Safety and efficacy of prothrombin complex concentrate as first-line treatment in bleeding after cardiac surgery

Between January 2005 and December 2013, all consecutive patients undergoing isolated coronary artery bypass graft (CABG), valve surgery (with or without concomitant CABG) and proximal aortic procedures at Varese University Hospital were included in this observational study. Elective, urgent or emergency procedures were all included. Off-pump CABG procedures, along with other cardiac operations (cardiac tumour removal, left ventricular remodelling, adult congenital cardiac operation, post-infarction ventricular septal defect and free wall rupture repairs), were not included. Patients who died intra-operatively without blood product administration were also excluded from the analysis. All data were prospectively collected and recorded in computerised database registries that remained consistent over the study period [4, 19, 20]. Information about demographics, co-morbidities, medical and surgical history, operative details and post-operative events during the hospital stay were all registered. The study protocol was approved by the local institutional review board (Comitato Etico Provinciale di Varese s.n. 07/04/2015). Patient consent was waived due to the retrospective and observational nature of the study.

Pre-operative management, anaesthetic and surgical techniques were standardised for all patients and have been reported previously [4, 19, 20]. Generally, anti-platelet drugs and anti-coagulation drugs were discontinued on the day of hospitalisation (median 2 and 3 days before surgery, respectively). Other medications were routinely omitted on the day of the operation and restarted on the first post-operative day, unless clinically contraindicated. All surgical procedures were performed through a median sternotomy approach, and CPB was undertaken in standardised fashion, with cannulation of the ascending aorta and right atrial or bicaval venous cannulation. Intravenous heparin was dosed as 300 IU/kg body weight, and the activated clotting time (ACT) was maintained above 450 seconds. In addition, in all these cases, tranexamic acid was intravenously administered after the induction of anaesthesia until the end of the operation (20 mg/kg for the first hour and 2 mg/kg thereafter). After the CPB, the circulating heparin was antagonised with protamine sulphate at a ratio of 1 mg of protamine per 100 IU of heparin. A prolonged ACT after surgery was treated with an additional dose of protamine sulphate. Generally, when visual inspection revealed microvascular bleeding or an important blood collection in the cardiotomy reservoir (generally 200 ml after weaning from CPB), the patient received an assessment of the haemostasis/coagulation profile through thromboelastography (TEG; Haemoscope, Niles, IL) with and without heparinase. Therefore, peri-operative need for blood products, including FFP and platelets, was determined on an individual basis. Transfusion was guided by point-of-care thromboelastography, prothrombin and activated partial thromboplastin times, and platelet count. Homologous red blood cells (RBC) were intra-operatively administered to maintain the haemoglobin concentration >7 g/dl or the haematocrit higher than 20 % during CPB, whilst they were post-operatively given when haemoglobin was <8 g/dl. Platelets were transfused when their count was ≤60 × 10⁹/L. Additional blood product transfusions, however, were done at the discretion of the individual surgeon or attending anaesthesiologist. Aprotinin or other haemostatic agents were not used in this series. At the end of surgery, patients were transferred to the intensive care unit (ICU) and managed according to the unit protocols [4, 19, 20].

The primary end-point was the impact of PCC on hospital mortality. Secondary end-points were the effect of PCC on post-operative complications and blood transfusion products.

Patients receiving PCC constituted the study group, and PCC was administered intra-operatively before chest closure or in the ICU within the first post-operative hours. Uman Complex D.I. (Kedrion; Castelvecchio Pascoli, Italy) was the sole PCC available in our institution, and starting in January 2012 it constituted the first-line therapy in coagulation management, replacing FFP. PCC contains clotting factors II, IX and X and is subjected to two steps of viral inactivation—first, solvent/detergent treatment and then heat treatment (100 °C for 30 minutes)—and is supplied as 500 IU of factor IX (20 ml) in vials [21]. Other analysed variables were defined as previously described [4, 19, 20]. Generally, blood product transfusions were counted by units. Haemorrhagic complications accounted for the need for reexploration for bleeding or cardiac tamponade. Generally, significant post-operative bleeding requiring surgical reexploration was defined as >300 ml during the first hour, >250 ml during the second hour, >200 ml during the third hour or a total of 1000 ml or more during the first 6 h. However, the decision regarding haemorrhagic reexploration was made by the surgeon in charge. Chest tube outputs were used as a measure of blood loss, and our analysis was based on the total volume of loss during the first 24 h of the patient’s stay in the ICU. Post-operative acute kidney injury (AKI) was defined according to the consensus RIFLE criteria (risk, injury, failure, loss of function, and end-stage renal disease) using the maximal change in serum creatinine and estimated glomerular filtration rate during the first 7 post-operative days compared with pre-operative baseline values [22].

Clinical data were prospectively recorded and tabulated using Microsoft Excel software (Microsoft, Redmond, WA, USA). Continuous data are reported as mean and standard deviation or median and interquartile range (IQR), as appropriate. Nominal variables were reported as counts and percentages. Fisher’s exact test, χ² test and the Mann-Whitney U test were used for univariate analysis. No attempt to replace missing values was made. Multivariate analysis was performed using logistic and linear regression. The area under the receiver operating characteristic (ROC) curve was used to represent the regression probabilities.

Since January 2012, PCC has been used systematically as first-line therapy in coagulation management, completely replacing FFP, and this PCC use was consistently followed. Therefore, the PCC study group was matched with the historical series of patients who received FFP before this time point. Because the study groups (i.e., the PCC and the FFP groups) significantly differed in a number of baseline and operative variables, a propensity score was calculated by logistic regression to estimate the probability of being assigned to each of the study treatments. The propensity score was calculated in a non-parsimonious way, including all 31 pre-operative and operative variables listed in Tables 1 and 2. The obtained propensity score was used for adjusted analysis in the overall series and for one-to-one propensity score caliper matching. The caliper width chosen was 0.2 times the standard deviation of the logit of the propensity score (i.e., 0.01). Propensity score was used as a covariate, along with the treatment method, in the multivariate analysis model for each outcome end-point. After the propensity score matching was performed, differences between the two groups were assessed. Absolute standardised differences were estimated to evaluate the pre-match and post-match imbalance, and a standardised difference <0.1 was considered a negligible difference in the mean or prevalence of a covariate between treatment groups (Fig. 1) [23, 24]. Finally, the significance within the models was evaluated with the Wald test, whereas the strength of the association of variables with post-operative outcomes was estimated by calculating the odds ratio (OR), the β unstandardised coefficient and 95 % confidence intervals (CIs). The model was calibrated using the Hosmer-Lemeshow goodness-of-fit test, as well as residual diagnostics (deviance and degrees of freedom of β values). Model discrimination was evaluated by using the area under the ROC curve. All tests were two-sided with the α level set at 0.05 for statistical significance. Statistical analysis was performed using IBM SPSS version 22.0 software (IBM, Armonk, NY, USA).