- Email: [email protected]
Three-year Follow-up Results of a Prospective, Multicenter Study in Overactive Bladder Subjects Treated With Sacral Neuromodulation
ARTICLE IN PRESS
Female Urology, Urodynamics, Incontinence, and Pelvic Floor Reconstructive Surgery Three-year Follow-up Results of a Prospective, Multicenter Study in Overactive Bladder Subjects Treated With Sacral Neuromodulation Steven Siegel, Karen Noblett, Jeffrey Mangel, Tomas L. Griebling, Suzette E. Sutherland, Erin T. Bird, Craig Comiter, Daniel Culkin, Jason Bennett, Samuel Zylstra, Fangyu Kan, and Elizabeth Thiery OBJECTIVE
METHODS
RESULTS
CONCLUSION
To evaluate the therapeutic success rate, and changes in quality of life (QOL) and safety in subjects using sacral neuromodulation (InterStim System) at 36 months. Subjects with bothersome symptoms of overactive bladder (OAB) including urinary urge incontinence (UI) and/or urgency frequency (UF), who had failed at least 1 anticholinergic medication, and had at least 1 untried medication were included. Subjects with successful test stimulation received an InterStim implant. Therapeutic success and quality of life through 36 months was evaluated in implanted subjects with data at baseline and follow-up. Safety was evaluated using reported adverse events. A total of 340 subjects received test stimulation resulting in 272 implanted subjects. Demographics include 91% female, mean age of 57 years, and baseline symptom severity of 3.1 ± 2.7 leaks/ day (UI) and 12.6 ± 4.5 voids/day (UF). The analysis showed an OAB therapeutic success rate of 83% (95% confidence interval: 78%-88%). UI subjects had a mean reduction from baseline of 2.3 ± 2.3 leaks/day whereas UF subjects had a mean reduction of 5.3 ± 4.0 voids/day (both P < .0001). Statistically significant improvements were observed in all measures of the International Consultation on Incontinence Modular Questionnaire-OABqol (all P < .0001). Eighty percent of subjects reported improvements in their urinary symptom interference. Device-related adverse events occurred in 47% (127/272) of subjects post-implant; 91% were resolved at the time of this analysis. The 36-month follow-up data from the multicenter study demonstrate sustained safety, effectiveness, and improved QOL in subjects implanted with InterStim, without requiring failure of all medications. UROLOGY ■■: ■■–■■, 2016. © 2016 Elsevier Inc.
Financial Disclosure: Steven Siegel is a patent holder at MDT, BSI, and QIG; and has received consulting fees from MDT, Allergan, and NuVectra, and speaking fee/ proctor from MDT and QIG. He has also contracted research for MDT and IPSEN. Karen Noblett received consulting fees from MDT, Axonics, and speaking fee/proctor from MDT and BSI. She also contracted research for MDT. Suzette E. Sutherland is a study investigator for Medtronic and Allergan, and a paid consultant for Medtronic, Allergan, and Axonics. Jason Bennett is a study investigator and consultant for Medtronic, and a consultant for Intuitive. Fangyu Kan and Elizabeth Thiery are employees of Medtronic. The remaining authors declare that they have no relevant financial interests. Funding Support: Medtronic, Inc., sponsored this study in full. ClinicalTrials.gov identifier: InSite for Overactive Bladder, NCT00547378. From the Metro Urology, Woodbury, MN; the University of California, Riverside, CA; the MetroHealth Medical Center, Cleveland, OH; the University of Kansas, Kansas City, KS; the University of Washington, Seattle, WA; the Scott and White Healthcare, Temple, TX; the Stanford University, Stanford, CA; the University of Oklahoma HSC, Oklahoma City, OK; the Female Pelvic Medicine, Grand Rapids, MI; the Milford Regional Medical Center, Whitinsville, MA; and the Medtronic, Inc., Minneapolis, MN Address correspondence to: Steven Siegel, M.D., Metro Urology, Woodbury, MN. E-mail: [email protected] Submitted: January 11, 2016, accepted (with revisions): April 19, 2016
© 2016 Elsevier Inc. All rights reserved.
S
ince its initial Food and Drug Administration approval for urge incontinence, urinary frequency, and urgency in 1997, InterStim, which delivers sacral neuromodulation (SNM), has become a standard of care and has been increasingly adopted around the world. With nearly 200,000 implants performed, the therapy has been incorporated into societal guidelines for the management of overactive bladder (OAB).1 Because OAB is a chronic condition requiring ongoing care over many years, a successful treatment with both enduring results and long term follow-up are critical to understand the relevant factors in weighing the risks and benefits of SNM vs other available third-line options. The InSite trial was designed to be implemented in two phases. Phase one was a prospective, multicenter, randomized trial comparing SNM to standard medical therapy with http://dx.doi.org/10.1016/j.urology.2016.04.024 0090-4295
1
ARTICLE IN PRESS a 6-month follow-up period.2 It provided level-1 evidence for the objective and subjective superiority of SNM over standard medical therapy among OAB refractory patients, and also confirmed the safety of currently used devices and techniques for SNM. The second phase of the InSite trial is a prospective evaluation of the safety and efficacy of SNM in 5 years. The primary objective of this portion of the study satisfies the Food and Drug Administrationmandated postapproval requirements to evaluate the longterm safety and effectiveness of the tined lead. Additional objectives include an estimation of lead migration and infection rates at 5 years, therapy success, quality of life (QOL), and sexual function outcomes. Results for subjects followed through 12 months have been previously reported.3 The objective of the current analysis is to describe results from the 36-month follow-up that includes all implanted subjects from both phases.
