5 years. The UI response rate was 64% for subjects characterized with UI at baseline. These subjects had an average reduction of 1.7 ± 2.1
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leaks/day as compared to baseline (p<0.0001). Complete continence at 5 years was achieved in 38% of subjects. For subjects with UF, a therapeutic response rate of 57% was observed.
These subjects had an average reduction of 4.4 ± 4.4 voids per day from baseline (p<0.0001). Using the completers analysis with no imputation of missing data (n=150/272), the
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overall OAB response rate demonstrating therapeutic success at 5 years was 82% (Figure 1). The UI response rate was 76% for subjects characterized with UI at baseline. These subjects had an average reduction of 2.0 ± 2.2 leaks/day as compared to baseline (p<0.0001). Complete
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continence at 5 years was achieved in 45% of subjects. For subjects with UF, a therapeutic response rate of 71% was observed. The mean reduction in voids/day was 5.4 ± 4.3 (p<0.0001). Response rates and mean reductions in leaks and voids show sustained efficacy of SNM through 5 years.
Sustained QOL improvements were reported from baseline to 5 years in all ICIQ-OABqol
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domains (all statistically significant with p<0.0001, Figure 2). At 5 years, 84% of subjects reported improved or greatly improved urinary symptom interference score (Figure 3). The impact on sexual function was evaluated using the MLUTSsex and FLUTSsex questionnaires. There was significant improvement from baseline to 5 years for females (p<0.0001, n=155) but
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no significant change for males was found which may be due to the small sample size (n=8). Depression, as measured by the BDI-II, significantly improved from baseline to 5 years
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(p<0.0001, n=168). The Visual Analog Scale (VAS) for pelvic pain was also significantly improved from baseline to 5 years (p<0.0001, n=166). Based on the 140 subjects who reached the 5-year visit and had programming data
available, 60.7% of the subjects were programmed to an amplitude less than 2 volts; the majority had a pulse width of 210 µsec; 63.6% had rate programmed to 14 hz and 67.9% were on continuous stimulation. The 5-year cumulative rate of AEs related to the tined lead that required surgery after full system implant was 22.4% (95% CI: 16.6%-27.7%), which fulfills the primary safety 6
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objective. There were no unanticipated adverse device effects. For subjects with a fully implanted system, undesirable change in stimulation was the most common AE occurring in 22% (60/272) of subjects, followed by implant site pain in 15% (40/272), and therapeutic
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product ineffective in 13% (36/272). All other device-related AEs occurring on or after implant were reported in less than 6% of subjects. One event was classified as serious: implant site erosion, which was resolved.
Surgical interventions including revision, replacement or permanent explant of any
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device component were also reported. A subject could experience multiple types of surgical interventions and an intervention could be due to multiple reasons such as AE, patient request, lack/loss of efficacy, or battery replacement. Eighty-four subjects (30.9%) had a surgical
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intervention due to an AE and 91 subjects (33.5%) had a surgical intervention due to battery replacement. In all 272 implanted subjects, the permanent explant rate was 19.1% (95% CI: 14.1%-23.9%) at 5 years. The top reason reported by investigators for permanent explant was due to an AE (11.0%, 30/272), most often for therapeutic product not effective (2.6%, 7/272). Other reasons include subject need for MRI, lack/loss of efficacy, and subject withdrew
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consent. A total of 8.5% (23/272) of permanent explants were associated with a lack or loss of efficacy. Ninety-one subjects (33.5%) had surgical interventions due to lack/loss of efficacy
DISCUSSION
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after full system implant.
