Triple-Target Treatment Versus Low-Frequency Electrostimulation for Anal Incontinence
A Randomized, Controlled Trial
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Background: In the nonsurgical treatment of anal incontinence, the combination of amplitude-modulated medium-frequency stimulation and electromyographic biofeedback (EMG-BF), known as triple-target treatment (3T), is superior to EMG-BF alone. The aim of this trial is to compare 3T with the standard treatment, low-frequency stimulation (LFS).
Methods: 80 patients with anal incontinence of Grade I or higher who presented to physicians or centers specialized in coloproctology were enrolled in this multicenter randomized trial with blinded observer. The trial had an open parallel-group design. Randomization was performed centrally by telephone. The primary endpoint was the Cleveland Clinic Score (CCS) after self-training at home with either 3T or LFS in two 20-minute sessions per day for 6 months. The secondary endpoints included the proportion of patients regaining continence, and the patients´ quality of life (QoL). On completion of the trial as planned, the results were evaluated with an intention-to-treat analysis. Study registration: DRKS00000138 (http://register.germanctr.de).
Results: 39 patients were randomized to 3T, and 41 to LFS. After 6 months of treatment, the CCS (mean ± standard deviation) was 3.1 ± 4.2 in the 3T group and 9.6 ± 3.9 in the LFS group. The median improvement in the CCS at 6 months compared to baseline was 7 points greater in the 3T group than in the LFS group (95% CI: 5–9, p<0.001). Anal continence was regained by 54% of the 3T patients, but none of the LFS patients (95% CI for the difference: 37.18% – 69.91%, p<0.001). QoL scores were higher in all dimensions in the 3T group than in the LFS group. No major adverse effects occurred in either group.
Conclusion: 3T is superior to LFS in the treatment of anal incontinence. The available evidence suggests that the success of 3T is based on the combined effect of biofeedback and medium-frequency stimulation. LFS of the type applied in this trial has no effect. 3T should be used in routine clinical practice instead of LFS.
Anal incontinence remains a major clinical challenge because it markedly impairs patients’ quality of life and because the available treatments to date have not been adequately effective. Currently, the treatment of anal incontinence generally begins with the elimination of individual factors that promote incontinence (1), involving, for example, bowel habits and food and fluid intake. Liquid stools are made more regular with solidifying fiber supplements or medications, while excess pressure on the bladder and bowel is avoided through changes in the patient’s everyday behavior. If these measures do not succeed in cases of chronic anal incontinence, the recommended next step usually consists of nonsurgical methods such as pelvic floor exercises, biofeedback (EMG-BF), and electrical stimulation (2), with the purpose of bolstering the strength and coordination of the sphincter muscles. Surgery is the first line of treatment for acute sphincter injuries (2).
In Germany, the Medical Aids Directory (Hilfsmittelverzeichnis, HMV) regulates the ordering of biofeedback and electrical stimulation and its reimbursement by the statutory health insurance companies (3). Reimbursability is predicated on the demonstration of efficacy and cost-effectiveness; level I evidence is usually required for the reimbursement of active medical products. Although the categories of EMG-BF and low-frequency electrical stimulation (LFS) have been included in the HMV as prescribable and reimbursable interventions for a number of years, their efficacy has never been adequately demonstrated. In multiple systematic reviews (4–6), it has been found that the flawed methods of the available clinical trials made it impossible to arrive at any definitive judgment about efficacy (7). Poor compliance also affects the effectiveness of LFS (8).
In view of the lack of evidence for the standard methods then in use and the availability of an alternative treatment for anal incontinence, namely, amplitude-modulated medium-frequency stimulation (AM-MF), an investigator-initiated, multicenter study group was founded in 2006. Its goal was to investigate the efficiacy of the three treatment components EMG-BF, LFS, and AM-MF in a series of randomized controlled trials and to determine the clinical value of a new combination called triple-target treatment (3T). An overview of these different techniques is provided in the Box (gif ppt).
