The association of estimated citrate load with frozen plasma versus four-factor prothrombin complex concentrate for coagulopathy after cardiac surgery: a post hoc exploratory analysis of the FARES-II randomised controlled trial

Background Frozen plasma (FP) is the standard haemostatic therapy after cardiopulmonary bypass, but recent trials indicate that FP is inferior to four-factor prothrombin complex concentrate (PCC). Citrate content may contribute to this difference. We compared estimated citrate exposure between patients receiving FP and those receiving PCC and explored its association with postoperative bleeding. Methods This post hoc analysis of the FARES-II randomised trial (30 November 2022 to 28 May 2024; 12 North American centres; 420 adults; 207 FP, 213 PCC) calculated estimated citrate load from all transfused products using published citrate-content data. The primary outcome was per-patient cumulative estimated citrate load at 12 and 24 h post-investigational medicinal product. Secondary outcomes were the hourly trajectory of group-total citrate delivery and its association with 12-h chest tube drainage by quartile. Results In the FP group, total estimated citrate exposure was substantially higher, and the median per-patient estimated citrate load was approximately six-fold greater at 12–24 h. Administration of citrate-containing products continued through 8 h in patients receiving FP but was largely confined to the first 2 h in patients receiving PCC. Across all quartiles of estimated 12-h citrate load, patients treated with FP had higher estimated citrate exposure and chest tube drainage; patients treated with PCC in the highest quartile exhibited drainage volumes similar to those of patients treated with FP in the third quartile. Conclusions This exploratory, hypothesis-generating analysis demonstrated markedly higher estimated citrate exposure with FP than PCC. Although causality cannot be established without direct citrate measurement, FP was associated with higher estimated citrate load and more variable chest tube drainage. Factor concentrates may reduce this burden, warranting further mechanistic investigation. ClinicalTrials.gov identifier: NCT05523297; https://clinicaltrials.gov/study/NCT05523297?term=NCT05523297&rank=1