4-factor Prothrombin Complex Concentrate Research Articles

Four-factor Prothrombin Complex Concentrate During Liver Transplantation: A Retrospective Cohort Study.

Four-factor prothrombin complex concentrate (PCC) is a plasma product that contains factors II, VII, IX, X, protein C, and protein S. PCC can be used off-label to treat coagulopathy during orthotopic liver transplantation (OLT). However, its use comes with safety concerns regarding thrombosis. The purpose of our study is to determine the safety of PCC in OLT. We conducted a retrospective cohort study of patients who received 4-factor PCC during OLT at our institution from January 1, 2018, to May 1, 2022, with a 1:1 match of 83 patients who received PCC and 83 patients who did not. We evaluated 30-d mortality, 1-y mortality, prevalence of thrombotic complications (portal vein thrombosis, deep venous thrombosis, myocardial infarction, and pulmonary embolus), and postoperative intensive care (ICU) length of stay (LOS). There was no significant difference in 30-d mortality (odds ratio [OR] 5; 95% confidence interval [CI], 0.58-42.8; P = 0.14), 1-y mortality (OR 3; 95% CI, 0.61-14.86; P = 0.18), or ICU LOS (OR -13.8; 95% CI, -39.2 to 11.6; P = 0.29). There was no increased incidence of thrombotic complications among patients receiving PCC 90 d after surgery, including portal vein thrombosis (OR 1.5; 95% CI, 0.42-5.32; P = 0.53), pulmonary embolus (OR 1; 95% CI, 0.14-7.1; P = 0.99), deep venous thrombosis (OR 0.67; 95% CI, 0.11-3.99; P = 0.66), and myocardial infarction (OR 1.67; 95% CI, 0.4-6.97; P = 0.48). Although there was a statistically insignificant increase in mortality after PCC administration during OLT, we did not see a significant increase in perioperative complications, including thrombotic events and increased ICU LOS.

4-factor prothrombin complex concentrate is not inferior to andexanet alfa for the reversal or oral factor Xa inhibitors: An Eastern Association for the Surgery of Trauma multicenter study.

Andexanet Alfa (AA) is the only FDA approved reversal agent for apixaban and rivaroxaban (DOAC). There are no studies comparing its efficacy with 4-Factor Prothrombin Complex Concentrate (PCC). This study aimed to compare PCC to AA for DOAC reversal, hypothesizing non-inferiority of PCC. We performed a retrospective, non-inferiority multicenter study of adult patients admitted from July 1, 2018 to December 31, 2019 who had taken a DOAC within 12 hours of injury, were transfused red blood cells (RBCs) or had traumatic brain injury, and received AA or PCC. Primary outcome was PRBC unit transfusion. Secondary outcome with ICU length of stay. MICE imputation was used to account for missing data and zero-inflated poisson regression was used to account for an excess of zero units of RBC transfused. 2 Units difference in RBC transfusion was selected as non-inferior. Results: From 263 patients at 10 centers, 77 (29%) received PCC and 186 (71%) AA. Patients had similar transfusion rates across reversal treatment groups (23.7% AA vs 19.5% PCC) with median transfusion in both groups of 0 RBC. According to the Poisson component, PCC increases the amount of RBC transfusion by 1.02 times (95% CI: 0.79-1.33) compared to AA after adjusting for other covariates. The averaged amount of RBC transfusion (non-zero group) is 6.13. Multiplying this number by the estimated rate ratio, PCC is estimated to have an increase RBC transfusion by 0.123 (95% CI: 0.53-2.02) units compared to AA. PCC appears non-inferior to AA for reversal of DOACs for RBC transfusion in traumatically injured patients. Additional prospective, randomized trials are necessary to compare PCC and AA for the treatment of hemorrhage in injured patients on DOACs. Therapeutic/Care Management, Level III.

Real-World Safety and Effectiveness of a 4-Factor Prothrombin Complex Concentrate in Japanese Patients Experiencing Major Bleeding: A Post-marketing Surveillance Study.

