Administering tranexamic acid (TxA) topically rather than intravenously during cardiac surgery did not meet its primary endpoint of reducing seizures, and the trial was terminated early due to an increased risk of bleeding events, according to results of the DEPOSITION trial presented during a Late-Breaking Clinical Trial Session at ACC.24 in Atlanta and simultaneously published in Circulation.

The multicenter, double dummy, blinded, randomized controlled trial, presented by Andre Lamy, MD, MHS, et al., assessed whether applying TxA directly to the heart at the end of the surgery instead of intravenously during surgery would help reduce seizures while maintaining the drug's benefits. The DEPOSITION trial enrolled 3,224 patients (mean age 66 years, 77.7% men) undergoing heart surgery with cardiopulmonary bypass at 16 academic hospitals in six countries between Sept. 17, 2019 and Nov. 28, 2023.

Participants were randomly assigned to receive either intravenous TxA and a topical placebo (1,628 patients) or topical TxA and an intravenous placebo (1,624 patients) during their procedure. The doses ranged from 5 grams to 10 grams and were determined by the anesthesiologist for intravenous administration and the surgeon for topical administration.

Before the trial was terminated, a prespecified interim analysis showed that blood transfusions was required by 35.1% of patients who received topical and 26.8% of patients who received intravenous TxA, representing a 31% increased risk of bleeding in the topical group. Four patients who received topical TxA (0.2%) and 11 patients who received intravenous TxA (0.7%) experienced seizures (absolute risk difference, –0.5%; 95% CI, –0.9-0.03; p=0.07). In addition, 570 patients required red blood cell transfusions (35.1%) in the topical group and in 433 (26.8%) in the intravenous group (absolute risk difference, 8.3%; 95% CI, 5.2-11.5; p=0.007). The absolute risk difference in transfusion of ≥4 units of red blood cells in the topical group compared to the intravenous group was 8.2% (95% CI, 3.4-12.9).

After the last planned interim analysis, when 75% of anticipated participants had completed follow-up, the Data and Safety Monitoring Board recommended terminating the trial, and upon unblinding, the Operations Committee stopped the trial for safety.

Although the trial did not meet its primary endpoint, Lamy said the study results could nevertheless help to shed light on the possible mechanisms through which the drug causes seizures when used in cardiac surgery. Of note, researchers observed seizures were more common with valve surgery than with bypass surgery. This suggestion is corroborated by the results of an additional analysis, which was not part of the planned study methodology, in which researchers analyzed all seizures (instead of just those not considered to be related to strokes), finding that in the more inclusive analysis, topical TxA (0.2%) significantly reduced seizures in comparison to intravenous TxA (0.9%).

"What we've never done is to refine the dose needed to have the full action of TxA," Lamy said. "The trial is disappointing, but we've learned a lot. I think there is a message that is much broader than just cardiac surgery, in that we have to look at this drug with new eyes and new technologies to improve its performance."

"The signal for harm with topical administration for increased blood transfusions was clearly significant," said Lamy. "Topical administration in its current form is inferior to intravenous TxA and should not be used."