Active-control Randomized Trial Comparing 4-factor Prothrombin Complex Concentrate With Frozen Plasma in Cardiac Surgery
- Conditions
- Bleeding Cardiac Surgery Patients
- Interventions
- Drug: Frozen Plasma Product, Human
- Registration Number
- NCT05523297
- Lead Sponsor
- Octapharma
- Brief Summary
This is a multicenter, active-control randomized, prospective, Phase 3 study in adult cardiac surgery patients. 420 patients were randomized at 12 hospitals.
- Detailed Description
Patients were randomized to receive either 4-factor PCC (Octaplex) or frozen plasma (FP). The study compared the hemostatic treatment response to Octaplex versus FP, defined as effective if no additional systemic or surgical hemostatic intervention is required from 60 minutes to 24 hours after initiation of the first treatment dose. The study includes adult (≥18 years old) patients who underwent cardiac surgery with cardiopulmonary bypass (CPB) and required coagulation factor replacement due to bleeding post-CPB and after adequate reversal of heparin with protamine (as assessed by the surgical staff based on clinical and laboratory criteria) during surgery, and who have a known (e.g., as indicated by INR) or suspected coagulation factor deficiency.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 420
-
Adult (≥18 years old) patients undergoing any index cardiac surgery employing CPB
-
Coagulation factor replacement with PCC or FP ordered in the operating room for:
- Management of bleeding, or
- Anticipated bleeding in a patient who has been on-pump for >2 hours or has undergone a complex procedure (e.g., aortocoronary bypass [ACB] plus aortic valve replacement)
-
Coagulation factor deficiency, either known to exist (e.g., as indicated by elevated EXTEM clotting time [CT] or INR) or suspected based on the clinical situation
-
Patients who have given written informed consent. In United States patients will provide informed consent prior to surgery. In Canada, informed consent will be obtained after surgery, in accordance with Article 3.7A of the 2018 Tri- Council Policy Statement on the Ethical Conduct for Research Involving Humans.
- Undergoing heart transplantation, insertion or removal of ventricular assist devices (not including intra-aortic balloon pump [IABP]) or repair of thoracoabdominal aneurysm
- Critical state immediately before surgery with high probability of death within 24 hours of surgery (e.g., acute aortic dissection, cardiac arrest within 24 hours before surgery)
- Severe right heart failure (clinical diagnosis ± echocardiography)
- Known contraindications to heparin
- PCC required for reversal of warfarin or direct oral anticoagulant (DOAC; dabigatran, rivaroxaban, apixaban or edoxaban) within 3 days prior to or during surgery
- Known thromboembolic event (TEE) within 3 months prior to surgery
- History of severe allergic reactions to PCC or FP
- Individuals who have immunoglobulin A (IgA) deficiency with known antibodies against IgA
- Refusal of allogeneic blood products
- Known pregnancy
- Currently enrolled in other interventional clinical trials
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Octaplex Octaplex Participants were administered Octaplex according to a recommended initial dose of 1,500 IU for patients weighing ≤60 kg and 2,000 IU for patients weighing \>60 kg. A second dose of IMP could be administered if the patient continued to have at least moderate bleeding and suspected coagulation deficiency (e.g., INR ≥1.5) after completion of the first dose, up to the maximum allowable dose (3,000 IU if ≤60 kg or 4,000 IU if \>60 kg). Octaplex: Prothrombin complex concentrate Frozen plasma Frozen Plasma Product, Human Participants were administered FP according to a recommended initial dose of 3 U for patients weighing ≤60 kg and 4 U for patients weighing \>60 kg. A second dose of IMP could be administered if the patient continued to have at least moderate bleeding and suspected coagulation deficiency (e.g., INR ≥1.5) after completion of the first dose, up to the maximum allowable dose (6 U if ≤60 kg or 8 U if \>60 kg). Frozen Plasma Product, Human
- Primary Outcome Measures
Name Time Method Number of Patients Requiring Additional Hemostatic Intervention 60 minutes to 24 hours after first dose of IMP Defined as 'effective' if no additional hemostatic intervention, such as administration of any systemic hemostatic agents (including platelets, cryoprecipitate, fibrinogen concentrate, activated recombinant factor VII \[rFVIIa\], other coagulation factor products or a second dose of IMP) or any hemostatic interventions (including surgical re-opening for bleeding) is required from 60 minutes to 24 hours after initiation of the first dose of IMP.
- Secondary Outcome Measures
Name Time Method Comparison of Global Hemostatic Response Based on Requirement of Additional Hemostatic Intervention and Decreased Hemoglobin Levels 60 minutes to 24 hours after first dose of IMP Defined as 'positive' if no additional hemostatic intervention is required and hemoglobin levels decrease by \<30% (after accounting for red cell transfusions) from 60 minutes to 24 hours after initiation of the first dose of IMP.
