Clinical trials evaluating red blood cell transfusion thresholds: An updated systematic review and with additional focus on patients with cardiovascular disease

doi:10.1016/j.ahj.2018.04.007

American Heart Journal

Volume 200, June 2018, Pages 96-101

https://doi.org/10.1016/j.ahj.2018.04.007 Get rights and content

Abstract

Background

Several new trials evaluating transfusion strategies in patients with cardiovascular disease have recently been published, increasing the number of enrolled patients by over 30%. The objective was to evaluate transfusion thresholds in patients with cardiovascular disease.

Methods

We conducted an updated systematic review of randomized trials that compared patients assigned to maintain a lower (restrictive transfusion strategy) or higher (liberal transfusion strategy) hemoglobin concentration. We focused on new trial data in patients with cardiovascular disease. The primary outcome was 30-day mortality. Specific subgroups were patients undergoing cardiac surgery and with acute myocardial infarction.

Results

A total of 37 trials that enrolled 19,049 patients were appraised. In cardiac surgery, mortality at 30 days was comparable between groups (risk ratio 0.99; 95% confidence interval 0.74-1.33). In 2 small trials (n = 154) in patients with myocardial infarction, the point estimate for the mortality risk ratio was 3.88 (95% CI, 0.83-18.13) favoring the liberal strategy. Overall, from 26 trials enrolling 15,681 patients, 30-day mortality was not different between restrictive and liberal transfusion strategies (risk ratio 1.0, 95% CI, 0.86-1.16). Overall and in the cardiovascular disease subgroup, there were no significant differences observed across a range of secondary outcomes.

Conclusions

New trials in patients undergoing cardiac surgery establish that a restrictive transfusion strategy of 7 to 8 g/dL is safe and decreased red cell use by 24%. Further research is needed to define the optimal transfusion threshold in patients with acute myocardial infarction.

Section snippets

Selection of trials

We performed a systematic review of the literature to identify randomized clinical trials that compared patients assigned to 2 different hemoglobin- or hematocrit-defined transfusion thresholds. At the trial level, the group assigned to receive transfusion at higher hemoglobin level is referred to as liberal transfusion, and those assigned to receive transfusion at lower hemoglobin level are referred to as restrictive transfusion. We were especially interested in reports of subgroups of

Results of the search

We conducted searches from May 27, 2016, through November 13, 2017, which identified 2,754 records once duplicates had been removed, which were reduced to 1,490 records once previously screened references were removed. From these 1,490 records, we identified 19 potential studies for inclusion, of which 13 were excluded as either non–randomized controlled trials(3 studies), review articles (4 studies), trials of infants (2 studies), trials with the wrong comparator or no clinical outcomes (3

Discussion

Our updated systematic review included an additional 5 trials in over 6,000 patients, yielding an analysis of 37 trials in over 19,000 patients, 8,898 with cardiovascular disease. Among the 8,645 patients undergoing cardiac surgery, the restrictive transfusion strategy was shown to safe. On average, a restrictive transfusion strategy decreased exposure to red cells by more than 30% while having no apparent adverse effects on clinically important outcomes such as survival and important

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Indeed, recent studies have shown superiority of hypoxic storage in 2-arm cross-sectional studies on posttransfusion recovery in healthy autologous volunteers.41 It must be noted that numerous clinical trials have failed to detect an effect of storage duration on clinical outcomes,10,11,12,13 but these studies have typically recruited people with stable anemia for whom a prompt restoration of oxygen release is not critical,49 rather than patients requiring massive transfusion to restore tissue oxygenation (ie, cohorts for whom impaired gas exchange kinetics is most relevant). Moreover, these trials have typically correlated clinical outcomes with storage duration, which is not the most appropriate choice of independent variable because of its complex relationship with RBC quality.
Stored red blood cells (RBCs) incur biochemical and morphological changes, collectively termed the storage lesion. Functionally, the storage lesion manifests as slower oxygen unloading from RBCs, which may compromise the efficacy of transfusions where the clinical imperative is to rapidly boost oxygen delivery to tissues. Recent analysis of large real-world data linked longer storage with increased recipient mortality. Biochemical rejuvenation with a formulation of adenosine, inosine, and pyruvate can restore gas-handling properties, but its implementation is impractical for most clinical scenarios. We tested whether storage under hypoxia, previously shown to slow biochemical degradation, also preserves gas-handling properties of RBCs. A microfluidic chamber, designed to rapidly switch between oxygenated and anoxic superfusates, was used for single-cell oxygen saturation imaging on samples stored for up to 49 days. Aliquots were also analyzed flow cytometrically for side-scatter (a proposed proxy of O₂ unloading kinetics), metabolomics, lipidomics, and redox proteomics. For benchmarking, units were biochemically rejuvenated at 4 weeks of standard storage. Hypoxic storage hastened O₂ unloading in units stored to 35 days, an effect that correlated with side-scatter but was not linked to posttranslational modifications of hemoglobin. Although hypoxic storage and rejuvenation produced distinct biochemical changes, a subset of metabolites including pyruvate, sedoheptulose 1-phosphate, and 2/3 phospho-d-glycerate, was a common signature that correlated with changes in O₂ unloading. Correlations between gas handling and lipidomic changes were modest. Thus, hypoxic storage of RBCs preserves key metabolic pathways and O₂ exchange properties, thereby improving the functional quality of blood products and potentially influencing transfusion outcomes.

View all citing articles on Scopus

: John K. French, MB, PhD, served as guest editor for this article.

: The authors have no industry conflicts to declare.

View full text

Clinical InvestigationClinical trials evaluating red blood cell transfusion thresholds: An updated systematic review and with additional focus on patients with cardiovascular disease

Abstract

Background

Methods

Results

Conclusions

Section snippets

Selection of trials

Results of the search

Discussion

Ann Thorac Surg

Control Clin Trials

Lancet

J Cardiothorac Vasc Anesth

J Thorac Cardiovasc Surg

Am J Cardiol

Am J Surg

Arch Gerontol Geriatr

J Arthroplast

Injury

Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion

Cochrane Database Syst Rev

Clinical practice guidelines from the AABB: red blood cell transfusion thresholds and storage

JAMA

Liberal or restrictive transfusion after cardiac surgery

N Engl J Med

Effect of restrictive versus liberal transfusion strategies on outcomes in patients with cardiovascular disease in a non-cardiac surgery setting: systematic review and meta-analysis

BMJ

Red blood cell transfusion triggers in acute leukemia: a randomized pilot study

Transfusion (Paris)

Liberal versus restrictive transfusion strategy in critically ill oncologic patients: the transfusion requirements in critically ill oncologic patients randomized controlled trial

Crit Care Med

Red-cell transfusion threshold for cardiac surgery

N Engl J Med

Transfusion requirement in burn care evaluation (TRIBE): a multicenter randomized prospective trial of blood transfusion in major burn injury

Ann Surg

Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]

The Cochrane Collaboration's tool for assessing risk of bias in randomised trials

BMJ

Review Manager 5 [computer program]

Transfusion strategies for acute upper gastrointestinal bleeding

N Engl J Med

A multicenter pilot-randomized controlled trial of the feasibility of an augmented red blood cell transfusion strategy for patients treated with induction chemotherapy for acute leukemia or stem cell transplantation

Transfusion (Paris)

Clinical Investigation
Clinical trials evaluating red blood cell transfusion thresholds: An updated systematic review and with additional focus on patients with cardiovascular disease