TITLE:

Percutaneous Tibial Nerve Stimulation for the Treatment of Overactive Bladder

AUTHOR:

Judith Walsh, MD, MPH Professor of Medicine Division of General Internal Medicine Department of Medicine University of California San Francisco

PUBLISHER:

California Technology Assessment Forum

DATE OF PUBLICATION: June 20, 2012

PLACE OF PUBLICATION: San Francisco, CA

Page 1 of 38

PERCUTANEOUS TIBIAL NERVE STIMULATION (PTNS) FOR THE TREATMENT OF OVERACTIVE BLADDER A Technology Assessment

INTRODUCTION

The California Technology Assessment Forum (CTAF) is requested to review the scientific evidence for the use of percutaneous tibial nerve stimulation (PTNS) for the treatment of overactive bladder (OAB). This is the first time that CTAF has addressed this topic.

BACKGROUND

Urinary incontinence, defined as the involuntary loss of urine, is common, particularly in women. Despite its significant consequences, it is often under recognized and under treated. In one survey of a multi-ethnic population, only 45% of women who reported at least one incontinence episode a week had sought out care for their symptoms of incontinence.1

There are several types of incontinence: urge incontinence, stress incontinence, mixed incontinence and overflow incontinence. Urge incontinence is thought to be related to detrusor overactivity. Stress incontinence is urine loss that occurs with an increase in abdominal pressure, and is often due to urethral hypermobility. It is the commonest type of incontinence in younger women.

Mixed incontinence (urge and stress) is the commonest type of incontinence in older women. Overflow incontinence describes dribbling or leaking associated with incomplete bladder emptying.

OAB definition The term voiding dysfunction has been used to refer to urinary incontinence, urinary retention and symptoms of frequency and urgency. Overactive bladder is a specific type of voiding dysfunction that includes any or all of the following symptoms: urinary frequency (bothersome urination eight or more times a day or two more times at night), urinary urgency (the sudden, strong need to urinate immediately), urge incontinence (leakage or gushing of urine that follows a sudden strong urge) and nocturia (awakening two or more times at night to urinate). It can be associated with neurologic conditions, such as Parkinsons disease or multiple sclerosis, but in most cases the cause is unknown. OAB can significantly impact quality of life; it can impact physical functioning, sexual function and social interactions.

Standard treatments The standard treatments for overactive bladder include lifestyle changes, bladder training, pelvic floor muscle training and anticholinergic (anti-muscarinic) drugs. Additional treatments for some types of incontinence include pessary placement and surgery. Sacral nerve stimulation has also been tried.

1. Lifestyle changes Weight loss has been shown to decrease episodes of urinary incontinence, although the impact seems to be more on stress than on urge incontinence.2-4 Other suggested approaches include elimination of alcohol, coffee or tea or carbonated beverages.

2. Bladder training The principles of bladder training include frequent voluntary voiding in order to keep the bladder volume low and therefore avoid detrusor contractions and timing of CNS and pelvic mechanisms to inhibit the urge to urinate. Patients are taught to use timed voiding (voiding at regular intervals regardless of urge to urinate) and also to use relaxation techniques to suppress urgency that occurs between voids. Over time the interval between voids is increased. Successful training can occur over a several week period.

3. Pelvic muscle exercises Pelvic muscle exercises (or Kegels) focus on strength training of the pelvic floor muscles. When patients are trained to do them correctly, they can improve symptoms of stress, urge or mixed incontinence.

4. Biofeedback Biofeedback is sometimes used as a supplement to bladder training. The biofeedback focuses on anorectal or vaginal biofeedback to help patients contract the pelvic muscles, and includes how to respond to feelings of urgency.5

5. Pharmacologic Therapy The most commonly used drugs are anticholinergic drugs that have antimuscarinic properties. Their main mechanism of action is to increase bladder capacity and decrease urgency.6 Systematic reviews have shown that these drugs are significantly better than placebo in decreasing the number of

incontinent episodes and voids over a 24 hour period.7,8 In general the efficacy of these drugs increases up to four weeks.

