National Medical Policy

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1 National Medical Policy Subject: Policy Number: Posterior Tibial Nerve Stimulation for Voiding Dysfunction NMP368 Effective Date*: September 2007 Updated: October 2015 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate State s Medicaid manual(s), publication(s), citation(s), and documented guidance for coverage criteria and benefit guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link National Coverage Determination (NCD) National Coverage Manual Citation X Local Coverage Determination (LCD)* Posterior Tibial Nerve Stimulation (PTNS) for Urinary Control; Posterior Tibial Nerve Stimulation (PTNS): x Article (Local)* Posterior Tibial Nerve Stimulation. Coverage R3: Other None Use Health Net Policy Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Tibial Nerve Stimulation for Urinary Incontinence Oct 15 1

2 Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Current Policy Statement Please refer to NMP Urinary Incontinence Devices and Treatments Health Net, Inc. considers posterior tibial nerve stimulation (PTNS) for the treatment of moderate to severe urinary dysfunction and overactive bladder symptoms medically necessary, up to 12 weeks only (i.e. 12 treatments of PTNS, 30 minutes, once-weekly, are usually needed for symptom relief)*. This would only be considered medically necessary when the following conditions are met: 1. The member has had urinary dysfunction for at least 12 months and the condition has resulted in significant disability (i.e., the urinary urgency, frequency and or the severity of symptoms are limiting the member's ability to participate activities of daily living); and 2. The member has tried various medications (e.g., alpha blockers and cholinergics, and antibiotics for urinary tract infections) that have failed or are not well-tolerated. *Note - If the member fails to improve after 12 PTNS treatments, continued treatment is considered not medically necessary. NOTE: This policy also applies to patients with interstitial cystitis who may have urgency and frequency. Definitions PTNS Posterior tibial nerve stimulation UUI Urge urinary incontinence QOL Quality of life OABS Overactive bladder syndrome HRQS Health-related quality of life LUTS Lower urinary tract symptoms Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or non-covered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures will be replaced by ICD-10 code sets. Health Net National Medical Policies will now include the preliminary ICD-10 codes in preparation for this transition. Please note that these may not be the final versions of the codes and that will not be accepted for billing or payment purposes until the October 1, 2015 implementation date. Tibial Nerve Stimulation for Urinary Incontinence Oct 15 2

3 ICD-9 Codes Urinary incontinence Urinary frequency Other abnormality of urination ICD-10 Codes N N39.9 Other disorders of urinary system R32 Unspecified urinary incontinence R35.0- R35.8 Polyuria R39.81 Functional urinary incontinence CPT Codes Posterior tibial neurostimulation, percutaneous needle electrode, single treatment, includes programming HCPCS Codes N/A Scientific Rationale Update October 2015 Gormley et al. (2015) completed a study with the goal to incorporate relevant newly published literature to better provide a clinical framework for the diagnosis and treatment of patients with non-neurogenic overactive bladder. The primary source of evidence for this guideline is the systematic review and data extraction conducted as part of the Agency for Healthcare Research and Quality Evidence Report/Technology Assessment Number 187 titled Treatment of Overactive Bladder in Women (2009). The AUA conducted additional literature searches to capture populations and treatments not covered in detail by the AHRQ report and relevant articles published through December The review yielded 151 treatment articles after application of inclusion/exclusion criteria. An additional systematic review conducted in February 2014 identified 72 additional articles relevant to treatment and made up the basis for the 2014 amendment. This amendment focused on four topic areas: mirabegron, peripheral tibial nerve stimulation, sacral neuromodulation and BTX-A. The additional literature provided the basis for an update of current guideline statements as well as the incorporation of new guideline statements related to the overall management of adults with OAB symptoms. New evidence-based statements and expert opinion supplement the original guideline published in 2012, which provided guidance for the diagnosis and overall management of OAB in adults. Scientific Rationale Update October 2014 Recently updated guidelines from the American Urological Association/SUFU (May 2014) on the diagnosis and treatment of overactive bladder state that clinicians may offer peripheral tibial nerve stimulation (PTNS) as third line treatment in a carefully selected patient population. Recommendation (Evidence Strength Grade C. i.e., low). The guidelines notes that the reviewed data indicates that PTNS can benefit a carefully selected group of patients characterized by moderately severe baseline incontinence and frequency and willingness to comply with the PTNS protocol. Patients must also have the resources to make frequent office visits both during the initial treatment phase and to obtain maintenance treatments in Tibial Nerve Stimulation for Urinary Incontinence Oct 15 3

4 order to achieve and maintain treatment effects obtain treatment because treatment effects dissipate once treatment ceases. Reported adverse events were minor; the most frequently reported events were painful sensation during stimulation that did not interfere with treatment and minor bleeding at the insertion site. In the Panel s view, benefits outweigh risks/burdens for the use of PTNS in the thoughtfully-selected and counseled patient who is highly-motivated to make the required office visits. As a group, the PTNS studies constitute Grade C evidence because of the predominant observational designs, varying patient inclusion criteria, small sample sizes, and short follow-up durations for most studies. Firstline treatments include behavioral therapies (e.g., bladder training, bladder control strategies, pelvic floor muscle training, fluid management) and second line therapies include pharmacologic management. Ammi et al (2014) evaluated the efficacy and tolerability of transcutaneous posterior tibial nerve stimulation (TPTNS) in the treatment of overactive bladder (OAB) after failure of a first-line anticholinergic treatment in a prospective observational study of 43 patients treated in a single center for OAB persisting after first-line anticholinergic treatment from November 2010 to May The protocol consisted of daily stimulation at home. The efficacy end point was defined as improvement on the Urinary Symptom Profile (USP) and the French-validated urinary symptom score Mesure du Handicap Urinaire (MHU). TPTNS was successful following 1 month of treatment in 23 (53%) patients. Bladder capacity was the only predictive factor for treatment success (p=0.044). For patients who showed improved symptoms (n=23; 53%), mean MHU and USP decreased significantly, from 11.8 ± 2.8 to 5.6 ± 3 (p<0.001) and from 14 ± 3.3 to 6.9 ± 3.2 (p<0.001), respectively. After a mean follow-up of 10.8 ± 1.6 months, 21 (49%) patients continued the TPTNS. Mean MHU and USP scores were 4.4 ± 2.8 and 5.4 ± 3.5, respectively, and stayed lower than baseline (p<.001). Patients reported no adverse events. Investigators concluded TPTNS is well tolerated and is effective in one half of the patients studied after they failed anticholinergic treatment. TPTNS could become a second therapeutic option before surgical treatment in the management strategy of OAB. Vecchioli-Scaldazza et al (2013) compared the effectiveness of solifenacin succinate (SS) versus PTNS in women with overactive bladder syndrome (OABS). A randomized controlled crossover study of 40 women with OABS was performed. Patients were randomized into two groups. In group A, patients received SS and then PTNS. In group B, patients underwent PTNS and then SS. Voiding diaries, quality of life surveys and patient perception of intensity of urgency questionnaire were performed before and after each treatment. The global impression of improvement questionnaire was performed at the end of the study. A reduction in the number of daily micturitions, episodes of nocturia and urge incontinence were found with both SS and PTNS in all groups, but PTNS showed a greater effectiveness than SS. There was an increase in voided volume in all groups with both SS and PTNS, but patients treated with PTNS had a greater increase. PTNS showed greater effectiveness in patient perception of urgency and quality of life. The authors concluded the study demonstrates the effectiveness of SS and PTNS In women with overactive bladder symptoms. However, greater improvements were found with PTNS. Scientific Rationale Update October 2012 California Technology Assessment Forum (CTAF, 2012) notes: It is recommended that treatment of overactive bladder with PTNS meets CTAF TA criteria 1 through 5 for short-term benefit. Tibial Nerve Stimulation for Urinary Incontinence Oct 15 4

