Publication

• Title: Effect of a Restrictive vs Liberal Blood Transfusion Strategy on Major Cardiovascular Events Among Patients With Acute Myocardial Infarction and Anemia: The REALITY Randomized Clinical Trial
• Acronym: REALITY
• Year: 2021
• Journal published in: JAMA
• Citation: Ducrocq G, Gonzalez-Juanatey JR, Puymirat E, Lemesle G, Cachanado M, Durand-Zaleski I, et al; REALITY Investigators. Effect of a Restrictive vs Liberal Blood Transfusion Strategy on Major Cardiovascular Events Among Patients With Acute Myocardial Infarction and Anemia: The REALITY Randomized Clinical Trial. JAMA. 2021;325(6):552-560.

Context & Rationale

• Background

  Anaemia is common during acute myocardial infarction and is associated with worse clinical outcomes, but causality is difficult to disentangle from comorbidity, bleeding, and illness severity.
  Red blood cell transfusion can increase oxygen delivery yet is biologically and clinically non-neutral (volume load, increased viscosity, immunomodulation, and storage-related effects), and observational associations in MI are highly confounded by indication and bleeding severity.
  Restrictive transfusion thresholds were supported by multiple RCTs in other acute-care contexts, but MI/acute coronary syndrome populations were often excluded, leaving genuine equipoise regarding ischaemia-sensitive patients.
• Research Question/Hypothesis

  In adults with acute myocardial infarction and haemoglobin 7–10 g/dL, is a restrictive transfusion strategy (trigger ≤8 g/dL; target 8–10 g/dL) non-inferior to a liberal strategy (trigger ≤10 g/dL; target >10 g/dL) for 30-day major adverse cardiovascular events?
• Why This Matters

  Transfusion thresholds in MI influence large numbers of patients, blood-product utilisation, and downstream harms/benefits; a defensible restrictive strategy could reduce exposure to transfusion without increasing ischaemic complications.

Design & Methods

• Research Question: Among adults with acute myocardial infarction and haemoglobin 7–10 g/dL, is a restrictive red blood cell transfusion strategy non-inferior to a liberal transfusion strategy for 30-day major adverse cardiovascular events?
• Study Type: Randomised, open-label, multicentre, international (France and Spain), pragmatic non-inferiority trial with blinded clinical end-point adjudication; randomisation stratified by centre; trial registration NCT02648113.
• Population:
  • Setting: 35 hospitals (26 France, 9 Spain); enrolment March 2016 to September 2019; 30-day follow-up completed November 2019.
  • Inclusion: adults (≥18 years) with acute myocardial infarction (STEMI or NSTEMI; Third Universal Definition) and anaemia (haemoglobin 7–10 g/dL) during the index admission; randomised within 10 days of admission.
  • Key exclusions: cardiogenic shock; myocardial infarction after PCI or CABG; major bleeding with haemodynamic shock or requiring urgent transfusion; red blood cell transfusion within the prior 30 days; malignant haematological disease.
• Intervention:
  • Restrictive transfusion strategy: transfuse when haemoglobin ≤8 g/dL.
  • Post-transfusion target haemoglobin: 8–10 g/dL.
• Comparison:
  • Liberal transfusion strategy: transfuse when haemoglobin ≤10 g/dL.
  • Post-transfusion target haemoglobin: >10 g/dL.
• Blinding: Clinicians and patients were not blinded; outcomes were adjudicated by an independent events committee blinded to treatment allocation (PROBE-style design).
• Statistics: Power calculation: 630 patients (315 per group) required for non-inferiority, assuming 11% MACE in the restrictive group and 15% in the liberal group, with a non-inferiority margin RR 1.25, 80% power, and one-sided α 2.5%, allowing for ~5% major protocol violations; non-inferiority required concordant results in as-randomised (modified intention-to-treat) and as-treated analyses.
• Follow-Up Period: 30 days for the primary clinical endpoint.

Key Results

This trial was not stopped early. The protocol specified no interim analyses, and recruitment continued until the planned sample size was achieved.

