Effect of High- vs Low-Dose Tranexamic Acid Infusion on Need for Red Blood Cell Transfusion and Adverse Events in Patients Undergoing Cardiac Surgery

Abstract

ImportanceTranexamic 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.ObjectiveTo 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 ParticipantsMulticenter, 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.InterventionsParticipants 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 MeasuresThe 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.ResultsAmong 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 RelevanceAmong 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.Trial RegistrationClinicalTrials.gov Identifier: NCT03782350

High- vs Low-Dose Tranexamic Acid Infusion and Need for Red Blood Cell Transfusion and Adverse Events in Cardiac Surgery

“…To the Editor A recent study demonstrated a modest but statistically significant reduction in the number of patients needing red blood cell transfusion with use of high-dose vs low-dose tranexamic acid.…”

“…In cardiac surgery, it is known that the benefits of tranexamic acid are counterbalanced by an increased risk of seizures, likely due to cardiopulmonary bypass–associated disturbance of the blood-brain barrier and a disinhibition of cerebral γ-aminobutyric acid receptors . Although the risk of seizure was increased in the high-dose tranexamic acid group in this study by Dr Shi and colleagues, the observed incidence of seizures in both groups (0.4%-1%) was lower than the 2.7% rate reported in a meta-analysis of studies of tranexamic acid use in cardiac surgery . Large studies have found a higher risk of seizures associated with open-chamber surgery, higher tranexamic acid dose, older age, and impaired kidney function .…”

“…Moreover, seizures are associated with increased early mortality . Although nearly 85% of patients underwent open-chamber surgery in this study, the mean age of patients in both groups was only 53 years. In addition, age greater than 70 years was an exclusion criterion for study participation, which prevents application of the study results to elderly high-risk patients, who are a large and increasing patient population in contemporary cardiac surgery.…”

The Effect of Cell Salvage on Bleeding and Transfusion Needs in Cardiac Surgery

“…The durations of ECC and aortic cross clamp were longer for the cell salvage group compared with the control group, but the difference of 10 minutes between groups is probably not clinically significant enough to seriously challenge the randomization benefits of this prospective study. The dose of tranexamic acid incorporated into our protocol is considered a “medium dose scheme” [ 28 , 29 ], which did not lead to increased bleeding that could obscure a potential positive effect of cell salvaging in bleeding and transfusion patterns [ 30 ]. Due to laboratory issues, we could not measure the heparin content, the coagulation factors, or perform thromboelastic and platelet function tests in our samples in order to elucidate their pro- or anticoagulant profiles.…”

Old issues and new challenges in cardiothoracic anesthesiology: Work in progress…

“…However, there is still a long way to go since all but ATACAS are relatively small studies and none of them shows outstanding effects on clinically relevant outcomes such as survival. Moreover, many aspects (e.g., the safety, transfusion triggers, target levels, best monitoring tools and dosing of fibrinogen [42] and the possible adverse effects, optimal dosing and mode of administration of tranexamic acid [43]) need to be further clarified. A large multicenter RCT investigating the role of preoperative acute normovolemic hemodilution on the risk of red blood cells transfusion (and on important clinical outcomes as secondary endpoints) is currently ongoing (ANH trial, http://clinicaltrials.gov/show/ NCT03913481).…”