Reducing transfusion while preserving Canada's blood supply: use of tranexamic acid in major non-cardiac surgeries at high-risk of transfusion

BACKGROUND: Tranexamic acid (TXA) inhibits fibrinolysis and has been shown to consistently reduce red blood cell (RBC) transfusion in cardiac and orthopedic surgery, where it is now incorporated into standard of care. Its efficacy and safety in other major surgeries at high risk of RBC transfusion is largely unknown. A randomized controlled trial (RCT) is needed to inform best practice. If TXA reduces RBC transfusion in this diverse surgical population, it is expected that this inexpensive and widely available medication will be incorporated into routine surgical care. OBJECTIVES: The overall objective was to inform the design and conduct of a registry-based RCT of TXA use to reduce RBC transfusion in major non-cardiac surgery. Specifically, we aimed to define a surgical population at high risk of RBC transfusion, evaluate real-world TXA use and variability in this at-risk population, examine TXA effectiveness, efficacy and safety in our at-risk surgical population and validate key transfusion variables critical to the planned RCT. METHODS: To evaluate surgery-specific RBC transfusion risk and TXA use we completed retrospective cohort studies of adult patients undergoing major non-cardiac surgery at 5 Canadian hospitals between January 2014 and December 2016. Variability in TXA use was further characterized using multivariable logistic regression analyses in 3 common orthopedic surgeries with higher rates of RBC transfusion (>5%) and TXA utilization (>10%). Real-world TXA effectiveness was studied using propensity analysis. A systematic review and meta-analysis was performed to evaluate TXA efficacy and safety. Agreement between RBC transfusion variables was assessed by comparing different measures of RBC transfusion in the patient record, discharge abstract database and transfusion databases. RESULTS: We identified 85 unique non-cardiac surgeries with an RBC transfusion rate ≥ 5%. We observed that prophylactic use of TXA varies widely according to surgical subtype, with limited use outside of orthopedic and spine surgery. We noted that TXA was most commonly administered as a bolus, with a median total dose of 1 gram. Variability in TXA use was higher among surgeries where TXA use was lower. Propensity analysis resulted in mixed results for TXA effectiveness to reduce RBC transfusion among 3 orthopedic surgeries, although methodologic limitations precluded robust interpretation of these results. We meta-analyzed 69 RCTs of TXA use in non-cardiac surgeries at increased risk for RBC transfusion, and found that TXA reduces both the proportion of patients transfused RBCs, as well as the volume of RBCs transfused. TXA use was not associated with differences in deep vein thrombosis or pulmonary embolism, although effect estimates were limited by lack of systematic screening and short duration of follow-up. Lastly, there was excellent agreement for documentation of RBC exposure between the patient record and transfusion databases, although agreement decreased with increasing number of RBC units transfused. CONCLUSION: This thesis has comprehensively informed the design and conduct of an RCT evaluating TXA use in non-cardiac surgeries at increased risk for RBC transfusion by informing trial inclusion criteria, equipoise, TXA dosing, outcomes, feasibility and sample size calculations. This trial has the potential to change the standard of care in perioperative medicine in Canada and around the world.

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