• Restrictive strategy produced major separation in transfusion exposure (35.7% vs 99.7%) and achieved a substantially lower discharge haemoglobin (9.7 vs 11.1 g/dL; mean difference -1.4; 95% CI -1.6 to -1.2).
• Non-inferiority for 30-day MACE was met in both as-randomised and as-treated analyses (as-randomised RR 0.78; 1-sided 97.5% CI 0.00 to 1.17).
• Clinical event counts were modest; no clear signal of excess acute heart failure, infection, or transfusion reactions was observed, but rare harms cannot be excluded.

Internal Validity

• Randomisation and allocation: Web-based randomisation stratified by centre; allocation concealed until randomisation.
• Dropout/exclusions: 668 patients randomised; 2 excluded from analysis due to consent issues (lost consent form with refusal to re-consent; withdrawal immediately post-randomisation); 666/666 had 30-day follow-up.
• Performance/detection bias: Open-label transfusion assignment could influence co-interventions and clinician-driven components; independent clinical events committee adjudicated outcomes blinded to group.
• Protocol adherence: Liberal arm: 323/324 (99.7%) received RBC; Restrictive arm: 122/342 (35.7%) received RBC; protocol deviations included 13 restrictive-arm patients transfused above the ≤8 g/dL trigger and 1 liberal-arm patient not transfused.
• Baseline characteristics: Groups were broadly comparable (median age 78 vs 76 years; NSTEMI 68.4% vs 71.3%; STEMI 31.6% vs 28.7%); baseline active bleeding was present in 10.5% vs 15.1%.
• Heterogeneity: Subgroup analyses did not identify convincing treatment–subgroup interactions; power for interaction testing was limited.
• Timing: Randomisation occurred a median of 1.6 vs 1.9 days after admission; this may dilute any strategy effect concentrated in the earliest ischaemic window.
• Dose: Clear dose separation was achieved (RBC units 342 vs 758; haemoglobin at discharge 9.7 vs 11.1 g/dL; nadir haemoglobin 8.3 vs 8.8 g/dL).
• Separation of the variable of interest: Restrictive vs liberal: transfused patients 35.7% vs 99.7%; discharge haemoglobin 9.7 (1.3) vs 11.1 (1.4) g/dL; mean difference -1.4 (95% CI -1.6 to -1.2).
• Outcome assessment: Primary endpoint was pre-specified and adjudicated; however, the composite included ischaemia-driven emergency revascularisation (a potentially management-sensitive component).
• Statistical rigour: Prespecified non-inferiority framework with a priori margin and requirement for concordant findings in as-randomised and as-treated populations; analysis aligns with the design.

Conclusion on Internal Validity: Overall, internal validity appears moderate-to-strong, supported by concealed, centre-stratified randomisation, excellent follow-up, and large biological separation, but tempered by open-label care and a composite endpoint containing potentially clinician-influenced elements.

External Validity

• Population representativeness: Enrolled an older MI population (median ~77 years) with both STEMI and NSTEMI, reflecting real-world anaemic MI patients in European cardiology services.
• Important exclusions: Cardiogenic shock, post-PCI/CABG MI, and major haemorrhage with haemodynamic shock/urgent transfusion were excluded; results should not be extrapolated to these high-acuity phenotypes.
• Applicability: Most applicable to haemodynamically stable MI patients with moderate anaemia (haemoglobin 7–10 g/dL) managed in similar resource settings; uncertainty remains for earlier transfusion decisions in the first hours of MI, profound anaemia <7 g/dL, or ongoing uncontrolled bleeding.
• Health-system considerations: The liberal strategy mandated near-universal transfusion at ≤10 g/dL (99.7%), which may exceed contemporary practice in some centres and influence generalisability.

Conclusion on External Validity: Generalisability is moderate for stable, hospitalised MI patients with haemoglobin 7–10 g/dL in high-resource systems, but limited for shock states, massive bleeding, very early MI presentations, and settings where transfusion practice already resembles a restrictive approach.

