Early versus deferred endovenous ablation of superficial venous reflux in patients with venous ulceration: the EVRA RCT

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 11/129/197. The contractual start date was in November 2016. The draft report began editorial review in May 2018 and was accepted for publication in September 2018. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Manjit S Gohel has received personal fees from Medtronic pLc (Minneapolis, MN, USA) and Cook Medical LLC (Bloomington, IN, USA), plus a grant from Laboratoires Urgo S.A. (Chenôve, France). Andrew Bradbury had committee membership for the National Institute for Health Research Health Technology Assessment (HTA) Prioritisation Group and HTA Surgery Themed Call Board 2012–13, HTA Efficient Study Designs Board 2014–16, HTA Interventional Procedures Methods Group 2015–19 and HTA IP Panel 2015–19. In addition, Andrew Bradbury has received funding from STD Pharmaceutical Products Ltd (Hereford, UK) to travel to a foam sclerotherapy workshop in Tehran, Iran, in October 2016 and a grant to cover costs of undertaking a post-authorisation safety study in the UK and Europe. He also sat on the National Institute for Health and Care Excellence (NICE) committee for a clinical guideline (CG168) for the diagnosis and management of varicose veins. Nicky Cullum had committee membership on the HTA Commissioning Board from 2003 to 2008. David M Epstein has received grant funding from Vascular Insights LLC (Quincy, MA, USA) which was administered by the University of Granada. Alun H Davies has received grant funding from Medtronic, Vascular Insights, Laboratoires Urgo, Vascutek (Inchinnan, UK) and Actegy Health Ltd (Bracknell, UK), which are administered by Imperial College London. In addition, Alun H Davies has chaired the NICE clinical guideline (CG168) for the diagnosis and management of varicose veins.

Copyright statement

© Queen’s Printer and Controller of HMSO 2019. This work was produced by Gohel et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

2019 Queen’s Printer and Controller of HMSO

Background of venous leg ulcers

Leg ulcers are open ‘sores’ on the lower limbs situated between the ankles and knees, and were defined in this trial as those that fail to heal within 6 weeks. These ulcers represent a source of great discomfort and social isolation to patients, who often complain of associated pain, odour and wound discharge. Ulcers often take many months to heal, meaning that the condition is also frustrating for health-care professionals involved in their management in hospital and community settings. In 70% of cases, the underlying cause of leg ulceration is lower limb venous disease, sometimes evident as varicose veins but often undetectable by visual examination alone. 1 The prevalence of venous leg ulcers in the adult population overall has been estimated at 0.03–1%, rising dramatically in those aged > 80 years. 2–4 As patients with venous ulceration often suffer episodes of recurrence, the number of patients at high risk of ulceration may actually be four- to fivefold higher. 5 It should also be noted that, with an ageing and increasingly obese population,6 the incidence and prevalence of venous ulceration are both likely to increase. Treatment of the condition in the UK incurs a substantial cost burden, estimated at £400M–600M per annum,7 although the figure could be higher. 8

Venous ulcers are characterised by protracted healing times. Despite recent advances in the management of patients with venous ulcers, 24-week healing rates in published randomised trials are around 60–65%,9,10 and the true population healing rates are likely to be significantly lower. Some ulcers may never heal, and patients whose ulcers do heal are at high risk of recurrent ulceration. These poor outcomes are likely to be a reflection of the severe underlying venous disease (reflux and, less commonly, obstruction) in this patient group, although inadequate assessment and suboptimal treatment of the venous disease are also likely to be important contributing factors.

Pathophysiology of venous leg ulcers

The venous circulation of the lower limb has two components: the deep and superficial systems. Blood normally flows from the superficial to the deep veins, stimulated by calf and foot muscle contractions. Blood is prevented from flowing back down the leg under the influence of gravity by ‘one-way’ bicuspid valves along the deep and superficial veins.

When these valves are damaged, they become incompetent, resulting in venous flow away from the heart. This results in the superficial veins usually becoming dilated and tortuous (varicose), and the resulting sustained high venous and capillary pressures lead to skin inflammation and breakdown of the skin, visible as ulceration. 11 The deep veins also have valves, which may also become incompetent and cause high venous pressure, but are not visible on the skin.

Duplex Doppler ultrasonography studies12–14 of patients attending leg ulcer clinics suggest that around 50% of patients with venous leg ulcers have disease only of the superficial veins, with a further 30–40% having a mixture of superficial and deep-venous disease. Surgical treatment of the superficial venous reflux can benefit both of these groups of patients, in terms of reducing ulcer recurrence. 15 Approximately 5–10% of patients with venous ulcers have diseased deep-venous systems only and are not amenable to surgical correction with current technology. These patients are usually treated with compression therapy alone.

Conservative management

Ulcer healing strategies are based on efforts to reduce the reflux of blood back down the leg and into the skin, as this is considered the most significant cause of high venous pressure and ulceration in most patients. Longstanding venous hypertension has been shown to cause a number of changes to the microcirculation in the lower leg, which can contribute to the chronic skin changes or eventual ulceration associated with chronic venous disease. 16

The mainstay of therapy for venous ulceration is compression therapy, which was first described around 2000 years ago. Compression bandaging is used to heal venous ulceration by counteracting the gravitational force on the blood, in effect temporarily replacing the incompetent valves. 17 Bandages are usually reapplied once to four times per week.

A Cochrane review18 of the effectiveness of compression reviewed 48 randomised controlled trials (RCTs) and found that the use of compression improved healing rates compared with no compression use and that multicomponent bandages are more effective than single-component systems, with two-component systems’ healing rates being equivalent to four-layer bandaging. An individual patient data meta-analysis18 found faster healing with four-layer bandaging use than with short-stretch bandaging use, and improved healing rates at 2–4 months using high-compression stockings compared with short-stretch bandaging. In addition, the meta-analysis showed the four-layer bandaging to be more cost-effective than short-stretch bandaging. 18

The haemodynamic benefit of compression is lost almost immediately after removal of compression, and so compression offers a treatment benefit only while in situ. 19 There are also side effects associated with compression, such as pressure damage, which can lead to reduced concordance rates, as highlighted by a recent Cochrane review. 20

Treatment options for superficial venous reflux

The treatment of superficial venous reflux offers a logical strategy for reducing chronic venous hypertension and so improving the healing of venous leg ulcers. Diseased superficial veins can be surgically removed (or ‘stripped’) by open varicose vein surgery or ablated using endovenous interventions without harming the overall venous function of the leg, theoretically removing a causative factor for recurrence of the ulcer after the compression bandaging has ceased.

Existing research

The ESCHAR randomised controlled trial

Aims and results

The most significant trial of superficial venous intervention in patients with venous ulceration is the Effect of Surgery and Compression on Healing And Recurrence (ESCHAR) trial (ISRCTN07549334). 9,15 The trial aimed to evaluate the role of traditional superficial venous surgery in reducing ulcer recurrence in patients with open or recently healed venous ulcers. Following prospective observational studies to inform power calculations, a total of 500 participants were randomised to compression therapy alone or to compression with open surgery for superficial venous reflux. The group randomised to surgical treatment had significantly lower venous ulcer recurrence rates at 4 years (Figure 1).

FIGURE 1.

The ESCHAR trial: ulcer recurrence. Reproduced from Long term results of compression therapy alone versus compression plus surgery in chronic venous ulceration (ESCHAR): randomised controlled trial, Gohel MS, Barwell JR, Taylor M, Chant T, Foy C, Earnshaw JJ, et al. ,15 vol. 335, p. 83, 2018, with permission from BMJ Publishing Group Ltd.

Reproduced from Long term results of compression therapy alone versus compression plus surgery in chronic venous ulceration (ESCHAR): randomised controlled trial, Gohel M, Barwell JR, Taylor M, Chant T, Foy C, Earnshaw JJ, et al. , 335, 2018, with permission from BMJ Publishing Group Ltd. 15

Analysis stratified by pattern of venous reflux demonstrated that this clinical benefit was present for patients with isolated superficial venous reflux and patients with superficial and segmental deep reflux. This clearly indicated that the majority of patients with venous ulceration could benefit from superficial venous intervention.

The ESCHAR trial was unable to detect an effect of surgery on ulcer healing (Figure 2). This finding has led many to conclude that treatment of venous reflux does not have a role in patients with open ulcers.

FIGURE 2.

The ESCHAR trial: ulcer healing. Reproduced from Long term results of compression therapy alone versus compression plus surgery in chronic venous ulceration (ESCHAR): randomised controlled trial, Gohel MS, Barwell JR, Taylor M, Chant T, Foy C, Earnshaw JJ, et al. ,15 vol. 335, p. 83, 2018, with permission from BMJ Publishing Group Ltd. 15

Reproduced from Long term results of compression therapy alone versus compression plus surgery in chronic venous ulceration (ESCHAR): randomised controlled trial, Gohel M, Barwell JR, Taylor M, Chant T, Foy C, Earnshaw JJ, et al. , 335, 2018, with permission from BMJ Publishing Group Ltd. 15

Weaknesses

There were, however, several limitations to the evidence from the ESCHAR trial. The trial was not powered to assess ulcer healing, as both patients with open ulcers and those with healed ulcers were included. The statistical power was further weakened by a high crossover rate, as around one-fifth of participants randomised to surgery later decided that they did not want to have the operation. Moreover, participants who consented to surgery waited a median of 7 weeks for intervention and so did not receive an immediate benefit. Consequently, some smaller ulcers might have already healed with compression bandaging. Finally, some of the surgical procedures used were suboptimal when judged by current standards and the use of local anaesthetic may have meant that some legs were left with residual venous incompetence. Thus, it is likely that the benefits of treating superficial venous reflux were underestimated in this trial, particularly for the assessment of ulcer healing. The poor patient acceptance of surgery emphasises the need for a minimally invasive superficial venous treatment modality in this patient group.

Current UK national guidelines

Rationale for the Early Venous Reflux Ablation trial

Despite the evidence that the treatment of superficial venous reflux reduces ulcer recurrence in patients with venous leg ulcers, there is currently no level 1 evidence demonstrating reductions in time to healing. 21 With this void in evidence, superficial venous reflux is often treated after ulcers have healed following conservative treatment involving compression bandaging. The danger of taking this approach is that, once the ulcer is healed and the symptoms have resolved, patients may not be referred. The resulting untreated superficial venous reflux contributes to an increased risk of ulcer recurrence, which is both costly for the health service and distressing for the patient. The previous RCT literature may have underestimated the clinical benefit of intervention, with recent prospective cohort studies of endovenous intervention in active leg ulceration clearly suggesting an adjuvant benefit compared with compression alone in terms of healing rates. Time to healing has been highlighted as the end point that is most important to patients, as demonstrated in the patient and public involvement (PPI) work (see Appendix 1) of this trial and even a modest improvement in ulcer healing would significantly reduce the health-service costs associated with the condition.

As the incidence and prevalence of venous ulcers are likely to increase as a result of the ageing population, it is important to clarify the role and timing of superficial endovenous ablation in venous ulceration to guide treatment recommendations and referral pathways. 44,45

Summary of main points

Venous leg ulcers are open wounds that have a detrimental effect on the quality of life of patients. Treatment of the condition in the UK represents a substantial economic burden to the NHS and Personal Social Services, amounting to many hundreds of millions of pounds per year.

Until recently, superficial venous reflux could be treated only by open surgery. Newer, endovenous techniques have been shown to be just as effective as open surgery in terms of clinical improvement, but with reduced complications and pain. These techniques do not need to be performed under general anaesthetic and therefore may be more suitable for elderly patients with significant comorbidities. The most recent UK guidelines for varicose veins43 recommend early referral to a vascular service for diagnosis and first-line treatment by means of endovenous interventions.

The ESCHAR trial9,15 indicated that the majority of patients with venous ulceration could benefit from superficial venous intervention with respect to ulcer recurrence; however, the study was not powered to detect an effect on ulcer healing and therefore further research into ulcer healing was required.

