Long-Term Durability of Percutaneous Tibial Nerve Stimulation for the Treatment of Overactive Bladder

Article Outline

• Abstract
• Materials and Methods
• Results
  • Population
  • Treatment Intervals
  • Outcome Measures
• Discussion
• Conclusions
• Acknowledgments
• References
• Copyright

Purpose

The Overactive Bladder Innovative Therapy Trial during phase 1 was a randomized trial demonstrating comparable effectiveness of percutaneous tibial nerve stimulation and extended-release tolterodine during 12 weeks of therapy for frequency, nocturia, urgency, voided volume and urge incontinence episodes. In this second phase of the Overactive Bladder Innovative Therapy Trial we assessed the sustained therapeutic efficacy of percutaneous tibial nerve stimulation in subjects with overactive bladder during 1 year.

Materials and Methods

After 12 weeks subjects randomized to weekly percutaneous tibial nerve stimulation 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.

Results

A total of 33 percutaneous tibial nerve stimulation responders continued therapy with 32 and 25 subjects completing 6 and 12 months of therapy, respectively. Subjects 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 (p <0.001), urge incontinence of 1.6 episodes daily (p <0.001), nocturia with 0.8 voids (p <0.05) and a voided volume of 39 cc (p <0.05). Overactive bladder questionnaire symptom severity was significantly improved from 12 weeks to 12 months (p <0.01) as well as from 6 to 12 months (p <0.01). No serious adverse events occurred.

Conclusions

Statistically significant overactive bladder symptom improvement achieved with 12 weekly percutaneous tibial nerve stimulation treatments demonstrates excellent durability through 12 months. The durability of response demonstrates the effectiveness of percutaneous tibial nerve stimulation as a viable, long-term therapy for overactive bladder.

Key Words: electric stimulation therapy, nocturia, tibial nerve, urinary bladder, overactive, urinary incontinence, urge

Abbreviations and Acronyms: GRA, global response assessment, OAB, overactive bladder, OAB-q, Overactive Bladder Questionnaire, OrBIT, Overactive Bladder Innovative Therapy, PTNS, percutaneous tibial nerve stimulation, SNS, sacral nerve stimulation

Overactive bladder is a symptom syndrome defined as urinary urgency with or without urge incontinence, usually associated with urinary frequency and nocturia (sleep disturbing voiding).¹ With a prevalence of approximately 16% of the adult U.S. population patients may be profoundly affected by OAB with significant disability including reduced quality of life and mobility, along with social relationship and sexual function deterioration, and sleep deprivation.², ³ This chronic condition requires lifelong therapy to control symptoms with the therapeutic goal of restoring quality of life while balancing efficacy and side effects. Early therapy involves conservative measures including dietary controls, fluid modification, bladder training and pelvic floor muscle rehabilitation. The mainstay of treatment is pharmacotherapy with the effectiveness of antimuscarinic agents well documented in the clinical literature.³ Patient adherence rates with medication decrease during 12 months of therapy for many reasons including intolerable side effects or lack of sufficient symptom relief.⁴ Recent research reports adherence rates during 12 months in 45,576 patients with OAB on drug therapy are low with a 32% average proportion of days covered.⁵

Neuromodulation therapy targets specific nerves in the sacral plexus that control the pelvic floor and bladder function. Sacral nerve stimulation with an implantable device has demonstrated the efficacy of neuromodulation to control OAB symptoms.⁶ Despite its effectiveness the therapeutic impact of sacral nerve stimulation has been limited in clinical practice due to several factors including invasiveness, associated costs, and its limitations in older adult patients and those who are frail or who have several medical comorbidities.⁷

Several single and multicenter studies have demonstrated the efficacy, safety and positive impact on urodynamic parameters of PTNS targeting the sacral plexus from an accessible, minimally invasive entry point into the nervous system via the posterior tibial nerve.⁸, ⁹, ¹⁰, ¹¹, ¹² This office based, neuromodulation therapy can be used for the treatment of OAB symptoms in women and men.