Although the anticholinergic drugs are efficacious for urge incontinence, their side effects can significantly limit their use. The commonest side effects include dry mouth and constipation. Other side effects can include blurred vision, drowsiness and decreased cognitive function. About 80% of patients discontinue treatment after a year ,9 and about 17% of the discontinuation is because of adverse side effects. 10

Other medications that have been used for some types of urinary incontinence include alpha-adrenergic agents, duloxitene and topical estrogen. Botulinum toxin has also been injected into the detrusor muscle with some success, although it can sometimes cause post treatment urinary retention.

6. Surgery Surgery is sometimes performed for incontinence refractory to other treatments, but can be associated with significant complications. It is not a standard treatment for OAB.

7. Pessaries Specially fitted pessaries can be used in women with prolapse and can relieve symptoms of incontinence.

Neurologic Stimulation Therapy The theory of neurologic stimulation therapy is that stimulation of the nerves can stimulate pelvic muscle contractions or detrusor contractions. The initial studies of neurologic stimulation therapy focused on the sacral nerve.11-14

Although sacral nerve stimulation can improve symptoms of incontinence, the implantable sacral nerve stimulators are somewhat invasive. Currently many studies are focusing on a less invasive approach, percutaneous tibial nerve stimulation (PTNS).

History of PTNS PTNS was developed by Dr. Marshall Stoller at UCSF as a less invasive alternative to sacral nerve stimulation (SNS). The first devices were called Stoller Afferent Nerve Stimulators (SANS). Although the exact mechanism of action is unclear, it is thought to interrupt abnormal reflex arcs that may affect bladder dysfunction.15 PTNS involves a needle electrode being inserted into the posterior tibial nerve at the medial malleolus of the ankle. It is inserted about 3-4 centimeters. The electrode is then connected to a hand held nerve stimulator which sends an electrical impulse to the nerve. This nerve impulse is then transmitted to the sacral plexus which regulates the control of bladder and pelvic floor muscles. The maximum treatment intensity is determined in the following way: the stimulus intensity is increased slowly until the patients great toe begins to curl. The level at which the patients toe curls is determined to be the maximum intensity for treatment. Currently a treatment course is defined as one treatment a week for 12 weeks. Each treatment session lasts 30 minutes. Maintenance treatment is given at intervals determined by whether and when symptoms recur.

The goal of this assessment will be to focus on the role of PTNS in the treatment of overactive bladder.

TECHNOLOGY ASSESSMENT (TA)

TA Criterion 1:

The technology must have final approval from the appropriate government regulatory bodies.

Percutaneous Tibial Nerve Stimulation (PTNS) is a procedure that delivers retrograde access to the sacral nerve plexus via electrical stimulation of the posterior tibial nerve using The Urgent PC Modulation System by Uroplasty. The device consists of the Urgent PC Stimulator, a battery operated external pulse generator, and the Urgent PC Stimulation Lead Set which transfers the electrical current from the Urgent PC Stimulator to the tibial nerve.

The Urgent PC Modulation System first received FDA 510K marketing clearance (K052025) in 2005 for the treatment of urinary urgency, urinary frequency, and urge incontinence. The FDA considers the Urgent PC Modulation system as a class II, nonimplanted peripheral nerve stimulator for pelvic floor dysfunction. The FDA deemed another device - Percutaneous Stoller Afferent Nerve Stimulation System (PerQ SANS) by Urosurge substantially equivalent to the Urgent PC Modulation System. PerQ SANS received FDA market clearance in 2000 (K992069). It is unclear if PerQ SANS is still available in the market as Urosurge has ceased operations.

TA Criterion #1 is met

TA Criterion #2: The scientific evidence must permit conclusions concerning the effectiveness of the technology regarding health outcomes.

The Medline database, Cochrane clinical trials database, Cochrane reviews database and Database of Abstracts of Reviews of Effects (DARE) were searched using the search terms urinary bladder, overactive or overactive bladder or bladder overactivity or urinary tract dysfunction or voiding dysfunction or urinary dysfunction or bladder dysfunction or detrusor dysfunction or urinary bladder disease or urination disorders or urinary incontinence AND electric stimulation therapy or transcutaneous electric nerve stimulation or tibial nerve or electric stimulation or stoller. The search was performed for the period from database inception to May, 2012. The earliest relevant article was published in 1982. The bibliographies of systematic reviews and key articles were manually searched for additional references and references were requested form the device manufacturer. The abstracts of citations were reviewed for relevance and all potentially relevant articles were reviewed in full.

