Transfusion thresholds for guiding red blood cell transfusion
Jeffrey L Carson, Simon J Stanworth, Jane A Dennis, Marialena Trivella, Nareg Roubinian, Dean A Fergusson, Darrell Triulzi, Carolyn Dorée, Paul C Hébert, Jeffrey L Carson, Simon J Stanworth, Jane A Dennis, Marialena Trivella, Nareg Roubinian, Dean A Fergusson, Darrell Triulzi, Carolyn Dorée, Paul C Hébert
Abstract
Background: The optimal haemoglobin threshold for use of red blood cell (RBC) transfusions in anaemic patients remains an active field of research. Blood is a scarce resource, and in some countries, transfusions are less safe than in others because of inadequate testing for viral pathogens. If a liberal transfusion policy does not improve clinical outcomes, or if it is equivalent, then adopting a more restrictive approach could be recognised as the standard of care. OBJECTIVES: The aim of this review update was to compare 30-day mortality and other clinical outcomes for participants randomised to restrictive versus liberal red blood cell (RBC) transfusion thresholds (triggers) for all clinical conditions. The restrictive transfusion threshold uses a lower haemoglobin concentration as a threshold for transfusion (most commonly, 7.0 g/dL to 8.0 g/dL), and the liberal transfusion threshold uses a higher haemoglobin concentration as a threshold for transfusion (most commonly, 9.0 g/dL to 10.0 g/dL).
Search methods: We identified trials through updated searches: CENTRAL (2020, Issue 11), MEDLINE (1946 to November 2020), Embase (1974 to November 2020), Transfusion Evidence Library (1950 to November 2020), Web of Science Conference Proceedings Citation Index (1990 to November 2020), and trial registries (November 2020). We checked the reference lists of other published reviews and relevant papers to identify additional trials. We were aware of one trial identified in earlier searching that was in the process of being published (in February 2021), and we were able to include it before this review was finalised.
Selection criteria: We included randomised trials of surgical or medical participants that recruited adults or children, or both. We excluded studies that focused on neonates. Eligible trials assigned intervention groups on the basis of different transfusion schedules or thresholds or 'triggers'. These thresholds would be defined by a haemoglobin (Hb) or haematocrit (Hct) concentration below which an RBC transfusion would be administered; the haemoglobin concentration remains the most commonly applied marker of the need for RBC transfusion in clinical practice. We included trials in which investigators had allocated participants to higher thresholds or more liberal transfusion strategies compared to more restrictive ones, which might include no transfusion. As in previous versions of this review, we did not exclude unregistered trials published after 2010 (as per the policy of the Cochrane Injuries Group, 2015), however, we did conduct analyses to consider the differential impact of results of trials for which prospective registration could not be confirmed. DATA COLLECTION AND ANALYSIS: We identified trials for inclusion and extracted data using Cochrane methods. We pooled risk ratios of clinical outcomes across trials using a random-effects model. Two review authors independently extracted data and assessed risk of bias. We conducted predefined analyses by clinical subgroups. We defined participants randomly allocated to the lower transfusion threshold as being in the 'restrictive transfusion' group and those randomly allocated to the higher transfusion threshold as being in the 'liberal transfusion' group.
Main results: A total of 48 trials, involving data from 21,433 participants (at baseline), across a range of clinical contexts (e.g. orthopaedic, cardiac, or vascular surgery; critical care; acute blood loss (including gastrointestinal bleeding); acute coronary syndrome; cancer; leukaemia; haematological malignancies), met the eligibility criteria. The haemoglobin concentration used to define the restrictive transfusion group in most trials (36) was between 7.0 g/dL and 8.0 g/dL. Most trials included only adults; three trials focused on children. The included studies were generally at low risk of bias for key domains including allocation concealment and incomplete outcome data. Restrictive transfusion strategies reduced the risk of receiving at least one RBC transfusion by 41% across a broad range of clinical contexts (risk ratio (RR) 0.59, 95% confidence interval (CI) 0.53 to 0.66; 42 studies, 20,057 participants; high-quality evidence), with a large amount of heterogeneity between trials (I² = 96%). Overall, restrictive transfusion strategies did not increase or decrease the risk of 30-day mortality compared with liberal transfusion strategies (RR 0.99, 95% CI 0.86 to 1.15; 31 studies, 16,729 participants; I² = 30%; moderate-quality evidence) or any of the other outcomes assessed (i.e. cardiac events (low-quality evidence), myocardial infarction, stroke, thromboembolism (all high-quality evidence)). High-quality evidence shows that the liberal transfusion threshold did not affect the risk of infection (pneumonia, wound infection, or bacteraemia). Transfusion-specific reactions are uncommon and were inconsistently reported within trials. We noted less certainty in the strength of evidence to support the safety of restrictive transfusion thresholds for the following predefined clinical subgroups: myocardial infarction, vascular surgery, haematological malignancies, and chronic bone-marrow disorders.