The first phase of the OrBIT Trial entered 100 subjects with OAB between June 2006 and September 2008 in an institutional review board approved, multicenter, nonblinded, randomized, controlled trial comparing the effectiveness of a series of 12 weekly, 30-minute office based PTNS treatments using Urgent PC and 12 weeks of 4 mg daily extended-release tolterodine tartrate (Detrol^® LA). Of the 44 subjects undergoing PTNS and the 43 on tolterodine who completed 12 weeks of therapy, similar results from voiding diaries were reported in reducing OAB symptoms of urgency, urge incontinence, nocturia and frequency. The GRA demonstrated a statistically significant improvement or cure over baseline in OAB symptoms in 79.5% of the PTNS group vs 54.8% of the tolterodine group (p = 0.01).¹², ¹³ In the second phase of the OrBIT Trial, reported here, we assessed the sustained effectiveness of PTNS therapy offered at individualized intervals during 1 year in subjects who finished an initial course of 12 consecutive weekly sessions.

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Materials and Methods 

OrBIT subjects who finished an initial course of 12 consecutive weekly PTNS treatments were offered ongoing sessions of therapy for an additional 9 months to monitor improvement in frequency, nocturia, urgency, urge incontinence episodes and voided volume. Subjects were required to be OAB drug-free throughout the study. Subjects were reimbursed for clinical trial associated expenses including time and travel. Under the supervision of the investigator the subjects selected treatment intervals allowing them to control OAB symptoms at an acceptable level. Sound clinical judgment was used to extend or shorten the treatment interval based on treatment efficacy and patient wishes in care decisions. The individual treatment sessions were 30 minutes in duration using a 34 gauge needle electrode inserted approximately 5 cm cephalad to the medial malleolus and slightly posterior to the tibia. When connected to the Urgent PC stimulator a current level of 0.5 to 9 mA at 20 Hz was selected based on patient sensory and motor response (fig. 1).

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• Figure 1. 

  Urgent PC system

An evaluation of OAB symptom control was completed at 6 and 12 months for comparison to baseline and the initial OrBIT 12-week evaluation. Assessments included an independent analysis of 2-day voiding diaries for the mean change in voids per 24 hours, number of nocturnal voids, volume voided, moderate to severe urgency episodes using the Indevus Urgency Severity Scale¹⁴ and improvement in OAB-q scales.¹⁵ Additional comparisons included investigator and subject GRA ratings of OAB symptoms between 12 weeks, and 6 and 12 months.

Data were entered into a double entry, password protected Clindex^® Clinical Trial and Data Management System. All data including voiding diaries were analyzed by an independent biostatistician using SAS^® version 9.2. Mean values were analyzed for significant change using a 2-sided paired t test and median values were analyzed using a Wilcoxon signed rank test with p <0.05 considered statistically significant. No corrections for multiple comparisons were made.

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Results 

Population 

Of the 44 OrBIT Trial subjects completing 12 weekly PTNS sessions 35 were responders and 33 chose to continue PTNS therapy beyond the initial treatment phase. Responders were defined as patients indicating a successful response to PTNS after 12 weeks on the GRA. These subjects were demographically similar to the entire cohort of the OrBIT Trial at baseline (table 1). Thirty subjects completed voiding diaries at 6 months and 25 completed voiding diaries at 12 months. While voiding diaries were missing from 2 subjects at 6 months, there was no missing data in the voiding diaries completed by other subjects at 6 and 12 months. Of the 8 subjects who discontinued treatment 1 withdrew due to lack of effectiveness, 1 switched back to drug treatment, 1 did not want further treatment, 2 withdrew to continue PTNS outside of the study, 1 was lost to followup and the remaining 2 left the study for nonurological health issues. One subject withdrew before the 6-month visit and 7 withdrew afterward (fig. 2). Of the 8 subjects who discontinued 7 were considered improved at the last assessment evaluation.

