TRICS-III: Restrictive vs Liberal Transfusion in Cardiac Surgery (2017)

“In patients undergoing cardiac surgery, a restrictive strategy for red-cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of all-cause mortality, myocardial infarction, stroke, or new-onset renal failure with dialysis at hospital discharge or 28 days, whichever came first.”

— The TRICS-III Investigators

1. Publication Details

  • Trial Title: Restrictive versus Liberal Red-Cell Transfusion for Cardiac Surgery.
  • Citation: Mazer CD, Whitlock RP, Fergusson DA, et al; for the TRICS Investigators and the Canadian Critical Care Trials Group. Restrictive versus Liberal Red-Cell Transfusion for Cardiac Surgery. N Engl J Med. 2017;377(22):2133-2144. doi:10.1056/NEJMoa1711818.
  • Published: November 30, 2017, in The New England Journal of Medicine.
  • Author: C. David Mazer, M.D.
  • Funding: Canadian Institutes of Health Research and others.

2. Keywords

Blood Transfusion, Cardiac Surgery, Anemia, Hemoglobin, Transfusion Trigger, Red Blood Cells.

3. The Clinical Question

In adult patients undergoing cardiac surgery who are at moderate-to-high risk for death (Population), is a restrictive red blood cell transfusion strategy (Intervention) non-inferior to a liberal transfusion strategy (Comparison) with respect to a composite outcome of all-cause mortality and major morbidity (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Anemia is common after cardiac surgery, and transfusions are frequently given. The landmark TRICC trial had established the safety of a restrictive transfusion strategy in a general ICU population, but there was concern that patients with cardiac disease, particularly in the perioperative period, might require higher hemoglobin levels to maintain adequate myocardial oxygen delivery.
  • Knowledge Gap: The optimal transfusion strategy specifically for patients undergoing cardiac surgery was unknown. Previous trials in this population were small and inconclusive, leaving significant clinical equipoise.
  • Proposed Hypothesis: The authors hypothesized that a restrictive strategy of red-cell transfusion would be non-inferior to a liberal strategy in patients undergoing cardiac surgery.

5. Study Design and Methods

  • Design: A prospective, multicenter, international, randomized, non-inferiority trial.
  • Setting: 74 centers in 19 countries.
  • Trial Period: Enrollment from November 2014 to June 2017.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) undergoing cardiac surgery with cardiopulmonary bypass who had a EuroSCORE I of ≥6 (indicating moderate-to-high risk).
    • Exclusion Criteria: Inability to receive blood products, ongoing bleeding, or preoperative use of an intra-aortic balloon pump.
  • Intervention: A restrictive transfusion strategy. RBCs were transfused if the hemoglobin concentration dropped below 7.5 g/dL intraoperatively or postoperatively in the ICU.
  • Control: A liberal transfusion strategy. RBCs were transfused if the hemoglobin dropped below 9.5 g/dL in the ICU or operating room, or below 8.5 g/dL on the ward.
  • Management Common to Both Groups: All other aspects of perioperative care were at the discretion of the local clinical team.
  • Power and Sample Size: The trial was designed as a non-inferiority study, requiring 4814 patients to have 90% power to exclude a 25% relative increase in the risk of the primary outcome with the restrictive strategy.
  • Outcomes:
    • Primary Outcome: A composite of all-cause mortality, myocardial infarction, stroke, or new-onset renal failure requiring dialysis, assessed at hospital discharge or 28 days, whichever came first.
    • Secondary Outcomes: Included the individual components of the primary outcome and duration of mechanical ventilation.

6. Key Results

  • Enrollment and Baseline: 5243 patients were randomized, with 4860 included in the final analysis (2430 in the restrictive group, 2430 in the liberal group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: The primary composite outcome occurred in 11.4% of patients in the restrictive-strategy group and 12.5% of patients in the liberal-strategy group. The restrictive strategy was found to be non-inferior to the liberal strategy.
  • Secondary Outcomes: There were no significant differences between the groups for any of the individual components of the primary outcome, including mortality.
  • Adverse Events: The rates of adverse events were similar between the two groups.

