We conducted a single center, double blind, placebo controlled, randomized pilot trial to assess the feasibility and safety of prophylactic FEIBA administration in patients undergoing elective major aortic cardiovascular surgery requiring CPB. The study was conducted at Oregon Health and Science University adult cardiac operating rooms between August 1, 2016 and August 31, 2017. The study protocol was approved by the Institutional Review Board. Patients were enrolled in the trial after providing written informed consent preoperatively. The study adheres to CONSORT guidelines.
Patients were eligible if they were adults 18 years or older, scheduled for elective aortic procedures, including ascending, arch, and descending repair or reconstruction, with cardiopulmonary bypass, aortic valve repair or replacement, coronary re-implantation (Bentall) and/or deep hypothermic circulatory arrest. Patients were excluded if they were unable to receive the study drug based on contraindications stated by the manufacturer, such as known anaphylactic or severe hypersensitivity reactions to FEIBA or any of its components or received a blood transfusion within 28 days. Patients were also excluded if their scheduled procedure included coronary artery bypass grafting, had history of myocardial infarction, thrombosis or embolism, disseminated intravascular coagulation, or were pregnant women, decisionally impaired, prisoners, or unwilling to provide informed consent.
Randomization and blinding
A random list equally assigning patient to either FEIBA or placebo was generated using a uniform distribution, maintained and assigned by the investigational pharmacy. Patients, surgeons, anesthesiologists, and nurses were blinded to treatment assignment. The research pharmacy prepared the FEIBA (at the concentration of 40 IU/mL) or placebo (normal saline) in an opaque syringe. To maintain blinding, the volume of FEIBA and the matched placebo were prepared based on an mL per kg basis. Blinded assessors collected data on primary and secondary endpoints, including transfusion requirements, safety endpoints, and protocol adherence auditing.
After anesthesia induction, patients were equally randomized to receive either a single dose of FEIBA or a matched volume of saline administered after separation from CPB. The active study drug was prepared in the dose of 20 IU per kilograms in a concentration of 40 IU/mL, at a rate of 0.5 mL/kg via infusion pump over 10 minutes. The placebo consisted of a matched volume of 0.9% sodium chloride supplied in an identical syringe and tubing at a rate of 0.5 mL/kg via infusion pump over 10 minutes. Patients were otherwise managed per usual care according to a standardized protocol.
After separation from CPB, a reversal dose of intravenous protamine sulfate, calculated according to the heparin dose response curve, was given with a target goal of a heparin concentration of zero or a return to baseline activated clotting time (ACT). As part of our standard care, routine post CPB labs, a complete blood count and coagulopathy panel including hemoglobin, hematocrit, platelet count, INR, aPTT and fibrinogen were sent after the administration of IV protamine immediately following separation from CPB, with a post protamine ACT and arterial blood gas. In addition, samples were collected for thromboelastogram (TEG) by the research lab. After ACT normalized and labs were drawn, the study drug was administered, and the field was subsequently inspected for ongoing microvascular bleeding. In the presence of refractory bleeding diathesis, the anesthesiologist was permitted to administer a dose of FEIBA in an open label manner as a rescue measure based on the algorithm described below and illustrated in Fig. 1. Patients who experienced hemorrhage received, as first line, standard therapy with blood products including fresh frozen plasma (FFP), platelets and packed red blood cells (PRBCs). Up to 1 apheresis platelets and 2 FFPs could be administered empirically, then additional products were administered based on coagulation panel (target INR ≤ 1.7 and aPTT ≤ 50 sec). PRBCs were administered with the goal of maintaining a hemoglobin level ≥ 7 mg/dL. If refractory bleeding persisted after the empiric or laboratory-based administration of at least 4 units of FFPs and 2 apheresis platelets, then rescue therapy of 10–20 IU/kg (or 1,500 units for patients > 150 kg) of open-label FEIBA was given to patients who displayed refractory bleeding diathesis. Subsequently, after the administration of FEIBA, cryoprecipitate and lab guided administration were continued. The study was designed such that the total dose of FEIBA would not exceed 40 IU/kg (including the presumed 20 IU/kg given as study drug). The supply of FEIBA for open label use was prepared by the anesthesiologist according to manufacturer recommendations.
We planned to enroll 12 patients for the initial feasibility and safety study. As this study was designed to evaluate the feasibility and safety of FEIBA administration in the setting of high-risk cardiovascular surgery with CBP, it did not have adequate power for efficacy endpoints.
The primary goal of this pilot trail was to document the feasibility of the prophylactic blinded administration of FEIBA in the context of cardiovascular procedures at high risk of coagulopathy and requirement for blood product transfusion. Indicators of feasibility were protocol violations, maintenance of blinding, use of open label FEIBA, and occurrence of serious adverse events. The primary endpoints for a larger pivotal trial would be cumulative volume of blood products transfused including packed red blood cells (PRBCs), fresh frozen plasma (FFP), platelets, and use of cryoprecipitate, after the administration of the study drug until the end of anesthesia, and the evaluation of the safety profile.
The study was analyzed using a modified intention-to-treat approach. Descriptive summaries are presented using means and standard deviations (SD) for quantitative characteristics and frequencies (%) for categorical characteristics. Since the study design was randomized, we tested for treatment differences using Welch’s t-tests for mean comparisons of quantitative characteristics and chi-square tests of associations for binary or categorical characteristics. Welch’s t-test was used to test for a treatment effect for the primary endpoint, volume in mL/kg body weight of any blood products transfused after randomization, and for the secondary endpoints. There were no plans for interim analysis, however, safety data was monitored on an ongoing basis during the study. All hypothesis tests evaluated were two-sided, and all analyses were conducted using the Stata (version 15.1) statistical package. The same statistical package was used to create the random sequence for the fair-coin randomization assignment.