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Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease
Eur J Vasc Endovasc Surg (2016)
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Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease R. Ravikumar *, K.J. Williams, A. Babber, T.R.A. Lane, H.M. Moore, A.H. Davies Academic Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, UK
WHAT THIS PAPER ADDS This pilot randomised clinical trial investigates the novel use of neuromuscular electrical stimulation (NMES) in treating patients with venous disease. NMES is a non-invasive method of activating the calf muscle pump to alter venous flow parameters. This is the first trial investigating the use of the REVITIVE device in the management of venous disease.
Objectives: Chronic venous disease (CVD) is common, affecting a quarter of the population. Current conservative methods of treatment aim to prevent progression of disease by reducing ambulatory venous pressure. Neuromuscular electrical stimulation (NMES) refers to the use of electrical impulses to elicit muscle contraction. This pilot randomised controlled trial investigates the effect of a footplate NMES device (REVITIVE) on venous flow parameters, limb oedema, and quality of life outcome measures in patients with CVD. Methods: Twenty-two patients with Clinical Etiological Anatomical and Pathophysiological (CEAP) clinical class C2eC4 venous disease were randomised to receive a sham or test device. The recommended duration of use was for 30 minutes daily for 6 weeks. Venous flow parameters (duplex ultrasound), limb volume (optoelectric volumeter), and quality of life outcome measures were measured at baseline and after 6 weeks. Results: The mean age of participants was 62 years, body mass index 28.6, with a 15:7 female preponderance. There was a significant difference in the percentage change in femoral vein flow parameters (from baseline) between the test and sham group while using the device (Week 0 time-averaged mean velocity 102.4% vs. 9.1%, p < .0001; volume flow 107.9% vs. 3.7%, p < .0001; peak velocity 377.7% vs. 6.7%, p < .0001). Limb volume was observed to increase significantly in the sham group (2.0% at Week 0 and 1.2% at Week 6; p < .01). This was prevented in the test group (þ0.8% at Week 0 and 1.0% at Week 6; p ¼ .06). There was a significant difference in the Aberdeen Varicose Vein Questionnaire between the two groups over the 6 weeks. Conclusions: This trial demonstrated a significant difference in venous flow parameters and prevention of orthostatic limb oedema with NMES. There was a positive effect on quality of life. Larger studies are required to determine the clinical significance of this in patients with venous disease. Ó 2016 Published by Elsevier Ltd on behalf of European Society for Vascular Surgery. Article history: Received 16 April 2016, Accepted 25 September 2016, Available online XXX Keywords: Neuromuscular electrical stimulation, Venous disease, Venous flow parameters, Oedema, Quality of life
INTRODUCTION Chronic venous disease (CVD) is a common condition affecting the lower limbs.1 Its clinical manifestations range from asymptomatic varicose veins to venous ulceration. Up to 50% of the general population have varicose veins, of whom 15% suffer from venous oedema and 5% from skin changes or ulceration.2,3 Venous ulceration affects * Corresponding author. Room 4N13C, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK. E-mail address: [email protected] (R. Ravikumar). 1078-5884/Ó 2016 Published by Elsevier Ltd on behalf of European Society for Vascular Surgery. http://dx.doi.org/10.1016/j.ejvs.2016.09.015
2.9% of the population and is a significant financial burden to the NHS.4 Ambulatory venous hypertension leads to the progression of venous disease, resulting in venous ulceration. The muscle pumps of the lower limbs are an important mechanism of reducing ambulatory venous pressure.5,6 Activation of the calf muscle pump can reduce ambulatory venous pressure by 50%.1 Current therapies used to treat venous disease aim to reduce ambulatory venous pressure by activating or augmenting the calf muscle pump through passive (e.g., graduated compression stockings [GCSs], multilayered bandaging and intermittent pneumatic compression [IPC]), and active mechanisms (e.g., exercise therapy7). However, patients with venous disease often
Please cite this article in press as: Ravikumar R, et al., Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/ j.ejvs.2016.09.015
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have several co-existent pathologies such as lack of ankle range of motion and muscle weakness, which impair the effect of the calf muscle pump.5,6 Neuromuscular electrical stimulation (NMES) has been shown in healthy individuals to increase venous blood flow parameters by artificially activating the muscle pumps of the lower limb.8 This pilot randomised controlled trial was conducted to investigate the effect of a NMES device on venous flow parameters, limb volume and quality of life of patients with chronic venous disease. METHOD Patient recruitment This study was a single-centre randomised controlled trial conducted at Charing Cross Hospital, London, between February and September 2014. Ethics approval for the study was obtained from the National Research Ethics Committee (NRES ref: 13/YH/0295) and the trial protocol was published on clinicaltrials.gov (NCT02114307). Patients with Clinical Etiological Anatomical and Pathophysiological (CEAP) clinical class C2eC4 and duplex ultrasound scan-confirmed diagnosis of superficial and/or deep venous disease were recruited from the vascular outpatient department. CEAP assessment, venous flow parameters, and limb volumes were measured in the affected or worse affected limb. Following written informed consent, patients were screened according to the inclusion and exclusion criteria (supplementary data). Medical history, medications, and anthropometric measurements were recorded at baseline. Patients in both groups were advised to continue with best medical therapy as prescribed by the clinical team. This includes compression stockings. Eligible patients were randomised on a 1:1 ratio with block randomisation, using a web-based randomisation service (www.sealedenvelope.com) to either a sham or test group. Sample size A power calculation was not available for this pilot trial as it was investigating a novel intervention. The neuromuscular electrical stimulation (NMES) device: REVITIVE IX The device investigated is a class IIa medical device, CE marked for use in healthy individuals (REVITIVE, Actegy Health Ltd, Bracknell, UK). It is used in the seated position, with the users’ bare feet placed on a pair of conductive footplate electrodes (Fig. 1). Electrical impulses are delivered to the muscles and nerves of the feet, which cause foot and calf muscle contraction at sufficient intensity. Direct contact between skin and electrodes is required for stimulation, precluding the use of compression stockings. Both feet have to be placed on the conductive footplates for the device to work. Patients were expected to use the device for 30 minutes daily over a 6-week period. A patient diary card was used to
Figure 1. Illustration of patient position while using the device.
