Effectiveness and Safety of Four-Factor Prothrombin Complex and Fresh Frozen Plasma in Cardiac Surgery

Objectives: The purpose of this study was to (i) describe the utilization pattern of four-factor prothrombin complex concentrate (4PCC) and fresh frozen plasma (FFP) used intraoperatively in coronary artery bypass graft (CABG) and valve surgeries requiring cardiopulmonary bypass (CPB) (ii) evaluate the factors associated with use of 4PCC or FFP intraoperatively in CABG and valve surgeries requiring CPB (iii) evaluate the effectiveness of 4PCC used intraoperatively in CABG and valve surgeries requiring CPB (iv), and assess the safety of 4PCC used intraoperatively in CABG and valve surgeries requiring CPB. Methods: This retrospective, cohort study identified all CABG, valve repair, and valve replacement surgeries from March 2014 to April 2016 at Houston Methodist Hospital (HMH), Houston, Texas. Patients included in the study were 18 years of age or older and receiving CABG and/or valve surgery requiring CPB. Patients who received other cardiac procedures during the CABG or valve procedure were excluded as well as patients receiving both FFP and 4PCC intraoperatively. The data sources for this study included institutional electronic health records (EHR), claims from Vizient, and clinical measures, comorbidities, and outcomes from the Society of Thoracic Surgeons (STS). The 4PCC and FFP exposures were identified from charge claims extracted from the Vizient database and validated from the EHR. Descriptive statistics were performed to assess the utilization pattern of 4PCC and FFP used intraoperatively in CABG and valve procedures, and three multivariable logistic regression models were created to determine the predictive factors of using 4PCC or FFP intraoperatively. The independent variables in the multivariable models were selected based on the Andersen Behavior Model and hypothesized that predisposing, enabling, and need factors that influence the use of these agents. The dependent variables in these logit models were the exposure of 4PCC, FFP, or 4PCC versus FFP. The primary endpoint evaluating the effectiveness of 4PCC versus FFP was the proportion of patients who received a red blood cell (RBC) transfusion intraoperatively or within 24 hours postoperatively. Multivariable logistic regression using backward elimination was performed to determine the effectiveness of 4PCC versus FFP administered intraoperatively with the dependent variable as RBC utilization. A sensitivity analyses on the primary endpoint was performed by creating a propensity score for the exposures of 4PCC versus FFP, then using the score as a regressor in a logistic regression model to validate the study findings. The safety of 4PCC compared to FFP was evaluated by performing bivariate statistical analysis with a focus on thromboembolic events. Results: During the study timeframe, a total of 924 patients were identified for the purpose of the study of the 1,946 patients who underwent CABG and/or valve surgery; 690 patients (70.2%) did not receive FFP or 4PCC intraoperatively (control), 166 patients (16.9%) received 4PCC only, 68 patients (6.9%) received FFP only, and 58 (5.9%) received both 4PCC and FFP intraoperatively. . More patients in the control and FFP groups underwent CABG alone (Control: 329 (56.8%); FFP: 33 (48.5%), and less patients in the control and FFP groups had valve procedures alone compared to the 4PCC group (Control: 247 (35.8%); FFP: 27 (39.7%). The control group also had significantly less repeat open-chests compared to the FFP and 4PCC groups (Control: 68 (9.9%); FFP: 14 (20.6%), 4PCC: 40 (24.1)). In addition, the control group had significantly shorter surgeries, CPB time, aortic cross-clamp time (ACT), and required less cell saver units compared to the FFP and 4PCC groups, while the FFP and 4PCC groups did not differ on any of the aforementioned measures. Factors positively associated receiving 4PCC compared to the control included the predisposing factor age (years) and need factors like international normalized ratio (INR), cell saver use (units), CPB time (min), and desmopressin use, and need factors negatively associated receiving 4PCC compared to the control included body mass index (BMI) (kg/m2), hematocrit (HCT) (%), platelets greater than 150 109/L, cardiac arrhythmia, dyslipidemia, and ε-aminocaproic acid (EACA) intraoperative use. Need factors associated with an increase in the odds of receiving FFP compared to the control were patients undergoing an emergent procedure, history of cerebrovascular disease (CVD), and cell saver use (units). Lastly, patients were more likely to receive 4PCC compared to FFP with each unit increase in cell saver use, if desmopressin was administered intraoperatively, and if the patient had HTN. Factors decreasing the likelihood of receiving 4PCC compared to FFP were patients that had dyslipidemia, liver dysfunction, and HCT (%). In the unadjusted bivariate comparison of patients requiring RBC transfusion, patients receiving 4PCC compared to FFP required less RBC transfusions intraoperatively and/or within 24 hours postoperatively (OR=0.43; 4PCC: 100/166 (60%) vs. FFP: 53/68 (78%); p-value=0.01). For the primary endpoint, the multivariable logistic regression model comparing patients receiving FFP intraoperatively to 4PCC found patients receiving 4PCC had a significant reduction in the odds of receiving an RBC transfusion intraoperatively and/or within 24 hours postoperatively (OR: 0.28; 95% CI: 0.13-0.62). The sensitivity analyses revealed patients receiving 4PCC compared to FFP also significantly reduced the odds of receiving an RBC transfusion intraoperatively and/or within 24 hours postoperatively (OR: 0.41; 95% CI: 0.19-0.89). More patients who received 4PCC had venous thromboembolism (8.4%) compared to the control (2.9%; p-value=0.001) but not compared to the FFP group (2.9%; p-value=0.162). No differences were found in the number of patients who had a stroke/ transient ischemic attack in the control (1.9%), FFP (0%), and 4PCC (3.0%) groups. Conclusions: This study found approximately 1 out of 5 patients received 4PCC intraoperatively with or without FFP, and approximately 1 out of 14 patients received FFP alone intraoperatively. The study findings suggest that intraoperative use of FFP and 4PCC is mainly occurring in patients with excessive bleeding evidenced by the significant relationship of need factors including cell saver use with their administration. In patients undergoing isolated CABG and/or valve surgery requiring CPB with indications of excessive bleeding, intraoperative administration of 4PCC compared to FFP can reduce a patient’s likelihood of requiring an RBC transfusion intraoperatively and up to 24 hours postoperatively. 4PCC should be used cautiously in hypercoaguable patients or patients with a history of thrombosis and only prescribed in the context of excessive bleeding.