Four-factor Prothrombin Complex Research Articles

Fixed vs Weight-Based Dosing of Four-Factor Prothrombin Complex Concentrate for Factor Xa Inhibitor Reversal in Patients With a Non-Neurologic Hemorrhage.

Background: There is a growing body of evidence to support that utilizing fixed dose vs weight-based dosing of Four-Factor prothrombin complex concentrate (4F-PCC) for Factor Xa inhibitor (FXaI) reversal is safe and efficacious. Objectives: The primary objective of this study was the rate of hemostatic efficacy of weight-based (50 units/kg) vs fixed dose (2000 units) 4F-PCC for FXaI reversal in patients presenting with a non-neurologic hemorrhage. Methods: This was a multi-center, retrospective chart review from January 21, 2020, to January 21, 2022. Patients were included if they were greater than or equal to 18years of age and received one dose of 4F-PCC for FXaI reversal for a non-neurologic bleed. Hemostatic efficacy for this study was defined as the absence of hemorrhagic progression confirmed with imaging, >2g/dl decrease in Hgb within 6hours of 4F-PCC administration, reports of further significant bleeding in chart note documentation within 48hours and a maintained or increased anti-factor Xa level from baseline. Results: Fifty-nine patients were included in this study (29 in the weight-based group and 30 in the fixed dose group). Rate of hemostatic efficacy was similar between fixed and weight-based dosing (93.3% vs 93.1% P = 1). Conclusions: This study adds to current evidence suggesting that a fixed dose 4F-PCC is both safe and efficacious for FXaI reversal in non-neurologic bleeds.

Comparison of outcomes for fixed and weight-based four-factor prothrombin complex concentrate dosing regimens

ObjectivesAlthough fixed dose regimens using four-factor prothrombin complex concentrate (4F-PCC) are more widely accepted, using a ‘one size fits all’ approach remains an area of uncertainty. The primary objective of...

Thrombin generation after prothrombin complex concentrate or plasma transfusion during cardiac surgery.

Thrombin generation (TG) is reduced after cardiac surgery using cardiopulmonary bypass (CPB), contributing to coagulopathy and bleeding. Plasma transfusion or four-factor prothrombin complex concentrate (PCC) are commonly used to treat coagulopathic bleeding after CPB without knowledge of how each may restore TG. To determine the effect of PCC infusion on restoration of thrombin generation compared with plasma transfusion, we performed a laboratory-based secondary analysis of a randomized, controlled trial of adult patients undergoing cardiac surgery to assess efficacy and safety of 4F-PCC versus plasma for treatment of perioperative coagulopathic bleeding after CPB. Participants were randomized to receive either PCC (15 IU/kg) or plasma (10-15ml/kg) after separation from CPB. Participant blood samples were obtained at pre-specified serial timepoints, with laboratory assays for TG and factor levels subsequently performed. The primary outcome was change in thrombin generation (TG) parameters after each randomized treatment through postoperative day 5. Secondary outcomes included serially derived clotting factor levels. Of 100 randomized participants, 99 were included in this laboratory analysis (PCC group, N = 51; plasma group, N = 48). After treatment, participants in the PCC group compared with those in the plasma group showed higher endogenous thrombin potential (ETP, Median, Interquartile range, IQR: 688 [371-1069] vs. 1088 [550-1691] nM minutes, P = 0.01), a greater increase din ETP (P = 0.002) and peak TG (P = 0.01) in the timepoints between heparin reversal and after treatment administration. Both groups demonstrated similar values in all TG assays by postoperative day 1 (P > 0.05). The PCC group also demonstrated higher levels of proteins C, S, and Factors II, VII, IX and X, early after treatment (P < 0.001 for all comparisons). Antithrombin levels were initially higher in the plasma group after treatment (Median, IQR: 66% [61-71%] vs. 56% [51-65%], P = 0.002) but differences did not persist beyond postoperative day 3. In this laboratory analysis from a recent randomized trial in adult cardiac surgery, PCC administration restored thrombin generation more rapidly than plasma in the early postoperative period without laboratory evidence of hypercoagulability. ClinicalTrials.gov identifier: NCT02557672 [1].

Management of factor Xa inhibitor-related traumatic non-intracranial bleeding events with andexanet alfa or four-factor prothrombin complex concentrate in a US multicenter observational study.