monitor compliance. This was compared with a data logger, which monitored the electrical activity of the device. Patients were required to continue with best medical therapy (e.g., compression stockings) as prescribed by the clinical team, which was independent from the trial. The investigator was not blinded to the allocation as this would not be possible. Test device The test device runs a 30-minute programme of NMES consisting of 15 different waveform patterns, each with varying electrical output characteristics. The intensity of stimulation ranges from 1 to 99 units, delivering a maximum current of 13 mA (r.m.s., root mean square) at 500 U resistance. Stimulation intensity is increased by the subject until visible contraction is seen. This threshold intensity level is then doubled for the purposes of stimulation in this trial. The intensity of stimulation varies for each individual, and is affected by oedema and moisture. Patients were advised to use the highest intensity that was comfortable for them. The additional isorocker feature involves a fulcrum across the middle of the device over which the device can pivot to an angle of up to 15 . This allows the foot to remain in contact with the conductive footplate electrodes during ankle flexion and dorsiflexion. The isorocker can be disabled by pulling out the lever of the fulcrum, which sets the device at a 15 inclination. Sham device The sham device was identical to the test device, but delivered no electrical impulses. Patients were advised to set the intensity to 25 and to disable the isorocker. Hence, it simulated the effect of sitting still for 30 minutes. Patients were blinded as they were not informed which group they
Please cite this article in press as: Ravikumar R, et al., Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/ j.ejvs.2016.09.015
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were allocated to, had never used NMES previously, and therefore had no preconceptions of what it entailed. Both devices looked identical externally. Outcome assessments Outcome measures for venous flow parameters and limb volume were performed on the affected or worse affected limb. The primary outcome measure was a percentage change in venous flow parameters compared with baseline. Measurements were taken before, during, and after using the device, both at Week 0 and Week 6. The secondary outcome measures included limb volume (measured using an optoelectronic limb volumeter; Perometer, Pero-System Messgeraete GmbH) and quality of life outcome measures. Limb volume was measured before and after using the device at Week 0 and Week 6. Quality of life outcome measure questionnaires were compared between Week 0 and Week 6. Venous flow parameters A Philips (Guildford, UK) iU22 duplex ultrasound machine was used to measure venous flow parameters. Timeaveraged mean velocity (TAMV), peak venous velocity (PV), and volume flow (VF) were the components of venous flow parameters selected as outcome measures at the outset. These parameters have been described in other trials reporting venous flow parameters as an outcome measure. Patients were scanned in the seated position with their bare feet on the test or sham device (Fig. 1). Venous haemodynamic measurements were taken from the femoral vein of the affected or worse affected limb, 3e5 cm from the saphenofemoral junction or as proximal as possible, depending on the patients’ body habitus. The limb was marked for repeated measurements. Venous flow parameter measurements were taken at baseline and whilst using the device (6 repeat measurements at 4, 9, 14, 19, 24, and 29 minutes) and during a 10-minute recovery period (3 repeat measurements at 2, 5, and 10 minutes). Fifteen-second screenshots were saved and analysed offline. TAMV and VF were calculated using built-in software. PV was measured with the image J 1.47V program (Wayne Rasband, National Institutes of Health, Bethesda, MD, USA). The highest single peak in each 15-second screenshot was used taken as the peak venous velocity. All six repeat venous haemodynamic measurements (of TAMV, PV, and VF) while using the device and three repeat measurements during the recovery period were used for the analysis. Reliability. Accuracy of data was determined by intrarater and inter-rater reliability measurements conducted by two investigators with experience in measuring venous flow parameters. Two sets of 10 repeat measurements were performed on a healthy subject at rest per investigator. BlandeAltman analysis (Fig. 2AeD) and coefficient of variation were calculated using Prism 6 (GraphPad software Inc, La Jolla, CA, USA). The mean difference in intrarater
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reliability for TAMV and VF was 0.002 cm/s (95% CI 1.115 to 1.111) and 11.52 mL/min (95% CI 50.77 to 27.73), respectively. The coefficient of variation (CoV) for venous TAMV and VF were 17.5% and 22.7%, respectively. A single investigator performed all measurements in this trial. Measurement of limb volume Limb volume was measured using an optoelectronic limb volumeter (Perometer 350 NT, Pero-System Meßgeräte GmbH, Wuppertal, Germany). Patients using compression stockings were advised to remove stockings 2 h prior to their appointment. Measurements were taken with the patient seated and the affected leg in a horizontal position. Five readings were taken before and after device usage at Week 0 and Week 6. Reliability. The accuracy of measurement was determined by performing repeat measurements on a healthy subject. BlandeAltman analysis (Fig. 2E,F) was performed to measure intrarater and inter-rater reliability (Prism 6, GraphPad Software Inc). The mean difference in intrarater and inter-rater reliability for limb volume measurements were 3.667 mL (95% CI 26.34 to 19.01 mL) and 15.93 mL (95% CI 45.63 to 13.76 mL), respectively. The CoV was 0.2%. Quality of life outcome measurements Clinical severity was compared at Week 0 and Week 6 using the Venous Clinical Severity Score (VCSS). Quality of life outcome measures were assessed with disease specific (Aberdeen Varicose Vein Questionnaire [AVVQ]) and generic quality of life questionnaires (EQ5D and SF-12) at Week 0 and Week 6. Patient diary Compliance to protocol was determined using a patient diary over the 6 weeks of device usage. This was corroborated by information obtained from the data logger (YLM33, Grant Instruments Ltd, Royston, UK). Statistical analysis Statistical analysis was performed according to the intention to treat principle. Data was analysed using Prism 6 software (GraphPad Software Inc). Intergroup comparison of categorical variables such as CEAP classification and compression stocking usage was analysed using the chisquare or Fisher exact test. Parametric data were analysed using t test statistics. Non-parametric data were analysed using the Wilcoxon test for paired and ManneWhitney test for non-paired data. In all analyses, p < .05 was considered statistically significant. RESULTS Baseline characteristics Twenty-two patients with C2eC4 disease were recruited into the trial. No patients with C5 disease were identified for recruitment in the trial. Eleven patients were
Please cite this article in press as: Ravikumar R, et al., Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/ j.ejvs.2016.09.015
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Figure 2. BlandeAltman plot of intrarater (A,C,E) and inter-rater (B,D,F) reliability of TAMV (A,B), VF (C,D), and limb volume (E,F). Bias is shown as solid line; 95% confidence interval is shown with dotted lines. CI ¼ confidence interval; TAMV ¼ time-averaged mean velocity; VF ¼ volume flow.
randomised to the sham and test groups, respectively. One patient in the test group withdrew from the trial after 3 weeks as she developed pain from a ruptured Baker’s cyst (Fig. 3). Despite randomisation, there was a significant difference in the age and BMI of patients between the two groups. This is due to the small sample size of the pilot trial. There was no significant difference in the CEAP classification of patients between the sham and test group. There was no significant difference in the use of compression stockings
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Figure 3. Trial CONSORT diagram.
between the two groups. Data on patient demographics, CEAP classification, and compression stocking usage are shown in Table 1. Venous flow parameters Effect of NMES on venous flow parameters. Venous flow parameters (TAMV, PV, and VF) during device usage were compared with baseline and reported as a percentage change due to variation in baseline venous flow parameters. There was a significant difference in the percentage change in TAMV (median 102.4% vs. 9.1%, p < .0001), VF (107.9% vs. 3.7%, p < .0001), and PV (median 264.8% vs. 6.8%, p < .0001) between the test and sham group at Week 0 (Fig. 4). The effect of NMES was variable in the test group as evidenced by the wide range of values in TAMV (34.7% to 507.6%), VF (53.9% to 819.1%) and PV (11.8% to 923.6%). This trend was also seen in both groups at Week 6. In the test group, there was no significant difference in the median percentage change in TAMV (102.4% vs. 94.8%, p ¼ .307) and VF (107.9% vs. 78.2%, p ¼ .394) between Week 6 and Week 0. However, the percentage change in PV while using the device increased significantly (381% vs. 264.8%, p ¼ .012).
Please cite this article in press as: Ravikumar R, et al., Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/ j.ejvs.2016.09.015
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Effect of NMES on limb volume
Table 1. Patient demographic data. Test 54.6 13.7 8:3 26.3 2.6
p .012* e .042*
Age (years) Gender (F:M) BMI CEAP classification Clinical .298** C2 1 4 C3 8 6 C4 2 1 Aetiology .387*** Congenital 0 0 Primary 5 8 Secondary 6 3 Anatomy .278*** Superficial veins 7 9 Deep veins 7 3 Perforating veins 0 0 Pathophysiology .526** Reflux 6 8 Obstruction 2 2 Reflux and obstruction 3 1 Compression stockings .065** Worn daily 5 2 Worn most days 2 1 Intermittent use 2 0 Not used 2 8 Note. BMI ¼ body mass index; SD ¼ standard deviation. *p < .05 (t test); **p < .05 (chi-square test); ***p < .05 (Fisher’s exact test).
Venous flow parameters during the recovery period The effect of NMES on venous flow parameters persisted after the device was turned off (recovery period) in the test group. There was a significant difference in the percentage change in TAMV (sham 14.8% vs. test þ8.9%, p ¼ .001) and PV (sham 8.0% vs. test 16.0%, p ¼ .003) from baseline between the two groups during this recovery period at Week 0.
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Effect of NMES on quality of life measures There was no significant difference in the VCSS in between Week 0 and Week 6 in either group. In comparing Week 0 and Week 6, patients in the test group showed an improvement in the clinical and quality of life scores whereas the sham group reported a deterioration. For example, the mean AVVQ score increased from 18.67 to 21.11 in the sham group, and decreased from 16.16 to 10.44 in the test group. The difference in AVVQ score over the 6 weeks was not significantly different between the groups (sham 2.43 12.6 vs. test 4.17; p ¼ .15). The percentage difference AVVQ (32.816 vs. 3.005%, p ¼ .045) and short form (SF)-12: mental component score (SF-12: MCS) (16.28 vs. 9.977%, p ¼ .037) was significantly different between the two groups (Table 3). Patient compliance Patient compliance was assessed using a patient diary and a data logger. One patient did not complete the diary appropriately. The overall compliance in the remaining 20 patients was 96.9% (99.2% for sham group and 94.6% for test group).