Table 1. OrBIT Trial subject baseline characteristics

	No. Baseline Group	No. PTNS Post-12-Wk Followup Group
Pt age (mean ± SD)	100 (57.9±13.3)	33 (59.0±13.9)
Wt (kg) (mean ± SD)	99 (81.4±20.3)	33 (86.0±19.1)
Yrs OAB symptoms (mean ± SD)	99 (9.6±12.1)	32 (10.6±13.8)
Voids/day (mean ± SD)⁎	100 (12.3±3.3)	33 (12.4±3.2)
Urge incontinence episodes/day (mean ± SD)⁎	74 (3.6±2.9)	26 (3.4±2.2)
65 Yrs old or older (%)	32 (32)	11 (33)
Race/ethnicity (%):
Caucasian	86 (86)	28 (85)
African-American	9 (9)	3 (9)
Native American	2 (2)	1 (3)
Hispanic	2 (2)	1 (3)
Asian or Pacific Islander	1 (1)	0 (0)
Gender (%):
F	94 (94)	31 (94)
M	6 (6)	2 (6)

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• Figure 2. 

  OrBIT Trial continued followup therapy consort diagram

Treatment Intervals 

During the 9 months of followup therapy the 33 subjects received a mean of 12.1 ± 4.9 treatments during an average of 263 days. Median number of days between treatments was 17 from the 12-week visit through the 12-month visit, 14 between the 12-week and the 6-month visit, and 24 between the 6-month and the 12-month visit. Mean number of days between treatments was 21 from the 12-week visit through the 12-month visit.

Outcome Measures 

Figure 3 illustrates that mean OAB symptom improvements including frequency, nocturia, urgency, voided volume and urge incontinence episodes were sustained for all outcomes from 12 weeks through 6 and 12 months. At 6 and 12 months all voiding diary parameters showed statistically significant improvements in mean values compared to baseline. Mean improvements at 12 months from baseline included frequency decreased by 2.8 voids daily (p <0.001), urge incontinence decreased by 1.6 episodes daily (p <0.001), moderate to severe urgency episodes decreased by 3.7 episodes daily (p <0.01), nocturia decreased by 0.8 voids (p <0.05) and voided volume improved by a mean of 39 cc (p <0.05). At 12 months further significant mean improvements were reported from the 12-week assessment for mean moderate to severe urgency episodes per day (p <0.05). A borderline significant reduction at 12 months from 12 weeks was noted for average daily urge incontinence episodes (p = 0.051) (table 2). The 6 and 12-month improvements in voiding diary parameters as percent changes from baseline are reported in table 3. Substantial percent reductions were reported at 6 and 12 months in moderate to severe urgency episodes (50% or greater, p <0.001), and urge incontinence episodes continued to decrease from baseline through 6 and 12 months with 63.6% and 77.9% reductions, respectively (p <0.001).

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• Figure 3. 