Limited data are available regarding the safety and effectiveness of 4-factor prothrombin complex concentrate (4F-PCC) in patients experiencing major hemorrhage or requiring expeditious surgical intervention, both globally and within Japan. We executed a prospective, observational post-marketing surveillance study of patients receiving 4F-PCC for the first time between September 19, 2017 and August 15, 2018 in Japan. Patients were subjected to a comprehensive follow-up for a duration of 4weeks. Of 1381 eligible patients, 1271 (92%) received a vitaminK antagonist. Among these, 58% were aged ≥ 75years, 49% manifested atrial fibrillation, 17% presented with valvular heart disease, and 6% exhibited venous thromboembolism. The median (range) international normalized ratio was 2.67 (0.96-27.11) at baseline and 1.21 (0.45-6.61) at first measurement post-administration of 4F-PCC. The most common reason for 4F-PCC administration was intracranial hemorrhage (59.6%), followed by gastrointestinal bleeding (6.6%). Hemostatic effectiveness was achieved in 85.8% of patients. The incidences of adverse drug reactions (ADRs) and serious ADRs were 3.9% and 2.8%, respectively. Thromboembolic events (TEEs) occurred in 20 (1.5%) patients, with a mean onset of 10days. The majority of TEEs were classified as nervous system disorders (55%). At the time of TEE, only 13% of patients resumed anticoagulant therapy. The incidence of TEEs following treatment with 4F-PCC did not surpass those observed in phase3 trials. No novel safety signals were identified. The safety and effectiveness of 4F-PCC in Japanese real-world practice were in harmony with the observations of prior studies.

Abstract WP169: Thromboelastography as a Biomarker of Emergent Direct-Acting Oral Anticoagulant Reversal With Prothrombin Complex Concentrates for Intracranial Hemorrhage

Prothrombin complex concentrates (PCCs) are used to emergently reverse direct-acting oral anticoagulant (DOAC) activity. PCCs are recommended as an alternative to recombinant coagulation factor-Xa to reverse anticoagulation activity of apixaban or rivaroxaban. Measuring the degree of anticoagulation reversal in this population is limited. Thromboelastography (TEG) has been used to detect the presence of DOAC plasma levels in patients chronically taking a DOAC but has not been utilized to measure the effect on anticoagulant activity after PCC administration. We aimed to determine whether TEG R-time is useful in detecting the impact of PCC administration on anticoagulation activity in patients with anti-factor Xa-associated intracranial hemorrhage (ICH). We prospectively evaluated the utility of TEG to assess anticoagulation activity after factor Xa inhibitor reversal with 4-factor PCC. Adults with ICH taking apixaban or rivaroxaban were included. Patients were excluded if their last known dose of anticoagulation was >48 hours prior to arrival, had known apixaban or rivaroxaban blood levels <20 ng/mL, or had the following comorbidities: hepatic failure, hereditary disorders of hemostasis, polytrauma, or pregnancy. TEG samples were collected before PCC administration (if available), and 0.5, 12, and 24 hours after PCC administration. Thirty-one patients were enrolled between November 2022 and August 2023. The median PCC dose was 24.5 units/kg (IQR 20.3-26.9 units/kg; n=29). Nine patients received anticoagulation reversal after baseline TEG collection; the remainder received anticoagulation reversal at transferring facilities. Baseline R-time was negatively correlated with time since last dose of DOAC (n=9). A median decrease in R-time of 0.8 minutes after PCC (IQR -1.6 - 0.3; n=8) was found in patients with baseline TEG collection. R-time rebounded by a median of 0.75 minutes (IQR 0.2-2.0; n=8) from 0.5 hours to 12 hours after PCC administration (n=8). TEG R-time, a measure that inversely correlates with the degree of anticoagulant effect, rapidly decreases after PCC in patients taking DOACs that present with acute ICH. TEG R-time rebounds 12 hours after PCC administration. TEG-R time may be a useful biomarker in DOAC reversal with PCC.

Comparison of Low Dose Recombinant Factor VIIa and 4-Factor Prothrombin Complex Concentrate for Treatment of Bleeding Related to Cardiac Surgery.

Background: Recombinant factor VIIa (rFVIIa) and prothrombin concentrate complex (PCC) are used for uncontrolled bleeding in cardiac surgery (CS), however, there are limited direct comparisons of these agents. Objective: To evaluate the efficacy and safety of rFVIIa and PCC in CS related bleeding. Methods: This retrospective study included adult CS patients who received either low dose rFVIIa (<30mcg/kg) or 4-factor PCC. The primary outcome was transfusion requirements of packed red blood cells (pRBC) within 6 hours of factor administration. Secondary efficacy outcomes included transfusion requirements 0-18hours, doses of additional factor product, thrombotic events, and acute kidney injury (AKI). Results: A total of 179 patients were included (n = 78 rFVIIa; n = 101 PCC). Of patients who received blood products, there was no difference in the requirement of pRBCs within 6 hours (73.8 vs 68.9%, P = .5359) or in the median amount of pRBC transfused (500mL vs 640mL, P = .0723) in the rFVIIa and PCC groups respectively. Patients in the PCC group were more likely to require additional factor products (24.4% vs 47.5%, P = .0015), develop AKI (12.8% vs 25.7%, P = .0325), have longer ICU lengths of stay [2 (IQR 1-5) vs 4 (IQR 2-6), P = .0487] and greater in-hospital mortality (2.6% vs 10.9%, P = .033). There was no difference in thrombotic events. Conclusion: Although, there was no difference in pRBC transfusion requirements between PCC and rFVIIa, more patients in the PCC group required additional factor products and had increased adverse effects. Further comparisons of PCC and rFVIIa are warranted.