OAB is a common, chronic condition that significantly impacts QOL. Therefore, it is
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important for a successful therapy to achieve substantial and sustained symptom relief. This prospective study demonstrates sustained efficacy and safety of SNM in OAB subjects after 5 years of treatment. The therapeutic success rate was 82% at 5 years and 85% at 1 year,13 which strongly demonstrates the long-term durability for SNM patients in clinical practice. The 60 month dry rate for the 118 UI patients was 45%, which is considerably higher than the dry rates at 6 months reported in the recent Rosetta trial comparing SNM to BoNT 200 units; 2% (N=174 patients) vs 20% (N= 190 patients), respectively.18 Speculations why include differences in analysis methods, the high rate of experience among InSite study implanters, predominant use 7
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of the 3889 lead vs the 3093 lead (extended number one electrode, now discontinued) that was exclusively used in the Rosetta trial, and the opportunity in InSite to adjust for sub-optimal responses via reprogramming or lead revision. The mean reduction in leaks and voids/day were
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2.0 and 5.4 at 60 months in the current study vs 3.3 and not reported in Rosetta at 6 months.18 The differences could be due to purposeful selection of patients with more severe UI in Rosetta (baseline mean of 5.4 leaks/day) and excluding those with UF only, in order to justify the BoNT treatment arm dose used. A sub-analysis of InSite patients showed that SNM was effective in
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treating both severe and less severe UI and UF at 12 and 24 months follow-up.19
Improvements in QOL, sexual function in female subjects, and pelvic pain measures were also sustained over 5 years. The rate of device-related AEs and surgical intervention
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remains significantly lower than previously published studies using older techniques and devices,20 but must be acknowledged as a consideration when evaluating candidates for this therapy. Investigators were required to report all device-related undesirable changes experienced in subjects regardless of the clinical significance. In addition, the Clinical Events Committee had a rigorous process for AE adjudication. The fact that one-third of the device-
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related AEs occurred within the first 12 months of implant may suggest that further refinements of lead placement technique or patient selection could result in improvements in safety profile.2120 During the long follow-up of 5 years, more subjects chose to replace their device rather than have it permanently explanted. Most AEs were minor and could be treated
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with non-invasive measures. Over time, it is expected that all the subjects who have been successfully managed will need device replacements to maintain benefit due to the nature of
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treatment and the underlying chronic condition. Most surgical interventions were performed to allow for continuation of the therapy. Of all implanted subjects, less than 20% underwent permanent explant for various reasons including AEs, patient request, or lack/loss of efficacy. Few studies have published outcome data or continuation rates of other advanced OAB
treatments beyond 36 months. In the multicenter STEP study,5 50 out of 60 subjects were enrolled and outcomes for PTNM were documented for a total of 29 (58%) subjects at 36 months. Although only a small number of subjects were included, PTNM showed safety with sustained improvements after 3 years. In a single-center study measuring long-term outcome of 8
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of BoNT for the treatment of OAB, 137 out of 268 subjects were followed for ≥36 months.4 In that study, 61.3% had discontinued therapy by 36 months, which included initial therapy failures. The main reasons for discontinuation from the study were tolerability issues including
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the need for intermittent catheterization and urinary tract infections. Initial costs are predictably lower for PTNM and BoNT versus SNM. To be more cost effective, it is necessary for SNM to provide long-term benefit. Previous studies have shown SNM becomes more cost effective compared to BoNT after 3-5 years, indicating SNM may be
technological advances including longer lasting batteries.
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comparatively cost saving in the long term.22, 23 This advantage could be magnified with
The strengths of the InSite study include the large number of subjects with protocol-
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mandated follow-up, and the rigorous modified completer analysis including subjects withdrawn for lack of benefit or device-related complications as failures. Additionally, the private practice and academic centers contributing subjects reflect real-world experience with the therapy, and thus the results are more generalizable. Limitations include the homogeneous population, with a minority of male subjects, which could detract from generalizability.
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Furthermore, centers could follow individual protocols regarding perioperative antibiotics, lead choice, and procedure techniques. Although this approximates what is occurring in general practice with SNM therapy, this lack of standardization along with the potential impact on infection rates, device-related complications, and ultimate therapy success or failure rates may
CONCLUSION
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have impacted overall study results.
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InterStim therapy provides a durable treatment effect from implant to 60 months.
Statistically significant treatment effects from baseline to 60 months were shown in both the cardinal symptoms of OAB (leaks and/or voids) and in QOL. In addition, the InSite study shows a safety profile for InterStim therapy that indicates low rates of serious device-related AEs and types of device-related AEs that are consistent with product labeling and published literature.
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Reference List
6.
7. 8.
9.
10.
11.
12.
13.
14. 15.
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5.
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4.
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3.
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2.
