The Dawning of a New Horizon For Venous Leg Ulcer Treatment

Editorial Summary

A high percentage of patients present with chronic or recurrent venous leg ulcers that are associated with a reduction in health-related quality of life and an increased economic burden to healthcare systems. The current challenge of generating high quality evidence for potential treatments is detrimental to patient outcomes. Implementing a self-controlled trial design in addition to using more achievable trial endpoints may provide a solution to the current lack of evidence. Furthermore, the use of a neuromuscular electrical stimulator as well as standard wound care may improve ulcer management. This article provides an overview of a study implementing a randomised self-controlled study design to assess the efficacy of a wearable device neuromuscular electrostimulator.

Introduction

Venous leg ulcers (VLU) inflict a substantial burden on healthcare services, demanding significant resources.1-3

It is estimated that 3% of the adult population worldwide are affected by VLUs.4 In the United Kingdom alone, approximately 3.8 million adults are affected by a wound. Many become chronic and difficult to manage, despite following treatment guidelines. More than 50% of VLUs do not heal within 12 months,5 and that number is predicted to grow.6 The cost of VLUs to overburdened healthcare systems is also staggering, higher than that of both cancer and cardiovascular disease. Annually, the cost to the NHS of managing wounds is £8.3 billion, £5.6 billion of which is for the treatment of wounds that fail to heal.5 Nurse visits in addition to dressings and compression bandages contribute to the huge financial burden faced by healthcare providers when managing patients with recurrent and difficult to treat VLUs.7 Most individuals with leg ulceration have venous disease, however around 20% have arterial disease. There are some patients for whom both arterial and venous disease is a factor.8 Because chronic venous insufficiency (CVI) is not diagnosed until VLUs have developed, treatment is often complex and a large proportion of patients experience recurrent ulceration. 7 Although VLUs can arise spontaneously, they often appear following minor trauma and exist clinically as part of CVI.2

Challenges to Proving Treatment Efficacy

Generally, when investigating the effectiveness of treatments for healing wounds, the outcome of the study is complete wound resolution. There are numerous problems associated with this strategy. Given that a large percentage of leg ulcers become chronic, taking potentially months to resolve fully, using complete healing as the primary outcome means lengthy trial periods would be needed to reach any statistical significance. The adoption of conventional randomised controlled trials (RCT) introduces a supplementary problem. The heterogeneity of ulcers makes matching trial control and intervention participant groups impossibly challenging. 12

Adopting alternative trial endpoints like speed of wound healing presents a viable option to assess the efficacy of possible treatments. In addition, modifying trial design to a self-controlled model, collecting data post-intervention, and comparing it with data from the same individual’s control data pre-intervention, removes confounding heterogeneity present in typical RCT models. This technique has been approved by opinion leaders in a consensus document who have concluded that self-controlled study designs might be more suitable for investigating treatment efficacy than more usual RCTs.12

The Neuromuscular Electrostimulator

The geko™ device (Firstkind Ltd, Daresbury) is a small, self-adhesive, wearable neuromuscular electro stimulator (NMES). It is placed on the lateral aspect of the leg just below the knee, over the head of the fibula. The NMES is designed to sit on the skin’s surface and deliver a gentle electrical pulse once each second to the common peroneal nerve. This augments the venous, arterial and microvascular flow of the leg and foot by activating the muscle pumps, essentially mimicking the effects of exercise.13

Since leg ulcers form as a result of venous insufficiency, it follows that compression provides an effective treatment by opposing hydrostatic pressures in the leg and increasing venous flow. However, most venous blood flow in the lower limb is driven by muscle pumps. Therefore, immobility and muscle pump dysfunction can exacerbate venous insufficiency. Exercise has previously proven effective when combined with compression in patients with VLUs. Therefore, the benefits of using neuromuscular electrical stimulation to activate muscle pumps in the legs are implied.12

The innovative application of non-invasive neuromuscular electrostimulation has been developed into a ground-breaking NMES platform called OnPulse™. This has then been integrated into its geko™ device, an industryleading product.14