Strengths & Limitations

• Strengths: Pragmatic multicentre design; centre-stratified randomisation; prespecified non-inferiority framework with concordant as-randomised/as-treated analyses; blinded endpoint adjudication; near-complete follow-up; large separation in transfusion exposure and achieved haemoglobin.
• Limitations: Open-label care; clinically debated non-inferiority margin; randomisation occurred ~2 days after admission; composite endpoint includes potentially management-sensitive components; modest sample size for low-frequency harms and for mortality inference; no maintained screening log (selection mechanisms cannot be fully audited); liberal arm may not reflect usual care in all settings.

Interpretation & Why It Matters

• Clinical signal

  In stable patients with acute MI and haemoglobin 7–10 g/dL, a restrictive transfusion threshold (≤8 g/dL) reduced transfusion exposure substantially and was non-inferior to a liberal threshold (≤10 g/dL) for 30-day MACE in this trial’s prespecified framework.
• Practical implication

  The results support considering a restrictive trigger in many hospitalised MI patients with moderate anaemia, while retaining clinical judgement for those with ongoing ischaemia, haemodynamic instability, or complex bleeding/ischaemia trade-offs.
• Methodological significance

  REALITY addressed confounding intrinsic to transfusion observational research by randomising strategy (not units), and demonstrated that large strategy separation is feasible in routine cardiology care.

Controversies & Subsequent Evidence

• Non-inferiority framing: Although non-inferiority was met (upper 1-sided 97.5% CI 1.17 vs margin 1.25), the confidence interval still allows small-to-moderate harm; the trial was not designed to establish superiority of either strategy.
• Open-label management: A strategy trial in MI unavoidably risks management-mediated effects (e.g., clinician thresholds for revascularisation or discharge), particularly for the ischaemia-driven emergency revascularisation component, despite blinded adjudication.
• Timing of enrolment: Median randomisation ~2 days after admission means results most directly inform in-hospital, post-acute-phase decisions rather than immediate early MI management.
• Bleeding–ischaemia entanglement: A meaningful minority had active bleeding prior to randomisation (10.5% vs 15.1%), complicating interpretability because transfusion can be both a treatment and a marker of bleeding severity.
• Subsequent evidence: Larger, later trials and more recent syntheses (including MI-specific strategy trials and patient-level/meta-analytic work) have broadened the evidence base beyond REALITY; updated guidance from haematology/critical care and cardiology societies should be consulted for current recommendations (see Further Reading).

Summary

• REALITY was a multicentre, open-label, centre-stratified non-inferiority RCT of transfusion thresholds in anaemic acute MI (haemoglobin 7–10 g/dL).
• Restrictive strategy (≤8 g/dL; target 8–10) reduced transfusion exposure (35.7% transfused) compared with liberal strategy (≤10 g/dL; target >10; 99.7% transfused).
• Primary 30-day MACE was 11.1% (restrictive) vs 14.2% (liberal); RR 0.78 with non-inferiority met (upper 1-sided 97.5% CI 1.17; margin 1.25).
• Mortality and ischaemic event components were numerically similar and infrequent; severe transfusion reactions were rare.
• Key interpretive constraints include open-label management effects, composite endpoint structure, and randomisation occurring a median ~2 days after admission.

Further Reading

Other Trials

• 2023Myocardial Ischemia and Transfusion (MINT) Trial Investigators. Restrictive or Liberal Transfusion Strategy in Myocardial Infarction and Anemia. N Engl J Med. 2023;389(26):2446-2456.
• 2011Cooper HA, Rao SV, Greenberg MD, et al. Conservative versus liberal red blood cell transfusion in acute myocardial infarction (the CRIT Randomized Pilot Study). Am J Cardiol. 2011;108(8):1108-1111.
• 2013Carson JL, Brooks MM, Abbott JD, et al. Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease. Am Heart J. 2013;165(6):964-971.e1.
• 2015Murphy GJ, Pike K, Rogers CA, et al. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med. 2015;372(11):997-1008.
• 2018Mazer CD, Whitlock RP, Fergusson DA, et al. Six-month outcomes after restrictive or liberal transfusion for cardiac surgery. N Engl J Med. 2018;379(13):1224-1233.

