Long-term Clinical and Cost-effectiveness of Early Endovenous Ablation in Venous Ulceration: A Randomized Clinical Trial

Importance One-year outcomes from the Early Venous Reflux Ablation (EVRA) randomized trial showed accelerated venous leg ulcer healing and greater ulcer-free time for participants who are treated with early endovenous ablation of lower extremity superficial reflux.Objective To evaluate the clinical and cost-effectiveness of early endovenous ablation of superficial venous reflux in patients with venous leg ulceration.Design, Setting, and Participants Between October 24, 2013, and September 27, 2016, the EVRA randomized clinical trial enrolled 450 participants (450 legs) with venous leg ulceration of less than 6 months’ duration and superficial venous reflux. Initially, 6555 patients were assessed for eligibility, and 6105 were excluded for reasons including ulcer duration greater than 6 months, healed ulcer by the time of randomization, deep venous occlusive disease, and insufficient superficial venous reflux to warrant ablation therapy, among others. A total of 426 of 450 participants (94.7%) from the vascular surgery departments of 20 hospitals in the United Kingdom were included in the analysis for ulcer recurrence. Surgeons, participants, and follow-up assessors were not blinded to the treatment group. Data were analyzed from August 11 to November 4, 2019.Interventions Patients were randomly assigned to receive compression therapy with early endovenous ablation within 2 weeks of randomization (early intervention, n = 224) or compression with deferred endovenous treatment of superficial venous reflux (deferred intervention, n = 226). Endovenous modality and strategy were left to the preference of the treating clinical team.Main Outcomes and Measures The primary outcome for the extended phase was time to first ulcer recurrence. Secondary outcomes included ulcer recurrence rate and cost-effectiveness.Results The early-intervention group consisted of 224 participants (mean [SD] age, 67.0 [15.5] years; 127 men [56.7%]; 206 White participants [92%]). The deferred-intervention group consisted of 226 participants (mean [SD] age, 68.9 [14.0] years; 120 men [53.1%]; 208 White participants [92%]). Of the 426 participants whose leg ulcer had healed, 121 (28.4%) experienced at least 1 recurrence during follow-up. There was no clear difference in time to first ulcer recurrence between the 2 groups (hazard ratio, 0.82; 95% CI, 0.57-1.17; P = .28). Ulcers recurred at a lower rate of 0.11 per person-year in the early-intervention group compared with 0.16 per person-year in the deferred-intervention group (incidence rate ratio, 0.658; 95% CI, 0.480-0.898; P = .003). Time to ulcer healing was shorter in the early-intervention group for primary ulcers (hazard ratio, 1.36; 95% CI, 1.12-1.64; P = .002). At 3 years, early intervention was 91.6% likely to be cost-effective at a willingness to pay of £20 000 ($26 283) per quality-adjusted life year and 90.8$45 995) per quality-adjusted life year.Conclusions and Relevance Early endovenous ablation of superficial venous reflux was highly likely to be cost-effective over a 3-year horizon compared with deferred intervention. Early intervention accelerated the healing of venous leg ulcers and reduced the overall incidence of ulcer recurrence

The relationship between cytokine concentrations and wound healing in chronic venous ulceration

ObjectiveThe importance of wound cytokine function in chronic venous leg ulcers remains poorly understood. This study evaluated the relationship between local and systemic concentrations of wound cytokines and wound healing in patients with chronic venous ulceration.MethodsThis prospective observational study was set in a community- and hospital-based leg ulcer clinic. Consecutive patients with chronic leg ulceration and ankle-brachial pressure index >0.85 were prospectively investigated. All patients were treated with multilayer compression bandaging. Wound fluid and venous blood samples were collected at recruitment and 5 weeks later. In the wound fluid and venous blood, cytokines and factors reflecting the processes of inflammation (interleukin 1β, tumor necrosis factor-α), proteolysis (matrix metalloproteinases-2 and -9), angiogenesis (basic fibroblast growth factor [bFGF], vascular endothelial growth factor), and fibrosis (transforming growth factor-β1 [TGFβ1]) were measured. Ulcer healing was assessed using digital planimetry at both assessments.ResultsThe study comprised 80 patients (43 men, 37 women). Median (range) ulcer size reduced from 4.4 (0.1-142.4) cm2 to 2.2 (0-135.5) cm2 after 5 weeks (P < .001; Wilcoxon signed rank), although 17 of 80 ulcers increased in size. The volume of wound fluid collected strongly correlated with ulcer size (Spearman rank = 0.801, P < .01). Initial wound fluid concentrations of bFGF correlated with ulcer size (Pearson coefficient = 0.641, P < .01), and changes in wound fluid TGFβ1 concentrations inversely correlated with changes in ulcer size (Spearman rank = −0.645, P = .032). There were no significant correlations between changes in other factors and ulcer healing. Wound fluid and serum cytokine concentrations correlated poorly.ConclusionWound fluid collection volume correlates with ulcer size. Ulcer healing correlated with increased concentrations of TGFβ1, possibly reflecting increased fibrogenesis in the proliferating wound. Aside from this, there was a large variation in wound and serum cytokine levels that largely limits their usefulness as markers of healing

