Enrico Finazzi-Agrò,*, Filomena Petta, Francesco Sciobica, Patrizio Pasqualetti, Stefania Musco and Pierluigi Bove

Transcription

1 Percutaneous Tibial Nerve Stimulation Effects on Detrusor Overactivity Incontinence are Not Due to a Placebo Effect: A Randomized, Double-Blind, Placebo Controlled Trial Enrico Finazzi-Agrò,*, Filomena Petta, Francesco Sciobica, Patrizio Pasqualetti, Stefania Musco and Pierluigi Bove From the Department of Surgery/Urology, Tor Vergata University (EFA, FP, FS, PB), SeSMIT, Service for Medical Statistics and Information Technology, AFaR, Fatebenefratelli Hospital, Isola Tiberina (PP) and Fondazione S. Lucia (SM), Rome, Italy Purpose: This is a prospective, double-blind, placebo controlled study, based on an original placebo technique, performed to evaluate the efficacy of percutaneous tibial nerve stimulation in female patients with detrusor overactivity incontinence. Materials and Methods: A total of 35 female patients presenting with detrusor overactivity incontinence that did not respond to antimuscarinic therapy were randomly assigned to percutaneous tibial nerve stimulation or to a control group. The percutaneous tibial nerve stimulation group (18 patients) was treated with 12 percutaneous tibial nerve stimulation sessions. The control group (17 patients) received an original placebo treatment using a 34 gauge needle placed in the medial part of the gastrocnemius muscle. The sessions lasted for 30 minutes and were performed 3 times weekly as percutaneous tibial nerve stimulation sessions. All patients were evaluated with bladder diaries as well as quality of life scores before and after treatment. Patients showing a reduction in urge incontinence episodes greater than 50% were considered responders. Results: Some patients (1 in the percutaneous tibial nerve stimulation group and 2 in the placebo group) did not complete the study for reasons not related to the technique. Of 17 patients in the percutaneous tibial nerve stimulation group 12 (71%) and of 15 in placebo group 0 were considered responders according to the previously reported definition (p 0.001). Improvement in the number of incontinence episodes, number of voids, voided volume and incontinence quality of life score were statistically significant in the percutaneous tibial nerve stimulation group but not in the placebo group. Conclusions: Percutaneous tibial nerve stimulation can be considered an effective treatment for detrusor overactivity incontinence with 71% of patients considered responders, while none of those treated with placebo was considered a responder. The relevance of a placebo effect seems to be negligible in this patient population. Abbreviations and Acronyms DO detrusor overactivity GEE general estimating equations I-QoL incontinence quality of life LUT lower urinary tract OAB overactive bladder syndrome PTNS percutaneous tibial nerve stimulation Submitted for publication January 23, Supported by a grant from Uroplasty, Inc. Study received local ethics committee approval. * Correspondence: Department of Urology, University of Rome Tor Vergata, V. R. Venuti 21 Rome, Italy ( efinazzi@tin.it). Financial interest and/or other relationship with Astellas, Uroplasty and Bioniche. See Editorial on page For other articles on a related topic see pages 2179 and Key Words: electric stimulation therapy, tibial nerve, urinary incontinence, placebos PERCUTANEOUS tibial nerve stimulation, as described by Stoller in the late 1990s, 1 can be considered a technique of interventional neuromodulation. 2 Several articles have been published evaluating the efficacy of PTNS in the /10/ /0 Vol. 184, , November 2010 THE JOURNAL OF UROLOGY Printed in U.S.A by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. DOI: /j.juro

2 2002 PERCUTANEOUS TIBIAL NERVE STIMULATION FOR URGE INCONTINENCE treatment of overactive bladder syndrome 3 5 and nonobstructive urinary retention. 6,7 Data show that PTNS could result in significant clinical improvement in 55% to 71% of patients with OAB and in 41% to 67% of those with nonobstructive urinary retention. 3 7 Unfortunately the previous studies are noncontrolled and the results could be influenced by a placebo effect. According to pharmacological placebo controlled trials of patients with urge incontinence or detrusor overactivity, a placebo effect can be responsible for clinical improvement in as much as 28% to 43% of patients. 