Individual Patient Data Meta-Analysis of Red Blood Cell Transfusion Trials Comparing Liberal versus Restrictive Thresholds

Project Summary
Accumulating evidence from individual clinical trials and conventional trial level meta-analysis suggests that
restrictive transfusion threshold of 7 to 8 g/dL is as safe and effective as the 9 to10 g/dL threshold, based
largely on an analysis of the primary outcome of mortality. However, it is much less clear whether the safety of
restrictive hemoglobin thresholds applies to all patient groups. In this revised application, we focus the aims on
patients with underlying cardiovascular disease given recent results that suggest patients with acute
myocardial infarction could be harmed by restrictive transfusion strategy and that it is especially important to
evaluate restrictive transfusion in patients with pre-existing cardiovascular disease. Individual clinical trials do
not have adequate sample size and conventional trial level meta-analysis lack the specific detail to examine
the effect of transfusion in specific subgroups. An individual patient data meta-analysis (IPDMA) will have the
power and detail to fully explore the effects of transfusion thresholds across clinically important subgroups.
For this IPDMA, randomized clinical trials that assigned patients red blood cell transfusions based on
transfusion threshold (sometimes also referred to as trigger) have been identified from systematic searches of
the literature. The search will be updated and supplemented by direct query of experts in the field prior
finalizing the studies that are included. Data use agreements and letters of support document the
commitments of investigators to provide individual patient data from 89% of the participants included in these
trials. The IPDMA will be combined into a single comprehensive analysis database. The aims of the analysis
are to 1) Primary Aim: To estimate the treatment effect of liberal versus restrictive transfusion thresholds in
patients with cardiovascular disease including those with myocardial infarction, pre-existing cardiovascular
disease and cardiac surgery. We will evaluate clinically important pre-specified risk factors including older age,
sex, heart failure, type of MI, baseline hemoglobin concentration, and others on primary and secondary
outcomes. 2) Secondary Aim: To estimate the treatment effect of liberal versus restrictive transfusion
thresholds in other clinically important pre-specified subgroups with severe chronic illnesses including cancers
and chronic renal diseases, GI bleeding and by age and sex. 3)Exploratory: Use a personalized medicine
approach to create models designed to identify risk factors and combinations of risk factors that modify the
effect of transfusion strategy on the primary and secondary outcomes.
The results will advance our knowledge about the impact of transfusion threshold in cardiovascular and other
clinically important patient groups, where there is concern about the safety of applying a universal `restrictive'
hemoglobin threshold for transfusion. If liberal transfusion is shown to be superior to restrictive transfusion in
patient groups, guidelines will be updated and clinical practice will need to change.

Grant Number: 5R01HL171977-02
NIH Institute/Center: NIH
Principal Investigator: Jeffrey Carson