Randomised Placebo Controlled Trial of Intravenous Iron for Improving Physical Performance and Quality of Life in patients with Chronic Limb-Threatening Ischaemia and Anaemia Following Revascularisation

Research question: Does intravenous iron after revascularisation in patients with chronic limb-threatening ischaemia and anaemia improve physical performance and/or quality of life? Background: Peripheral arterial disease (PAD), mainly caused by smoking-induced atherosclerosis, affects one in five people over 55. Severe PAD reduces blood supply to the legs, causing ischaemic pain, tissue loss, ulceration, and gangrene, known as chronic limb-threatening ischaemia (CLTI). CLTI affects around 800,000 people in the UK, accounting for over 13,000 revascularisation procedures and 4,500 amputations annually within the NHS. This "heart attack" of the leg is life- and limb-threatening: within a year of diagnosis, one in four patients undergoes amputation, and one in eight dies, even after revascularisation. CLTI is a "whole-body" issue associated with inflammation, muscle atrophy, mitochondrial dysfunction, and iron deficiency—problems not resolved by revascularisation alone. Effective management requires optimising deficiencies and modifying health behaviors—known as rehabilitation. Research on rehabilitation for CLTI is limited, revealing inequities compared to other cardiovascular diseases. This was highlighted by the Vascular Society of Great Britain and Ireland-James Lind Alliance PAD research prioritisation exercise, which ranked "how can outcomes be improved for patients with CLTI?" as a top priority. Discussions with RIVIVAL PPI reported months of decline and the need for better physical performance and quality of life after surgery. Half of CLTI patients are anaemic at intervention, rising to 80% at discharge. Anaemia may result from inflammation-mediated iron transport disruption and blood loss during surgery. Research indicates that mild anaemia increases the risk of amputation or death by 30%, and moderate/severe anaemia by 50%. Iron deficiency also causes mitochondrial dysfunction, limiting ATP resynthesis needed for muscle function and impairing protein synthesis. Correcting iron deficiencies is a promising rehabilitation strategy. IV iron is a simple intervention that can be safely given post-surgery. Though not specifically tested in CLTI patients, IV iron corrects anaemia, improves muscle function by enhancing mitochondrial oxidative capacity, reduces hospital stays, and lowers readmission rates. CLTI patients desire better physical performance and IV iron may help meet these needs. Due to the frailty of CLTI patients, traditional walking-based assessments are unsuitable. Grip strength predicts clinical outcomes and is a powerful surrogate for physical performance. Our pilot study found anaemic CLTI patients had worse grip strength than non-anaemic patients, linking physical performance to anaemia and health status. Methods: Anaemic CLTI patients will be recruited from seven UK NHS hospitals and randomised 1:1 to receive either IV iron or no iron after revascularisation. To detect a 20% grip strength difference and change in VascuQOL, 254 participants will be recruited. Timelines: Total duration 36 months 9-month setup 14-month recruitment 4-month follow-up 9-month analysis/dissemination Impact and Dissemination: IV iron could improve rehabilitation for CLTI patients, impacting NHS care and addressing inequities for these people. Results will be shared through video summaries, publications, conferences, and collaborations with patient groups. An onward funding application to assess cost-effectiveness will be considered.