Inclusion criteria: Study had to evaluate percutaneous tibial nerve stimulation (PTNS) in patients with overactive bladder and/or incontinence. Study had to be prospective Study had to measure clinical outcomes Included only humans Published in English as a peer reviewed article Studies were excluded if they only focused on non-clinical outcomes.

A total of 78 potentially relevant articles were identified. All 78 titles were reviewed. Sixty two were excluded for not addressing the research question. A total of 16 abstracts were evaluated. Four abstracts were excluded. Reasons for exclusion included not addressing the research question, not using PTNS, not focusing on clinical outcomes, or not being prospective. Of these, eight published prospective studies and four clinical trials are included in this evaluation (one study had two publications).

Details of the observational studies assessing the impact of PTNS on OAB symptoms are described in Table 1. Details of the clinical trials assessing the impact of PTNS on OAB symptoms are described in Tables 2 and 3.

Outcomes There are several clinical outcomes relevant to urinary incontinence. Typical outcomes include a reduction in episodes of urinary incontinence (e.g. number or percent reduction per day), or cure which is defined as a complete absence or urinary incontinence episodes over a particular time period. Other outcomes include urinary frequency (number of daily episodes), frequency of urgency symptoms or nocturia or bladder capacity. Many of these outcomes are measured through the use of voiding diaries. Another outcome commonly used in urinary incontinence trials is a Global Response Assessment (GRA). In one study, a responder is defined as reporting bladder symptoms as moderately to markedly improved on a 7 level GRA scale.16 In at least one study, patients with at least a 50% reduction in urge incontinence episodes are considered responders to the intervention.17 Other

outcomes include objective success (percent reporting >50% reduction in symptoms) or subjective success (percent requesting ongoing treatment).

Objective measures of urinary incontinence episodes may not adequately reflect the impact of the incontinence on the individuals quality of life. Thus some urinary incontinence specific quality of life measures have been developed. These include Urogenital Distress Inventory (UDI-6) and the Incontinence Impact Questionnaire (IIQ-7).18 These are self administered scales which are validated and where higher scores indicate more bothersome symptoms. Other scales measuring the impact of overactive bladder on quality of life include the Overactive Bladder Questionnaire (OAB-q)19 and the Incontinence Quality of Life Scales (IQOL).20 The IQOL measures avoidance and limiting behavior, psychosocial impact and social embarrassment.

Finally, the natural history of urinary incontinence is that remission rates can range from 0-13% a year.21 Contributing factors may include changes in fluid intake, voiding habits or activity levels, treatment of co-morbid conditions or medication changes. In addition, the placebo response rate in incontinence studies tends to be high- about 30-40%.8

Level of Evidence: 1,2,5 TA Criterion # 2 is met

10

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Table 1: Prospective Observational Studies of PTNS Study, year, location N Intervention Inclusion Duration Outcomes of followup 12 weeks 25% reduction in mean daytime and 21% reduction in mean nighttime voids (p<0.05) 12 weeks Objective success (defined as >50% reduction in symptoms/24 hours) in 37% of participants. Subjective success 55% (requested ongoing treatment) 12 weeks Subjective success 59%(requesting ongoing treatment) Reduced urinary frequency (2.8 (-0.8 to -4.9) Improved disease specific QOL 10.9 Reduction in pelvic pain on months VAS from mean 7.6 (5 to 10( down to 3,1 (1 to 7) Comments

Govier, 2001, USA22

53

Weekly PTNS

Patients with OAB who had failed traditional therapy Patients with OAB

No treatment related adverse effects

Van Balken, 83 2006, Netherlands23

PTNS weekly for 12 weeks

No adverse events reported

Van Balken, 37 2001, Netherlands24

PTNS weekly for 12 weeks

Patients with OAB

Minor bleeding and temporary pain at insertion site

Klinger, 2000 Austria25

15

PTNS weekly for 12 weeks

Patients with urgency-frequency due to OAB

No complications

12

Study, year, location

Intervention

Inclusion

Duration of followup

Outcomes

Comments

Vandonnick, 2003 Austria26

90

PTNS weekly for 12 weeks

Patients with symptoms of OAB

Van der Pal, 30 2006 Netherlands27 Congregrado Ruiz, 2004 Spain28 51

PTNS 3x a week for 4 weeks SANS once a week for 12 weeks

Refractory UUI (3 leaks per 24 hours)