METHODS Enrollment criteria and design were published previously.2,3 Subjects had a primary diagnosis of OAB as demonstrated on a 3-day voiding diary demonstrating ≥ 8 voids per day (urgency frequency, UF) and/or ≥ 2 involuntary leaking episodes in 72 hours (urinary incontinence, UI). Institutional Review Boards approved the protocol and informed consent forms were signed prior to participation in study activities. All subjects underwent a staged implant procedure with the InterStim System (neurostimulator models 3023/3058, lead models 3093/ 3889; Medtronic, Inc., Minneapolis, MN). Test stimulation success was defined as improvement from baseline, specifically 50% or greater improvement in average voids/ day or a return to normal voiding (<8 voids/day) for subjects with UF, and 50% improvement in average leaks per day for subjects with UI. After successful completion of the test stimulation phase, those subjects who met criteria for success were implanted with the neurostimulator. Subjects returned for follow-up visits postimplant at 3 months, 6 months, 12 months, and yearly thereafter for 5 years. Electronic voiding diaries were used at study visits, which allowed collection of real-time OAB data. QOL was assessed using the validated International Consultation on Incontinence Modular Questionnaire (ICIQ)-OABqol that evaluated total health-related QOL and 4 subscales (Concern, Coping, Sleep, and Social).4 The ICIQ-OABqol provides a detailed, robust measure of OAB symptoms and the correlating impact on quality of life. Responses to the “interference” question on the OABqol measured how much urinary symptoms interfere with everyday activities overall. Other QOL and sexual function tools used include the Male/Female Lower Urinary Track Symptoms-Sex (MLUTSsex5 and FLUTSsex6), Beck Depression Inventory II (BDI-II),7 and visual analog scale for pelvic pain. All adverse events (AE) (serious and nonserious) were reported. The results section will detail an overview of device-related AEs, defined as events related to the implant procedure, therapy, device, or implant site. A Clinical Events 2
Committee consisting of 3 physicians experienced in SNM reviewed and adjudicated all AEs. This paper reports the results for all implanted subjects up to 3 years. Subjects will continue to be followed for 5 years to collect additional long-term data. Statistical Analyses Various outcome measures were evaluated to determine the 36-month 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. Descriptive statistics were reported for these measures, and P values for paired comparison between follow-up visits through 36 months and baseline in terms of leaking and voiding episodes per day were presented using a Wilcoxon signed-rank test. Two analyses for efficacy at 36 months were conducted. The first analysis is a Modified Completers analysis evaluating all subjects who received a full system implant and either had a baseline and 36-month evaluation, or 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 therefore considered failures. Implanted subjects who withdrew for reasons unrelated to the device were excluded from the primary efficacy analysis. The second sensitivity analysis is a Completers analysis and includes all implanted subjects with diary data at baseline and at 36 months. To assess the trend of efficacy over time, outcomes were evaluated for subjects with data available at baseline and at each follow-up. To assess QOL, data through 36 months were analyzed as changes from baseline to follow-up visits. No data were imputed for missing values. Descriptive statistics were reported for these measures. Within-treatment comparisons were made using a Wilcoxon signed-rank test. All subjects that had device implant and the required outcome data at both baseline and follow-up visits through 36 months were included. Published scoring criteria were followed for ICIQ-OABqol.4 “Overall, how much do your urinary symptoms interfere with your everyday life?” on the OABqol was measured on a scale from 0 to 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. 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 subjects were implanted with the InterStim System. Baseline demographics are listed in Supplementary Table S1. Subjects had tried a median of 2 OAB medications prior to full system implant. On average, UI subjects had 3.1 ± 2.7 leaks/day; UF subjects had 12.6 ± 4.5 voids/day at baseUROLOGY ■■ (■■), 2016
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Figure 2. Leaks reduction for UI and voids reduction for UF over time. In both A and B, error bars represent 95% confidence intervals. ***P < .0001. OAB, overactive bladder; UF, urgency frequency; UI, urinary incontinence.