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Pre-stimulation limb volume did not differ significantly between Week 0 and Week 6 in the sham (Week 0 5,131 1,250 mL vs. Week 6 5,158 1,272 mL; p ¼ .39) nor test (Week 0 5,377 1,122 mL vs. Week 6 5,498 1,171 mL; p ¼ .80) group. Limb volume (pre- vs. post-device usage) increased significantly in the sham group by 2.0% (p ¼ .0001) and 1.2% (p ¼ .002) at Week 0 and Week 6, respectively.The increase in the limb volume in the test group at Week 0 and Week 6 (0.8% and 1.0%) was not significant (Table 2). Both groups showed a median increase in limb volume, but this was greater in the sham group, which represented the effect of venous stasis that occurs during a period of quiet sitting.
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Figure 4. Box and whiskers plot showing percentage (%) change in venous haemodynamics from baseline for sham and test groups during device usage (A) at Week 0 (B) at Week 6. PV ¼ peak velocity; TAMV ¼ time-averaged mean velocity; VF ¼ volume flow. * Statistically significant difference (p < .0001) between sham and test group (ManneWhitney test). Please cite this article in press as: Ravikumar R, et al., Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/ j.ejvs.2016.09.015
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Table 2. Limb volume in sham and test group pre- and post-stimulation at week 0 and week 6. Week
Sham Pre-stimulation, Post-stimulation, mean SD (mL) mean SD (mL) 0 5,107 1,252 5,208 1,252 6 5,143 1,269 5,203 1,272 SD ¼ standard deviation. a Statistically significant difference (paired t test).
p .0001a .0023a
The data logger was not returned by three patients and not interpretable in seven patients. Information from the patient diary and data logger did not correlate (Pearson’s r2 ¼ .204, p ¼ .285). This was attributed to a fault in the data logger system. DISCUSSION This pilot randomised controlled trial was designed to investigate the potential benefit of NMES in managing patients with venous disease. As this was a novel device, sample size calculation was not undertaken and any significant results in the trial were designed to power future trials. This study has demonstrated that NMES significantly alters venous flow parameters while using the device. The sham group simulated the effect of sitting still for 30 minutes (orthostasis), which showed a median decrease in venous flow parameters from baseline (TAMV 9.1%, PV 6.8%, and VF 3.7%). The test group showed a median increase in venous flow parameters (TAMV 102.4%, PV 264.8%, and VF 107.9%). Limitations of venous flow parameters are discussed below. Limb volumes were compared before and after NMES separately at Week 0 and Week 6 because of the presumed effect of NMES, as an adjunct to exercise, on the calf muscle pump. The sham group simulated the effect of orthostasis on limb volume, leading to a significant increase in limb volume. The increase in limb volume in the test group was not significant, suggesting that NMES prevents limb oedema. There was no significant difference in limb volume between Week 0 and 6 in either group, suggesting no midterm effect of NMES on limb volume. Although there was no significant improvement in the absolute quality of life outcome measure scores in the sham
Test Pre-stimulation mean SD (mL) 5,377 1,122 5,500 1,173
Post-stimulation mean SD (mL) 5,422 1,127 5,553 1,168
p .0623 .0815
and test groups, there was a significant difference in the AVVQ and SF-12: MCS scores over the 6 weeks between the two groups. This was due to a non-significant improvement in the score in the test group and deterioration in the sham group. The SF-12: MCS may reflect the consequence of being allocated to the sham group, although the authors of this paper do believe there was adequate participant blinding. No adverse events were reported in this trial, supporting the good safety profile of the device. Patient compliance to device usage was good according to the patient diary. Several trials, utilising various NMES devices have demonstrated the beneficial effect of NMES on venous flow parameters.9e12 The effect of NMES on venous flow parameters is transient, limited to the duration of device usage as demonstrated by this trial. Several studies have found NMES to have a comparable,13 if not superior,12,14,15 effect on venous flow parameters compared to IPC. On the basis of improvement in venous flow parameters, NMES devices have been used for thromboprophylaxis in a few studies.16e19 It is endorsed by the National Institute for Health and Care Excellence (NICE) in patients with no alternative option for thromboprophylaxis.20 In patients with venous disease, NMES simulates the effect of exercise by activating the calf muscle pump. Exercise reduces ambulatory venous pressure by 50%1 and has been shown to improve calf muscle pump function (residual volume and ejection fraction) in patients with venous disease.7,21,22 CEAP C2 venous disease may be treated using various ablative and surgical procedures. However, CEAP C3 disease employs conservative methods of treatment such as compression stockings,23 limb elevation,24,25 and intermittent pneumatic compression.26,27 NMES may be useful in
Table 3. Percentage difference (%) in questionnaire scores over 6 weeks in the sham and test group. Sham Test Statistical analysis Difference in QOL score Difference in QOL score p VCSS 6.4 20.7a 11.8 31.2a .127a AVVQ 3.0 (15.3 to 68.3)b 28.4 (84.7 to 3.1)b .045 *,b EQ5D 0.00 (17.53 to 18.20)b 0.00 (7.55 to 1.14)b .739b b b EQ5D:VAS 14.3 (37.5 to 20.0) 5.0 (11.5 to 4.2) .321b a a SF-12: PCS 10.9 24.7 0.6 12.7 .254a SF-12: MCS 10.0 22.5a 9.4 16.3a .037**,a AVVQ ¼ Aberdeen Varicose Vein Questionnaire; EQ5D ¼ EuroQol-5D; EQ5D:VAS ¼ EuroQol-5D Visual Analogue Score; SF-12:PCS ¼ Short Form 12 Physical Component Score; SF-12:MCS ¼ Short Form 12 Mental Component Score. *p < .05 (t test); **p < .05 (ManneWhitney test). a Mean and standard deviation (SD) for parametric data (unpaired t test for statistical significance). b Median value and interquartile range (IQR) for non-parametric data (ManneWhitney test for statistical significance). Please cite this article in press as: Ravikumar R, et al., Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/ j.ejvs.2016.09.015
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treating orthostatic limb oedema in patients who remain seated for long periods of time. A cohort study in patients with CEAP C3 venous disease demonstrated a significant reduction in limb circumference, improvement in pain scores, venous refill time, and quality of life outcome measures following a 30-day trial with NMES.28 In the study, the duration of NMES daily usage was longer, with a schedule for reducing usage every 10 days. Venous ulceration is a significant and costly cause of morbidity.29 Conservative management involves the use of compression therapy in the form of single or multicomponent compression bandaging and short stretch bandaging.30 The role of IPC in treating venous ulceration shows a benefit compared with no compression but no benefit over compression therapy.31 A recent trial demonstrated a threefold increase in number of healed ulcers with NMES.32 The use of the REVITIVE device is limited in patients with venous ulceration as it requires skin contact while best medical practice involves the use of multilayered compression bandaging. The results of the trial should be interpreted with caution because of several limitations. Despite randomisation, the small sample size resulted in a significant difference in patient demographics between the two groups. Patients in the sham group were older and had a higher BMI than patients in the test group. In addition, the complexity of categorising patients with venous disease with the CEAP criteria, precluded intergroup comparison of these (clinical, aetiology, anatomical, and pathological groups) variables. Challenges to the study design include the ability to blind patients with an interventional device. In this study, both groups received identical devices. It is believed that patients in the sham group were truly blinded to the device as they had no preconception of the effect of NMES. However, assessment of success of blinding was not performed. Conducting a crossover trial to assess the efficacy of NMES in patients would not be possible as patients would know to expect the effect of NMES such as muscle contraction. A trial duration of 6 weeks was chosen as it represents the routine initial follow-up of patients with venous disease in this department. However, it is possible that significant changes are likely to require a longer duration of follow-up. Venous flow parameters were selected as the primary outcome measure as it demonstrates an improvement in circulation. The variability in venous flow parameters can be attributed to a combination of factors. The varying electrical waveform patterns, which change every minute, result in different maximum strength of muscle contraction as well as duration of contraction and relaxation phases. Hence, certain rapid contractions may not be beneficial as it is akin to trying to pump water from an empty well. In addition, operator reliability, pressure by the ultrasound probe or operators’ hand on vein diameter, breathing, and movement influence venous flow parameters. Movement caused by the powerful muscle contractions results in a reduction of vein diameter during the contraction phase as well as movement artefact. Owing to these limitations, repeat venous haemodynamic measurements
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were taken at the same 5-minute intervals to minimise device-related variations. The effect of NMES on venous flow parameters was therefore compared with the effect of orthostasis on venous disease using a sham device. The sham device did not administer any NMES and by disabling the isorocker (by pulling up a lever inclined at 15 ), it prevented inadvertent calf muscle pump activation by limiting ankle movement. NMES has a variable effect on patients because of several factors. Pain thresholds affect the intensity tolerated by patients. Oedema and dry skin are a barrier to stimulation. Patients were advised to apply moisturiser if the effect of NMES was diminished. Patients with asymmetric disease (e.g., post-thrombotic syndrome) receive a lower intensity of stimulation on the affected limb, therefore reducing strength of muscle contraction and improvement in venous flow parameters in the affected side. The intensity of stimulation is often limited by pain due to the stronger muscle contractions on the unaffected limb. Ideally, a unilateral device would allow for different settings for each limb. CONCLUSION This pilot trial suggests a promising role for NMES in managing patients with venous disease, in particular to prevent orthostatic limb oedema and improve quality of life outcome measures. A powered trial should be conducted, to detect clinical significance in limb volume and quality of life outcome measures. ACKNOWLEDGEMENTS We would like to acknowledge Mr Roshan Bootun, Mr Andrew Busuttil, and Miss Kaji Sritharan for their help with patient recruitment. CONFLICT OF INTEREST The department received an academic grant from Actegy Healthy Ltd. FUNDING The department receives funding from Actegy Health Ltd. This research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre. APPENDIX A. SUPPLEMENTARY DATA Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejvs.2016.09.015. REFERENCES 1 Eberhardt RT, Raffetto JD. Chronic venous insufficiency. Circulation 2005;111:2398e409. 2 Moore HM, Lane TR, Thapar A, Franklin IJ, Davies AH. The European burden of primary varicose veins. Phlebology 2013;28(suppl. 1):141e7. 3 Robertson L, Evans C, Fowkes FG. Epidemiology of chronic venous disease. Phlebology 2008;23:103e11.
