Tilbrook H, Clark L, Cook L, Bland M, Buckley H, Chetter I, Dumville J, Fenner C, Forsythe R, Gabe R, Harding K, Layton A, Lindsay E, McDaid C, Moffatt C, Rolfe D, Sbizzera I, Stansby G, Torgerson D, Vowden P, Williams L, Hinchliffe R, et al.
Health technology assessment (Winchester, England). Date of publication 2018 Oct 1;volume 22(55):1-138.
1. Health Technol Assess. 2018 Oct;22(55):1-138. doi: 10.3310/hta22550.
AVURT: aspirin versus placebo for the treatment of venous leg ulcers - a Phase II
pilot randomised controlled trial.
Tilbrook H(1), Clark L(1), Cook L(1), Bland M(2), Buckley H(3), Chetter I(4),
Dumville J(5), Fenner C(6), Forsythe R(7), Gabe R(8), Harding K(9), Layton A(10),
Lindsay E(11), McDaid C(1), Moffatt C(12), Rolfe D(13), Sbizzera I(1), Stansby
G(14), Torgerson D(1), Vowden P(15), Williams L(16), Hinchliffe R(17).
Author information:
(1)York Trials Unit, Department of Health Sciences, University of York, York, UK.
(2)Department of Health Sciences, University of York, York, UK.
(3)Cancer Division, Clinical Trials Research Unit, Leeds Institute of Clinical
Trials Research, University of Leeds, Leeds, UK.
(4)Academic Vascular Surgical Unit, Hull Royal Infirmary, Hull, UK.
(5)Division of Nursing, Midwifery and Social Work, School of Health Sciences,
Faculty of Biology, Medicine and Health, University of Manchester, Manchester,
UK.
(6)Orthopaedic Department, West Middlesex Hospital, Isleworth, UK.
(7)Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
(8)Hull York Medical School and York Trials Unit, Department of Health Sciences,
University of York, York, UK.
(9)Wound Healing, School of Medicine, Cardiff University, Cardiff, UK.
(10)Harrogate and District NHS Foundation Trust, Harrogate, UK.
(11)The Lindsay Leg Club Foundation, Ipswich, UK.
(12)School of Health Sciences, University of Nottingham, Royal Derby Hospital,
Derby, UK.
(13)Joint Research and Enterprise Office, St George's University of London,
London, UK.
(14)Freeman Hospital, Newcastle upon Tyne, UK.
(15)Bradford Teaching Hospitals NHS Foundation Trust, Bradford Royal Infirmary,
Bradford, UK.
(16)Lay representative.
(17)Bristol Centre for Surgical Research, National Institute for Health Research
(NIHR) Biomedical Research Centre, University of Bristol, Bristol, UK.
BACKGROUND: Venous leg ulcers (VLUs) are the most common cause of leg ulceration,
affecting 1 in 100 adults. VLUs may take many months to heal (25% fail to heal).
Estimated prevalence is between 1% and 3% of the elderly population. Compression
is the mainstay of treatment and few additional therapies exist to improve
healing. Two previous trials have indicated that low-dose aspirin, as an adjunct
to standard care, may improve healing time, but these trials were insufficiently
robust. Aspirin is an inexpensive, widely used medication but its safety and
efficacy in the treatment of VLUs remains to be established.
OBJECTIVES: Primary objective - to assess the effects of 300 mg of aspirin
(daily) versus placebo on the time to healing of the reference VLU. Secondary
objectives - to assess the feasibility of leading into a larger pragmatic Phase
III trial and the safety of aspirin in this population.
DESIGN: A multicentred, pilot, Phase II randomised double-blind, parallel-group,
placebo-controlled efficacy trial.
SETTING: Community leg ulcer clinics or services, hospital outpatient clinics,
leg ulcer clinics, tissue viability clinics and wound clinics in England, Wales
and Scotland.
PARTICIPANTS: Patients aged ≥ 18 years with a chronic VLU (i.e. the VLU is > 6
weeks in duration or the patient has a history of VLU) and who are not regularly
taking aspirin.
INTERVENTIONS: 300 mg of daily oral aspirin versus placebo. All patients were
offered care in accordance with Scottish Intercollegiate Guidelines Network
(SIGN) guidance with multicomponent compression therapy aiming to deliver 40 mmHg
at the ankle when possible.
RANDOMISATION: Participants were allocated in a 1 : 1 (aspirin : placebo) ratio
by the Research Pharmacy, St George's University Hospitals NHS Foundation Trust,
using a randomisation schedule generated in advance by the investigational
medicinal product manufacturer. Randomisation was stratified according to ulcer
size (≤ 5cm2 or > 5cm2).
MAIN OUTCOME MEASURE: The primary outcome was time to healing of the largest
eligible ulcer (reference ulcer).
FEASIBILITY RESULTS – RECRUITMENT: 27 patients were recruited from eight sites
over a period of 8 months. The target of 100 patients was not achieved and two
sites did not recruit. Barriers to recruitment included a short recruitment
window and a large proportion of participants failing to meet the eligibility
criteria.
RESULTS: The average age of the 27 randomised participants (placebo, n = 13;
aspirin, n = 14) was 62 years (standard deviation 13 years), and two-thirds were
male (n = 18). Participants had their reference ulcer for a median of 15 months,
and the median size of ulcer was 17.1 cm2. There was no evidence of a difference
in time to healing of the reference ulcer between groups in an adjusted analysis
for log-ulcer area and duration (hazard ratio 0.58, 95% confidence interval 0.18
to 1.85; p = 0.357). One expected, related serious adverse event was recorded for
a participant in the aspirin group.
LIMITATIONS: The trial under-recruited because many patients did not meet the
eligibility criteria.
CONCLUSIONS: There was no evidence that aspirin was efficacious in hastening the
healing of chronic VLUs. It can be concluded that a larger Phase III
(effectiveness) trial would not be feasible.
TRIAL REGISTRATION: Clinical Trials.gov NCT02333123; European Clinical Trials
Database (EudraCT) 2014-003979-39.
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. 22, No. 55. See the NIHR Journals Library
website for further project information.
DOI: 10.3310/hta22550
PMCID: PMC6204573
PMID: 30325305 [Indexed for MEDLINE]
Conflict of interest statement: Catriona McDaid is a member of the National
Institute for Health Research Health Technology Assessment and Efficacy and
Mechanism Evaluation Editorial Board. Christine Moffatt has received grant
funding from 3M UK PLC and Smith and Nephew, two health science-based technology
companies, outside the submitted work.