4 weeks

Urgency/frequency 21 or UUI not months responding to anticholinergics

Reduced frequency and urgency episodes (Main outcomes were bladder capacity related) 56% objective success (Reduction in urinary leakage episodes of 50% or more in 24 hours) 64% subjective success (request for continuation of treatment) Improvement in incontinence QOL scores Improvement in nocturia (-0.8 (-1.3 to -0.2) Improved I-QOL score: 11.8 (4.5-19.1) Among 26 with urgency/frequency, 20/26 evaluated results as excellent/favorable, improved frequency nocturia Among 22 with UUI, 12/22

Some bleeding or pain at insertion site Rare numbness sole of foot No pain infection or SANS problem

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Study, year, location

Intervention

Inclusion

Duration of followup

Outcomes

Comments

Nuhoglu, 2005 Turkey29

35

SANS 30 min treatment 1x a week for 10 weeks

Patients with OAB who failed treatment with oxybutinin

1 year

rated results as excellent or favorable; significant improvement in QOL 54% Complete recovery (<8 No adverse effects voids per 24 hours. 0-1 urgency episodes per day and no UUI) Increase in quality of life score

Table 2: Characteristics of Clinical Trials of PTNS Study, year, location Peters, 2010 (SUMIT), USA17 N 220 Type Intervention Duration of Follow-Up 13 weeks Outcomes Assessed Global Response Assessment (% moderately or markedly improved)

Randomized, Weekly PTNS vs sham double blind

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Study, year, location Finazzi-Agro, 2010, Italy30

N 35

Type Double blind placebo controlled

Intervention PTNS 3 times a week vs placebo sham injection

Duration of Follow-Up 4 weeks

Outcomes Assessed % responders (reduction in UI episodes >50%) Improvement in # incontinence and #voids Incontinence QOL (IQOL) Number of voids per 24 hours Global response assessment 7 day voiding diaries Incontinence Impact Questionnaire

Peters, 2010 (ORBIT), USA31 Sancaktar, 2010, Turkey32

100

40

Randomized, Weekly PTNS vs 4 mg nonblinded extended release tolterodine Randomized, 4 mg tolterodine vs weekly nonblinded PTNS plus tolterodine

12 weeks

12 weeks

15

Table 3: Outcomes of Clinical Trials of PTNS for Urinary Incontinence Trial Peters, 2010 (SUMIT)17 N (%female) 220 (79%) Average Age 62.5 (PTNS) 60.2 (placebo) Main outcomes 54.5% of PTNS subjects vs 20.9% of placebo subjects report moderate or marked improvement on GRA Voiding diary outcomes showed reduction in frequency of nighttime voids, urge incontinence and voids with moderate to severe urgency compared with placebo 71% responders in PTNS group vs 0% in placebo group Reduced number of incontinence episodes (4.1 to 1.8: p,0.001) and voids (13.6 to 9.5: p<0.001) in PTNS group No difference between groups in number of voids per 24 hour (primary outcome) 79.5% of PTNS group report cure or improvement vs 54.8% of tolterodine group (P=0.01) Frequency, urgency and Safety Outcomes 6/110 PTNS subjects (5.4%) had treatment related adverse effects including ankle bruising, bleeding or discomfort at needle site, leg tingling No local side effects in sham group No systemic side effects in either group

Finazzi-Agro, 35(100%) 201030

44.9 (PTNS) 45.5 (placebo)

No serious side effects in either group but occasional transient pain at treatment site in both groups

Peters, 2010 (ORBIT)31

100 (94%)

57.5 (PTNS) 58.2 (tolterodine)

Less dry mouth in PTNS group (p<0.01) More bleeding at needle site, discomfort, redness or inflammation at needle site in PTNS group (exact numbers not given)

Sancaktar,

40 (38

45.4 (meds)

No differences in number or severity of

16

Trial 2010 32

N (%female) completed study)

Average Age 47.4 (meds plus PTNS)

Main outcomes incontinence episodes decreased in both groups- more in combined group; improved IIQ07 scores in both groups

Safety Outcomes side effects between the two groups

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TA Criterion #3: The technology must improve the net health outcomes.