Please cite this article in press as: Ravikumar R, et al., Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/ j.ejvs.2016.09.015
8 4 Fowkes FG, Evans CJ, Lee AJ. Prevalence and risk factors of chronic venous insufficiency. Angiology 2001;52(suppl. 1):S5e15. 5 Araki CT, Back TL, Padberg FT, Thompson PN, Hobson RW. The significance of calf muscle pump function in venous ulceration. J Vasc Surg 1994;20:872e7. discussion 8e9. 6 Back TL, Padberg Jr FT, Araki CT, Thompson PN, Hobson 2nd RW. Limited range of motion is a significant factor in venous ulceration. J Vasc Surg 1995;22:519e23. 7 Padberg Jr FT, Johnston MV, Sisto SA. Structured exercise improves calf muscle pump function in chronic venous insufficiency: a randomized trial. J Vasc Surg 2004;39:79e87. 8 Varatharajan L, Williams K, Moore H, Davies AH. The effect of footplate neuromuscular electrical stimulation on venous and arterial haemodynamics. Phlebology 2015;30(9):648e50. 9 Broderick BJ, Breathnach O, Condon F, Masterson E, Olaighin G. Haemodynamic performance of neuromuscular electrical stimulation (NMES) during recovery from total hip arthroplasty. J Orthop Surg Res 2013;8:3. 10 Clarke Moloney M, Lyons GM, Breen P, Burke PE, Grace PA. Haemodynamic study examining the response of venous blood flow to electrical stimulation of the gastrocnemius muscle in patients with chronic venous disease. Eur J Vasc Endovasc Surg 2006;31:300e5. 11 Kaplan RE, Czyrny JJ, Fung TS, Unsworth JD, Hirsh J. Electrical foot stimulation and implications for the prevention of venous thromboembolic disease. Thromb Haem 2002;88:200e4. 12 Izumi M, Ikeuchi M, Mitani T, Taniguchi S, Tani T. Prevention of venous stasis in the lower limb by transcutaneous electrical nerve stimulation. Eur J Vasc Endovasc Surg 2010;39:642e5. 13 Jorgensen JO, Lalak NJ, North L, Hanel K, Hunt DR, Morris DL. Venous stasis during laparoscopic cholecystectomy. Surg Laparosc Endosc 1994;4:128e33. 14 Faghri PD, Pompe Van Meerdervort HF, Glaser RM, Figoni SF. Electrical stimulation-induced contraction to reduce blood stasis during arthroplasty. IEEE Trans Rehab Eng 1997;5:62e9. 15 Williams K, Moore H, Davies A. Haemodynamic changes with the use of neuromuscular electrical stimulation compared to intermittent pneumatic compression. Phlebology 2014;30:365e72. 16 Merli GJ, Herbison GJ, Ditunno JF, Weitz HH, Henzes JH, Park CH, et al. Deep vein thrombosis: Prophylaxis in acute spinal cord injured patients. Arch Phys Med Rehab 1988;69: 661e4. 17 Lobastov K, Barinov V, Laberko L, Obolensky V, Boyarintsev V, Rodoman G. Electrical calf muscle stimulation with Veinoplus device in postoperative venous thromboembolism prevention. Int Angiol 2014;33:42e9. 18 Izumi M, Ikeuchi M, Aso K, Sugimura N, Kamimoto Y, Mitani T, et al. Less deep vein thrombosis due to transcutaneous fibular nerve stimulation in total knee arthroplasty: a randomized
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controlled trial. Knee Surg Sports Traumatol Arthrosc 2015;23(11):3317e23. Velmahos GC, Petrone P, Chan LS, Hanks SE, Brown CV, Demetriades D. Electrostimulation for the prevention of deep venous thrombosis in patients with major trauma: a prospective randomized study. Surgery 2005;137:493e8. Anonymous. NICE endorses geko device for VTE care. Nurs Times 2014;110:4. O’Brien J, Edwards H, Stewart I, Gibbs H. A home-based progressive resistance exercise programme for patients with venous leg ulcers: a feasibility study. Int Wound J 2013;10: 389e96. Yang D, Vandongen YK, Stacey MC. Effect of exercise on calf muscle pump function in patients with chronic venous disease. Br J Surg 1999;86:338e41. Mosti G, Picerni P, Partsch H. Compression stockings with moderate pressure are able to reduce chronic leg oedema. Phlebology 2012;27:289e96. Felty CL, Rooke TW. Compression therapy for chronic venous insufficiency. Semin Vasc Surg 2005;18:36e40. Dix FP, Reilly B, David MC, Simon D, Dowding E, Ivers L, et al. Effect of leg elevation on healing, venous velocity and ambulatory venous pressure in venous ulceration. Phlebology 2005;20:87e94. Kearon C, Kahn SR, Agnelli G, Goldhaber G, Raskob S, Comerota GE, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:454Se545S. Raines JK, O’Donnell Jr TF, Kalisher L, Darling RC. Selection of patients with lymphedema for compression therapy. Am J Surg 1977;133:430e7. Bogachev VY, Golovanova OV, Kuznetsov AN, Shekoyan AO, Bogacheva NV. Electromuscular stimulation with VEINOPLUS(R) for the treatment of chronic venous edema. Int Angiol 2011;30: 567e90. Moffatt CJ, Franks PJ, Oldroyd M, Bosanquet N, Brown P, Greenhalgh RM, McCollum CN. Community clinics for leg ulcers and impact on healing. BMJ 1992;305:1389e92. O’Meara S, Cullum N, Nelson EA, Dumville JC. Compression for venous leg ulcers. Cochrane Database Syst Rev 2012;11: CD000265. Nelson EA, Hillman A, Thomas K. Intermittent pneumatic compression for treating venous leg ulcers. Cochrane Database Syst Rev 2014;5:CD001899. Bogachev VY, Lobanov VN, Golovanova OV, Kuznetsov AN, Yershov PV. Electrical muscle stimulation with Veinoplus(R) device in the treatment of venous ulcers. Int Angiol 2015;34: 257e62.