5 It is recommended that treatment of overactive bladder with PTNS does not meet CTAF TA Criteria 4 and 5 for long-term benefit. CTAF based their summary on the following studies: The Overactive Bladder Innovative Therapy Trial (ORBIT) was a randomized multicenter trial that compared PTNS to extended release tolterodine, a drug commonly used for the treatment of overactive bladder. A total of 100 adults with urinary frequency were randomized to receive 12 weeks of treatment with weekly PTNS or daily extended release tolterodine (4mg dose). Participants completed a voiding diary at baseline and at follow-up. They also completed an overactive bladder questionnaire both at baseline and at follow-up. Main outcomes were 24 hour voiding frequency, number of urinary urge incontinence episodes and quality of life outcomes. Global response assessments were completed by participants and study investigators after 12 weeks. Global response was measured as the percentage of participants reporting cure or improvement in symptoms. This study showed that PTNS was safe and efficacious at 12 weeks. Compared with pharmacotherapy, it resulted in improvement in patient assessment of bladder symptoms and in objective measures of bladder dysfunction. Efficacy was similar to that seen with pharmacotherapy (tolterodine). In the second phase of the ORBIT trial, study participants who had been randomized to PTNS were offered an additional nine months of treatment. They were assessed for OAB outcomes at six and 12 months. Study outcomes included voiding diaries, overactive bladder questionnaires, global response assessments and safety assessments. Forty five participants were originally included in the PTNS arm of ORBIT. Thirty five participants were responders and of those responders, 33 chose to continue PTNS treatment for the longer follow-up study. Participants needed to remain off OAB drugs for the study duration. With investigator supervision and using sound clinical judgment, participants were allowed to select the frequency of PTNS treatment that best controlled their symptoms. These treatments were all 30 minutes in duration. OAB symptoms were evaluated at six and 12 months and were compared to baseline and to the end of the initial 12 week treatment period. A total of 32 participants completed six months of follow up and 25 completed 12 months of follow-up. During the nine month follow-up period, the participants received a mean of 12.1 ± 4.9 treatments over 263 days. At six and 12 months, all voiding diary outcomes showed improvement compared with baseline. At 12 months, frequency was decreased by 2.8 voids daily (p<0.001) and urge incontinence was decreased by 1.6 episodes daily (p<0.001). All 33 subjects who completed the PTNS therapy rated symptoms on the GRA at the end of the initial 12 weeks of therapy as improved from baseline. At six months, 94% of patients rated OAB symptoms as improved from baseline and at 12 months, 96% rated symptoms as improved from baseline. Thus among individuals who respond to a 12 week course of once weekly PTNS, continued treatment for nine months results in continued symptom improvement at 12 month follow up. The authors do not currently know how they would respond to treatment beyond one year, or what the impact would be for those who did not respond to the initial treatment. In addition, these conclusions about long term efficacy are based on 33 patients enrolled in a single trial. The Position Statements noted below in the Scientific Rationale Updates for July 2012, as well as June 2011, for the following societies have not changed regarding PTNS, AHRQ 2012, and National Institute for Health and Clinical Evidence (NICE, 2010). The position statement regarding Blue Cross Blue Shield TEC (2011) now notes: In a technology assessment on percutaneous tibial nerve stimulation (PTNS), the BlueCross BlueShield Association (2011) concluded that the evidence in three randomized controlled Tibial Nerve Stimulation for Urinary Incontinence Oct 15 5

6 trials established a short-term benefit (up to 12 weeks) for PTNS, but there is insufficient evidence to establish durability of treatment effect. According to the assessment, beyond 12 weeks, there is no high-quality evidence that supports efficacy over longer periods of time. Studies Gobbi et al. (2011) completed a study to evaluate efficacy, safety and impact on quality of life (QoL) of PTNS on patients with multiple sclerosis (MS) who have lower urinary tract systems (LUTS). 21 patients (5 men, 16 women) with MS and LUTS unresponsive to anticholinergics were treated with 12 sessions of PTNS. Assessment of LUTS was by validated, self-administered chart and questionnaires, testing the subjective and objective relevance of LUTS for patients and their impact on QoL before and after treatment; the mean post-micturition residual was assessed by trans-abdominal ultrasound scanning. Analysis was by intention to treat. RESULTS: There was a significant reduction of daytime frequency (from 9 to 6, p = 0.04), nocturia (from 3 to 1, p = 0.002) and mean postmicturition residual (from 98 ± 124 ml to 43 ± 45 ml, p = 0.02). The mean voided volume increased from 182 ± 50 ml to 225 ± 50 ml (p = 0.003). Eighty-nine percent of patients reported a treatment satisfaction of 70%. Significant improvement in QoL was seen in most domains of the King's Health QoL questionnaire (p < 0.05). No adverse events were reported. Although this is a very small study of only 21 individuals, PTNS seems to be an effective, safe and well-tolerated treatment for lower urinary tract symptoms in patients with MS, for the initial 12 weeks of treatment. Per Wein: Campbell-Walsh Urology, 10th. ed. (2011), although clinical trials have produced variable results, PTNS is minimally invasive, demonstrates efficacy, and is easily applicable and well tolerated in all the lower urinary tract conditions studied. Recent urodynamic outcomes have been shown in an MS subpopulation and improvements during PTNS have been demonstrated, including increases in mean first involuntary detrusor contractions and mean cystometric capacity (Kabay et al, 2008). One major limitation of PTNS is that there does appear to be the need for chronic treatment that may be better derived from an implantable subcutaneous stimulation device (van Balken et al, 2003) and even continuous stimulation. Pediatric Clinics of North America (2012) Transcutaneous PTNS has been evaluated in clinical trials with variable results. More substantial data are necessary, but some reports in adults indicate that it seems beneficial. Limited reports of its use in children have indicated efficacy as well. One study by Hoebeke et al. (2002] showed that 17 of 28 children who had been refractory to medical treatment had a resolution or improvement in their symptoms. Sixteen of 19 patients who had abnormal frequency showed marked improvement, and overall for the group, mean bladder capacity increased significantly. Capitanucci et al. (2009) analyzed long-term results of their longitudinal cohort of children, obtaining level 3 evidence evaluating PTNS efficacy and durability of results. Improvement was significantly greater (P<.002) in nonneurogenic (78%) than in neurogenic (14%) patients. Among nonneurogenic lower urinary tract (LUT) disease, at 2-year follow-up 5 of 12 (41%) children with OAB and 10 of 14 (71%) with dysfunctional voiding (DV) were completely cured. By repeating a second PTNS cycle and by maintaining chronic monthly stimulation, 9 additional children (5 with OAB and 4 with DV) resolved LUTS, which relapsed 1 year after the first PTNS cycle. Overall, at long-term follow-up, 10 of 12 children with OAB and 14 of 14 patients with DV were asymptomatic; chronic PTNS was required in 50% and 29% of children, respectively, with OAB or DV, to maintain results. These studies indicate a role for an improvement in BBD in children with peripheral nerve stimulation. On the other hand, per the experience of the Pediatrics Clinics of North America (2012), this modality in a limited number of patients has not been as Tibial Nerve Stimulation for Urinary Incontinence Oct 15 6

