Objective: The objective of this study was to analyse the reversibility of the anticoagulant effect of warfarin by comparing prothrombin complex concentrate (PCC) versus frozen fresh plasma (FFP) in cardiology patients with serious warfarin intoxication. Methods: This was an observational and retrospective study comprising 67 patients (18 in group I [PCC] and 49 in group II [FFP]). The primary endpoint was the reversal of anticoagulant effect of warfarin after 2 and 24 hours of PCC or FFP administration. Comparisons between the groups were made using T-test and Q-square. Multivariate analyses were conducted using logistic regression, and the results were considered significant when p < 0.05. Complementary analysis was performed using the ROC curve, calculating the area under the curve (AUC), and calculating the cut-off score for the relation between PCC (UI/kg) or FFP (ml/kg) and INR reversibility. Results: The medium dose used was 27.6 UI/kg of PCC and 14.5 ml/kg of FFP. Significant differences were observed between groups I and II in the INR reversibility measurements after 2 hours (33.3% vs. 6.1%, p = 0.001) and 24 hours (38.9% vs. 12.2%, p = 0.009) as well as in the occurrence of pulmonary edema (5.6% vs. 42.9%, OR = 11.10, p = 0.04). The AUC for PCC was 0.891 (CI 95% [0.72 - 1.0]), and for FFP, it was 0.291 (CI 95% [0.09 - 0.49]). Conclusions: PCC is better than FFP treatment in reversing the warfarin intoxication after 2 and 24 hours of administration. Furthermore, PCC showed lower pulmonary edema in cardiology patients.
Bleeding in patients using warfarin is common and is often associated with the risk of death. The comparison between the in vivo use of prothrombin complex concentrate (PCC) and frozen fresh plasma (FFP) in cardiology patients remains uncertain. Recent studies have shown superiority of prothrombin complex concentrate (PCC) over frozen fresh plasma (FFP) administration in situations, such as in surgical patients or patients with intracranial bleeding, reducing transfusion requirements and even mortality [
The objective of this study was to analyse the reversibility of the anticoagulant effect of warfarin by comparing PCC versus FFP in cardiology patients with serious warfarin intoxication.
This study was an observational, unicentric and retrospective data bank analysis study performed in a tertiary health centre involving 67 patients, conducted between January 2015 and January 2016. The study included all patients with serious bleeding related to warfarin use when the prothrombin time/INR values were more than 20 or upon occurrence of haemorrhagic stroke, haemorrhagic shock, retroperitoneal bleeding, a decrease of 2 mg/dL in the haemoglobin levels, or a transfusion of 2 or more red blood cell concentrates. There were no exclusion criteria.
Patients were divided into two groups, the patients who received PCC (group I, n = 18) and the patients who received FFP (group II, n = 49). In addition to PCC or FFP, all patients received vitamin k (10 mg EV) within the first hour. Reversibility was achieved when INR < 1.5.
The study was approved by the ethics and research committee, and informed consent was obtained from the patient or a family member in all cases. This study was registered in clinicaltrial.gov as ROAD-BRAZIL Registry?NCT02753023.