Research objectives

Trial design

We conducted a pragmatic, multicentre, open RCT with participants randomised 1 : 1 to either (1) deferred (standard) therapy, consisting of multilayer elastic compression therapy, with deferred endovenous ablation of superficial reflux once the ulcer has healed, or (2) early endovenous ablation of superficial venous reflux (within 2 weeks) in addition to standard compression therapy.

Amendments to the protocol

Substantial amendments to the trial protocol were submitted after the initial approval, in order to increase recruitment and retention, correct the sample size calculation and clarify the health economic evaluation:

• Version 2.0, dated 6 January 2014: amended to provide a clearer definition of ulcer healing, clarify the per-protocol analyses and safety sections, and to clarify that participants could be offered endovenous ablation of superficial venous reflux in the deferred group if their ulcer had not healed at 6 months.

• Version 3.0, dated 10 March 2014: amended in order to allow the display of posters and dissemination of leaflets and participant information sheets in primary care sites.

• Version 4.0, dated 16 March 2016: amended to correct the sample size from 500 participants to 450 participants (which was originally calculated erroneously), and to allow for a reduction in the number of photograph verification visits performed if the core laboratory confirms that the ulcer is healed in order to prevent unnecessary visits and enhance participant retention.

• Version 5.0, dated 6 April 2017 [see the project web page: www.journalslibrary.nihr.ac.uk/programmes/hta/11129197/#/ (accessed 23 April 2019)]: amended to (1) incorporate a Health Technology Assessment (HTA) funding extension to allow for the collection of longer-term follow-up during October 2018 and March 2019 and (2) make revisions to the health economics section to clarify and update the protocol to reflect new National Institute for Health Research (NIHR) guidelines. The follow-up period is now complete (31 March 2019) and, at the time of publication, we are cleaning and locking the database prior to data analysis.

Ethics and research and development approvals

A favourable ethics opinion was given by the National Research Ethics Service Committee South West – Central Bristol on 15 August 2013 (reference number 13/SW/0199). For a copy of the original approval see Report Supplementary Material 1. Annual reports were submitted to this committee, which confirmed that the ethics approval continued to apply.

The study-wide governance review was undertaken by the Clinical Research Network North West London in August 2013. Research and development NHS approvals were granted at participating sites between October 2013 and March 2015. The trial was granted the new Health Research Authority approval on 30 June 2016.

Sponsorship

The trial was sponsored by Imperial College London.

Trial management

The trial was supported by the Imperial Clinical Trials Unit (ICTU) and the day-to-day trial management was performed by the trial manager based in the academic vascular department of Charing Cross Hospital, London. The trial manager was responsible for co-ordinating the data collection; follow-up; data cleaning; monitoring visits; communication with the sites, participants and collaborators; and answering trial-specific queries. The trial manager and chief investigator met at least monthly during the course of the trial.

Participants

All patients aged ≥ 18 years presenting with a leg ulcer of venous origin who were able to tolerate compression therapy and were suitable for endovenous ablation of superficial venous reflux could be included.

Inclusion criteria

Patients with all of the criteria listed below were deemed eligible:

• current leg ulceration duration of > 6 weeks’ but < 6 months

• able to give informed consent to participate in the trial after reading the patient information documentation

• patient aged ≥ 18 years

• ankle–brachial pressure index (ABPI) of ≥ 0.8

• primary or recurrent superficial truncal venous reflux on colour duplex assessment deemed by the treating clinician to be significant enough to warrant endovenous ablation.

Patients who could not speak/understand English were eligible for inclusion. Informed consent was obtained with assistance from translation services as per standard clinical practice; however, in view of the lack of cross-cultural validation for quality-of-life tools, only healing outcome data were collected.

Exclusion criteria

Patients meeting any of the criteria listed below were ineligible:

• presence of deep-venous occlusive disease or other conditions precluding endovenous superficial venous ablation (at the discretion of the treating clinician)

• patients unable to tolerate multilayer compression therapy (as concordance with compression therapy can be variable for patients at different times, patients who were generally concordant with compression, but unable to tolerate short periods, were still deemed eligible)

• inability of the patient to receive prompt endovenous ablation by recruiting centre

• pregnancy

• leg ulcer of non-venous aetiology as assessed by the treating clinician

• patients deemed to require skin grafting as assessed by the treating clinician.

Sample size

The sample size calculation for this trial was based on the primary outcome of time to ulcer healing. In the ESCHAR trial, the 24-week healing rate in participants randomised to compression alone was approximately 60%. 46 Two prospective studies evaluating the early endovenous ablation of superficial venous reflux suggested that the 24-week healing rate may be as high as 82%. 35,36

In order to calculate a sample size for this trial, the desirable absolute benefit associated with early endovenous ablation of superficial truncal reflux was estimated to be 15%. Assuming that the 24-week healing rate in the deferred (standard) group is 60%, to identify an absolute difference in 24-week healing rates between the two groups of 15% (60% vs. 75%), with 90% power and allowing for 10% dropout, the trial required 416 subjects (208 in each group, 254 healed leg ulcers in total). 47 To incorporate further allowances for protocol violations and unexpected dropouts, the target sample size was set at 450 participants.

Settings and locations

Participants were recruited from the vascular departments of 20 secondary care NHS trusts throughout England: Bradford Teaching Hospitals NHS Foundation Trust, Cambridge University Hospitals NHS Foundation Trust, Frimley Health NHS Foundation Trust, Gloucestershire Hospitals NHS Foundation Trust, Heart of England NHS Trust (now University Hospitals Birmingham NHS Foundation Trust), Hull and East Yorkshire Hospitals NHS Trust, Imperial College Healthcare NHS Trust, Leeds Teaching Hospitals NHS Trust, North Cumbria University Hospitals NHS Trust, North West London Hospitals NHS Trust, University Hospitals Plymouth NHS Trust, Salisbury NHS Foundation Trust, Sheffield Teaching Hospitals NHS Foundation Trust, Taunton & Somerset NHS Foundation Trust, The Dudley Group NHS Foundation Trust, the Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Royal Wolverhampton NHS Trust, University Hospital Birmingham NHS Trust, Worcestershire Acute Hospitals NHS Trust, and York Teaching Hospital NHS Foundation Trust. For a list of participating hospitals see Acknowledgements, Local vascular research teams.

Recruitment procedure

Prior to commencing the trial, information was disseminated to general practices in each recruiting region. In addition, selected primary care trusts (PCTs) not currently involved in the trial were set up as patient identification centre sites displaying posters and leaflets and disseminating patient information sheets to patients once the protocol amendment had been approved. As per the July 2013 NICE guidelines on varicose veins,40 patients with venous ulcers were required to be referred from primary to secondary care as part of the standard care pathway.

Patients were screened from secondary care vascular, ulcer and tissue viability clinics. As part of standard care, patients are evaluated by clinical assessment and colour duplex examination. Depending on the results of these tests, the patients were given a short leaflet containing a summary of the trial and, if interested, then given the more detailed patient information sheet to read.

The details of patients who were eligible for the trial but did not agree to participate, and patients with ulcers who were not eligible for the trial, were recorded anonymously on screening logs along with a minimal data set (including age, ulcer duration and venous duplex/ABPI findings, if known, and reason for non-inclusion).

Informed consent

Patients were given a minimum of 24 hours to consider the trial in addition to the opportunity to discuss all aspects of the trial with their family and/or general practitioner (GP). Patients were then contacted by telephone by the research nurse so that any further questions could be answered. All willing patients were booked in to the leg ulcer clinic to undergo a baseline visit.

Written consent was obtained from each participant at the baseline visit. The patient information sheet and informed consent form (see Report Supplementary Material 2) both refer to the possibility of long-term follow-up if the trial is extended and seek permission to access to their NHS records for these purposes. With the participant’s consent, a letter was also sent to the participant’s GP (see Report Supplementary Material 3). A copy of the patient information sheet and informed consent form was filed in the participant’s hospital notes and the local research file and a copy was also given to the participant.

All trial documentation contained the contact details of the Early Venous Reflux Ablation (EVRA) trial chief investigator and trial manager to enable participants to obtain further information from the trial team if required.

Baseline assessment

Once written consent was given by the participant, eligibility was confirmed and baseline data were collected by the research nurse using the case report form (CRF) (see Report Supplementary Material 4).

Randomisation and treatment allocation

Separate randomisation lists for each centre were prepared by a statistician prior to recruitment using randomly permuted blocks in two block sizes (‘ralloc’ command; Stata^® v14.2, StataCorp LP, College Station, TX, USA) and loaded onto the InForm™ version 4.6 (Oracle^® Health Sciences, CA, USA) system. Access to the allocation sequence was strictly restricted to the statistician and appropriate members of the InForm technical support team to maintain allocation concealment.

Consenting participants were registered on the InForm integrated trial management system, a web-based data entry system maintained by the ICTU, and their eligibility for the trial verified. Once eligibility was confirmed, online randomisation was performed remotely by the research nurse.

Each participant was automatically assigned the next available treatment allocation in the appropriate randomisation list and allocated a unique trial number. The randomisation ratio was 1 : 1 with participants allocated to either:

• early (within 2 weeks) endovenous ablation of superficial venous reflux in addition to compression therapy or

• deferred (standard) therapy consisting of multilayer elastic compression therapy with deferred endovenous ablation of superficial reflux once the ulcer healed.

Blinding

It was not possible to blind either the treating team or the participant to the allocated treatment. The primary outcome, time to ulcer healing, was determined by two expert assessors who were blinded to participant details, including the treatment group.

Deferred ablation (standard care): control group

Participants in the deferred (standard) care group were randomised to receive multilayer compression therapy alone with endovenous ablation of superficial reflux once ulcer healing had been confirmed. Participants whose ulcer had not healed at 6 months post randomisation or who experienced clinical deterioration in the active leg ulcer during the control treatment, could be offered endovenous interventions if it was felt that the participant would benefit from expedited endovenous ablation (at the discretion of the local responsible clinician). The post-ablation duplex ultrasonography strategy for participants in the standard care group was left to local policy.

Early ablation: interventional group

Participants in the interventional group were randomised to receive endovenous ablation of superficial truncal reflux within 2 weeks of randomisation in addition to compression therapy. Post-ablation duplex ultrasonography was performed 6 weeks from randomisation.

Standardisation of compression therapy

As a wide range of compression types are currently used within the NHS, the specific therapy was left to the discretion of individual centres and primary care professionals. Multilayer elastic (two, three or four layer), short stretch and hosiery compression were all deemed acceptable for inclusion in the trial. All participants were advised to use compression hosiery post healing, in line with local policy.

Endovenous interventions

A wide range of endovenous ablation modalities are currently available and in widespread use. The following interventions were permitted in the trial: EVLA or RFA, UGFS, mechanochemical ablation and cyanoacrylate glue closure. These interventions could be performed alone or in combination, as directed by clinical need at the discretion of the responsible vascular specialist.

It was noted that the interventional strategies varied between institutions and between individual clinicians within the same department. Heterogeneity existed for site of vein cannulation (and, therefore, the length of vein ablated), the location of intervention (‘office’ or clinic based vs. operating theatre), interventional strategy for subulcer venous plexus (to ablate or not), the ablation of visible varicose veins (no treatment, UGFS or surgical avulsion) and the timing of any secondary interventions. As there was neither current research evidence nor consensus as to a single, optimal endovenous interventional strategy for superficial reflux in patients with leg ulceration, local and individual variation was allowed, subject to the following stipulations:

• The endovenous strategy had to include ablation of the main truncal venous reflux.

• Truncal venous reflux had to be treated to the lowest point of incompetence, where possible.

• Significant (as deemed by the treating clinician) residual/recurrent superficial reflux on the 6-week duplex scan was to be ablated.

• Participants had to continue with multilayer compression/stockings immediately after ablation.

Participant follow-up

All randomised participants were followed up until one of the following:

• 1 year after randomisation

• the participant chose to withdraw from the trial

• death.