Please cite this article in press as: Ravikumar R, et al., Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/ j.ejvs.2016.09.015
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Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease R. Ravikumar *, K.J. Williams, A. Babber, T.R.A. Lane, H.M. Moore, A.H. Davies Academic Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, UK
WHAT THIS PAPER ADDS This pilot randomised clinical trial investigates the novel use of neuromuscular electrical stimulation (NMES) in treating patients with venous disease. NMES is a non-invasive method of activating the calf muscle pump to alter venous flow parameters. This is the first trial investigating the use of the REVITIVE device in the management of venous disease.
Objectives: Chronic venous disease (CVD) is common, affecting a quarter of the population. Current conservative methods of treatment aim to prevent progression of disease by reducing ambulatory venous pressure. Neuromuscular electrical stimulation (NMES) refers to the use of electrical impulses to elicit muscle contraction. This pilot randomised controlled trial investigates the effect of a footplate NMES device (REVITIVE) on venous flow parameters, limb oedema, and quality of life outcome measures in patients with CVD. Methods: Twenty-two patients with Clinical Etiological Anatomical and Pathophysiological (CEAP) clinical class C2eC4 venous disease were randomised to receive a sham or test device. The recommended duration of use was for 30 minutes daily for 6 weeks. Venous flow parameters (duplex ultrasound), limb volume (optoelectric volumeter), and quality of life outcome measures were measured at baseline and after 6 weeks. Results: The mean age of participants was 62 years, body mass index 28.6, with a 15:7 female preponderance. There was a significant difference in the percentage change in femoral vein flow parameters (from baseline) between the test and sham group while using the device (Week 0 time-averaged mean velocity 102.4% vs. 9.1%, p < .0001; volume flow 107.9% vs. 3.7%, p < .0001; peak velocity 377.7% vs. 6.7%, p < .0001). Limb volume was observed to increase significantly in the sham group (2.0% at Week 0 and 1.2% at Week 6; p < .01). This was prevented in the test group (þ0.8% at Week 0 and 1.0% at Week 6; p ¼ .06). There was a significant difference in the Aberdeen Varicose Vein Questionnaire between the two groups over the 6 weeks. Conclusions: This trial demonstrated a significant difference in venous flow parameters and prevention of orthostatic limb oedema with NMES. There was a positive effect on quality of life. Larger studies are required to determine the clinical significance of this in patients with venous disease. Ó 2016 Published by Elsevier Ltd on behalf of European Society for Vascular Surgery. Article history: Received 16 April 2016, Accepted 25 September 2016, Available online XXX Keywords: Neuromuscular electrical stimulation, Venous disease, Venous flow parameters, Oedema, Quality of life
INTRODUCTION Chronic venous disease (CVD) is a common condition affecting the lower limbs.1 Its clinical manifestations range from asymptomatic varicose veins to venous ulceration. Up to 50% of the general population have varicose veins, of whom 15% suffer from venous oedema and 5% from skin changes or ulceration.2,3 Venous ulceration affects * Corresponding author. Room 4N13C, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK. E-mail address: [email protected] (R. Ravikumar). 1078-5884/Ó 2016 Published by Elsevier Ltd on behalf of European Society for Vascular Surgery. http://dx.doi.org/10.1016/j.ejvs.2016.09.015
2.9% of the population and is a significant financial burden to the NHS.4 Ambulatory venous hypertension leads to the progression of venous disease, resulting in venous ulceration. The muscle pumps of the lower limbs are an important mechanism of reducing ambulatory venous pressure.5,6 Activation of the calf muscle pump can reduce ambulatory venous pressure by 50%.1 Current therapies used to treat venous disease aim to reduce ambulatory venous pressure by activating or augmenting the calf muscle pump through passive (e.g., graduated compression stockings [GCSs], multilayered bandaging and intermittent pneumatic compression [IPC]), and active mechanisms (e.g., exercise therapy7). However, patients with venous disease often
Please cite this article in press as: Ravikumar R, et al., Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/ j.ejvs.2016.09.015
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have several co-existent pathologies such as lack of ankle range of motion and muscle weakness, which impair the effect of the calf muscle pump.5,6 Neuromuscular electrical stimulation (NMES) has been shown in healthy individuals to increase venous blood flow parameters by artificially activating the muscle pumps of the lower limb.8 This pilot randomised controlled trial was conducted to investigate the effect of a NMES device on venous flow parameters, limb volume and quality of life of patients with chronic venous disease. METHOD Patient recruitment This study was a single-centre randomised controlled trial conducted at Charing Cross Hospital, London, between February and September 2014. Ethics approval for the study was obtained from the National Research Ethics Committee (NRES ref: 13/YH/0295) and the trial protocol was published on clinicaltrials.gov (NCT02114307). Patients with Clinical Etiological Anatomical and Pathophysiological (CEAP) clinical class C2eC4 and duplex ultrasound scan-confirmed diagnosis of superficial and/or deep venous disease were recruited from the vascular outpatient department. CEAP assessment, venous flow parameters, and limb volumes were measured in the affected or worse affected limb. Following written informed consent, patients were screened according to the inclusion and exclusion criteria (supplementary data). Medical history, medications, and anthropometric measurements were recorded at baseline. Patients in both groups were advised to continue with best medical therapy as prescribed by the clinical team. This includes compression stockings. Eligible patients were randomised on a 1:1 ratio with block randomisation, using a web-based randomisation service (www.sealedenvelope.com) to either a sham or test group. Sample size A power calculation was not available for this pilot trial as it was investigating a novel intervention. The neuromuscular electrical stimulation (NMES) device: REVITIVE IX The device investigated is a class IIa medical device, CE marked for use in healthy individuals (REVITIVE, Actegy Health Ltd, Bracknell, UK). It is used in the seated position, with the users’ bare feet placed on a pair of conductive footplate electrodes (Fig. 1). Electrical impulses are delivered to the muscles and nerves of the feet, which cause foot and calf muscle contraction at sufficient intensity. Direct contact between skin and electrodes is required for stimulation, precluding the use of compression stockings. Both feet have to be placed on the conductive footplates for the device to work. Patients were expected to use the device for 30 minutes daily over a 6-week period. A patient diary card was used to
Figure 1. Illustration of patient position while using the device.
