When should patients receive a blood transfusion?
The haemoglobin level at which it is recommended that patients with a chronic cardiac disease should receive a blood transfusion has been gradually lowered over several years. Professor Pär Ingemar Johansson is investigating whether some patients would have better survival prospects if they received blood at a higher haemoglobin trigger than currently recommended.
Blood transfusion is an iconic medical intervention and is a prerequisite for most advanced therapeutic capabilities, with more than 110 million red blood cell (RBC) units transfused annually. Consequently, evidence supporting strategies for RBC transfusions in various clinical settings are pivotal. Currently, the transfusion guidelines are based on patients’ hemoglobin (HGB) concentrations where a restrictive RBC transfusion threshold (trigger) of 7.0 g/dL to 8.0 g/dL is recommended for most patient groups, including patients undergoing cardiac surgery. The guidelines are grounded in systematic reviews and meta-analyses of several randomized controlled trials (RCTs) finding no significant differences in adverse patient outcomes under a restrictive versus a liberal (HGB 9.0 g/dL to 10.0 g/dL) transfusion strategy. There is still, however, insufficient evidence to assess the safety of a restrictive transfusion strategy in patients with cardiovascular disease. In addition, Prof. Johansson questions the overarching assumption of these classical randomised trials, namely that all patients with similar HGB level have similar need for oxygen transporting capacity and, thereby, need for blood transfusion. The current trial designs include far too few patients to be able identify small, but clinically relevant, subpopulations of patients who actually would benefit from a liberal transfusion trigger.
To overcome these limitations, and provide evidence-based transfusion triggers that also take into account patient heterogeneity in the need for oxygen transporting capacity, Prof. Johansson is introducing causal inference methodologies using real-world data in a new Independent Research Fund Denmark (DFF)backed project. This approach was previously used by Prof. Johansson to investigate the potential harmful effects of the RBC storage
lesions which develop when RBC units are stored for many weeks in Blood Banks on transfusion recipient mortality. A cohort of 89.000 patients transfused with 340.000 RBC units were used to emulate randomized trials testing the comparative effect of transfusing exclusively older vs fresher RBC units on death. Prof. Johansson found that transfusion of RBC units stored for one and two weeks were associated with > 10 percent higher survival rates compared to being transfused exclusively with ‘older’ RBC units, translating into many thousands of deaths annually. These results contradict the findings of the randomized clinical trials conducted to date and also highlight their limitations in terms of identifying small but clinically important differences in patient outcome.
Chronic heart disease
As part of his role in the DFF-backed project, Professor Johansson is now looking at the treatment of patients with chronic heart disease. Similarly to the storage problem, there have been a number of randomized control trials involving more than 21,000 patients on this topic looking at different transfusion triggers – the haemoglobin level at which a physician decides that the patient needs a transfusion of red blood cells. “These trials have been negative –meaning that no difference has been found between the restrictive and the liberal
triggers in any patient profiles. The problem is that these clinical trials have been too small to identify any potentially clinically relevant differences between the triggers in subpopulations of the patients,” outlines Professor Johansson. This is a topic that he plans to probe further in the project.
“Haemoglobin triggers have been lowered for many years, based on these randomized controlled trials, showing no difference between a high and a low haemoglobin level,” he continues. “I don’t think that that is correct for all patients because there is a high degree of heterogeneity between individual patients, likely also in the need for oxygen transporting capacity.”
A larger clinical trial with more data could allow researchers to dig deeper and uncover some of this heterogeneity, a topic central to the DFF-backed project. The hypothesis here is that there is a sub-population of patients with cardiac diseases that would have better survival prospects if they received blood at a higher trigger than the current guidelines recommend. “The reason for focusing on patients with cardiac disease is that anaemia, in these patients, has long been recognised to be an independent predictor of major adverse cardiovascular events including death. This hypothesis is what I would like to test, using the causal inference approach,” explains Professor Johansson.
Uniquely, the causal inference methodology allows researchers to use real-world observational data, enabling the analysis of a much larger group of transfused patients with anaemia and cardiac disease than is practically possible using the classical randomised controlled trial design. Another unique feature of the causal inference methodology is that several randomised clinical trials can be emulated in parallel using the same data set.
“Hereby, I can take the observational dataset
“Haemoglobin triggers have been lowered for many years, based on randomized controlled trials, showing no difference between a high and a low haemoglobin level. I don’t think that that is necessarily correct for all patients however, because there is a high degree of heterogeneity between individual patients.”
from Copenhagen, where we have around 50,000 anaemic cardiac patients, and test if there are subpopulations of these patients that benefit from a particular trigger different to that recommended under the current guidelines,” continues Professor Johansson.