The trial design is summarised in Appendix 4.

As per standard care, participants received routine leg ulcer care in the community and/or hospitals in accordance with local policies.

Participant withdrawal

Participants could withdraw from the trial at any time without giving a reason; however, efforts were made to identify the reason for withdrawal whenever possible.

Participants who expressed a wish to withdraw from the trial visits were asked to confirm if they agreed to the trial team retaining their existing trial data and accessing trial-related NHS data; this was documented in the patient notes. If possible, participants were asked for permission to retain primary outcome data.

Participants who declined endovenous ablation remained in the trial for assessment of primary and secondary outcomes [and analysis on intention to treat (ITT)] unless they specifically withdrew their consent.

Measurement and verification of primary outcome measure

Measurement and verification of secondary outcome measures

Utility and resource use

Participant-reported utility and resource use was collected by the research nurses up to 12 months from randomisation or trial exit via monthly telephone calls to the participant, or at clinic visits if these occurred as part of clinical care. The participants were provided at baseline with diaries in which any visits to health-care providers could be recorded. All utility and resource use data were collected, whether or not deemed to be related to the reference leg.

Participant communications

Participants were kept updated on trial progress via the trial Facebook (Facebook, Inc., Menlo Park, CA, USA) and Twitter (Twitter, Inc., San Francisco, CA, USA) accounts. Two participant newsletters were circulated during the follow-up stage (for participants who had not withdrawn from the trial), to keep them updated with trial progress. A newsletter summarising the main results from the EVRA trial was also sent to non-withdrawn participants.

Statistical methods

The trial analysis was carried out on an ITT basis (all participants remained in the group allocated at randomisation). Histograms and box plots were used to check the distribution and possible outliers for continuous variables. Mathematical transformations were applied, when appropriate, in order to render the continuous variables distribution normally distributed. Continuous variables that follow an approximately normal distribution were summarised using means and standard deviations (SDs). Skewed continuous variables were summarised using medians and interquartile ranges (IQRs). Categorical variables were summarised using frequencies and percentages.

All hypothesis testing was planned to be two-tailed with a 5% significance level and no adjustment for multiple testing. Analyses were performed using Stata v14.2.

As the randomisation was stratified by centre, when possible, analyses are adjusted by trial centre. Potentially, this is done by including trial centre as either a fixed or a random effect in any regression models. As the centres that participated in the trial could be viewed as a random sample of all possible trial centres, random-effects models were preferred. However, in cases where random-effects models could not be fitted (e.g. owing to lack of convergence), trial centre was included in models as a fixed effect.

Ulcer-related health-care use

The participants in this trial tended to be elderly with comorbidities and, therefore, significant users of health-care resources. To obtain a precise estimate of the effect of the intervention on health-care use, and avoid statistical ‘noise’, the trial aimed to include only resource use related to the ulcer. The trial CRF collected the reason for the use of health-care resources and the procedure undertaken as free text. Keywords indicating ulcer-related activity included ulcer care, skin care, leg care, venous procedures, angiography, infection, rehabilitation, DVT and related keywords (see Table 4). Ulcer-related health care was included in the total cost per patient, whereas non-ulcer-related health care was tabulated but not included in total cost. Non-ulcer-related care was excluded from inpatient admissions, day case admissions and outpatient consultations. These health-care resources and costs, along with out-of-pocket expenses and time lost from usual activities, were tabulated but not included in the total mean cost per patient. It was assumed that all district nurse visits, primary care visits, physiotherapy and occupational therapy were definitely or probably ulcer related.

Unit costs

Costs were estimated by multiplying resource use by unit costs obtained from published literature, England and Wales Healthcare Resource Group costs and manufacturers’ list prices for catheters and other disposable kit (see Appendix 6).

Handling of missing data

A small number of trial data were missing because of withdrawal or for other reasons. The extent and pattern of missing data were assessed. Costs and EQ-5D-5L index were set to zero after the date of death. For the cost-effectiveness analysis, the base case uses ‘complete cases’ in an ITT analysis. A participant was considered to be a complete case if he or she completed all the EQ-5D questions at baseline, 6 weeks, 6 months and 1 year, and did not withdraw from the trial before 1 year.

As a sensitivity analysis, multiple imputation using chained equations was used to impute the remaining missing data by regression, under the assumption of ‘missingness at random’. 60 This means that missing costs are considered predictable from observed data, plus or minus a random error. For each participant lost to follow-up, costs were imputed at each month after the time of withdrawal and the EQ-5D-5L index was imputed at 6 weeks, 6 months and 1 year if these data were missing. Ten imputed data sets were created and analysed using Rubin’s rules (this was sufficient to give stable results allowing for Monte Carlo error). 60

Handling of protocol deviations

In the clinical trial, protocol deviations were seen in 117 patients (59 and 58 in early and deferred groups, respectively), the majority of which were late or missed follow-up appointments (n/N = 40/59 patients in the early-intervention group and n/N = 34/58 in the deferred-intervention group). A sensitivity analysis was carried out excluding these participants.

Cost-effectiveness analysis

The difference in mean total costs and mean total QALYs per participant between the treatment groups was estimated using bivariate normal regression (seemingly unrelated regression using the Stata command ‘surreg’), including baseline EQ-5D-5L in the QALY regression. 69

The incremental cost-effectiveness ratio (ICER) was calculated. The probability that early ablation was more cost-effective than deferred ablation was estimated at different cost-effectiveness thresholds using two methods. The first method assumed bivariate normality in the distribution of total costs and QALYs. The second method used the bootstrapping method, with 1000 Monte Carlo resamples. The bootstrap was used only for the analysis of complete cases. Bootstrap combined with multiple imputation can be very computationally demanding. If 1000 bootstrap resamples were used with 10 multiple imputations, 10,000 data sets would need to be generated and analysed. 70

Sensitivity analyses

Five models were estimated: (1) base case – complete cases with bootstrap standard errors (SEs) and crosswalk EQ-5D tariff; (2) complete case with bivariate normal SEs and crosswalk EQ-5D tariff; (3) multiple imputation with bivariate normal SEs and crosswalk EQ-5D tariff; (4) complete case with bootstrap SEs and EQ-5D-5L tariff estimated by Devlin et al. ;55 and (5) as model 1, excluding participants with protocol deviations.

Database and data processing

Screening and recruitment

Recruitment commenced in October 2013 and was completed at the end of September 2016. In total, 6555 patients were screened for potential inclusion in the trial and, of these, 450 (6.9%) were randomised. The reasons for exclusion are presented in the Consolidated Standards of Reporting Trials (CONSORT) diagram (Figure 3).

FIGURE 3.

Consolidated Standards of Reporting Trials diagram of the trial population. The cumulative number of participants who had withdrawn, died, had failed to comply with the protocol or had been lost to follow-up by each time point are presented. Reproduced from The New England Journal of Medicine, Gohel et al. 57 A randomized trial of early endovenous ablation in venous ulceration, vol. 378, pp. 2105–14. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission.

Reproduced from The New England Journal of Medicine, Gohel et al. 57 A randomized trial of early endovenous ablation in venous ulceration, vol. 378, pp. 2105–14. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission.

Trial site recruitment

Ten sites were initially activated for recruitment, with a further 11 sites activated as it became apparent that the original sites would be unable to reach their recruitment targets. Over the recruitment period, 21 sites participated in the trial, with one site failing to recruit any participants.

Appendix 7 shows the total number of participants recruited per site in order of the total number of weeks recruiting. The first six sites opened benefited from a dedicated part-time research nurse, whereas the remaining sites were supported by Clinical Research Network or local research nurses working across multiple studies.

Appendix 8 details the overall recruitment per month against the targets. At trial commencement, the monthly target recruitment was 24 participants per month. When it became apparent that this was not achievable (October 2015), the target was reduced to 13 participants per month, adding an additional 8 months to the recruitment period. The target of 450 participants was achieved on 30 September 2016.

Follow-up

Follow-up of the last recruited participant was competed on 28 September 2017. A total of 407 participants attended the 12-month follow-up and the median follow-up period for both the deferred- and early-ablation groups was 365 (IQR 364–370) days. Figure 3 details the trial exit time points. The cumulative numbers of participants who had withdrawn, died, failed to comply with the protocol or been lost to follow-up by each time point are presented.

Ineligible participants

Six ineligible participants were randomised to the trial: two participants in the early-ablation group (one with leg ulceration of > 6 months’ duration and one with no active ulceration) and four participants in the deferred-ablation group (two participants with leg ulceration of > 6 months’ duration, one participant with no active leg ulceration and one participant with deep-venous occlusive disease). These participants were included in the ITT analysis but excluded from the per-protocol analysis (see Figure 3).

Baseline characteristics of participants by trial group

The baseline characteristics, medical history, current medication, ulcer history and baseline compression therapy are summarised in Tables 5–7. The two trial groups were well matched in terms of baseline characteristics, including the following potential prognostic factors: ulcer duration, ulcer size, participant age and history of DVT.

Slightly more men than women were randomised (55% vs. 45%). The mean participant BMI was 30.3 kg/m² (clinically obese).

The baseline ulcer characteristics are summarised in Table 8. Ulcer duration was slightly greater in participants randomised to early ablation [median 3.2 months (IQR 2.3–4.2 months)] than in the deferred-ablation group [median 3.0 months (IQR 1.7–4.2 months)]. The median ulcer size in the early-ablation group was 2.4 cm² (IQR 1.0–7.1 cm²), compared with 2.9 cm² (IQR 1.1–8.2 cm²) in the deferred-ablation group.

The six ineligible participants included two participants who had a healed ulcer at the time of randomisation (which was confirmed after randomisation). The ineligible participant with deep-venous occlusive disease was confirmed to have both deep vein reflux and outflow obstruction by baseline duplex ultrasonography scan. In general, ulcer characteristics were well matched between the two groups.

Table 9 details the patterns of superficial truncal venous reflux at baseline.

Interventions

Ablation method and timing of the first ablation are summarised in Table 10. There were 55 participants who did not undergo ablation in the deferred-intervention group and seven in the early-ablation group, including one in whom the procedure was abandoned before completion. The most common intervention was UGFS alone (47%), followed by endothermal ablation alone (29%).

Among the 55 participants in the deferred-ablation group who did not undergo endovenous ablation up to 1 year, 19 participants died, withdrew or were lost to follow-up from the trial and 36 participants completed the trial, including 27 participants with healed ulcer and nine participants with unhealed ulcer at 1 year (Table 11).

Regarding the timing of ablation, the majority of participants (90.6%) in the early-ablation group underwent ablation within 2 weeks of randomisation. In the deferred-ablation group, one participant was treated before 2 weeks and five participants were treated prior to ulcer healing between 2 weeks and 6 months. The reasons for the ablation before ulcer healing in the six participants in the deferred-ablation group were clinical deterioration of ulcer (n = 3), participant request for intervention (participant unwilling to continue with deferred ablation strategy) (n = 2) and participant treated early in error (n = 1).

Primary outcome: ulcer healing

Figure 4 shows the KM curve for time to ulcer healing. Among the 450 participants were two ineligible participants whose ulcer had healed by the time of randomisation and who did not contribute to the survival analysis. The median healing time was 56 (95% CI 49 to 66) days and 82 (95% CI 69 to 92) days in the early- and deferred-ablation groups, respectively.

FIGURE 4.

Kaplan–Meier curve showing ulcer healing time in the early- and deferred-ablation groups (p = 0.001, log-rank test). Ulcer healing rates were greater in participants randomised to early ablation. Reproduced from The New England Journal of Medicine, Gohel et al. 57 A randomized trial of early endovenous ablation in venous ulceration, vol. 378, pp. 2105–14. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission.

Reproduced from The New England Journal of Medicine, Gohel et al. 57 A randomized trial of early endovenous ablation in venous ulceration, vol. 378, pp. 2105–14. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission.

