Introduction and Purpose
Chronic venous insufficiency and varicose veins are a common condition with a broad prevalence in males and females. Risk factors for venous insufficiency including older age, female gender, pregnancy and obesity among others . Venous disease can result in leg ulcerations. Conservative treatments for varicose veins include leg elevation and compression stockings. Common interventions include laser and thermal ablation , ultrasound guided foam sclerotherapy, and vascular surgery. Foam sclerotherapy involves injection of a foam sclerosant, hypertonic saline, sodium tetradecyl sulfate, polidocanol, and chromatid glycerin in appropriate venous structures. The goal of foam sclerotherapy is to destroy the problematic refluxing vein by inducing venous endothelial cell death. One meta-analysis pooling several observational studies implicated endovenous treatment, including foam sclerotherapy, as a suitable therapeutic option for patients with venous insufficiency ulcers . The Early Venous Reflux Ablation (EVRA) randomized controlled trial further endorsed a role endogenous therapy has in patients with venous ulcers due to superficial venous reflux.
The study was designed an independent randomized controlled trial from with strict eligibility criteria. Patients were at least 18 years of age with an open venous leg ulcer present for minimum of 6 weeks and at most 6 months. This requirement maintains that the patient had had chronic disease with venous reflux defined as retrograde flow greater than 0.5 seconds in superficial veins. The trial did not exclude deep vein reflux patients even if the endogenous treatment would not affect deep vein reflex. Patients also needed to have an Ankle-Brachial Index (a ratio of ankle to brachial blood pressure and one indicator of potential peripheral artery disease) > 0.8. Poor arterial flow can cause ulcers to develop separate from venous insufficiency.
Exclusion criteria included patients who were pregnant, noncompliance with compression therapy, deep venous occlusive disease, conditions preventing superficial venous ablation, leg ulcers of an unknown cause, or skin grafting procedures in the past. These exclusion criteria were intended to exclude skin ulcers with non-venous sources.
Patients were randomly assigned to the following groups: 1) compression therapy and early endovenous ablation (early intervention group) and 2) compression therapy alone with endovenous ablation deferred at a later date (delayed intervention group). Patients in the early intervention group received superficial venous reflux ablated within 2 weeks after randomization. Patients in the early-intervention group had duplex ultrasonography performed 6 weeks post intervention. For the delayed-intervention group, endovenous intervention was done after the ulcer was healed within a 6 month period. If the ulcer was not healed at 6 months post randomization, patients were given endovenous intervention, After ulcer healing, patients were offered elastic compression stockings for treatment.
Endovenous therapy included laser or radio frequency ablation, ultrasound-guided foam sclerotherapy, cyanoacrylate glue, and mechanical ablation. Regardless of treatment modality, clinicians ablated at the main refluxing truncal vein.
The primary outcome measure was the time to ulcer healing up until 12 months post randomization. Patients with no ulcer healing verification were censored, or removed, from the analysis.
Secondary outcome measures included rate of ulcer healing at 24 weeks, rate of ulcer recurrence, ulcer-free time, ad patient reported health quality of life during the one-month period. Quality of live and clinical disease was assessed using the Venous Clinical Severity Score (VCSS) assessment tool and Aberdeen Varicose Vein Questionnaire (0-100 with higher scores indicating worse quality of life), the EuroQol Group5-Dimension quality-of-life assessments, and the medical outcomes study-36 Item Short-Form. These quality-of-life assessments were performed at randomizations, 6 weeks, 6 months, and 12 months post-randomization.
Statistical Analysis: Unadjusted rates of ulcer healing at 12 and 24 weeks was calculated using the Kaplan-Meier method. The study tested time in ulcer healing between the two using a Cox regression model. Clinicians adjusted for key factors that can influence ulcer healing including patient age, length of time ulcer has been present, and ulcer size. Other analyses, including ordered and mixed model logistic regression, were used to assess both ulcer-free time and patient quality of life respectively between both early and deferred treatment groups. Statistical significance was determined at a two-sided alpha level of 5%.