A total of eight prospective observational studies have assessed the impact of PTNS or SANS on clinical outcomes (Table 1). All but one of the studies were done outside the U.S. All of the studies have been relatively small, ranging in size from 15 to 90 patients. The majority have used weekly PTNS for 12 weeks, although in one study the protocol was PTNS once a week for 10 weeks,29 and in one Dutch study, participants received PTNS three times a week for four weeks.27 Outcomes included objective outcomes (number of voids, number of incontinence episodes, frequency of nocturia). Additional outcomes included incontinence quality of life outcomes (eg IQOL), objective success (>50% reduction in symptoms in 24 hours) and subjective success (the percentage of those who would like to continue the treatment). The duration of follow-up ranged from four weeks to 21 months.

In general, these studies showed benefits of PTNS. Beneficial outcomes included decreased frequency, urgency and frequency of nocturia, both objective and subjective success and improvement in quality of life, although not all studies noted improvements on all outcomes.

However, since none of these studies had comparison groups, the extent to which these improvements are more than would have happened either over time or with other treatments is not known. Finally, the natural history of urinary incontinence is that remission rates can range from 0-13% a year,21 making a comparison group particularly important. Contributing factors may include changes in fluid intake, voiding habits or activity levels, treatment of co-morbid conditions or medication changes. In addition, the placebo response rate in

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incontinence studies tends to be high - about 30-40%,8 which further highlights the importance of having a comparison group.

Potential Benefits The potential benefits of PTNS are improvement in objective voiding symptoms, improvement in quality of life and subjective improvement. Among those in whom PTNS is successful, an additional benefit is being able to avoid taking anticholinergic medications for OAB, which although efficacious for many, are also associated with significant side effects..

Potential Harms PTNS is generally considered low risk. The most common side effects are local and related to placement of the electrode. They include minor bleeding and bruising, mild pain, tingling and inflammation of the skin. To date, in all the observational studies and clinical trials which have reported on adverse events, there have been no serious events in either group. Generally, there has been a higher incidence of local side effects in the PTNS group. In the clinical trials which have systematically assessed adverse effects, overall rates of bruising, bleeding, discomfort and leg tingling have been low, although not all studies have reported the exact percentages.

In summary, observational studies have shown a benefit of PTNS on objective symptoms, subjective symptoms and quality of life measurements. Overall, the harms seem to be relatively few and are mostly local side effects. Thus, the potential benefits appear to outweigh the potential risks for PTNS as a treatment for OAB.

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TA Criterion #3 is met

TA Criterion #4: The technology must be as beneficial as any established alternatives.

An important question is how PTNS compares with the established alternatives for the treatment of overactive bladder. Established treatments would include non-pharmacologic measures such as bladder training, pelvic floor exercises and anti-cholinergic medications including oxybutynin or tolterodine.

Four randomized controlled trials have assessed PTNS in comparison with another intervention. In two of those studies, PTNS was compared with a sham treatment 17,30 and in the remaining study, PTNS is compared with extended release tolterodine.31 One small RCT tested the impact of adding PTNS to antimuscarinic therapy. 32

Because placebo response rates have previously been shown to be high in urinary incontinence trials (about 30-40%) 8 and because spontaneous remission is also relatively common (from 0-13%) a year,21 careful selection of the comparison group for a placebo controlled trial is critical.

Two trials used a sham control. The sham control was carefully developed, tested and validated. The sham was designed to mimic the actual PTNS as much as possible. The participants legs and feet were draped to keep them blinded. Then the investigators simulated placement of a needle at the tibial

20

nerve site using a validated Streitberger placebo needle.