This study describes clinical characteristics and management strategies for patients with factor Xa (FXa) inhibitor-related traumatic non-intracranial bleeds who were treated with andexanet alfa or four-factor prothrombin complex concentrate (4F-PCC). An observational cohort study (ClinicalTrials.gov Identifier: NCT05548777) was conducted using electronic health records from 354 US hospitals. Included patients were hospitalized with rivaroxaban- or apixaban-related bleeding, had received andexanet alfa or 4F-PCC treatment during their hospitalization, and were discharged between May 2018 and September 2022. This analysis was performed in the subgroup of patients with traumatic non-intracranial critical compartment/non-compressible bleeds or other traumatic bleeds. The study population included 250 patients (andexanet alfa, n=116; 4F-PCC, n=134). Critical compartment bleeds were the most common (86.8%), with retroperitoneal bleeds the most common subtype (30.9%). Most patients were admitted via the emergency department (82.0%). The median time from presentation to reversal/replacement treatment was 2.7 (interquartile range, 1.2, 6.6) h. For patients treated with andexanet alfa, 63.8% were administered the low-dose regimen. For 4F-PCC, a median of 2000 total units was administered per patient. Other treatment strategies used included intravenous fluids (26.0%), fresh frozen plasma (16.0%), and packed red blood cells (13.2%). Prior to hospital discharge, oral anticoagulants were restarted in 20.4% of patients. Overall, 25 (10.0%) patients died in hospital. This analysis provides insights into the clinical characteristics and management strategies, including time to treatment, for patients treated with andexanet alfa or 4F-PCC while hospitalized for FXa inhibitor-related traumatic bleeds.

Systematic vitamin K antagonist reversal with prothrombin complex concentrate in patients with mild traumatic brain injury: randomized controlled trial.

Traumatic brain injury (TBI) in patients on vitamin K antagonists (VKAs) is linked to a high rate of intracranial hemorrhage (ICH). Rapid reversal can reduce ICH progression and mortality, but its effectiveness depends on the time between bleeding onset and coagulation normalization. The PREVACT study aimed to assess the efficacy and safety of prompt systematic reversal of anticoagulation in patients presenting to emergency departments (EDs) for recent mild-TBI while receiving a VKA. A randomized, open-label, blinded-endpoint clinical trial was conducted in 21 French EDs. Patients receiving a VKA, having experienced a TBI within the last 6 h, and presenting a Glasgow Coma Score ≥13 were included. Patients were randomized to systematic immediate VKA reversal with 25 IU/kg of four-factor prothrombin complex concentrate (4f-PCC) before any investigation (intervention group) or standard-of-care signifying reversal only if the initial cranial computed tomography (CT) scan indicated ICH (control group). The primary outcome was the rate of ICH detected on a cranial CT scan 24 h post-inclusion. The study was prematurely stopped for logistic reasons after the randomization of 202 patients (101 and 101 in the intervention and control groups, respectively, mean age 90; 51.8% female). On the 24-h cranial CT scan, 6 of 98 patients (6.1%) in the intervention group manifested ICH vs. 12 of 99 patients (12.1%) in the control group [odds ratio: 0.47 (95% confidence interval: 0.14-1.44); P = 0.215]. In patients with recent mild-TBI receiving a VKA, systematic prompt reversal with 4f-PCC did not statistically significantly reduce ICH rate at 24 h. However, the study was prematurely stopped and does not exclude a clinically relevant benefit of the strategy tested. Clinicaltrials.gov (NCT01961804).

Four-factor Prothrombin Complex Concentrate Use for Bleeding Management in Adult Trauma.

The clinical use of four-factor prothrombin complex concentrate in adult trauma patients at risk of bleeding is supported by evidence for urgent reversal of oral anticoagulants but is controversial in acquired traumatic coagulopathy.

Efficacy and Safety of Andexanet Alfa Versus Four Factor Prothrombin Complex Concentrate for Emergent Reversal of Factor Xa Inhibitor Associated Intracranial Hemorrhage: A Systematic Review and Meta-Analysis.

