Title: Alternatives and adjuncts to transfusion to prevent and treat bleeding in people who are at risk of serious or life-threatening bleeding
Funder: Department of Health and Social Care

Abstract: Bleeding is a serious condition related to surgery and trauma and accounts for 40% of all trauma deaths. In managing patients, it is crucial to stop the source of this bleeding. Bleeding may be exacerbated by abnormal blood coagulation and a number of local or systemic adjuvant or replacement therapies are available to manage or reduce bleeding but the optimal use (route, timing, dose) of these interventions is poorly understood. NICE guidelines have assessed the use of tranexamic acid (TXA) but did not assess the use of other alternatives to reduce bleeding. Their analysis and those of other systematic reviews (SRs) did not differentiate between route, timing, or dose of TXA or other alternatives. Most of the included studies in previous SRs have compared the intervention with placebo or with no treatment. None of the previous systematic reviews have compared the use of different alternatives (e.g. fibrinogen, antifibrinolytics, and desmopressin) within the same review. Severe or massive bleeding occurs in approximately 10% of cardiac surgery patients, and is associated with a high risk of death (22.3%). This increased risk of death remains after adjusting for confounding factors (duration of operation, pre-existing anaemia, co-morbidities). This increased risk is seen when a patient only requires a transfusion of one or two units of red blood cells (RBC). These findings suggest that reducing bleeding and avoiding transfusion may improve outcomes after cardiac surgery. In the UK cardiovascular disease is the leading cause of death from conditions amenable to healthcare. Bleeding and the need for a RBC transfusion have been shown to increase the duration of hospital stay and the costs associated with surgery, after taking into consideration confounding factors. Reducing bleeding associated with surgery could therefore reduce hospital stay and NHS costs associated with surgery. Reduction in blood usage is important because blood is a limited and expensive resource, it also has side-effects. Many of the alternative drugs e.g. TXA and desmopressin are relatively cheap in comparison. Many of the audits in surgical patients have shown that there is poor uptake of the use of alternatives to blood e.g. TXA to prevent bleeding. Only 7% vascular surgery and 32% of orthopaedic surgery used TXA. Barriers to use include, not knowing what dose or timing is most effective. These barriers are concerning because in CRASH-2 (a large international multicentre trial of TXA versus placebo in adult trauma patients with ongoing significant haemorrhage or at risk of significant haemorrhage, within 8 hours of injury) timing of TXA was found to be important. TXA was beneficial (decreased mortality) within 3 hours of trauma but was harmful (increased mortality) if given after 3 hours.The dose of drug is also important as clinicians want to give the minimum effective dose so that other side-effects are minimised. This will also reduce drug costs to the NHS. We will focus on four patient groups who are at risk of clinically significant or severe bleeding: 1) Individuals with heart disease e.g. receiving valve replacements or coronary artery bypass surgery; 2) Individuals with vascular disease e.g. people requiring aortic aneurysm repair; 3) Individuals requiring orthopaedic surgery e.g. people requiring hip or knee replacement surgery; 4) People who have had a traumatic injury who are at high risk of bleeding or who are bleeding. For these patient groups we want to identify the most appropriate treatment or combination of treatments. These treatments are expected to be assessed on their ability to: reduce all-cause mortality; reduce risk of re-operation due to bleeding; reduce demand for blood components; reduce hospital stay; and not increase the risk of thromboembolism. All planned reviews are designed to be network meta-analyses that only include RCTs, they will compare different treatments to prevent bleeding, and will also compare different doses, timings, and routes of administration. Each review will be undertaken by a team made up of: a systematic reviewer and clinical fellow; information specialist, methodologist; statistician and expert clinicians. The grant will be used to develop the Systematic Review Initiative’s capacity to perform complex systematic reviews in blood transfusion and their alternatives. The Systematic Review Initiative is a clinical research group established by NHS Blood and Transplant and funded through the four UK Blood Services.The primary objective of the SRI is to “develop the evidence base for the practice of transfusion medicine”, achieved through undertaking relevant systematic reviews (with NHS clinical colleagues) and developing an online library of transfusion medicine studies. (www.transfusionevidencelibrary.com). The Heart Group, Vascular Group and Injuries Group will provide editorial support for the reviews registered with their groups. The search strategies will be provided by the Systematic Review Initiative. Expert statistical and methodological advice and support will be provided by the Complex Reviews Support Unit. We will use the same review strategy for all proposed reviews. SEARCH STRATEGY: This will be developed in MEDLINE and will be modified for searching in other databases. Searches will use a combination of medical subheadings and free text terms. Searches in MEDLINE, EMBASE and CINAHL will be combined with adaptations of the Cochrane RCT search filter. There will be no restriction by language or publication status and the following resources will be searched: MEDLINE; EMBASE; CENTRAL, DARE & NHSEED (The Cochrane Library, current issue); PubMed (epublications only); CINAHL; the Transfusion Evidence Library, and two ongoing trials databases ClinicalTrials.gov, and WHO ICTRP. SELECTION OF STUDIES: One author will initially screen all citations and exclude duplicates. Two authors will then independently assess titles and abstracts of all remaining citations for eligibility against pre-determined criteria. We will retrieve the full text of references when eligibility cannot be assessed by title and abstract alone. OUTCOMES: will include all-cause mortality; major bleeding (need for a transfusion, re-operation); hospital stay; thrombotic events; other serious adverse events. While a full-scale economic evaluation is beyond the scope of this grant, we will review and summarise economic evidence alongside the clinical evidence. DATA EXTRACTION AND MANAGEMENT: Data extraction forms will be designed, piloted and modified (as required) for each systematic review. Data extraction will be undertaken independently by 2 reviewers. RISK OF BIAS ASSESSMENT: This will follow the current Cochrane guidelines outlined in the Cochrane Handbook. Study authors will be contacted where clarification is required or to request missing data. MEASURES OF TREATMENT EFFECT: These will be undertaken using the criteria laid out by Cochrane for dichotomous outcomes, continuous outcomes, and time-to-event outcomes. If we cannot report the available data in any of these formats we will provide a descriptive summary of the available information. TREATMENT NETWORK: We will include network graphs to summarise: numbers of studies that compared different treatments and numbers of patients that have received each treatment. These graphs will help us to determine whether a network meta-analysis is feasible (whether the interventions are connected), and whether the network contains closed loops (consistency between direct and indirect estimates of effects can be assessed). We will provide a qualitative description of network geometry and a quantitative assessment, if appropriate. RELATIVE TREATMENT RANKING: We will obtain a hierarchy of the competing interventions using the surface area under the cumulative ranking curve (SUCRA) for primary outcomes and adverse events. As SUCRA can be difficult to interpret, we will also report estimates of probabilities being first, second, and third most effective, as well as an objective assessment of the strength of information in the network and the magnitude of absolute benefits to accompany the rankings to minimise potential biases. DATA SYNTHESIS: If we consider the clinical and methodological characteristics of individual studies to be sufficiently homogenous, we will combine the data to perform a meta-analysis. In standard pairwise meta-analyses, we will estimate different heterogeneity variances for each pairwise comparison. In network meta-analysis we will assume a common estimate for heterogeneity variance across the different comparisons, this assumption could potentially be relaxed if sufficient data are available. DIRECT AND INDIRECT COMPARISONS: We will include both direct and indirect evidence when available to inform effect estimates. We will evaluate consistency between direct and indirect comparisons for closed loops within the networks. ASSESSMENT OF HETEROGENEITY: We will assess statistical heterogeneity within each pairwise comparison using the I2 statistic and its 95% confidence interval, which measures the percentage of variability that cannot be attributed to random error. The assessment of statistical heterogeneity in the entire network will be based on the magnitude of the heterogeneity variance parameter (Tau2) estimated from the network meta-analysis models. For dichotomous outcomes, we will compare the magnitude of the heterogeneity variance with the empirical distribution. We will also estimate a total I2 value for heterogeneity in the network. Where appropriate we will account for observed heterogeneity by stratification and/or regression analysis (meta-regression). SUB-GROUPS: If adequate data are available we will perform subgroup analyses and network metaregression. We will explore the effects of different route, timing or dose of administration through meta-regression, hierarchical modelling, or other appropriate methodologies.

