Protocol for a phase 3, randomised, active-control study of four-factor prothrombin complex concentrate versus frozen plasma in bleeding adult cardiac surgery patients requiring coagulation factor replacement: the LEX-211 (FARES-II) trial

Abstract

Introduction: Reduced thrombin generation is an important component of post cardiopulmonary bypass (CPB) coagulopathy. To replenish coagulation factors and enhance thrombin generation in bleeding surgical patients, frozen plasma (FP) and four-factor prothrombin complex concentrate (4F-PCC) are used. However, the efficacy-safety balance of 4F-PCC relative to FP in cardiac surgery is unconfirmed.

Methods and analysis: LEX-211 (FARES-II) is an active-control, randomised, phase 3 study comparing two coagulation factor replacement therapies in bleeding adult cardiac surgical patients at 12 hospitals in Canada and the USA. The primary objective is to determine whether 4F-PCC (Octaplex/Balfaxar, Octapharma) is clinically non-inferior to FP for haemostatic effectiveness. Inclusion criteria are any index (elective or non-elective) cardiac surgery employing CPB and coagulation factor replacement with 4F-PCC or FP ordered in the operating room for bleeding management. Patients will be randomised to receive 1500 or 2000 international units of 4F-PCC or 3 or 4 units of FP, depending on body weight. The primary endpoint of haemostatic treatment response is 'effective' if no additional haemostatic intervention is required from 60 min to 24 hours after the first initiation of 4F-PCC or FP; or 'ineffective' if any other haemostatic intervention (including a second dose of study drug) is required. An estimated 410 evaluable patients will be required to demonstrate non-inferiority (one-sided α of 0.025, power ≥90%, non-inferiority margin 0.10). Secondary outcomes include transfusions, bleeding-related clinical endpoints, coagulation parameters and safety.

Ethics and dissemination: The trial has been approved by the institutional review boards of all participating centres. Trial completion is anticipated at the end of 2024, and results will be disseminated via publications in peer-reviewed journals and conference presentations in 2025. The results will advance our understanding of coagulation management in bleeding surgical patients, potentially reducing the need for allogeneic blood products and improving outcomes in surgical patients.

Trial registration number: NCT05523297.

Keywords: Bleeding disorders & coagulopathies; Blood bank & transfusion medicine; Cardiac surgery; Randomized Controlled Trial.

Figure 1. Cardiac surgery blood transfusion algorithm (updated from TACS)*. *To determine the need for RBC transfusion, consider patient status and haemoglobin. Transfuse red cells if Hb<70 g/L during CPB; <80 g/L post-CPB and <90 g/L in bleeding or unstable patients. †In general, the initial protamine dose should not exceed 400 mg, irrespective of the amount of heparin given. If an additional protamine dose does not shorten ACT, consider low fibrinogen levels or deficiency of enzymatic coagulation factors as a reason for the prolonged ACT and treat according to the algorithm. ‡BSS<2 (less than moderate)=no therapy; BSS 2–3 (moderate-severe)=institute stepwise treatment; assess bleeding after each product; BSS 4 (life-threatening)=administer therapy as necessary without waiting for laboratory results and combine therapies as appropriate. §POC INR should be performed >10–15 min after protamine or results may be inaccurate. ACT, activated clotting time; Blwk, bloodwork; BSS, bleeding severity scale; CBC, complete blood count; CPB, cardiopulmonary bypass; CT, clotting time; Hb, haemoglobin; IMP, investigational medicinal product; INR, international normalised ratio; POC, point of care.

Figure 2. Study design. *OR personnel will remain blinded to treatment until treatment decision; patients will be blinded to treatment allocation. †A second dose of 4F-PCC or FP (as per original randomised allocation) can be given within the 24-hour treatment period (ie, within 24 hours after the first dose of IMP) if the patient continues to have at least a grade 2 bleed and an INR≥1.5 after the first dose; for subsequent doses, the patient will receive FP. ‡FP in 1–4 U increments at the discretion of the ordering physician. 4F-PCC, four-factor prothrombin complex concentrate; BW, body weight; FP, frozen plasma; IMP, investigational medicinal product; IU, international units; OR, operating room; U, units.