Gohel MS, Heatley F, Liu X, Bradbury A, Bulbulia R, Cullum N, Epstein DM, Nyamekye I, Poskitt KR, Renton S, Warwick J, Davies AH, et al.
Health technology assessment (Winchester, England). Date of publication 2019 May 1;volume 23(24):1-96.
1. Health Technol Assess. 2019 May;23(24):1-96. doi: 10.3310/hta23240.
Early versus deferred endovenous ablation of superficial venous reflux in
patients with venous ulceration: the EVRA RCT.
Gohel MS(1)(2), Heatley F(2), Liu X(3), Bradbury A(4), Bulbulia R(5)(6)(7),
Cullum N(8), Epstein DM(9), Nyamekye I(10), Poskitt KR(5), Renton S(11), Warwick
J(3)(12), Davies AH(2).
Author information:
(1)Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
(2)Department of Surgery and Cancer, Imperial College London, London, UK.
(3)Imperial Clinical Trials Unit, Imperial College London, London, UK.
(4)College of Medical and Dental Sciences, University of Birmingham, Birmingham,
UK.
(5)Gloucestershire Hospitals NHS Foundation Trust, Gloucester, UK.
(6)Medical Research Council Population Health Research Unit, Nuffield Department
of Population Health, University of Oxford, Oxford, UK.
(7)Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield
Department of Population Health, University of Oxford, Oxford, UK.
(8)School of Health Sciences, University of Manchester, Manchester, UK.
(9)Department of Applied Economics, University of Granada, Granada, Spain.
(10)Worcestershire Acute Hospitals NHS Trust, Worcester, UK.
(11)North West London Hospitals NHS Trust, London, UK.
(12)Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick,
Coventry, UK.
BACKGROUND: Venous ulceration is a common and costly health-care issue worldwide,
with poor healing rates greatly affecting patient quality of life. Compression
bandaging has been shown to improve healing rates and reduce recurrence, but does
not address the underlying cause, which is often superficial venous reflux.
Surgical correction of the reflux reduces ulcer recurrence; however, the effect
of early endovenous ablation of superficial venous reflux on ulcer healing is
unclear.
OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of
compression therapy with early endovenous ablation of superficial venous reflux
compared with compression therapy with deferred endovenous ablation in patients
with venous ulceration.
DESIGN: A pragmatic, two-arm, multicentre, parallel-group, open randomised
controlled trial with a health economic evaluation.
SETTING: Secondary care vascular centres in England.
PARTICIPANTS: Patients aged ≥ 18 years with a venous leg ulcer of between 6
weeks' and 6 months' duration and an ankle-brachial pressure index of ≥ 0.8 who
could tolerate compression and were deemed suitable for endovenous ablation of
superficial venous reflux.
INTERVENTIONS: Participants were randomised 1 : 1 to either early ablation
(compression therapy and superficial endovenous ablation within 2 weeks of
randomisation) or deferred ablation (compression therapy followed by endovenous
ablation once the ulcer had healed).
MAIN OUTCOME MEASURES: The primary outcome measure was time from randomisation to
ulcer healing, confirmed by blinded assessment. Secondary outcomes included
24-week ulcer healing rates, ulcer-free time, clinical success (in addition to
quality of life), costs and quality-adjusted life-years (QALYs). All analyses
were performed on an intention-to-treat basis.
RESULTS: A total of 450 participants were recruited (224 to early and 226 to
deferred superficial endovenous ablation). Baseline characteristics were similar
between the two groups. Time to ulcer healing was shorter in participants
randomised to early superficial endovenous ablation than in those randomised to
deferred ablation [hazard ratio 1.38, 95% confidence interval (CI) 1.13 to 1.68;
p = 0.001]. Median time to ulcer healing was 56 (95% CI 49 to 66) days in the
early ablation group and 82 (95% CI 69 to 92) days in the deferred ablation
group. The ulcer healing rate at 24 weeks was 85.6% in the early ablation group,
compared with 76.3% in the deferred ablation group. Median ulcer-free time was
306 [interquartile range (IQR) 240-328] days in the early ablation group and 278
(IQR 175-324) days in the deferred endovenous ablation group (p = 0.002). The
most common complications of superficial endovenous ablation were pain and
deep-vein thrombosis. Differences in repeated measures of Aberdeen Varicose Vein
Questionnaire scores (p < 0.001), EuroQol-5 Dimensions index values (p = 0.03)
and Short Form questionnaire-36 items body pain (p = 0.05) over the follow-up
period were observed, in favour of early ablation. The mean difference in total
costs between the early ablation and deferred ablation groups was £163 [standard
error (SE) £318; p = 0.607]; however, there was a substantial and statistically
significant gain in QALY over 1 year [mean difference between groups 0.041 (SE
0.017) QALYs; p = 0.017]. The incremental cost-effectiveness ratio of early
ablation at 1 year was £3976 per QALY, with a high probability (89%) of being
more cost-effective than deferred ablation at conventional UK decision-making
thresholds (currently £20,000 per QALY). Sensitivity analyses using alternative
statistical models give qualitatively similar results.
LIMITATIONS: Only 7% of screened patients were recruited, treatment regimens
varied significantly and technical success was assessed only in the early
ablation group.
CONCLUSIONS: Early endovenous ablation of superficial venous reflux, in addition
to compression therapy and wound dressings, reduces the time to healing of venous
leg ulcers, increases ulcer-free time and is highly likely to be cost-effective.
FUTURE WORK: Longer-term follow-up is ongoing and will determine if early
ablation will affect recurrence rates in the medium and long term.
TRIAL REGISTRATION: Current Controlled Trials ISRCTN02335796.
FUNDING: This project was funded by the National Institute for Health Research
(NIHR) Health Technology Assessment programme and will be published in full in
Health Technology Assessment; Vol. 23, No. 24. See the NIHR Journals Library
website for further project information.
plain-language-summary: Venous leg ulcers are open wounds occurring on the legs
of patients with venous disease. They are common, painful and distressing and
reduce patient quality of life. Leg ulcers often result from valves in the leg
veins not working properly. The valves normally force blood back up towards the
heart; however, blood can flow backwards (reflux) when valves do not work
properly, and this can cause swelling and ulceration. Compression therapy
(wrapping bandages around the legs) has been shown to help ulcers heal, but it
does not treat the underlying reflux problem with the veins. Newer, less
invasive, techniques (known as endovenous ablation) have taken over from surgery
to correct venous reflux and are more acceptable to patients as they can be
performed quickly under local anaesthetic. The aim of the trial was to find out
if treating patients with leg ulcers by early endovenous ablation (within 2
weeks) and standard compression therapy can increase ulcer healing compared with
standard compression therapy and delayed endovenous ablation once the ulcer has
healed. In total, 450 people agreed to take part in this study and were treated
in 20 hospitals across England. Participants were randomly allocated to either
early or delayed endovenous ablation and followed up for 12 months. The trial
found that treating the veins early resulted in quicker ulcer healing than
delaying treatment until the ulcer had healed. The trial also showed that
participants had more time without an ulcer if the treatment was performed early
rather than after ulcer healing. No safety issues with early intervention were
identified. There is some evidence that quality of life was better in the early
treatment group and that people in this group had less body pain. Treating ulcers
early appears likely to be more cost-effective (i.e. a better use of NHS
resources) than delayed treatment. Future work will focus on collecting
longer-term follow-up data to find out if early endovenous ablation also reduces
the chances of the ulcer coming back.
DOI: 10.3310/hta23240
PMCID: PMC6556965
PMID: 31140402
Conflict of interest statement: 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.