Lay abstract: Bleeding associated with surgery and trauma can be serious and accounts for 40% of all deaths due to trauma. In treating patients who are bleeding it is crucial to stop the source of this bleeding. Bleeding may be reduced by treatments (alternatives to transfusion) applied to the site of bleeding or via injection in to a vein. However which is the best treatment or combination of treatments in a particular situation is poorly understood. We have focused on four patient groups who are at risk of clinically significant or severe bleeding: 1) people requiring major heart surgery; 2) people requiring aortic aneurysm repair; 3) people requiring hip or knee replacement surgery; and 4) people who have had a major injury who are at high risk of bleeding or who are bleeding. Nearly 15% of all red cell units are used in these surgical groups, costing the NHS 33.4 million per year. This does not take into account costs of re-operation, prolonged admissions and impact on patients. For these patient groups we want to identify the most appropriate treatment or combination of treatments. These treatments are expected to be assessed on their ability to: reduce the risk of death due to any cause; reduce risk of re-operation due to bleeding; reduce demand for blood transfusions; reduce hospital stay; and not increase the risk of a blood clot. The need for this research is justified by: a) The high burden of bleeding for patients and the NHS. Trauma is the leading cause of death in people less than 44 years. b) 2.3 million people in the UK have heart disease. 35,000 major heart operations occur in the UK every year. Risk of re-operation due to bleeding is between 2 and 9%. Patients who need to return to theatre are more likely to die (3 to 6 x risk), and more likely to develop complications that require prolonged hospital admissions. c) People who require heart surgery are the surgical group that uses the highest number of red cell transfusions in the UK, followed by trauma and orthopaedic surgery. d) Patient groups differ in the cause of any associated underlying inability to form a blood clot. Therefore different patient groups may benefit most from different treatments, combinations of treatments or different routes of administration. e) Despite guidance on the use of alternatives to transfusion in surgery, there is significant variability in its use. Clearer guidance on when and how they should be given are likely to lead to increased use. f) Concerns over safety in patients at high risk of stroke or a heart attack have led to limited uptake of use of treatments injected in to a vein. Treatments applied to the site of bleeding may stop bleeding whilst minimising side-effects. g) The Department of Health initiative on patient blood management focuses on improving patients' clinical outcomes by preventing exposure to donor blood. h) Providing universal access to blood supplies is a key objective for global health agencies, including the World Health Organization, because it saves and improves lives. However, unnecessary transfusions and unsafe transfusion practices expose individuals to the risk of serious adverse transfusion reactions and transfusion-transmitted infections as well as reducing the availability of blood products for patients who are in need. i) Bleeding and the need for transfusion are known to increase inpatient stay. j) Blood transfusions are an expensive and limited resource. Any evidence that leads to a reduction in their use could have a significant impact on NHS costs. Within the UK 311,000 units of platelets and 1.89 million units of red cells were issued last year at a total cost of £287 million. Any reduction in usage due to evidence provided by our reviews would lead to a significant financial benefit, as the cost of the alternatives is much cheaper.

Research activity codes: 6.1 PHARMACEUTICALS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: CARDIOVASCULAR;INJURIES AND ACCIDENTS;MUSCULOSKELETAL