Factor Xa inhibitors (FXaI) are increasingly used for anticoagulation therapy, yet their association with intracranial hemorrhage poses a significant challenge. Although andexanet alfa (AA) and four-factor prothrombin complex concentrate (4F-PCC) have shown promise in reversing FXaI effects, their comparative efficacy and safety remain uncertain. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a literature search on electronic databases to obtain the relevant studies until May 16, 2024. Our primary outcomes were successful anticoagulation reversal, overall mortality (including 30-day and in-hospital mortality), and thromboembolic events. Secondary outcomes were length of hospital and intensive care unit stay and hematoma volume expansion. Data were pooled using a random-effects model. We included 16 eligible studies with a total of 2,977 patients. A statistically significant improvement in hemostatic efficacy rates was in favor of the AA group (risk ratio [RR] 1.10, 95% confidence interval [CI] 1.01-1.20, P = 0.02). Lower overall mortality rates were found in the AA group (RR 0.67, 95% CI 0.51-0.88, P = 0.004). However, no difference was found in 30-day mortality rates (RR 0.82, 95% CI 0.58-1.16, P = 0.26). In terms of thromboembolic events, more events were found in the AA group (RR 1.47, 95% CI 1.01-2.15, P = 0.046). AA was associated with a longer duration of hospital stay compared to 4F-PCC (mean difference [MD] 0.64, 95% CI 0.07-1.22, P = 0.03). Neither a significant difference in length of intensive care unit stay (MD 0.25, 95% CI - 0.36 to 0.86, P = 0.41) nor a significant difference in hematoma volume expansion was reported (MD - 0.89, 95% CI - 3.11 to 1.34, P = 0.435). Our results suggest that AA is superior to 4F-PCC in enhancing the hemostatic efficacy and reducing the overall and in-hospital mortality rates. More thromboembolic events are thought to be associated with the use of AA. However, more studies are required to validate whether the better results of AA in improving hemostatic efficacy are enough to make up for their higher cost and their possible risk of thromboembolic events.

111 Impact of Pharmacist Preparation of Four-Factor Prothrombin Complex Concentrate at the Bedside in Patients With Life-Threatening Hemorrhage in the Emergency Department

111 Impact of Pharmacist Preparation of Four-Factor Prothrombin Complex Concentrate at the Bedside in Patients With Life-Threatening Hemorrhage in the Emergency Department

Major Publications in the Critical Care Pharmacotherapy Literature: 2023.

We aimed to summarize the most significant and impactful publications describing the pharmacotherapeutic care of critically ill patients in 2023. PubMed/MEDLINE and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update. Randomized controlled trials and prospective studies of adult critically ill patients assessing a pharmacotherapeutic intervention and reporting clinical endpoints published between January 1, 2023, and December 31, 2023, were eligible for inclusion in this article. Articles from a systematic search and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update were included. An a priori defined three-round modified Delphi process was employed to achieve consensus on the most impactful publications based on the following considerations: 1) overall contribution to scientific knowledge and 2) novelty to the literature. The systematic search and Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update returned a total of 1202 articles, of which 1164 were excluded. The remaining 38 articles underwent a three-round modified Delphi process. In each round, articles were independently scored based on overall contribution to scientific knowledge and novelty to the literature. Included articles are summarized and their impact discussed. Article topics included hydrocortisone for severe community-acquired pneumonia, inhaled amikacin for prevention of ventilator-associated pneumonia, methylene blue for septic shock, restrictive vs. liberal fluid management for sepsis-induced hypotension, andexanet alfa for major bleeding associated with factor Xa inhibitors, and early administration of four-factor prothrombin complex concentrate in patients with trauma at risk for massive transfusion. This review provides a summary and perspective on the potential impact of the most relevant articles in 2023 describing advances in the pharmacotherapeutic care of critically ill patients.

Protocol for a phase 3, randomised, active-control study of four-factor prothrombin complex concentrate versus frozen plasma in bleeding adult cardiac surgery patients requiring coagulation factor replacement: the LEX-211 (FARES-II) trial

IntroductionReduced thrombin generation is an important component of post cardiopulmonary bypass (CPB) coagulopathy. To replenish coagulation factors and enhance thrombin generation in bleeding surgical patients, frozen plasma (FP) and four-factor...

Safety and Effectiveness of Four-Factor Prothrombin Complex Concentrate in Special Populations with INR Below 2: A Post-Marketing Surveillance Study.

