TRICS-III 6 month follow up

Six-Month Outcomes after Restrictive or Liberal Transfusion for Cardiac Surgery

Mazer CD. NEJM 2018; 379:1224-1233. DOI: 10.1056/NEJMoa1808561

Clinical Question

  • In patients undergoing cardiac surgery, who have a moderate-to-high risk of death, does a restrictive transfusion strategy compared with a liberal strategy impact on a composite outcome of death, myocardial infarction, stroke and acute kidney injury requiring dialysis at 6 months after surgery?

Background

  • TRICS-III was published in Nov 2017. At 28 days, a restrictive transfusion strategy was found to be non-inferior to a liberal transfusion strategy in cardiac surgery patients with a moderate-to-high risk of death with regards to a composite outcome of death and major disability
  • This is the follow up data at 6 months

Design

  • Randomised controlled trial
  • 1:1 ratio of restrictive vs liberal strategy
  • Allocation concealment (central web-based allocation)
  • Permuted blocks of varying size, stratified to centre
  • Unblinded, although the outcomes were evaluated by those unaware of the trial-group assignment
  • A modified intention-to-treat analysis was also conducted
  • Power calculation: The event rate of the primary composite outcome was assumed to be 10%. Partway through the trial, the power of the trial was increased from 85% to 90%, which required a sample size of 5000 patients. The aim was to detect non-inferiority at a one-sided alpha of 0.025, with a non-inferiority margin of 3%

Setting

  • 19 countries, 74 sites
  • Randomisation from January 20th 2014 to March 20th 2017

Population

  • Inclusion: patients 18 years or older undergoing cardiac surgery with a pre-operative EuroSCORE I of 6 or higher (the EuroSCORE I is a validated scoring system that is predictive of in-hospital mortality)
  • Exclusion
    • unable to receive or declined blood products
    • pre-operative autologous donation program
    • heart transplant surgery
    • surgery for ventricular assist device
    • pregnant or lactating
  • 5243 randomised; 5092 of these patients were included in the modified intention-to-treat analysis, and 4860 (2430 in each treatment group) were included in the primary per-protocol analysis
    • Six-month follow-up data on the primary outcome were available for 96% of the patients
    • Baseline demographics similar in both groups

Intervention

  • Patients in the restrictive group received a red-cell transfusion if the haemoglobin concentration was less than 7.5g/dL intra-operatively or post-operatively

Control

  • Patients in the liberal group received a red-cell transfusion if the haemoglobin concentration was less than 9.5g/dL intra-operatively or post-operatively or less than 8.5g/dL in the non-ICU ward

Management common to both groups

  • Haemoglobin level was measured pre-operatively, intra-operatively and post-operatively at specified intervals. If the haemoglobin fell below the threshold, 1 unit of red cells was administered followed by reassessment of the level
  • All other aspects of care were directed by the treating medical teams
  • The treating physicians followed the transfusion protocol until 28 days after surgery or hospital discharge, whichever came first

Outcome

  • Primary outcome: A restrictive transfusion threshold was non-inferior to the liberal transfusion group for a composite outcome of death from any cause, myocardial infarction, new focal neurologic deficit (stroke), or new-onset renal failure with dialysis occurring within 6 months after the index surgery:
    • Restrictive-threshold group: 402 of 2317 patients (17.4%)
    • Liberal-threshold group: 402 of 2347 patients (17.1%)
    • Absolute risk difference: 0.22% (95% CI -1.95% to 2.39%; P=0.006 for non-inferiority)
    • Odds Ratio: 1.02 (95% CI 0.87 to 1.18)
  • Secondary outcome (restrictive vs liberal threshold group) occurring within 6 months after the index surgery:
    • Death from any cause: 6.2% vs 6.4%
      • Odds ratio: 0.95 (95% CI 0.75 to 1.21)
    • Myocardial infarction: 7.3% vs 7.3%
      • Odds ratio: 0.99 (95% CI 0.79 to 1.24)
    • Stroke: 4% vs 3.3%
      • Odds ratio: 1.21 (95% CI 0.88 to 1.66)
    • New onset renal failure with dialysis: 3.9% vs 4.2%
      • Odds ratio: 0.93 (95% CI 0.69 to 1.25)
    • Expanded secondary composite outcome
      • All the components of the primary outcome as well as emergency department visit, hospital readmission, or coronary revascularization occurring within 6 months after the index surgery)
        • 43.8% vs 42.8%
        • Odds ratio: 1.04 (95% CI 0.93 to 1.17)
      • Coronary revascularisation: 0.7% vs 0.9%
      • Hospital readmission or emergency department visit: 35.5% vs 33.6%
      • Hospital readmission: 26.2% vs 23.6%
      • Number of hospital readmissions per patient: 0.38±0.76 vs 0.34±0.74
      • Emergency department visit: 26.3% vs 25.4%
      • Number of emergency department visits per patient: 0.44±1.18 vs 0.40±0.95

Authors’ Conclusions

  • In patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive strategy for red-cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis at 6 months after surgery

Strengths

  • Multi-centre design improves generalisability
  • Concealled allocation via web interface prevents selection bias
  • Objective outcomes reduces bias that may occur due to the open-label (unblinded) design
  • Patients were randomised before surgery meaning that the effect of two transfusion strategies was examined for the whole of their journey as a cardiac surgery patient
  • The sample population were a sick group of cardiac surgery patients, so treatment effect, if any would likely be more obvious than low-risk cardiac surgery patients
  • Appropriate analysis ‘per-protocol’ (compared to the more common ‘intention-to-treat’) as this was a non-inferiority design
    • Per-protocol statistical analysis will tend to exaggerate any difference between groups
    • If no difference is found it strengthens the non-inferiority conclusion
  • This is the largest study with the longest follow up for the long-term outcomes of peri-operative transfusion strategies

Weaknesses

  • Physicians were not required to follow the transfusion protocol after day 28 or hospital discharge and it is therefore not possible to determine the degree to which the differences in haemoglobin concentrations or transfusions continued thereafter
  • Outcome data were obtained from a variety of sources, including telephone contact, hospital records, and database registries. It is possible that some follow-up visits were missed, although there is no reason to believe that missed visits would be more frequent in one treatment group than in the other
  • Determination of cause of death was not possible

The Bottom Line

  • In patients who had a moderate to high risk of death after cardiac surgery, a restrictive strategy of red cell transfusion was non-inferior to a liberal strategy in terms of the pre-specified primary composite outcome of death from any cause, myocardial infarction, stroke, or renal failure with dialysis
  • This follow up data shows that at 6 months, a restrictive transfusion strategy is still non-inferior to a liberal strategy

External Links

Metadata

Summary author: Steve Mathieu
Summary date: 3rd October 2018
Peer-review editor: Duncan Chambler

Leave a Reply

This site uses Akismet to reduce spam. Learn how your comment data is processed.