The proportional hazards assumption, assessed graphically, by plotting –ln{–ln[Ŝ(t)]} versus –ln(t), and numerically, using Grambsch and Therneau tests, was not violated.

Table 12 shows the Cox proportional hazards regression results. In the univariate model, with trial centre as a random effect, the hazard ratio (HR) for ulcer healing in the early-ablation group is 1.38 (95% CI 1.13 to 1.68) (p = 0.001) compared with participants randomised to deferred ablation. After further adjusting for age, ulcer duration and ulcer size at baseline, the HR is 1.42 (95% CI 1.16 to 1.73) (p = 0.001).

The HRs from the multivariable Cox regression model for specific (pre-planned) subgroups are presented in Figure 5. There is considerable consistency except for ulcer duration, where an interesting trend is observed. In the prespecified subgroup analysis to investigate any differential treatment effects of ulcer duration, the HR in the early ablation group increases across the quartiles of ulcer duration. In the first and second quartiles of ulcer duration, early ablation does not make a difference to ulcer healing relative to deferred ablation. However, this study is not powered to investigate any interactions and thus the above finding will need further studies to confirm.

FIGURE 5.

Forest plot of subgroup analysis for primary outcome. The healing advantage in prespecified subgroups was consistent with the overall healing benefit observed with early ablation. The broken line indicates overall HR for ulcer healing in entire study population. Reproduced from The New England Journal of Medicine, Gohel et al. 57 A randomized trial of early endovenous ablation in venous ulceration, vol. 378, pp. 2105–14. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission.

Reproduced from The New England Journal of Medicine, Gohel et al. 57 A randomized trial of early endovenous ablation in venous ulceration, vol. 378, pp. 2105–14. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission.

Figure 6 shows the HRs for different treatments in the early ablation group compared with deferred ablation. As numbers in the MOCA only group, endothermal and UGFS group, and MOCA and UGFS group are small, the three ablation groups are merged into one group as ‘other ablation’. The HRs for the groups of endothermal only, UGFS only and other treatment are consistent.

FIGURE 6.

Forest plot of different endovenous ablation techniques for primary outcome. The healing advantage in prespecified subgroups treated with different ablation techniques was consistent with the overall healing benefit. The broken line indicates overall HR for ulcer healing in entire study population. Reproduced from The New England Journal of Medicine, Gohel et al. 57 A randomized trial of early endovenous ablation in venous ulceration, vol. 378, pp. 2105–14. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission.

Reproduced from The New England Journal of Medicine, Gohel et al. 57 A randomized trial of early endovenous ablation in venous ulceration, vol. 378, pp. 2105–14. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission.

Secondary outcomes

Ulcer-free time to 1 year

Of the 450 participants, 407 attended the 12-month follow-up visit and were included in the analysis of ulcer-free time to 1 year. There were 203 and 204 participants in the deferred- and early-ablation groups, respectively. The median ulcer-free time to 1 year was 278 (IQR 175–324) days and 306 (IQR 240–328) days in the deferred- and early-ablation groups, respectively.

As the ulcer-free time to 1 year did not follow a normal distribution and mathematical transformation was not possible because of a few participants with zero days ulcer-free time, ulcer-free time to 1 year was categorised (into quartiles) and ordinal regression was used to assess the difference between the treatment groups. The proportionality assumption was not violated (assessed using the Brant test). The results are presented in Table 13. In the univariable analysis, with trial centre as a random effect, the odds ratio (OR) for being in a higher quartile was 1.60 (95% CI 1.13 to 2.27) for the early-ablation group. Further adjustment for age, ulcer duration and size at baseline did not affect the result. The OR in the multivariable model is 1.54 (95% CI 1.07 to 2.21; p = 0.02).

TABLE 13 - Ordinal logistic regression for ulcer-free time to 1 year (quartiles) in participants with venous ulceration

Adjusted by centre (centre included in the model as a random effect).

Adjusted by centre, age, duration and size (centre included in the model as random effect and age, ulcer duration and size as fixed effects).

Variable	Univariable modela		Multivariable modelb
	Coefficient (95% CI)	p-value	Coefficient (95% CI)	p-value
Treatment group
Deferred	Reference		Reference
Early	1.60 (1.13 to 2.27)	0.009	1.54 (1.07 to 2.21)	0.02
Age (years)	0.99 (0.98 to 1.00)	0.14	1.00 (0.98 to 1.01)	0.57
Ulcer duration (months)
First quartile (0.9–2.2)	Reference		Reference
Second quartile (2.3–3.1)	0.87 (0.53 to 1.44)	0.59	0.94 (0.56 to 1.56)	0.80
Third quartile (3.1–4.2)	0.94 (0.57 to 1.55)	0.82	0.96 (0.58 to 1.60)	0.89
Fourth quartile (4.2–8.4)	0.55 (0.33 to 0.92)	0.02	0.64 (0.38 to 1.08)	0.10
Ulcer size (cm2)
First quartile (0.4–1.5)	Reference		Reference
Second quartile (1.6–2.9)	0.50 (0.30 to 0.82)	0.006	0.48 (0.29 to 0.79)	0.004
Third quartile (3–7.5)	0.23 (0.14 to 0.39)	< 0.001	0.23 (0.14 to 0.39)	< 0.001
Fourth quartile (8–235)	0.09 (0.05 to 0.16)	< 0.001	0.10 (0.06 to 0.17)	< 0.001

Figure 7 shows the results of ordinal logistic regression in different subgroups. The results are consistent across different subgroups. The pattern observed is similar to that seen in the subgroup analysis by ulcer size and duration.

FIGURE 7.

Forest plot showing the treatment effect on ulcer-free time by predefined subgroups.

Figure 8 shows the ORs for the treatment effect on ulcer-free time by type of endovenous ablation. The ORs are consistent in the groups of endothermal only and UGFS only, whereas the OR in the other treatment group is 1.06 (95% CI 0.56 to 2.02). The lack of treatment effect here may be due to the small number in the other treatment group.

FIGURE 8.

Forest plot showing the treatment effect on ulcer-free time by different ablation techniques.

Quality of life

Table 15 and Figures 9 and 10 summarise the HRQoL data at baseline, 6 weeks and 6 and 12 months for the two trial groups. The AVVQ has scores ranging from 0 to 100, with 0 representing the best score and 100 the worst score, whereas, for EQ-5D and SF-36, the higher the score, the better the HRQoL. A decreasing trend of AVVQ score across time is observed for both the deferred- and early-ablation groups.

TABLE 15 - Summary of quality of life (AVVQ, EQ-5D, SF-36) at baseline and at 6 weeks and 6 and 12 months after randomisation

p-value for the overall difference between the two groups over the whole trial period.

Difference between two groups estimated using a mixed model with adjustment for time, age, ulcer duration and size as fixed effects, with trial centre and participant as random effects. Deferred-ablation group used as reference.

EQ-5D index calculated using the value set for England. 57

Reproduced from The New England Journal of Medicine, Gohel et al. 57 A randomized trial of early endovenous ablation in venous ulceration, vol. 378, pp. 2105–14. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission.

Variable	Baseline	6 weeks	6 months	12 months	p-valuea
Early, n	226	21	204	199
Deferred, n	224	219	208	203
AVVQ score, mean (SD)
Deferred	44.3 (8.7), n = 192	41.2 (9.3), n = 170	39.5 (10.3), n = 140	34.3 (10.4), n = 130
Early	44.1 (9.0), n = 200	39.4 (10.2), n = 176	34.6 (9.4) n = 139	32.4 (8.3), n = 127
Difference (95% CI)b	–0.2 (–2.0 to, 1.6)	–2.1 (–4.0 to –0.2)	–4.8 (–6.9 to –2.7)	–1.8 (–4.0 to 0.3)	0.0008
EQ-5D health score, mean (SD)
Deferred	70.1 (17.1), n = 225	71.1 (18.7), n = 205	71.4 (19.6), n = 193	73.7 (17.4), n = 184
Early	70.2 (17.7), n = 222	72.7 (18.6), n = 212	74.1 (15.8), n = 185	74.8 (16.9), n = 183
Difference (95% CI)b	0.1 (–3.1 to 3.4)	1.7 (–1.6 to 5.1)	1.8 (–1.6 to 5.2)	1.3 (–2.1 to 4.8)	0.72
EQ-5D index value, mean (SD)c
Deferred	0.73 (0.2), n = 226	0.75 (0.2), n = 208	0.76 (0.2), n = 192	0.80 (0.2), n = 182
Early	0.73 (0.2), n = 222	0.79 (0.2), n = 211	0.81 (0.2), n = 186	0.83 (0.2), n = 184
Difference (95% CI)b	–0.01 (–0.04 to 0.03)	0.04 (0.00 to 0.08)	0.04 (0.00 to 0.08)	0.03 (–0.01 to 0.07)	0.03
SF-36 physical function score, mean (SD)
Deferred	37.5 (12.5), n = 225	37.4 (13.0), n = 207	37.4 (13.7), n = 193	38.7 (13.4), n = 180
Early	37.3 (12.0), n = 223	39.1 (12.7), n = 212	39.1 (12.8), n = 187	39.4 (12.9), n = 182
Difference (95% CI)b	–1.0 (–3.1 to 1.1)	1.0 (–1.2 to 3.1)	0.7 (–1.5 to 2.8)	0.3 (–1.9 to 2.6)	0.09
SF-36 role-physical score, mean (SD)
Deferred	39.7 (12.1), n = 224	41.4 (12.7), n = 207	42.4 (12.7), n = 192	44.3 (12.9), n = 180
Early	39.0 (12.2), n = 223	40.3 (12.5), n = 211	43.6 (12.6), n = 187	43.0 (12.7), n = 181
Difference (95% CI)b	–1.3 (–3.5 to 0.9)	–1.7 (–4.0 to 0.6)	0.4 (–2.0 to 2.7)	–1.7 (–4.1 to 0.7)	0.28
SF-36 body pain score, mean (SD)
Deferred	41.6 (11.9), n = 224	44.3 (12.3), n = 207	45.9 (12.2), n = 193	47.8 (11.2), n = 180
Early	41.3 (11.1), n = 223	46.6 (10.6), n = 212	48.2 (11.0), n = 187	49.3 (11.0), n = 182
Difference (95% CI)b	–0.5 (–2.6 to 1.6)	2.2 (0.1 to 4.4)	2.1 (–0.2 to 4.3)	1.1 (–1.1 to 3.3)	0.05
SF-36 general health score, mean (SD)
Deferred	46.0 (9.8), n = 225	45.6 (9.2), n = 207	44.5 (10.1), n = 193	45.1 (10), n = 181
Early	45.8 (9.2), n = 223	45.7 (9.1), n = 212	44.9 (9.8), n = 187	45.3 (10), n = 183
Difference (95% CI)b	–0.3 (–2.0 to 1.5)	0.0 (–1.8 to 1.8)	0.0 (–1.9 to 1.8)	0.4 (–1.5 to 2.3)	0.86
SF-36 vitality score, mean (SD)
Deferred	47.8 (10.6), n = 224	47.5 (11.3), n = 207	48.8 (10.8), n = 193	49.6 (9.8), n = 179
Early	48.2 (10.2), n = 222	49.1 (10.0), n = 212	49.4 (9.5), n = 187	50.5 (9.4), n = 182
Difference (95% CI)b	0.1 (–1.7 to 2.0)	1.4 (–0.5 to 3.3)	0.0 (–1.9 to 2.0)	0.9 (–1.0 to 2.9)	0.31
SF-36 social functioning score, mean (SD)
Deferred	42.4 (13.5), n = 224	44.0 (12.1), n = 207	44.7 (12.5), n = 193	47.3 (11.4), n = 181
Early	42.6 (12.4), n = 223	44.9 (11.6), n = 212	47.0 (10.5), n = 186	47.4 (10.7), n = 182
Difference (95% CI)b	–0.1 (–2.3 to 2.0)	0.6 (–1.6 to 2.8)	1.5 (–0.8 to 3.7)	–0.4 (–2.7 to 2.0)	0.40
SF-36 role-emotional score, mean (SD)
Deferred	43.7 (13.6), n = 224	45.9 (13.3), n = 207	45.1 (13.2), n = 193	47.5 (12.2), n = 179
Early	42.7 (13.8), n = 222	46.1 (12.8), n = 212	47.2 (12.2), n = 187	45.9 (13.0), n = 182
Difference (95% CI)b	–1.4 (–3.8 to 1.0)	0.0 (–2.5 to 2.5)	1.7 (–0.9 to 4.2)	–1.7 (–4.3 to 0.9)	0.08
SF-36 mental health score, mean (SD)
Deferred	49.3 (10.7), n = 224	49.2 (10.8), n = 207	49.5 (10.4), n = 193	50.7 (10.1), n = 179
Early	49.2 (10.3), n = 222	50.6 (10.4), n = 212	51.7 (9.7), n = 187	51.0 (9.3), n = 182
Difference (95% CI)b	–0.2 (–2.1 to 1.7)	1.3 (–0.7 to 3.2)	1.7 (–0.3 to 3.7)	–0.2 (–2.2 to 1.8)	0.07
SF-36 physical component summary score, mean (SD)
Deferred	38.8 (10.8), n = 223	39.6 (11.6), n = 207	40.4 (12.1), n = 193	41.8 (12.0), n = 178
Early	38.5 (9.9), n = 222	40.4 (10.2), n = 212	41.5 (11.5), n = 187	42.1 (11.6), n = 181
Difference (95% CI)b	–0.8 (–2.8 to 1.1)	0.3 (–1.7 to 2.2)	0.3 (–1.7 to 2.3)	0.3 (–1.7 to 2.3)	0.41
SF-36 mental component summary score, mean (SD)
Deferred	49.4 (11.6), n = 223	50.2 (11.0), n = 207	50.2 (10.4), n = 193	52.0 (10.0), n = 178
Early	49.2 (10.9), n = 222	51.1 (10.4), n = 212	52.2 (9.8), n = 187	51.6 (9.5), n = 181
Difference (95% CI)b	–0.3 (–2.2 to 1.7)	0.9 (–1.1 to 2.9)	1.5 (–0.5 to 3.6)	–0.7 (–2.7 to 1.4)	0.09