The concept of 3T is based on the finding that cortical activation differs in healthy and incontinent persons (9). In incontinent persons, the brain sends “corrupt” motor programs to the organs of continence, receives abnormally weak sensory feedback in return, and, as a result, is in a permanently stressed state. Coordination training with the aid of EMG-BF strengthens activity in the premotor cortex and the submotor area, while simultaneously lessening sensory and emotional activity in the rostral portion of the cingulate gyrus. This effect provides a theoretical basis for the use of EMG-BF and EMG-triggered stimulation as components of 3T.
A central hypothesis of the 3T concept is that treating the sphincter muscles alone is not enough. Healthy persons, while in resting state, can generate a roughly 90° angulation of the anal canal toward the pubic bone by contracting the puborectal sling; this anorectal angle is an important static factor for continence. Strengthening the tensile force of the puborectalis muscle (10) to aid in the generation of this angle and thereby close off the anal canal is one of the main therapeutic aims of 3T.
It is not possible, however, to strengthen all of the muscles involved in anal continence with exercises alone. The internal anal sphincter consists of smooth muscles and is not amenable to voluntary exercises; furthermore, it is difficult to actively reach the slow-twitch type I fibres (11, 12). It thus makes sense to used electrical stimulation on the smooth and slow muscular components.
Low-frequency stimulation, as used in most studies of anal incontinence, can be very painful when applied to the pelvic floor (13–15). Natural muscle fiber recruitment begins with the slow fibers and reaches the rapid ones last, but the activation of muscle fibers by low-frequency stimulation proceeds in the opposite sequence (16). Thus, the slow fibers are activated only at the end, and only with intense stimulation. As the pelvic floor is a densely innervated area, the therapeutic window for electrical stimulation in it is narrow; as a result, many patients cannot tolerate the intense stimulation needed to activate the slow muscle fibers (8, 17).
Stimulation with alternating current at medium frequency (MF > 1000 Hz) does not have this disadvantage, because its biological effect is based on a different principle than the all-or-nothing effect of low-frequency stimulation (18). Any individual impulse is too weak to depolarize nerve cell membranes; instead, the effect arises through asynchronous summation, and therefore fewer nociceptive neurons are excited, and the penetration is deeper. Patients can tolerate much more intense currents with this technique than with LFS, leading to strong contractions of the sphincter muscles and the pelvic floor (12, 14, 17).
In 3T, medium-frequency stimulation is also delivered with EMG triggering, which has found other useful applications in neurology for the recovery of motor capabilities (19). EMG-triggered stimulation uses weak anal EMG signals as the trigger for electrical induction of muscle contraction. This strengthens proprioceptive feedback and thereby enhances both central and decentral rehabilitative processes.
In summary, the 3T concept comprises the following components:
- Goal 1: Perineal and puborectal stimulation of the inaccessible smooth fibers and poorly accessible tonic fibers with AM-MF.
- Goal 2: Performance-coupled training of phasic voluntary muscle with EMG-biofeedback.
- Goal 3: Central and decentral neuroplastic training with EMG-triggered stimulation.
The first trial comparing 3T to EMG-BF alone (12, 20) was completed in 2008. Twice as many patients became continent with 3T as with EMG-BF alone (50% vs. 25%). Thus, the additional application of medium-frequency stimulation in the 3T group led to continence in an additional 25% of patients. Many of these patients had sphincter injuries; EMG-BF alone was only moderately effective in such cases (20).
We now report the findings of a further trial, which is the first randomized controlled trial comparing 3T to LFS.
The supplementary material (eSupplement pdf, eBox gif ppt) contains a detailed description of the methods of this trial, as well as further items that we report in accordance with the CONSORT 2010 recommendations (21).