8,9 We conducted this prospective, double-blind, placebo controlled study based on an original placebo technique to evaluate the efficacy of PTNS vs placebo in patients with DO incontinence. MATERIALS AND METHODS Study Design This prospective, placebo controlled, double-blind study was approved by our local ethics committee and a specific informed consent was prepared. The study was conducted at Tor Vergata University Hospital in Rome. From February 2007 to February 2009 a total of 73 consecutive female patients were approached to participate in the study. After signing the informed consent patients were randomly assigned to PTNS or a placebo group following a computer generated randomization list. Study inclusion and exclusion criteria are listed in the Appendix. Only female patients were enrolled in the study to avoid the gender variable in the interpretation of results. Patients in the PTNS group were treated with 12, 30-minute PTNS sessions, performed 3 times a week according to the technique described by Vandoninck et al. 3 A 34 gauge needle was inserted percutaneously approximately 5 cm cephalad to the medial malleolus of the right or left ankle. A surface electrode was placed on the medial aspect of the ipsilateral calcaneus. The needle and electrode were connected to a low voltage (9 V) electrical stimulator (Urgent PC). Stimulation current (0 to 10 ma) with a fixed frequency of 20 Hz and a pulse width of 200 msec was increased until flexion of the big toe or fanning of all toes became noticeable. If no clear motor response was found the needle was removed and the insertion procedure was repeated. In most of the patients the motor response was accompanied by a sensory response of a radiating sensation spreading in the sole of the foot. The current was set at the highest level that was tolerable to the patient. Patients in the placebo group were treated with 12, 30-minute sham stimulation sessions performed 3 times per week. A 34 gauge needle was inserted in the medial head of the gastrocnemius muscle. The stimulator was briefly activated for approximately 30 seconds so the patient felt a minor electrical sensation in the skin, and then was turned off during the rest of the treatment. The choice of a different needle position for the placebo therapy was to eliminate any possible effects on LUT behavior due to any acupuncture effect from piercing the skin cephalad to the medial malleolus. 10 The electric current was given only for a few seconds to avoid possible effects of electric stimulation of the lower limb on the LUT as shown by Lindstrom and Sudsuang in animal models. 11 Patients in both groups were told that they may not have any perception of the electrical sensation due to adaptation and they were blinded regarding the procedure (PTNS or sham) used. At baseline and after 12 treatments all patients completed a 3-day voiding diary reporting the number of incontinence episodes, number of micturitions, voided volumes and I-QoL score. 12 Patients with a 50% or greater reduction in urge incontinence episodes were considered responders. The primary outcome measure was the percent of responders in the 2 groups. Secondary outcome measures, analyzed at baseline and after 12 PTNS/placebo treatments, were number of incontinence episodes, number of micturitions, mean voided volume and I-QoL score. To verify patient blindness with respect to the assigned treatment after 3 sessions patients were asked which procedure they believed they received. This evaluation was performed after 3 sessions to avoid answers being influenced by clinical improvement. Concordance between believed treatment and administered treatment was then analyzed. The results of the 2 groups were collected by 2 physicians, and analyzed by a third physician and a statistician, both of whom were blinded regarding the procedure used in any single patient. Sample Size and Power Analysis We evaluated the efficacy of PTNS compared to a sham treatment. Accordingly the working hypothesis was that PTNS would provide a clinically relevant increase of responders while the null hypothesis was of equality of responder proportion in the 2 groups (superiority trial). The criterion for significance (alpha) was set at (2 tails). With a sample size of 15 in each group this study had a power of 82.3% to yield a statistically significant result assuming that the difference in proportions was 0.45 (specifically 0.05 vs 0.50). This effect was selected because the magnitude is reasonable according to previously published findings. 13 To account for a dropout rate of 10% the number of patients to be recruited was set at 17 for each group, 34 total. Statistical Analysis To test the main end point (percentage of responders) a chi-square test was applied. The number of incontinence episodes, number of micturitions, voided volume and I- QoL were also evaluated. The first 2 variables were count data and typically they should not be analyzed assuming gaussianity. Therefore, such variables were analyzed by a GEE model, assuming a Poisson distribution. For this type of model the ANOVA F statistic was replaced by the Wald statistic. Post hoc comparisons were performed according to Sidak s procedure. GEE also allowed us to model voided volume that was approximately log normally distributed. This procedure was equivalent to the ANOVA

