Prothrombin complex concentrate vs. fresh frozen plasma in adult patients undergoing heart surgery – a pilot randomised controlled trial (PROPHESY trial)

Abstract

There is equipoise regarding the use of prothrombin complex concentrate vs. fresh frozen plasma in bleeding patients undergoing cardiac surgery. We performed a pilot randomised controlled trial to determine the recruitment rate for a large trial, comparing the impact of prothrombin complex concentrate vs. fresh frozen plasma on haemostasis (1 h and 24 h post-intervention), and assessing safety. Adult patients who developed bleeding within 24 h of cardiac surgery that required coagulation factor replacement were randomly allocated to receive prothrombin complex concentrate (15 IU.kg À1 based on factor IX) or fresh frozen plasma (15 ml.kg À1 ). If bleeding continued after the first administration of prothrombin complex concentrate or fresh frozen plasma administration, standard care was administered. From February 2019 to October 2019, 180 patients were screened, of which 134 (74.4% (95%CI 67-81%)) consented, 59 bled excessively and 50 were randomly allocated; 25 in each arm, recruitment rate 35% (95%CI 27-44%). There were 23 trial protocol deviations, 137 adverse events (75 prothrombin complex concentrate vs. 62 fresh frozen plasma) and 18 serious adverse events (5 prothrombin complex concentrate vs. 13 fresh frozen plasma). There was no increase in thromboembolic events with prothrombin complex concentrate. No patient withdrew from the study, four were lost to follow-up and two died. At 1 h after administration of the intervention there was a significant increase in fibrinogen, Factor V, Factor XII, Factor XIII, a 2 -antiplasmin and antithrombin levels in the fresh frozen plasma arm, while Factor II and Factor X were significantly higher in the prothrombin complex concentrate group. At 24 h, there were no significant differences in clotting factor levels. We conclude that recruitment to a larger study is feasible. Haemostatic tests have provided useful insight into the haemostatic changes following prothrombin complex concentrate or fresh frozen plasma administration. A definitive trial is needed to ascertain the benefits and safety for each.

Impact of prothrombin complex concentrate and fresh frozen plasma on correction of haemostatic abnormalities in bleeding patients undergoing cardiac surgery (PROPHESY trial results)

“…Secondly, lower doses of PCC (500 IU) and FFP (3 units) are suboptimal in correcting these abnormalities. Our data support the need for adequate clotting factor replacement therapies in cardiac surgical patients with complications of bleeding.We have shown that, for a range of haemostatic factors, a more balanced increase in clotting factors is seen with FFP compared with PCC[1], which is not surprising considering the content of both blood products. However, in this study,…”

The association of prothrombin complex concentrates with postoperative outcomes in cardiac surgery: an observational substudy of the FIBRES randomized controlled trial

“…28 The variability in practice pertaining to administration of PCC vs FP should be explored further, and extends to the doses utilized by clinicians. Currently there is no clear consensus on the optimal dose of PCC for coagulopathy related to cardiac surgery, 17,29,30 with doses in our study ranging from 500 to 2,000 IU for a single administration. Given the significant differences in transfusion avoidance in favour of the PCC group in this study, our results suggest a dose between 1,000 IU and 2,000 IU is likely to be effective.…”

“…doses of 15-25 IUÁkg -1 (1,000-2,000 IU for an average sized patient), with observed hemostatic effects comparable with FP observed throughout this dose range, albeit in small numbers of patients. 29,30 This study builds on existing evidence and re-examines the efficacy of PCCs, while adding to the sparse published data on the safety of PCCs in the context of bleeding after cardiac surgery. Previously published work has been limited by small sample sizes, making comparisons of rare outcomes between groups difficult because of insufficient power.…”

“…Recent pilot randomized controlled trials have used PCC doses of 15–25 IU·kg -1 (1,000–2,000 IU for an average sized patient), with observed hemostatic effects comparable with FP observed throughout this dose range, albeit in small numbers of patients. 29 , 30 …”

“…Our study attempts to address these limitations by including only a higher risk cohort of patients with active bleeding, removing some elements of confounding related to the indication for PCC administration and improving the power of our study to detect a difference in adverse outcomes. 29 Additionally, safety data utilized in this study was prospectively collected, and included renal and thromboembolic outcomes, some of the most disputed and concerning outcomes in the literature.…”