33

This needle has a

needle handle and a blunt tip shaft. A slight prick is felt at the time the needle touches the skin, but then the needle retracts when it seems to enter the skin and there is no puncturing of the skin. The needle activates the dorsolateral prefrontal cortex which is associated with the placebo effect.33 Then, instead of the inactive grounding pad that is used on the PTNS leg, the active grounding pad is placed on the bottom of the foot just below the smallest toe, a location that is chosen because it is not part of the acupuncture or acupressure pathway connected to the bladder, pelvis or any other major organs. The sham was then tested in 30 volunteers. They were randomized into two groups, one received PTNS on the left and sham on the right and the other group received PTNS on the right and sham on the left. Their legs were covered and then subjects completed a questionnaire to indicate which leg they thought received the PTNS and which leg they thought received the sham treatment. Overall, only in 30% of patients was the sham correctly identified, indicating that this procedure is a feasible sham for PTNS. 34

This sham was used in the placebo arm of the Study of Urgent PC vs Sham Effectiveness in Treatment of Overactive Bladder Symptoms (SUmiT) trial. This was a multicenter, placebo controlled, double blind trial comparing the efficacy of 12 weeks of PTNS to a sham treatment. Baseline assessments included overactive bladder and quality of life questionnaires as well as three day voiding diaries. The same outcomes were assessed at 13 weeks. The Global Response Assessment (here defined as reporting bladder symptoms as moderately to markedly improved on a 7 point scale at 13 weeks) was also measured.

At thirteen weeks, the GRA indicated that more in the PTNS group had a moderate or marked improvement in bladder symptoms compared with the sham

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placebo group (54.5% vs 20.9%; p<0.01). Compared with sham, PTNS recipients reported statistically significant improvements in frequency, nighttime voids, voids with urgency and urinary urge incontinence episodes compared with the sham group. There were no serious device related adverse events or malfunctions. This study showed that PTNS was safe and effective at 13 weeks compared with sham.

The second RCT comparing PTNS with a sham treatment was conducted in Italy.30 This study included 35 participants - 18 received PTNS and 17 received the sham treatment. Participants were blinded to the treatment that they received. In this study the sham consisted of a 34 gauge needle being inserted into the gastrocnemius muscle. The stimulator was activated for 30 seconds and then turned off. Similarly to the other placebo controlled study, the location of the stimulator was intentionally different from the PTNS location to avoid any acupuncture effect.

At baseline and at 12 week follow-up, participants completed a three day voiding diary which included the number of incontinence episodes, number of micturitions, voided volume and Incontinence Quality of Life (IQOL) scores.35 Patients with a 50% or more reduction in UI episodes were considered responders. In addition, to assess the degree of blinding, participants were also asked what treatment they thought they received.

Three patients (one in the PTNS group and two in the placebo group) did not complete the study. Twelve of seventeen patients (71%) in the PTNS group and 0/15 (0%) in the placebo group were considered responders (p<0.001). There were statistically significant changes in incontinence episodes, number of voids, volume voided and IQOL scores in the PTNS group but not in the placebo group.

22

In this small study, PTNS was an effective treatment of overactive bladder and the placebo effect appeared to be minimal.

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.

The main outcome was the patient global response assessment where 79.5 % of those in the PTNS arm reported cure or improvement after 12 weeks compared with 54.8% of those in the tolterodine arm (p<0.05). At twelve weeks, both groups reported similar improvement in objective measures such as reduction in urinary frequency, urge urinary incontinence episodes, urge severity and nighttime voiding. There were no differences between groups in these outcomes. There were no serious adverse events or device malfunctions.

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

23

dysfunction. Efficacy was similar to that seen with pharmacotherapy (tolterodine).

A small study conducted in Turkey evaluated the impact of adding peripheral neuromodulation ie SANS to anti-muscarinic therapy.32 Forty women were enrolled in this study and either received daily tolterodine or tolterodine plus weekly SANS for 12 weeks. There was no sham for SANS and participants were not blinded. Objective outcomes (frequency, urgency and incontinence episodes per week) improved in both groups, but the improvement was greater in the combined group. A similar trend was seen for IIQ-7 (Incontinence Impact Questionnaire which measures incontinence quality of life) outcomes. Adverse effects were minimal and included dry mouth, constipation, and local irritation at the puncture site. This small study suggested that PTNS or SANS may have an additive benefit to anti-muscarinic therapy.

Longer term outcomes In the second phase of the ORBIT trial, investigators offered those study participants who had been randomized to PTNS 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

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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. We do not currently know how they would respond to treatment beyond one year, nor 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.