3 PERCUTANEOUS TIBIAL NERVE STIMULATION FOR URGE INCONTINENCE 2003 Figure 1. Study flowchart according to CONSORT (Consolidated Standards of Reporting Trials) flow diagram. model after log transformation of data. I-QoL showed a gaussian distribution and was analyzed with traditional ANOVA. The concordance between type of administered treatment and type of believed treatment was assessed with Cohen s Kappa index. RESULTS From February 2007 to February 2009 a total of 35 female patients were enrolled in this study with 18 randomly assigned to the PTNS group (mean age 44.9 years) and 17 (mean age 45.5 years) to the placebo group. Groups were comparable for all demographic aspects. In the PTNS group 1 patient and in the placebo group 2 did not complete the study for personal reasons not related to the used technique. Data from 17 patients in the PTNS group and 15 in the placebo group were available for analysis (fig. 1). Baseline measures for the 2 arms are reported in table 1. The number of responders who reported a 50% or greater reduction in incontinence episodes was 12 of 17 (71%) in the PTNS arm and 0 of 15 (0%) in the placebo arm (chi-square 16.9, df 1, p 0.001). The GEE model with incontinence episodes as a dependent Poisson variable indicated that both main terms (treatment p 0.001, time p 0.001) were significant. However, the main finding was the strong significance of the treatment time interaction (p 0.001), indicating that the pre-post differences were dependent on the type of treatment. Looking at estimated means in the placebo arm the number of incontinence episodes changed from 4.2 to 3.8, which was not significant (p 0.394). On the other hand in the PTNS arm there was a statistically significant decrease in incontinence episodes from 4.1 to 1.8 (p 0.001). A similar analysis was performed with the number of micturitions as the dependent Poisson variable. Again both main factors (treatment p 0.007, time p 0.001) were significant, as was the treatment time interaction (p 0.001). In the placebo arm the change in number of micturitions from 14.7 to 13.9 was not statistically significant (p 0.960). However, in the PTNS arm the decrease in the number of incontinence episodes from 13.6 to 9.5 was a statistically significant reduction (p 0.001). Voided volume, entered as a dependent log-normal variable, was analyzed in association with treatment (p 0.030), time (p 0.001) and to their interaction (p 0.001). No difference was observed in the placebo arm (from to 150.4, p 0.879) while a statistically significant increase was found in the PTNS arm (from to 186.5, p 0.001). The last considered measure I-QoL showed a similar pattern. ANOVA for repeated measures indicated that in addition to the main effects the treatment time interaction was significant (p 0.027) due to the lack of significant change after placebo (from 69.5 to 70.6, p 0.619) and to the significant increase after PTNS (from 69.6 to 81.3, p 0.025, table 2 and fig. 2). To verify patient blindness with respect to assigned treatment we observed that patient concordance between type of administered treatment and type of believed treatment was low (60%). This concordance was not significantly different from chance (Kappa 0.18, p 0.305), suggesting a low ability Table 1. Baseline measures Placebo Group PTNS Group Mean (SD) Median (range) Mean (SD) Median (range) Incontinence episodes/3 days 4.2 (2.1) 5 (2 8) 4.1 (1.8) 4 (1 7) Micturitions/day 15.0 (5.7) 15 (8 25) 13.6 (4.0) 12 (9 21) Voided vol (ml) (46.7) 125 (90 270) (51.6) 129 (90 250) I-QoL score 69.5 (7.8) 70 (58 82) 69.6 (7.4) 68 (55 82)

4 2004 PERCUTANEOUS TIBIAL NERVE STIMULATION FOR URGE INCONTINENCE Table 2. Efficacy measures Before Placebo After Placebo Before PTNS After PTNS Mean incontinence episodes/3 days (range) 4.2 ( ) 3.8 ( ) 4.1 ( ) 1.8 ( ) Mean micturitions/day (range) 14.7 ( ) 13.9 ( ) 13.6 ( ) 9.5 ( ) Mean ml voided vol (range) ( ) ( ) ( ) ( ) Mean I-QoL score (range) 69.5 ( ) 70.6 ( ) 69.6 ( ) 81.3 ( ) No. perception of treatment: Placebo 8 6 PTNS 7 11 to recognize the received treatment. No serious side effects were reported in either group but patients in both groups reported occasional transient pain at the stimulation site. DISCUSSION Percutaneous tibial nerve stimulation has been evaluated for the treatment of OAB in several published studies. 3 5 The heterogeneity of data in literature and the lack of controlled studies give a level of evidence of 3 for the efficacy of PTNS in the treatment of OAB as recently reported by the International Consultation on Incontinence (ICI) Unfortunately the ICI was not able to analyze the controlled study on PTNS published by Peters et al after the end of the 2008 work. 15 This randomized, multicenter, controlled study compared the effectiveness of PTNS to extended-release tolterodine. After 12 weeks of therapy objective measures improved similarly in both groups for reduction in urinary frequency, urge urinary incontinence episodes, urge severity and nighttime voids, as well as for improvement in voided volume. The authors concluded that PTNS is safe with statistically significant improvements in patient assessment of overactive bladder symptoms and with objective effectiveness comparable to that of pharmacotherapy. According to the authors a study limitation was having no Figure 2. Comparison of outcome measures from baseline to after treatment (mean and 95% CI)