Figure 1. OAB therapeutic success rate over time. Analyses included subjects with diary data at baseline and followup visits (3 months, 6 months, 12 months, 24 months, 36 months). (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. (B) UI response was defined as ≥50% improvement in leaks/day. (C) UF response was defined as ≥50% improvement in voids/day or a return to normal voiding frequency (<8 voids/day).
line. There were 217 subjects followed up until 36 months, with 193 subjects with a voiding diary at baseline and at 36 months. Seventeen subjects who discontinued prior to 36 months due to a device-related AE or lack of efficacy resulting in a full system explant had their 36-month data imputed to their baseline assessment in Modified Completers analysis. Using the Modified Completers analysis, the overall OAB response rate demonstrating therapeutic success was 79% at 24 months and 76% at 36 months. The UI response rate was 76% for subjects characterized with UI at baseline. These subjects had an average reduction of 2.1 ± 2.3 leaks per day as compared to baseline (P < .0001). Complete continence at 36 months was achieved in 43% of subjects. For subjects with UF, a therapeutic response rate of 64% was observed. These subjects had an average of reduction of 4.8 ± 4.1 voids per day from baseline (P < .0001). Using the Completers analysis with no imputation of missing data, the overall OAB response rate demonstrating therapeutic success at 36 months was 83% (Fig. 1). The UROLOGY ■■ (■■), 2016
UI response rate was 82% for subjects characterized with UI at baseline. These subjects had an average reduction of 2.3 ± 2.3 leaks per day as compared to baseline (P < .0001, Fig. 2). Complete continence at 36 months was achieved in 46% of subjects. For subjects with UF, a therapeutic response rate of 70% was observed. The mean reduction in voids per day was 5.3 ± 4.0 (P < .0001). Response rates and mean reductions in leaks and voids show sustained efficacy of SNM through 36 months. QOL data were available on 208 subjects at 36 months. Sustained QOL improvements were reported from baseline to 36 months in all ICIQ-OABqol domains (all statistically significant with P < .0001, Fig. 3). At 36 months, 80% of subjects reported improved or greatly improved urinary symptom interference score that is consistent with the results reported at 3 months postimplant (Fig. 4). Sexual matters were evaluated through the MLUTSsex and FLUTSsex questionnaires. There was significant improvement from baseline to 36 months for females (P < .0001) but no significant change for males was found, which could be due to the small sample size. Depression, as measured by the BDI-II, significantly improved from baseline to 36 months (P < .0001). The visual analog scale for pelvic pain was also significantly improved from baseline to 36 months (P < .0001). There were no unanticipated adverse device effects. As previously reported3, the device-related AE rate was 16% (56/340) for subjects with a lead placed during the test stimulation phase, with 3 of the AEs classified as serious: implant site infection, skin infection, and respiratory arrest during surgery. From neurostimulator implant through the 36-month visit, device-related AEs were reported in 47% of subjects (127/272); 91% of these were resolved at the 3
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Figure 3. OABqol—Improvement from baseline over time. Baseline = 33.84 (Concern); 37.00 (Coping); 37.61 (Sleep); 62.75 (Social); 41.39 (HRQL). HRQL total and all four subscales (Concern, Coping, Sleep, Social) showed greater improvement at follow-up visits compared to baseline (all P < .0001). Error bars are 95% confidence intervals. 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.8 The MID for the OABqol subscales has been suggested to be 10 points. MID, minimally important difference.
Figure 4. Urinary symptom interference. OABqol—“Overall, how much do your urinary symptoms interfere with your everyday life?”
time of analysis. One event was classified as serious: implant site erosion, which was resolved at the time of analysis. The most frequent AE types reported were undesirable change in stimulation (49/272, 18%), implant site pain (34/272, 13%), and therapeutic product ineffective (16/272, 6%). Lead migrations were reported in 4% of subjects (12/ 272), with the majority of lead migrations reported between 12 and 24 months postimplant. Implant site infections were reported in 4% of implanted subjects (10/272), with half reported between the implant procedure and 3 months postimplant. Surgical interventions including revision, replacement, or permanent explant on any 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 and/ or loss of efficacy, or battery replacement. Surgical 4
interventions related to the neurostimulator, lead, or chronic extension were experienced in 32% of subjects (86/272) after implant. The rate of device replacement was 20% (55/ 272) and device revision was 4% (11/272). Surgical interventions due to battery replacement occurred in 11% (29/272) of subjects, and 93% (27/29) of these neurostimulators were assessed to be within the expected longevity ranges based on the set parameters of the device. Not enough information was available to determine longevity status on the remaining 2 neurostimulators. In total, 13% (34/272) of subjects underwent permanent explant. The top reason reported by investigators for permanent explant was due to an AE (8%). Other reasons include subject’s need for magnetic resonance imaging, lack and/or loss of efficacy, subject withdrew consent, and other. Only 3% (9/272) of permanent explants were associated with a lack or loss of efficacy. UROLOGY ■■ (■■), 2016