Publication of a landmark multi-centre randomised self-controlled trial (RCT. Sky Medical Technology work to develop products specifically tailored to suit different medical needs. The company delivers products in a range of clinical settings with an interest in chronic wounds, treating and preventing oedema, and the prevention of venous thromboembolism (VTE). The overarching aim in any setting is to work collaboratively with healthcare professionals to achieve better patient outcomes while delivering cost-effective treatment.14

Overview of Study

The study to assess the effectiveness of the NMES (geko™ device) was conducted using the self-controlled trial design to combat the challenge of collecting sufficient evidence, figure 1. This was combined with the use of two metrics of short-term intermediate determinants of efficacy. Healing rate outcomes were used in place of complete healing. This offered the opportunity to assess the efficacy of the novel treatment swiftly, with greater sensitivity and with more nuance. The primary endpoint of the study was the rate of Wound Margin Advance (WMA). The study compared standard of care (SoC), which consisted of multi-layer compression bandaging or hosiery kits, with SoC supplemented with the use of NMES (geko™ device).12

Interim analysis of the first 20 participants was performed to determine sample size. Ultimately, 60 patients participated.12 Participants were randomised to receive either SoC alone or NMES (geko™) for 12 hours each day in addition to SoC. Randomisation was 1:1 using the Castor EDC platform using variable block size and differences in group sizes were due to patient exclusion post-randomisation. 12 To be included in the trial, participants had to meet various inclusion criteria. This included being 18 years or older, being able to give written informed consent and having a chronic venous leg ulcer due to underlying venous disease that had been present for at least 6 weeks, but not more than five years before entry into the study. The size of the ulcer was also specified at between 3 cm2 and 39 cm 2, with an anklebrachial pressure index (ABPI) of 0.8-1.2. No active wound infection could be present for at least 48 hours before commencing the study and no systemic antimicrobial for a minimum of 7 days prior to the start of the study was permitted.12

Overall, there were 22 participants in the SoC arm and 29 in the NMES arm. Nine patients were withdrawn post-randomisation because they failed to meet the study criteria, withdrew consent, or did not comply. There was no difference in the ratio of male to female patients between the groups and no significant differences were found between the two cohorts according to unpaired t-tests.12

Patients in both arms spent 4 weeks on a runin phase where they received only SoC. This phase was then able to be used as within-patient control for those on the NMES arm of the trial. After the initial run-in phase, the 29 patients on the NMES randomised arm went on to receive 4 weeks of NMES with the geko™ device, in addition to SoC. The 22 patients in the SoC cohort continued to receive SoC alone for a further 4 weeks.

The study was powered to allow comparison between the run-in and trial phases within each cohort but not between the SoC and NMES cohorts.12 Wounds were photographed prior to debridement at day 0 and at every weekly visit. The Aranz SilhouetteStar™, a digital camera which is part of the Silhouette™ wound assessment system, was used. This is a portable, non-contact device which can image and measure ulcers. The collected images were sent in a random order to be assessed by an international independent wound expert for delineation of the wound perimeter. From this, the wound area and perimeter could be calculated. The independent assessor was blinded to the image date as well as trial arm.12 Patients were followed up for 3 months following the 4-week intervention phase. However, complete wound healing during this time was only reported using patient self-report with no clinical measurements or examinations performed. Patients in both arms of the study were provided with SoC only during this time.12

Assessed Endpoints

A prerequisite for the use of speed of healing as a primary endpoint when comparing the control and intervention arm, is that the endpoint is linear in its trajectory. A mathematical method for calculating wound margin advancement (WMA) has previously been developed. The advancement of the wound margin in leg ulcers treated with compression therapy has subsequently been shown to follow a linear trajectory over a 4-week period.15-16 Therefore, a 4-week run-in phase and 4-week trial phase was appropriate to assess the efficacy of the NMES device.

WMA, the primary endpoint of the study, is powerful predictor of wound healing. Vidal’s method was used to calculate WMA ,15 where area/perimeter of the wound was calculated and then regressed against time. Rate of wound healing was also calculated using the metric of Percentage Area Reduction (PAR). PAR was represented by the reduction in total wound area as a percentage of the initial wound area at the beginning of the 4-week trial period.12

The study also assessed several secondary endpoints for descriptive analysis. These included adherence, rates of infection, percentage complete healing, quality of life scores EQ-5D-5L, Cardiff Wound Impact Schedule (CWIS), Venous Clinical Severity Score (VCSS), and Visual Analog Score (VAS) for pain.