Systematic Review & Meta Analysis

• 2024Restrictive versus Liberal Transfusion in Myocardial Infarction — A Patient-Level Meta-Analysis. NEJM Evid. Published online 2024 Dec 23.
• 2016Docherty AB, O'Donnell R, Brunskill S, Trivella M, Doree C, Stanworth S. Effect of restrictive versus liberal transfusion strategies on outcomes in patients with cardiovascular disease: systematic review and meta-analysis. BMJ. 2016;352:i1351.
• 2013Chatterjee S, Wetterslev J, Sharma A, Lichstein E, Mukherjee D. Association of blood transfusion with increased mortality in myocardial infarction: a meta-analysis and diversity-adjusted study sequential analysis. JAMA Intern Med. 2013;173(2):132-139.
• 2021Carson JL, Stanworth SJ, Roubinian N, Fergusson DA, Triulzi DJ, Doree C, Hébert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev. 2021;CD002042.

Observational Studies

• 2001Wu WC, Rathore SS, Wang Y, Radford MJ, Krumholz HM. Blood transfusion in elderly patients with acute myocardial infarction. N Engl J Med. 2001;345(17):1230-1236.
• 2004Rao SV, Jollis JG, Harrington RA, Granger CB, Newby LK, Armstrong PW, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA. 2004;292(13):1555-1562.
• 2005Sabatine MS, Morrow DA, Giugliano RP, Burton PBJ, Murphy SA, McCabe CH, Gibson CM, Braunwald E. Association of hemoglobin levels with clinical outcomes in acute coronary syndromes. Circulation. 2005;111(16):2042-2049.
• 2008Alexander KP, Chen AY, Wang TY, Rao SV, Newby LK, LaPointe NMA, et al. Transfusion practice and outcomes in non–ST-segment elevation acute coronary syndromes. Am Heart J. 2008;155(6):1047-1053.
• 2015Ducrocq G, Puymirat E, Steg PG, et al. Blood transfusion, bleeding, and mortality in patients with ST-segment elevation myocardial infarction: the FAST-MI registry. Am Heart J. 2015;170(4):631-640.

Guidelines

• 2025Red Cell Transfusion in Acute Myocardial Infarction: AABB International Clinical Practice Guidelines. Ann Intern Med. Published online 2025 Aug 19.
• 2023Red blood cell transfusion: 2023 AABB international guidelines. JAMA. 2023;330(19):1892-1902.
• 2025Clinical practice guideline on red blood cell transfusion in critically ill adults. Chest. 2025;167(2):477-489.
• 20252025 ACC/AHA/ACEP/NAEMSP/SCAI guideline for the management of patients with acute coronary syndromes. J Am Coll Cardiol. 2025;86(6):e1-e128.
• 20232023 ESC Guidelines for the management of acute coronary syndromes. Eur Heart J. 2023;44(38):3720-3826.

Notes

• When applying REALITY in practice, the core decision is not “transfuse or not” but “which haemoglobin threshold strategy best balances ischaemic risk against bleeding risk and transfusion-related harms” in the individual patient.
• For contemporary practice, integrate REALITY with later MI-specific trials and updated guidelines (listed above), especially where local transfusion practice differs from the liberal trigger used in REALITY.

Overall Takeaway

REALITY provided pivotal randomised evidence that, in haemodynamically stable patients hospitalised with acute myocardial infarction and moderate anaemia, a restrictive transfusion strategy (≤8 g/dL) can markedly reduce transfusion exposure while remaining non-inferior to a liberal strategy (≤10 g/dL) for 30-day major cardiovascular events. Its pragmatic design and clear haemoglobin separation make it influential, while open-label care and the non-inferiority framework mean subsequent larger trials and updated guidance remain essential for defining best practice in MI.

Bibliography