Retrospective Comparison of Recombinant Activated Factor VII Versus 4-Factor Prothrombin Complex Concentrate in Cardiac Surgical Patients

ObjectivesTo compare the incidence of postoperative thrombotic complications, transfusion of blood products, and chest tube output in congenital cardiac surgical patients who received either recombinant activated factor VII (rFVIIa) or four-factor prothrombin complex concentrate (4F-PCC) DesignRetrospective analysis SettingTertiary academic hospital ParticipantsPediatric patients who underwent cardiac surgery. InterventionsNone Measurements and Main ResultsData were obtained from the Society of Thoracic Surgeons and the Pediatric Cardiac Critical Care Consortium databases, as well as from manual chart review. Adjusted p-values were obtained from multivariable regression using age (days), surgeon (number), cardiopulmonary bypass time (minutes), and need for deep hypothermic circulatory arrest (yes/no). We included 55 patients in the 4F-PCC group and 89 in the rFVIIa group. The median dose of rFVIIa was 77 mcg/kg (46-88) and the median dose of 4F-PCC was 31 IU/kg (24-43). The incidence of thrombotic complications was 8% in the 4F-PCC group and 30% in the rFVIIa group (adjusted P= 0.023). No difference was reported between the group in terms of chest tube output on day 1 and 2, or transfusion of blood products. Using a sensitivity analysis with propensity matching, the incidence of thrombosis was 10% in the 4F-PCC group (n=38) and 31% in the rFVIIa group (n=39) (P=0.036). No difference was reported in term of bleeding or transfusion. ConclusionsThis retrospective study suggests that the administration of rFVIIa is associated with a higher risk of thrombotic complications when compared to 4F-PCC without benefits in term of bleeding and transfusions.

OC 31.2 Andexanet Alfa is Associated with Lower In-Hospital Mortality Compared to 4-Factor Prothrombin Complex Concentrate in Patients with Factor Xa Inhibitor–Related Major Bleeding

OC 31.2 Andexanet Alfa is Associated with Lower In-Hospital Mortality Compared to 4-Factor Prothrombin Complex Concentrate in Patients with Factor Xa Inhibitor–Related Major Bleeding

PB0555 Efficacy and Safety of 4-Factor Prothrombin Complex Concentrate for Management for Direct Xa Inhibitor-Induced Major Bleeding

PB0555 Efficacy and Safety of 4-Factor Prothrombin Complex Concentrate for Management for Direct Xa Inhibitor-Induced Major Bleeding

Efficacy and Safety of Early Administration of 4-Factor Prothrombin Complex Concentrate in Patients With Trauma at Risk of Massive Transfusion

Optimal transfusion strategies in traumatic hemorrhage are unknown. Reports suggest a beneficial effect of 4-factor prothrombin complex concentrate (4F-PCC) on blood product consumption. To investigate the efficacy and safety of 4F-PCC administration in patients at risk of massive transfusion. Double-blind, randomized, placebo-controlled superiority trial in 12 French designated level I trauma centers from December 29, 2017, to August 31, 2021, involving consecutive patients with trauma at risk of massive transfusion. Follow-up was completed on August 31, 2021. Intravenous administration of 1 mL/kg of 4F-PCC (25 IU of factor IX/kg) vs 1 mL/kg of saline solution (placebo). Patients, investigators, and data analysts were blinded to treatment assignment. All patients received early ratio-based transfusion (packed red blood cells:fresh frozen plasma ratio of 1:1 to 2:1) and were treated according to European traumatic hemorrhage guidelines. The primary outcome was 24-hour all blood product consumption (efficacy); arterial or venous thromboembolic events were a secondary outcome (safety). Of 4313 patients with the highest trauma level activation, 350 were eligible for emergency inclusion, 327 were randomized, and 324 were analyzed (164 in the 4F-PCC group and 160 in the placebo group). The median (IQR) age of participants was 39 (27-56) years, Injury Severity Score was 36 (26-50 [major trauma]), and admission blood lactate level was 4.6 (2.8-7.4) mmol/L; prehospital arterial systolic blood pressure was less than 90 mm Hg in 179 of 324 patients (59%), 233 patients (73%) were men, and 226 (69%) required expedient hemorrhage control. There was no statistically or clinically significant between-group difference in median (IQR) total 24-hour blood product consumption (12 [5-19] U in the 4F-PCC group vs 11 [6-19] U in the placebo group; absolute difference, 0.2 U [95% CI, -2.99 to 3.33]; P = .72). In the 4F-PCC group, 56 patients (35%) presented with at least 1 thromboembolic event vs 37 patients (24%) in the placebo group (absolute difference, 11% [95% CI, 1%-21%]; relative risk, 1.48 [95% CI, 1.04-2.10]; P = .03). Among patients with trauma at risk of massive transfusion, there was no significant reduction of 24-hour blood product consumption after administration of 4F-PCC, but thromboembolic events were more common. These findings do not support systematic use of 4F-PCC in patients at risk of massive transfusion. ClinicalTrials.gov Identifier: NCT03218722.