Compare the Amount of Chest Tube Drainage Between the Octaplex and FP Groups. 12 and 24 hours after chest closure Compare the Incidence of Severe to Massive Bleeding Between the Octaplex and FP Groups Using a Modification of the Universal Definition of Perioperative Bleeding (UDPB). 24 hours after surgery start, after the end of CPB and after IMP initiation Yes or no refers to whether severe to massive bleeding was present.
Compare Efficacy in Terms of the Mean Number of Total Allogeneic Blood Products (ABPs) (IMP and Non-IMP) Transfused Between the Octaplex and FP Groups. First 24 hours after the end of CPB Compare Efficacy in Terms of the Mean Number of Total Non-IMP Allogeneic Blood Products Transfused Between the Octaplex and FP Groups. First 24 hours after the end of CPB Compare Efficacy in Terms of the Mean Number of Total Non-IMP Allogeneic Blood Components Transfused Between the Octaplex and FP Groups. First 24 hours and 7 days after IMP initiation Compare Mean Number of Individual Allogeneic Blood Components Transfused Between the Octaplex and FP Groups. 24 hours and 7 days after start of surgery, and after the end of CPB and after IMP initiation Compare Efficacy in Terms of the Incidence of Transfusion of Individual Allogeneic Blood Components Transfused Between the Octaplex and FP Groups. 24 hours and 7 days after start of surgery and after the end of CPB and after IMP initiation Compare Incidence of Administration of Non-IMP Coagulation Factor Products Between Octaplex and FP Groups 24 hours and 7 days after the start of surgery, after the end of CPB and after IMP initiation Compare Incidence of Intracerebral Hemorrhage Between the Octaplex and FP Groups 24 hours after start of surgery, after the end of CPB and after IMP initiation Compare Incidence of Gastrointestinal Hemorrhage Between Octaplex and FP Groups 24 hours after start of surgery, after the end of CPB and after IMP initiation Compare Incidence of Surgical Re-exploration Between Octaplex and FP Groups 24 hours after start of surgery, after the end of CPB and after IMP initiation Comparison of the Effect of Octaplex Versus FP Administration on the Change in International Normalised Ratio (INR) Before and After Therapy Administration. Within 30 minutes before to 60 minutes after the initiation of IMP administration. The international normalized ratio (INR) is a standardized measure of prothrombin time (PT), ensuring consistency in results across different laboratories. The normal range for INR is around 0.8 to 1.2. Higher INR values indicate a slower clotting time and are associated with bleeding. Effective procoagulant therapy can reduce/normalize the INR.
INR reduction was considered successful if the magnitude of the reduction was \>1.0 or the post-treatment level dropped below 1.5 (INR \>1.5 indicates that one or more coagulation factor levels are below the 30% critical threshold)Comparison of the Effect of Octaplex Versus FP Administration on the Change in Prothrombin Time (PT) Within 75 minutes before to within 75 minutes after the initiation of IMP administration The prothrombin time (PT) measures the time it takes for clotting to occur, primarily assessing the extrinsic pathway of the coagulation cascade. Normal PT values range from 9 to 13 seconds. Higher PT values indicate a prolonged clotting time, suggesting potential issues with clotting factors such as fibrinogen, factors V, VII, and X and prothrombin, and are associated with bleeding. Effective procoagulant therapy can reduce/normalize the PT.
Comparison of the Effect of Octaplex Versus FP Administration on the Change in Activated Partial Thromboplastin Time (aPTT) Within 75 minutes before to within 75 minutes after the initiation of IMP administration Activated partial thromboplastin time (aPTT) is a standard laboratory test that measures how long it takes (in seconds) for clotting to occur (in the presence of an activator). It evaluates the intrinsic and common pathways of the coagulation cascade, assessing factors such as VIII, IX, XI, and XII, as well as fibrinogen. Prolonged aPTT may signify deficiencies in these clotting factors and is associated with bleeding. Effective procoagulant therapy can shorten/normalize the aPTT.
Comparison of the Effect of Octaplex Versus FP Administration on the Change in Fibrinogen Activity Within 75 minutes before to within 75 minutes after the initiation of IMP administration Comparison of the Effect of Octaplex Versus FP Administration on the Change in ROTEM EXTEM CT Within 75 minutes before to within 75 minutes after the initiation of IMP administration A rotational thromboelastometry (ROTEM; Werfen) device can be used at the bedside to rapidly assess the patient's coagulation status. Different viscoelastic tests can be performed to assess the dynamics of clot formation and lysis. Specifically, the EXTEM test is activated with tissue factor and evaluates the extrinsic coagulation pathway, with clotting time (CT) providing a measure (in seconds) of how quickly a clot starts forming. Prolonged EXTEM CT is associated with bleeding. Effective procoagulant therapy can reduce/normalize the EXTEM CT.