ARTICLE IN PRESS DISCUSSION OAB is a chronic condition that must be managed successfully over time to provide meaningful benefit. This prospective study demonstrates sustained safety and efficacy of SNM in OAB subjects after 36 months of treatment and will continue to follow study subjects up to 60 months. There is minimal drop-off in therapeutic success when compared to results at 1 year.3 Improvements in QOL, sexual function in female subjects, and pelvic pain measures were sustained. The rate of device-related AE (47%) and surgical intervention (32%) remains significantly lower than previously published studies using older techniques and devices,9 but still must be acknowledged as a consideration when evaluating candidates for this therapy. The majority of surgical interventions were due to replacements of the neurostimulator, lead and/or chronic extension, rather than cessation of the 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 adjudication of all AEs. The fact that a third of the device-related AEs up to 36 months occurred within the first 12 months of implant implies that further refinements of technique or patient selection could result in significant reductions.10 These refinements include methods to optimize lead placement, which were not as well understood or uniformly employed by the implanters in this study. By 36 months, 11% of subjects required battery replacement due to depletion. Over time, it is likely that all of the subjects who have been successfully managed will need device replacements to maintain benefit due to the nature of treatment. Of all implanted subjects, 13% underwent permanent explant for various reasons, indicating probable abandonment of the therapy. Few studies have published data regarding other advanced OAB treatments at 36 months or beyond. In the multicenter STEP study,11 50 out of 60 subjects were enrolled and outcomes for percutaneous tibial nerve stimulation were documented for a total of 29 (58%) subjects at 36 months. Although only a small number of subjects were included, percutaneous tibial nerve stimulation showed safety with sustained improvements after 3 years. In a singlecenter, long-term study measuring the long-term outcome of the use of intravesical botulinum toxin (BoNT) for the treatment of OAB, 137 out of 268 subjects were followed for ≥36 months.12 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 the need for intermittent catheterization and urinary tract infections. Based on published literature, the long-term benefit of the therapy of SNM is also significant when considering cost-effectiveness. Although the initial cost of treatment is clearly greater for SNM compared to intravesical BoNT or percutaneous tibial nerve stimulation, studies have demonstrated that SNM becomes more cost-effective over time. In a study evaluating cost-effectiveness of SNM vs optimal medical therapy and intravesical BoNT in the Canadian UROLOGY ■■ (■■), 2016
healthcare system, SNM became cost-effective and dominated (ie, became more effective and less costly) in comparison to BoNT during the first 5 years. 13 Another cost-utility analysis from the Italian healthcare system confirmed that SNM appeared to be cost effective from 3 years onwards.14 They concluded that SNM may be considered cost-effective in the midterm and cost saving in the long term. These findings underscore the importance of maintained SNM therapy benefit over the 3 to 5-year time frame relative to cost-effectiveness. The strengths of the InSite study include the large number of subjects with protocol-mandated follow-up, and the rigorous modified completer analysis with ongoing inclusion of subjects withdrawn for lack of benefit or devicerelated complications as failures. Additionally, the private practice and academic centers contributing subjects reflect real-world experience with the therapy, and thus the results are likely applicable to real-world use. The weaknesses of this InSite study include the homogeneous population, with a minority of male subjects, which could detract from generalizability. Furthermore, centers were allowed to 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 have impacted overall study results.
CONCLUSION The InSite trial is an ongoing, large, prospective multicenter study designed to evaluate the long-term safety and efficacy of SNM for subjects with refractory symptoms of OAB. This paper reports the results after 3 years of therapy, demonstrating that implanted subjects maintained improvements in OAB symptoms and QOL. Whereas the rate of AEs and the need for reoperation are acknowledged concerns related to this therapy, they are reduced compared to prior studies. References 1. 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;193:1572-1580. 2. 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;34:224-230. 3. 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;35:246-251. doi:10.1002/ nau.22707. 4. 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;11:563-574. 5. Frankel SJ, Donovan JL, Peters TI, et al. Sexual dysfunction in men with lower urinary tract symptoms. J Clin Epidemiol. 1998;51:677685.
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ARTICLE IN PRESS 6. 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;77:805812. 7. Beck AT, Steer RA, Brown GK. Manual for the Beck Depression Inventory II. San Antonio, TX: The Psychological Corporation; 1996. 8. Jaeschke R, Singer J, Guyatt GH. Measurement of health status. Ascertaining the minimal clinically important difference. Control Clin Trials. 1989;10:407-415. 9. van Kerrebroeck PE, van Voskuilen AC, Heesakkers JP, et al. Results of sacral neuromodulation therapy for urinary voiding dysfunction: outcomes of a prospective, worldwide clinical study. J Urol. 2007;178:2029-2034. 10. Noblett K, Benson K, Kreder K. Detailed analysis of adverse events and surgical intervention in a large prospective trial of sacral neuromodulation therapy for overactive bladder patients. Neurourol Urodyn. 2015;34:S237. [Abstract]. 11. Peters KM, Carrico DJ, Wooldridge LS, Miller CJ, MacDiarmid SA. Percutaneous tibial nerve stimulation for the long-term treatment
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of overactive bladder: 3-year results of the STEP study. J Urol. 2013;189:2194-2201. 12. Mohee A, Khan A, Harris N, Eardley I. Long-term outcome of the use of intravesical botulinum toxin for the treatment of overactive bladder (OAB). BJU Int. 2013;111:106-113. 13. Hassouna MM, Sadri H. Economic evaluation of sacral neuromodulation in overactive bladder: a Canadian perspective. Can Urol Assoc J. 2015;9:242-247. 14. Bertapelle MP, Vottero M, Popolo GD, 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. 2015;33:1109-1117.
