Percutaneous Tibial Nerve Stimulation for the Treatment of Voiding Dysfunction
Executive Summary
Background
Voiding dysfunction includes urinary retention, incontinence, and symptoms of frequency and urgency. Overactive bladder (OAB) is the current term used to describe urgency symptoms and/ or urge incontinence. The majority of research in percutaneous tibial nerve stimulation (PTNS) has been for treatment of OAB and/or urge incontinence. OAB is common and can have a negative impact on multiple dimensions of quality of life (QOL), including physical functioning, psychological well-being, social interactions, sexual relations, and interpersonal relations.
There are a variety of treatment options for OAB. Conservative treatment starts with bladder training techniques, such as education, timed voiding, restriction of fluid intake, and distraction/ relaxation. These can be combined with pelvic floor training exercises that are intended to strengthen and support the pelvic floor muscles. A number of medications are effective for treating OAB. Anticholinergic (antimuscarinic) agents and agents with mixed anticholinergic and bladder wall effects are widely prescribed for OAB. Numerous randomized, controlled trials and systematic reviews have established that these drugs have efficacy over placebo, but the magnitude of benefit in reducing OAB symptoms is modest, a substantial number of patients will not achieve adequate symptom relief, and there are relatively high rates of adverse effects. For patients with OAB refractory to standard treatments, more invasive treatment options are available, such as intravesicular administration of botulinum toxin A, sacral nerve stimulation, or augmentation cytoplasty.
PTNS is a type of neuromodulation. The mechanism of action in neuromodulation of the bladder is not precisely understood, but neuromodulation likely interrupts abnormal reflex neurologic arcs, thus improving coordination of the detrusor and sphincter muscles. Sacral nerve stimulation has been shown to be effective in reducing urgency and urge incontinence in women with symptoms refractory to other treatments. PTNS was developed as a less-invasive alternative to sacral nerve stimulation. A needle electrode is inserted at a depth of 3 to 4 cm near the tibial nerve at the medial malleolus. The needle is connected to a low-voltage, adjustable, hand-held stimulator, which sends an electrical impulse through the tibial nerve.
PTNS treatment includes a 12-week initial treatment phase followed by an indefinite maintenance treatment phase, with each of these phases having different treatment protocols. The initial treatment phase consists of 1 to 3 weekly 30-minute treatment sessions for 12 weeks. Following the initial treatment phase, maintenance treatment is continued. The protocol for maintenance treatment is less well defined, with repeat sessions administered at intervals generally dictated by the patient and based on the return of symptoms. The manufacturer recommends that these maintenance treatment sessions will, on average, be required every 2 to 3 weeks.
In 2005, the Urgent® PC Neuromodulation System (Uroplasty, Inc.) received 510(k) marketing clearance from the U.S. Food and Drug Administration (FDA) for percutaneous tibial nerve stimulation to treat patients with urinary urgency, urinary frequency, and urge incontinence. This device was cleared as a class II, nonimplantable, peripheral nerve stimulator for pelvic floor dysfunction that was substantially equivalent to the previously cleared percutaneous Stoller afferent nerve system (PerQ SANS System) in 2001 (K992069, UroSurge, Inc.).
Objective
The objective of this Assessment is to determine whether percutaneous tibial nerve stimulation improves health outcomes when used to treat voiding dysfunction. Evidence on both the short-term efficacy of treatment and longer-term durability will be reviewed.
Search Strategy
A literature search was performed on MEDLINE® (via PubMed) for the period of 1995 to December 2010, using the terms “percutaneous tibial nerve stimulation” and “PTNS.” These terms were cross-referenced with the search terms “overactive bladder,” “OAB,” “urgency-frequency,” “urge incontinence,” “retention,” and “voiding dysfunction.” The initial search was supplemented by use of the “related articles” function in PubMed for key citations. The electronic search was supplemented by hand searching of relevant bibliographies.
Selection Criteria For studies on efficacy, articles were selected that: 1) were randomized, controlled trials; 2) enrolled patients with OAB, urge incontinence, or urinary retention; 3) used a commercially available device for PTNS; 4) compared PTNS with placebo or an alternative treatment for OAB; 5) reported on at least one relevant health outcome; and 6) enrolled at least 10 patients per treatment group.
