Abstract
Introduction: Cardiac surgery involving cardiopulmonary bypass (CPB) is associated with coagulopathy and excessive bleeding. This often requires the transfusion of large volumes of allogeneic blood products and is linked to an increased risk of adverse outcomes. A primary cause of coagulopathy is acquired hypofibrinogenemia; when fibrinogen levels drop below 1.5-2 mg/L, fibrinogen supplementation is required to maintain hemostasis. The FIBrinogen REplenishment in Surgery (FIBRES) study aims to compare the standard intervention, cryoprecipitate, with a new highly purified, double virus-inactivated human fibrinogen concentrate.
Methods: The FIBRES study (NCT03037424) is a pragmatic, multicenter, active-control, randomized, single-blinded, non-inferiority phase 3 trial in adult patients undergoing cardiac surgery with CPB. The study will enroll patients with clinically significant bleeding associated with acquired hypofibrinogenemia. Patients for whom fibrinogen supplementation is ordered within 24 hours of surgery will be randomized to receive fibrinogen concentrate (4 g; Fibryga; Octapharma) or cryoprecipitate (10 units; dose equivalent to 4 g fibrinogen concentrate) (Figure 1). All randomized patients will receive fibrinogen supplementation as clinically indicated. Owing to the emergency nature of the clinical setting, patient consent at the point of randomization will be waived, with written informed consent obtained within 24-48 hours thereafter. The primary outcome is total allogeneic blood products (red blood cells, plasma, platelets) administered within the first 24 hours of surgery. Secondary outcomes include blood product use within 7 days, incidence of major bleeding within 24 hours, fibrinogen levels, and adverse events (AEs) and serious AEs within 28 days. Enrolment of 1,200 patients will provide >90% power to demonstrate non-inferiority, assuming a 20% non-inferiority margin, ≥550 patients per group, and an approximate 10% drop-out rate. One pre-planned interim analysis will be conducted after data are available for 600 evaluable patients with the option to stop early for futility or overwhelming efficacy. The pragmatic design and treatment algorithm align with standard practice, aiding adherence and generalizability.
Results: To date, 530 patients have been treated across 11 sites. An IDMEAC review of safety has been performed every 100 patients enrolled, with the recommendation to continue as planned each time. The study is expected to complete in late 2018, with results available in early 2019.
Conclusions: The FIBRES study is the largest randomized study to date of fibrinogen concentrate versus cryoprecipitate in adult cardiac surgical patients, an under-studied yet high-risk population. Non-inferiority of the new fibrinogen concentrate would support its use for patients developing acquired hypofibrinogenemia during cardiac surgery. Results from the FIBRES study are likely to improve care for cardiac surgical patients experiencing significant bleeding.
Disclosures
Karkouti: Octapharma US: Research Funding.
Over-the-counter natural products in cardiac surgery: a case of ginseng-related massive perioperative bleeding