7. Medical Statistics

  • Analysis Principle: A modified intention-to-treat analysis was performed for the non-inferiority comparison.
  • Statistical Tests Used: The primary outcome was analyzed using a Cox proportional-hazards model.
  • Primary Outcome Analysis: The primary analysis tested whether the upper boundary of the confidence interval for the hazard ratio of the primary outcome in the restrictive group was less than the pre-specified non-inferiority margin of 1.25.
  • Key Statistic(s) Reported: Hazard Ratio (HR) for the primary composite outcome: 0.92 (95% CI, 0.76 to 1.11).
  • Interpretation of Key Statistic(s):
    • Hazard Ratio (HR):
      • Formula: Conceptually, HR represents the instantaneous risk of the composite outcome in the intervention group relative to the control group.
      • Calculation: The paper reports the HR as 0.92.
      • Clinical Meaning: An HR of 0.92 means there was an 8% lower hazard of the primary outcome in the restrictive group compared to the liberal group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was 0.76 to 1.11.
      • Clinical Meaning: The upper bound of the 95% CI is 1.11. Because this value is less than the pre-specified non-inferiority margin of 1.25, the trial successfully demonstrated that the restrictive strategy was non-inferior to the liberal strategy.
    • P-value: Not applicable for the primary non-inferiority analysis, but the p-value for superiority was 0.30.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group).
      • Calculation: ARR = 12.5% – 11.4% = 1.1%.
      • Clinical Meaning: The restrictive strategy was associated with a non-significant 1.1% absolute reduction in the risk of the primary composite outcome.
    • Number Needed to Treat (NNT): Not applicable, as the goal was to prove non-inferiority, not superiority.
  • Subgroup Analyses: The finding of non-inferiority was consistent across all pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: This was a very large, international, multicenter, randomized non-inferiority trial that provided a robust and definitive answer to a critical clinical question.
  • Generalizability: The inclusion of 74 centers worldwide and a large, diverse population of cardiac surgery patients increases the external validity of the findings.
  • Patient-Centered Outcomes: The primary outcome was a composite of important, patient-centered clinical events.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which could introduce performance bias.
  • External Validity (Generalizability): The results apply to moderate-to-high risk patients undergoing cardiac surgery and may not be generalizable to very low-risk or emergent/salvage cases.
  • Other: The event rate was lower than anticipated, but the large sample size still allowed for a definitive conclusion of non-inferiority.

10. Conclusion of the Authors

“In patients undergoing cardiac surgery, a restrictive strategy for red-cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death, myocardial infarction, stroke, or new-onset renal failure with dialysis, with fewer red-cell units transfused.”

11. To Summarize

  • Impact on Current Practice: The TRICS-III trial was a landmark study that definitively extended the safety of a restrictive transfusion strategy to the high-risk cardiac surgery population. It provided strong evidence to counter the long-held belief that these patients required higher hemoglobin levels. This has reinforced restrictive transfusion as the standard of care for most patients, including those undergoing cardiac surgery.
  • Specific Recommendations:
    • Patient Selection: For adult patients at moderate-to-high risk undergoing cardiac surgery.
    • Actionable Intervention: Adopt a restrictive transfusion strategy, using a hemoglobin threshold of 7.5 g/dL as the trigger for transfusion in the perioperative period.
    • Expected Benefit: No worse outcomes compared to a liberal strategy, with a significant reduction in the number of blood products used.
  • What This Trial Does NOT Mean: This trial does not mean that the 7.5 g/dL trigger is an absolute rule. Clinical judgment is still required, especially in cases of massive hemorrhage or signs of inadequate oxygen delivery despite a hemoglobin >7.5 g/dL.
  • Implementation Caveats: Adopting a restrictive strategy requires a culture shift and clear institutional protocols but leads to significant savings in blood products and associated costs.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was the definitive successor to the TRICC trial (1999), specifically addressing the cardiac patient population that was a key area of uncertainty after TRICC. It also built upon the smaller FOCUS trial (2011) in high-risk hip surgery patients.
  • Influence on Subsequent Research: TRICS-III has largely settled the debate for the majority of cardiac surgery patients. Future research is likely to focus on even more specific high-risk subgroups (e.g., patients with pre-existing severe LV dysfunction) or on the impact of other blood products.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: What is the optimal transfusion strategy in patients with acute coronary syndromes who do not undergo surgery?
  • Future Directions: Research continues to refine transfusion practices, with a focus on patient blood management strategies that aim to minimize anemia and bleeding in the first place, thereby reducing the need for any transfusion.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant, addressing a common and costly intervention in a very large and important patient population where practice was uncertain.
  • Methods: The large, international, randomized non-inferiority design was methodologically superb and appropriate for the clinical question.
  • Results: The trial had a clear and robust result, successfully demonstrating that a restrictive strategy was non-inferior to a liberal one.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The results are highly applicable to the global cardiac surgery community and provide a definitive, evidence-based rationale to adopt a restrictive transfusion strategy as the standard of care.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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