APPENDIX SUPPLEMENTARY DATA
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.urology .2016.04.024.
UROLOGY ■■ (■■), 2016
Female Urology, Urodynamics, Incontinence, and Pelvic Floor Reconstructive Surgery Three-year Follow-up Results of a Prospective, Multicenter Study in Overactive Bladder Subjects Treated With Sacral Neuromodulation Steven Siegel, Karen Noblett, Jeffrey Mangel, Tomas L. Griebling, Suzette E. Sutherland, Erin T. Bird, Craig Comiter, Daniel Culkin, Jason Bennett, Samuel Zylstra, Fangyu Kan, and Elizabeth Thiery OBJECTIVE
METHODS
RESULTS
CONCLUSION
To evaluate the therapeutic success rate, and changes in quality of life (QOL) and safety in subjects using sacral neuromodulation (InterStim System) at 36 months. Subjects with bothersome symptoms of overactive bladder (OAB) including urinary urge incontinence (UI) and/or urgency frequency (UF), who had failed at least 1 anticholinergic medication, and had at least 1 untried medication were included. Subjects with successful test stimulation received an InterStim implant. Therapeutic success and quality of life through 36 months was evaluated in implanted subjects with data at baseline and follow-up. Safety was evaluated using reported adverse events. A total of 340 subjects received test stimulation resulting in 272 implanted subjects. Demographics include 91% female, mean age of 57 years, and baseline symptom severity of 3.1 ± 2.7 leaks/ day (UI) and 12.6 ± 4.5 voids/day (UF). The analysis showed an OAB therapeutic success rate of 83% (95% confidence interval: 78%-88%). UI subjects had a mean reduction from baseline of 2.3 ± 2.3 leaks/day whereas UF subjects had a mean reduction of 5.3 ± 4.0 voids/day (both P < .0001). Statistically significant improvements were observed in all measures of the International Consultation on Incontinence Modular Questionnaire-OABqol (all P < .0001). Eighty percent of subjects reported improvements in their urinary symptom interference. Device-related adverse events occurred in 47% (127/272) of subjects post-implant; 91% were resolved at the time of this analysis. The 36-month follow-up data from the multicenter study demonstrate sustained safety, effectiveness, and improved QOL in subjects implanted with InterStim, without requiring failure of all medications. UROLOGY ■■: ■■–■■, 2016. © 2016 Elsevier Inc.
Financial Disclosure: Steven Siegel is a patent holder at MDT, BSI, and QIG; and has received consulting fees from MDT, Allergan, and NuVectra, and speaking fee/ proctor from MDT and QIG. He has also contracted research for MDT and IPSEN. Karen Noblett received consulting fees from MDT, Axonics, and speaking fee/proctor from MDT and BSI. She also contracted research for MDT. Suzette E. Sutherland is a study investigator for Medtronic and Allergan, and a paid consultant for Medtronic, Allergan, and Axonics. Jason Bennett is a study investigator and consultant for Medtronic, and a consultant for Intuitive. Fangyu Kan and Elizabeth Thiery are employees of Medtronic. The remaining authors declare that they have no relevant financial interests. Funding Support: Medtronic, Inc., sponsored this study in full. ClinicalTrials.gov identifier: InSite for Overactive Bladder, NCT00547378. From the Metro Urology, Woodbury, MN; the University of California, Riverside, CA; the MetroHealth Medical Center, Cleveland, OH; the University of Kansas, Kansas City, KS; the University of Washington, Seattle, WA; the Scott and White Healthcare, Temple, TX; the Stanford University, Stanford, CA; the University of Oklahoma HSC, Oklahoma City, OK; the Female Pelvic Medicine, Grand Rapids, MI; the Milford Regional Medical Center, Whitinsville, MA; and the Medtronic, Inc., Minneapolis, MN Address correspondence to: Steven Siegel, M.D., Metro Urology, Woodbury, MN. E-mail: [email protected] Submitted: January 11, 2016, accepted (with revisions): April 19, 2016
© 2016 Elsevier Inc. All rights reserved.
S
ince its initial Food and Drug Administration approval for urge incontinence, urinary frequency, and urgency in 1997, InterStim, which delivers sacral neuromodulation (SNM), has become a standard of care and has been increasingly adopted around the world. With nearly 200,000 implants performed, the therapy has been incorporated into societal guidelines for the management of overactive bladder (OAB).1 Because OAB is a chronic condition requiring ongoing care over many years, a successful treatment with both enduring results and long term follow-up are critical to understand the relevant factors in weighing the risks and benefits of SNM vs other available third-line options. The InSite trial was designed to be implemented in two phases. Phase one was a prospective, multicenter, randomized trial comparing SNM to standard medical therapy with http://dx.doi.org/10.1016/j.urology.2016.04.024 0090-4295
1
ARTICLE IN PRESS a 6-month follow-up period.2 It provided level-1 evidence for the objective and subjective superiority of SNM over standard medical therapy among OAB refractory patients, and also confirmed the safety of currently used devices and techniques for SNM. The second phase of the InSite trial is a prospective evaluation of the safety and efficacy of SNM in 5 years. The primary objective of this portion of the study satisfies the Food and Drug Administrationmandated postapproval requirements to evaluate the longterm safety and effectiveness of the tined lead. Additional objectives include an estimation of lead migration and infection rates at 5 years, therapy success, quality of life (QOL), and sexual function outcomes. Results for subjects followed through 12 months have been previously reported.3 The objective of the current analysis is to describe results from the 36-month follow-up that includes all implanted subjects from both phases.