For studies on durability of treatment effect, articles were selected that: 1) were randomized controlled trials or cohort studies; 2) enrolled patients with OAB, urge incontinence, or urinary retention; 3) followed patients for at least an additional 12 weeks past the initial 12-week treatment period; 4) reported on at least one relevant health outcome; and 5) enrolled at least 10 patients treated with PTNS. For cohort studies, an additional requirement was that the article provide data that would allow determination of the percent of responders at the completion of the study in relation to the total number of patients initially treated.
Main Results
The evidence on PTNS was evaluated separately for the initial treatment phase and the maintenance phase, given that the treatment protocols differ for each phase. Because of the differences in treatment protocol, efficacy in the initial treatment phase cannot automatically be extrapolated as demonstrating efficacy in the maintenance phase. Furthermore, OAB is a chronic condition and, as such, it is important to establish efficacy over periods of time longer than several months. Therefore, for the purpose of this Assessment, the efficacy of PTNS in reducing OAB symptoms in the initial treatment phase was first evaluated. Following this, the durability of the treatment effect in the maintenance phase was evaluated. It was determined prior to formal review of the evidence that efficacy needed to be established for both phases in order for PTNS to demonstrate benefit in treating the chronic condition of OAB.
1. In patients with OAB, is percutaneous tibial nerve stimulation effective in reducing urgency symptoms and/or urge incontinence during the initial treatment phase?
Three randomized controlled trials evaluating PTNS for treating OAB have been published, each of which was intended to evaluate the initial treatment phase. 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 measure 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 36.7 ± 21.5 in the PTNS group and 29.2 ± 20.0 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 34.2 ± 21.3 in the PTNS group and 20.6 ± 20.6 in the sham group, for a mean treatment difference of 13.8 (p=0.006).
For the 4 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 -2.4 ± 2.5 in the PTNS group and -1.5 ± 2.4 in the sham group (difference between groups -0.9 ± 2.5 voids per day, p=0.01). The mean change in nocturia episodes was -0.7 ± 1.2 in the PTNS group and -0.3 ± 1.4 in the sham group (difference between groups -0.4 ± 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%).
Finazzi-Agro and colleagues also conducted a sham-controlled randomized, controlled trial of PTNS in treating urge incontinence. This was a small trial of 35 women that did not meet all formal quality indicators and therefore received a “fair” quality rating on formal quality review. The trial was not double-blinded and the outcomes were not ascertained in an independent, blinded manner. Intention-to-treat analysis was not performed. There were some baseline differences on the voiding diary parameters between the PTNS and placebo groups.
This trial by Finazzi-Agro 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 3 times per week for 4 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 minimal important difference (MID) for this scale.
The third randomized, controlled trial 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. 2.4 ± 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 other secondary outcomes utilizing the GRA, 35 of 44 patients (79.5%) in the PTNS group and 23 of 42 (54.8%) in the tolterodine group were classified as responders, defined by a rating of improvement or cure in symptoms on the GRA. This difference was statistically significant (p=0.01), favoring the PTNS group. Findings were similar for investigator assessments of patient improvement and/or cure (79.5% vs. 60.5%, respectively), although the p value for this difference was of marginal statistical significance (p=0.05).
Adverse effects of treatment reported by these trials were mild and well tolerated. In the SUmiT trial, 12% of patients (6/50) reported 9 adverse events, consisting of ankle bruising, discomfort and/or bleeding at the needle site, and tingling of the leg. In the OrBIT trial, 16.3% of patients (8/49) reported an adverse effect of treatment. These reported events were generalized swelling, worsened incontinence, headache, hematuria, inability to tolerate stimulation, leg cramps, intermittent foot/toe pain, and vasovagal response to needle insertion.
2. In patients with OAB treated with PTNS, what is the durability of treatment response beyond the initial 12-week treatment period?
One study met the inclusion criteria for this question. This was a 1 year follow-up for patients from the OrBIT trial who had been assigned to the PTNS group and had responded to the initial course of treatment. Of the 35 responders in the initial randomized, controlled trial, 33 agreed to continue with maintenance PTNS treatment. These 33 patients received a mean of 12.1 (SD=4.9) treatments between the 12-week and 12-month visits, and there was a median of 17 days between treatments. After 12 months of follow-up, 24 patients completed the study and were still judged to be responders by GRA criteria.
