Importance  Tranexamic acid is recommended for reducing blood loss and transfusion in cardiac surgery. However, it remains unknown whether a high dose of tranexamic acid provides better blood-sparing effect than a low dose without increasing the risk of thrombotic complications or seizures in cardiac surgery.

Objective  To compare the efficacy and adverse events of high-dose vs low-dose tranexamic acid in patients undergoing cardiac surgery with cardiopulmonary bypass.

Design, Setting, and Participants  Multicenter, double-blind, randomized clinical trial among adult patients undergoing cardiac surgery with cardiopulmonary bypass. The study enrolled 3079 patients at 4 hospitals in China from December 26, 2018, to April 21, 2021; final follow-up was on May 21, 2021.

Interventions  Participants received either a high-dose tranexamic acid regimen comprising a 30-mg/kg bolus, a 16-mg/kg/h maintenance dose, and a 2-mg/kg prime (n = 1525) or a low-dose regimen comprising a 10-mg/kg bolus, a 2-mg/kg/h maintenance dose, and a 1-mg/kg prime (n = 1506).

Main Outcomes and Measures  The primary efficacy end point was the rate of allogeneic red blood cell transfusion after start of operation (superiority hypothesis), and the primary safety end point was a composite of the 30-day postoperative rate of mortality, seizure, kidney dysfunction (stage 2 or 3 Kidney Disease: Improving Global Outcomes [KDIGO] criteria), and thrombotic events (myocardial infarction, ischemic stroke, deep vein thrombosis, and pulmonary embolism) (noninferiority hypothesis with a margin of 5%). There were 15 secondary end points, including the individual components of the primary safety end point.

Results  Among 3079 patients who were randomized to treatment groups (mean age, 52.8 years; 38.1% women), 3031 (98.4%) completed the trial. Allogeneic red blood cell transfusion occurred in 333 of 1525 patients (21.8%) in the high-dose group and 391 of 1506 patients (26.0%) in the low-dose group (risk difference [RD], −4.1% [1-sided 97.55% CI, −∞ to −1.1%]; relative risk, 0.84 [1-sided 97.55% CI, −∞ to 0.96; P = .004]). The composite of postoperative seizure, thrombotic events, kidney dysfunction, and death occurred in 265 patients in the high-dose group (17.6%) and 249 patients in the low-dose group (16.8%) (RD, 0.8%; 1-sided 97.55% CI, −∞ to 3.9%; P = .003 for noninferiority). Fourteen of the 15 prespecified secondary end points were not significantly different between groups, including seizure, which occurred in 15 patients (1.0%) in the high-dose group and 6 patients (0.4%) in the low-dose group (RD, 0.6%; 95% CI, −0.0% to 1.2%; P = .05).

Conclusions and Relevance  Among patients who underwent cardiac surgery with cardiopulmonary bypass, high-dose compared with low-dose tranexamic acid infusion resulted in a modest statistically significant reduction in the proportion of patients who received allogeneic red blood cell transfusion and met criteria for noninferiority with respect to a composite primary safety end point consisting of 30-day mortality, seizure, kidney dysfunction, and thrombotic events.