Coyne KS, Sexton CC, Thompson CL, et al. The prevalence of lower urinary tract symptoms (LUTS) in the USA, the UK andSweden: results from the Epidemiology of LUTS (EpiLUTS) study. BJU Int. 2009;104(3):352-360. doi:10.1111/j.1464-410X.2009.08427.x. Gormley EA, Lightner DJ, Faraday M, Vasavada SP. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline amendment. J Urol. 2015;193(5):15721580. doi:10.1016/j.juro.2015.01.087. Osman NI, Chapple CR. The management of overactive bladder syndrome: A review of the European Association of Urology Guidelines. Clin Pract. 2013;10(5):593-606. doi:10.2217/cpr.13.48. Mohee A, Khan A, Harris N, Eardley I. Long-term outcome of the use of intravesical botulinum toxin for thetreatment of overactive bladder (OAB). BJU International. 2013;111(1):106-113. doi:doi:10.1111/j.1464-410X.2012.11282.x. Peters KM, Carrico DJ, Wooldridge LS, Miller CJ, MacDiarmid SA. Percutaneous tibial nerve stimulation for the long-term treatment of overactive bladder: 3-year results of the STEP study. J Urol. 2013;189(6):2194-2201. doi:10.1016/j.juro.2012.11.175. Groenendijk PM, Lycklama A Nijeholt AAB, Ouwerkerk TJ, van den Hombergh U. Five-Year Follow-up After Sacral Neuromodulation: Single Center Experience. Neuromodulation. 2007;10(4):363-368. doi:10.1111/j.1525-1403.2007.00122.x . Peeters K, Sahai A, De Ridder D, Van Der Aa F. Long-term follow-up of sacral neuromodulation for lower urinary tract dysfunction. BJU Int. 2014;113(5):789-794. doi:10.1111/bju.12571. Marinkovic SP, Gillen LM, Marinkovic CM. Neuromodulation for Overactive Bladder Symptoms in Women Utilizing Either Motor or Sensory/Motor Provocation with a Minimum Nine-Year FollowUp. Neuromodulation. 2015;18(6):517-521. doi:10.1111/ner.12291. Kessler TM, Buchser E, Meyer S, et al. Sacral Neuromodulation for Refractory Lower Urinary Tract Dysfunction: Results of a Nationwide Registry in Switzerland. Eur Urol. 2007;51(5):13571363. doi:10.1016/j.eururo.2006.11.011. Sutherland SE, Lavers A, Carlson A, Holtz C, Kesha J, Siegel SW. Sacral nerve stimulation for voiding dysfunction: One institution’s 11-year experience. Neurourol Urodyn. 2007;26(1):19-28. doi:10.1002/nau.20345. Siegel S, Noblett K, Mangel J, et al. Results of a prospective, randomized, multicenter study evaluating sacral neuromodulation with InterStim therapy compared to standard medical therapy at 6-months in subjects with mild symptoms of overactive bladder. Neurourol Urodyn. 2015;34(3):224-230. doi:10.1002/nau.22544. Siegel S, Noblett K, Mangel J, et al. Three-year Follow-up Results of a Prospective, Multicenter Study in Overactive Bladder Subjects Treated With Sacral Neuromodulation. Urology. 2016;94:57-63. doi:10.1016/j.urology.2016.04.024. Noblett K, Siegel S, Mangel J, et al. Results of a prospective, multicenter study evaluating quality of life, safety, and efficacy of sacral neuromodulation at twelve months in subjects with symptoms of overactive bladder. Neurourol Urodyn. 2016;35(2):246-251. doi:10.1002/nau.22707. Coyne K, Revicki D, Hunt T, et al. Psychometric validation of an overactive bladder symptom and health-related quality of life questionnaire: the OAB-q. Qual Life Res. 2002;11(6):563-574. Frankel SJ, Donovan JL, Peters TI, et al. Sexual dysfunction in men with lower urinary tract symptoms. J Clin Epidemiol. 1998;51(8):677-685. https://libcontent.medtronic.com:2908/pubmed/9743316.
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1.
10
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21.
22.
23.
RI PT
SC
20.
M AN U
19.
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18.
EP
17.
Jackson S, Donovan J, Brookes S, Eckford S, Swithinbank L, Abrams P. The Bristol Female Lower Urinary Tract Symptoms questionnaire: development and psychometric testing. Br J Urol. 1996;77(6):805-812. https://libcontent.medtronic.com:2908/pubmed/8705212. Beck AT, Steer RA, Brown GK. Manual for the Beck Depression Inventory II. San Antonio, TX: The Psychological Corporation; 1996. Amundsen CL, Richter HE, Menefee SA, et al. OnabotulinumtoxinA vs Sacral Neuromodulation on Refractory Urgency Urinary Incontinence in Women: A Randomized Clinical Trial. JAMA. 2016;316(13):1366-1374. doi:10.1001/jama.2016.14617. Noblett K, Berg KC, Kan F, Siegel S. Baseline Symptom Severity and Therapeutic Success in a Large Prospective Trial of Sacral Neuromodulation Therapy For Overactive Bladder Patients. FPMRS. In press. Van Kerrebroeck PEV, van Voskuilen AC, Heesakkers JPFA, et al. Results of sacral neuromodulation therapy for urinary voiding dysfunction: outcomes of a prospective, worldwide clinical study. J Urol. 2007;178(5):2029-2034. doi:10.1016/j.juro.2007.07.032. Noblett K, Benson K, Kreder K. Detailed analysis of adverse events and surgical interventions in a large prospective trial of sacral neuromodulation therapy for overactive bladder patients. Neurourol Urodyn. August 2016. doi:10.1002/nau.23076. Bertapelle MP, Vottero M, Del Popolo G, et al. Sacral neuromodulation and Botulinum toxin A for refractory idiopathic overactive bladder: a cost-utility analysis in the perspective of Italian Healthcare System. World J Urol. September 2014. doi:10.1007/s00345-014-1401-7. Hassouna MM, Sadri H. Economic evaluation of sacral neuromodulation in overactive bladder: A Canadian perspective. Can Urol Assoc J. 2015;9(7-8):242-247. doi:10.5489/cuaj.2711.