  Changes in study parameters from baseline through 12 months of followup

Table 2. Voiding diary parameters at baseline, 12 weeks, 6 months and 12 months

	No.	Mean ± SD Frequency (95% CI)⁎	Mean ± SD Nocturia (95% CI)†	Mean ± SD Moderate–Severe Urgency (95% CI)‡	Mean ± SD Urge Incontinence (95% CI)§	Mean ± SD Voided Vol (95% CI)∥
6-Mo visit:
Baseline	30	12.6±3.3	2.6±1.3	6.8±4.2	2.4±2.2	145±78
12 Wks	29	9.8±3.0	1.8±1.1	3.7±2.6	0.9±1.2	187±87
6 Mos	30	9.4±2.8	1.4±1.2	3.0±2.4	0.8±1.1	177±82
Change from baseline	30	−3.2±3.7(−4.6,−1.8)	−1.2±1.5(−1.8,−0.6)	−3.8±4.0(−5.3,−2.3)	−1.6±1.7(−2.2,−1.0)	31±72(4,58)
p Value		<0.001	<0.001	<0.001	<0.001	<0.05
Change from 12 wks	29	−0.3±2.0(−1.1,0.4)	−0.4±1.3(−0.9,0.0)	−0.7±2.5(−1.7,0.2)	−0.2±0.7(−0.5,0.1)	−9±63(−33,16)
p Value		0.36	0.07	0.12	0.22	0.47
12-Mo visit:
Baseline	25	12.4±3.5	2.5±1.3	6.3±4.4	2.2±2.1	154±82
12 Wks	24	9.8±3.0	1.8±1.1	3.6±2.8	0.8±1.1	199±88
6 Mos	24	9.1±2.5	1.2±1.1	2.5±2.3	0.6±0.8	192±84
12 Mos	25	9.6±2.9	1.6±1.1	2.7±2.3	0.5±1.0	193±79
Change from baseline	25	−2.8±3.7(−4.4,−1.3)	−0.8±1.5(−1.4,−0.2)	−3.7±4.9(−5.7,−1.6)	−1.6±2.0(−2.5,−0.8)	39±92(1,77)
p Value		<0.001	<0.05	<0.01	<0.001	<0.05
Change from 12 wks	24	−0.1±2.3(−1.1,0.8)	−0.2±0.9(−0.6,0.2)	−1.2±2.6(−2.2,−0.1)	−0.4±0.9(−0.8,0.0)	−1.0±77(−33,31)
p Value		0.79	0.29	<0.05	0.051	0.95

p <0.05 for all parameters at 12 weeks.

Table 3. Change from baseline in voiding diary parameters

	No.	6 Mos Mean % Change (95% CI)	p Value (2-sided t test)	No.	12 Mos Mean % Change (95% CI)	p Value (2-sided t test)
Frequency	30	−22.7 (−31.5,−13.9)	<0.001	25	−19.3 (−30.6,−8.1)	<0.01
Nocturia episodes	30	−35.1 (−62.1,−8.1)	<0.05	25	−12.4 (−48.7,23.8)	0.49
Moderate–severe urgency episodes	30	−50.6 (−64.5,−36.8)	<0.001	24⁎	−50.0 (−69.8,−30.1)	<0.001
Vol voided	30	36.0 (10.4,61.7)	<0.01	25	54.7 (12.1,97.3)	<0.05
Urge incontinence	24⁎	−63.6 (−83.2,−43.9)	<0.001	19⁎	−77.9 (−94.7,−61.1)	<0.001

All 33 subjects who continued PTNS therapy rated symptoms on the GRA at the end of the initial 12 weeks of therapy as improved or cured from baseline. At 6 months 94% of subjects classified OAB symptoms as improved from baseline and 96% reported improvement at 12 months. Similarly investigators classified subject OAB symptoms as improved from baseline for 97% and 96% of those evaluated at 6 and 12 months, respectively (table 4). The change from baseline on the OAB-q at 6 and 12 months showed statistically significant improvement (p <0.001) in symptom severity and health related quality of life (table 5). Symptom severity was significantly improved from 12 weeks to 12 months (p <0.01) as well as from 6 to 12 months (p <0.01).

Table 4. Global response assessment of OAB symptom improvement from baseline

	No./Total No. Investigator GRA (%)	No./Total No. Subject GRA (%)
12 Wks:
Cured	2/33 (6)	1/33 (3)
Improved	30/33 (91)	32/33 (97)
No improvement/worsened	1/33 (3)	0/33 (0)
Any improvement	32/33 (96)	33/33 (100)
6 Mos:
Cured	3/32 (9)	4/32 (13)
Improved	28/32 (88)	26/32 (81)
No improvement/worsened	1/32 (3)	2/32 (6)
Any improvement	31/32 (97)	30/32 (94)
12 Mos:
Cured	5/25 (20)	4/25 (16)
Improved	19/25 (76)	20/25 (80)
No improvement/worsened	1/25 (4)	1/25 (4)
Any improvement	24/25 (96)	24/25 (96)

Table 5. OAB-q changes from baseline

	Symptom Severity (lower is better)	Health Related Quality of Life (higher is better)
12 Wks:
No.	32	33
Mean change from baseline (95% CI)	30.9(−37.9,−23.9)	31.0(23.4,38.5)
6 Mos:
No.	32	32
Mean change from baseline (95% CI)	−28.7(−36.7,−20.6)	31.0(24.3,37.7)
12 Mos:
No.	25	25
Mean change from baseline (95% CI)	−38.8(−47.7,−29.9)⁎	34.1(24.6,43.6)

All changes p <0.001 from baseline, 2-sided paired t test.