Authors’ Conclusions and Comments
PTNS is a variation of neuromodulation that is less invasive than sacral nerve stimulation and does not involve implantation of a permanent device. It has a physiologic rationale for benefit, given the known benefit of sacral nerve stimulation, and the similar physiologic changes induced by PTNS. It has been tested in the literature primarily to treat OAB; other forms of voiding dysfunction are not addressed at this time.
Due to the nature of this treatment, which has a different treatment protocol for initial treatment and maintenance treatment, it is important to document both short-term efficacy and durability in order to conclude that PTNS improves health outcomes for the chronic condition of OAB. Specifically, evidence for efficacy in the initial treatment period cannot be assumed to demonstrate efficacy for the maintenance phase.
Three randomized, controlled trials report short-term efficacy of PTNS. There were consistent improvements across all outcome measures used, with few adverse effects. The SUmiT trial was a high-quality trial that compared PTNS to a sham placebo control and reported superior outcomes for PTNS. The results of this trial were corroborated in a second sham-controlled trial by Finazzi-Agro in a somewhat different population, i.e., women with urge incontinence rather than OAB. This trial had some methodologic limitations and was given a fair rating. The third randomized, controlled trial, the OrBIT trial, which was planned as a noninferiority trial comparing PTNS to medications, had several methodologic limitations, resulting in a quality rating of poor.
The magnitude of treatment benefit is less certain. For the SUmiT trial, the magnitude of the treatment response is of uncertain clinical significance. The definition of “responders” used by the authors was a rating of either “improved” or “cured” on a GRA, and the GRA was the only outcome reported at the patient level. Defining responders in this way is not a standard approach in incontinence research. While the GRA outcome measure was previously validated and not overly susceptible to placebo bias since a sham control was used, it is the most subjective and least rigorous outcome measure. Since the magnitude of difference between groups appears to be considerably larger for the GRA compared to other outcome measures, it is possible that this GRA outcome measure overestimated the true magnitude of effect.
Finazzi-Agro et al. corroborated the results of the SUmiT trial in women with incontinence, using a modified treatment protocol and a different definition of response. Importantly, this trial used the more standardized definition of treatment response, a greater than 50% reduction in incontinent episodes or nocturnal voids, and reported a large difference in responders in a small number of patients. This large difference in response rates is not likely to be biased by the outcome measure used, but only applies to patients with urge incontinence, and not the larger group of patients with OAB. This trial also reported statistically significant differences in QOL, using a different QOL measure, the incontinence quality of life scale (I-QOL).
The clinical significance of the change in QOL scores can be judged in relation to the minimal important difference (MID) for each scale. For the OAB-q measure used in the SUmiT trial, the MID was estimated to be 10 points for the overall score and each subscale. The mean treatment difference for the health-related QOL subscale exceeded this MID at 13.8, while the mean treatment difference on the symptom bother scale was less than the MID at 7.5. For the I-QOL measure used in the Finazzi-Agro trial, the mean improvement over placebo of 16.8% exceeded the estimated MID of 2 to 5%. These data establish that the mean treatment effect over placebo exceeds or is in the range of the empirically derived MID.
For the urinary diary outcomes, the magnitude of treatment response is modest, as evidenced by the relatively small absolute differences in means between groups. The magnitude of response for these outcomes is greater in the Finazzi-Agro trial, which included only women with urge incontinence, compared to SUmiT. In each of the 2 sham-controlled trials, the percent improvement in incontinence episodes (43–56%) was higher than the percent improvement for total voiding or nocturnal voiding episodes (20–30%). These factors suggest that the efficacy of PTNS may be greater for incontinence, compared to urgency-frequency symptoms without incontinence.
The OrBIT trial provides weak evidence for the comparability of PTNS compared with medications, given the numerous methodologic limitations of the trial. The changes in the PTNS group were similar to those seen in the SUmiT trial. However, the lack of placebo control limits the interpretation of these results, since the magnitude of treatment response with medications is generally modest and both groups may have been prone to bias. The other methodologic limitations for this trial further limit confidence in the validity of the reported results.