We previously conducted a prospective, observational post-marketing surveillance study to assess the safety and effectiveness of four-factor prothrombin complex concentrate (4F-PCC) for rapid vitaminK antagonist (VKA) reversal in Japanese patients. This subgroup analysis compared the safety, especially thromboembolic events (TEEs), and effectiveness of 4F-PCC by stratifying patients into two subgroups according to baseline international normalized ratio (INR) levels with < 2.0 and ≥ 2.0. Of 1271 eligible patients, 215 (17.9%) had INR < 2.0 and 987 (82.1%) had INR ≥ 2.0. Overall baseline characteristics were similar between groups; age (74.0years vs 74.0years), body mass index (22.1kg/m2 vs 21.9kg/m2), ratio of inpatients (90.2% vs 88.7%), manifested atrial fibrillation (46.0% vs 48.8%). Median INRs at baseline were 1.72 (minimum 0.92, maximum 1.99) in the INR < 2.0 group and 2.95 (2.00, 27.11) in the INR ≥ 2.0 group. The most common reason for 4F-PCC administration was intracranial hemorrhage (67.0% vs 59.5%), and lesser gastrointestinal bleeding (0.9% vs 7.5%). After 4F-PCC administration (average doses 24.5IU/kg [INR < 2.0 group] and 29.2IU/kg [INR ≥ 2.0 group]), INRs were significantly reduced to 1.21 (- 28%) and 1.31 (- 68%), respectively, and resulted in hemostasis in a similarly rapid manner. The incidences of adverse drug reactions were 3.7% in each group. TEEs occurred in 4 (1.9%) patients in the INR < 2.0 group and 11 (1.1%) patients in the INR ≥ 2.0 group and were predominantly composed of stroke, while similar rates (67.0% vs 62.9%) of bleeding events post-anticoagulant resumption were observed between groups. This study supports the favorable tolerability and efficacy of 4F-PCC regardless of baseline INR (< 2.0 or ≥ 2.0), with a prompt reduction of INR and substantial hemostatic effectiveness in the real-world setting for patients requiring urgent VKA reversal, although no indicated 4F-PCC dose for VKA reversal exists for INR < 2.0 to date.

Long-Term Safety of a Four-Factor Prothrombin Complex Concentrate (Kcentra®/Beriplex® P/N): An Updated Pharmacovigilance Review.

Four-factor prothrombin complex concentrate (4F-PCC) is recommended for vitamin K antagonist reversal in patients with major bleeding or in need of surgery. The most important risk associated with the use of 4F-PCC is the occurrence of thromboembolic events (TEEs). In this review, we aim to evaluate the safety profile of a 4F-PCC (Kcentra®/Beriplex® P/N; CSL Behring, Marburg, Germany) by reviewing pharmacovigilance data. A retrospective analysis of postmarketing pharmacovigilance data of Kcentra®/Beriplex® P/N from February 1996 to April 2022 was performed and complemented by a review of clinical studies published between January 2012 and April 2022. A total of 2,321,443 standard infusions of Kcentra®/Beriplex® P/N were administered during the evaluation period. Adverse drug reactions (ADRs) were reported in 614 cases (∼1 per 3,781 standard infusions) and 233 of these cases (37.9%) experienced suspected TEEs related to 4F-PCC (∼1 per 9,963 standard infusions); most of these cases had pre-existing or concomitant conditions likely to be significant risk factors for thrombosis. TEE rates were similar when 4F-PCC was used on-label or off-label for direct oral anticoagulant-associated bleeding. Thirty-six cases (5.9%) reported hypersensitivity type reactions (∼1 per 64,485 standard infusions). No confirmed case of viral transmission related to 4F-PCC use was reported. The published literature also revealed a favorable safety profile of 4F-PCC. Analysis of postmarketing pharmacovigilance safety reports demonstrated that treatment with 4F-PCC was associated with few ADRs and a low rate of TEEs across multiple indications and settings, thus confirming a positive safety profile of 4F-PCC.

Andexanet Alfa versus Four-Factor Prothrombin Complex Concentrate for the Reversal of Factor Xa (FXa) Inhibitor-Associated Intracranial Hemorrhage: A Systematic Review of Retrospective Studies.

Background/Objectives: There are limited data on the risks and benefits of using Andexanet alfa (AA) compared with four-factor prothrombin complex concentrate (4F-PCC) for the reversal of factor Xa inhibitor-associated intracranial hemorrhage (ICH). Our aim was to describe a compilation of the information available in the literature to date. Methods: PubMed, Embase, Web of Science (Clarivate Analytics) and the Cochrane Central Register of Controlled Trials were searched until December 2023. Following the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)" guidelines, our systematic literature review included studies that were retrospective in design and evaluated both drugs to control bleeding and complications (death and thromboembolic events). Two researchers re-examined the studies for relevance, extracted the data and assessed the risk of bias. No meta-analyses were performed for the results. Results: In this limited patient sample, we found no differences between published articles in terms of neuroimaging stability or thrombotic events. However, some studies show significant differences in mortality, suggesting that one of the AAs may be superior to 4F-PCC. Conclusions: Our qualitative analysis shows that AA has a better efficacy profile compared with 4F-PCC. However, further studies monitoring these patients and a multicenter collaborative network dedicated to this topic are needed.

