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Examining the Methodology of the Transfusion Requirements in Cardiac Surgery-III (TRICS-III) Trial: Third Time’s a Charm?

      Few subjects inspire the amount of discussion and debate as the appropriate threshold for blood transfusion in hospitalized patients. Numerous randomized trials comparing liberal versus restrictive transfusion strategies have been conducted.
      • Holst L.B.
      • Petersen M.W.
      • Haase N.
      • Perner A.
      • Wetterslev J.
      Restrictive versus liberal transfusion strategy for red blood cell transfusion: systematic review of randomised trials with meta-analysis and trial sequential analysis.
      • Hovaguimian F.
      • Myles P.S.
      Restrictive versus Liberal Transfusion Strategy in the Perioperative and Acute Care Settings.
      • Bergamin F.S.
      • Almeida J.P.
      • Landoni G.
      • et al.
      Liberal Versus Restrictive Transfusion Strategy in Critically Ill Oncologic Patients.
      • Holst L.B.
      • Haase N.
      • Wetterslev J.
      • et al.
      Lower versus Higher Hemoglobin Threshold for Transfusion in Septic Shock.
      While many thought leaders initially called for restrictive transfusion thresholds in all patients (i.e., at a hemoglobin of approximately 7 g/dL), recent guidelines are more nuanced and suggest that higher thresholds may be appropriate in certain patients, such as those with cardiovascular disease or ongoing ischemia.
      • Holst L.B.
      • Petersen M.W.
      • Haase N.
      • Perner A.
      • Wetterslev J.
      Restrictive versus liberal transfusion strategy for red blood cell transfusion: systematic review of randomised trials with meta-analysis and trial sequential analysis.
      • Carson J.L.
      • Guyatt G.
      • Heddle N.M.
      • et al.
      Clinical Practice Guidelines From the AABB.
      Still, confusion remains as to what, if any, transfusion threshold is the correct one in cardiac surgery.
      The TRICS-III: Transfusion Requirements in Cardiac Surgery-III Trial (clinicaltrials.gov, NCT02042898) is one of the largest trials ever performed comparing a liberal versus restrictive transfusion strategy in cardiac surgery patients.
      • Mazer C.D.
      • Whitlock R.P.
      • Fergusson D.A.
      • et al.
      Restrictive or Liberal Red-Cell Transfusion for Cardiac Surgery.
      In this edition of JCVA, the TRICS-III research group reports the methods of their trial: Transfusion Requirements in Cardiac Surgery-III (TRICS-III): Study Design of a Randomized Controlled Trial. A publication such as this, which focuses on the “methods” or “protocol”, allows the investigators to describe and justify the trial’s methods in greater detail than is possible in the primary results manuscript. Indeed, word restrictions in many journals severely limit the detail with which methods can be reported (often to 250-500 words, or less). A methods paper such as this allows for a detailed reporting of the trial’s methods so the ultimate research report can use valuable words to present and discuss the trial’s results, and so readers can gain a richer understanding of the conduct of the study itself.
      So what did the TRICS-III researchers do well? In this article, the authors have done a good job of reporting their trial methodology in compliance with SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines for reporting of protocol papers (http://www.spirit-statement.org). First, the rationale for TRICS-III is made clear. The “optimal” transfusion strategy has yet to be elucidated in cardiac surgical patients. In addition, the authors point out that TRICS-III came about to address challenges with enrollment/adherence and feasibility of study design that were apparent in pilot versions of this trial (TRICS-I and II).
      • Shehata N.
      • Burns L.A.
      • Nathan H.
      • et al.
      A randomized controlled pilot study of adherence to transfusion strategies in cardiac surgery.
      The methods of the trial are well-described and justified. Briefly, participants were adults scheduled for cardiac surgery with cardiopulmonary bypass and a EuroSCORE I of 6 or more (to ensure subjects’ medical homogeneity and risk of transfusion). The trial employed a multi-center, international, open label randomized controlled design and compared the two transfusion strategies (restrictive versus liberal) in a non-inferiority design. Randomization occurred prior to surgery and was in a 1:1 ratio. CONSORT statement criteria were incorporated to ensure compliance with randomized trial reporting standards. Inclusion and exclusion criteria are well-documented and justified, and reasons for withdrawal/study suspension such as rapid blood loss and hemodynamic instability have face-validity. The authors also describe monitoring of adherence to the protocol, which is important to our understanding of whether the study procedures were carried out as intended.
      The randomization scheme is described, and the statistical groundwork informing the sample size is excellent. The authors used their previous work to inform trial size and powered the trial to 90%, after securing funding to do so. In total, 74 sites (21 Canadian and 8 U.S.), were used to enroll 5000 patients. An independent data safety monitoring board assured the well-being of subjects and web-based electronic data capture was used to optimize data integrity. The trial was registered (NCT02042898) and its brief description there is consistent with this methods publication this month in JCVA.
      Vital to any methods paper is a reporting of the study limitations. By the very nature of the trial, there was a lack of blinding. While it was likely not feasible to conduct the trial otherwise, it is an important limitation nonetheless. The hemoglobin thresholds chosen for the study, i.e., 7.5 g/dL in the restrictive group and 8.5 g/dL (ward) /9.5 g/dL (OR, ICU) in the liberal group are in keeping with prior studies of a similar nature, but readers might wonder if a lower threshold would have allowed detection of a “benefit” to more liberal transfusion, rather than non-inferiority. The researchers justify these thresholds based on adherence issues they had with earlier pilot trials, but they represent a methodological trade-off that can lead some readers to wonder if there is enough of a difference in the two study arms to expect any difference in outcome. Further, transfusion is often driven by factors besides hemoglobin concentration, which may be a late finding in ongoing hemorrhage. Markers of oxygen delivery (e.g., mixed venous oxygen saturation, cerebral oxygenation) or hemodynamic variables were not taken into account, as the decision to transfuse centered around the hemoglobin threshold. This limitation is not specific to TRICS III, since most large trials have been designed in similar fashion.
      The outcomes the authors have chosen seem reasonable. Use of a composite outcome results in a higher event rate and thus may allow for smaller sample size. However, employing a composite of mortality and cardiac, renal and neurologic events has limitations. Composite outcomes may be confusing for the average clinician to interpret, as they involve combinations of sometimes disparate events. For example, in this case, the stroke component of the endpoint might be expected to be largely embolic based upon prior knowledge of these phenomena, which many clinicians might not assume to be related to a relatively small hemoglobin difference of 2 g/dL between study arms.
      The TRICS-III trial results will be a welcome addition to the pool of knowledge surrounding the debate over restrictive versus liberal transfusion strategies in cardiac surgery. Large trials such as these are complex and challenging to conduct, and the authors have taken an important step by publishing their methods here in JCVA. We encourage readers to review these methods closely and encourage other investigators on large trials to publish their detailed methods so that the scientific community can have a richer understanding of these important studies that might influence our practice.

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