The following patient data were obtained: age; sex; weight; heart rate; systolic arterial pressure; medications used; platelet count; and the creatinine, C-reactive protein, and haemoglobin levels. The patient’s histories of smoking, alcoholism, diabetes, systemic arterial hypertension, dyslipidemia, atrial fibrillation, heart failure, stroke, recent surgery, and implantation of prosthetic mechanical valve were also considered. The INR at admission, left ventricle ejection fraction, red blood cell transfusions, administration of endovenous fluids and the use of vasoactive drugs were also noted (
PCC | FFP | p | |
---|---|---|---|
Male (%) | 33.3 | 38.8 | 0.683 |
Age (median) | 65.6 ± 11.68 | 67.8 ± 14.54 | 0.539 |
BMI (kg/m2) (median) | 26.2 + 7.56 | 27.2 ± 8.27 | 0.222 |
CHADSVASC2 (median) | 3.28 ± 1.74 | 3.24 ± 2.05 | 0.946 |
HASBLED (median) | 1.33 ± 1.16 | 1.13 ± 0.95 | 0.822 |
Mechanical valves (%) | 5.9 | 4.1 | 0.796 |
Previous thromboembolic event (%) | 27.8 | 16.3 | 0.293 |
Thrombus of LV (%) | 11.1 | 2 | 0.112 |
Deep vein thrombosis (%) | 11.1 | 2 | 0.112 |
Valvular disease (%) | 22.2 | 24.5 | 0.847 |
Atrial fibrilation (%) | 66.7 | 91.8 | 0.01 |
Diabetes mellitus (%) | 22.2 | 32.7 | 0.408 |
Hypertension (%) | 55.5 | 75.5 | 0.114 |
Heart failure (%) | 44.4 | 28.6 | 0.22 |
Dyslipidemia (%) | 27.8 | 16.3 | 0.293 |
Etilism (%) | 0 | 2 | 0.541 |
Tabagism (%) | 5.6 | 16.3 | 0.252 |
Previous stroke (%) | 22.2 | 20.4 | 0.871 |
Recent surgery (%) | 5.6 | 2 | 0.454 |
Previous acute myocardial infarction (%) | 22.2 | 30.6 | 0.499 |
Previous gastrointestinal bleeding (%) | 0 | 6.1 | 0.283 |
Heart rate (median) | 85.2 ± 18.92 | 83.9 ± 16.45 | 0.803 |
Systolic arterial pressure (mmHg) (median) | 114.3 ± 23.03 | 111.6 ± 25.28 | 0.679 |
Hemoglobin (mg/dL) (median) | 8.78 ± 2.88 | 10.53 ± 3.23 | 0.029 |
Platelets (×103/mm3) (median) | 241 ± 122.34 | 252 ± 145.67 | 0.671 |
INR (median) | 12.48 ± 6.88 | 12.19 ± 7.23 | 0.007 |
Creatinin (mg/dL) (median) | 1.91 ± 1.05 | 1.6 ± 1.24 | 0.932 |
C-reactive protein (mg/dL) (median) | 49.1 ± 67.96 | 59.7 ± 72.35 | 0.605 |
LVEF (%) (median) | 47.3 ± 15.29 | 52.6 ± 13.54 | 0.228 |
ml/kg of cristaloids (median) | 15.4 ± 8.73 | 23.1 ± 13.27 | 0.056 |
Use of dobutamine (%) | 16.7 | 11.9 | 0.808 |
Use of norepinephrine (%) | 38.9 | 8.2 | 0.003 |
Aspirin (%) | 11.1 | 24.5 | 0.233 |
B-blocker (%) | 83.3 | 69.4 | 0.254 |
Proton pump inhibitor (%) | 55.6 | 51 | 0.742 |
Legend: PCC = prothrombin complex concentrate; FFP = frozen fresh plasma; BMI = body mass index; LV = left ventricle; INR = prothrombin time; EF = ejection fraction.
The primary endpoint was the reversibility of the anticoagulant effect of warfarin after 2 and 24 hours of PCC or FFP treatment. The secondary end points included the occurrence of an allergic reaction, thromboembolic events, acute renal failure, stroke, nosocomial infections, transfusion-related acute lung injury [TRALI], pulmonary edema, or death. Acute renal failure was defined as an abrupt (within 48 hours) reduction in kidney function, which is currently defined as an absolute increase in serum creatinine levels of more than or equal to 0.3 mg/dl, a percentage increase in serum creatinine of more than or equal to 50%, or a reduction in urine output (documented oliguria of less than 0.5 ml/kg per hour for more than six hours). Stroke was considered in cases of new focal neurological deficits in the participants, confirmed by cranial computerized tomography. TRALI was defined as the acute onset of non-cardiogenic pulmonary edema within 6 hours of transfusion of blood products. Pulmonary edema was considered cardiogenic only when there was the characteristic low oxygen saturation, and the chest X-rays exhibited fluid in the alveolar walls, Kerley B lines, increased vascular shadowing in a classical batwing perihilar pattern, upper lobe diversion and pleural effusions. Allergy was defined as experiencing difficulty in breathing, skin rashes or shock after administration of the drug. Nosocomial infections were defined as any type of infection acquired after 48 hours of hospital admission.