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.

Four-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 four-factor prothrombin complex concentrate (PCC). This study aimed to compare PCC to AA for DOAC reversal, hypothesizing noninferiority of PCC. We performed a retrospective, noninferiority 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 intensive care unit 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. Two units difference in RBC transfusion was selected as noninferior. 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% confidence interval, 0.79-1.33) compared with AA after adjusting for other covariates. The average amount of RBC transfusion (nonzero 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% confidence interval, 0.53-2.02) units compared with AA. PCC appears noninferior 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.

Evaluation of modified fixed dose four-factor prothrombin complex concentrate for warfarin reversal.

Non-activated four-factor prothrombin complex concentrate (4F-PCC) has emerged as the preferred reversal strategy for patients on warfarin with life-threatening bleeding. Current dosing recommendations for 4F-PCC require pre-treatment international normalized ratio (INR) and bodyweight values, resulting in ordering and administration delays. Studies have shown that alternative dosing regimens are safe and efficacious. This retrospective, single-center, pre- and post-protocol analysis was conducted to assess the efficacy of a pharmacist driven modified fixed-dose 4F-PCC regimen versus package insert weight- and INR-based dosing regimen for warfarin reversal. The primary outcome was achievement of INR less than two. Secondary outcomes included dose and cost of 4F-PCC, a time analysis, incidence of concomitant vitamin K administration, and incidence of thrombosis within seven days of 4F-PCC. There were 195 patients included in the analysis, with 74 in the pre-cohort and 121 in the post-cohort. Baseline characteristics were similar between cohorts with the most common indication for warfarin use being atrial fibrillation (48.6% versus 47.1%) and reversal being intracerebral hemorrhage (68.9% versus 43.0%). Achievement of the primary endpoint occurred in 92% versus 95% (p = 0.097) of patients. A statistically significant difference was seen between cohorts regarding median dose and cost of 4F-PCC administered (p < 0.001). Eleven thromboembolic events occurred with three events in the pre-cohort and eight events in the post-cohort (p = 0.453). A fixed-dose of 1500IU of 4F-PCC was effective in reversing INR to less than two in most patients regardless of reversal indication with minimal thrombotic risks.

Assessment of Temporary Warfarin Reversal in Patients With Left Ventricular Assist Devices: the KVAD Study*

Patients with left ventricular assist devices (LVADs) require interruption of warfarin for invasive procedures, but parenteral bridging is associated with many complications. Four-factor prothrombin complex concentrate (4F-PCC) can temporarily restore hemostasis in patients undergoing anticoagulation with warfarin. This pilot study evaluated the strategy of using variable-dose 4F-PCC to immediately and temporarily reverse warfarin before invasive procedures without holding warfarin in patients with LVADs. The duration of effect of 4F-PCC on factor levels and time to reestablish therapeutic anticoagulation post procedure were assessed. Adult patients with LVADs and planned invasive procedures were enrolled from a single center. Warfarin was continued uninterrupted. The 4F-PCC dose administered immediately pre-procedure was based on study protocol. International normalized ratio (INR)- and vitamin K-dependent factor levels were collected before and during the 48 hours after 4F-PCC administration. The use of parenteral bridging, International Society for Thrombosis and Haemostasis major and clinically relevant nonmajor bleeding (CRNMB) and thromboembolic events at 7 and 30 days were collected. In 21 episodes of 4F-PCC reversal, median baseline INR was 2.7 (IQR 2.2-3.2). The median dosage of 4F-PCC administered was 1794 units (IQR 1536-2130). At 24 and 48 hours post 4F-PCC administration, median INRs were 1.8 (IQR 1.7-2.0) and 2.0 (IQR 1.9-2.4). Two patients required postoperative bridging. One patient experienced major bleeding within 72 hours, and 2 experienced CRNMB within 30 days. There were no thromboembolic events. Baseline and post 4F-PCC vitamin K-dependent factor levels corresponded with changes in INR values. The median time to achieve therapeutic INR post-procedure was 2.5 days (IQR, 1-4). Administration of 4F-PCC for temporary reversal of warfarin for invasive procedures in patients with LVADs allowed for continued warfarin dosing with minimal use of post-intervention bridging, limited bleeding and no thromboembolic events.