Retrospective Analysis of the Real-World Utilization of 4-Factor Prothrombin Complex Concentrate and Plasma in Oral Anticoagulant-Associated Bleeding in US Hospitals.

Real-world utilization of 4-factor prothrombin complex concentrate (4F-PCC) and plasma for the management of oral anticoagulant (OAC)-associated bleeding in US trauma hospitals was described.This is amulticenter, retrospective chart review evaluating the use of 4F-PCC and plasma in OAC reversal across medical specialties. Physicians completed a survey and extracted data from 3 to 5 patient charts. Variables of interest included medical specialty, urgency, and bleed type. Two hundred and thirty-five physicians completed the survey, and 861 patient charts were included in the study. 4F-PCC was commonly used in life-threatening or emergent indications, whereas plasma was used in emergent and urgent indications. Plasma was used mostly for patients on warfarin (53% vs 47% 4F-PCC) and 4F-PCC for those on apixaban (82% vs 18% plasma) and rivaroxaban (77% vs 23% plasma). This retrospective analysis showed that 4F-PCC was predominantly used for OAC reversal despite available specific reversal agents for some of the OAC. Although it is not recommended by any reversal guidelines, plasma is still used for OAC reversal. Plasma should be avoided in the management of OAC-associated bleeding.

Hemostatic Efficacy and Safety of 4-Factor Prothrombin Complex Concentrate in Doac-Associated Intracranial Hemorrhage

Background: Factor Xa (FXa) inhibitor use has increased over the last decade and though associated rates of major bleeding are lower compared to warfarin, outcomes from intracranial hemorrhage (ICH) are still significant. Targeted FXa inhibitor reversal agent became available in 2018, however use of 4-factor prothrombin complex concentrate (4F-PCC) for FXa inhibitor-associated ICH continues at many institutions. Objective: Evaluate the safety and hemostatic efficacy of 4F-PCC for FXa inhibitor-associated ICH. Methods: Single-center, retrospective study of patients who received 4F-PCC for FXa inhibitor-associated ICH. The primary efficacy endpoint was hemostasis and thrombosis was the main safety endpoint. Secondary endpoints included in-hospital mortality and discharge disposition. Results: 76 patients on apixaban or rivaroxaban were included. Good or excellent hemostasis was achieved in 80.3% of patients. Five patients experienced a thrombotic event. Favorable discharge disposition and lower in-hospital mortality was more likely in patients who achieved excellent hemostasis. Conclusion: 4F-PCC is safe and effective for FXa inhibitor associated ICH.

Activated 4-Factor Prothrombin Complex Concentrate as a Hemostatic Adjunct for Neonatal Cardiac Surgery: A Propensity Score-Matched Cohort Study.

Prothrombin complex concentrates are an emerging "off-label" therapy to augment hemostasis after cardiopulmonary bypass (CPB), but data supporting their use for neonatal cardiac surgery are limited. We retrospectively reviewed neonates undergoing open heart surgery with first-time sternotomy between May 2014 and December 2018 from a hospital electronic health record database. Neonates who received activated 4-factor prothrombin complex concentrate (a4FPCC) after CPB were propensity score matched (PSM) to neonates who did not receive a4FPCC (control group). The primary efficacy outcome was total volume (mL/kg) of blood products transfused after CPB, including the first 24 hours on the cardiovascular intensive care unit (CVICU). The primary safety outcome was the incidence of 7- and 30-day postoperative thromboembolism. Secondary outcomes included 24 hours postoperative chest tube output, time to extubation, duration of CVICU stay, duration of hospital stay, 30-day mortality, and incidence of acute kidney injury on postoperative day 3. We used linear regression modeling on PSM data for the primary efficacy outcome. For the primary safety outcome, we tested for differences using McNemar test on PSM data. For secondary outcomes, we used linear regression, Fisher exact test, or survival analyses as appropriate, with false discovery rate-adjusted P values. A total of 165 neonates were included in the final data analysis: 86 in the control group and 79 in the a4FPCC group. After PSM, there were 43 patients in the control group and 43 in the a4FPCC group. We found a statistically significant difference in mean total blood products transfused for the a4FPCC group (47.5 mL/kg) compared with the control group (63.7 mL/kg) for PSM patients (adjusted difference, 15.3; 95% CI, 29.4-1.3; P = .032). We did not find a statistically significant difference in 7- or 30-day thromboembolic rate, postoperative chest tube output, time to extubation, incidence of postoperative acute kidney injury (AKI), or 30-day mortality between the groups. The a4FPCC group had a significantly longer length of intensive care unit stay (32.9 vs 13.3 days; adjusted P = .049) and hospital stay (44.6 vs 24.1 days; adjusted P = .049) compared with the control group. We found that the use of a4FPCC as a hemostatic adjunct for post-CPB bleeding in neonatal cardiac surgery was associated with a decrease in mean total blood products transfused after CPB without an increased rate of 7- or 30-day postoperative thromboembolism. Our findings suggest that a4FPCCs can be considered as part of a hemostasis pathway for refractory bleeding in neonatal cardiac surgery.

