Title: Renal Replacement Anticoagulant Management (RRAM)
Funder: Department of Health and Social Care

Abstract: Design: Observational comparative effectiveness and cost-effectiveness study of individual patient data using interrupted time series analysis techniques and linked data sources. Setting: 184 English non-specialist intensive care units (ICUs) within the Intensive Care National Audit and Research Centre (ICNARC) Case Mix Programme. Target Population: Critically unwell adults who received continuous renal replacement therapy (CRRT) whilst treated on an ICU. Health Technologies Being Assessed: Regional citrate anticoagulation (RCA) compared with systemic heparin anticoagulation (SHA) for continuous renal replacement therapy. Measurement of clinical outcomes: The primary effectiveness outcome will be all cause mortality 90 days after the first ICU admission in which CRRT was received. Secondary effectiveness outcomes will include: • mortality at hospital discharge, 30 days and one year after ICU admission • days of renal, cardiovascular, and advanced respiratory support whilst in an ICU • ICU and hospital length of stay • new dialysis-dependent renal disease at one year after ICU admission. Data sources for clinical outcomes: Mortality at hospital discharge, days of organ support, ICU and hospital length of stay are recorded in the Case Mix Programme dataset. Date of death after hospital discharge will be obtained by linkage with ONS data. Patients developing dialysis-dependent renal disease will be identified by linkage with the Renal Registry. Measurement of costs: The cost-effectiveness analysis will take a health services perspective. The primary economic outcome is the incremental net monetary benefit gained at one year at a willingness-to-pay of £20,000 per quality-adjusted life year associated with a change from SHA to RCA during CRRT. The secondary economic outcome is an estimated lifetime incremental net benefit associated with a change from SHA to RCA. Data sources for measurement of costs: We will obtain patient-level resource use data from CMP database, the Renal Registry, and HES data. Resource use associated with heparin and citrate anticoagulation will be estimated from a micro-costing study. We will apply NHS Reference Costs. We will obtain staff resource use and transfusion data from an existing detailed ICU database (PICRAM project). We will obtain quality of life data from patients in the ICON study (which is already cross-linked to the CMP dataset) who have had renal replacement therapy during their ICU stay. Sample Size: ~ 85,000 patients from 184 ICUs should allow ~81% power (P<0.05) to detect a step change in 90-day mortality corresponding to an odds ratio of 0.9 (based on simulation of 1000 replications of the study using available CMP data assuming 35 transitions from heparin to citrate). Project timetable: 15 months with HRA approval obtained prior to start. The identification of patients in the ICNARC Case Mix programme and Renal Registry will complete by month 5, with NHS Digital delivering the linked data by month 8. The health economics data will be available by month 10 leaving 5 months for analysis, write-up and dissemination. – see the Gantt chart in the Detailed Project Description for details. Expertise in team: The team combines experts in renal replacement therapy, pharmaceutical supplies, data linkage, health economics, quality of life following intensive care, statistics, case mix adjustment and long term renal outcomes.

Lay abstract: Patients who are sufficiently ill to need treatment on intensive care units (ICUs) often stop making urine for a few days to a few weeks. This causes a build-up of toxins and water that normally leave the body in urine. To avoid harm patients are treated with a machine that takes over the kidney functions until their own kidneys recover. This treatment is similar to dialysis and is called continuous renal replacement therapy (CRRT). The CRRT machine pumps blood out of the patient, along plastic tubes, through a filter device, and back to the patient. When blood touches the plastic tubes and filter device it tends to clot. This clogs the machine. To prevent clotting an anticoagulant drug called heparin is given. The machine does not remove much of the heparin. Most returns to the patient in their blood. This reduces the ability of all of the patient’s blood to clot, increasing their risk of bleeding. This is particularly dangerous for critically ill patients, who already have a high risk of bleeding. There is another way to prevent clotting in patients receiving CRRT. Citrate solution can be added to the blood as it enters the machine. Citrate mops up calcium, which is needed to make blood clot. When the blood leaves the machine extra calcium is added to the blood to restore its ability to clot. As a result only the blood in the machine doesn't clot. The blood in the patient clots normally so the bleeding risk is reduced. However there are other risks with citrate anticoagulation. Citrate can cause changes in the amount of calcium in circulating blood, and changes in the blood acid-alkali balance. These in turn can cause problems with muscle weakness, heart function, bone health and breathing. As a result, overall citrate could be better or worse than heparin for patients. Citrate anticoagulation is being increasingly used in UK ICUs because it may be more controllable and possibly cheaper. However there have not been any good direct comparisons of heparin and citrate. We don't know if overall citrate or heparin is the best anticoagulant. Some previous changes that have come into intensive care practice without proper testing have turned out to be either of no benefit to patients, or even harmful. A direct comparison study would be difficult and costly. However there is an alternative way to measure the overall benefits or harms from citrate use. Most ICUs make the change to citrate from heparin anticoagulation in a short time. Detailed electronic health records are available for all patients admitted to UK ICUs. We will use these records to examine the effects of a step change from heparin to citrate on patients’ well-being. We will look at patients' survival, degree of sickness and how fast they recover. Using medical records to track the effects of a change in medical practice can be difficult if other treatments may be changing at the same time. There are complex statistical techniques to check to see if this is happening, and we will use them in this study. There is enough information in the databases to measure the cost of the two types of anticoagulation so we can assess the cost/benefit trade-off for both types of anticoagulation. We will be using medical records and will ensure patient confidentiality is safeguarded throughout by adhering to the strict rules governing this sort of research. These techniques could be used to track the effects of other treatments as they are introduced into UK ICUs.

Research activity codes: 6.1 PHARMACEUTICALS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: RENAL AND UROGENITAL