METHODS Enrollment criteria and design were published previously.2,3 Subjects had a primary diagnosis of OAB as demonstrated on a 3-day voiding diary demonstrating ≥ 8 voids per day (urgency frequency, UF) and/or ≥ 2 involuntary leaking episodes in 72 hours (urinary incontinence, UI). Institutional Review Boards approved the protocol and informed consent forms were signed prior to participation in study activities. All subjects underwent a staged implant procedure with the InterStim System (neurostimulator models 3023/3058, lead models 3093/ 3889; Medtronic, Inc., Minneapolis, MN). Test stimulation success was defined as improvement from baseline, specifically 50% or greater improvement in average voids/ day or a return to normal voiding (<8 voids/day) for subjects with UF, and 50% improvement in average leaks per day for subjects with UI. After successful completion of the test stimulation phase, those subjects who met criteria for success were implanted with the neurostimulator. Subjects returned for follow-up visits postimplant at 3 months, 6 months, 12 months, and yearly thereafter for 5 years. Electronic voiding diaries were used at study visits, which allowed collection of real-time OAB data. QOL was assessed using the validated International Consultation on Incontinence Modular Questionnaire (ICIQ)-OABqol that evaluated total health-related QOL and 4 subscales (Concern, Coping, Sleep, and Social).4 The ICIQ-OABqol provides a detailed, robust measure of OAB symptoms and the correlating impact on quality of life. Responses to the “interference” question on the OABqol measured how much urinary symptoms interfere with everyday activities overall. Other QOL and sexual function tools used include the Male/Female Lower Urinary Track Symptoms-Sex (MLUTSsex5 and FLUTSsex6), Beck Depression Inventory II (BDI-II),7 and visual analog scale for pelvic pain. All adverse events (AE) (serious and nonserious) were reported. The results section will detail an overview of device-related AEs, defined as events related to the implant procedure, therapy, device, or implant site. A Clinical Events 2
Committee consisting of 3 physicians experienced in SNM reviewed and adjudicated all AEs. This paper reports the results for all implanted subjects up to 3 years. Subjects will continue to be followed for 5 years to collect additional long-term data. Statistical Analyses Various outcome measures were evaluated to determine the 36-month 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. Descriptive statistics were reported for these measures, and P values for paired comparison between follow-up visits through 36 months and baseline in terms of leaking and voiding episodes per day were presented using a Wilcoxon signed-rank test. Two analyses for efficacy at 36 months were conducted. The first analysis is a Modified Completers analysis evaluating all subjects who received a full system implant and either had a baseline and 36-month evaluation, or 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 therefore considered failures. Implanted subjects who withdrew for reasons unrelated to the device were excluded from the primary efficacy analysis. The second sensitivity analysis is a Completers analysis and includes all implanted subjects with diary data at baseline and at 36 months. To assess the trend of efficacy over time, outcomes were evaluated for subjects with data available at baseline and at each follow-up. To assess QOL, data through 36 months were analyzed as changes from baseline to follow-up visits. No data were imputed for missing values. Descriptive statistics were reported for these measures. Within-treatment comparisons were made using a Wilcoxon signed-rank test. All subjects that had device implant and the required outcome data at both baseline and follow-up visits through 36 months were included. Published scoring criteria were followed for ICIQ-OABqol.4 “Overall, how much do your urinary symptoms interfere with your everyday life?” on the OABqol was measured on a scale from 0 to 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. 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 subjects were implanted with the InterStim System. Baseline demographics are listed in Supplementary Table S1. Subjects had tried a median of 2 OAB medications prior to full system implant. On average, UI subjects had 3.1 ± 2.7 leaks/day; UF subjects had 12.6 ± 4.5 voids/day at baseUROLOGY ■■ (■■), 2016
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Figure 2. Leaks reduction for UI and voids reduction for UF over time. In both A and B, error bars represent 95% confidence intervals. ***P < .0001. OAB, overactive bladder; UF, urgency frequency; UI, urinary incontinence.