FIGURE 9.

The changes in AVVQ score over time in the early- and deferred-ablation groups.

FIGURE 10.

The changes in EQ-5D: (a) health score and (b) index value over time in the early- and deferred-ablation groups.

At baseline, AVVQ, EQ-5D-5L and SF-36 scores were similar in the early- and deferred-ablation groups. Overall, there was a significant difference in mean AVVQ scores between the treatment groups over time (p < 0.001), with lower mean scores, suggesting better disease-specific HRQoL, in the early-ablation group. There was a significant difference over time in mean EQ-5D index value between the treatment groups (p = 0.03), with more favourable scores in those randomised to early ablation, and in mean SF-36 body pain (p = 0.05). Observed differences between the groups for the other generic HRQoL measures were not statistically significant. However, as there was no control for multiple testing, these results should be interpreted with caution.

Table 16 summarises the HRQoL data with multiple imputation of missing values, which produces similar values.

TABLE 16 - Summary of quality-of-life outcomes with multiple imputation of missing values

Difference between two groups estimated by mixed model, adjusting for time, age, ulcer size and duration as a fixed effect and trial centre and participant as a random effect. Deferred-ablation group as reference. The 95% CIs have not been adjusted for multiplicity.

EQ-5D index calculated using the value set for England. 57

Notes

Data presented as mean (SD). Widths of the CIs have not been adjusted for multiplicity and should not be used for formal inference. Missing scores were imputed using chained equation.

Reproduced from The New England Journal of Medicine, Gohel et al. 57 A randomized trial of early endovenous ablation in venous ulceration, vol. 378, pp. 2105–14. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission.

Variable	Baseline	6 weeks	6 months	12 months
AVVQ score, mean (SD)
Early ablation	44.0 (9.0)	39.1 (10.2)	34.9 (10.1)	33.0 (9.7)
Deferred ablation	44.2 (8.9)	41.2 (9.7)	39.4 (10.3)	34.8 (10.8)
Difference (95% CI)a	–0.2 (–2.1 to 1.7)	–2.2 (–4.7 to 0.3)	–4.5 (–6.5 to –2.5)	–1.8 (–4.1 to 0.5)
EQ-5D health score, mean (SD)
Early ablation	70.2 (17.7)	72.6 (18.7)	73.6 (16.3)	74.8 (17.5)
Deferred ablation	70.0 (17.1)	70.7 (19.1)	71.5 (19.4)	73.0 (17.8)
Difference (95% CI)a	0 (–3.3 to 3.3)	1.8 (–1.8 to 5.4)	1.8 (–2.0 to 5.7)	1.8 (–1.6 to 5.1)
EQ-5D index value, mean (SD)b
Early ablation	0.73 (0.2)	0.79 (0.2)	0.81 (0.2)	0.83 (0.2)
Deferred ablation	0.73 (0.2)	0.74 (0.2)	0.77 (0.2)	0.80 (0.2)
Difference (95% CI)a	–0.01 (–0.05 to 0.03)	0.04 (0 to 0.09)	0.04 (0 to 0.08)	0.03 (–0.01 to 0.07)
SF-36 physical function score, mean (SD)
Early ablation	37.4 (12.0)	39.1 (12.9)	39.4 (12.9)	39.7 (13.3)
Deferred ablation	37.5 (12.5)	37.4 (13.0)	37.9 (13.6)	38.3 (13.7)
Difference (95% CI)a	–1.0 (–3.2 to 1.1)	0.8 (–1.4 to 3.1)	0.6 (–1.7 to 3.0)	0.7 (–1.6 to 3.0)
SF-36 role-physical score, mean (SD)
Early ablation	39.1 (12.2)	40.3 (12.6)	43.6 (12.6)	43.3 (12.9)
Deferred ablation	39.7 (12.1)	41.5 (12.6)	42.6 (12.8)	43.8 (13.1)
Difference (95% CI)a	–1.2 (–3.5 to 1.0)	–1.9 (–4.1 to 0.4)	0.4 (–2.6 to 3.3)	–0.9 (–3.4 to 1.5)
SF-36 body pain score, mean (SD)
Early ablation	41.3 (11.1)	46.6 (10.6)	48.3 (11)	49.4 (11.1)
Deferred ablation	41.6 (11.9)	44.0 (12.2)	46.1 (12)	47.5 (11.5)
Difference (95% CI)a	–0.5 (–2.6 to 1.6)	2.4 (0 to 4.7)	2.1 (–0.2 to 4.4)	1.9 (–0.3 to 4.0)
SF-36 general health score, mean (SD)
Early ablation	45.8 (9.2)	45.5 (9.1)	44.8 (9.8)	45.1 (10.0)
Deferred ablation	46.0 (9.8)	45.5 (9.3)	44.7 (10.2)	44.6 (10.2)
Difference (95% CI)a	–0.3 (–2.1 to 1.5)	–0.1 (–1.9 to 1.8)	–0.1 (–2.1 to 2.0)	0.4 (–1.4 to 2.2)
SF-36 vitality score, mean (SD)
Early ablation	48.2 (10.2)	49.0 (10.2)	49.1 (9.6)	50.2 (9.7)
Deferred ablation	47.9 (10.5)	47.4 (11.2)	48.7 (10.7)	49.0 (10.0)
Difference (95% CI)a	0.1 (–1.7 to 2.0)	1.3 (–0.6 to 3.2)	0.2 (–2.0 to 2.4)	1.0 (–0.9 to 3.0)
SF-36 social functioning score, mean (SD)
Early ablation	42.6 (12.4)	44.8 (11.6)	46.9 (10.7)	47.1 (11.0)
Deferred ablation	42.4 (13.5)	43.8 (12.1)	44.9 (12.4)	46.7 (11.7)
Difference (95% CI)a	–0.1 (–2.2 to 2.1)	0.6 (–1.7 to 2.9)	1.6 (–0.9 to 4.1)	0.1 (–2.1 to 2.4)
SF-36 role-emotional score, mean (SD)
Early ablation	42.7 (13.7)	46.1 (12.8)	47.0 (12.5)	45.6 (13.4)
Deferred ablation	43.7 (13.6)	45.8 (13.3)	45.1 (13.1)	47.1 (12.7)
Difference (95% CI)a	–1.4 (–3.8 to 1.0)	0 (–2.7 to 2.7)	1.4 (–1.3 to 4.1)	–1.9 (–4.5 to 0.8)
SF-36 mental health score, mean (SD)
Early ablation	49.2 (10.3)	50.4 (10.5)	51.2 (10.1)	50.5 (10.2)
Deferred ablation	49.3 (10.7)	49.0 (10.8)	49.4 (10.5)	50.2 (10.6)
Difference (95% CI)a	–0.2 (–2.1 to 1.8)	1.4 (–0.7 to 3.4)	1.6 (–0.7 to 4.0)	0.1 (–1.9 to 2.2)
SF-36 physical component summary score, mean (SD)
Early ablation	38.5 (10.0)	40.4 (10.4)	41.8 (11.4)	42.6 (11.8)
Deferred ablation	38.8 (10.7)	39.6 (11.5)	40.8 (12.1)	41.2 (12.2)
Difference (95% CI)a	–0.8 (–2.7 to 1.2)	0.2 (–1.8 to 2.2)	0.4 (–1.9 to 2.7)	1.0 (–1.1 to 3.1)
SF-36 mental component summary score, mean (SD)
Early ablation	49.2 (10.8)	51 (10.4)	51.7 (10.2)	50.9 (10.2)
Deferred ablation	49.4 (11.5)	50 (11.1)	50.1 (10.4)	51.5 (10.4)
Difference (95% CI)a	–0.2 (–2.2 to 1.7)	0.9 (–1.2 to 3.1)	1.5 (–0.8 to 3.8)	–0.7 (–2.8 to 1.4)

Clinical and technical success

Table 17 and Figure 11 show the clinical success at 6 weeks. The number of participants with improvement of clinical grade is 72 (31.9%) and 106 (47.3%) in deferred and early ablation groups, respectively.

TABLE 17 - Summary of clinical success at 6 weeks after randomisation

p-value for t-test.

p-value for Pearson’s chi-squared test.

Reproduced from The New England Journal of Medicine, Gohel et al. 57 A randomized trial of early endovenous ablation in venous ulceration, vol. 378, pp. 2105–14. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission.

Variable	Treatment group		p-value
	Early (N = 224)	Deferred (N = 226)
VCSS total score, mean (SD)
Baseline	15.8 (3.3), n = 223	15.7 (3.1), n = 226
Week 6	10.5 (4.7), n = 218	12.6 (4.4), n = 210	< 0.001a
Clinical classification downgrade (C6 to C5), n (%)
Yes	106 (47.3)	72 (31.9)	0.001b
No	112 (50.0)	139 (61.5)
Missing	6 (2.7)	15 (6.6)

FIGURE 11.

Summary of VCSS score in early- and deferred-ablation groups: VCSS score at baseline and 6 weeks after randomisation.

The VCSS evaluates changes in condition over time, with lower scores indicating better condition. Figure 11 clearly shows that early ablation was associated with a lower VCSS at week 6 than deferred ablation, whereas the VCSS at baseline was similar in both groups.

On assessment of post-ablation duplex ultrasound scans at 6 weeks, treated segments were completely ablated in 179 (83.3%) of 215 scanned participants and 74.8% of legs had no evidence of residual reflux.

Protocol deviations

There were 89 and 74 protocol deviations in early- and deferred-ablation groups, respectively. Table 22 shows the summary of the protocol deviations. The number of protocol deviations related to trial treatment was 38 (involving 32 participants) in the early-ablation group and 32 (involving 31 participants) in the deferred-ablation group. Participants with protocol deviations related to treatment were excluded from the per-protocol analysis.