55 Andexanet Alfa Is Associated With Reduced In-hospital Mortality Compared to 4-Factor Prothrombin Complex Concentrate Among Patients With Intracranial or Gastrointestinal Bleeding

There are limited data on real-world effectiveness of the specific factor Xa (FXa) inhibitor reversal agent andexanet alfa (AA) in comparison with 4-factor prothrombin complex concentrates (4F-PCC). We compared in-hospital mortality in patients hospitalized with oral FXa inhibitor- or enoxaparin- related intracranial hemorrhage (ICH) or gastrointestinal (GI) bleeds who were treated with AA or 4F-PCC.

Efficacy of prothrombin complex concentrate (PCC) versus fresh frozen plasma (FFP) in reducing perioperative blood loss in cardiac surgery: study protocol for a non-inferiority, randomised controlled trial

ObjectiveTo explore whether prothrombin complex concentrate (PCC) is not inferior to fresh frozen plasma (FFP) with regard to reducing perioperative blood loss in patients undergoing cardiac surgery under cardiopulmonary bypass...

The Off-Label Use of Four-Factor Prothrombin Complex Concentrate: A Single Institution Retrospective Study

Background/Introduction: 4-factor prothrombin complex concentrate (PCC) is currently approved in the United States for the urgent reversal of warfarin-induced coagulopathy in adults with acute major bleeding. However, the way in which 4-factor PCC is used in a real-world setting and the outcomes associated with off-label use is less clear. The objective of this study is to identify the indications that lead to 4-factor PCC use and the associated outcomes at a single university hospital.Methods: This was a single center retrospective cohort study of patients who received 4-factor PCC for any indication between July 2015 and April 2017 at Oregon Health & Science University. Patients were followed from index date until hospital discharge or in-hospital death. A given dose was considered “on-label” if it was given specifically for major bleeding secondary to warfarin-induced coagulopathy, whereas doses given for any other reason were considered “off-label”. Patients were also categorized based on the specific indication for receiving 4-factor PCC, which included intracranial hemorrhage, trauma-related bleeding, non-trauma-related bleeding, reversal of coagulopathy prior to an urgent procedure in non-bleeding patients, and intra- or post-operative bleeding. Also documented were baseline INR/PT/PTT and which form of anticoagulation, if any, a patient was on at baseline. Outcomes included duration of time between dose and INR normalization (defined as INR <1.5), duration of time between dose and ordering of follow-up coagulation parameters, duration of time between dose and hemostasis (determined based on vital signs, hemoglobin measurements, and/or imaging assessments), incidence of thromboembolic complications, and survival to hospital discharge.Results: In total,154 patients received 4-factor PCC during the study period accounting for 165 total doses. Ninety doses (54.5%) were considered on-label, while 75 doses (45.5%) were considered off-label. Of these off-label doses, 61 doses (81.3%) were considered off-label as they were given to patients not on warfarin therapy at baseline, while 14 doses (18.7%) were considered off-label due to lack of major bleeding. Intracranial hemorrhage was the most common indication (91 doses, 55.2%), followed by non-trauma-related bleeding (26 doses, 15.8%), pre-procedural reversal of coagulopathy without bleeding (21 doses, 12.7%), intra- and post-operative bleeding (13 doses, 7.9%), trauma-related bleeding (12 doses, 7.2%), and reversal of coagulopathy without bleeding in those not undergoing a procedure (2 doses, 1.2%). One-hundred patients (64.9%) were on warfarin at baseline, while the remainder were on direct oral anticoagulants (24 patients, 15.6%), heparin (3 patients, 1.9%), or no anticoagulation (25 patients, 16.2%), as depicted in Figure 1.Comparing on-label versus off-label use of PCC, there was no difference in time to INR normalization (p=0.24) or time to hemostasis (p=0.25). There was significantly shorter duration of time to ordering follow-up coagulation parameters in on-label versus off-label use (2.52 hours vs 3.97 hours, p=0.04). Comparing on-label versus off-label use, there was no difference in incidence of thromboembolic complications (8.9% vs 5.9%, p=0.76) or survival to hospital discharge (81.4% vs 67.6%, p=0.06).Conclusion: Despite being approved only for major bleeding related to vitamin K-antagonist use, 4-factor PCC is often administered in a wide variety of other settings in patients without major bleeding and those not on warfarin therapies. With the exception of duration of time to ordering follow-up coagulation parameters, outcomes in this single-center analysis comparing on-label versus off-label use were generally equivalent. Given the frequent use of 4-factor PCC outside of its currently approved indication, larger scale prospective trials studying specific indications are needed to validate its use in these settings. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Single Centre Retrospective Analysis of Patients Who Underwent Emergency Reversal of Warfarin Anticoagulation

