Efficacy of Prothrombin Complex Concentrate Reducing Perioperative Blood Loss in Cardiac Surgery

Sponsor

Chinese Academy of Medical Sciences, Fuwai Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04244981

Collaborator

Peking Union Medical College Hospital (Other)

560

Enrollment

Arms

25.9

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

This study is a non-inferiority, randomized controlled trial, based on the hypothesis that 4-factor PCC is not inferior to FFP in reducing perioperative blood loss in patients undergoing cardiac surgery under cardiopulmonary bypass. 560 subjects will be randomly divided into 2 groups (group PCC and group FFP), with 280 cases in each group. Patients will be given a 4-factor PCC based on the patients' body weight and INR in group PCC and a dose of 10-15 ml/kg FFP in group FFP. All the patients will be followed up respectively at 24 hours, 48 hours, 72 hours and 7 days after the surgery. The primary outcome is the volume of blood loss during and within 24 hours after surgery. The secondary outcomes include (1) the total units of allogeneic red blood cells (RBCs) transfused during and within 7 days after surgery and (2) re-exploration due to postoperative bleeding within 7 days after surgery.

Condition or Disease	Intervention/Treatment	Phase
Cardiac Surgical Procedures	Drug: Prothrombin Complex Concentrate, Human Drug: Fresh Frozen Plasma	Phase 4

Detailed Description

Perioperative blood loss and allogeneic blood transfusion are major complications of cardiac surgery, which increase perioperative complications, perioperative mortality and medical costs.This study is a non-inferiority, randomized controlled trial, in order to determine whether PCC is no worse than FFP in reducing perioperative blood loss and allogeneic blood transfusion in patients undergoing cardiac surgery under CPB. Patients signed the informed consent, aged 18 to 80 years, receiving elective CABG or valve replacement or valvuloplasty under CPB in Fu Wai Hospital and Peking Union Medical College Hospital will be included. 560 subjects will be randomly divided into 2 groups (group PCC and group FFP), with 280 cases in each group. Preoperative management, anesthetic and surgical techniques will be standardized for both groups. When APTT is prolonged (>1.5 times normal), patients will be given a 4-factor PCC based on the patients' body weight and INR (INR 2-4, PCC 25 IU/kg; INR 4-6, PCC 35 IU/kg; INR>6, PCC 50 IU/kg) in group PCC and a dose of 10-15 ml/kg FFP in group FFP. All the patients will be followed up respectively at 24 hours, 48 hours, 72 hours and 7 days after the surgery to record observations relevant to the study and the results of laboratory testing. The laboratory tests include hemoglobin concentration, hematocrit, platelet count, INR, PT, APTT, fibrinogen levels and blood biochemistry parameters. The primary outcome is the volume of blood loss during and within 24 hours after surgery. The secondary outcomes include (1) the total units of allogeneic red blood cells (RBCs) transfused during and within 7 days after surgery and (2) re-exploration due to postoperative bleeding within 7 days after surgery. Modified intent-to-treat analysis will be used for all valid variables. All randomized subjects in the study, regardless of adherence to the study process or whether an adverse event occurs before or after the intervention, should be included in the analysis. Sensitivity analysis will be performed to assess the bias that may be introduced due to nonadherence to the protocol or missing data. Baseline characteristics will be tabulated and compared between the PCC and FFP groups using standardized differences, and a value larger than 0.2 will be regarded as a clinically relevant difference between groups.The primary outcome, the volume of blood loss during and within 24 hours after surgery, will be compared using the t-test with log transformation of the variable. Continuous secondary outcomes and the total units of allogeneic RBCs transfused during and within 7 days after surgery will be compared using a t-test with log transformation of the variable. The rate of re-exploration due to bleeding within 7 days after surgery will be compared using the chi-square test. Treatment effect will be measured by odds ratio and mean difference for binary and continuous outcomes with corresponding 95% confidence intervals. No correction for multiple comparisons will be conducted in the analysis of the secondary outcomes; hence, the findings for secondary outcomes will be interpreted only as explanatory results. A two-sided P-value < 0.05 was considered indicative of statistical significance.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

560 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

560 patients who meet the criteria will be randomly divided into 2 groups, named prothrombin complex concentrate group (group PCC) and fresh frozen plasma group (control group, group FFP), with 280 cases in each group. Preoperative management, anesthetic and surgical techniques will be standardized for all patients. Prolonged APTT (>1.5 times normal) will be regarded as a trigger for administration of PCC or FFP, according to the randomized groups. In group PCC, patients will be given a 4-factor PCC based on the patients' body weight and INR (INR 2-4, PCC 25 IU/kg; INR 4-6, PCC 35 IU/kg; INR>6, PCC 50 IU/kg). In group FFP, patients will be given FFP based on the patients' body weight (10-15 mL/kg).560 patients who meet the criteria will be randomly divided into 2 groups, named prothrombin complex concentrate group (group PCC) and fresh frozen plasma group (control group, group FFP), with 280 cases in each group. Preoperative management, anesthetic and surgical techniques will be standardized for all patients. Prolonged APTT (>1.5 times normal) will be regarded as a trigger for administration of PCC or FFP, according to the randomized groups. In group PCC, patients will be given a 4-factor PCC based on the patients' body weight and INR (INR 2-4, PCC 25 IU/kg; INR 4-6, PCC 35 IU/kg; INR>6, PCC 50 IU/kg). In group FFP, patients will be given FFP based on the patients' body weight (10-15 mL/kg).