During the 9-month continued treatment phase 1 subject had 2 events of abdominal pain classified as related to the system. Two subjects had 3 events classified as unknown relationship, and included urinary tract infection, worsening hypertension and diarrhea. All other adverse events were reported as nontreatment related. There were no device malfunctions reported throughout the trial.

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Discussion 

The 12-week initial phase of the OrBIT Trial demonstrated that PTNS successfully improved OAB symptoms of frequency, nocturia, urgency, voided volume and urge incontinence episodes corroborating previously published studies.¹² This report of the OrBIT Trial long-term phase demonstrated the durability of that improvement through 12 months of continued therapy at tapering intervals. The benefit from PTNS therapy that occurred by 12 weeks remained stable thereafter.

Neuromodulation therapy targets specific nerves in the sacral plexus that control bladder function.¹⁶, ¹⁷ SNS with an implantable device clearly demonstrates the efficacy of neuromodulation in OAB management and voiding dysfunction.⁶, ¹⁸ Despite its effectiveness SNS does not fill the therapeutic void in managing OAB refractory to medical and behavioral therapy due to its invasiveness, costs and limited use in elderly patients.⁷ Injection of botulinum A toxin has demonstrated effectiveness for the management of nonneurogenic OAB in clinical trials, but use has been limited by lack of Food and Drug Administration approval, limited durability and the risk of urinary retention.¹⁹ Clearly new OAB treatment modalities are needed.

Multiple publications have demonstrated the effectiveness of PTNS for various urinary problems.⁷, ⁸, ⁹, ¹⁰, ¹¹ In a multicenter study Govier et al showed a 71% treatment success rate (25% reduction in mean daytime voids, 21% reduction in mean nighttime voids, 35% improvement in urge incontinence, 30% improvement in pain and 20% improvement in quality of life) without significant adverse events.⁸ Klingler et al demonstrated objective urodynamic changes after PTNS therapy with mean total bladder capacity increased significantly from 197 to 252 cc (p = 0.020), and mean volume at first unstable bladder contraction increased from 95 to 133 cc.⁹ A study on urodynamic parameters in 46 patients by Vandoninck et al demonstrated a statistically significant increase (p = 0.043) in cystometric bladder capacity, increasing from a mean of 243 cc (range 30 to 745) at baseline to 340 cc (range 70 to 500) after 12 PTNS treatments.¹⁰ In the OrBIT long-term phase mean change in voided volume (39 cc) was statistically significant (p <0.05) with a mean 54.7% increase at 12 months vs baseline. The increase in bladder volume demonstrated in patients treated with PTNS was greater than the 20 to 30 ml increase typically seen with antimuscarinic agents.²⁰, ²¹, ²²

A recent meta-analysis of 244 patients treated with PTNS in 7 studies show a statistically significant improvement in the number of daytime voids (244, p <0.001), nocturia (151, p <0.002), voided volume (182, p <0.001), number of urge incontinence episodes (167, p = 0.023) and incontinence quality of life (122, p = 0.033). It is unlikely that these results can be attributed to a placebo effect given the average duration of patient symptoms was nearly 7 years in which they had tried other therapies without success.²³

The OrBIT Trial represents the first U.S. multicenter study to systematically examine and document the durability of PTNS, demonstrating that symptom improvements after 12 initial treatments are sustained with ongoing therapy. At 12 months investigators and subjects assessed OAB symptoms as similarly improved from baseline (96%) and comparable to improvement documented at 12 weeks. Results were confirmed by voiding diary data and OAB-q results. Additionally, patients can sustain symptom improvements by attending a 30-minute PTNS session approximately once every 3 weeks. Offering patients individualized treatment intervals in consultation with the physician replicates community practices. Their incentive to continue periodic PTNS treatment is the symptom improvement patients experience as OAB is a chronic syndrome requiring lifelong therapy. For some patients a periodic PTNS treatment with comparable efficacy may be preferable to prescription management and pharmacotherapy side effects.