Utilization and safety of off-label prothrombin complex concentrate (four-factor prothrombin complex concentrate) in a surgical population.

The aim of this study is to evaluate and describe the utilization and safety of 4F-PCC in a nonanticoagulated, surgical patient population at an academic, tertiary care center. This retrospective, single-center chart review evaluated nonanticoagulated adult patients at least 18 years of age who had at least one dose of 4F-PCC administered between 1 January 2017 and 30 September 2022 for a surgical or peri-procedural indication. Hemostatic efficacy following 4F-PCC administration was the primary outcome, assessed by subsequent blood product administration and hemoglobin and hematocrit reduction. Secondary outcomes included an assessment of thrombotic events within 30 days post-4F-PCC administration, in-hospital mortality, and the length of hospital stay. A total of 71 patients met the inclusion criteria, with 61 patients receiving 4F-PCC for cardiac surgery and 10 patients for other intraoperative or peri-procedural indications. The mean total 4F-PCC dose was 25.0 U/kg. For the primary outcome of hemostatic efficacy, 81% of patients had excellent hemostasis; however, blood product administration was reported in 95.8% of patients post-4F-PCC. Thromboembolic events occurred in 10 (14.1%) patients and 21.1% of patients expired prior to discharge in the total cohort. Off-label 4F-PCC use in nonanticoagulated patients is reported despite a lack of robust guidance for use. Following 4F-PCC administration, hemostatic efficacy based on hemoglobin and hematocrit changes was observed; however, blood product use was frequent, and 4F-PCC administration was not without risks, including thromboembolic complications such deep vein thrombosis (DVT), pulmonary embolism, and stroke. Further studies are needed to validate the off-label administration of 4F-PCC in nonanticoagulated patients.

Balfaxar: Another four-factor PCC for warfarin reversal.

Balfaxar (Octapharma), a human plasma-derived four-factor prothrombin complex concentrate (PCC), has been approved by the FDA for rapid reversal of warfarin anticoagulation in adults who require an urgent surgical/invasive procedure. It is the second four-factor PCC to become available in the US; Kcentra, which has been available since 2013, is approved for the same indication and for urgent reversal of warfarin anticoagulation in adults with acute major bleeding. Balfaxar is marketed in Canada and Europe as Octaplex.

Fixed- Versus Variable-Dose Prothrombin Complex Concentrate for the Emergent Reversal of Vitamin K Antagonists: A Systematic Review and Meta-Analysis.

Four-factor prothrombin complex concentrate (4-PCC) is recommended for rapid reversal of vitamin K antagonists (VKAs) such as warfarin, yet optimal dosing remains uncertain. A systematic review was conducted of PubMed, Embase, and Ovid MEDLINE (Wolters Kluwer) databases from January 2000 to August 2023 for clinical studies comparing fixed- vs. variable-dose 4-PCC for emergent VKA reversal with at least one reported clinical outcome. Abstracts and full texts were assessed independently and in duplicate by two reviewers. Data were extracted independently and in duplicate by two reviewers using predefined extraction forms. The analysis comprised three randomized trials and 16 cohort studies comprising a total of 323 participants in randomized trials (161 in fixed dosage and 162 in variable dosage) and 1912 patients in cohort studies (858 in fixed-dose and 1054 in variable dose). Extracranial bleeding was the predominant indication, while intracranial hemorrhage varied. Overall, a fixed-dose regimen may be associated with a lower dose of 4-PCC and results in a reduction in 4-PCC administration time compared with a variable-dose regimen. A fixed-dose regimen also likely results in increased clinical hemostasis. While there is no clear difference between the two regimens in terms of achieving a goal international normalized ratio (INR) less than 2, a fixed-dose regimen is less likely to achieve a goal INR less than 1.5. High certainty evidence indicates that the fixed-dose regimen reduces both mortality and the occurrence of thromboembolic events. Additional subgroup analyses provides exploratory data to guide future studies. A fixed-dose regimen for 4-PCC administration provides benefits over a variable-dose regimen in terms of dose reduction, faster administration time, improved clinical hemostasis, and reduced mortality and thromboembolic events. Further studies are warranted to better refine the optimal fixed-dose regimen.