Briefly stated, patients in the 3T group were treated with the Contrain® multifunction trainer (Procon GmbH, Hamburg, Germany), while patients in the comparison (LFS) group were treated with the EMS H5 4000 digital device. The two devices were fitted with electrodes of identical type, with longitudinal transmission, in order to make the mode of application of the two treatments as similar as possible. The patients were followed up at monthly intervals and informed that the devices stored data relating to their training. The number of exercises per day, and the performance in each exercise, were detected and recorded by the Contrain device, while the H5 device recorded the stimulation time.
3T consisted of AM-MF stimulation combined with EMG-BF; a detailed description of the treatment protocol is found in reference (12). Patients were instructed to train at home for 20 minutes every morning with an alternating combination and for another 20 minutes every evening with EMG-triggered stimulation.
In the LFS group, the usual settings for LFS in anal incontinence were used (14). The LFS patients, like the 3T patients, were encouraged to participate actively in their stimulation. To avoid biasing the results of the trial through differences between the two groups in the duration of training and time of day at which it was performed, the LFS patients were instructed to train for 20 minutes every morning and every evening, like their counterparts in the 3T group.
Patients were included in the trial if they were at least 18 years old, had anal incontinence of grade I or higher of any cause, and had not obtained satisfactory relief from an initial phase of intervention consisting of regulation of bowel habits, behavior changes, and pelvic floor exercises. Patients were excluded if they had overflow incontinence, grade III0 rectal prolapse, or chronic inflammatory bowel disease of any kind; if they were emotionally or intellectually unable to carry out the required training without help; if they were pregnant or thought they might be pregnant; and if they did not give their consent in writing to participation in the study.
In distinction to the 3T-AI trial (12), the patients were not recruited on the same day they were informed about the trial, but had one to two weeks to think about it before being recruited.
The goal of the trial was to show a difference, if present, between the results of 3T and those of LFS in the treatment of anal incontinence after six months of treatment.
The primary endpoint was the Cleveland Clinic Incontinence Score (CCS) in its validated German version (22) after six months of treatment in comparison to baseline. Possible CCS scores range from 0 (continent) to 20 (totally incontinent). Treatment was begun on the day of randomization. The secondary endpoints are described in detail in the supplementary material (eBox). Patients filled out questionnaires themselves at baseline as well as three and six months after randomization.
Randomization, blinding, sample size calculation, and statistical analysis are described in detail in the supplementary material.
The Universitätsklinikum Giessen-Marburg, Campus Giessen, was the sponsor of the trial. The trial was financially supported by Procon GmbH.
Details of the clinical trial
As planned, 80 patients were included in the trial, out of a total of 109 patients who were screened for eligibility. The trial began on 25 May 2009 and ended as planned on 10 November 2010, after the last recruited patient had been followed up for six months. The patients were randomized to receive either 3T or LFS (Figure gif ppt). The baseline characteristics of each group of trial participants are given in Table 1 (gif ppt) and in the part of Table 2 (gif ppt) that concerns baseline characteristics. The groups were comparable with respect to the balancing variables used at the time of randomization. 65 (81%) of the patients were female. At baseline, 9 (11%) had grade I incontinence, 66 (83%) grade II, and 5 (6%) grade III. About 18% had endosonographically diagnosed sphincter damage; the location and extent were similar. 36% were incontinent of both urine and stool.
In the intention-to-treat analysis, the reduction of CCS from baseline to six months after the start of treatment was significantly larger in the 3T group than in the LFS group (p = 9.8 × 10–10) (Table 2). The median improvement in CCS over baseline at six months in the 3T group was 7 points (95% confidence interval, 5.5–9; p = 5.8×10–11), while the LFS group had no significant change in CCS over baseline at six months (median, worsening by one point; 95% CI, 0–2; p = 0.0645). Per-protocol analysis yielded similar findings (eTable gif ppt).