5 PERCUTANEOUS TIBIAL NERVE STIMULATION FOR URGE INCONTINENCE 2005 placebo in the tolterodine arm and no sham in the PTNS arm. Thus, a possible placebo effect, affecting the results, cannot be excluded in this as in previous cited studies. The placebo effect is the capability of patients to influence symptoms by their behaviors and beliefs. Thus, in nonplacebo controlled studies the influence of patient behaviors and beliefs is not separable from the effect of therapy. Our study is a placebo controlled study on the results of PTNS in patients with OAB, in particular female patients with detrusor overactivity. The first problem that needed to be solved in the design of this study was finding a placebo technique for PTNS. When the study was designed the data published by Peters et al were not available. 16 In this study a Streitberger placebo needle was used at the tibial nerve insertion site. The sensation of electric stimulation was given by a transcutaneous electrical nerve stimulation unit device, stimulating a different site of the foot. Patients were able to recognize PTNS and sham correctly in only 33% of cases, thus validating this technique as a feasible sham for PTNS. The placebo technique in our study was used to avoid any possible effects of acupuncture near the PTNS point. Therefore, a different location for needle insertion (gastrocnemius muscle) was chosen and the stimulator was activated only briefly to avoid possible effects of the electric stimulation of the lower limb on the LUT. This placebo technique, similarly to what Peters et al observed, was not easily recognized by patients. 16 In fact only in 60% of patients was treatment or placebo correctly recognized and this percentage is not significantly different from chance (Kappa 0.18, p 0.305). The primary outcome measure of this study, as with that by Vandoninck et al, 7 was the percent of responders in each group, defined as patients with a reduction of 50% or more in incontinence episodes. In the PTNS arm 12 (71%) but in the placebo arm zero were considered responders (p 0.001). In the placebo arm the number of incontinence episodes decreased from 4.2 to 3.8 but this change was not significant. However, in the PTNS arm incontinence episodes decreased from 4.1 to 1.8, which was a statistically significant reduction (p 0.001). Similar findings were observed for the number of micturitions and voided volumes. Both parameters improved significantly in patients treated with PTNS and were almost unchanged in those receiving placebo. Interestingly even I-QoL scores in the PTNS group were increased significantly (69.6 to 81.3, p 0.025) but not in the placebo group (69.5 to 70.6, p 0.619). These findings confirm that PTNS is a good therapeutic option for patients with OAB, in particular for women with DO incontinence. PTNS is able to improve not only voiding diary parameters but also the quality of life of women with urge incontinence. Furthermore, it is a minimally invasive technique that does not need continuous stimulation but only periodic stimulation sessions, with no serious adverse events reported. 3 7,15 Recently reported results show that in patients with OAB the symptom improvement achieved with 12 weekly PTNS treatments is maintained or even improved at 12-month followup. 17 In our study we were able to exclude a relevant placebo effect of PTNS. No patient on placebo was considered a responder according to the established definition. Our results seem to confirm recent data from the literature. In fact, a randomized trial of percutaneous tibial nerve stimulation vs sham was recently published by Peters et al. 18 According to this study PTNS subjects achieved statistically significant improvement in bladder symptoms with 54.5% reporting moderately or markedly improved responses from baseline vs 20.9% of sham subjects (p 0.001). All considered parameters demonstrated statistically significant improvement from baseline to end of treatment for PTNS vs sham. In our series no patient was considered a responder after placebo. The lack of placebo effect in patients in this study can be due to the primary outcome measure used (number of incontinence episodes) and the responder definition (50% or greater reduction in urge incontinence episodes). Nevertheless, Peters et al found a statistically significant reduction in the number of urge incontinence episodes after sham, while in our patients only a small (nonsignificant) change was observed. 18 This discrepancy in results could be due to differing inclusion criteria. In our study we enrolled only female patients with DO incontinence that did not respond to the conservative treatments. In the study by Peters et al male and female patients with OAB (not necessarily affected by DO) who self-reported failure of conservative care were enrolled in study. CONCLUSIONS This is a placebo controlled trial of a neuromodulation technique aimed at influencing LUT behavior. According to this study the placebo effect seems to be negligible for female patients with DO incontinence after PTNS. On the other hand, for these patients PTNS is an effective treatment with 71% classified as responders. The placebo technique described in our study seems to mimic PTNS with no therapeutic effect.