7 positive as that of Hoebeke et al. or Capitanucci et al.. It could be that patients selected had failed all other treatment modalities, and difficult patients may not respond so readily. However, although these results may seem positive, the studies were very small, and additional larger peer-reviewed studies are necessary with long-term outcomes. Biemens et al. (2012) completed a systematic review aimed to determine the efficacy and effectiveness of percutaneous tibial nerve stimulation (PTNS) on symptoms of overactive bladder (OAB) and pelvic organ disorders, pain, adverse events (AEs), and quality of life (QoL). A literature search was performed in September 2011 in the databases MEDLINE, CINAHL, and EMBASE. Only randomized controlled trials (RCTs) and controlled clinical trials (CCTs) with adult patients were included. Seven studies met the eligibility criteria. Five RCTs indicated improvement (range %) on OAB symptoms, frequency, urgency, nocturia, and incontinence. One CCT reported improvement (mean 15.7) in 53% of the subjects on fecal incontinence (FI) symptoms on an FI Questionnaire (range 0-20). One RCT showed more than 50% improvement on pain (40%) and symptom scores (66.6%) in chronic pelvic pain (CPP). Limitations are the small amount, overall low quality, and variety in outcome measures of included studies. Only minor AEs were reported. No meta-analysis was performed as a consequence of heterogeneous data. This systematic review provides evidence for the efficacy of PTNS on symptoms, pain, and QoL measures of OAB, FI and category IIIB CP/CPP. Evidence of effectiveness was found on symptoms and QoL for OAB. The total amount of seven included studies, from which even the most favorable study has some potential bias, is too small to draw firm conclusions. Although PTNS seems to be a safe intervention, independent high quality RCTs are necessary to confirm and delineate the range of therapeutic effects of PTNS. Yoong et al. (2012) completed a study with the goal to describe effectiveness and safety of PTNS at 2 years in women with overactive bladder (OAB) syndrome unresponsive to pharmacotherapy. Of 30 women who had initial positive response to PTNS, 23 continued to receive maintenance treatment and were reassessed at 2 years using bladder symptom diaries and the Incontinence Impact Questionnaire (IIQ-7). They were also questioned on acceptability and any adverse effects of long-term peripheral neuromodulative treatment. Data from 23 women were available and 7 had been lost to follow-up. With maintenance treatment, the median nocturnal frequency at 2 years had decreased by 57 % (3.5 to 1.5 times/night), while the median IIQ-7 had reduced from 30.4 to 21.5 (both p<0.01) compared to pre-treatment baseline. Median nocturnal frequency and IIQ-7 scores at 2 years were comparable to those documented after initial response to treatment at 6 weeks, suggesting that maintenance therapy continued to suppress OAB symptoms. Daytime frequency and daily urgency incontinence episodes at 2 years were statistically similar to those documented at 6 weeks and remained lower than pre-treatment baseline (6.5 vs 11.8 and 2.0 vs 3.5, respectively, p<0.05). The women received a median of 8.42 treatments per year and the median length between treatments was 64.3 days. Apart from hypaesthesia in the toe of one responder lasting for 4 months, there were no reported side effects. Women receiving PTNS for intractable OAB syndrome reported significant symptom relief at 2 years. This remains a safe mode of second-line treatment with excellent durability. However, this study was very small and based on only 23 women. Additional, larger, peer reviewed studies are needed with long-term outcomes. Moossdorff-Steinhauser et al. (2012) completed a study to assess the effectiveness of PTNS on adult patients with overactive bladder syndrome, using a systematic review of randomized controlled trials (RCTs), clinical controlled trials (CCTs), and prospective observational cohort studies. A computer-aided literature search was performed in: PubMed, Tibial Nerve Stimulation for Urinary Incontinence Oct 15 7

8 EMBASE and CENTRAL (2000 to November 15, 2011) to identify RCTs, CCTs, and prospective observational cohort studies. The study had to investigate the effect of PTNS on overactive bladder syndrome. The methodological quality of each study was assessed and a qualitative analysis was performed to establish the levels of evidence. Four RCTs and six prospective observational cohort studies were identified. There is strong evidence for the efficacy of PTNS versus a sham treatment. There is limited evidence that the use of PTNS and tolterodine ER is equally effective. No additional effect of a combination of Stoller afferent nerve stimulation (SANS) and anticholinergic medication compared to SANS alone. Most cohort studies suggested decreased frequency and improvement of incontinence and nocturia. However, the level of evidence was insufficient to make any firm conclusions. Because the total duration of all included trials varied between 6 and 12 weeks, so far there is little information on treatment periods. PTNS is efficacious for frequency and urgency urinary incontinence. More high quality studies are needed to improve the level of evidence concerning the efficacy of PTNS with regard to urgency and nocturia, to specify patient selection criteria, optimal treatment modalities and long-term effects as well as the effectiveness in more pragmatic trials. Burton et al. (2012) completed a recent systematic review and meta analysis and reports variable success rates (37 82%) for treating OAB symptoms with PTNS. There were four randomised trials included in this analysis, which compared PTNS with sham treatment which showed a significant difference favouring PTNS while two randomised trials compared PTNS with antimuscarinic medication with no significant difference in the change in bladder diary parameters between the treatments. The overall subjective success rate was 61.4% (and objective success rate was 60.6% The authors noted that a significant drawback of PTNS in treating a chronic condition such as OAB is the need for repeated stimulations without which symptoms deteriorate by 6 12 weeks. They also state an absence of long term data in the literature with few studies looking at ongoing treatment over 12 months. There is evidence of significant improvement in OAB symptoms with short-term use of PTNS. This is comparable to the effect of antimuscarinics but with a better side effect profile. The long-term use of PTNS therapy needs further rigorous investigation. The American Urological Association (2012), Overactive Bladder, Guideline Statements. Treatments: First Line Treatments Clinicians should offer behavioral therapies (e.g., bladder training, bladder control strategies, pelvic floor muscle training, fluid management) as first line therapy to all patients with OAB. Standard (Evidence Strength B) Behavioral therapies may be combined with anti-muscarinic therapies. Recommendation ( Evidence Strength Grade C) Second Line Treatments Clinicians should offer oral pharmacological medications as noted on the website by AUA. Standard (Evidence Strength B) Transdermal oxybutynin (patch or gel) may be offered Recommendation ( Evidence Strength Grade C) Third Line Treatments (FDA Approval) Clinicians may offer PTNS in carefully selected patients. Option ( Evidence Strength Grade C) Follow-up Tibial Nerve Stimulation for Urinary Incontinence Oct 15 8

9 Clinicians should offer follow up with the patient to assess compliance, efficacy, side effects and possible alternative treatments. Expert Opinion *NOTE: Grade B: RCTs with some weaknesses of procedure or generalizability or generally strong observational studies Grade C: Observational studies that are inconsistent, have small sample sizes, or have other problems that potentially confound interpretation of data). Because treatment data for this condition are difficult to interpret in the absence of a placebo control, bodies of evidence comprised entirely of studies that lacked placebo control groups (i.e., observational studies) were assigned a strength rating of Grade C. Expert Opinion refers to a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge and judgment for which there may be no evidence. Scientific Rationale Update July 2012 Position Statements The American Urological Association (AUA, 2012) Guideline for the Diagnosis and Treatment of Overactive Bladder (Non-Neurogenic) in Adults: The Panel interpreted the data from recently reviewed studies to indicate that posterior tibial nerve stimulation (PTNS) can benefit a carefully selected group of patients characterized by moderately severe baseline incontinence and frequency and willingness to comply with the PTNS protocol. Patients must also have the resources to make frequent office visits in order to obtain treatment because treatment effects dissipate once treatment ceases. As a group, the PTNS studies constitute Grade C* evidence because of the predominant observational designs, varying patient inclusion criteria and short follow-up durations for most studies. (NOTE*: Grade C - Balance between benefits and risks/burdens is uncertain). AHRQ Comparative Effectiveness Review on Urinary Incontinence, Number 36. (April 2012), Nonsurgical Treatments for Urinary Incontinence in Adult Women: Percutaneous tibial nerve stimulation improved urinary incontinence (UI). Individual RCTs indicated no difference in adverse effects and treatment discontinuation with active or sham stimulation. For women with urgency UI whose conservative treatments failed, percutaneous tibial nerve stimulation, sacral neuromodulation and botulinum toxin injections may be of benefit. BlueCross BlueShield Technology Evaluation Center (TEC, December 2011): There is fairly strong evidence for short-term efficacy of PTNS up to 12 weeks, but insufficient evidence to establish durability of treatment effect. Whether PTNS for the treatment of voiding dysfunction improves the net health outcome has not been demonstrated in the investigational setting. PTNS does not meet the TEC criteria at this time. (No changes noted since information listed in Scientific Rationale dated June 2011) Tibial Nerve Stimulation for Urinary Incontinence Oct 15 9