The results for the primary endpoint were confirmed by the results for the secondary endpoints (Table 2). The 3T and LFS groups differed in the change of CCS from baseline to 3 months after the start of treatment, just as they did in the change from baseline to 6 months. Significantly better results were obtained with 3T than with LFS in the adapted Vaizey score, in every dimension of the quality of life, in urinary incontinence, and in manometry (Table 2).
The results of treatment were significantly better with 3T than with LFS in the entire patient group, as shown in Table 3 (gif ppt) (p = 3.4 × 10–12). At the end of treatment, 53.85% of the 3T patients but none of the LFS patients were continent (95% CI for absolute risk reduction, 37.18%–69.91%; p = 1.01 × 10–6). Incontinence did not improve or became worse in only 10% of the 3T patients, compared to 82.9% of the LFS patients (odds ratio for a 1-point change, 0.1880; 95% CI, 0.0839–0.3470; p = 1.3 × 10–13).
No side effects were reported in the 3T group. In the LFS group, about half of the patients complained of pain during stimulation. Some reported a feeling of pressure that persisted for hours after training. Some patients could be motivated to use a high enough current intensity to induce motor activity during their training, but 22% of the LFS patients could not tolerate such intensities and therefore stimulated at levels below the motor threshold (roughly 20 mA).
This randomized trial confirms our earlier results showing the superiority of 3T over EMG-BF alone. The difference is even greater in the present trial, because many patients became totally asymptomatic with 3T, while many patients who had LFS experienced no benefit whatsoever. The ineffectiveness of LFS is particularly striking in view of its current monopoly position in the German Medical Aids Directory. Other randomized trials have also shown it to be ineffective (14, 23).
While planning this trial, we hypothesized that LFS would not work because LFS at intensities high enough to induce muscle contraction would be intolerably painful (14). The trial results partly bear out this hypothesis: 22% of patients stimulated themselves at levels below the motor threshold. Other patients, however, were able to get used to higher intensities. The average current intensity at the end of treatment was 45.6 mA (SD, 14.27 mA). Nonetheless, even the patients who tolerated stimulation above the motor threshold did not obtain any functional improvement from it.
Our current hypothesis to explain the difference in efficacy of LFS and AM-MF is that the depth to which the stimulation penetrates is the most important determinant of its effect: the levator plate, and especially the puborectalis muscle, should be entirely under the influence of the stimulation. This hypothesis is derived from the two patient groups’ differing perceptions of passive contractions: both groups had the identical type of rectal electrode (to prevent bias related to differences in transmission), yet the LFS patients felt nothing more than sphincteric contractions, even at intensities above 40 mA, which some patients described as very unpleasant. In contrast, most 3T patients reported an “elevator feeling” that came about only with strong contractions of the puborectal sling, during which the pelvic floor visibly rose. The maximum tolerated intensity was markedly higher in medium-freqency stimulation than in LFS; the mean difference between the two was 127 mA (SD 34 mA) at the beginning of stimulation and 253 mA (SD 95 mA) at the end.
A further component of 3T, namely, EMG-triggered stimulation with a computer-generated sliding trigger threshold, may well make a large contribution to its sucess. The strong mental concentration that the device demands of the patient during this exercise probably leads to better central motor presence and control (24) than does traditional EMG-BF without electrical stimulation. In the usual alternating combination of stimulation and biofeedback, the patient repeats a four-component cycle consisting of contraction, relaxation, stimulation, and relaxation). Experience reveals, however, that only well-rested patients are able to keep concentrating on this sequence. In contrast, in EMG-triggered stimulation, stimulation is given, as it were, only as a reward for correct contraction, while the program oversees the patient’s performance: contraction, stimulation, relaxation. The EMG-triggered program may be more effective than the alternating training regime. As soon as the trigger program is switched on, the device’s EMG recordings often show an increase of 50% or more, leading us in turn to ask why alternating EMG-BF is ever used at all. As a didactic matter, however, many patients can only understand the trigger program once they have experienced the alternating program.