IntroductionWarfarin is used in the treatment and prevention of thromboembolic disorders, with the risk of bleeding ranging from 1% to 3% per year resulting in hospitalisation or death. Emergency reversal of warfarin is indicated when warfarin therapy is complicated by bleeding, prior to emergency procedures / surgeries, and in patients who have supra-therapeutic INR with high risk of bleeding. Launceston General Hospital is a 330-bed hospital in regional Australia and we practise warfarin reversal in accordance with the national guidelines. Prothrombinex-VF (PTx-VF) is a 3-factor prothrombin complex concentrate (PCC) used in Australia, which contains factors II, IX, and X mainly. Due to low factor VII levels in PTx-VF, addition of 1 unit of FFP with PTx-VF is generally recommended, however there is lack of supportive evidence. There are a few reports of successful use of 3-factor PCC without the use of FFP. Hence in our hospital, the addition of FFP to PTx-VF for warfarin reversal is based on clinician's preference.Aim of studyTo study the clinical, laboratory, therapeutic and outcome data on patients who underwent emergency reversal of warfarin anticoagulation, and to compare the warfarin reversal (INR values) after administration of PTx-VF vs PTx-VF + FFP.MethodsWe performed a retrospective study of patients who underwent emergency reversal of warfarin in our hospital between January 2011 and December 2013. All the patients who underwent emergency reversal of warfarin with PTx-VF +/- FFP were captured from the blood bank database. Patients who received PTx-VF for indications other than emergency warfarin reversal and those with insufficient data were excluded from the study. The clinical, laboratory and transfusion data of these patients and the warfarin reversal strategies and clinical outcomes across different clinical settings were analysed. Non-parametric statistical analysis was used to compare the differences in post-treatment INR values in the PTx-VF vs PTx-VF + FFP groups and statistical significance was assumed at a P value of less than 0.05.ResultsA total number of 125 patients who underwent emergency warfarin reversal were included in the study. The median age was 77 years (range: 28 - 95) with 78 males (62%) and 48 females (38%). Table-1 presents clinical characteristics of the patients. Three clinical subgroups were identified - major bleeding in 61 patients (49%), emergency surgery in 54 patients (43%) and supra-therapeutic INR with high risk of bleeding in 10 patients (8%). Table-2 compares the clinical, laboratory, management and outcome characteristics in these subgroups. According to clinicians' preference, 56% of patients received PTx-VF alone, while 44% received PTx-VF + FFP. Statistically there were no differences in median INR values performed within 6 - 12 hours after administration of PTx-VF vs PTx-VF + FFP in all patients (P = 0.10), bleeding subgroup (P = 0.08) and emergency surgery subgroup (P = 0.24); and the number of patients in the supra-therapeutic INR subgroup was very small for evaluation. Overall 4 patients died due to warfarin-related complications, all of them in the bleeding subgroup.ConclusionIn our study majority (64%) of patients were above 75 years and the most common (69%) reason for warfarin anticoagulation was atrial fibrillation, which were similar in other studies. We observed that GI bleeding was the most common cause for warfarin reversal. Rapid INR correction with good clinical haemostasis occurred in most of the patients after administration of PTx-VF +/- FFP. The mortality rate in our cohort was 3% (4 of 125), and intracranial bleeding accounted for 75% (3 of 4) deaths. Among 14 patients who experienced intracranial bleeding, either spontaneous or induced by trauma, three (21%) died. There were no significant differences in the post-treatment INR values with PTx-VF alone when compared to PTx-VF + FFP, overall and also in the clinical subgroups. The major advantage of warfarin over DOACs is the rapid reversibility in emergency settings and we demonstrated that our 3-factor PCC (PTx-VF) was effective in emergency reversal of warfarin, without the need for FFP. There are a few limitations in this study since it is retrospective and observational. Hence prospective studies are required for better evaluation of the clinical characteristics, and the efficacy of 3-factor PCC without FFP in emergency reversal of warfarin anticoagulation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Comparison of 4-Factor Prothrombin Complex Concentrate With Frozen Plasma for Management of Hemorrhage During and After Cardiac Surgery