Success of NMES (geko™ device):

The study described demonstrated that the NMES device, when used in combination with SoC, was successful in increasing the rate of wound healing. In comparison to SoC alone, the intervention arm saw a statistically significant (p=0.016) two-fold increase in the rate of healing, as measured by the primary outcome, WMA. The control arm saw no significant difference in the rate of healing between each trial phase.12

PAR of the ulcer was also analysed. This too showed a two-fold acceleration in healing rate (p=0.011) during the treatment phase for the intervention arm of the trial. The rate of healing remained the same throughout the run-in and treatment study phases for the SoC cohort.12

Images of each wound were taken throughout the trial to be independently assessed. For the patients in the intervention group, the size and perimeter of the wound was largely unchanged for the run-in phase of the trial when only SoC was provided. The wound margin is then seen to progressively advance and the wound area reduce during the second half of the trial, when patients received treatment with the NMES device (geko™).

Regardless of efficacy, the device would not be suitable for clinical application without the approval of patient populations. Concordance with treatment plays an important role in treatment outcome. In the trial, the NMES device (geko™) was reported to be well tolerated with a concordance rate of 94.1% among study participants. Self-administration was also reported to be simple and without issue.12 Other important findings among patients in the treatment arm was a greater reduction in Visual Analogue Score (VAS) for pain and improved Venous Clinical Severity Score (VCSS). More patients in the treatment arm saw their wound completely heal from the start of the trial to the end of the follow-up period.12 The descriptive reporting of secondary outcomes is most likely linked to the reduction in wound size that was seen in patients who were treated with the NMES device (geko™). As ulcers healed more quickly, it is reasonable that they would report a greater reduction in pain and more frequent complete wound healing.

Clinical Implications

This study was the first of its kind to demonstrate a statistically significant increase in rate of healing. The use of an NMES device (geko™) to stimulate the common peroneal nerve in patients with chronic, difficult to treat VLUs has proven effective in significantly accelerating the rate of healing. The rate of wound healing in these patients more than doubled, 12 which if applied on a wider scale could prove beneficial in improving the quality of life of the patient, in addition to being hugely cost-effective it appears to shorten the time for complete wound resolution which will reduce costs associated with nursing visits, dressings, and associated co-morbidities. Rate of wound healing is a clinically important parameter when treating patients with VLUs. Chronic and recurrent ulceration is associated with a reduction in mobility, pain, and quality of life.2 Treatments which accelerate the healing process can therefore have a positive effect on patient outcomes. The NMES device (geko™) appears to demonstrate this potential.

“As a clinician in wound care.. the results of this RCT are extremely impressive. NonhealingVLUsstoppatientslivingtheirlives and robs them of hope. The geko™ device consistently accelerates VLU healing in the patients I treat.” Agnes Juguilon Collarte Tissue Viability Specialist Nurse Lead, Inner Northwest Division (Central London, Hammersmith & Fulham, West London) .12

The device demonstrated simplicity of use with high rates of compliance seen among participants. The study was also able to continue throughout the pandemic even with the enforcement of COVID-19 protocols.12 This again demonstrates the ease of use of these remote devices and the potential for their implementation into clinical practice to relieve pressure on burdened healthcare systems. Empowering patients to deliver their own care remotely will not only be cost-efficient but enable patients to receive high quality and efficacious treatment without the need for repeated hospital appointments. Using a self-controlled study model with the introduction of short-term endpoints in place of full wound healing not only allowed for statistically significant results to be achieved quickly, but also eliminated confounding heterogeneity between cohorts.12 Assessing WMA and PAR as endpoints enabled clinicians to determine more nuanced and sensitive improvements in wound healing in patients treated with NMES when compared to the SoC group. Using this trial design also enables researchers to achieve results with fewer study participants. 12 This study sets a precedence for the implementation of this trial design in future to gather more substantial evidence. It also begins to address the current lack of evidence base surrounding treatments for VLUs.