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In patients with venous leg ulceration and superficial reflux, what is the clinical and cost-effectiveness of early endovenous ablation of reflux?
In this 450-patient, multicenter, randomized clinical trial, early endovenous ablation with compression accelerated venous ulcer healing, reduced the overall incidence of ulcer recurrence, and was highly cost-effective compared with compression with deferred intervention.
To deliver clinical and cost benefits, leg ulcer care pathways should be revised to include early assessment and treatment of superficial venous reflux.
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.
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.
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.
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% likely at a threshold of £35 000 ($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.
ClinicalTrials.gov identifier: ISRCTN02335796
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Accepted for Publication: June 2, 2020.
Published Online: September 23, 2020. doi:10.1001/jamasurg.2020.3845
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Gohel MS et al. JAMA Surgery.
Corresponding Author: Alun H. Davies, DSc, Section of Vascular Surgery, Department of Surgery & Cancer, Imperial College London, 4th Floor, East Wing, Charing Cross Hospital, Fulham Palace Rd, London W6 8RF, United Kingdom (firstname.lastname@example.org).
Author Contributions: Dr Davies had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Gohel, Epstein, Heatley, Bradbury, Bulbulia, Cullum, Nyamekye, Poskitt, Warwick, Davies.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Gohel, Mora, Szigeti, Epstein, Bradbury, Nyamekye, Warwick, Davies.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Szigeti, Epstein, Warwick.
Obtained funding: Gohel, Heatley, Bradbury, Bulbulia, Cullum, Poskitt, Warwick, Davies.
Administrative, technical, or material support: Gohel, Mora, Heatley, Bradbury, Nyamekye, Poskitt, Warwick, Davies.
Supervision: Gohel, Bradbury, Poskitt, Renton, Warwick, Davies.
Early Venous Reflux Ablation Trial Group Members: Manjit S. Gohel, MD, Cambridge University Hospitals NHS Foundation Trust, United Kingdom; Manjit S. Gohel, MD, Jocelyn Mora, MSc, Francine Heatley, BSc, Alun H. Davies, DSc, Department of Surgery and Cancer, Imperial College London, United Kingdom; Matyas Szigeti, MSc, Jane Warwick, PhD, Imperial Clinical Trials Unit, School of Public Health, Imperial College London, United Kingdom; David M. Epstein, PhD, University of Granada, Spain; Andrew Bradbury, MD, University of Birmingham, United Kingdom; Richard Bulbulia, MD, Keith R. Poskitt, MD, Gloucestershire Hospitals National Health Service Foundation Trust, United Kingdom; Richard Bulbulia, MD, Medical Research Council Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom; Richard Bulbulia, MD, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom; Nicky Cullum, PhD, University of Manchester & Manchester University National Health Service Foundation Trust, United Kingdom; Isaac Nyamekye, MD, Worcestershire Acute Hospitals National Health Service Trust, United Kingdom; Sophie Renton, MS, North West London Hospitals National Health Service Trust, United Kingdom; Jane Warwick, PhD, Warwick Clinical Trials Unit, University of Warwick, United Kingdom.
Conflict of Interest Disclosures: Dr Gohel reported receiving grants from the National Institute for Health Research during the conduct of the study and personal fees from Medtronic and Cook Medical outside the submitted work. Dr Epstein reported receiving grants from the National Institute for Health Research during the conduct of the study. Dr Heatley reported receiving grants from the National Institute for Health Research during the conduct of the study. Dr Bradbury reported receiving grants from the National Institute for Health Research Health Technology Assessment during the conduct of the study. Dr. Bulbulia reported receiving grants from the United Kingdom Medical Research Council during the conduct of the study and outside the submitted work. Dr Cullum reported receiving grants from the National Institute for Health Research during the conduct of the study. Dr Nyamekye reported receiving grants from the National Institute for Health Research during the conduct of the study. Dr Davies reported receiving grants from the National Institute for Health Research during the conduct of the study. No other disclosures were reported.
Funding/Support: This study was supported by grant Health Technology Assessment 11/129/197 from the National Institute for Health Research.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The Sponsor, Imperial College, was responsible for ensuring the study was conducted in accordance with the ethical and national regulations. Additional funding for extended follow-up was approved by the National Institute for Health Research in November 2016.
Additional Information: The National Institute for Health Research Health Technology Assessment grant applicants, collaborators, and details are listed in the additional contributions section.
Data Sharing Statement: See Supplement 3.