6 2006 PERCUTANEOUS TIBIAL NERVE STIMULATION FOR URGE INCONTINENCE APPENDIX Inclusion and exclusion criteria Inclusion Criteria Female Urge incontinence and urodynamically diagnosed detrusor overactivity incontinence Unresponsive to behavioral and rehabilitation therapy or antimuscarinics Able to give written, informed consent 18 years of age or older Mentally competent and able to understand all study requirements Able to understand the procedures, advantages and possible side effects Willing and able to complete a 3-day voiding diary and I-QoL questionnaire Bladder capacity 100 ml or greater No signs of neurologic abnormalities at objective examination; no history of neurologic pathology No pharmacological treatment or pharmacological treatment unchanged for 30 days before beginning the study Exclusion Criteria Pregnancy or intention to become pregnant during the study Active urinary tract infection or recurrent urinary tract infections (more than 4 per year) Presence of urinary fistula, bladder or kidney stones, interstitial cystitis, cystoscopic abnormalities that could be malignant Diabetes mellitus Cardiac pacemaker or implanted defibrillator REFERENCES 1. Stoller ML: Afferent nerve stimulation for pelvic floor dysfunction. Eur Urol 1999; 35: Abejón D and Reig E: Is pulsed radiofrequency a neuromodulation technique? Neuromodulation 2003; 6: Vandoninck V, Van Balken MR, Finazzi Agrò E et al: Posterior tibial nerve stimulation in the treatment of urge incontinence. Neurourol Urodyn 2003; 22: Klingler HC, Pycha A, Schmidbauer J et al: Use of peripheral neuromodulation of the S3 region for treatment of detrusor overactivity: a urodynamicbased study. Urology 2000; 56: Govier FE, Litwiller S, Nitti V et al: Percutaneous afferent neuromodulation for the refractory overactive bladder: results of a multicenter study. J Urol 2001; 165: Vandoninck V, van Balken MR, Finazzi Agrò E et al: Posterior tibial nerve stimulation in the treatment of idiopathic nonobstructive voiding dysfunction. Urology 2003; 61: Vandoninck V, van Balken MR, Finazzi Agrò E et al: Posterior tibial nerve stimulation in the treatment of voiding dysfunction: urodynamic data. Neurourol Urodyn 2004; 23: Burgio KL, Locher JL, Goode PS et al: Behavioral vs drug treatment for urge urinary incontinence in older women: a randomized controlled trial. JAMA 1998; 280: Thuroff JW, Bunke B, Ebner A et al: Randomized, double-blind, multicenter trial on treatment of frequency, urgency and incontinence related to detrusor hyperactivity: oxybutynin versus propantheline versus placebo. J Urol 1991; 145: Chang PL: Urodynamic studies in acupuncture for women with frequency, urgency and dysuria. J Urol 1988; 140: Lindstrom S and Sudsuang R: Functionally specific bladder reflexes from pelvic and pudendal nerve branches; an experimental study in cat. Neurourol Urodyn 1989; 8: Wagner TH, Patrick DL, Bavendam TG et al: Quality of life of persons with urinary incontinence: development of a new measure. Urology 1996; 47: Finazzi Agrò E, Petta F, Bove P et al: Percutaneous tibial nerve stimulation (PTNS) in the treatment of urge incontinence: a double blind, placebo controlled study. Urodinamica 2005; 15: Abrams P, Cardozo L, Khoury S et al: Incontinence, 4th ed. Plymouth: Health Publications Ltd Peters KM, Macdiarmid SA, Wooldridge LS et al: Randomized trial of percutaneous tibial nerve stimulation versus extended-release tolterodine: results from the Overactive Bladder Innovative Therapy trial. J Urol 2009; 182: Peters K, Carrico D and Burks F: Validation of a sham for percutaneous tibial nerve stimulation (PTNS). Neurourol Urodyn 2009; 28: MacDiarmid SA, Peters KM, Shobeiri SA et al: Long-term durability of percutaneous tibial nerve stimulation for the treatment of overactive bladder. J Urol 2010; 183: Peters KM, Carrico DJ, Perez-Marrero RA et al: Randomized trial of percutaneous tibial nerve stimulation versus sham efficacy in the treatment of overactive bladder syndrome: results from the SUmiT trial. J Urol 2010; 183: 1438.