Blood was sampled immediately after admission before administration of medications (baseline) and after 2 and 24 hours of drug administration, according to the institutional protocols. The PCC used was an octaplex (Octapharma Inc., Switzerland).
Descriptive analysis of the data collected includes the median and the minimum and maximum values. Comparison between the groups was made using T-test and Q-square. If the Kolmogorov-Smirnov tests confirmed normal distribution, continuous variables were summarized using the mean ± standard deviation and were compared using Student’s t-test for independent samples. The Mann- Whitney U test was used to compare continuous variables if they were not normally distributed.
The multivariate analyses were performed on the clinical outcomes by logistic regression only if significant univariate analyses were observed. The results were considered significant when p < 0.05. As shown in
Complementary analysis was conducted using the Receiver Operating Characteristic (ROC) curve, calculating the area under the curve (AUC) and calculating the cut-off score for the relation between PCC (UI/kg) or FFP (ml/kg) administration and INR measurements after 2 and 24 hours. The confidence interval used was 95%.
All statistical analyses were performed using statistical software program SPSS v10.0.
The median age of the participants was 68 years, and approximately 37% were male patients with a median left ventricle ejection fraction of 52%. The most common case of bleeding was upper gastrointestinal bleeding (31.7%), followed by muscular (24.4%), urinary (18.1%) and intracranial (13.2%) bleeding. The medium dose used was 27.6 UI/kg for PCC and 14.5 ml/kg for FFP. The median CHADSVASC score was 3.2, and the HASBLED score was 1.2.
We observed significant differences between groups I and II in the prevalence of atrial fibrillation (66.7% vs. 91.8%, p = 0.01), haemoglobin levels (8.78 mg/dL vs. 10.53 mg/dL, p = 0.029), INR values at admission (12.48 vs. 12.19, p = 0.007) and use of norepinephrine (38.9% vs. 8.2%, p = 0.003) (
Significant differences were observed between groups I and II in INR reversibility after 2 (33.3% vs. 6.1%, p = 0.001) and 24 hours (38.9% vs. 12.2%, p = 0.009). The incidence of pulmonary edema between groups I and II was different as well (5.6% vs. 42.9%, OR = 11.10, p = 0.04). The univariate and multivariate analyses are shown in
After 2 hours, the AUCs calculated from the ROC curve were 0.891 (CI 95% [0.72 - 1.0]) and 0.291 (CI 95% [0.09 - 0.49]) for PCC and FFP, respectively. The cut-off scores were 30.8 UI/kg for PCC (sensitivity = 83.3% and specificity = 92%) and 11.76 ml/kg (sensitivity = 66.7% and specificity = 36%) for FFP. After 24 hours, the AUC for PCC was 0.744 (CI 95% [0.52 - 0.97]) and for FFP was 0.503 (CI 95% [0.30 - 0.51]). The cut-off scores were 24.03 UI/kg for PCC (sensitivity = 87.5% and specificity = 64%) and 15.76 ml/kg for FFP (sensitivity = 57.1% and specificity = 61%) (
PCC | FFP | p | |
---|---|---|---|
Mortality (%) | 16.7 | 12.2 | 0.638 |
Allergy (%) | 5.8 | 2.1 | 0.454 |
Thromboembolic events (%) | 0 | 2.1 | 0.541 |
Acute renal failure (%) | 66.7 | 59.2 | 0.577 |
Stroke (%) | 0 | 2.1 | 0.541 |
Nosocomial infection (%) | 77.8 | 69.4 | 0.499 |
TRALI (%) | 0 | 2.1 | 0.541 |
Pulmonary edema (%) | 5.6 | 42.9 | 0.04 |
Combined events (%) | 83.3 | 83.7 | 0.973 |
PCC | FFP | OR | CI 95% | p | |
---|---|---|---|---|---|
Pulmonary edema (%) | 5.6 | 42.9 | 11.1 | 1.04 - 11.9 | 0.04 |
Legend: PCC = prothrombin complex concentrate; FFP = frozen fresh plasma; CI = confidence interval; OR = odds ratio.
