Title: T4P (Threshold for Platelets)
Funder: Department of Health and Social Care

Abstract: Our study aims to discover the platelet count below which patients requiring Intensive Care should be given platelets to have a procedure that may cause bleeding. _x000D_ _x000D_ Platelets are cells in your blood that help form clots and stop bleeding. Patients treated in an Intensive Care Unit (ICU) often have fewer platelets in their blood than healthy people._x000D_ _x000D_ The platelet count is the number of platelets in the blood. If a patient’s platelet count is low, doctors often give platelets collected from a healthy blood donor. This is called a platelet transfusion. The aim of giving a platelet transfusion during a procedure is to prevent bleeding. _x000D_ _x000D_ As with all treatments, platelet transfusions have risks. Many patients treated on an ICU have underlying inflammation, where the body is trying to repair or heal itself from severe illness or infection. In this inflamed state, platelet transfusions may not work effectively to increase the platelet count. As a result, they may not help to stop bleeding. Instead, they may cause further damage to inflamed organs such as the lungs and increase the risk of developing an infection. _x000D_ _x000D_ We do not know what level the platelet count should fall below before the benefits of platelet transfusions to prevent bleeding outweigh the risks._x000D_ _x000D_ ICU doctors are often unsure at what level they should give a platelet transfusion. We have shown by looking at NHS hospital data and by asking ICU doctors that patients in the UK are given platelet transfusions over a wide range of platelet counts, and the same is true globally. This absence of knowledge is very likely to be causing harm to patients and unnecessary cost to the NHS._x000D_ _x000D_ The James Lind Alliance (JLA) brings patients, clinicians and carers together to choose what should be researched. In blood transfusion and donation the JLA made the appropriate use of blood products, such as platelet transfusions, the second highest research priority. Internationally expert guidance groups have asked for more research to guide when to give platelet transfusions to patients on an ICU. Local patient groups have highlighted that this research needs to be carried out. Patient members have joined us, helped develop this application and will work with us on the study._x000D_ _x000D_ Most studies of platelet transfusions outside ICU only test two platelet counts, for example, 20 versus 50x10^9/L. These studies do not give doctors clear information about what to do for an individual patient, or if a platelet transfusion would help patients with platelet counts different from the two tested. Instead, we designed our study to test a range of different platelet counts. Patients will be placed (by chance) in different platelet count groups at which they will be given a platelet transfusion for an intervention that may cause bleeding. We will gradually put more patients into groups likely to be the safest. We will use the results to find the safest platelet count below which platelets should be given. Our main study outcomes will be mortality and costs._x000D_ _x000D_ As we need to recruit 2550 patients, we will use routinely collected healthcare data to make our study run as efficiently as possible._x000D_ _x000D_ We will create a project-specific website and use social media to publicise trial progress. With our patient and public members, we will write outputs for different audiences in several formats. We will update guideline-writing groups nationally and internationally.

Lay abstract: Research question_x000D_ In critically ill patients, below what platelet count should platelets be transfused for a planned procedure that might cause bleeding?_x000D_ _x000D_ Background_x000D_ Intensive care units (ICUs) are the highest platelet transfusion users after cancer services. Platelet transfusions are given to prevent procedure-induced bleeding in patients with low platelet counts. However recent trials outside adult ICUs show giving platelets may cause harm. Systematic reviews and a literature search for this application reveal a lack of evidence for prophylactic platelet transfusions in critically ill patients. Recent practice guidelines, unable to recommend a platelet count below which giving platelets is beneficial, call for new research._x000D_ _x000D_ Aims_x000D_ • To define the platelet count below which platelets should be transfused in critically ill patients undergoing low risk planned invasive procedures._x000D_ • To explore whether the threshold varies with patient characteristics._x000D_ _x000D_ Objectives_x000D_ • To model the platelet transfusion threshold-mortality curve for critically ill patients with planned low-risk invasive procedures._x000D_ • To evaluate whether the curve varies with the cause of low platelets._x000D_ • To evaluate the net monetary benefit (NMB) of practice standardisation at the optimum threshold versus current practice._x000D_ _x000D_ Methods_x000D_ An open-label, randomised, Bayesian adaptive, comparative effectiveness trial with an internal pilot across five equally-spaced platelet count thresholds (<10 - <50x10^9/L) in critically ill patients._x000D_ _x000D_ Participants_x000D_ Patients accepted for admission or within an ICU, requiring an invasive procedure, with a current platelet count <50x10^9/L._x000D_ _x000D_ Intervention/comparator_x000D_ Patients will be randomised to one of five platelet thresholds below which they will receive a single adult equivalent dose of platelet transfusion for the index procedure and subsequent procedures during their ICU stay._x000D_ _x000D_ Outcomes (90 days after randomisation)_x000D_ Primary clinical effectiveness outcome: all-cause mortality_x000D_ Primary cost-effectiveness outcome: NMB_x000D_ _x000D_ Data collection_x000D_ We will use:_x000D_ • data linkage for routinely collected patient data_x000D_ • additional in-hospital data collection into a case report form_x000D_ • 3 and 12 month post-hospital questionnaires. _x000D_ _x000D_ Statistics_x000D_ We will:_x000D_ • estimate a continuous non-linear relationship between the allocated platelet count threshold and mortality. The primary estimate will be the location of the optimum of the threshold-mortality curve with a 95% credible interval._x000D_ • compare the estimated NMB at the optimum threshold with the NMB across the range of thresholds in the clinician survey._x000D_ _x000D_ Internal pilot_x000D_ Over the first 9 recruitment months we will assess recruitment, willingness to randomise, protocol adherence and data quality._x000D_ _x000D_ Timelines_x000D_ 60 months (6 months set-up, 42 months recruitment, 12 months follow-up, analysis and dissemination)._x000D_ _x000D_ Impact and dissemination_x000D_ With our patient representatives, the ICU patient group “ICUsteps”, and stakeholder groups including the National Blood Transfusion Committee and the Intensive Care Society, we will write outputs for a range of audiences in different formats. Our results will inform guideline-writing groups internationally (with which we are involved) to rapidly translate our findings into clinical practice. Demonstrating the threshold-response curve methodology will enable application to many other settings where treatment decisions are made based on physiological parameters.

Research activity codes: 6.4 SURGERY;7.3 MANAGEMENT AND DECISION MAKING
Health categories: GENERIC HEALTH RELEVANCE