BACKGROUND: Fibrinogen concentrate (FCH) has been successfully used in perioperative bleeding in complex cardiac surgery (CCS), as reported in several single center trials; a global, multicenter randomized clinical trial did not show efficacy superiority over placebo, while the safety endpoints were favorable to FCH. As part of the 2015 periodic safety update report (PSUR) submitted to the European Medicines Agency (EMA), the sponsor conducted a benefit-risk assessment (BRA) using the CIRS-BRAT framework, to evaluate the evidence for the use of FCH in cardiac surgery. The EMA agreed that the benefit-risk profile was favorable and requested an update of the BRA for the 2018 PSUR.
OBJECTIVES: To update the benefit-risk profile of FCH in the clinical setting of CCS taking into account all published evidence and completed clinical trials as of April 2018.
METHODS: The CIRS-BRAT framework was followed to establish the decision frame, identify key benefits and risks and gather and interpret data. and produce visualizations to display the results. An updated systematic literature review was conducted to identify new studies published since the original BRA. Forest plots were generated to show the benefits and risks of FCH compared to placebo or standard of care in randomized and observational studies by key benefits and risks, by study, and by crude pooled analyses of identified placebo-controlled clinical trials.
RESULTS: The original BRA included 6 studies and the updated literature search identified 1 new randomized clinical trial and 1 new observational study that met criteria included in the decision frame. The updated BRA showed that the evaluated benefits (avoidance of allogeneic blood product transfusion within 24 hours, survival at 30 days and avoidance of re-operation due to bleeding) favored FCH in most studies. For the risk outcomes, in all studies the point estimates for TEEs and anaphylactic and hypersensitivity reactions were similar in the FCH and comparator groups. The benefit-risk profile of FCH in the setting of complex cardiac surgery was determined to still be favorable.
CONCLUSIONS: The use of a structured approach (CIRS-BRAT framework) facilitated assessment of a large volume of information in a complex setting, including both randomized trials and observational studies. The favorable benefit-risk profile of FCH in the setting of complex cardiac surgery was reconfirmed.
