Active-control Randomized Trial Comparing 4-factor Prothrombin Complex Concentrate With Frozen Plasma in Cardiac Surgery

Octapharma420 enrolled

Overview

This is a multicenter, active-control randomized, prospective, Phase 3 study in adult cardiac surgery patients. 420 patients were randomized at 12 hospitals.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

420

Conditions

Bleeding Cardiac Surgery Patients

Interventions

OctaplexDRUG

Prothrombin complex concentrate

Frozen Plasma Product, HumanDRUG

If additional treatment is required after the maximum dose of IMP is administered or the treatment period has elapsed, patients in both groups will receive frozen plasma

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Adult (≥18 years old) patients undergoing any index cardiac surgery employing CPB 2. Coagulation factor replacement with PCC or FP ordered in the operating room for: 1. Management of bleeding, or 2. 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) 3. 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 4. 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. Exclusion Criteria: 1. Undergoing heart transplantation, insertion or removal of ventricular assist devices (not including intra-aortic balloon pump \[IABP\]) or repair of thoracoabdominal aneurysm 2. 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) 3. Severe right heart failure (clinical diagnosis ± echocardiography) 4. Known contraindications to heparin 5. PCC required for reversal of warfarin or direct oral anticoagulant (DOAC; dabigatran, rivaroxaban, apixaban or edoxaban) within 3 days prior to or during surgery 6. Known thromboembolic event (TEE) within 3 months prior to surgery 7. History of severe allergic reactions to PCC or FP 8. Individuals who have immunoglobulin A (IgA) deficiency with known antibodies against IgA 9. Refusal of allogeneic blood products 10. Known pregnancy 11. Currently enrolled in other interventional clinical trials

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

Outcomes

Primary Outcomes

Number of Patients Requiring Additional Hemostatic Intervention

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.

Time frame: 60 minutes to 24 hours after first dose of IMP

Secondary Outcomes

Comparison of Global Hemostatic Response Based on Requirement of Additional Hemostatic Intervention and Decreased Hemoglobin Levels

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.

Time frame: 60 minutes to 24 hours after first dose of IMP

Compare the Amount of Chest Tube Drainage Between the Octaplex and FP Groups.

Time frame: 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).

Yes or no refers to whether severe to massive bleeding was present.

Time frame: 24 hours after surgery start, after the end of CPB and after IMP initiation

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.

Time frame: 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.

Data from ClinicalTrials.gov

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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

...and 3 more locations

Time frame: 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.

Time frame: First 24 hours and 7 days after IMP initiation

Compare Mean Number of Individual Allogeneic Blood Components Transfused Between the Octaplex and FP Groups.

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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.

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)

Time frame: Within 30 minutes before to 60 minutes after the initiation of IMP administration.

Comparison of the Effect of Octaplex Versus FP Administration on the Change in Prothrombin Time (PT)

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.