Sensitivity analysis

The per-protocol analyses included 387 participants after excluding those with protocol deviation related to treatment. Figure 12 shows the KM curve based on the per-protocol analysis. The difference between the two groups is less pronounced than in the ITT analysis as the participants with protocol deviations in the deferred group experienced particularly poor healing (Figure 13). The smaller difference between the treatment groups in Table 23 also illustrates that the participants in the deferred group who did not have a protocol deviation had less severe ulcers. The 24-week ulcer healing rate in the deferred group was 76.3% in the ITT analysis and 82.6% in the per-protocol analysis. After adjusting for covariates in the Cox regression, in the per-protocol analysis the HR for time to healing associated with early compared with deferred ablation is 1.31 (95% CI 1.06 to 1.63; p = 0.01) (Table 24). In summary, although the deferred-intervention participants in the per-protocol analysis had less severe ulcers, it was still observed that early ablation led to more rapid ulcer healing in the per-protocol analysis.

FIGURE 12.

Per-protocol analysis (excluding participants with a protocol deviation) KM curve showing ulcer healing in the early and deferred (standard) ablation groups (p = 0.04).

FIGURE 13.

Kaplan–Meier curve showing ulcer healing time in the early- and deferred-ablation groups among participants with protocol deviations (p < 0.001).

Resource use and total cost analysis

Figure 14 and Appendix 9 show initial ablation procedures and overall subsequent resource use in the 450 randomised participants. Total mean cost per patient was calculated over 1 year. Participants who withdrew from the trial before 12 months were not included in the cost analysis. Participants who died during the year were included in the cost analysis, with costs set to £0 after the date of death. Hence, for the purposes of the total cost analysis, 211 participants in the deferred-ablation group (226 randomised minus 15 withdrawals, i.e. lost to follow-up or protocol deviations) and 208 participants in the early-ablation group (224 randomised minus 16 withdrawals, i.e. lost to follow-up or protocol deviations) completed 12 months of the trial or died (see Figure 3).

FIGURE 14.

NHS and Personal Social Services costs (£) of early vs. deferred strategies over 1 year, n = 208 (early-ablation group) and n = 211 (deferred-ablation group). Reproduced with permission from Cost-effectiveness analysis of a randomized clinical trial of early versus deferred endovenous ablation of superficial venous reflux in patients with venous ulceration. Epstein et al. 71 British Journal of Surgery, vol. 106, © 2019 BJS Society Ltd Published by John Wiley & Sons Ltd.

Reproduced with permission from Cost-effectiveness analysis of a randomized clinical trial of early versus deferred endovenous ablation of superficial venous reflux in patients with venous ulceration. Epstein et al. British Journal of Surgery 2019 © 2019 BJS Society Ltd Published by John Wiley & Sons Ltd. 71

The total mean cost over 1 year was very similar in the two trial groups: £2514 (SD £2770) in participants randomised to early ablation and £2516 (SD £3242) in the deferred-ablation group.

The early-ablation group incurred a greater initial cost due to the allocated ablation procedure, even though the trial protocol suggested that participants in the deferred group should have an ablation procedure once the ulcer was healed. Reasons for non-ablation in participants randomised to deferred ablation are unclear, but both participant and clinician preferences are likely to have played a role. The greater initial costs in the early-ablation group were compensated for by the lower costs of district nurse visits and consumables to quicker wound healing. Other resource use was similar in the two groups.

Table 10 shows the number of index endovenous ablation procedures performed. The trial also recorded further interventions in the treatment visit CRF and in the monthly telephone follow-up. These may include, for example, reinterventions for return of symptoms. Some of these may be non-protocol ablations (e.g. ablation in the non-trial leg), but there is insufficient information to be certain.

Table 25 shows the total number of vein procedures recorded in the trial, including those reported in the monthly telephone follow-up. To avoid double-counting, a record was assumed to be duplicated if a participant reported a vein procedure in the same month both on the CRF and during the telephone follow-up.

Cost-effectiveness analysis

The cost-effectiveness analysis uses data on both total costs and QALYs over 1 year. A total of 344 (76%) of 450 participants were included in the complete-case cost-effectiveness analysis. Table 26 summarises the pattern of missing data. Thirty-one (7%) participants had missing data for costs (because either they withdrew from the trial or there was a protocol deviation). A greater proportion (16%) had some missing data at 12 months for EQ-5D-5L. This arose because of withdrawal and because not all participants fully completed all the questions in the HRQoL questionnaires at each follow-up. Overall, 24% had some missing EQ-5D or cost data over the year.

Table 27 shows the results of the cost and QALY regressions for the cost-effectiveness analysis.

In the complete-case analysis (model 1), the difference in cost was £163 (SE £318), the difference in QALYs gained at 1 year was 0.041 (SE 0.017) and the ICER was £3976 per QALY. There was an 89% probability that early venous surgery is cost-effective at the current willingness-to-pay (WTP) threshold of £20,000 per QALY (Figure 15). Assuming bivariate normality to estimate SEs gave very similar results (model 2). There was a significant negative correlation between costs and QALYs, indicating that participants with a worse quality of life were also those who tended to incur greater health-care costs (correlation –0.294; p < 0.001).

FIGURE 15.

Cost-effectiveness acceptability curves for each model. Model 1: complete case (dashed line); Model 2: complete case using bivariate normal model; Model 3: multiple imputation; Model 4: alternative EQ-5D-5L tariff; Model 5: Per-protocol. Reproduced with permission from Cost-effectiveness analysis of a randomized clinical trial of early versus deferred endovenous ablation of superficial venous reflux in patients with venous ulceration. Epstein et al. 71 British Journal of Surgery, vol. 106, © 2019 BJS Society Ltd Published by John Wiley & Sons Ltd.

Reproduced with permission from Cost-effectiveness analysis of a randomized clinical trial of early versus deferred endovenous ablation of superficial venous reflux in patients with venous ulceration. Epstein et al. British Journal of Surgery 2019 © 2019 BJS Society Ltd Published by John Wiley & Sons Ltd. 71

In model 3, missing data were imputed. The mean difference in total cost was –£72 (SE £290, i.e. early intervention was cheaper at 1 year), and the mean difference in QALYs gained over 1 year was 0.058 (SE 0.018). There was a 99% probability of early intervention being cost-effective at a threshold of £20,000 per QALY.

Using alternative tariff values for the EQ-5D-5L resulted in a slightly smaller difference in QALY between the treatment groups, but the ICER was similar to the base case (model 4).

The per-protocol analysis used the same approach as model 1, but excluded patients with protocol deviations. Protocol deviations were seen in 117 patients (59 and 58 in the early and deferred groups, respectively), of whom 71 had complete data. This left 273 patients for analysis (344 with complete data at 12 months minus 71 protocol deviations). The ICER in this model was £8679 per QALY (model 5).

Interpretation

The EVRA trial is the first multicentre RCT to assess the effect of early endovenous ablation for superficial venous reflux on ulcer healing in participants with venous ulceration. As standard care in the UK does not usually involve venous surgery (and, if surgery is performed, it is generally deferred until after ulcer healing with compression therapy), the results should be of interest to patients, clinicians and policy-makers.

The trial showed that early ablation of superficial reflux in addition to compression therapy significantly accelerates ulcer healing. Participants randomised to the early-ablation group also benefited from more ulcer-free time over the 12 months post randomisation.

Venous guidelines, worldwide,40,45 recommend the ablation of superficial venous reflux based on the results of the ESCHAR trial, which demonstrated that superficial venous surgery reduced ulcer recurrence compared with compression therapy alone. 9,15 ESCHAR, however, did not show a benefit in terms of ulcer healing, which may explain why leg ulcer care pathways usually do not include provisions for early assessment and treatment of superficial reflux. The exception is the US Society for Vascular Surgery and the American Venous Forum Guidelines, which make a weak recommendation (grade 2, level C) for endovenous ablation in active ulceration based on the results of some cohort studies. 45 In addition, the lack of standardised leg ulcer pathways and the involvement of a range of specialists may contribute to the inconsistent care delivered. 8,41,44

It is interesting to note that the healing rates at 12 and 24 weeks achieved in the deferred-ablation group (51.6% and 76.3%, respectively) are higher than those previously reported in the literature and seen in the general venous leg ulcer population. 72 This is likely to be as a result of good-quality compression applied by the specialised, highly trained research staff and not representative of usual care (which varies across regions and can suffer from lack of staffing and resource). 44,73

Despite the excellent healing rates in the deferred-ablation group in this trial, participants randomised to early ablation still demonstrated a shorter time to healing. A widespread strategy of early ablation is likely to show an even greater benefit, as endovenous interventions are usually delivered as a single treatment episode, in contrast with compression therapy, which requires ongoing compliance for optimal outcomes. Implementation of early endovenous ablation for patients with venous leg ulceration will require considerable changes to current care pathways and treatment paradigms. The EVRA trial results reinforce the NICE recommendation that patients with leg ulceration not healed within 2 weeks should be referred promptly to a vascular service for evaluation and treatment of venous disease.

Although the results of the subgroup analysis should be interpreted with caution, there is a clear trend for a greater benefit from early ablation as ulcer duration increases. The inclusion criteria for the trial stipulated an upper limit of 6 months in duration for ulcers. This was to minimise heterogeneity within the trial population, but also because investigators expressed concerns about withholding endovenous ablation from patients with ulcers that had failed to respond to 6 months of compression therapy. Whether or not an even greater benefit would exist in those with an ulcer duration of > 6 months remains unclear.

Adverse events

The most common complications of endovenous ablation were pain and DVT. The DVT rate seen in the early-ablation group was high compared with other literature. However, in six of the participants DVT was infrapopliteal, and in four of these the thrombosis was identified on routine post-UGFS duplex ultrasonography performed 7 days post ablation (as per the local scanning regimen in one of the recruiting centres). Therefore, it is likely that this represents a very high level of detection of subclinical DVT.

Although 98 SAEs were reported over the course of the trial, as may be expected given the age of the trial population, only seven were deemed to be possibly, probably or definitely related to the ablation procedures.

Health-related quality of life

Early ablation led to significant improvements in disease-specific (AVVQ) and general HRQoL (EQ-5D index value) and body pain (SF-36 body pain), over the follow-up period. Differences were most pronounced at 6 weeks and 6 months post randomisation, which is consistent with more rapid healing.

Costs and cost-effectiveness

The complete-case analysis shows little difference in total mean cost per patient over 1 year between early and deferred ablation [mean difference £163 (SE £318); p = 0.607]. The greater initial mean cost of the early-ablation strategy is mostly offset by the reduced cost of treating unhealed leg ulcers. There is, however, a substantial and statistically significant QALY gain over 1 year, with a mean difference of 0.041 (SE 0.017) QALYs; p = 0.017. The ICER of early ablation at 1 year is, therefore, £3976 per QALY, compared with deferred ablation, with a high probability (89%) that early ablation is more cost-effective at conventional UK WTP thresholds (£20,000 per QALY). Sensitivity analyses using alternative statistical models give qualitatively similar results.

The difference in HRQoL appears to narrow at 1 year. Further follow-up is required to understand whether or not the gains from early ablation are maintained in the longer term. If early ablation results in lower recurrence risk in addition to reducing the time to healing, then even greater cost-effectiveness may be present over the lifetime of the patient. 74

The economic analysis protocol envisaged a within-trial cost-effectiveness analysis at 1 year and a decision model [for details, see the health economic plan on the project web page: www.journalslibrary.nihr.ac.uk/programmes/hta/11129197/#/ (accessed 18 April 2019)]. The purpose of the decision model was to extrapolate recurrence rates in order to assess whether or not early ablation might be cost-effective over a patient’s lifetime. At 1 year, there were insufficient recurrence events to reliably compare early with delayed ablation. Hence, the decision model results based on EVRA trial data will be reported when the trial extension results become available in late 2019.