monitor compliance. This was compared with a data logger, which monitored the electrical activity of the device. Patients were required to continue with best medical therapy (e.g., compression stockings) as prescribed by the clinical team, which was independent from the trial. The investigator was not blinded to the allocation as this would not be possible. Test device The test device runs a 30-minute programme of NMES consisting of 15 different waveform patterns, each with varying electrical output characteristics. The intensity of stimulation ranges from 1 to 99 units, delivering a maximum current of 13 mA (r.m.s., root mean square) at 500 U resistance. Stimulation intensity is increased by the subject until visible contraction is seen. This threshold intensity level is then doubled for the purposes of stimulation in this trial. The intensity of stimulation varies for each individual, and is affected by oedema and moisture. Patients were advised to use the highest intensity that was comfortable for them. The additional isorocker feature involves a fulcrum across the middle of the device over which the device can pivot to an angle of up to 15 . This allows the foot to remain in contact with the conductive footplate electrodes during ankle flexion and dorsiflexion. The isorocker can be disabled by pulling out the lever of the fulcrum, which sets the device at a 15 inclination. Sham device The sham device was identical to the test device, but delivered no electrical impulses. Patients were advised to set the intensity to 25 and to disable the isorocker. Hence, it simulated the effect of sitting still for 30 minutes. Patients were blinded as they were not informed which group they
Please cite this article in press as: Ravikumar R, et al., Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/ j.ejvs.2016.09.015
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were allocated to, had never used NMES previously, and therefore had no preconceptions of what it entailed. Both devices looked identical externally. Outcome assessments Outcome measures for venous flow parameters and limb volume were performed on the affected or worse affected limb. The primary outcome measure was a percentage change in venous flow parameters compared with baseline. Measurements were taken before, during, and after using the device, both at Week 0 and Week 6. The secondary outcome measures included limb volume (measured using an optoelectronic limb volumeter; Perometer, Pero-System Messgeraete GmbH) and quality of life outcome measures. Limb volume was measured before and after using the device at Week 0 and Week 6. Quality of life outcome measure questionnaires were compared between Week 0 and Week 6. Venous flow parameters A Philips (Guildford, UK) iU22 duplex ultrasound machine was used to measure venous flow parameters. Timeaveraged mean velocity (TAMV), peak venous velocity (PV), and volume flow (VF) were the components of venous flow parameters selected as outcome measures at the outset. These parameters have been described in other trials reporting venous flow parameters as an outcome measure. Patients were scanned in the seated position with their bare feet on the test or sham device (Fig. 1). Venous haemodynamic measurements were taken from the femoral vein of the affected or worse affected limb, 3e5 cm from the saphenofemoral junction or as proximal as possible, depending on the patients’ body habitus. The limb was marked for repeated measurements. Venous flow parameter measurements were taken at baseline and whilst using the device (6 repeat measurements at 4, 9, 14, 19, 24, and 29 minutes) and during a 10-minute recovery period (3 repeat measurements at 2, 5, and 10 minutes). Fifteen-second screenshots were saved and analysed offline. TAMV and VF were calculated using built-in software. PV was measured with the image J 1.47V program (Wayne Rasband, National Institutes of Health, Bethesda, MD, USA). The highest single peak in each 15-second screenshot was used taken as the peak venous velocity. All six repeat venous haemodynamic measurements (of TAMV, PV, and VF) while using the device and three repeat measurements during the recovery period were used for the analysis. Reliability. Accuracy of data was determined by intrarater and inter-rater reliability measurements conducted by two investigators with experience in measuring venous flow parameters. Two sets of 10 repeat measurements were performed on a healthy subject at rest per investigator. BlandeAltman analysis (Fig. 2AeD) and coefficient of variation were calculated using Prism 6 (GraphPad software Inc, La Jolla, CA, USA). The mean difference in intrarater
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reliability for TAMV and VF was 0.002 cm/s (95% CI 1.115 to 1.111) and 11.52 mL/min (95% CI 50.77 to 27.73), respectively. The coefficient of variation (CoV) for venous TAMV and VF were 17.5% and 22.7%, respectively. A single investigator performed all measurements in this trial. Measurement of limb volume Limb volume was measured using an optoelectronic limb volumeter (Perometer 350 NT, Pero-System Meßgeräte GmbH, Wuppertal, Germany). Patients using compression stockings were advised to remove stockings 2 h prior to their appointment. Measurements were taken with the patient seated and the affected leg in a horizontal position. Five readings were taken before and after device usage at Week 0 and Week 6. Reliability. The accuracy of measurement was determined by performing repeat measurements on a healthy subject. BlandeAltman analysis (Fig. 2E,F) was performed to measure intrarater and inter-rater reliability (Prism 6, GraphPad Software Inc). The mean difference in intrarater and inter-rater reliability for limb volume measurements were 3.667 mL (95% CI 26.34 to 19.01 mL) and 15.93 mL (95% CI 45.63 to 13.76 mL), respectively. The CoV was 0.2%. Quality of life outcome measurements Clinical severity was compared at Week 0 and Week 6 using the Venous Clinical Severity Score (VCSS). Quality of life outcome measures were assessed with disease specific (Aberdeen Varicose Vein Questionnaire [AVVQ]) and generic quality of life questionnaires (EQ5D and SF-12) at Week 0 and Week 6. Patient diary Compliance to protocol was determined using a patient diary over the 6 weeks of device usage. This was corroborated by information obtained from the data logger (YLM33, Grant Instruments Ltd, Royston, UK). Statistical analysis Statistical analysis was performed according to the intention to treat principle. Data was analysed using Prism 6 software (GraphPad Software Inc). Intergroup comparison of categorical variables such as CEAP classification and compression stocking usage was analysed using the chisquare or Fisher exact test. Parametric data were analysed using t test statistics. Non-parametric data were analysed using the Wilcoxon test for paired and ManneWhitney test for non-paired data. In all analyses, p < .05 was considered statistically significant. RESULTS Baseline characteristics Twenty-two patients with C2eC4 disease were recruited into the trial. No patients with C5 disease were identified for recruitment in the trial. Eleven patients were
Please cite this article in press as: Ravikumar R, et al., Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/ j.ejvs.2016.09.015
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Figure 2. BlandeAltman plot of intrarater (A,C,E) and inter-rater (B,D,F) reliability of TAMV (A,B), VF (C,D), and limb volume (E,F). Bias is shown as solid line; 95% confidence interval is shown with dotted lines. CI ¼ confidence interval; TAMV ¼ time-averaged mean velocity; VF ¼ volume flow.
randomised to the sham and test groups, respectively. One patient in the test group withdrew from the trial after 3 weeks as she developed pain from a ruptured Baker’s cyst (Fig. 3). Despite randomisation, there was a significant difference in the age and BMI of patients between the two groups. This is due to the small sample size of the pilot trial. There was no significant difference in the CEAP classification of patients between the sham and test group. There was no significant difference in the use of compression stockings
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Figure 3. Trial CONSORT diagram.
between the two groups. Data on patient demographics, CEAP classification, and compression stocking usage are shown in Table 1. Venous flow parameters Effect of NMES on venous flow parameters. Venous flow parameters (TAMV, PV, and VF) during device usage were compared with baseline and reported as a percentage change due to variation in baseline venous flow parameters. There was a significant difference in the percentage change in TAMV (median 102.4% vs. 9.1%, p < .0001), VF (107.9% vs. 3.7%, p < .0001), and PV (median 264.8% vs. 6.8%, p < .0001) between the test and sham group at Week 0 (Fig. 4). The effect of NMES was variable in the test group as evidenced by the wide range of values in TAMV (34.7% to 507.6%), VF (53.9% to 819.1%) and PV (11.8% to 923.6%). This trend was also seen in both groups at Week 6. In the test group, there was no significant difference in the median percentage change in TAMV (102.4% vs. 94.8%, p ¼ .307) and VF (107.9% vs. 78.2%, p ¼ .394) between Week 6 and Week 0. However, the percentage change in PV while using the device increased significantly (381% vs. 264.8%, p ¼ .012).
Please cite this article in press as: Ravikumar R, et al., Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/ j.ejvs.2016.09.015
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Table 1. Patient demographic data. Test 54.6 13.7 8:3 26.3 2.6
p .012* e .042*
Age (years) Gender (F:M) BMI CEAP classification Clinical .298** C2 1 4 C3 8 6 C4 2 1 Aetiology .387*** Congenital 0 0 Primary 5 8 Secondary 6 3 Anatomy .278*** Superficial veins 7 9 Deep veins 7 3 Perforating veins 0 0 Pathophysiology .526** Reflux 6 8 Obstruction 2 2 Reflux and obstruction 3 1 Compression stockings .065** Worn daily 5 2 Worn most days 2 1 Intermittent use 2 0 Not used 2 8 Note. BMI ¼ body mass index; SD ¼ standard deviation. *p < .05 (t test); **p < .05 (chi-square test); ***p < .05 (Fisher’s exact test).
Venous flow parameters during the recovery period The effect of NMES on venous flow parameters persisted after the device was turned off (recovery period) in the test group. There was a significant difference in the percentage change in TAMV (sham 14.8% vs. test þ8.9%, p ¼ .001) and PV (sham 8.0% vs. test 16.0%, p ¼ .003) from baseline between the two groups during this recovery period at Week 0.
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Effect of NMES on quality of life measures There was no significant difference in the VCSS in between Week 0 and Week 6 in either group. In comparing Week 0 and Week 6, patients in the test group showed an improvement in the clinical and quality of life scores whereas the sham group reported a deterioration. For example, the mean AVVQ score increased from 18.67 to 21.11 in the sham group, and decreased from 16.16 to 10.44 in the test group. The difference in AVVQ score over the 6 weeks was not significantly different between the groups (sham 2.43 12.6 vs. test 4.17; p ¼ .15). The percentage difference AVVQ (32.816 vs. 3.005%, p ¼ .045) and short form (SF)-12: mental component score (SF-12: MCS) (16.28 vs. 9.977%, p ¼ .037) was significantly different between the two groups (Table 3). Patient compliance Patient compliance was assessed using a patient diary and a data logger. One patient did not complete the diary appropriately. The overall compliance in the remaining 20 patients was 96.9% (99.2% for sham group and 94.6% for test group).
