Clinical trial NCT04244981: Efficacy of Prothrombin Complex Concentrate Reducing Perioperative Blood Loss in Cardiac Surgery
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Cardiac Surgical Procedures
Keywords: prothrombin complex concentrate
fresh frozen plasma
perioperative blood loss
efficacy
cardiac surgery
cardiopulmonary bypass
Lead sponsor: Chinese Academy of Medical Sciences, Fuwai Hospital
Sponsor class: OTHER
Collaborators: name: Peking Union Medical College Hospital
name: Beijing Anzhen Hospital
name: Guizhou Provincial People's Hospital
name: Zunyi Medical College
First posted: 2020-01-28
Enrollment: 796
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 796 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 398 cases in each group. Preoperative management, anesthetic and surgical techniques will be standardized for all patients. Prolonged APTT (\> 45 s) will be regarded as a trigger for administration of PCC or FFP, according to the randomized groups. In group PCC, patients will be given 8\~15 IU/kg PCC. In group FFP, patients will be given 6\~10 mL/kg FFP.
Primary purpose: TREATMENT

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. 796 subjects will be randomly divided into 2 groups (group PCC and group FFP), with 398 cases in each group. Patients will be given 8\~15 IU/kg 4-factor PCC in group PCC and 6\~10 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 within 24 hours after surgery. The secondary outcomes include (1) the total units of allogeneic red blood cells (RBCs) transfused within 7 days after surgery and (2) length of intensive care unit (ICU) stay. Adverse events and serious adverse events will be monitored as safety outcomes. Exploratory outcomes include re-exploration due to postoperative bleeding within 7 days after surgery and length of hospital stay.

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 will be included. 796 subjects will be randomly divided into 2 groups (group PCC and group FFP), with 398 cases in each group. Preoperative management, anesthetic and surgical techniques will be standardized for both groups. When APTT is prolonged (\> 45 s), patients will be given 8\~15 IU/kg PCC in group PCC and 6\~10 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 within 24 hours after surgery. The secondary outcomes include (1) the total units of allogeneic red blood cells (RBCs) transfused within 7 days after surgery and (2) length of intensive care unit (ICU) stay. Adverse events and serious adverse events will be monitored as safety outcomes. Exploratory outcomes include re-exploration due to postoperative bleeding within 7 days after surgery and length of hospital stay. Modified intent-to-treat analysis will be used for all valid variables. All randomised 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 absolute standardised differences, and a value larger than 0.1 will be regarded as a clinically relevant difference between groups. Unbalanced baseline factors will be further adjusted by multivariable regression models. The primary outcome, the volume of blood loss 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 risk ratio and mean difference for binary and continuous outcomes with corresponding 95% confidence intervals. Bonferroni's correction for multiple comparisons will be conducted in the analysis of the secondary outcomes. If there exists unbalanced baseline characteristics, the primary outcome and secondary outcomes will be regressed against the group allocation and the unbalanced factors using liner regression and Cox regression models. Proportional hazard assumption will be checked by the Schoenfeld's residual plot. For safety outcomes, we will only describe the incidence of overall adverse events, SAEs, and component adverse events without statistical tests between two groups. A two-sided P-value \< 0.05 was considered indicative of statistical significance.

Our independent Data Safety Monitoring Board (DSMB), which includes epidemiologists, cardiovascular surgeons, anesthesiologists, and blood transfusion specialists, conducted an interim review of our study. Considering the shortage of blood resources and the difficulties in large-sample recruitment, the DSMB recommended adding an interim analysis. Therefore, we decided to conduct an interim analysis after recruiting 50% of the patients, applying Bonferroni correction for alpha spending with a two-sided alpha of 0.025. And the final analysis will be at 100% patients recruited with a two-sided alpha of 0.025. With the same standard deviation (824.38mL) and the superior margin (200mL) is, as well as the 90% power and 10% dropout rate, we recalculated the sample size and found out that 938 patients in total should be recruited. Thus our interim analysis will be conducted when 469 patients recruited.

Eligibility criteria: Inclusion Criteria:

1. Age between 18 and 80 years.
2. Undergoing elective coronary artery bypass grafting (CABG) or valve replacement or valvuloplasty through CPB.
3. Signing of the informed consent form.
4. Developing coagulation factor deficiency or coagulopathic bleeding during the surgery, meeting the indications of PCC or FFP treatment: a) prolonged APTT (\> 45 s) measured 20 minutes after CPB, and b) excessive bleeding observed.

Exclusion Criteria:

1. History of cardiac surgery.
2. Severe hepatic dysfunction before surgery.
3. Coagulopathy before surgery, including inherited or acquired coagulation factor deficiencies, thrombocytopenia, platelet dysfunction and other bleeding disorders.
4. Use of warfarin and INR \> 1.2 before surgery.
5. Withdrawal of clopidogrel less than 5 days and low molecular weight heparin less than 12 hours before surgery.
6. Allergy to allogeneic blood products.
7. Pregnancy.
8. Other serious diseases that may affect patient survival time, such as cancers.

Primary outcomes:
measure: volume of blood loss within 24 hours after surgery
timeFrame: postoperative period up to 24 hours after surgery
Secondary outcomes:
measure: total units of allogeneic RBCs transfused within 7 days after surgery
timeFrame: during the intraoperative and postoperative period up to 7 days after surgery
measure: length of intensive care unit (ICU) stay
timeFrame: postoperative period
Other outcomes:
measure: re-exploration within 7 days after surgery
timeFrame: within 7 days after surgery
measure: length of hospital stay
timeFrame: postoperative period
Locations:
city: Beijing
country: China
facility: Cardiovascular Institute and Fuwai Hospital, CAMS&PUMC
state: Beijing
city: Beijing
country: China
facility: Peking Union Medical College Hospital
state: Beijing
Study officials:
affiliation: Peking Union Medical College Hospital
name: Lijian Pei, M.D.
role: STUDY_CHAIR
affiliation: Chinese Academy of Medical Sciences, Fuwai Hospital
name: Jia Shi, M.D.
role: PRINCIPAL_INVESTIGATOR
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