As it was not possible to construct an economic model incorporating recurrence rates based on EVRA trial data at 1 year, an interim analysis was undertaken based on recurrence and healing rates obtained from the literature. 31 These studies compared early ablation (with surgery or endothermal techniques) plus compression versus compression only. None of these studies compared early ablation with delayed ablation; hence, they are not directly comparable with the strategies under comparison in the EVRA trial and are therefore not described in detail in this report. Nevertheless, the analysis showed that even if early ablation reduced the rate of recurrence only, and did not have an impact on healing, this strategy would be very cost-effective over a patient’s lifetime. 74

Generalisability

The trial was designed to be as pragmatic as possible, with broad inclusion criteria and interventional strategies guided by the treating clinicians. Participants were recruited from 20 centres across England and, although the trial had only a 7% inclusion rate and screened > 6500 patients to randomise 450, the baseline characteristics of the trial participants appear representative of the target population, when compared with other leg ulcer studies. 46,75,76 Of those screened but not randomised, who were excluded for not meeting the eligibility criteria, the two largest groups were those who had their ulcer for > 6 months (1772/6105, 29%) and those whose ulcer had healed by the time of randomisation (610/6105, 10%), largely as a result of delays in referral from primary to secondary care. Those with ulcers already healed have been shown in the ESCHAR trial to benefit from superficial venous intervention. Findings from the pre-planned subgroup analyses suggest that those with an ulcer duration of > 6 months may also benefit from early endovenous ablation. The results from the EVRA trial may therefore be more generalisable than initially apparent. Furthermore, as > 90% of those in the early-ablation group were treated within 2 weeks and 79.4% of these participants required only one procedure, implementation in a NHS setting seems highly feasible. Patient concordance is also likely to be higher with early ablation than with compression alone, as treatment success is less dependent on ongoing patient compliance.

Strengths of the EVRA trial

Limitations of the EVRA trial

Overall conclusions

Early endovenous ablation of superficial truncal reflux in addition to compression therapy accelerates the healing of venous leg ulcers compared with deferred ablation.

Although there is little difference between early and deferred ablation for endovenous superficial venous ablation in terms of the total mean cost per patient over 1 year, early ablation results in a significant gain in QALYs compared with deferred ablation. Therefore, early ablation has a high probability of being cost-effective at NICE WTP thresholds.

Implications for health care

Findings from this trial suggest that, for people with venous leg ulcers, early assessment and ablation of superficial venous reflux, in addition to compression therapy, accelerates healing and produces health economic benefits. Implementation of early assessment and endovenous ablation of superficial venous reflux will require further development of care pathways between primary and secondary care.

Recommendations for research (numbered in order of priority)

1. Follow up patients for longer to determine if early endovenous ablation influences ulcer recurrence rates in the medium and long term.

2. Evaluate the benefit of early ablation for superficial venous reflux in patients with venous leg ulceration of > 6 months’ duration.

3. Determine the implications of deep-venous incompetence and occlusive, and the potential role of deep-venous stenting to improve venous outflow of the limb.

4. Evaluate the optimal technique and the extent of eradication of superficial venous incompetence in patients with venous ulceration.

Trial applicants

Alun H Davies, Manjit S Gohel, Jane Warwick, David M Epstein, Andrew Bradbury, Keith R Poskitt, Richard Bulbulia and Nicky Cullum.

Trial Management Group

Alun H Davies (chief investigator), Francine Heatley (trial manager), Xinxue Liu (statistician) and Jane Warwick (senior statistician).

Imperial Clinical Trials Unit

The following members were part of the wider ICTU trial team: Claire Smith, Hilda Tsang, Hema Collappen and Natalia Klimowska-Nassar (operation managers); Amanda Bravery, Sandra Griffiths, Joseph Fryer, Kayode Disu, Nayan Das, Ayse Depsen, Dinesh Sivakumar, Fiona Persaud (InForm database team); Ginny Picot (quality assurance).

Department of Surgery and Cancer, Imperial College London

The following members were part of the wider EVRA trial team: Rebecca Lawton (trial manager); Becky Ward (sponsor); Matt Ryan (research manager); and Kirti Patel and Zara Collard (contracts).

Trial Steering Committee

We would like to thank Professor Julie Brittenden (chairperson); Miss Rebecca Jane Winterborn (Consultant Vascular Surgeon); Professor Andrea Nelson (Head of School and Professor of Wound Healing); Dr Richard Haynes (Research Fellow and Honorary Consultant Nephrologist); and Mr Bruce Ley-Greaves (lay member), who all provided invaluable input and advice as an independent TSC member over the course of the trial.

Data Monitoring Committee

The team would also like to thank the independent DMC members: Professor Gerard Stansby (chairperson, Professor of Vascular Surgery), Professor Frank Smith (Professor of Vascular Surgery and Surgical Education), Professor Marcus Flather (Professor of Medicine, Clinical Trials) and Dr Ian Nunney (Medical Statistician).

Patient and public involvement

Bruce Ley-Greaves was involved in the original design during the grant application stages and was an active member of the TSC throughout the trial. Bruce’s involvement is detailed in Appendix 1.

Core laboratory

We are thankful to Chen Liu and Rahul Velineni for core laboratory review and data activity.

Health economics

David Epstein (Health Economist) conducted the analysis of economic models for the trial.

Data cleaning

We are thankful to Yujin Lee for assistance with data cleaning and validation.

Local vascular research teams

The EVRA team would like to thank the NHS trusts, the participating principal investigators and their colleagues for recruiting and monitoring trial participants. These include (in alphabetical order of participating hospitals followed by the local principal investigators and their colleagues): Mr Kevin Mercer, Fazah Gill, Alan Liu, Wendy Jepson, Amy Wormwell and Helen Rafferty (Bradford Royal Infirmary); Mr Manjit Gohel, Debbie Read, Simone Hargreaves, Karen Dhillon, Muzaffar Anwar, Ailsa Liddle and Helen Brown (Addenbrooke’s Hospital); Alun Davies, Karen Dhillon, Raman Kaur, Emma Solomon, Kaji Sritharan, Rahul Velineni, Chung Sim Lim, Andrew Busuttil and Roshan Bootun (Charing Cross Hospital); Keith Poskitt, Richard Bulbulia, Jo Waldron, Gina Wolfrey, Fiona Slim, Colin Davies, Lorraine Emerson, Marianne Grasty, Mark Whyman, Clare Wakley, Andrew Cooper, Jo Clapp, Nicola Hogg, Julia Howard, Jackie Dyer, Sheri Lyes, Danita Teemul, Kate Harvey, Mandy Pride, Andrew Kindon, Hannah Price, Laura Flemming, Gemma Birch, Helen Holmes and Jodie Weston (Cheltenham General Hospital); Thomas Joseph, Ron Eiffel, Theo Ojimba, Toni Wilson, Adrian Hodgson, Lesley Robinson, Jane Todhunter, Dean Heagarty, Anna Mckeane and Rachel McCarthy (Cumberland Infirmary); Jamie Barwell, Clare Northcott, Alan Elstone and Clare West (Derriford Hospital); Patrick Chong, David Gerrard, Andrea Croucher, Stephanie Levy, Claire Martin and Tracey Craig (Frimley Park Hospital); Daniel Carradice, Anna Firth, Emma Clarke, Angie Oswald, Judith Sinclair, Ian Chetter, Joseph El-Sheikha, Sandip Nandhra and Clement Leung (Hull Royal Infirmary); Julian Scott, Nikki Dewhirst, Janet Woods, David Russell, Rosie Darwood, Max Troxler, Julie Thackeray, Deborah Bell, David Watson and Louise Williamson (Leeds General Infirmary); James Coulston, Paul Eyers, Katy Darvall, Ian Hunter, Andrew Stewart, Alison Moss, Jane Rewbury, Claire Adams, Louise Vickery, Leanne Foote, Helen Durman, Frances Venn, Paula Hill, Kate James, Fliss Luxton, Denise Greenwell. Karen Roberts, Suzette Mitchell, Moira Tate and Helen Mills (Musgrove Park Hospital); Andrew Garnham, Simon Hobbs, Donna Mcintosh, Marie Green, Kate Collins, Jayne Rankin, Paula Poulton and Val Isgar (New Cross Hospital); Sophie Renton, Karen Dhillon, Manoj Trivedi, Marina Kafeza, Shadeh Parsapour, Hayley Moore, Mojahid Najem, Sean Connarty, Hazel Albon, Chris Lloyd and Jackie Trant (Northwick Park Hospital); Rajiv Vohra, Jo McCormack, Jeanette Marshall, Victoria Hardy, Radu Rogoveanu and Will Goff (Queen Elizabeth Hospital Birmingham); Andrew Garnham, Ranjit Gidda, Sue Merotra, Sandy Shiralkar, Agantha Jayatunga, Rajiv Pathak, Atiq Rehman, Kiran Randhawa, Joy Lewis, Sarah Fullwood, Stacey Jennings, Sharon Cole and Michael Wall (Russells Hall Hospital); Charles Ranaboldo, Sarah Hulin, Caroline Clarke, Ruth Fennelly, Robin Cooper, Ruth Boyes, Charlotte Draper, Linda Harris and Dee Mead (Salisbury District Hospital); Andrew Bradbury, Lisa Kelly, Gareth Bate, Huw Davies, Matt Popplewell, Martin Claridge, Mark Gannon, Harmeet Khaira, Mark Scriven, Teun Wilmink, Donald Adam and Hosaam Nasr (Solihull Hospital); Colin Bicknell, Mike Jenkins, Tristan Lane and Emily Serjeant (St Mary’s Hospital, London); Dominic Dodd, Shah Nawaz, John Humpreys, Mathew Barnes, Julie Sorrell, Diane Swift, Patrick Phillips, Hazel Trender and Nikki Fenwick (Northern General Hospital); Dynesh Rittoo, Sara Baker, Rebecca Mitchell, Sarah Andrews, Steve Williams and Jane Stephenson (Royal Bournemouth General Hospital); Isaac Nyamekye, Sarah Holloway, Wendy Hayes, Julie Day, Claire Clayton and Daniel Harding (Worcestershire Royal Hospital); Andrew Thompson, Andy Gibson, Zoe Murphy and Thomas Smith (York Hospital).

National Institute for Health Research Clinical Research Networks

We would like to thank the following Clinical Research Networks for their help and support throughout the study (in particular helping facilitate the set-up of patient identification centres): Clinical Research Network North West London (lead site); East Midlands; Eastern; Greater Manchester, Kent, Surrey and Sussex; North East and North Cumbria; North Thames; South London; South West Peninsular; Thames Valley and South Midlands; Wessex; West Midlands (in particular Shahnaz Khan); West of England; and Yorkshire and the Humber.