Demographics- Out of 6555 patients screened, 450 were included and consented for participation on trial. The most common causes for ineligibility were an ulcer present for more than 6 months, presence of arterial disease, or an ulcer healed prior to treatment. Patient demographics were similar between the two groups including factors that affect ulcer health such as ulcer duration, ulcer size, patient age, and DVT history.
Out of total patients included in the study, 203/224 patients in the early-intervention procedure had early intervention within 2 weeks after being randomized. In the deferred-intervention treatment, 103 patients (45.6%) had treatment between 4 weeks and 6 months and the rest got treatment after 6 months. Of the patients who had endovenous intervention, a majority of patients were treated with foam sclerotherapy (49.6 vs 44.2%- early vs deferred respectively). Other treatments included endothermal and mechanothermal ablation as well as combinations of endothermal and foam sclerotherapy.
Primary Outcome- The median time to ulcer healing was 56 days (95% confidence interval- 49 to 66 days) compared to 82 days (95% confidence interval- 69 to 92 days). Patients in the early intervention groups had more healed ulcers with a hazard ratio (HR) of 1.38 [95% confidence interval 1.13, 1.68], p = 0.001. Within the multivariate Cox model, quicker ulcer healing was observed in the early versus deferred-intervention group (HR: 1.42, 95% CI: 1.16, 1.73], p = 0.001).
Secondary Outcomes– 404/450 patients had healed ulcers within 1 year after randomization with more, 93.8% of patients, had ulcer healing the early-treatment group. Ulcer recurrence rate after one year only happened for 24/210 (11.4%) patients in the early-intervention group rather than 32/194 (16.5%) patients in the deferred-intervention group. Patients with early treatment had lower rate of ulcer recurrence compared to the deferred-intervention group by 0.08 events/person year (95% CI: -0.02, 0.18). Median ulcer-free time was 306 days (interquartile range: 240-328 days) in the early-intervention group compared to 278 days (175 to 324 days (p = 0.002) in the deferred-intervention group. Multivariate analysis, adjusting for variables that affect ulcer healing and recurrence such as patient age, ulcer size and duration suggested that patients with early-intervention group was more likely to have longer ulcer-free time (odds ratio of having a higher ulcer-free time quartile: 1.54; 95% CI: 1.07-2.21].
Patients had similar mean Venous Clinical Severity Score assessments (15.1 vs. 15.7) between early and delayed-intervention treatment. Venous Clinical Severity Score assessment tool scores after 6 weeks was better with less severe symptoms for early-intervention (10.5) versus the delayed-intervention (12.6) group. Further analysis of other quality of life surveys suggested no difference in terms of quality of life between treatment groups.
Conclusions/Discussion and Implications for IR
The study was a randomized controlled trial suggesting that early endovenous ablation could lead to better venous leg ulcer healing time compared to compression therapy and delayed intervention alone. The study was important as it suggested that varicose vein treatment, contrary to current guidelines, was effective for managing venous leg ulcer treatment. The trial did not evaluate treatment effectiveness for various endovenous treatment modalities including thermal, mechanothermal, and ultrasound foam-guided sclerotherapy. The study also did not factor in it’s analysis how primary care referral can affect and for this study, limit the total number of eligible patient recruitment. Finally by having an earlier follow-up ultrasound at 6 weeks, early-intervention patients were potentially exposure to more vein ablation treatments than the delayed-intervention group. Trial results favoring the early-intervention group could be due to increased number of treatments rather than due to early endovenous ablation treatment.
From an IR perspective, this research is very interesting as it suggests how IR therapy could be used for venous ulcer/ chronic venous insufficiency patients at earlier disease presentation. Randomized controlled trials are also Level I, gold standard, research evidence; this trial legitimized prior observational research studies suggesting the benefits of endovenous over conservative therapy. Venous insufficiency treatment is an additional therapy option IR can offer for their patients. This article, as a randomized controlled trial, further validates endovenous reflux treatment as valid options for this patient population.
Review by: Mahati Mokkarala, Washington University School of Medicine, 2019
Editor: Giovanni C. Santoro, DO
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Gohel MS, Heatley F, Liu X, et al. A Randomized Trial of Early Endovenous Ablation in Venous Ulceration. New England Journal of Medicine. 378;22 (2018)).