Effect of a Restrictive vs Liberal Blood Transfusion Strategy on Major Cardiovascular Events Among Patients With Acute Myocardial Infarction and Anaemia

Ducrocq G. JAMA 2021:325(6):552-560 doi:10.1001/jama.2021.0135

Clinical Question

• In patients with acute myocardial infarction and anaemia is a restrictive, compared with a liberal transfusion strategy, non-inferior with respect to major adverse cardiovascular outcomes at 30 days?

Background

• Anaemia is associated with major adverse cardiovascular events in patients with acute coronary syndrome
• It is not known if transfusing patients with anaemia and AMI ameliorates this risk and often patients with acute coronary syndromes are excluded from trials comparing liberal and restrictive transfusion strategies
• Previous trials have been very small with poor methodology
• There is wide variation in practice
• There is a growing body of evidence demonstrating harm from transfusion in several patient groups
• TRICS-III, a trial in patients undergoing cardiac surgery with moderate-to-high risk of death showed a restrictive strategy of transfusion was non-inferior to a liberal strategy with respect to a composite outcome
• The TRISS trial investigated liberal versus restrictive transfusion in patients with septic shock and demonstrated no significant difference in 90 day mortality
• Patients with acute upper gastrointestinal bleeding had lower mortality with a restrictive strategy (Villanueva, NEJM 2013;368(1)11-21)
• The TRICC trial assessed a liberal versus restrictive strategy in 838 ICU patients expected to stay >24 hours and showed no mortality difference. However, patients who were admitted after cardiac surgery were excluded from this study
• Transfusion may cause platelet activation and increase thrombotic risk by causing platelet activation, aggregation and vasoconstriction
• A storage defect in blood causing depletion in nitric oxide and 2,3 DPG may mean that the desired effect of improving O2 delivery may not be achieved with transfused blood

Design

• Randomised controlled trial
• 1:1 randomisation to liberal or restrictive transfusion
• Allocation concealment achieved by a web-based randomisation method with block randomisation and variable size blocks, stratified by centre
• Initially the design had the restrictive group being transfused if Hb<7g/dL but this was changed to Hb<8g/dL to improve investigator adherence to the protocol
• The patient could be randomised at any time from admission up to 30 days into their hospital stay
• Patients consented to involvement in the trial prior to randomisation
• Unblinded, although the outcomes were objective
• The outcome was a composite MACE (major acute cardiovascular event) at 30 days. The outcomes of interest were all-cause death, recurrent myocardial infarction, emergency revascularisation prompted by ischaemia, stroke.
• The analysis was as-randomised and as-treated (in non-inferiority trials this is done instead of intention to treat analysis)
• The power calculation was based on observational data from the French registry of AMI which demonstrated MACE at 30 days to be 11% in a restrictive transfusion group and 15% in a liberal transfusion group
• 630 patients were deemed necessary to achieve an 80% power to demonstrate non-inferiority in the restrictive group (assuming 5% would have protocol variation)

Setting

• France (26 centres) and Spain (9 centres)
• Enrolment occurred between March 2016 to September 2019

Population

• Inclusion: AMI (with or without ST elevation, symptoms in the last 48 hours and elevated biomarkers of myocardial injury) AND Haemoglobin between 7 and 10 g/dL during the admission. Age > 18 years
• Exclusion:
  • Shock (SBP <90mmHg) with clinical signs of low cardiac output
  • AMI after CAGs or PCI
  • Life-threatening bleeding
  • Blood transfusion in last 30 days
  • Malignant haematologic disease
• Participant numbers: 668 patients were randomised
• Baseline characteristics: patients were well-matched at baseline
  • The median age was 77 years
  • 57.8% were male
  • 70% had NSTEMI, 30% had STEMI

Intervention

• Liberal transfusion (n=324)
  • transfusion for all patients with Hb < 10g/dL with a target post-transfusion Hb > 11g/d

Control

• Restrictive transfusion (n=342)
  • transfusion if Hb < 8g/dL with a target 8-10g/dL. Originally the threshold was 7g/dL but was changed to maximise investigator adherence to the protocol, before the first patient was included

Management common to both groups

• Leukodepleted red cells were used
• Transfusion could be administered at any time if there was a suspected massive bleeding event, before waiting for a haemoglobin result

Outcome

• Primary outcome: 30 day MACE (a composite score of major adverse cardiovascular events – all-cause death, stroke, recurrent MI, emergency revascularisation prompted by ischaemia)
  • At day 30, MACE had occurred in 14% in liberal group and 11% in restrictive group (45 vs 36 patients, between group difference -3% 95% CI -8.4% to 2.4%). This met the pre-specified non-inferiority criterion
  • Primary outcome analysis was of the as-treated population
  • As-randomised population had very similar results
• Secondary outcomes: The components of the Day 30 MACE were reported as secondary outcomes. Due to high risk of Type 1 error, no formal statistical comparisons are made
• Comparing Liberal Transfusion vs. Restrictive Transfusion
  • Death 25 vs 19 people (7.7% vs 5.6%)
  • Nonfatal recurrent myocardial infarction 10 vs 7 people (3.1% vs 2.1%)
  • Emergency revascularisation 6 vs 5 people (1.9% vs 1.5%)
  • Non-fatal ischemic stroke 2 vs 2 (0.6% vs 0.6%)
• Patients who received >=1 unit blood transfusion
  • greater in liberal group (99.7% vs 35.7%)
• Evidence of Harm: patients in the liberal group were more likely to
  • have acute lung injury
    • 7 vs 1 people (2.2% vs 0.3%)
  • develop infection (documented bacteremia or bacterial infection)
    • 5 vs 0 (1.5% vs 0%)

Authors’ Conclusions

• In patients with AMI and anaemia, a restrictive transfusion strategy compared with a liberal transfusion strategy was non-inferior in regards to 30 day MACE outcomes

Strengths

• An important study in a key population where a paucity of evidence exists
• Clinically important outcomes
• Patients were analysed as randomised AND as treated
• Follow-up was near complete (2 patients withdrew consent)
• Allocation concealment

Weaknesses

• Physicians were unblinded to the therapy but the outcome measures were objective so bias to outcome likely low
• The margin for non-inferiority was 25% so although this pre-specified margin was reached, this trial does not completely eliminate that a restrictive strategy is non-inferior. This minimal clinically important difference is arbitrarily agreed to in non-inferiority trials
• Statistical significance for superiority was not met so a larger trial would need to be conducted to demonstrate superiority. This trial could be used to estimate sample size in a future larger trial
• Outcome was assessed at Day 30. This is relatively short and could miss key events. A longer period for follow-up would add to the validity

The Bottom Line

• Although not definitive this trial suggests that a restrictive transfusion strategy in patients with AMI and anaemia is safe with a non-statistically significant trend towards superiority
• A larger trial would be needed to definitely guide management of anaemia in this patient population

External Links

• The REALITY trial

Metadata

Summary author:Celia Bradford @celiabradford
Summary date: 25/1/21
Peer-review editor: @davidslessor

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