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August - 2022

   

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

J Shi, C Zhou, W Pan et al for the OPTIMAL Study Group JAMA, 2022, 328(4):336-347

Comment

Tranexamic acid is the mainstay antifibrinolytic agent used to reduce blood loss after cardiac surgery. However there are ongoing concerns regarding associated seizures (increased risk of seizure, stroke, death at 1-year with single dose of 50 or 100 mg/kg in 4631 patients undergoing CABG),  and thrombosis. In addition, the use of infusion may be more effective at producing stable antifibrinolytic efffect and lower peak levels with associated decreased risk of adverse effects. 

The Outcome Impact of Different Tranexamic Acid Regimens in Cardiac Surgery With Cardiopulmonary Bypass (OPTIMAL)  aimed to compare the effect of high and low dose of tranexamic acid for continuous infusion in 1-year outcomes in patients undergoing cardiac surgery. What did they do;

  • 4 sites in China enrolled 3079 adult patients undergoing elective cardiopulmonary bypass (excluding risk of thrombosis, seizure, allergy, terminal illness)
  • Randomised to;
    • High-dose tranexamic acid: 30 mg/kg bolus after anaesthesia induction then maintenance 16 mg/kg/hr through operation with pump-prime 2mg/kg
    • Low-dose tranexamic acid: 10 mg/kg bolus after anaesthesia induction then maintenance 2 mg/kg/hr through operation with pump-prime 1 mg/kg
    • These were considered the minimum effective and maximal dose based on previous work
  • Demographics: Mean age 53 year, 63% male, BMI 24, 95% LVEF >50, 2% urgent surgery. Participants well matched at baseline, overall 98.4% participants completed the trial.
  • Outcomes: 
    • Primary efficacy end point rate of allogeneic red blood cell transfusion after start of operation (superiority hypothesis): 21.8% high-dose vs 26.0% low-dose group, risk difference −4.1% [1-sided 97.55% CI, −∞ to −1.1%]; RR, 0.84 [1-sided 97.55% CI, −∞ to 0.96; P = .004]. This effect remained after post hoc stratified analysis.
    • Primary safety end point composite of 30-day postoperative rate of mortality, seizure, kidney dysfunction (stage 2 or 3 KDIGO criteria), and thrombotic events (myocardial infarction, ischemic stroke, deep vein thrombosis, and pulmonary embolism) (noninferiority hypothesis with a margin of 5%): 17.6% high-dose vs 16.8% low-dose, RD, 0.8%; 1-sided 97.55% CI, −∞ to 3.9%; P = .003 for noninferiority).
    • Secondary end points, including the individual components of the primary safety end point: Fourteen of the 15 prespecified secondary end points no difference, including seizure (1.0%  high-dose vs 0.4% low-dose, RD, 0.6%; 95% CI, −0.0% to 1.2%; P = .05).
    • Tertiary outcomes: Serum D-dimer levels were lower in high-dose than low-dose at 6-hrs (median 0.3 vs 0.5 UHG/ml, diff -0.2 UHG/ml, 95% CI -0.2 to -0.2, p<0.001) and 1-day.
    • Post hoc subgroup analysis:
      • When arch replacement patients removed, median chest drain output was 480 ml vs 520 ml high vs low, p=.03.
      • In patients who underwent open chamber cardiac surgery the seizure difference was higher in high-dose group (1.2% vs 0.4%, RD 0.8%, 95% CI 0.1-1.5%, p=0.04)

Overall this large RCT undertaken in adult patients undergoing cardiac surgery with cardiopulmonary bypass reported high vs low dose tranexamic acid bolus and infusion was associated wth modest but statistically significant reduction in proportion of patients receiving red cell transfusion, and non-inferiority with respect to a composite outcome of 30-day mortality, seizure, renal dysfunction and thrombotic events.

The proportion of post-operative seizures alone in secondary and post-hoc analysis requires further consideration. This trial reports point estimate of higher seizures with high-dose, although not significant. However, similar to the ATACAS trial, a higher incidence was observed in patients undergoing open chamber surgery with high-dose. It is interesting to not the total dose used in this study was 103 mg/kg vs 19.9 my/hg, compared to the 100 and 50 ml/kg bolus in prior studies.

 

Abstract

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.

August


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