“We are using already existing data from Danish health registries, electronic patient records (EPIC) and the Blood Bank transfusion system to conduct this study.”
This provides researchers with a wealth of real-world data from which Professor Johansson and his colleagues can look to build a deeper picture. An individual patient with a certain severity of cardiac disease will not necessarily respond to a transfusion in the same way as another with a similar health status, while some patients may have other co-morbidities, another topic of interest in the project. “Patients with other co-morbidities
EMULATED RANDOMIZED TRIALS USING REALWORLD DATA
Emulated Randomized Trials using Realworld data – Optimal and Personalized Red Blood Cell Transfusion Strategies for Hospitalized Chronic Patients
Project Objectives
The project tests if a sub-population of patients with cardiac diseases would have better survival prospects if they received blood at a higher trigger than the current guidelines recommend. An emulated clinical trial in anaemic cardiac patients is done using the causal inference approach, that allows to use real-world observational data.
Project Funding
Funded by Independent Research Fund Denmark (DFF) 1,930,032 DKR
Project Partners
• Prof. Per I Johansson, Head of Transfusion Medicine in the Capital Region Blood Bank at Rigshospitalet (Project Leader)
• Prof. Christian Hassager, Dept. of Cardiology at Rigshospitalet
• Professor in Biostatistics Per Kragh Andersen, Dept. of Public Health, University of Copenhagen
Contact Details
Project Coordinator, Pär Ingemar Johansson
Rigshospitalet, Department of Clinical Immunology, Blegdamsvej 9, 2100 Copenhagen, Denmark
T: +45 35 45 20 30
E: per.johansson@regionh.dk
W: https://gchsp.dk/en/cag/cag-center-forendotheliomics/
W: https://www.rigshospitalet.dk/english/ Pages/default.aspx
Pär Ingemar Johansson is Professor in Clinical Immunology and Transfusion Medicine at the University of Copenhagen in Denmark. He is a founding member of the International Trauma Research Network and serves as an advisory board expert at the European Medicines Agency.
alongside chronic cardiac disease may have a need for a higher transfusion trigger. That is one of the things that we hope to find out in this project,” continues Professor Johansson.
Current guidelines
The current guidelines are that patients with a chronic cardiac disease should receive a blood transfusion when their haemoglobin level is somewhere around 7-8 grammes per litre, now Professor Johansson plans to explore the impact of different triggers. The trial has been designed, all the data has been secured, and Professor Johansson is now looking to move forward with the research. “We are currently finalising the programming of the algorithms
is a particular sub-group of patients who would benefit from receiving transfusions at a higher haemoglobin trigger, then it would also be important to identify them so that clinical staff could respond effectively, another topic that Professor Johansson plans to address. “We hope to identify biomarkers that pinpoint these patients, so that they can then receive a transfusion that is more precisely tailored to their own needs than they do today,” he outlines. This could help dramatically improve recovery and thereby reduce healthcare costs, which is a prominent issue across Europe. “It’s mainly older people who receive transfusions. If they are transfused at the right trigger then you
“Improving survival rates following blood transfusions, even by relatively small amounts, translates into a lot of financial savings on an annual basis, at the country level.”
that will be run, and we expect to start running the analysis early in 2025,” he says. The aim is not necessarily to find evidence supporting the underlying hypothesis behind the research, but rather to provide a greater degree of clarity on the effectiveness of transfusions at different triggers. “If our results show that the current transfusion triggers are the best for all patients then that would be an incredibly important result. That would support the existing guidelines, which would be extremely positive,” says Professor Johansson. “Equally, if we find that there are sub-groups of patients who would benefit from a different trigger, then I think that would also be very important.”
This could eventually become part of new treatment guidelines in future, saving patient lives and potentially helping to reduce the cost of healthcare. If researchers find there
would reduce hospital costs enormously,” stresses Professor Johansson. “Improving survival rates following blood transfusions, even by relatively small amounts, translates into a lot of financial savings on an annual basis, at the country level.”
It can be difficult to challenge the existing transfusion protocols, but clear evidence of benefits to patients would provide a powerful argument for a new approach. These findings could be translated into practice, and Professor Johansson is keen to share his findings more widely. “I am the head of the transfusion service in the Capital Region of Denmark, which soon will include the Eastern part of Denmark,” he says. “We have held discussions, and plan to inform the Danish health authority and the Danish medicines agency about this trial, and we will share our findings when we have results.”