Figure 1. OAB therapeutic success rate over time. Analyses included subjects with diary data at baseline and followup visits (3 months, 6 months, 12 months, 24 months, 36 months). (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. (B) UI response was defined as ≥50% improvement in leaks/day. (C) UF response was defined as ≥50% improvement in voids/day or a return to normal voiding frequency (<8 voids/day).
line. There were 217 subjects followed up until 36 months, with 193 subjects with a voiding diary at baseline and at 36 months. Seventeen subjects who discontinued prior to 36 months due to a device-related AE or lack of efficacy resulting in a full system explant had their 36-month data imputed to their baseline assessment in Modified Completers analysis. Using the Modified Completers analysis, the overall OAB response rate demonstrating therapeutic success was 79% at 24 months and 76% at 36 months. The UI response rate was 76% for subjects characterized with UI at baseline. These subjects had an average reduction of 2.1 ± 2.3 leaks per day as compared to baseline (P < .0001). Complete continence at 36 months was achieved in 43% of subjects. For subjects with UF, a therapeutic response rate of 64% was observed. These subjects had an average of reduction of 4.8 ± 4.1 voids per day from baseline (P < .0001). Using the Completers analysis with no imputation of missing data, the overall OAB response rate demonstrating therapeutic success at 36 months was 83% (Fig. 1). The UROLOGY ■■ (■■), 2016
UI response rate was 82% for subjects characterized with UI at baseline. These subjects had an average reduction of 2.3 ± 2.3 leaks per day as compared to baseline (P < .0001, Fig. 2). Complete continence at 36 months was achieved in 46% of subjects. For subjects with UF, a therapeutic response rate of 70% was observed. The mean reduction in voids per day was 5.3 ± 4.0 (P < .0001). Response rates and mean reductions in leaks and voids show sustained efficacy of SNM through 36 months. QOL data were available on 208 subjects at 36 months. Sustained QOL improvements were reported from baseline to 36 months in all ICIQ-OABqol domains (all statistically significant with P < .0001, Fig. 3). At 36 months, 80% of subjects reported improved or greatly improved urinary symptom interference score that is consistent with the results reported at 3 months postimplant (Fig. 4). Sexual matters were evaluated through the MLUTSsex and FLUTSsex questionnaires. There was significant improvement from baseline to 36 months for females (P < .0001) but no significant change for males was found, which could be due to the small sample size. Depression, as measured by the BDI-II, significantly improved from baseline to 36 months (P < .0001). The visual analog scale for pelvic pain was also significantly improved from baseline to 36 months (P < .0001). There were no unanticipated adverse device effects. As previously reported3, the device-related AE rate was 16% (56/340) for subjects with a lead placed during the test stimulation phase, with 3 of the AEs classified as serious: implant site infection, skin infection, and respiratory arrest during surgery. From neurostimulator implant through the 36-month visit, device-related AEs were reported in 47% of subjects (127/272); 91% of these were resolved at the 3
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Figure 3. OABqol—Improvement from baseline over time. Baseline = 33.84 (Concern); 37.00 (Coping); 37.61 (Sleep); 62.75 (Social); 41.39 (HRQL). HRQL total and all four subscales (Concern, Coping, Sleep, Social) showed greater improvement at follow-up visits compared to baseline (all P < .0001). Error bars are 95% confidence intervals. 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.8 The MID for the OABqol subscales has been suggested to be 10 points. MID, minimally important difference.
Figure 4. Urinary symptom interference. OABqol—“Overall, how much do your urinary symptoms interfere with your everyday life?”
time of analysis. One event was classified as serious: implant site erosion, which was resolved at the time of analysis. The most frequent AE types reported were undesirable change in stimulation (49/272, 18%), implant site pain (34/272, 13%), and therapeutic product ineffective (16/272, 6%). Lead migrations were reported in 4% of subjects (12/ 272), with the majority of lead migrations reported between 12 and 24 months postimplant. Implant site infections were reported in 4% of implanted subjects (10/272), with half reported between the implant procedure and 3 months postimplant. Surgical interventions including revision, replacement, or permanent explant on any 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 and/ or loss of efficacy, or battery replacement. Surgical 4
interventions related to the neurostimulator, lead, or chronic extension were experienced in 32% of subjects (86/272) after implant. The rate of device replacement was 20% (55/ 272) and device revision was 4% (11/272). Surgical interventions due to battery replacement occurred in 11% (29/272) of subjects, and 93% (27/29) of these neurostimulators were assessed to be within the expected longevity ranges based on the set parameters of the device. Not enough information was available to determine longevity status on the remaining 2 neurostimulators. In total, 13% (34/272) of subjects underwent permanent explant. The top reason reported by investigators for permanent explant was due to an AE (8%). Other reasons include subject’s need for magnetic resonance imaging, lack and/or loss of efficacy, subject withdrew consent, and other. Only 3% (9/272) of permanent explants were associated with a lack or loss of efficacy. UROLOGY ■■ (■■), 2016