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Table 1. Baseline demographics Demographic
Total (n=272)
Gender 248 (91%)
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Female Male
24 (9%)
Race
243 (89%)
Black
19 (7%)
Asian/White
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White
1 (<1%)
American Indian or Alaska Native
Native Hawaiian or Other Pacific Islander Other
2 (<1%)
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American Indian or Alaska Native/White
1 (<1%)
1 (<1%) 5 (2%)
Primary Pre-study Diagnosis
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Urge Incontinence Urgency-Frequency Interstitial Cystitis
157 (58%) 110 (40%) 5 (2%)
OAB Qualification per Diary*
UI only
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UF only
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Both
Age at implant
Years since diagnosis
128 (47%) 74 (27%) 61 (22%) 57.0 ± 14.2 8.3 ± 9.9
OAB medications tried prior to implant† 1
60 (22%)
2
84 (31%)
3
56 (21%)
4-7
67 (25%)
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Baseline leaks/day‡
3.1 ± 2.7 (n=202) 1.7 ± 2.2 (n=202)
Urgency of leaks§
3.0 ± 0.8 (n=202)
Baseline voids/day‡
12.6 ± 4.5 (n=189)
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Pads replaced/day
Void volume/void (ml)¶
159.1 ± 87.1 (n=154)
Urgency of voids§
3.0 ± 0.5 (n=189)
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* Baseline qualification not available for 9 subjects. † Five subjects did not have medication use prior to implant (either a protocol deviation or a contraindication for OAB medication.) ‡ Leaks and voids include only those subjects who qualified for UI (leaks) or UF (voids) at baseline. A subject could qualify for both. § Urgency of each leak and void was rated on the following scale: 1=no urgency, 2=mild, 3=moderate, 4=severe. ¶Void volume was only summarized for subjects reporting volume on at least 50% of their voids.
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Figure 1. OAB therapeutic success rate over time
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B.
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Completers analyses included subjects with diary data at baseline and follow-up visits. N’s are the number of subjects included in the analysis at each visit. Panel A: OAB response was defined as either ≥50% improvement in leaks/day for UI subjects or ≥50% improvement in voids/day or a return to normal voiding frequency (<8 voids/day) for UF subjects.
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Panels B: UI response was defined as ≥50% improvement in leaks/day. Panel C: UF response was defined as ≥50% improvement in voids/day or a return to normal voiding frequency (<8
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voids/day).
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Figure 2. OABqol – Improvement from baseline over time
Baseline= 33.8 (Concern); 37.0 (Coping); 37.6 (Sleep); 62.8 (Social); 41.4 (HRQL).
HRQL total and all four subscales (Concern, Coping, Sleep, Social) showed greater improvement at follow-up visits
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compared to baseline (all p<0.0001). Error bars are 95% confidence intervals. MID=Minimally Important Difference. The MID is the smallest score change that is perceived beneficial to patients and is often used to determine whether changes in scores are considered clinically significant. been suggested to be 10 points.
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N’s are the numbers of subjects included in the analysis at each visit.
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The MID for the OABqol subscales has
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Figure 3. Urinary Symptom Interference
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OABqol – “Overall, how much do your urinary symptoms interfere with your everyday life?”
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N’s are the numbers of subjects included in the analysis at each visit.
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Frequently used abbreviations: OAB – overactive bladder UI – urinary incontinence
AE – adverse event QOL – quality of life
SNM - sacral neuromodulation PTNM - percutaneous tibial nerve modulation
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BoNT - intradetrusor onabotulinum toxin
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UF – urgency frequency
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ICIQ-OABqol - International Consultation on Incontinence Modular Questionnaire