Although the duration of follow-up in this trial (six months) is three months shorter than in the 3T-AI trial, the 3T patients achieved essentially the same good results in this trial as in the earlier one. This should not be misunderstood as implying that six months of stimulation suffice for an optimal result. The apparently more rapid improvement is, in part, due to a statistical effect arising from the different mode of recruitment in the two studies. The additional one to two weeks that we gave prospective participants in the present trial to make up their minds about participation led to a better selection of motivated patients, and higher compliance in the present trial also undoubtedly accounts for some of the observed difference in results. Empirical experience outside the setting of the 3T trials reveals that the good result lasts three to four years in about half of all patients, and that a second treatment is often requested after that. 10% to 15% of patients seem to benefit more from permanent treatment; in others, the results deteriorate as the patient grows older. For harder evidence in these matters, further controlled trials are needed.
It is a limitation of this trial that, for technical reasons, the two devices we tested cannot be applied in blinded fashion, and the trial could therefore be performed only with blinding of the investigators doing the follow-up evaluation. A further aspect is that the control group was tested with LFS alone, not in combination with biofeedback. If we had compared 3T with a combination of EMG-BF and LFS, rather than with LFS alone, we would have expected to obtain the same results as the 3T-AI trial, because the inefficacy of LFS has already been demonstrated (14, 23). We would have needed four times as many patients to conduct such a trial but would not have gained any further useful knowledge from it.
Taken together with the 3T-AI trial, this trial shows that 3T is superior to both EMG-BF and LFS. It also shows that LFS fails to relieve anal incontinence. 3T, not LFS, should be the routinely used clinical treatment, and this evidence-based judgment should be reflected by a corresponding change in the German Medical Aids Directory.
http://register.germanctr.de, DRKS-ID: DRKS00000138
The entire trial protocol as submitted to the Ethics Committee is available from the corresponding author on request.
Conflict of interest statement
The trial was supported by Procon GmbH, Hamburg.
Thilo Schwandner accepted support from the Procon company in the setting of this trial. The company’s financial support extended to the provision of the electrical stimulation devices that were used in the trial.
Walter Kierer and Thilo Schwandner received reimbursement from Procon GmbH of travel expenses and fees for a course on the subject of constipation.
Thilo Schwandner has a “flying doctor” contract with the Ethicon company for STARR and TRANSTARR operations (constipation). The Department of General, Visceral, Thoracic, and Transplantation Surgery of the University of Giessen receives fees for the training of visiting physicians in the area of coloproctology at the Giessener Klinik.
Thilo Schwandner receives honoraria for lectures in coloproctology from the Ethicon company and for lectures on fistula surgery from the Cook company. He has also received financial support for research from the Cook company.
The remaining authors state that they have no conflicts of interest.
Manuscript submitted on 24 February 2011, revised version accepted on 20 July 2011.
Translated from the original German by Ethan Taub, M.D.
Univ.-Prof. Dr. rer. nat. Andreas Ziegler
Institut für Medizinische Biometrie und Statistik
Universität zu Lübeck
Universitätsklinikum Schleswig-Holstein, Campus Lübeck
23562 Lübeck, Germany
@For eReferences please refer to:
eSupplement, eBox, eFigure:
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Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck: Dr. rer. hum. biol. Hemmelmann, Dr. rer. pol. Vonthein, Univ.-Prof. Dr. rer. nat. Ziegler
Zentrum für Klinische Studien Lübeck, Universität zu Lübeck: Dr. rer. nat. hum. biol. Hemmelmann, Dr. rer. pol. Vonthein, Univ-Prof. Dr. rer. nat. Ziegler
Enddarmzentrum Hessen-Mitte, Pohlheim: Dr. med. Kierer
Koloproktologische Praxis, Marburg: Priv.-Doz. Dr. med. Weinel
End- und Dickdarmzentrum Hannover: Dr. med. Kolbert
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