An ongoing study, a modified extension to the SUmiT protocol, the STEP study (Sustained Therapeutic Effects of Percutaneous Tibial Nerve Stimulation) has the goal of evaluating the long term effectiveness of treatment with PTNS on overactive bladder symptoms. The STEP study has a planned follow-up duration of 36 months. The 24 month follow-up results were just published36. Among the 110 participants assigned to PTNS in the SUmiT trial, 103 met protocol requirements. Over 14 weeks, they received a tapering protocol of five

25

treatments. The frequency of subsequent treatment was determined by each individuals response to an individual personal treatment plan.. Questionnaires were completed every three months and voiding diaries were completed every six months. At the end of the main trial, sixty participants considered themselves moderately or markedly improved and 50 of the 60 participants consented and enrolled in the STEP follow-up study. After 24 months, 35 of the 50 participants remained in the study. Participants reported improvements from baseline for all objective voiding diary parameters of frequency, urge incontinence, night time voids, moderate to severe urgency episodes. Health related quality of life was also improved compared with baseline. This study showed that the efficacy of PTNS was sustained at 24 month follow-up among individuals who responded initially. However, there was no comparison group and we do not know what the outcomes would have been had PTNS not been continued. Another study to evaluate long term efficacy of PTNS was started in 2009.37 The goal was to randomize those who had responded to PTNS after 12 weeks of treatment to once a month maintenance treatment or no maintenance treatment. According to the clinicaltrials.gov website, this trial was reportedly suspended in March, 2010 due to low enrollment.

In summary, three randomized controlled trials have demonstrated efficacy of PTNS compared with sham or tolterodine in improving symptoms of overactive bladder at 12 week follow-up. One additional small study has suggested an added benefit of adding neuromodulation to anti-muscarinic therapy at short term follow-up. Two small studies of initial responders has shown that treatment benefit continues up to 24 months , although neither study had a comparison group that did not receive ongoing PTNS.

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TA Criterion 4 is met for the use of PTNS for the treatment of overactive bladder symptoms for short term (12 weeks) benefit.

TA Criterion 4 is not met for the use of PTNS for the treatment of overactive bladder symptoms for long term benefit.

TA criterion #5: The improvement must be attainable outside the investigational settings.

PTNS has been shown to have some short term health benefits in almost all settings in which it has been evaluated. In addition, it is widely offered in urologists offices across the country. The ideal way to evaluate whether or not the improvement is attainable outside investigational settings would be to evaluate registry data. To date, no registry data have been published on the use of PTNS. However, the technique and the protocol are standardly used by physicians and physician extenders in practice. One retrospective study, conducted in a community based clinic evaluated the impact of PTNS in 52 patients. All received a 12 week course of treatment and all treatment was prescribed and administered in the context of a nurse practitioner led continence practice. These patients had an improvement in day and night voids as well as in urge incontinence, suggesting that PTNS can have the same benefits in community practice as seen in investigational settings.38

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Since we do not currently have enough evidence to evaluate whether PTNS improves OAB symptoms over the long term in investigational settings, we cannot evaluate its long term impact outside investigational settings.

TA Criterion 5 is met for the use of PTNS for the treatment of overactive bladder symptoms for short term (12 week) benefit.

TA Criterion 5 is not met for the use of PTNS for the treatment of overactive bladder symptoms for long term benefit.

SUMMARY

In summary, PTNS is a noninvasive treatment for OAB and it has been shown to be useful in reducing overactive bladder symptoms when given weekly for 12 weeks. Improvement has been seen in objective and subjective measures of bladder function as well as in outcomes related to incontinence quality of life. There are relatively few adverse effects - mostly local, making the risk benefit profile favorable. Only one small study (which included only individuals who had initially responded to PTNS) showed some evidence of continued benefit at one year follow-up. Studies are ongoing to address the extent to which there are or are not long term benefits and if there are, to determine the optimal frequency for ongoing treatments. At this time, evidence supports short term benefits to the use of PTNS, but there is currently inadequate evidence to support longer term use. RECOMMENDATION

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Recommendation #1: It is recommended that treatment of overactive bladder with PTNS meets CTAF criteria 1-5 for short term benefit.