Approximately 15% of patients undergoing cardiac surgery receive frozen plasma (FP) for bleeding. Four-factor prothrombin complex concentrates (PCCs) have logistical and safety advantages over FP and may be a suitable alternative. To determine the proportion of patients who received PCC and then required FP, explore hemostatic effects and safety, and assess the feasibility of study procedures. Parallel-group randomized pilot study conducted at 2 Canadian hospitals. Adult patients requiring coagulation factor replacement for bleeding during cardiac surgery (from September 23, 2019, to June 19, 2020; final 28-day follow-up visit, July 17, 2020). Data analysis was initiated on September 15, 2020. Prothrombin complex concentrate (1500 IU for patients weighing ≤60 kg and 2000 IU for patients weighing >60 kg) or FP (3 U for patients weighing ≤60 kg and 4 U for patients weighing >60 kg), repeated once as needed within 24 hours (FP used for any subsequent doses in both groups). Patients and outcome assessors were blinded to treatment allocation. Hemostatic effectiveness (whether patients received any hemostatic therapies from 60 minutes to 4 and 24 hours after initiation of the intervention, amount of allogeneic blood components administered within 24 hours after start of surgery, and avoidance of red cell transfusions within 24 hours after start of surgery), protocol adherence, and adverse events. The analysis set comprised all randomized patients who had undergone cardiac surgery, received at least 1 dose of either treatment, and provided informed consent after surgery. Of 169 screened patients, 131 were randomized, and 101 were treated (54 with PCC and 47 with FP), provided consent, and were included in the analysis (median age, 64 years; interquartile range [IQR], 54-73 years; 28 [28%] were female; 82 [81%] underwent complex operations). The PCC group received a median 24.9 IU/kg (IQR, 21.8-27.0 IU/kg) of PCC (2 patients [3.7%; 95% CI, 0.4%-12.7%] required FP). The FP group received a median 12.5 mL/kg (IQR, 10.0-15.0 mL/kg) of FP (4 patients [8.5%; 95% CI, 2.4%-20.4%] required >2 doses of FP). Hemostatic therapy was not required at the 4-hour time point for 43 patients (80%) in the PCC group and for 32 patients (68%) in the FP group (P = .25) nor at the 24-hour time point for 41 patients (76%) in the PCC group and for 31 patients (66%) patients in the FP group (P = .28). The median numbers of units for 24-hour cumulative allogeneic transfusions (red blood cells, platelets, and FP) were 6.0 U (IQR, 4.0-11.0 U) in the PCC group and 14.0 U (IQR, 8.0-20.0 U) in the FP group (ratio, 0.58; 95% CI, 0.45-0.77; P < .001). After exclusion of FP administered as part of the investigational medicinal product, the median numbers of units were 6.0 U (IQR, 4.0-11.0 U) in the PCC group and 10.0 U (IQR, 6.0-16.0 U) in the FP group (ratio, 0.80; 95% CI, 0.59-1.08; P = .15). For red blood cells alone, the median numbers were 1.5 U (IQR, 0.0-4.0 U) in the PCC group and 3.0 U (IQR, 1.0-5.0 U) in the FP group (ratio, 0.69; 95% CI, 0.47-0.99; P = .05). During the first 24 hours after start of surgery, 15 patients in the PCC group (28%) and 8 patients in the FP group (17%) received no red blood cells (P = .24). Adverse event profiles were similar. This randomized clinical trial found that the study protocols were feasible. Adequately powered randomized clinical trials are warranted to determine whether PCC is a suitable substitute for FP for mitigation of bleeding in cardiac surgery. ClinicalTrials.gov Identifier: NCT04114643.

Abstract P415: Is Hemostatic Efficacy of Four Factor Prothrombin Complex Concentrate Similar in Intracerebral Hemorrhage Patients Receiving Warfarin vs Non-Vitamin K Anticoagulants?

