Tranexamic acid dose–response relationship for antifibrinolysis in postpartum haemorrhage during Caesarean delivery: TRACES, a double-blind, placebo-controlled, multicentre, dose-ranging biomarker study

Abstract

BackgroundThe optimal dose of tranexamic acid to inhibit hyperfibrinolysis in postpartum haemorrhage is unclear. Tranexamic Acid to Reduce Blood Loss in Hemorrhagic Cesarean Delivery (TRACES) was a double-blind, placebo-controlled, randomised, multicentre dose-ranging study to determine the dose–effect relationship for two regimens of intravenous tranexamic acid vs placebo. MethodsWomen experiencing postpartum haemorrhage during Caesarean delivery were randomised to receive placebo (n=60), tranexamic acid 0.5 g (n=57), or tranexamic acid 1 g i.v. (n=58). Biomarkers of fibrinolytic activation were assayed at five time points, with inhibition of hyperfibrinolysis defined as reductions in the increase over baseline in D-dimer and plasmin–antiplasmin levels and in the plasmin peak time. ResultsIn the placebo group, hyperfibrinolysis was evidenced by a mean increase over baseline [95% confidence interval] of 93% [68–118] for D-dimer level at 120 min and 56% [25–87] for the plasmin–antiplasmin level at 30 min. A dose of tranexamic acid 1 g was associated with smaller increases over baseline (D-dimers: 38% [13–63] [P=0.003 vs placebo]; plasmin–antiplasmin: –2% [–32 to 28] [P=0.009 vs placebo]). A dose of tranexamic acid 0.5 g was less potent, with non-significant reductions (D-dimers: 58% [32–84] [P=0.06 vs placebo]; plasmin–antiplasmin: 13% [18–43] [P=0.051]). Although both tranexamic acid doses reduced the plasmin peak, reduction in plasmin peak time was significant only for the 1 g dose of tranexamic acid. ConclusionsFibrinolytic activation was significantly inhibited by a dose of intravenous tranexamic acid 1 g but not 0.5 g. Pharmacokinetic–pharmacodynamic modelling of these data might identify the best pharmacodynamic monitoring criteria and the optimal tranexamic acid dosing regimen for treatment of postpartum haemorrhage. Clinical trial registrationNCT 02797119.