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Pre-stimulation limb volume did not differ significantly between Week 0 and Week 6 in the sham (Week 0 5,131 1,250 mL vs. Week 6 5,158 1,272 mL; p ¼ .39) nor test (Week 0 5,377 1,122 mL vs. Week 6 5,498 1,171 mL; p ¼ .80) group. Limb volume (pre- vs. post-device usage) increased significantly in the sham group by 2.0% (p ¼ .0001) and 1.2% (p ¼ .002) at Week 0 and Week 6, respectively.The increase in the limb volume in the test group at Week 0 and Week 6 (0.8% and 1.0%) was not significant (Table 2). Both groups showed a median increase in limb volume, but this was greater in the sham group, which represented the effect of venous stasis that occurs during a period of quiet sitting.
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Figure 4. Box and whiskers plot showing percentage (%) change in venous haemodynamics from baseline for sham and test groups during device usage (A) at Week 0 (B) at Week 6. PV ¼ peak velocity; TAMV ¼ time-averaged mean velocity; VF ¼ volume flow. * Statistically significant difference (p < .0001) between sham and test group (ManneWhitney test). Please cite this article in press as: Ravikumar R, et al., Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/ j.ejvs.2016.09.015
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Table 2. Limb volume in sham and test group pre- and post-stimulation at week 0 and week 6. Week
Sham Pre-stimulation, Post-stimulation, mean SD (mL) mean SD (mL) 0 5,107 1,252 5,208 1,252 6 5,143 1,269 5,203 1,272 SD ¼ standard deviation. a Statistically significant difference (paired t test).
p .0001a .0023a
The data logger was not returned by three patients and not interpretable in seven patients. Information from the patient diary and data logger did not correlate (Pearson’s r2 ¼ .204, p ¼ .285). This was attributed to a fault in the data logger system. DISCUSSION This pilot randomised controlled trial was designed to investigate the potential benefit of NMES in managing patients with venous disease. As this was a novel device, sample size calculation was not undertaken and any significant results in the trial were designed to power future trials. This study has demonstrated that NMES significantly alters venous flow parameters while using the device. The sham group simulated the effect of sitting still for 30 minutes (orthostasis), which showed a median decrease in venous flow parameters from baseline (TAMV 9.1%, PV 6.8%, and VF 3.7%). The test group showed a median increase in venous flow parameters (TAMV 102.4%, PV 264.8%, and VF 107.9%). Limitations of venous flow parameters are discussed below. Limb volumes were compared before and after NMES separately at Week 0 and Week 6 because of the presumed effect of NMES, as an adjunct to exercise, on the calf muscle pump. The sham group simulated the effect of orthostasis on limb volume, leading to a significant increase in limb volume. The increase in limb volume in the test group was not significant, suggesting that NMES prevents limb oedema. There was no significant difference in limb volume between Week 0 and 6 in either group, suggesting no midterm effect of NMES on limb volume. Although there was no significant improvement in the absolute quality of life outcome measure scores in the sham
Test Pre-stimulation mean SD (mL) 5,377 1,122 5,500 1,173
Post-stimulation mean SD (mL) 5,422 1,127 5,553 1,168
p .0623 .0815
and test groups, there was a significant difference in the AVVQ and SF-12: MCS scores over the 6 weeks between the two groups. This was due to a non-significant improvement in the score in the test group and deterioration in the sham group. The SF-12: MCS may reflect the consequence of being allocated to the sham group, although the authors of this paper do believe there was adequate participant blinding. No adverse events were reported in this trial, supporting the good safety profile of the device. Patient compliance to device usage was good according to the patient diary. Several trials, utilising various NMES devices have demonstrated the beneficial effect of NMES on venous flow parameters.9e12 The effect of NMES on venous flow parameters is transient, limited to the duration of device usage as demonstrated by this trial. Several studies have found NMES to have a comparable,13 if not superior,12,14,15 effect on venous flow parameters compared to IPC. On the basis of improvement in venous flow parameters, NMES devices have been used for thromboprophylaxis in a few studies.16e19 It is endorsed by the National Institute for Health and Care Excellence (NICE) in patients with no alternative option for thromboprophylaxis.20 In patients with venous disease, NMES simulates the effect of exercise by activating the calf muscle pump. Exercise reduces ambulatory venous pressure by 50%1 and has been shown to improve calf muscle pump function (residual volume and ejection fraction) in patients with venous disease.7,21,22 CEAP C2 venous disease may be treated using various ablative and surgical procedures. However, CEAP C3 disease employs conservative methods of treatment such as compression stockings,23 limb elevation,24,25 and intermittent pneumatic compression.26,27 NMES may be useful in
Table 3. Percentage difference (%) in questionnaire scores over 6 weeks in the sham and test group. Sham Test Statistical analysis Difference in QOL score Difference in QOL score p VCSS 6.4 20.7a 11.8 31.2a .127a AVVQ 3.0 (15.3 to 68.3)b 28.4 (84.7 to 3.1)b .045 *,b EQ5D 0.00 (17.53 to 18.20)b 0.00 (7.55 to 1.14)b .739b b b EQ5D:VAS 14.3 (37.5 to 20.0) 5.0 (11.5 to 4.2) .321b a a SF-12: PCS 10.9 24.7 0.6 12.7 .254a SF-12: MCS 10.0 22.5a 9.4 16.3a .037**,a AVVQ ¼ Aberdeen Varicose Vein Questionnaire; EQ5D ¼ EuroQol-5D; EQ5D:VAS ¼ EuroQol-5D Visual Analogue Score; SF-12:PCS ¼ Short Form 12 Physical Component Score; SF-12:MCS ¼ Short Form 12 Mental Component Score. *p < .05 (t test); **p < .05 (ManneWhitney test). a Mean and standard deviation (SD) for parametric data (unpaired t test for statistical significance). b Median value and interquartile range (IQR) for non-parametric data (ManneWhitney test for statistical significance). Please cite this article in press as: Ravikumar R, et al., Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/ j.ejvs.2016.09.015
NMES Venous Disease
treating orthostatic limb oedema in patients who remain seated for long periods of time. A cohort study in patients with CEAP C3 venous disease demonstrated a significant reduction in limb circumference, improvement in pain scores, venous refill time, and quality of life outcome measures following a 30-day trial with NMES.28 In the study, the duration of NMES daily usage was longer, with a schedule for reducing usage every 10 days. Venous ulceration is a significant and costly cause of morbidity.29 Conservative management involves the use of compression therapy in the form of single or multicomponent compression bandaging and short stretch bandaging.30 The role of IPC in treating venous ulceration shows a benefit compared with no compression but no benefit over compression therapy.31 A recent trial demonstrated a threefold increase in number of healed ulcers with NMES.32 The use of the REVITIVE device is limited in patients with venous ulceration as it requires skin contact while best medical practice involves the use of multilayered compression bandaging. The results of the trial should be interpreted with caution because of several limitations. Despite randomisation, the small sample size resulted in a significant difference in patient demographics between the two groups. Patients in the sham group were older and had a higher BMI than patients in the test group. In addition, the complexity of categorising patients with venous disease with the CEAP criteria, precluded intergroup comparison of these (clinical, aetiology, anatomical, and pathological groups) variables. Challenges to the study design include the ability to blind patients with an interventional device. In this study, both groups received identical devices. It is believed that patients in the sham group were truly blinded to the device as they had no preconception of the effect of NMES. However, assessment of success of blinding was not performed. Conducting a crossover trial to assess the efficacy of NMES in patients would not be possible as patients would know to expect the effect of NMES such as muscle contraction. A trial duration of 6 weeks was chosen as it represents the routine initial follow-up of patients with venous disease in this department. However, it is possible that significant changes are likely to require a longer duration of follow-up. Venous flow parameters were selected as the primary outcome measure as it demonstrates an improvement in circulation. The variability in venous flow parameters can be attributed to a combination of factors. The varying electrical waveform patterns, which change every minute, result in different maximum strength of muscle contraction as well as duration of contraction and relaxation phases. Hence, certain rapid contractions may not be beneficial as it is akin to trying to pump water from an empty well. In addition, operator reliability, pressure by the ultrasound probe or operators’ hand on vein diameter, breathing, and movement influence venous flow parameters. Movement caused by the powerful muscle contractions results in a reduction of vein diameter during the contraction phase as well as movement artefact. Owing to these limitations, repeat venous haemodynamic measurements
7
were taken at the same 5-minute intervals to minimise device-related variations. The effect of NMES on venous flow parameters was therefore compared with the effect of orthostasis on venous disease using a sham device. The sham device did not administer any NMES and by disabling the isorocker (by pulling up a lever inclined at 15 ), it prevented inadvertent calf muscle pump activation by limiting ankle movement. NMES has a variable effect on patients because of several factors. Pain thresholds affect the intensity tolerated by patients. Oedema and dry skin are a barrier to stimulation. Patients were advised to apply moisturiser if the effect of NMES was diminished. Patients with asymmetric disease (e.g., post-thrombotic syndrome) receive a lower intensity of stimulation on the affected limb, therefore reducing strength of muscle contraction and improvement in venous flow parameters in the affected side. The intensity of stimulation is often limited by pain due to the stronger muscle contractions on the unaffected limb. Ideally, a unilateral device would allow for different settings for each limb. CONCLUSION This pilot trial suggests a promising role for NMES in managing patients with venous disease, in particular to prevent orthostatic limb oedema and improve quality of life outcome measures. A powered trial should be conducted, to detect clinical significance in limb volume and quality of life outcome measures. ACKNOWLEDGEMENTS We would like to acknowledge Mr Roshan Bootun, Mr Andrew Busuttil, and Miss Kaji Sritharan for their help with patient recruitment. CONFLICT OF INTEREST The department received an academic grant from Actegy Healthy Ltd. FUNDING The department receives funding from Actegy Health Ltd. This research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre. APPENDIX A. SUPPLEMENTARY DATA Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejvs.2016.09.015. REFERENCES 1 Eberhardt RT, Raffetto JD. Chronic venous insufficiency. Circulation 2005;111:2398e409. 2 Moore HM, Lane TR, Thapar A, Franklin IJ, Davies AH. The European burden of primary varicose veins. Phlebology 2013;28(suppl. 1):141e7. 3 Robertson L, Evans C, Fowkes FG. Epidemiology of chronic venous disease. Phlebology 2008;23:103e11.