Masking:

Triple (Participant, Care Provider, Outcomes Assessor)

Masking Description:

Stratified randomization will be used to assign the patients to two groups (group PCC and FFP). After enrollment, 1 hour before the operation, the patients will be randomized by a specific computer randomization system based on the type of surgery (CABG or valve replacement/valvuloplasty). Anesthesia nurses will prepare the corresponding products for each patient according to the group assignments in an anesthesia preparation room. Participants, anesthesiologists, surgeons, and outcome assessors will all be blinded to the group assignments throughout the trial.

Primary Purpose:

Treatment

Official Title:

Efficacy of Prothrombin Complex Concentrate Reducing Perioperative Blood Loss in Cardiac Surgery, Compared With Fresh Frozen Plasma: Study Protocol for a Non-inferiority, Randomized Controlled Trial

Anticipated Study Start Date :

Jan 1, 2021

Anticipated Primary Completion Date :

Dec 31, 2022

Anticipated Study Completion Date :

Mar 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PCC group When APTT is prolonged (>1.5 times normal), patients will be given a 4-factor PCC based on the patients' body weight and INR (INR 2-4, PCC 25 IU/kg; INR 4-6, PCC 35 IU/kg; INR>6, PCC 50 IU/kg).	Drug: Prothrombin Complex Concentrate, Human A 4-factor prothrombin complex concentrate (Confidex®, CSL Behring, Marburg, Germany), containing a defined concentration of the four vitamin K-dependent clotting factors (II, VII, IX and X) and the thrombo-inhibitor proteins C and S. Each vial of Confidex® contains a relatively high concentration of coagulation factor II (20-48 IU/mL), factor VII (10-25 IU/mL), factor IX (20-31 IU/mL), factor X (22-60 IU/mL), proteins C (15-45 IU/mL), proteins S (13-38 IU/mL), Heparin (0.5 IU/mL), and antithrombin (0.6 IU/mL). The administration is based on the patients' body weight and INR (INR 2-4, PCC 25 IU/kg; INR 4-6, PCC 35 IU/kg; INR>6, PCC 50 IU/kg)
Active Comparator: FFP group When APTT is prolonged (>1.5 times normal), patients will be given a dose of 10-15 ml/kg FFP.	Drug: Fresh Frozen Plasma FFP will be given based on the patients' body weight (10-15 mL/kg).

Arm

Intervention/Treatment

Experimental: PCC group

When APTT is prolonged (>1.5 times normal), patients will be given a 4-factor PCC based on the patients' body weight and INR (INR 2-4, PCC 25 IU/kg; INR 4-6, PCC 35 IU/kg; INR>6, PCC 50 IU/kg).

Drug: Prothrombin Complex Concentrate, Human

A 4-factor prothrombin complex concentrate (Confidex®, CSL Behring, Marburg, Germany), containing a defined concentration of the four vitamin K-dependent clotting factors (II, VII, IX and X) and the thrombo-inhibitor proteins C and S. Each vial of Confidex® contains a relatively high concentration of coagulation factor II (20-48 IU/mL), factor VII (10-25 IU/mL), factor IX (20-31 IU/mL), factor X (22-60 IU/mL), proteins C (15-45 IU/mL), proteins S (13-38 IU/mL), Heparin (0.5 IU/mL), and antithrombin (0.6 IU/mL). The administration is based on the patients' body weight and INR (INR 2-4, PCC 25 IU/kg; INR 4-6, PCC 35 IU/kg; INR>6, PCC 50 IU/kg)

Active Comparator: FFP group

When APTT is prolonged (>1.5 times normal), patients will be given a dose of 10-15 ml/kg FFP.

Drug: Fresh Frozen Plasma

FFP will be given based on the patients' body weight (10-15 mL/kg).

Outcome Measures

Primary Outcome Measures

volume of blood loss during and within 24 hours after surgery [during the intraoperative and postoperative period up to 24 hours after surgery]
the volume of blood loss during and within 24 hours after surgery

Secondary Outcome Measures

total units of allogeneic RBCs transfused during and within 7 days after surgery [during the intraoperative and postoperative period up to 7 days after surgery]
the total units of allogeneic RBC transfused during the intraoperative and postoperative period up to 7 days after surgery
re-exploration due to postoperative bleeding [within 7 days after surgery]
re-exploration due to postoperative bleeding within 7 days after surgery

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Receiving elective coronary artery bypass grafting (CABG), or valve replacement or valvuloplasty with cardiopulmonary bypass
Sign the informed consent

Exclusion Criteria:

History of cardiac surgery;
Hepatic dysfunction;
Renal insufficiency (serum creatinine higher than 176 µmol/l);
Severe coagulopathy;
Withdrawal of clopidogrel or aspirin less than 7 days and low molecular weight heparin less than 24 hours before surgery;
Hematological disorders;
Mass blood transfusion 24 hours before surgery;
Allergy to allogeneic blood products;
Pregnancy;
Other serious diseases that may affect patient survival time, such as tumors.