The California Technology Assessment Forum Panel voted unanimously in favor of the recommendation as written.

Recommendation #2: It is recommended that treatment of overactive bladder with PTNS does not meet CTAF Criteria 4 or 5 for long term benefit.

The California Technology Assessment Forum Panel voted five in favor of the recommendation and four opposed as written.

June 20, 2012 This is the first review of this technology by the California Technology Assessment Forum.

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RECOMMENDATIONS OF OTHERS

Blue Cross Blue Shield Association (BCBSA) The BCBSA Technology Evaluation Center (TEC) published its assessment of PTNS in March, 2011. http://www.bcbs.com/blueresources/tec/vols/25/percutaneous-tibial-nerve.html The final outcome of the assessment was that PTNS did not meet TEC criteria.

Canadian Agency for Drugs and Technologies in Health (CADTH) No reports were found on this topic at the CADTH website.

National Institute for Health and Clinical Excellence (NICE) NICE issued guidance on PTNS on October, 2010 stating Current evidence on PTNS for overactive bladder syndrome (OAB) shows that it is efficacious in reducing symptoms in the short and medium termandthere are no major safety concerns. http://www.nice.org.uk/nicemedia/live/12412/51304/51304.pdf

Centers for Medicare and Medicaid Services (CMS) There is no National Coverage Determinations (NCD) for PTNS. Medicare carriers cover PTNS through a formal LCD or coverage article

Agency for Healthcare Research and Quality (AHRQ) In April 2012, AHRQ published the report: Nonsurgical Treatments for Urinary Incontinence in Adult Women: Diagnosis and Comparative Effectiveness.39 The report can be found at this link: http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviewsand-reports/?pageaction=displayproduct&productID=834&ECem=120409

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http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviewsand-reports/?pageaction=displayproduct&productID=834&ECem=120409 Through a systematic review of diagnostic, randomized and nonrandomized studies found in major databases, FDA reviews, trial registries and research grant databases, the report goals were to assess methods to diagnose urinary incontinence (UI), monitor treatment effectiveness, and assess clinical efficacy and comparative effectiveness of pharmacological and nonsurgical treatments for UI. Key report conclusions relevant to this assessment include Benefits from pelvic floor muscle training, bladder training, and electrical stimulation are large, and adverse effects are uncommon. Benefits from drugs are small.

American Urology Association (AUA) In partnership with the Society of Urodynamics and Female Urology, the AUA published .Diagnosis and Treatment of Overactive Bladder (non-Neurogenic) in Adults: AUA/SUFU Guideline in May 2012. The guideline offers the following statements about PTNS: Clinicians may offer percutaneous tibial nerve stimulation (PTNS) as third-line treatment in a carefully selected patient population. 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.

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The AUA was invited to send an opinion on this technology and to send a representative to the meeting. The AUA did not send an opinion nor send a representative to the meeting.

American College of Obstetricians and Gynecologists (ACOG) The ACOG guideline, Urinary Incontinence for Women,39 did not mention PTNS as a management option for urinary incontinence.

The ACOG was invited to send an opinion on this technology and to send a representative to the meeting. The ACOG did not send an opinion nor send a representative to the meeting.

International Incontinence Society (IIS) The IIS was invited to send an opinion on this technology and to send a representative to the meeting. IIS did not send an opinion nor send a representative to the meeting.

Society of Urodynamics and Female Urology (SUFU) SUFU partnered with the AUA to develop and publish Diagnosis and Treatment of Overactive Bladder (non-Neurogenic) in Adults: AUA/SUFU Guideline in May 2012. Please see comments under AUA. SUFU was invited to send an opinion on this technology and to send a representative to the meeting. SUFU did not send an opinion nor send a representative to the meeting.

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ABBREVIATIONS: CNS Central Nervous System DARE Database of Abstracts of Reviews of Effects GRA Global Response Assessment IIQ Incontinence Impact Questionnaire OAB Overactive Bladder PTNS Percutaneous Tibial Nerve Stimulation IQOL Incontinence Quality of Life SANS Stoller Afferent Nerve Stimulator STEP Sustained Therapeutic Effects of Percutaneous tibial nerve stimulation UDI Urogenital Distress Inventory UI Urinary incontinence UUI Urge urinary incontinence

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