Please cite this article in press as: Ravikumar R, et al., Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/ j.ejvs.2016.09.015
8 4 Fowkes FG, Evans CJ, Lee AJ. Prevalence and risk factors of chronic venous insufficiency. Angiology 2001;52(suppl. 1):S5e15. 5 Araki CT, Back TL, Padberg FT, Thompson PN, Hobson RW. The significance of calf muscle pump function in venous ulceration. J Vasc Surg 1994;20:872e7. discussion 8e9. 6 Back TL, Padberg Jr FT, Araki CT, Thompson PN, Hobson 2nd RW. Limited range of motion is a significant factor in venous ulceration. J Vasc Surg 1995;22:519e23. 7 Padberg Jr FT, Johnston MV, Sisto SA. Structured exercise improves calf muscle pump function in chronic venous insufficiency: a randomized trial. J Vasc Surg 2004;39:79e87. 8 Varatharajan L, Williams K, Moore H, Davies AH. The effect of footplate neuromuscular electrical stimulation on venous and arterial haemodynamics. Phlebology 2015;30(9):648e50. 9 Broderick BJ, Breathnach O, Condon F, Masterson E, Olaighin G. Haemodynamic performance of neuromuscular electrical stimulation (NMES) during recovery from total hip arthroplasty. J Orthop Surg Res 2013;8:3. 10 Clarke Moloney M, Lyons GM, Breen P, Burke PE, Grace PA. Haemodynamic study examining the response of venous blood flow to electrical stimulation of the gastrocnemius muscle in patients with chronic venous disease. Eur J Vasc Endovasc Surg 2006;31:300e5. 11 Kaplan RE, Czyrny JJ, Fung TS, Unsworth JD, Hirsh J. Electrical foot stimulation and implications for the prevention of venous thromboembolic disease. Thromb Haem 2002;88:200e4. 12 Izumi M, Ikeuchi M, Mitani T, Taniguchi S, Tani T. Prevention of venous stasis in the lower limb by transcutaneous electrical nerve stimulation. Eur J Vasc Endovasc Surg 2010;39:642e5. 13 Jorgensen JO, Lalak NJ, North L, Hanel K, Hunt DR, Morris DL. Venous stasis during laparoscopic cholecystectomy. Surg Laparosc Endosc 1994;4:128e33. 14 Faghri PD, Pompe Van Meerdervort HF, Glaser RM, Figoni SF. Electrical stimulation-induced contraction to reduce blood stasis during arthroplasty. IEEE Trans Rehab Eng 1997;5:62e9. 15 Williams K, Moore H, Davies A. Haemodynamic changes with the use of neuromuscular electrical stimulation compared to intermittent pneumatic compression. Phlebology 2014;30:365e72. 16 Merli GJ, Herbison GJ, Ditunno JF, Weitz HH, Henzes JH, Park CH, et al. Deep vein thrombosis: Prophylaxis in acute spinal cord injured patients. Arch Phys Med Rehab 1988;69: 661e4. 17 Lobastov K, Barinov V, Laberko L, Obolensky V, Boyarintsev V, Rodoman G. Electrical calf muscle stimulation with Veinoplus device in postoperative venous thromboembolism prevention. Int Angiol 2014;33:42e9. 18 Izumi M, Ikeuchi M, Aso K, Sugimura N, Kamimoto Y, Mitani T, et al. Less deep vein thrombosis due to transcutaneous fibular nerve stimulation in total knee arthroplasty: a randomized
R. Ravikumar et al.
19
20 21
22
23
24 25
26
27
28
29
30
31
32
controlled trial. Knee Surg Sports Traumatol Arthrosc 2015;23(11):3317e23. Velmahos GC, Petrone P, Chan LS, Hanks SE, Brown CV, Demetriades D. Electrostimulation for the prevention of deep venous thrombosis in patients with major trauma: a prospective randomized study. Surgery 2005;137:493e8. Anonymous. NICE endorses geko device for VTE care. Nurs Times 2014;110:4. O’Brien J, Edwards H, Stewart I, Gibbs H. A home-based progressive resistance exercise programme for patients with venous leg ulcers: a feasibility study. Int Wound J 2013;10: 389e96. Yang D, Vandongen YK, Stacey MC. Effect of exercise on calf muscle pump function in patients with chronic venous disease. Br J Surg 1999;86:338e41. Mosti G, Picerni P, Partsch H. Compression stockings with moderate pressure are able to reduce chronic leg oedema. Phlebology 2012;27:289e96. Felty CL, Rooke TW. Compression therapy for chronic venous insufficiency. Semin Vasc Surg 2005;18:36e40. Dix FP, Reilly B, David MC, Simon D, Dowding E, Ivers L, et al. Effect of leg elevation on healing, venous velocity and ambulatory venous pressure in venous ulceration. Phlebology 2005;20:87e94. Kearon C, Kahn SR, Agnelli G, Goldhaber G, Raskob S, Comerota GE, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:454Se545S. Raines JK, O’Donnell Jr TF, Kalisher L, Darling RC. Selection of patients with lymphedema for compression therapy. Am J Surg 1977;133:430e7. Bogachev VY, Golovanova OV, Kuznetsov AN, Shekoyan AO, Bogacheva NV. Electromuscular stimulation with VEINOPLUS(R) for the treatment of chronic venous edema. Int Angiol 2011;30: 567e90. Moffatt CJ, Franks PJ, Oldroyd M, Bosanquet N, Brown P, Greenhalgh RM, McCollum CN. Community clinics for leg ulcers and impact on healing. BMJ 1992;305:1389e92. O’Meara S, Cullum N, Nelson EA, Dumville JC. Compression for venous leg ulcers. Cochrane Database Syst Rev 2012;11: CD000265. Nelson EA, Hillman A, Thomas K. Intermittent pneumatic compression for treating venous leg ulcers. Cochrane Database Syst Rev 2014;5:CD001899. Bogachev VY, Lobanov VN, Golovanova OV, Kuznetsov AN, Yershov PV. Electrical muscle stimulation with Veinoplus(R) device in the treatment of venous ulcers. Int Angiol 2015;34: 257e62.
Please cite this article in press as: Ravikumar R, et al., Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/ j.ejvs.2016.09.015