As time progressed there was statistically significant improvement in the OrBIT subject OAB-q symptom severity score observed at 12 months vs 12 weeks and 6 months (p <0.01), demonstrating further improvement during the course of individualized treatment intervals. These improvements occurred concurrently with decreases in the mean number of moderate to severe urgency episodes observed at 6 and 12 months vs 12 weeks (p = 0.12 and p <0.05, respectively). When examined together these data may indicate that subjects on PTNS therapy gradually experienced improvements to urgency symptoms which translated to an improved symptom severity score.

In this trial investigators and subjects were instructed to increase the interval between PTNS treatments based on patient response and sound clinical judgment to maintain OAB symptom improvement. Median number of days between treatments from 12 weeks to 6 months was 14 compared to the longer interval of 24 days between 6 and 12 months. Longer therapy intervals after the initial 12 weekly treatments may contribute to long-term patient compliance and lessen the long-term economic impact on the health care system.

It is worthwhile to consider the potential place for PTNS within an OAB algorithm of care. Kohli and Rosenblatt examined the role of neuromodulation in overall OAB therapy.²⁴ An integrated treatment plan may initially include behavior training, dietary and fluid modifications, and pharmacotherapy before considering neuromodulation, PTNS or SNS, which should be reserved for patients with overactive bladder that is not amenable to treatment by less invasive means.

Patients with OAB present a clinical treatment challenge, especially those with treatment refractory symptoms or those who are unable to tolerate first line pharmacotherapy. PTNS represents another option to provide relief to patients with drug refractory symptoms or those who do not want to be on long-term pharmacotherapy. Many patients with OAB are elderly, frail and/or have multiple medical comorbidities that preclude the option of surgery. In addition, they may not want a permanent SNS device or they may not have the cognitive ability to maintain one. Amundsen et al reported the cure rate with SNS was associated with age, with individuals younger than 55 years having a statistically significant greater cure rate (65% vs 37% for older individuals, p <0.05).²⁵ Having 3 or more chronic conditions was associated with a lower cure rate in younger and older individuals. PTNS may be the only option for treatment. Additionally, since drugs and PTNS have different mechanisms of action they can be used concurrently when patients seek additional measures to control OAB symptoms.²⁶

Limitations to the study include a potential placebo effect based on subject time spent with clinicians, no prescribed tapering schedule to evaluate when treatment effects fail, no cost analysis and no device sham effect. Subjects were not counseled on fluid management and it is unknown if subject fluid management habits influenced results. With an average OAB symptom duration of more than 10 years subjects may have already learned fluid management as a means to mediate OAB symptoms. A sham PTNS procedure was recently validated and will be used for a future sham vs active treatment study.²⁷ Individual practitioners may determine how these study results apply to the patient population they see in their own practice.

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Conclusions 

The statistically significant efficacy of PTNS achieved after 12 weekly treatments to improve frequency, nocturia, urgency, voided volume and urge incontinence episodes is durable through 12 months of prolonged therapy offered at individualized tapering intervals. PTNS offers patients with OAB and physicians an efficacious and well tolerated treatment option for long-term OAB therapy.

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Acknowledgments 

Additional fellow investigators from the initial 12-week OrBIT Trial include Dr. Barry K. Jarnagin, Vanderbilt University, Nashville, Tennessee and Dr. Peter L. Rosenblatt, Boston Urogynecology Associates, Cambridge, Massachusetts.

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