Title: PREVENTT (Preoperative intravenous iron to treat anaemia in major surgery)
Funder: Department of Health and Social Care

Abstract: •• Design: PREVENTT is a double blind phase III randomised controlled trial. •• Setting: The trial is pragmatic and aims to incorporate the intervention into current normal standard of patient care. Pilot studies confirm the protocol can be performed in existing preoperative surgical pathways; hospital outpatients and surgical preassessment clinics. •• Target population: Patients who are anaemic (Hb of 90-120g/L in women and 90-13-g/L in men) a minimum of 10 and maximum 42 days before undergoing elective major surgery. •• Health technologies assessed: The role of Ferric Carboxymaltose given to patients who are anaemic before they undergo major elective surgery. •• Measurement of costs and outcomes: Surgeons and trial nurses will be blinded to the intervention received by the patient. •Primary outcome is the proportion of patients receiving a blood transfusion in the period from randomisation until thirty days after elective surgery. •Secondary outcomes include: Post-operative complications assessed by the Post Operative Morbidity Survey (POMS) - a validated scoring system used in several NIHR trails; Length of hospital stay; The effect of anaemia on patient quality of life assessed by the Multidimensional Fatigue Inventory (MFI) - a 20-item measure of fatigue - and European Quality of Life-5 Dimensions (EQ-5D); Change in haemoglobin levels from randomisation to operation; total number of units cross matched; total number of packed red cells and any blood products transfused; Safety data will be collected on any reaction or side effect from trial therapy or transfusion reaction; Mortality during follow up. We will also estimate the cost effectiveness of the intervention from the perspective of the NHS using a lifetime horizon. Costs will include length of hospital stay, drug costs, transfusion costs and costs of treating complications following surgery, utilisation of critical care and ward beds. Outcomes in the cost effectiveness analysis will be measured in terms of the primary and secondary outcome measures and QALYs. •• Sample size: Transfusion rates in anaemic patients in pilot studies and the literature described were approximately 40% in all patients undergoing major surgery. Assuming that 40% of patients not receiving intravenous iron undergo transfusion within 30 days a sample size of 500 would give 90% power to detect a 35% relative reduction in the need for transfusion, i.e. to 26% in patients receiving intravenous iron, using a 5% significance level. The sample size allows for losses of up to 5% although these are expected to be minimal for the primary outcome in this patient population. •• Project timetables including recruitment rate: Mths 0 to 6: Initial phase (hiring/training staff, preparation of protocol & study docs) Mths 7-11. Trial set-up phase (ethics, regulatory and R&D approvals, database and randomisation set-up, site set-up) Mths 13 to 72: Recruitment. It is estimated that 300 new patients will undergo planned major surgery p.a. at each centre, half will have anaemia at presentation. Patients will be identified by review of the blood results from either multidisciplinary meetings or preassessment clinics (both methods were successful in pilot studies). We anticipate a minimum 10% consent rate so 15 patients per centre p.a. Approximately 35-40 UK centres will take part. The aim is to complete recruitment within 5.0 yrs (i.e. an average target of 10 pts/per centre/p.a. assuming 5 initial centres, 10 centres open by mth 6 & 20 centres open by mth 12). Mths 73-79: follow-up of pts (three month assessment). Mths 80-86: final data cleaning/validation, Mths 80-86 principal analysis & manuscript preparation, economic health analysis. Total project duration 7.0 yrs.

Lay abstract: Anaemia is a common problem in patients undergoing surgery. About half of patients undergoing a major operation have anaemia, often as a consequence of the disease requiring surgery. Anaemia causes patients to feel tired and unwell. Anaemia at the time of surgery increases the requirement for blood transfusion (50% if anaemic compared to only 15% without anaemia). Both anaemia and blood transfusions are associated with increased complications from surgery, delayed recovery and prolonged hospital stay. We propose that giving intravenous iron before operation can be used to correct anaemia in these patients. Consequently if patients are not anaemic they are less likey to need blood transfusion. Also if patients feel better and their health is improved before their operation they are more likely to tolerate the surgery, recover faster, be less likely to have complications from surgery and return home sooner. This will have benefits to the individual patient and also the NHS by reducing costs. Oral Iron tablets are not effective as they take 3-6 months to increase blood levels, the tablets are often not tolerated as they cause constipation or stomach pain, overall only 30-50% of people continue taking oral iron. A full treatment dose of intravenous iron can be given in 15 minutes with minimal side effects. The effect is to rapidly increase blood counts in 2-4 weeks. We propose that this treatment can be incorporated into patient preparation pathways for surgery as an outpatient without the need for additional visits to hospital. Small studies have suggested a benefit of iron therapy in orthopaedic and gynaecological surgery. This study will look at patients undergoing major surgery at 10-20 hospitals in the UK. We anticipate half of patients treated will have their anaemia corrected before operation. Patients with anaemia will be identified as part of the routine blood tests taken preoperatively and invited to take part in the study. Following informed consent, half will be randomly allocated to receive intravenous iron and half a placebo infusion of saline. Intravenous iron is a dark liquid given continuously into a vein over 15 minutes. To ensure neither doctor nor patient knows which treatment is being given both infusions will be made up by pharmacy and administered in a black bag through black tubing. There will be no other change to the patient's normal treatment. The main aim of this study is to assess if intravenous iron will reduce the need for blood transfusion in the time period around the operation. Further outcome measures will include; patient-reported quality of life, complications, length of hospital stay and cost. Outcomes will be assessed both during hospital stay and after the patient has been discharged. The team undertaking this research are working in collaboration with NHS Blood and Transplant (NHSBT), which provides blood services to the NHS. The project is supported by the British Blood Transfusion Society (BBTS) and the international Network for Advancement of Transfusion Alternatives (NATA). The trial will be run through a Clinical Trials Unit with considerable experience in conducting large trails. The team has a large range of experience in anaemia management and assessment of complications, quality of life and the cost of health care.

Research activity codes: 6.1 PHARMACEUTICALS;6.4 SURGERY
Health categories: BLOOD;GENERIC HEALTH RELEVANCE