There is scant evidence on the durability of the PTNS treatment effect, which is a major concern in evaluating its effectiveness. Only one study met the inclusion criteria for relevant data on the durability of treatment effect. This study, which was a follow-up from the OrBIT trial, had several limitations. The OrBIT trial was rated the weakest of the 3 trials on formal quality review, receiving a “poor” rating. For the follow-up study, there was no control group to compare long-term response rates; therefore, only within-group changes could be evaluated. The sole outcome measure used to assess response was the GRA, which is the most subjective of the outcome measures. The GRA used for this study was not fully described in the study methods, and appeared to differ somewhat from the GRA as described in the SUmiT trial.
The lack of evidence of durability raises the question of whether short-term efficacy can be maintained over the longer term. PTNS will have little practical utility unless the treatment effect can be maintained over longer periods. This will require demonstration in high-quality trials that the maintenance phase of treatment is efficacious in maintaining the treatment benefit over placebo. Also, it is important to demonstrate that this treatment has adequate acceptability as a chronic intervention, given that treatments are given in a clinic setting, rather than at home.
In conclusion, there is fairly strong evidence for short-term efficacy of PTNS 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 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.
Based on the available evidence, the Blue Cross and Blue Shield Medical Advisory Panel made the following judgments about whether PTNS treatment for voiding dysfunction meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria.
1. The technology must have final approval from the appropriate governmental regulatory bodies.
In 2005, the Urgent® PC Neuromodulation System (Uroplasty, Inc.) received 510(k) marketing clearance from the U.S. Food and Drug Administration (FDA) for percutaneous tibial nerve stimulation to treat patients with urinary urgency, urinary frequency, and urge incontinence. This device was cleared as a class II, nonimplantable, peripheral nerve stimulator for pelvic floor dysfunction that was substantially equivalent to the previously cleared percutaneous Stoller afferent nerve system (PerQ SANS System) in 2001 (K992069, UroSurge, Inc.).
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.
The scientific evidence is not sufficient to permit conclusions on the long-term efficacy of PTNS treatment. Three randomized, controlled trials, 2 comparing PTNS to placebo and 1 comparing PTNS to medication, report benefit for the initial treatment period. These studies report superiority of PTNS treatment over placebo, and similar outcomes compared to medication. This evidence is sufficient to establish a short-term treatment benefit for PTNS.
However, the evidence on durability of treatment is lacking. Durability of PTNS treatment effect for OAB cannot be extrapolated from results of short-term trials. This is because the PTNS treatment algorithm is altered after the initial 12-week treatment period, with fewer treatment periods and little standardization in intervals between treatments. Also, since the treatment requires repeated office visits with needle insertion and nerve stimulation, the long-term acceptability of the device may be suboptimal. For these reasons, it is important that durability of treatment effect be demonstrated prior to determining the effect on health outcomes for a chronic condition such as OAB.
Only one trial, a 12-month follow-up of one of the randomized, controlled trials, reports any evidence on durability. This follow-up study was performed in PTNS responders only without a control group. The definition of response used was not standardized and based entirely on a 7-item GRA. There was not a standardized treatment protocol, patients returned for maintenance therapy at irregular intervals as dictated by patient preference. By the end of the 12-month period, only 25 patients remained out of a total of 100 that were originally randomized. This evidence suggests that some patients may have a long-term response, but is not sufficient to permit further conclusions on the durability of treatment effect.
3. The technology must improve the net health outcome; and
4. The technology must be as beneficial as any established alternatives.
The evidence is not sufficient to permit conclusions; therefore, the evidence is not sufficient to determine the effect on the net health outcome and/or whether it is as beneficial as alternatives.
5. The improvement must be attainable outside the investigational settings.
Whether PTNS for the treatment of voiding dysfunction improves the net health outcome has not been demonstrated in the investigational setting. Based on the above, PTNS as treatment for voiding dysfunction does not meet the TEC criteria.
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afferent; anticholinergic; antimuscarinic; antispasmodic; AUA; bladder; cystogram; cystoscope; detrusor; diaries; diary; dysfunction; frequency; I-QOL; neurogenic; neuromodulation; neuromodulative; OAB; OAB-q; overactive; posterior; PPBC; prevalence; psychometric; QOL; quality of life; questionnaire; retention; root; sacral; scores; spasm; Stoller; subscales; tolterodine; urgency; Urgent PC; urinary; urodynamic; urologic; urology; validation; void; voiding