ARTICLE IN PRESS DISCUSSION OAB is a chronic condition that must be managed successfully over time to provide meaningful benefit. This prospective study demonstrates sustained safety and efficacy of SNM in OAB subjects after 36 months of treatment and will continue to follow study subjects up to 60 months. There is minimal drop-off in therapeutic success when compared to results at 1 year.3 Improvements in QOL, sexual function in female subjects, and pelvic pain measures were sustained. The rate of device-related AE (47%) and surgical intervention (32%) remains significantly lower than previously published studies using older techniques and devices,9 but still must be acknowledged as a consideration when evaluating candidates for this therapy. The majority of surgical interventions were due to replacements of the neurostimulator, lead and/or chronic extension, rather than cessation of the 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 adjudication of all AEs. The fact that a third of the device-related AEs up to 36 months occurred within the first 12 months of implant implies that further refinements of technique or patient selection could result in significant reductions.10 These refinements include methods to optimize lead placement, which were not as well understood or uniformly employed by the implanters in this study. By 36 months, 11% of subjects required battery replacement due to depletion. Over time, it is likely that all of the subjects who have been successfully managed will need device replacements to maintain benefit due to the nature of treatment. Of all implanted subjects, 13% underwent permanent explant for various reasons, indicating probable abandonment of the therapy. Few studies have published data regarding other advanced OAB treatments at 36 months or beyond. In the multicenter STEP study,11 50 out of 60 subjects were enrolled and outcomes for percutaneous tibial nerve stimulation were documented for a total of 29 (58%) subjects at 36 months. Although only a small number of subjects were included, percutaneous tibial nerve stimulation showed safety with sustained improvements after 3 years. In a singlecenter, long-term study measuring the long-term outcome of the use of intravesical botulinum toxin (BoNT) for the treatment of OAB, 137 out of 268 subjects were followed for ≥36 months.12 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 the need for intermittent catheterization and urinary tract infections. Based on published literature, the long-term benefit of the therapy of SNM is also significant when considering cost-effectiveness. Although the initial cost of treatment is clearly greater for SNM compared to intravesical BoNT or percutaneous tibial nerve stimulation, studies have demonstrated that SNM becomes more cost-effective over time. In a study evaluating cost-effectiveness of SNM vs optimal medical therapy and intravesical BoNT in the Canadian UROLOGY ■■ (■■), 2016
healthcare system, SNM became cost-effective and dominated (ie, became more effective and less costly) in comparison to BoNT during the first 5 years. 13 Another cost-utility analysis from the Italian healthcare system confirmed that SNM appeared to be cost effective from 3 years onwards.14 They concluded that SNM may be considered cost-effective in the midterm and cost saving in the long term. These findings underscore the importance of maintained SNM therapy benefit over the 3 to 5-year time frame relative to cost-effectiveness. The strengths of the InSite study include the large number of subjects with protocol-mandated follow-up, and the rigorous modified completer analysis with ongoing inclusion of subjects withdrawn for lack of benefit or devicerelated complications as failures. Additionally, the private practice and academic centers contributing subjects reflect real-world experience with the therapy, and thus the results are likely applicable to real-world use. The weaknesses of this InSite study include the homogeneous population, with a minority of male subjects, which could detract from generalizability. Furthermore, centers were allowed to 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 have impacted overall study results.
CONCLUSION The InSite trial is an ongoing, large, prospective multicenter study designed to evaluate the long-term safety and efficacy of SNM for subjects with refractory symptoms of OAB. This paper reports the results after 3 years of therapy, demonstrating that implanted subjects maintained improvements in OAB symptoms and QOL. Whereas the rate of AEs and the need for reoperation are acknowledged concerns related to this therapy, they are reduced compared to prior studies. References 1. 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;193:1572-1580. 2. 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;34:224-230. 3. 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;35:246-251. doi:10.1002/ nau.22707. 4. 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;11:563-574. 5. Frankel SJ, Donovan JL, Peters TI, et al. Sexual dysfunction in men with lower urinary tract symptoms. J Clin Epidemiol. 1998;51:677685.
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ARTICLE IN PRESS 6. 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;77:805812. 7. Beck AT, Steer RA, Brown GK. Manual for the Beck Depression Inventory II. San Antonio, TX: The Psychological Corporation; 1996. 8. Jaeschke R, Singer J, Guyatt GH. Measurement of health status. Ascertaining the minimal clinically important difference. Control Clin Trials. 1989;10:407-415. 9. van Kerrebroeck PE, van Voskuilen AC, Heesakkers JP, et al. Results of sacral neuromodulation therapy for urinary voiding dysfunction: outcomes of a prospective, worldwide clinical study. J Urol. 2007;178:2029-2034. 10. Noblett K, Benson K, Kreder K. Detailed analysis of adverse events and surgical intervention in a large prospective trial of sacral neuromodulation therapy for overactive bladder patients. Neurourol Urodyn. 2015;34:S237. [Abstract]. 11. Peters KM, Carrico DJ, Wooldridge LS, Miller CJ, MacDiarmid SA. Percutaneous tibial nerve stimulation for the long-term treatment
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of overactive bladder: 3-year results of the STEP study. J Urol. 2013;189:2194-2201. 12. Mohee A, Khan A, Harris N, Eardley I. Long-term outcome of the use of intravesical botulinum toxin for the treatment of overactive bladder (OAB). BJU Int. 2013;111:106-113. 13. Hassouna MM, Sadri H. Economic evaluation of sacral neuromodulation in overactive bladder: a Canadian perspective. Can Urol Assoc J. 2015;9:242-247. 14. Bertapelle MP, Vottero M, Popolo GD, 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. 2015;33:1109-1117.
APPENDIX SUPPLEMENTARY DATA
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.urology .2016.04.024.
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