10 Studies Monga et al. (2012) completed a systematic literature review of clinical trial evidence for a range of electrical stimulation therapies in the treatment of lower urinary tract symptoms (LUTS). The databases MEDLINE, BIOSIS Previews, Inside Conferences, and EMBASE were searched. Original clinical studies with greater than 15 subjects were included. Seventythree studies were included, representing implanted sacral nerve stimulation (SNS), percutaneous posterior tibial nerve stimulation (PTNS), and transcutaneous electrical stimulation (TENS) therapy modalities. Median mean reductions in incontinence episodes and voiding frequency were similar for implanted SNS and PTNS. However, long-term follow-up data to validate the sustained benefit of PTNS are lacking. Despite a substantial body of research devoted to SNS validation, it is not possible to definitively define the appropriate role of this therapy owing largely to study design flaws that inhibited rigorous intention to treat analyses for the majority of these studies. Burton et al. (2012) completed a systematic literature search (up to April 2011). Relevant randomized controlled trials (RCTs) and prospective studies were selected and a metaanalysis was done by two-independent reviewers. The studies report variable initial success rates (37-82%) for treating OAB symptoms with PTNS. Four randomized trials compared PTNS with Sham treatment showing a significant difference favoring PTNS [RR % confidence interval (CI) ]. Two randomized trials compared PTNS with antimuscarinic medication with no significant difference in the change in bladder diary parameters between the treatments. Ten prospective non-randomized studies were included. The definitions of success were varied. The pooled subjective success rate was 61.4% (95% CI ) and objective success rate was 60.6% (95% CI ). There is evidence of significant improvement in OAB symptoms using PTNS which is comparable to the effect of antimuscarinics but with a better side effect profile. However, the studies included in the review only considered short-term outcomes after initial treatment. In order to recommend PTNS as a practical treatment option, long-term data and health economic analysis are needed. Peters et al. (2012) completed a prospective RCT with 24 month follow-up to evaluate the sustained effectiveness and treatment interval for PTNS therapy for overactive bladder (OAB). This study followed treatment after 12 weekly PTNS treatments, in which patients were prescribed a 14-week tapering protocol, followed by ongoing therapy with a Personal Treatment Plan determined by the investigator and subject to OAB symptom improvement. Questionnaires were completed every 3 months, voiding diaries every 6 months; adverse events were reported throughout. Of 50 subjects enrolled, who were also noted within the SUmiT trial, 35 remained in the study at 24 months. During the 24 months following initial treatment success and a 14-week tapering protocol, mean treatments per month was 1.3. Voiding diary and OAB-q data demonstrate sustained improvement reported at 13 weeks through 24 months. Improvements in frequency, urge incontinence episodes, night-time voids and moderate-to-severe urgency episodes from voiding diaries at 6, 12, 18, and 24 months were statistically significant compared to baseline (prior to initial 12 weekly treatments). Compared to baseline, OAB symptom severity scores and health related quality of life scores were statistically significant for improvement at each tested time point. Five mild adverse events of unknown relation to treatment were reported. Sustained safety and efficacy of PTNS were demonstrated over 24 months with initial success after 12 weekly treatments, followed by a 14-week prescribed tapering protocol and a Personalized Treatment Plan. With an average of 1.3 PTNS treatments per month, 82% reported moderate or marked improvement in OAB symptoms compared to baseline after 24 months. PTNS therapy seems to be a safe, OAB treatment option to sustain clinically significant OAB symptom control in the short-term up to a 24 month period. However, additional studies are Tibial Nerve Stimulation for Urinary Incontinence Oct 15 10

11 needed to compare PTNS to other methods currently being used for overactive bladder. In addition, this study had no placebo or sham group. There is an ongoing clinical trial on Modified Extension Study to the SUmiT Trial: Evaluation of Long Term Therapy with Percutaneous Tibial Nerve Stimulation (PTNS) for Overactive Bladder Symptoms (STEP). This clinical trial has the identifier of NCT , was last updated on April 13, 2012, and is no longer recruiting participants. This is a modified extension study to the SUmiT protocol UPC to observe and evaluate long-term therapy with PTNS on overactive bladder symptoms. Subjects must have completed the 12 weekly treatments of the original protocol, the 13 week follow up assessment, be randomized to the PTNS arm, and be considered a positive responder with moderate or marked improvement in the SUmiT Trial to be enrolled in this study. All consenting responders will continue with active PTNS therapy at an initially prescribed protocol for approximately 3 months followed by individualized symptom-based frequency of visits as determined by the subject along with their treating clinician, for up to a total of 33 months post initial 12-week therapy for a total of 3 years. The estimated primary completion date is June This is noted as the final data collection date for primary outcome measure. However, this is not completed at this time. The sponsor is Uroplasty, Inc. There is a randomized, double-blind clinical trial that was recently completed on the Study of Urgent PC Versus Sham Effectiveness in Treatment of Overactive Bladder Symptoms (SUmiT). The clinical trials identifier is NCT Information was provided by Uroplasty, Inc. There were 220 participants, 110 had the Urgent PC, and 110 had the placebo. The primary outcome was the global response assessment (GRA) for overall bladder symptoms to compare the proportion of subjects reporting "moderately" or "markedly improved" responses on the ggra after 12 interventions of randomized therapy, in an intent to treat analysis. The time frame was 13 weeks. After 12 Interventions of randomized therapy, 60 participants noted moderate or marked improvement with the Urgent PC, and 23 noted improvement after the placebo. Scientific Rationale Update June 2011 Agency for Healthcare Research and Quality (AHRQ), in the Treatment of Overactive Bladder in Women, Evidence Report/Technology Assessment, Number 187, 2009, states: Techniques for neuromodulation involve stimulating the S3 nerve fibers more peripherally, at the posterior tibial nerve. Only small case series suggest that posterior tibial nerve stimulation may improve overactive bladder (OAB) symptoms. Other forms of peripheral neuromodulation such as posterior tibial stimulation were not reviewed. Per the National Institute for Health and Clinical Evidence (NICE, 2010) Current evidence on percutaneous posterior tibial nerve stimulation (PTNS) for overactive bladder (OAB) syndrome shows that it is efficacious in reducing symptoms in the short and medium term, but not in the long-term. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC Assessments, December 2010, Volume 25) completed a study on Percutaneous tibial nerve stimulation for the treatment of voiding dysfunction, that states the following: This assessment reviewed three randomized control trials (RCTs) described below and concluded that posterior tibial nerve stimulation (PTNS) as treatment for voiding Tibial Nerve Stimulation for Urinary Incontinence Oct 15 11