Patient identification centres

The EVRA team would like to thank the following NHS trusts for allowing some of their general practices to display posters and leaflets to help promote the trial and enhance recruitment: Lincolnshire Community Health Services NHS Trust, Lincolnshire Clinical Commissioning Groups (CCGs); Nottingham CityCare Partnership and County Health Partnerships within Nottinghamshire Healthcare NHS Foundation Trust, Nottingham City CCG and Nottinghamshire County CCGs; Derbyshire County and Derby City PCT; Derbyshire Community Health Services; Northamptonshire Healthcare NHS Foundation Trust; Leicestershire Partnership NHS Trust; Cambridgeshire Community Services NHS Trust; Cambridgeshire and Peterborough CCG; Hertfordshire Community NHS Trust; Hertfordshire Partnership NHS Foundation Trust; North Essex Partnership University NHS Foundation Trust; NHS South Norfolk CCG; Ashton Leigh and Wigan PCT; Bolton PCT; Bury PCT; Heywood, Middleton and Rochdale PCT; Manchester PCT; Oldham PCT; Salford PCT; Stockport PCT; Trafford PCT; Crawley CCG; Coastal West Sussex; Horsham & Mid Sussex; Eastbourne, Hailsham and Seaford CCG (formerly NHS East Sussex Downs and Weald); High Weald Lewes Havens CCG (formerly NHS East Sussex Downs and Weald); Hastings and Rother CCG (formerly NHS Hastings and Rother); East Surrey CCG (formerly NHS Surrey); Guildford and Waverley CCG (formerly NHS Surrey); North East Hampshire and Farnham CCG (formerly NHS Surrey); North West Surrey CCG (formerly NHS Surrey); Surrey Downs CCG (formerly NHS Surrey); Surrey Heath CCG (formerly NHS Surrey); Brighton and Hove CCG (formerly NHS Brighton and Hove); Ken and Medway CCGs; Medway Community Healthcare; North of England Commissioning CCGs; Central and North West London NHS Foundation Trust; Brent CCG; Central London Community Healthcare NHS Trust; Chelsea and Westminster Hospital NHS Foundation Trust; Hounslow and Richmond Community Healthcare NHS Trust; Bexley CCG; Lewisham CCG; Royal Devon and Exeter NHS Foundation Trust; Somerset CCG; Dorset CCG; Fareham and Gosport CCG; Isle of Wight CCG; North Hampshire CCG; North East Hampshire; Portsmouth CCG; Southampton CCG; South Eastern Hampshire CCG; Wilshire CCG; Birmingham Community Healthcare NHS Trust; Black Country Partnership NHS Foundation Trust; Worcestershire Health and Care NHS Trust; Worcestershire PCT; Walsall Healthcare NHS Trust; Royal Wolverhampton NHS Trust; Coventry and Warwickshire Partnership Trust; Bristol PCT; North Somerset and South Gloucestershire PCT; Banes CCG; NHS Swindon CCG; City Health Care Partnership; Humber NHS Foundation Trust; NHS Doncaster CCG; Airedale, Wharfedale and Craven CCG; Bradford City CCG; Bradford District CCG; Calderdale CCG; Leeds North CCG; Leeds South and East CCG; Leeds West CCG; Wakefield CCG; Vale of York CCG; Scarborough and Rydale CCG; Hambleton, Richmondshire and Whitby CCGs; Harrogate Rural and District CCG; Hull CCG; East Riding of Yorkshire CCG; and North Lincolnshire CCG.

Contributions of authors

Manjit S Gohel (Consultant Vascular Surgeon and co-applicant) was responsible for the design, conduct, supervision of the trial, acquisition of the data, interpretation of analysis and dissemination, drafting relevant chapters and final approval.

Francine Heatley (Trial Manager) managed and monitored the trial as trial manager, assisted with acquisition of the data, drafted relevant chapters and approved the final version of the report.

Xinxue Liu (Trial Statistician) was responsible for the conduct of the statistical analysis.

Andrew Bradbury (Consultant Vascular Surgeon and co-applicant) was responsible for the design of the trial, acquisition of the data and review of the final draft.

Richard Bulbulia (Consultant Vascular Surgeon and co-applicant) was responsible for the design of the trial and review of the final draft.

Nicky Cullum (Professor of Nursing, Head of the Division of Nursing, Midwifery & Social Work and co-applicant) was responsible for the design of the trial and review of the final draft.

David M Epstein (Lecturer, Applied Economics) was responsible for the design, conduct, analysis, dissemination and drafting of the cost-effectiveness chapter and review of the final draft.

Isaac Nyamekye (Consultant Vascular Surgeon) assisted with acquisition of the data and review of the final draft.

Keith R Poskitt (Consultant Vascular Surgeon and co-applicant) was responsible for the design of the trial, acquisition of the data and review of the final draft.

Sophie Renton (Consultant Vascular Surgeon) assisted with acquisition of the data and review of the final draft.

Jane Warwick (Senior Statistician and co-applicant) was involved in the design of both the trial and the statistical analysis plan, conduct of the statistical analysis and drafting of relevant chapters.

Alun H Davies (Professor of Vascular Surgery) was the chief investigator and was responsible for the design, conduct and supervision of the trial; interpretation of analysis and dissemination; drafting relevant chapters; and co-ordination of the report including final approval.

Francine Heatley, Alun H Davies, Manjit S Gohel, Jane Warwick and David M Epstein were responsible for drafting this report, although all authors provided comments on drafts and approved the final version.

Publications

Gohel MS, Heatley F, Liu X, Bradbury A, Bulbulia R, Cullum N, et al. A randomized trial of early endovenous ablation in venous ulceration. N Engl J Med 2018;378:2105–114.

Epstein DM, Gohel MS, Heatley F, Liu X, Bradbury A, Bulbulia R, et al. Cost-effectiveness analysis of a randomized clinical trial of early versus deferred endovenous ablation of superficial venous reflux in patients with venous ulceration. Br J Surg 2019;106:555–62.

Data-sharing statement

All data requests should be submitted to the corresponding author for consideration. Access to available anonymised data may be granted following review and appropriate agreements being in place.

Disclaimers

This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care.

Introduction

In addition to the ethical obligation of researchers to include patients and the public in research, the NIHR grant application process requires an element of public consultation from the outset. The benefits of public involvement have been shown throughout all stages of research, including identifying outcome measures. 79,80 More recent systematic reviews of patient involvement in research highlighted that active participation in research can lead to more relevant research by identifying patient-important outcomes and more credible results. 81,82

In order to avoid a tokenistic approach to PPI, the INVOLVE Briefing Notes for Researchers: Public Involvement in NHS, Public Health and Social Care Research were consulted from the outset to plan PPI involvement in the trial. 83 The notes reinforce the importance of early engagement of lay members to enhance inclusivity, ownership of the study and a sense of purpose.

How patient and public involvement influenced the research design

Role description and expectations

In line with INVOLVE guidance, a role description was drafted to detail the expectations, commitment levels of the post, details of reimbursement for travel/time and some training and support resource links, including a link to the INVOLVE jargon buster (see Appendix 10). 84

The lay member co-applicant agreed to act as our trial-specific PPI representative for the duration of the trial and join the TSC that met on an annual basis at a minimum. The trial manager and PPI representative met several times on an informal basis throughout the trial. All out-of-pocket expenses were covered for travel to the meeting and refreshments were provided at each meeting.

Trial set-up phase

As part of the set-up phase, the PPI representative reviewed all the patient-facing documents, including, but not limited to, the patient information sheet, consent form and patient diaries prior to Research Ethics Committee submission, to ensure that the language was appropriate and easily understood and that jargon was eliminated. Feedback from sites during the recruiting phase indicated that this was a successful exercise as patients needed little clarification after reading the patient information sheet.

Recruitment phase

The PPI representative attended the first TSC meeting and contributed and co-approved the charter. During the recruitment phase, he was an active member of the committee and attended all the TSC meetings, either in person or via teleconference, depending on availability.

To aid recruitment, he suggested that recruitment posters and leaflets were placed in GP surgeries to help recruit patients from primary care and contributed to the design of these. The impact of the recruitment posters and leaflets was difficult to evaluate; however, several patients who saw the posters requested referral to the recruiting hospitals and subsequently participated in the trial.

The trial manager kept in regular contact with the PPI representative in between TSC meetings to keep him engaged and informed of trial progress, particularly recruitment numbers. A shopping voucher was offered as recognition for his time.

Follow-up phase

Trial participants were e-mailed a newsletter during the follow-up phase to keep them updated on trial progress and timelines, and when they could expect to find out the results of the trial. The PPI representative helped design this newsletter, which also included a one-page article on the PPI involvement within the trial.

Results

The PPI representative attended the TSC/DMC results meeting to help provide a public/patient perspective on the interpretation of trial findings.

Dissemination

The PPI representative contributed to the design of the dissemination plan to ensure that the research team will disseminate the results to trial participants, the general public and health professionals, and has contributed to and reviewed the plain English summary for this report.

Measuring the impact of the EVRA trial

As the HTA programme has granted an extension to the trial to collect recurrence data, there will be an opportunity for the PPI representative to be involved in the adoption of the trial results in clinical practice and measuring the impact of a trial’s findings and informing future trial design.

The EVRA trial team eagerly await the findings from the current University of Oxford study Patient and Public Involvement Intervention to Enhance Recruitment and Retention in Surgical Trials (PIRRIST),85 which aims to determine if PPI can improve recruitment and retention in clinical trials.

Evaluating patient and public involvement

A PPI involvement feedback meeting was convened in August 2017 to obtain the PPI representative’s views on his involvement to date. The results of this meeting are summarised in Table 28. Written consent was obtained to use direct quotations.

Interestingly, these opinions are in line with results of the 2013 Evidence Base for Patient and Public Involvement in Clinical Trials (EPIC) study,86 which concluded that involvement from patients and the public is successful if the ‘goals are clear, if there are well developed plans for PPI in a trial, and if models of PPI are more responsive and managerial (e.g. membership of a Trial Management Group) rather than restricted to general oversight (e.g. membership of a TSC)’.

Summary

Based on the findings of the lay member involvement feedback, when designing future studies the research team would aim to:

• involve more than one member from the outset (e.g. a patient representative, someone newly diagnosed with the condition and a member of the public)

• include the members in the Trial Management Group discussions if appropriate

• ensure that the trial manager spends time with the members before and after meetings to explain reports and debrief

• ensure that TSC meetings are always held face to face

• provide an additional study-specific ‘jargon buster’ dictionary

• ensure that the reimbursement schedule is clear at the outset and calculated in line with the INVOLVE Policy on Payments and Expenses for Members of the Public87 advice, considering an hourly rate of payment for time.

By incorporating these findings in future trial design, the EVRA trial team hopes to aid the INVOLVE vision: by 2025 INVOLVE expect ‘all people using health and social care, and increasing numbers of the public, to be aware of and choosing to contribute to research by identifying future research priorities and research questions, informing the design and development of innovations, participating in research studies, advocating for the adoption and implementation of research in the NHS’. 88

Data Monitoring and Ethics Committee

• 21 October 2013.

• 30 June 2014.

• 22 April 2015.

• 15 January 2016.

• 26 July 2016.

• 17 January 2018.

Trial Steering Committee

• 12 December 2013.

• 24 April 2014.

• 5 November 2014.

• 19 October 2015.

• 23 June 2016.

• 4 May 2017.

• 17 January 2018.

Investigator meetings

• 25 April 2013.

• 20 June 2013.

• 27 November 2013.

• 24 April 2014.

• 28 November 2014.

• 25 May 2015.

• 11 November 2015.

• 8 July 2016.

• 11 July 2017.

• 28 February 2018.

Ulcer tracing

The ulcer size was determined at the baseline and 6-week clinic visit via manual tracing:

• Place planimetry (with 1 cm² markers) grids over the wound.

• Trace around end of ulcer with an indelible pen.

• Count the square descriptive units (cm²) and enter into InForm.

• Scan tracing and save as PtTrialnumber_Baseline_tracing_dd/mm/yy.

• E-mail to EVRAtrial@imperial.ac.uk via the Imperial College FileExchange: https://icseclzt.cc.ic.ac.uk/.

Digital photograph of the ulcer

The ulcer size was determined at the baseline and 6-week clinic visit via digital photograph:

• A digital camera (minimum 8 megapixel) should be used (recommended trial camera is the Sony Cyber-shot DSC-WX60 16.2 Megapixel Digital Camera).

• Write the patient trial ID on the 3-cm calibration strip (red and white strips found in the site file) and place in the field of vision of camera on the leg but not obscuring wound edge.

• Enable flash (all other camera macros should be disabled, i.e. general mode).

• Position camera 15 cm from wound perpendicular to mid-point.

• Capture two images to ensure one suitable image for analysis.

• If wound cannot be captured in one single image, divide wound into two or more segments and summate images.

• Save photo as PtTrialnumber_Baseline_Photo_dd/mm/yy.

• E-mail to EVRAtrial@imperial.ac.uk via the Imperial College FileExchange: https://icseclzt.cc.ic.ac.uk/.