Additional Contributions: We thank the patient focus group who helped ascertain the importance of the research question, identify the most important outcome measures, and confirm the acceptability of trial interventions and follow-up protocols. The Early Venous Reflux Ablation Trial Group thanks the National Health Service centers and participating principal investigators and their colleagues for recruiting and monitoring trial participants: Addenbrooke’s Hospital: Manjit Gohel, MD, D. Read, P. Hayes, S. Hargreaves, K. Dhillon, M. Anwar, A. Liddle, and H. Brown; Bradford Royal Infirmary, Bradford: K. Mercer, F. Gill, A. Liu, W. Jepson, A. Wormwell, H. Rafferty, and K. Storton. Charing Cross & St Mary’s Hospitals, London: A.H. Davies, K. Dhillon, R. Kaur, E. Solomon, K. Sritharan, R. Velineni, C. S. Lim, A. Busuttil, R. Bootun, C. Bicknell, M. Jenkins, T. Lane, and E. Serjeant. Cheltenham General Hospital: K. Poskitt, R. Bulbulia, J. Waldron, G. Wolfrey, F. Slim, C. Davies, L. Emerson, M. Grasty, M. Whyman, C. Wakeley, A. Cooper, J. Clapp, N. Hogg, J. Howard, J. Dyer, S. Lyes, D. Teemul, K. Harvey, M. Pride, A. Kindon, H. Price, L. Flemming, G. Birch, H. Holmes, and J. Weston. Cumberland Infirmary: T. Joseph, R. Eiffel, T. Ojimba, T. Wilson, A. Hodgson, L. Robinson, J. Todhunter, D. Heagarty, A. Mckeane, and R. McCarthy. Derriford Hospital, Plymouth: J. Barwell, C. Northcott, A. Elstone, and C. West. Frimley Park Hospital: P. Chong, D. Gerrard, A. Croucher, S. Levy, C. Martin, and T. Craig. Hull Royal Infirmary: D. Carradice, A. Firth, E. Clarke, A. Oswald, J. Sinclair, I. Chetter, J. El-Sheikha, S. Nandhra, C. Leung, and J. Hatfield. Leeds General Infirmary: J. Scott, N. Dewhirst, J. Woods, D. Russell, R. Darwood, M. Troxler, J. Thackeray, D. Bell, D. Watson, L. Williamson, and M. Todd. Musgrove Park Hospital, Taunton: J. Coulston, P. Eyers, K. Darvall, I. Hunter, A. Stewart, A. Moss, J. Rewbury, C. Adams, L. Vickery, L. Foote, H. Durman, F. Venn, P. Hill, K. James, F. Luxton, D. Greenwell, K. Roberts, S. Mitchell, M. Tate, and H. Mills. New Cross Hospital, Wolverhampton: A. Garnham, D. McIntosh, M. Green, K. Collins, J. Rankin, P. Poulton, V. Isgar, and S. Hobbs. Northwick Park Hospital, Harrow: S. Renton, K. Dhillon, M. Trivedi, M. Kafeza, S. Parsapour, H. Moore, M. Najem, S. Connarty, H. Albon, C. Lloyd, J. Trant, and S. Chhabra. Queen Elizabeth Hospital, Birmingham: R. Vohra, J. McCormack, J. Marshall, V. Hardy, R. Rogoveanu, W. Goff, and D. Gardiner. Russells Hall Hospital, Dudley: A. Garnham, R. Gidda, S. Merotra, S. Shiralkar, A. Jayatunga, R. Pathak, A. Rehman, K. Randhawa, J. Lewis, S. Fullwood, S. Jennings, S. Cole, and M. Wall. Salisbury District Hospital: C. Ranaboldo, S. Hulin, C. Clarke, R. Fennelly, R. Cooper, R. Boyes, C. Draper, L. Harris, and D. Mead. Solihull Hospital (part of the University Hospitals Birmingham National Health System Foundation Trust): A. Bradbury, L. Kelly, G. Bate, H. Davies, M. Popplewell, M. Claridge, M. Gannon, H. Khaira, M. Scriven, T. Wilmink, D. Adam, and H. Nasr. Northern General Hospital, Sheffield: D. Dodd, S. Nawaz, J. Humphreys, M. Barnes, J. Sorrell, D. Swift, P. Phillips, H. Trender, N. Fenwick, H. Newell, and C. Mason. Royal Bournemouth General Hospital: D. Rittoo, S. Baker, R. Mitchell, S. Andrews, S. Williams, J. Stephenson, and L. Vamplew. Worcester Royal Hospital: I. Nyamekye, S. Holloway, W. Hayes, J. Day, C. Clayton, and D. Harding. York Hospital: A. Thompson, A. Gibson, Z. Murphy, T. Smith, and J. Whitwell. We thank members of our 2 oversight committees, the Trial Steering Committee (Professor Julie Brittenden [Chair]; 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 provided invaluable input and advice as the independent lay member over the course of the study) and the Data Monitoring Committee (Professor Gerard Stansby [Chair, Professor of Vascular Surgery]; Professor Frank Smith [Professor of Vascular Surgery & Surgical Education]; Professor Marcus Flather [Professor of Medicine - Clinical Trials]; Dr Ian Nunney [Medical Statistician]) for their support and guidance. There was no financial compensation for these contributions.
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