12 dysfunction does not meet the TEC criteria due to insufficient data on durability of treatment. TEC stated that, although there is sufficient evidence the RCTs to establish a short-term benefit for PTNS, the evidence is not sufficient to permit conclusions on the long-term efficacy of PTNS treatment. Three randomized controlled trials evaluating percutaneous tibial nerve stimulation (PTNS) for treating OAB have been published, each of which was intended to evaluate the initial treatment phase: 1. Peters et al. (2010) The Study of Urgent PC Versus Sham Effectiveness in Treatment of Overactive Bladder Symptoms (SUmiT) trial was a multicenter randomized, controlled trial comparing PTNS, using the Urgent PC device, Uroplasty, Inc., to a sham placebo control group. A total of 220 patients were randomized, 110 to the PTNS group and 110 to the sham group. Both groups received 12 weekly 30-minute intervention sessions. The SUmiT trial received a quality rating of good using the U.S. Preventive Services Task Force (USPSTF) quality assessment measure, meeting all of the quality indicators and without evidence of systematic bias. One concern in interpreting the results of the SumiT trial was that the primary outcome measured used was a single-item global response assessment (GRA). A responder on this GRA scale was defined as a patient who reported moderate or marked improvement in symptoms at the end of the trial. This GRA measure did not include any pretreatment measure, thus precluding the calculation of change over time. The proportion of responders based on the primary outcome was 60 of 110 (54.5%) in the PTNS group and 23 of 110 (20.9%) in the sham group; this difference was statistically significant (p<0.001). All secondary outcomes also favored the PTNS group. The mean reduction in the symptom severity subscore of the OAB-q was / in the PTNS group and / in the sham group, for a mean treatment difference of 7.5 (p=0.01). The mean reduction in the health-related quality of life subscale of the OAB-q was / in the PTNS group and / in the sham group, for a mean treatment difference of 13.8 (p=0.006). For the four voiding diary variables used, there was a statistically significant difference between groups favoring PTNS. The mean change from baseline in the number of voids per day was /- 2.5 in the PTNS group and /- 2.4 in the sham group (difference between groups /- 2.5 voids per day, p=0.01). The mean change in nocturia episodes was /- 1.2 in the PTNS group and /- 1.4 in the sham group (difference between groups /- 1.3 nighttime voids, p=0.04). The mean change in moderate to severe urgency per day was -3.7 in the PTNS group and -2.0 in the sham group (difference between groups -1.7 episodes, p<0.001). Finally, the mean change in urge incontinence episodes was -1.3 in the PTNS group and -0.3 in the sham group (difference between groups -1 episode per day, p<0.002). The percent improvement for urinary incontinence (43%) was somewhat higher than the improvement in other voiding outcomes (20-24%). The question of clinical significance versus statistical significance is raised. Although percutaneous tibial nerve stimulation therapy is safe and effective in treating overactive bladder symptoms, this was a short-term study of only 12 weeks. There were no longterm results. 2. Finazzi et al. (2010) published a RCT from Italy with 35 female patients who had urge incontinence and detrusor overactivity on urodynamic testing. Patients were randomized to 30-minute PTNS sessions 3 times a week for 4 weeks Tibial Nerve Stimulation for Urinary Incontinence Oct 15 12

13 (n=18) or sham treatment (n=17). One patient dropped out of the PTNS group and 2 dropped out of the sham group. The primary outcome, percent responders at 4 weeks (defined as at least 50% reduction in incontinent episodes) was attained by 12/17 (71%) in the PTNS group and 0/15 (0%) in the sham group. The study did not conduct intention-to-treat analysis, was not double-blind and did not report follow-up data beyond 4 weeks. (There were some baseline differences on the voiding diary parameters between the PTNS and placebo groups). This trial by Finazzi et al. differed from the SUmiT in a number of other ways. A primary outcome measure of response was used that is more standard, i.e., greater than 50% reduction in incontinent or voiding episodes. Thirty-five women with urge incontinence and documented detrusor instability on urodynamic testing were enrolled, representing a subset of patients with OAB. The trial also treated patients three times per week for four weeks, rather than once per week for 12 weeks. This trial reported a large difference in response rates for the frequency of incontinent episodes (71% vs. 0%). A QOL measure specific to incontinence was used (I-QOL); the authors reported improvements in QOL over placebo that exceeded the MID for this scale. 3. MacDiarmid et al. (2010) completed the third RCT that was an unblinded comparison of 12 weeks of treatment with PTNS versus extended-release tolterodine (the Overactive Bladder Innovative Therapy or OrBIT trial, also evaluating the Urgent PC device). This study included 100 patients from 11 clinical centers. This trial received a quality rating of poor based on the USPSTF quality assessment measure. The trial did not meet several of the quality indicators, including a lack of double blinding, unequal intensity of treatment with no placebo control, and lack of an intention-to-treat analysis. The methods state that this was planned as a noninferiority study, but results of noninferiority testing are not reported correctly. These numerous methodologic limitations were judged to be a fatal flaw for the study, thus resulting in the poor quality rating. The primary outcome was the mean reduction in the number of voids per 24 hours. Results showed a similar decrease in number of voids per day in the PTNS and tolterodine groups (2.5 +/- 3.9 vs /- 4.0, respectively, p=ns). The study also reported a number of secondary outcomes based on voiding diaries. There were no statistically significant differences between the PTNS and tolterodine groups for other voiding diary parameters, including mean change in episodes of nocturia (-0.7 and -0.6, respectively), episodes of moderate to severe urgency per day (-2.2 and -2.9, respectively) and episodes of urge incontinence per day (-1.0 and -1.7, respectively). There were also no significant differences in the improvement reported in quality of life as measured by the OAB-q scale. In conclusion, there is fairly strong evidence for short-term efficacy up to 12 weeks, but insufficient evidence to establish durability of treatment effect. The overall quality of the short-term evidence, as rated by the GRADE method, was moderate for the outcomes of incontinence and QOL, and poor for other outcomes. Longer-term durability of treatment response has not been demonstrated. Beyond 12 weeks, there is no high-quality evidence that supports efficacy over longer periods of time. The available evidence on durability consists of one follow-up study of responders from an unblinded randomized, controlled trial that was rated of poor quality. This follow-up study did not include any credible control group and therefore cannot be used to draw inferences about the efficacy of treatment over longer periods of time. As a result, the evidence is not Tibial Nerve Stimulation for Urinary Incontinence Oct 15 13

