Title: The clinical benefits and cost-effectiveness and safety of haematopoietic interventions for patients with anaemia following major emergency surgery: a phase IV, multicentre, multi-arm randomised controlled trial: Peri-op Iron and EPO Intervention Study - POP-I
Funder: Department of Health and Social Care

Abstract: BACKGROUND TO THE RESEARCH_x000D_ Each year over 100,000 people over 60 years of age in the UK are admitted to hospital for lifesaving emergency operations. Two of the most common emergency operations are for hip fracture and severe abdominal problems. Many of these people have anaemia (a reduced number of red blood cells). Anaemia increases the risk of dying after surgery and those that do survive have a slower recovery, more complications, and therefore spend more time in hospital. Anaemia can be treated with drugs such as iron, but whether this improves survival and the general health of people who require an emergency operation is not known. _x000D_ _x000D_ AIM OF THE RESEARCH_x000D_ Our aim is to improve outcomes for people who are anaemic following emergency surgery, and to determine the cost-effectiveness of drug treatment for anaemia compared with usual care. One treatment option is a single injection of iron, given through a small drip. Another treatment option, that has been used in combination with iron, is a form of a naturally occurring substance called erythropoietin (known as EPO). This works in combination with iron to improve anaemia. Research in other groups of patients, such as those with heart and kidney problems, has shown that both treatments work very well. However, we do not know whether they would help patients recovering from emergency surgery._x000D_ _x000D_ These treatments also carry risks such as causing infection and blood clots. Both are also costly. Some of our research has shown that these treatments are increasingly being used in the NHS in patients undergoing emergency surgery. The absence of high-quality research to guide this practice may be causing harm to some patients and unnecessary costs to the NHS._x000D_ _x000D_ The James Lind Alliance is a national partnership of patients, clinicians and carers who look at research priorities. Improving patient care around the time of emergency surgery and the timely identification and management of patients with anaemia have been listed as Top 10 research priorities in anaesthesia, perioperative care and haematology. Our own patient involvement work has also highlighted that this research needs to be carried out. _x000D_ _x000D_ DESIGN AND METHODS USED_x000D_ We have designed a study to investigate whether treating anaemia after emergency surgery leads to people having more days at home after their operation. The study will recruit patients who have had different types of emergency surgery for abdominal problems or hip fracture. These patients will enter the study 2–10 days after their emergency operation and then assigned randomly (by chance) to one of three study groups: 1: usual care, 2: iron injection 3: iron + EPO injection. We will also measure quality of life, safety, and cost or savings associated with either of the treatments. _x000D_ _x000D_ PATIENT AND PUBLIC INVOLVEMENT_x000D_ Patient representatives have guided all elements of this research including: the identification of patients having emergency surgery, the outcomes that are most important to patients, the acceptability of the interventions, consent procedures and follow-up plan. Patients co-produced this plain English summary._x000D_ _x000D_ DISSEMINATION_x000D_ The study will start in January 2022 and run for 4 years. The results will be presented at scientific meetings and published in leading medical journals. We will work with our patient partners and relevant Royal Colleges to ensure rapid dissemination amongst healthcare professionals and changes to national treatment guidelines.

Lay abstract: RESEARCH QUESTION_x000D_ In patients 60 years or older recovering from major emergency surgery (P), is treating postoperative anaemia with IV iron (I1), or IV iron + erythropoiesis-stimulating agents (ESAs) (I2), more clinically and cost-effective compared to usual care (C), from the patients’ perspective (O)? _x000D_ _x000D_ BACKGROUND_x000D_ Postoperative anaemia is associated with increased mortality, longer length of hospital stay and poorer quality of life (QOL). Current evidence and guidance is in favour of restrictive use of blood transfusion. Iron and ESAs are increasingly used in this context but there is no high-grade evidence to support their use. _x000D_ _x000D_ AIMS AND OBJECTIVES _x000D_ Aim: to improve outcomes for people who are anaemic following emergency surgery, and to determine the cost-effectiveness of drug treatments for anaemia compared with usual care. Objectives: 1. To assess the clinical effectiveness of postoperative IV iron and IV iron + ESA versus usual care respectively, for the treatment of anaemia across two major patient groups requiring emergency surgery; 2. To monitor safety of the interventions; 3. To conduct an internal pilot to evaluate recruitment, uptake and retention rates, sample size parameter estimates, clinician protocol adherence, safety, acceptability and adherence, completeness and quality of data collection; 4. To assess the cost effectiveness/cost utility of postoperative intravenous iron and intravenous iron + ESA versus usual care respectively, and impact on resource use and QOL from a healthcare, social care and broader societal viewpoint. _x000D_ _x000D_ METHODS_x000D_ Multicentre multi-arm open-label pragmatic randomised controlled trial with integral internal pilot and concurrent economic evaluation. Setting: UK secondary care hospitals providing care for emergency laparotomy and hip fracture patients. Population: Patients >60 years, 2-10 days following emergency laparotomy or hip fracture surgery with confirmed anaemia (haemoglobin 80–110g/l). Interventions [1: usual care, 2: iron injection (iron isomaltoside (20 mg/kg)), 3: iron (dose) + darbepoetin (1.5 mcg/kg) injection] assigned (ratio 1:1:1) using a probabilistic minimisation algorithm balancing on important prognostic factors (centre, type of surgery, age, sex, and postoperative haemoglobin concentration). Outcomes: Primary – Days at home within 30 days after surgery (DAH30); Secondary: quality of life (EQ-5D-5L), safety and costs/savings. Sample size: 792 patients/group to achieve 90% power (2-sided 2.5% alpha adjusted for 2 principal comparisons, maximum 5% attrition) to detect a difference of 2 days in DAH30 (SD 11) between an active treatment versus usual care. Target 2,400 patients overall (rounded up). Primary analysis: generalised linear mixed effects regression modelling to compare DAH30 between groups (each active treatment group versus usual care respectively), adjusting for minimisation factors, including random effects to adjust for clustering within surgery type and centres. We will present the mean difference, plus 95% confidence intervals for each principal comparison on an intention-to-treat basis. _x000D_ _x000D_ TIMELINE_x000D_ 4 years_x000D_ _x000D_ IMPACT AND DISSEMINATION_x000D_ The results will be presented at scientific meetings and published in leading peer-reviewed medical journals. We will work with our patient partners, guideline writers and Royal Colleges to ensure rapid dissemination amongst healthcare professionals and changes to national treatment guidelines.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: BLOOD