Comparison of the Effect of Octaplex Versus FP Administration on the Change in ROTEM EXTEM MCF Within 75 minutes before to within 75 minutes after the initiation of IMP administration A rotational thromboelastometry (ROTEM; Werfen) device can be used at the bedside to rapidly assess the patient's coagulation status. Different viscoelastic tests can be performed to assess the dynamics of clot formation and lysis. Specifically, the EXTEM test is activated with tissue factor and evaluates the extrinsic coagulation pathway, with maximum clot firmness (MCF) providing a measure (in mm) of the strength of the clot. Reduced EXTEM MCF is associated with bleeding. Effective procoagulant therapy can increase/normalize the EXTEM MCF.
Comparison of the Effect of Octaplex Versus FP Administration on the Change in ROTEM FIBTEM MCF Within 75 minutes before to within 75 minutes after the initiation of IMP administration A rotational thromboelastometry (ROTEM; Werfen) device can be used at the bedside to rapidly assess the patient's coagulation status. Different viscoelastic tests can be performed to assess the dynamics of clot formation and lysis. Specifically, the FIBTEM test evaluates fibrin-based clotting - it is extrinsically activated with tissue factor and additionally incorporates an inhibitor to eliminate the contribution of platelets to clotting. Maximum clot firmness (MCF) in the FIBTEM test provides a measure (in mm) of the strength of the fibrin-based clot. Reduced FIBTEM MCF is associated with bleeding. Effective procoagulant therapy to restore fibrinogen can increase/normalize the FIBTEM MCF.
Comparison of the Effect of Octaplex Versus FP Administration on the Change in Platelet Count Measured by Plateletworks Within 75 minutes before to within 75 minutes after the initiation of IMP administration Comparison of the Effect of Octaplex Versus FP Administration on the Change in Platelet Function Measured by Plateletworks Within 75 minutes before to within 75 minutes after the initiation of IMP administration The Plateletworks device (Helena Laboratories) enables rapid bedside screening of platelet function. The system uses an impedance cell counter and Plateletworks reagent tubes to evaluate platelet function and monitor treatment effects. By comparing a baseline total platelet count against the platelet count measured in the presence of an agonist used to stimulate platelet aggregation (ADP, collagen, or arachidonic acid), the tests determine the percent aggregation or inhibition of functional platelets. Manufacturer reference ranges, determined by testing blood samples from healthy volunteers, are 86-100% for ADP, 70-100% for collagen, and 60-100% for arachidonic acid. Values within these ranges indicate 'normal (positive)' platelet aggregation, which is important for clotting; lower values may be considered 'abnormal (negative)' and reflective of platelet inhibition. The manufacturer advises each laboratory to establish their own reference ranges for their patient population.
Comparison of Total Time Elapsed From Initiation of the First Dose of IMP to Arrival Into the ICU Between the Octaplex and FP Groups. From initiation of IMP to arrival at ICU room (within 24 hours) Comparison of Incidence of Serious Treatment-emergent Adverse Events Between Octaplex and FP Groups From the beginning of surgery up to postoperative day 30 Comparison of the Duration of Mechanical Ventilation Between Octaplex and FP Groups From the beginning of surgery up to postoperative day 30 Comparison of the Duration of ICU Stay Between Octaplex and FP Groups From the beginning of surgery up to postoperative day 30 Comparison of the Duration of Hospitalization Between Octaplex and FP Groups From the beginning of surgery up to postoperative day 30 Comparison of the Incidence of Death Between Octaplex and FP Groups Up to 30 days after the end of CPB Comparison of the Number of Days Alive and Out of Hospital Between Octaplex and FP Groups From the beginning of surgery up to postoperative day 30
Trial Locations
- Locations (13)
Duke University Health System
🇺🇸Durham, North Carolina, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Royal Columbian Hospital
🇨🇦New Westminster, British Columbia, Canada
University of British Columbia and Vancouver Coastal Health Authority
🇨🇦Vancouver, British Columbia, Canada
Hamilton Health Sciences Corporation
🇨🇦Hamilton, Ontario, Canada
Kingston General Hospital
🇨🇦Kingston, Ontario, Canada
London Health Sciences
🇨🇦London, Ontario, Canada
University of Ottawa Heart Institute
🇨🇦Ottawa, Ontario, Canada
Sunnybrook Hospital
🇨🇦Toronto, Ontario, Canada
St. Michael's Hospital
🇨🇦Toronto, Ontario, Canada
Scroll for more (3 remaining)Duke University Health System🇺🇸Durham, North Carolina, United States