14 sufficient to determine whether health outcomes are improved following treatment with PTNS. Future research should concentrate on longer-term controlled trials that evaluate whether PTNS provides benefit for patients with OAB beyond the initial treatment period. Per TEC, the evidence is not sufficient to determine the effect on net health outcome and/or whether it is as beneficial as alternatives, and whether PTNS for the treatment of voiding dysfunction improves the net health outcome, has not been demonstrated. Until the durability of percutaneous tibial nerve stimulation has been demonstrated in well-designed long-term comparative studies and its clinical impact more clearly shown, its efficacy for treating overactive bladder syndrome remains uncertain. Additional Study Peters et al. (2009) completed a non-blinded, multicenter trial of 100 patients with overactive bladder symptoms randomly assigned to either percutaneous tibial nerve stimulation or tolterodine extended release 4 mg daily. After 12 weeks of therapy, there was no difference between the groups in the primary outcome, urinary frequency, or secondary outcomes including urge urinary incontinence episodes, urge severity, and nighttime voids. Overactive bladder is a condition whose prevalence increases with aging, and which can substantially impair quality of life. It is defined by presence of urinary urgency, in the absence of other causes of similar problems. The underlying mechanisms are incompletely understood, but may include increased excitability of smooth muscle, abnormal spread of excitation through the bladder wall, increased sensory nerve activity, and altered processing of information in the central nervous system. Clinical assessment requires evaluation of symptoms and their impact, and exclusion of confounding co-morbidities. Initial treatment comprises fluid advice and bladder training, followed by drug prescription. Antimuscarinic drugs can improve symptom severity and quality of life, but adverse effects include dry mouth, constipation and cognitive impairment. Optimising medical management requires tailoring drugs according to efficacy and adverse effects, and also checking compliance. Refractory bothersome symptoms merit secondary care input, usually with urodynamic evaluation to define underlying mechanisms. Neuromodulatory techniques (sacral or tibial nerve stimulation) and reconstructive surgery (augmentation cystoplasty, detrusor myectomy or urinary diversion) can be offered in severe cases, but can have inadequate outcomes and significant implications. Newer approaches under investigation include pharmaceutical interventions to reduce cellular excitability or generation of sensory nerve activity; potential targets include beta-3 adrenergic receptors, Transient Receptor Potential (TRP) channels and surface ion channels. Voiding dysfunction is common and long-term effects uncertain. In summary, the evidence is not sufficient at this time to determine whether health outcomes regarding urinary dysfunction are improved following treatment with PTNS. There is currently no data that shows sustained improved overactive bladder (OAB) symptoms after one year. Future research should concentrate on longer-term controlled trials that evaluate whether PTNS provides benefit for patients with overactive bladder beyond the initial treatment period. Scientific Rationale Update March 2011 de Sèze et al (2011) investigated the efficacy of the noninvasive technique of PTNS in a multicenter study of 70 patients with multiple sclerosis (MS), with OAB for a 3-month study period. Daily sessions of 20 min of PTNS were provided. No change of associated treatments Tibial Nerve Stimulation for Urinary Incontinence Oct 15 14

15 during the study period. The primary outcome measurement was Urgency and Frequency reported by bladder diary and symptom score performed before the treatment (Day 0, D0) and at D30 and D90. The secondary outcomes measurements were continence, symptom score, quality of life, psychosocial burden at DO, D30, and D90 and cystometry at baseline, with and without PTNS and at D90. Clinical improvement of OAB was shown in 82.6% and 83.3% of the patients on D30 and D90, respectively, with significant improvement of primary and secondary outcomes compared to baseline. The initial acute cystometric response to PTNS was positive in 51.2% of the patients (increase of >30% of cystometric capacity and/or reflex volume), without correlation with PTNS clinical efficiency. The procedure was well tolerated. The investigators concluded chronic PTNS appears to be effective in the management of severe OAB in MS, without compromising bladder emptying or inducing side effect. Treatment may be effective even in the absence of an acute cystometric effect. Additional works are required to demonstrate long-term efficacy of PTNS. MacDiarmid et al (2010) reported on the second phase of the Overactive Bladder Innovative Therapy Trial, a randomized trial that demonstrated comparable effectiveness of percutaneous tibial nerve stimulation (PTNS) and extended-release tolterodine during 12 weeks of therapy for frequency, nocturia, urgency, voided volume and urge incontinence, assessing the sustained therapeutic efficacy of PTNS in individuals with overactive bladder during 1 year. After 12 weeks individuals randomized to weekly PTNS with Urgent PC were offered an additional 9 months of treatment with assessments at 6 and 12 months from baseline. Outcome measures included voiding diary data, overactive bladder questionnaires, global response assessments and safety assessments. A total of 33 PTNS responders continued therapy with 32 and 25 individuals completing 6 and 12 months of therapy, respectively. Individuals received a mean of 12.1 treatments during an average of 263 days, with a mean of 21 days (median 17) between treatments. Subject global response assessments showed sustained improvement from 12 weeks at 6 and 12 months, with 94% and 96% of responders, respectively. At 12 months mean improvements from baseline included a frequency of 2.8 voids daily, urge incontinence of 1.6 episodes daily, nocturia with 0.8 voids and a voided volume of 39 cc. Overactive bladder questionnaire symptom severity was significantly improved from 12 weeks to 12 months as well as from 6 to 12 months. No serious adverse events occurred. The investigators concluded statistically significant overactive bladder symptom improvement achieved with 12 weekly PTNS treatments demonstrates excellent durability through 12 months. Peters et al (2010) reported results of a multicenter, double-blind, randomized, controlled trial [Study of Urgent PC vs Sham Effectiveness in Treatment of Overactive Bladder Symptoms (SUmiT)] comparing the efficacy of PTNS to sham through 12 weeks of therapy. The improvement in global response assessment, voiding diary parameters, and overactive bladder and quality of life questionnaires was evaluated. 220 adults with overactive bladder symptoms were randomized 1:1 to 12 weeks of treatment with weekly PTNS or sham therapy. Overactive bladder and quality of life questionnaires as well as 3-day voiding diaries were completed at baseline and at 13 weeks. Subject global response assessments were completed at week 13. The 13-week subject global response assessment for overall bladder symptoms demonstrated that PTNS subjects achieved statistically significant improvement in bladder symptoms with 54.5% reporting moderately or markedly improved responses compared to 20.9% of sham subjects from baseline. All individual global response assessment subset symptom components demonstrated statistically significant improvement from baseline to 13 weeks for PTNS compared to sham. Voiding diary parameters after 12 weeks of therapy showed PTNS subjects had statistically significant improvements in frequency, nighttime voids, voids with moderate to severe urgency and urinary urge incontinence episodes compared to sham. No serious device related adverse Tibial Nerve Stimulation for Urinary Incontinence Oct 15 15

16 events or malfunctions were reported. The authors concluded this trial provides level I evidence that PTNS is safe and effective in treating overactive bladder symptoms. Schreiner et al (2010) investigated 51 elderly women (>60 years) with urge urinary incontinence (UUI) treated with 12 weeks of bladder retraining and pelvic floor muscle exercises. In addition 25 were randomly selected to receive PTNS in addition to the standard therapy. The cases were evaluated at the baseline and after the end of therapy by 3-day bladder diary, quality of life questionnaires (QoL), and subjective response. Of the patients, 68.0% in PTNS group reported cure or improvement vs. 34.6% in the control group. PTNS showed significant improvement in most areas of QoL and in UUI parameters when compared with the control group. The investigators concluded PTNS is efficacious to treat UUI in older women. Yoong et al (2010) described initial outcome data following a shortened 6-week treatment protocol with PTNS in women with overactive bladder syndrome (OABS) unresponsive to bladder retraining and anticholinergic therapy in a prospective observational study over a 6- month period. In all, 43 women with OABS refractory to medical therapy were treated with a shortened PTNS protocol that consisted of 6 weekly 30 min sessions. Bladder symptom diaries and health-related quality of life (HRQL) assessed using the short-form seven-item self-report. Incontinence Impact Questionnaire (IIQ-7) were completed before and after treatment. A positive response was defined as: OAB symptoms no longer being bothersome; reduction by half in frequency episodes and reduction by 25% in IIQ-7 outcomes. All 43 women (median age 55.3 years) completed six treatments with a positive response rate of 69.7%. In the positive responders, the median daytime and nocturnal frequency was reduced by half after 6 weeks of treatment (11.8 vs 6.9 and 3.5 vs 1.8, respectively and the patients reported fewer urge leak episodes per 24 h (median 3.5 vs 2.4). The median IIQ-7 scores improved by 25% (30.4 vs 24.35) in responders, while the median number of pads changed in 24 h also decreased by 34% (3.8 vs 2.5). The median acceptability of the technique when scored by Visual Analogue Score was 9.6/10 and no side-effects were reported. The investigators concluded a shortened 6-week treatment with PTNS appears to be successful, with a significant reduction in symptoms and improvement in HRQL. This early data suggest that the duration of treatment for peripheral neuromodulation can be halved compared with the conventional 12 weeks, which would make it more acceptable and cost effective for patients. A randomized controlled trial of 6 weeks vs 12 weeks of PTNS therapy would be useful in determining the optimal duration of treatment. There is some evidence from uncontrolled studies indicating that percutaneous tibial nerve stimulation may be an effective and safe therapy for adult patients with urinary frequency, urgency, and urge incontinence, however, most studies were limited by their small size. Scientific Rationale Update September 2009 Peters et al (2009) randomized 100 adults with urinary frequency 1:1 to 12 weeks of treatment with weekly percutaneous tibial nerve stimulation (PTNS) or to 4 mg daily extended-release tolterodine in the Overactive Bladder Innovative Therapy trial. Voiding diaries and an overactive bladder questionnaire completed at baseline and at the end of therapy compared 24-hour voiding frequency, urinary urge incontinence episodes, voids causing waking, volume voided, urgency episodes and quality of life indices. Global response assessments were completed by subjects and investigators after 12 weeks of therapy. The global response assessment demonstrated that subject assessment of overactive bladder symptoms compared to baseline was statistically significant in the percutaneous tibial nerve stimulation arm with 79.5% reporting cure or improvement Tibial Nerve Stimulation for Urinary Incontinence Oct 15 16

