Randomised trial examining clinical and cost effectiveness of three antithrombotic regimens following endovascular lower limb revascularisation for chronic limb threatening ischaemia: CLARITY (CLopidogrel, Aspirin and RIvaroxaban after revascularIsation with angioplasTY)

Background: Chronic Limb Threatening Ischaemia (CLTI) is the most serious manifestation of peripheral arterial disease. Patients undergo revascularisation of the affected limb to reduce morbidity including pain, gangrene and the risk of amputation or death. Revascularisation is common; over 4,400 endovascular procedures are performed each year in the UK.

Antithrombotic (antiplatelet and/or anticoagulation) therapy is given to all patients after endovascular intervention to reduce the risk of subsequent ischaemic events such as acute limb ischemia or myocardial infarction. Clinicians and patients strongly feel a randomised trial is required to determine the clinical and cost effectiveness of the commonly used antithrombotic regimens.

Aims and objectives: To compare clinical and cost effectiveness of three commonly used antithrombotic regimens following endovascular intervention for CLTI.

James Lind research priority: CLARITY addresses six of the top ten James Lind research priorities for peripheral arterial disease research from the UK vascular surgery priority setting process, including the number one priority: ‘What can be done to improve outcomes in CLTI?’ The target population fit within multiple groups identified as under-served by clinical research by the INCLUDE project and National Confidential Enquiry into Patient Outcome and Death 2022 healthcare inequalities review.

Design: Pragmatic adaptive multicentre open label individually randomised trial, with adaptive interim analysis to examine futility of the arm with lowest predicted clinical effectiveness.

Health Technology being assessed: Participants will be randomised in a 1:1:1 ratio to receive clopidogrel: aspirin plus clopidogrel: aspirin plus rivaroxaban for up to 36 months.

Outcome measures: The primary effectiveness composite outcome is time until one of the following: acute limb ischaemia, major amputation, myocardial infarction, ischaemic stroke or all-cause mortality. The primary safety outcome is major bleeding. Secondary outcomes including major adverse cardiovascular and limb events will also be evaluated.

A qualitative process evaluation will be conducted. A cost utility analysis from a UK NHS/Personal Social Services Perspective at 12 and 36 months will be performed. A cost effectiveness analysis using VascuQoL will also be undertaken.

Sample size: 1239 participants will be followed-up for a maximum of 36 months to provide 90% power to detect an increase in the 12-month event-free survival rate from 65.0% in the clopidogrel alone arm to 75.6% in at least one of the intervention arms, corresponding to a hazard ratio of 0.65; using 5% two-sided statistical significance and allowing for 8% annual dropout.

Timelines for delivery: Internal pilot in 8 sites with strict progression criteria. Target randomisation rate of 2.3 patients/centre/month in 20 sites. Study duration 60 months: 6 months set up, 48 months recruitment and follow up (including 9 months internal pilot), 6 months final analysis and reporting.

Anticipated impact and dissemination: CLARITY aims to provide definitive clinical and cost effectiveness evidence for antithrombotic therapy following endovascular intervention for patients with CLTI. We will run a multi-stakeholder pathway-to-impact event to ensure findings are widely disseminated and translated into NHS clinical practice. We will publish academic outputs in peer reviewed journals and update major guidelines.