Countryside Survey: national "soil change" 1978-2007 for topsoils in Great Britain - acidity, carbon, and total nitrogen status

Understanding global environmental change is a major challenge for 21st-century science; monitoring and understanding national soil change is no exception. National scale monitoring results for soil pH, carbon, and total nitrogen status for Great Britain show that soil change is occurring on anthropogenic time scales and that environmental protection legislation is an important tool for reversing potential detrimental impacts. Understanding “soil change” at the national scale, in addition to soil status, is a key challenge for national scale soil monitoring programs and is essential if more sustainable use of this finite resource is to be achieved. We present results from the first national scale survey of soil change to be reported three times within Europe and perhaps globally, covering a 30-yr time span. Countryside Survey is an integrated national monitoring program that makes measurements of vegetation; topsoil physical, chemical, and biological characteristics (0–15 cm); water quality; and land use across Great Britain (GB), thus recognizing their interdependence. Here we report on change in fundamental soil chemical characteristics. Soil pH and loss on ignition (LOI) were measured in 1978, 1998, and 2007 and soil total nitrogen (total N) concentration and C/N ratio in 1998 and 2007. Bulk density was measured in 2007. Mean soil pH increased significantly in less acidic soils from 1978 through 1998 to 2007. Mean pH increased significantly in more acidic, organic-rich soils from 1978 to 1998 but not between 1998 and 2007, indicating spatial trends in both sulfur deposition reductions and soil sensitivity. There was a small increase (8%) in GB topsoil C concentration (calculated from LOI) between 1978 and 1998, a small decrease (6.5%) between 1998 and 2007, and no significant overall change between 1978 and 2007. The unresolved difference between these results and those from the National Soil Inventory of England and Wales that reported wide-scale large decreases in soil C concentrations in 2005 are discussed. There were unexpected small but significant decreases in total N concentration in many broad habitats despite continuing atmospheric nitrogen deposition. In seminatural and woodland habitats, this was accompanied by an increase in the C to N ratio, indicating one possible explanation is dilution of the nitrogen signal due to high C/N litter inputs resulting from increased primary productivity as reported elsewhere due to a range of global drivers such as increased CO2, N, and temperature. In arable systems, comparable rates of loss of C and N suggest erosion losses or deep plowing are reducing soil condition. The results are discussed in relation to the influences on soil processes of key drivers of environmental change and the importance of considering habitat-specific trends

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

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

Long term results of compression therapy alone versus compression plus surgery in chronic venous ulceration (ESCHAR): randomised controlled trial

Objective To determine whether recurrence of leg ulcers may be prevented by surgical correction of superficial venous reflux in addition to compression

Study protocol for a multicentre, randomised controlled trial to compare the use of the decellularised dermis allograft in addition to standard care versus standard care alone for the treatment of venous leg ulceration: DAVE trial.

INTRODUCTION Venous leg ulceration (VLU), the most common type of chronic ulcer, can be difficult to heal and is a major cause of morbidity and reduced quality of life. Although compression bandaging is the principal treatment, it is time-consuming and bandage application requires specific training. There is evidence that intervention on superficial venous incompetence can help ulcer healing and recurrence, but this is not accessible to all patients. Hence, new treatments are required to address these chronic wounds. One possible adjuvant treatment for VLU is human decellularised dermis (DCD), a type of skin graft derived from skin from deceased tissue donors. Although DCD has the potential to promote ulcer healing, there is a paucity of data for its use in patients with VLU. METHODS AND ANALYSIS This is a multicentre, parallel group, pragmatic randomised controlled trial. One hundred and ninety-six patients with VLU will be randomly assigned to receive either the DCD allograft in addition to standard care or standard care alone. The primary outcome is the proportion of participants with a healed index ulcer at 12 weeks post-randomisation in each treatment arm. Secondary outcomes include the time to index ulcer healing and the proportion of participants with a healed index ulcer at 12 months. Changes in quality of life scores and cost-effectiveness will also be assessed. All analyses will be carried out on an intention-to-treat (ITT) basis. A mixed-effects, logistic regression on the outcome of the proportion of those with the index ulcer healed at 12 weeks will be performed. Secondary outcomes will be assessed using various statistical models appropriate to the distribution and nature of these outcomes. ETHICS AND DISSEMINATION Ethical approval was granted by the Bloomsbury Research Ethics Committee (19/LO/1271). Findings will be published in a peer-reviewed journal and presented at national and international conferences. TRIAL REGISTRATION NUMBER ISRCTN21541209