In this study, we present results that are different from those suggested by the recent data. According to our results, the use of PCC lowered the INR measurements more than those of FFP after 2 and 24 hours of administration and with more regularity and predictability. The number of thromboembolic events did not increase with PCC administration, and a reduction in pulmonary edema was observed.
Karaca et al. [
In neurologic patients, the use of PCC has demonstrated more benefits than the use of FFP [
In another retrospective study published in Germany, 50 patients requiring urgent oral anticoagulation reversal or management of perioperative coagulopathic bleeding received PCC treatment (median dose of 1500 UI). The median PT value decreased from 2.8 to 1.5 (p < 0.001) after PCC administration. There were no major bleeding and thrombotic events related to the surgeries. Furthermore, a correlation was observed between the use of PCC and stabilization of the median arterial pressure [
Similarly, in 2016, Cappabianca et al. [
Although PCC has been associated with better reversal of coagulopathy induced by warfarin, the impact of PCC on real clinical outcomes is not clearly demonstrated [
To compare the clinical outcomes of PCC and FFP treatments, a group in New Zealand used an improved reversal protocol in patients with intracranial haemorrhage. The data from 88 patients with median INR value 2.9 were analysed, and a higher reduction in mortality rate was observed with PCC than with FFP administration (HR = 0.25, p = 0.01). When PCC was administered sooner, the benefits trended to be higher [
Our work did not show a reduction in mortality rate, possibly due to the small number of patients participating in the study. Nevertheless, the incidence of pulmonary edema was higher with FFP than with PCC in the cardiology patients at the tertiary complex centre where the study was conducted.
Although the dose of PCC (27.6 UI/kg) used in this study was lower than the dose (35 - 50 UI/kg) established for the full effect, its influence on anticoagulation reversal was better than the effect of the full dose of FFP (14.5 ml/kg). Similar results were reported by a retrospective study involving 103 patients with warfarin intoxication who received only 1,000 UI of PCC, which was considered a sub-optimal dose. The INR values were reduced to less than 1.5 and between 1.6 and 2.0 for 48.1% and 43.7% of the participants, respectively. Bleeding stopped in 83.5% of patients [
A limiting factor in the widespread use of PCC has been its high cost. A cost-effectiveness analysis of UK National Health Service showed that in patients with warfarin-related bleeding (intracranial, retroperitoneal or gastrointestinal), the use of PCC comprises only 15% of the total cost of treatment. The cost per life-year gained was estimated to be £1000 to £2000 [
This study has some limitations, such as the design was observational and had a small number of patients. The groups were different in some baseline characteristics. Additionally, we did not control the doses of PCC or FFP that the patients received. All medications used in the patients were administered according to the preference of the physician. The rationale behind which medications were administered was not described. Furthermore, this study was not designed to describe clinical outcomes.
In summary, PCC is better than FFP in reversing warfarin intoxication after 2 and 24 hours of administration. Furthermore, PCC showed lower pulmonary edema in cardiology patients.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
de M. Soeiro, A., César, M.C., Biselli, B., Bossa, A.S., de C.A.T. Leal, T., de A. Soeiro, M.C.F., Serrano Jr., C.V., Hajjar, L.A. and Oliveira Jr., M.T. (2017) Superiority of Prothrombin Complex Concentrate versus Frozen Fresh Plasma in Cardiology Patients with Warfarin Intoxication?Observational Study. Open Journal of Emergency Medicine, 5, 75-84. https://doi.org/10.4236/ojem.2017.52007