17 compared to 54.8% of subjects on tolterodine. Assessments by investigators were similar but did not reach statistical significance. After 12 weeks of therapy objective measures improved similarly in both groups for reductions in urinary frequency, urge urinary incontinence episodes, urge severity and nighttime voids, as well as for improvement in voided volume. There were no serious adverse events or device malfunctions. The investigators concluded that PTNS is safe with statistically significant improvements in patient assessment of overactive bladder symptoms, and with objective effectiveness comparable to that of pharmacotherapy. Kabay et al (2009) investigated the effect of PTNS after 12 weeks, on the urodynamic findings in 19 patients with Multiple Sclerosis (MS) with neurogenic detrusor overactivity (NDO). Urodynamic studies before and after 12 weeks PTNS were performed. The improvements in the 1st involuntary detrusor contraction (IDCV) and Mean maximum cystometric capacity (MCC) were statistically significant after stimulation. Mean P (detmax) at first involuntary detrusor contraction, maximal detrusor pressure at maximum cystometric capacity, detrusor pressure at maximal flow [P(detQmax)] and maximal flow rate [Q(max)] were statistically significant after PTNS for 12 weeks. The investigator concluded that the use of PTNS for DO in MS patients is promising. Kabay et al (2009) also evaluated the acute effects of PTNS in 32 patients with Parkinson's disease and neurogenic detrusor overactivity (NDO). Urodynamic studies before and during PTNS were performed. Electrical stimulation was applied unilaterally from the medial malleolus and posterior to the edge of the tibia by using charge-compensated 200 microsec pulses with a pulse rate of 20 Hz. Mean first involuntary detrusor (1st IDCV) contractions and means maximum cystometric capacity (MCC) before and during PTNS was compared. Mean 1st IDC and mean MCC were significantly improved during PTNS. van der Pal et al (2006) investigated the effect of a pause in PTNS in successfully treated patients with an overactive bladder (OAB), and the reproducibility of successful treatment when restored. Eleven patients with refractory OAB (more than seven voids and/or three or more urge incontinence episodes per day) were successfully treated with PTNS, and then discontinued treatment. Patients completed bladder diaries and quality-of-life (QoL) questionnaires (Short Form-36 and I-QoL) before (T1) and after a 6-week pause (T2) of maintenance PTNS, and again after re-treatment (T3). The first objective was defined as a > or = 50% increase in the incontinence episodes and/or voiding frequency in the bladder diary after T2. The second objective was defined as > or = 50% fewer incontinence episodes and/or voiding frequency in bladder diary after T3. At T2, seven of the 11 patients had a > 50% increase in incontinence episodes and/or voiding frequency in the bladder diary. The mean voided volume, nocturia, number of incontinence episodes and incontinence severity deteriorated significantly. At T3, nine patients had > 50% fewer incontinence episodes and/or voiding frequency in the bladder diary. Nocturia, the number of incontinence episodes, incontinence severity, mean voided volume and quality of life improved significantly. The investigators concluded that continuous therapy is necessary in patients with OAB treated successfully by PTNS and efficacy of PTNS can be reproduced in patients formerly treated successfully. Several local Medicare carriers have issued non-coverage policies regarding posterior tibial nerve stimulation (PTNS) for diverse pelvic floor dysfunction including but not limited to urinary frequency, urgency, incontinence, non-obstructive retention, detrusor hypocontractility, bowel dysfunction, interstitial cystitis, pelvic pain and overactive bladder. They note that due to insufficient scientific data supporting it use, PTNS, is considered investigational and therefore, not reasonable and necessary. Tibial Nerve Stimulation for Urinary Incontinence Oct 15 17

18 Scientific Rationale Initial Urinary incontinence is a prevalent condition that impacts many lives. The primary symptom is leakage of urine. Stress incontinence can occur during activities that apply pressure to a full bladder, even with minor activities such as coughing, sneezing, laughing and lifting. The leakage stops when the activity stops. Stress incontinence occurs because the internal sphincter does not close completely. In both men and women, the aging process causes a general weakening of the sphincter muscles and a decrease in bladder capacity. Many women who have had many children through vaginal deliveries are prone to one or both of these problems. In such cases, pregnancy and childbirth strain the muscles of the pelvic floor. Of note is prolapsed uterus, in which the uterus protrudes into the vagina, which occurs in at least half of all women who have given birth. This condition can often cause incontinence. In urethral hypermobility the urethra does not close properly because it is too hypermobile. This condition typically occurs when the pelvic floor muscles in women become weak and the following events occur: (1) the weakened pelvic floor muscles stretch; (2) the bladder sags downward within the abdomen; and (3) the sagging bladder pulls on the muscles surrounding the internal sphincter of the bladder neck. In men, prostate treatments, such as surgery or radiation, can impair the sphincter muscles. Incontinence occurs in nearly all male patients for the first three to six months after radical prostatectomy. After a year of the procedure, most men retain continence, although leakage can occur. Stress incontinence can also occur in 1% to 5% of men after transurethral resection of the prostate (TURP), the standard treatment for severe benign prostatic hyperplasia. When incontinence persists or is not related to activities that apply pressure to a full bladder, it is more likely to be urge incontinence. Urge incontinence involves a strong and sudden need to urinate, followed by a bladder contraction, which results in leakage. The primary symptom of urge incontinence is the need to urinate frequently with subsequent leakage. In some people, it occurs only at night (called nocturnal enuresis). All cases of urge incontinence (also called hyperactive or irritable bladder) involve an overactive bladder. In such cases, the detrusor muscle, which surrounds the bladder, contracts inappropriately during the filling stage. When this occurs, the urge to urinate cannot be voluntarily suppressed, even temporarily. There is usually one of two types: (1) idiopathic detrusor overactivity in which the nerves serving the bladder have signaled the brain appropriately that the bladder is full, but the detrusor muscles are unable to be suppressed; and (2) neurogenic detrusor overactivity in which a known neurologic abnormality impairs the signaling systems between the bladder and the central nervous system, and the brain is unable to inhibit the detrusor muscles controlling urination. Overflow incontinence happens when there is an impediment to the normal flow of urine out of the bladder and the bladder cannot empty completely. It can be due to a number of conditions. In the case of a partial obstruction, the urine cannot flow completely out of the bladder or a person can have an inactive bladder muscle such that the bladder cannot empty properly and becomes distended. Eventually this distention stretches the internal sphincter until it opens partially and leakage occurs. The causes of the conditions leading to overflow incontinence include tumors, certain medications (anticholinergics, antidepressants, antipsychotics, sedatives, narcotics, alpha-adrenergic agonists, beta-adrenergic agonists, calcium channel blockers), benign prostatic hyperplasia, scar tissue and nerve damage. In the case of the latter, nerves in the bladder are damaged so that they are not sensitive to fullness and so do not trigger contraction. Damage can be caused by spinal cord injuries, previous surgery in the colon or rectum, and pelvic fractures. Diabetes, multiple sclerosis, and shingles can also affect nerves in this way. Tibial Nerve Stimulation for Urinary Incontinence Oct 15 18