Introduction: Four Factor Prothrombin Complex Concentrate (4F-PCC) is indicated for reversal of warfarin-induced coagulopathy. In small cohort studies, 4F-PCC has similar hemostatic efficacy rates reversing non-vitamin K anticoagulants (NOACs). There are no comparison studies evaluating 4F-PCC for the reversal of warfarin versus NOACs in the setting of intracerebral hemorrhage (ICH). Methods: A multicenter retrospective cohort study was conducted between 2013-2020 at a comprehensive stroke system in ICH patients who received 4F-PCC for the reversal of warfarin or a NOAC. Patients were included if they were adults with an acute ICH, anticoagulant regimen of warfarin (INR 1.3 or greater) or NOAC, and 2 head CT scans within 24 hours to determine hemostatic efficacy. Hemostatic efficacy was evaluated by the Sarode scale. The chi square and t-test were used as appropriate for demographic and clinical data, with multivariable regression analysis conducted in a forward stepwise manner, retaining variables with significance less than 0.05. Results: One hundred fifty-seven patients were included (baseline characteristics in Table 1). There was no statistically significant difference in effective hemostasis observed between warfarin and NOAC patients (83% vs 75%, p=0.33). Similarly, multivariable analysis did not demonstrate a significant difference in effective hemostasis (OR 0.55, 95% CI: 0.2-1.3, p=0.2). However, due to wide 95% confidence intervals, we cannot exclude a key treatment effect from PCC. After controlling for baseline characteristics, patients treated with NOACs had 53% lower odds of a good clinical outcome compared to those treated with warfarin (Figure 1; OR 0.47, 95% CI: 0.2-1.3, p=0.13). Conclusions: In conclusion, there was no statistically significant difference in hemostatic efficacy or clinical outcomes between warfarin and NOAC patients following reversal with 4F-PCC.

A Comparison of Prothrombin Complex Concentrate and Recombinant Activated Factor VII for the Management of Bleeding With Cardiac Surgery.

Bleeding following cardiac surgery that warrants transfusion of blood products is associated with significant complications, including increased mortality at 1 year following surgery. Factor concentrates, such as prothrombin complex concentrate (PCC), or recombinant activated factor VII (rFVIIa) have been used off-label for bleeding in cardiac surgery that is refractory to conventional therapy. The objective of this retrospective study is to assess the hemostatic effectiveness of 4-factor PCC or rFVIIa for bleeding after a broad range of cardiac surgeries. Patients were included if they were at least 18 years of age and had undergone cardiac surgery with bleeding requiring intervention with 4-factor PCC or rFVIIa. There were no differences observed in the number of packed red blood cells (4-factor PCC: 2 units vs. rFVIIa: 2 units), fresh frozen plasma (0 units vs. 1 unit) or platelet (2 units vs. 2 units) transfusions following the administration of 4-factor PCC or rFVIIa. The patients in the rFVIIa group, required more cryoprecipitate than those in the 4-factor PCC group (4-factor PCC: 2 units (range 0-6) vs. rFVIIa: 2 units (range 0-8), p = 0.03). There were no differences in secondary outcomes of chest tube output at 2, 6, 12 and 24 hours, nor was there a difference in reexploration rates or the median length of stay in the intensive care unit. Thromboembolic complications at 30 days were similar between the two groups (4-factor PCC: 13% vs. rFVIIa 26%, p = 0.08). The total median dose requirement for 4-factor PCC was 1000 units (15 units/kg) and 2 mg (20 mcg/kg) for rFVIIa. The results demonstrate feasibility of utilizing the minimum amount of drug in order to achieve a desired effect. Both 4-factor PCC and rFVIIa appear to be safe and effective options for the management of bleeding associated with cardiac surgery.

Comparison of 3 Different Prothrombin Complex Concentrate Regimens for Emergent Warfarin Reversal: PCCWaR Study.

The ideal dose and specific prothrombin complex concentrate (PCC) for warfarin reversal is unknown. To evaluate the reduction in international normalized ratio (INR) of 3 different PCC dosing regimens: fixed-dose activated 4-factor PCC (aPCC), fixed-dose 4-factor PCC (4PCC), and standard-dose 4PCC. This was a multicenter retrospective cohort review. Patients >18 years of age who received PCC for warfarin reversal between January 1, 2017, and December 31, 2017, were screened for inclusion. Patients were excluded if they did not receive the correct PCC dosing regimen, received PCC for nonwarfarin bleeding, had a baseline INR less than 2, or received a massive transfusion protocol. Two institutions utilized aPCC dosed at 500 IU for INR <5 and 1000 IU for INR ≥5. Two institutions utilized fixed-dose 4PCC at 1500 to 2000 units depending on patient factors. Two institutions utilized 4PCC package insert dosing. The primary outcome was achievement of post-PCC target INR ≤1.4. Secondary outcomes included percentage change in INR, lowest 24-hour INR, and mortality. A total of 154 patients were included (fixed-dose aPCC: n = 29; fixed-dose 4PCC: n = 53; standard-dose 4PCC: n = 72). There was no statistical difference between groups in achieving the primary outcome (58.6% vs 69.8% vs 79.2%, respectively; P = 0.103) or any secondary outcomes. There was no difference in the ability to achieve a post-PCC INR of ≤1.4 between 3 different PCC regimens for warfarin reversal. Additional research is warranted to determine the ideal dose and PCC agent for warfarin reversal.