Authors' conclusions: Transfusion at a restrictive haemoglobin concentration decreased the proportion of people exposed to RBC transfusion by 41% across a broad range of clinical contexts. Across all trials, no evidence suggests that a restrictive transfusion strategy impacted 30-day mortality, mortality at other time points, or morbidity (i.e. cardiac events, myocardial infarction, stroke, pneumonia, thromboembolism, infection) compared with a liberal transfusion strategy. Despite including 17 more randomised trials (and 8846 participants), data remain insufficient to inform the safety of transfusion policies in important and selected clinical contexts, such as myocardial infarction, chronic cardiovascular disease, neurological injury or traumatic brain injury, stroke, thrombocytopenia, and cancer or haematological malignancies, including chronic bone marrow failure. Further work is needed to improve our understanding of outcomes other than mortality. Most trials compared only two separate thresholds for haemoglobin concentration, which may not identify the actual optimal threshold for transfusion in a particular patient. Haemoglobin concentration may not be the most informative marker of the need for transfusion in individual patients with different degrees of physiological adaptation to anaemia. Notwithstanding these issues, overall findings provide good evidence that transfusions with allogeneic RBCs can be avoided in most patients with haemoglobin thresholds between the range of 7.0 g/dL and 8.0 g/dL. Some patient subgroups might benefit from RBCs to maintain higher haemoglobin concentrations; research efforts should focus on these clinical contexts.
Trial registration: ClinicalTrials.gov NCT01648946 NCT00071032 NCT01167582 NCT00126334 NCT01502215 NCT02086773 NCT02648113 NCT00162617 NCT03407573 NCT02203292 NCT01102010 NCT01021631 NCT01485315 NCT00651573 NCT02042898 NCT02465125 NCT00906295 NCT01079247 NCT00335023 NCT00470444 NCT01237639 NCT00414713 NCT00944112 NCT01116479 NCT01393496 NCT03419780 NCT02099669 NCT03369210 NCT02619136 NCT02981407 NCT03229941 NCT02483351 NCT03309579 NCT03871244 NCT04506125 NCT04754022.
Conflict of interest statement
We have considered disclosures relevant to this review.
Jeffrey Carson reports being the chief investigator on three trials included in this review (Carson 1998; Carson 2011 (FOCUS); Carson 2013). He has received multiple grants supporting his institution from the US National Institutes of Health. He has been involved with guideline development for red cell transfusions in the Association for the Advancement of Blood & Biotherapies (AABB). He has received a grant from the US National Institutes of Health to evaluate transfusion thresholds in patients with acute myocardial infarction in an ongoing trial (MINT ‐ NCT02981407).
Carolyn Dorée: nothing to declare.
Dean Fergusson reports being an author on three completed trials included within this review (Hébert 1999; Mazer 2017 (TRICS III); Shehata 2012). He was a Co‐Principal Investigator on the TRICSIII trial (Mazer 2017); he is a member of the Steering Committee for the ongoing MINT trial (NCT02981407).
Paul Hébert reports being an author on three completed trials identified in this review (Hébert 1995; Hébert 1999; Lacroix 2007 (TRIPICU). He is the lead investigator on the study NCT02619136, the Canadian pilot study for MINT (NCT02981407, for which he is a member of the Executive Committee); he has published six non‐Cochrane reviews in this area. He serves on a guideline panel for the American College of Chest Physicians (ACCP) and has written several editorials for leading journals concerning transfusion triggers.
Nareg Roubinian: nothing to declare.
Simon Stanworth reports being the chief investigator on one trial included in this review (Stanworth 2020); a coauthor on another (Gillies 2020 (RESULT‐NOF)); and is a co‐investigator on four ongoing trials (ISRCTN17438123; ACTRN12619001053112; NCT03871244; Morton 2020). He has received funding for four RBC transfusion trials, including three in patients with haematological malignancy. He has published three non‐Cochrane reviews in this area.
Darrell Triulzi is a member of the Steering Committee for the ongoing MINT trial (NCT02981407) and a member of the scientific advisory board for Fresenius‐Kabi.
Jane Dennis was employed by Cochrane Injuries during her involvement in development of the review.
Marialena Trivella was employed by Cochrane Injuries during her involvement in development of the review.
Data extraction for all trials was checked by NR. Final decisions on risk of bias assessments were made by review authors not involved in trials as researchers.
Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Source: PubMed