19 Pelvic floor dysfunction is a common problem affecting many women and men. This common pathophysiologic mechanism may manifest in diverse clinical scenarios including urinary frequency, urgency, incontinence, or retention. Existing pharmacologic options for urinary complaints referable to pelvic floor dysfunction remain suboptimal because of the high incidence of side effects, relatively modest benefit, and poor long-term patient compliance. Surgical therapy for what is primarily a functional rather than anatomic disorder does not yield consistently favorable results. In recent years, therefore, therapy of pelvic floor dysfunction by means of modulation of the sacral nervous outflow tract has been the subject of increasingly intense research and clinical applications. In the earlier studies, efforts have focused on stimulation of the sacral nerve roots at their egress from the spinal cord. Although successful for many patients, central sacral neuromodulation has significant drawbacks. Placement of the permanent stimulator is invasive and the system requires trial runs with percutaneous needles placed through the back and through the sacral foramina, and in the vast majority of cases requires a general anesthetic for placement. Moreover, the complication rate is relatively high, and as many as 30% of patients receiving sacral neuromodulators eventually require reoperation. Despite recent improvements, neural leads continue to migrate, limiting the long-term use of this central approach. Because of this, various other approaches have been investigated. One such method involves repetitive stimulation of the posterior tibial nerve, a mixed sensory-motor nerve containing fibers originating from spinal roots L4 through S3. This nerve comprises the outflow of the sacral nerves that modulate the somatic and autonomic nervous supply to the pelvic floor, which directly innervates the bladder and urinary sphincter. The procedure, called percutaneous tibial nerve stimulation (PTNS) involves identification of a consistent area of high impedence over the posterior tibial nerve above the medial malleolus. Studies have shown that PTNS abolishes inappropriate detrusor contractions, leaving the micturition reflex intact. Moreover, the therapeutic effect tends to increase with repetitive weekly treatments over 2 to 3 months, at which point treatment intervals can successfully be decreased for durable long-term results and minimal inconvenience to patients. PTNS has been studied primarily among patients with overactive bladder (OAB), urge incontinence, and detrusor hypocontractility. In 1983, McGuire et al first reported the use of transcutaneous tibial nerve stimulation to inhibit detrusor activity in 15 patients with a variety of neural lesions. They applied electrical stimulation by an adhesive electrode, achieving astonishingly good results among most of the patients with a range of bladder complaints including detrusor instability, interstitial cystitis, radiation cystitis, and neurogenic bladder. Eight of 11 patients with detrusor instability were judged dry with stimulation as assessed by urodynamics and cystography; an additional two (both patients with multiple sclerosis) were improved. Four of five neurogenic bladder patients were likewise dry and one improved, and four of six cystitis patients experienced some degree of improvement. These early data, even with outcomes not rigorously measured, collected or reported, made the potential use of peripheral neuromodulation for bladder symptoms seem quite promising with respect to the majority of patients with various types of incontinence. Four years later, the Stoller Afferent Nerve Stimulator (SANS) was introduced, offering a method for percutaneous tibial nerve stimulation (PTNS) by a solid 34-gauge needle. Rather than requiring an incision and placement of electrodes in the sacrum, PTNS utilizes the nerve root S3, but at a location much closer to the surface of the skin, i.e., slightly above the ankle. It has been approved by the FDA for use in refractory overactive bladder. During this technique, the patient is positioned in a frog-leg fashion. The needles are placed Tibial Nerve Stimulation for Urinary Incontinence Oct 15 19

20 bilaterally three finger-breadths superior to the medial malleolus and posterior to the tibia. They are advanced to a depth of approximately 4 cm, at roughly a 30-degree angle cephalad, and in a trajectory that exits anterior to the fibula. Electrical stimulation is typically administered from a 9-V battery-powered generator, at amplitude of 0.5 to 10 ma, with a fixed pulse width (200 μs) and frequency (20 Hz). Confirmation of appropriate needle localization is verified by great toe plantar flexion, or digits two through five fanning or plantar flexion in response to increasingly high amplitude stimulation. On the side with the more pronounced response to the test stimulation, the amplitude is then reduced to a level just below the somatic sensory threshold, and is applied continuously for 30 minutes. Sessions are repeated weekly for 10 to 12 weeks; repeated sessions are required to reverse chronic dysfunctional neural pathways. Patients complete voiding diaries before and throughout the duration of therapy; if they experience significant improvement in their symptoms, the frequency of therapy is tapered gradually after the 10- to 12-week induction period to every 3 or 4 weeks. Some patients have been treated continuously for up to 10 years with treatment every 4 to 6 weeks, enjoying consistent improvement of symptoms. It has been demonstrated that when the SANS sessions were stopped for longer periods of time for selected patients, symptoms returned within a period of weeks to months. Govier et al (2001) has reported the only prospective, multicenter United States experience with the SANS device. Fifty-three patients with overactive bladder refractory to standard medical treatments were treated with 12 weekly bilateral SANS sessions. Eighty-nine percent of patients completed the study. Seventy-one percent of patients overall met the study goal of a greater than or equal to 25% reduction in daytime or nighttime urinary frequency, with mean reductions in diurnal, nocturnal, 24-hour, and excess (>10 episodes per day) frequency of 25%, 21%, 22%, and 70%, respectively. On standardized questionnaires administered during the study, participants reported a mean 35% improvement in urge incontinence episodes and a 20% improvement in incontinence-related quality of life. Payne (1998) found a statistically significant improvement in diurnal and nocturnal frequency in 98 patients studied, with 80% of patients having a 75% reduction in incontinence. Van Balken et al (2001), in a prospective multicenter trial, evaluated posterior tibial nerve stimulation in 37 patients who presented with symptoms of bladder overactivity (urgency and frequency syndrome and/or urge incontinence), and 12 with nonobstructive urinary retention. Results were recorded in voiding diaries and on quality of life questionnaires before and after treatment. Patients were classified as responders, including those in whom therapy was successful and chose to continue treatment after the initial 12 weeks; nonresponders were those who chose to stop treatment. Overall, a positive response was seen in 60% of all patients. In patients with bladder overactivity, a statistically significant decrease was observed in leakage episodes, number of pads used, voiding frequency and nocturia, and an equal increase in mean and smallest volume voided. Improvements were also seen in nonobstructive urinary retention, including number of catheterizations, total and mean volume catheterized, and total and mean volume voided. Disease specific quality of life and some domains of general quality of life improved, especially in patients with bladder overactivity. They deduced that posterior tibial nerve stimulation is a minimally invasive and successful treatment option for patients with certain types of lower urinary tract dysfunction. The European experience to date has been more robust. The first published report was made by Klingler et al (2000) who studied the efficacy of peripheral neuromodulation of the S3 region in 15 OAB patients with urgency-frequency syndrome due to an overactive bladder. Full urodynamic workup was performed before and after 12 peripheral stimulations Tibial Nerve Stimulation for Urinary Incontinence Oct 15 20