Patients 4F-PCC Research Articles

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 review of Andexanet Alfa versus 4-Factor Prothrombin Complex Concentrate for reversal of DOAC-Associated Intracranial Hemorrhage

Background: Mortality of oral anticoagulation-associated ICH is around 60%, with oral anticoagulation increasing the risk of ICH seven to ten-fold compared to no anticoagulation. Current guidelines recommend DOACs (direct oral anticoagulants) as first-line therapy in the treatment of VTE (Venous Thromboembolism) due to their more favorable safety profile. There are two agents available for DOAC reversal, Coagulation Factor Xa (recombinant), inactivated-zhzo (andexanet alfa, Andexxa®) and 4-factor prothrombin complex concentrate (4FPCC). There is little data comparing the two agents in real-life clinical settings.Objective: The primary objective of this study was to determine if there was a difference in hemostatic efficacy of andexanet alfa and 4FPCC in patients with a factor Xa inhibitor-related intracranial hemorrhage.Methods: This was a retrospective, single-center study conducted in adult patients admitted at a quaternary academic medical center from September 2017 to March 2021. Adults with a diagnosis of intracranial hemorrhage (ICH) were included if they received either 4FPCC or andexanet alfa for reversal of apixaban or rivaroxaban. In addition to hemostatic efficacy per imaging, we assessed disposition location, cerebral performance score, blood product consumption, and the development of a new thrombus.Results: A total of 46 patients were included in this study, 15 received 4FPCC (32%) and 31 received andexanet alfa (68%). There was no difference in the proportion of patients with excellent (4FPCC 9 [60%] vs. andexanet alfa 16 [51.6%], p = 0.61), good (4FPCC 2 [13.3%] vs. andexanet alfa 7 [22.6%]), or poor (4FPCC 1 [6.7%] vs. andexanet alfa 5 [16.1%]) hemostasis after administration of each agent. There were no significant differences in any secondary outcomes.Conclusion and Relevance: Our study found no difference in hemostatic efficacy between andexanet alfa and 4FPCC. At this time, clinicians should choose an agent based on individual patient presentation and resource availability. Further research will help clarify the role of each agent in the management of DOAC-related intracranial hemorrhage.

Clinical outcomes after 4F-PCC for warfarin-associated ICH and baseline GCS less than or equal to 8

PurposeThere is limited evidence describing the mortality benefit of utilizing 4-factor prothrombin complex concentrate (4F-PCC) in patients presenting with a warfarin-associated intracerebral hemorrhage (ICH) and a Glasgow Coma Scale (GCS) of ≤8. The aim of this study is to determine the potential mortality benefit of 4F-PCC in this patient population. MethodsThis was a retrospective chart review, performed at a comprehensive stroke center from October 2013 through August 2020. Patients were included if they were ≥ 18 years of age, experienced a spontaneous ICH with baseline GCS ≤ 8, treated with warfarin prior to admission, had a baseline INR ≥ 1.7, and received 4F-PCC for INR normalization due to warfarin-associated ICH. The primary outcome was in-hospital mortality at 30 days. ResultsA total of 252 patients received 4F-PCC in the specified time period. Of those patients, 25 patients met inclusion criteria. Sixteen patients (64%) experienced in-hospital mortality. When compared to a historical estimated 80% mortality rate in the studied patient population, there was no statistically significant difference (p = 0.208) in mortality when 4F-PCC was utilized to reverse INR. ConclusionThe administration of 4F-PCC in patients presenting with warfarin-related ICH and GCS ≤ 8 did not result in statistically significant mortality benefit. Our results are limited by study design and sample size. Thus, larger studies are needed to determine if a benefit exists for 4F-PCC in this patient population. Although the results are not statistically significant, our small study suggests that there may be a clinically significant mortality benefit when 4F-PCC is utilized.

Comparative hemostatic efficacy of 4F-PCC in patients with intracranial hemorrhage on factor Xa inhibitors versus warfarin

ObjectivePatients experiencing an intracranial hemorrhage (ICH) on oral anticoagulants often require rapid reversal. This study evaluated patients taking factor Xa inhibitors or warfarin that received reversal with 4-factor prothrombin complex concentrate (4F-PCC) for an ICH. The objective of the study was to determine if the efficacy of 4F-PCC for the reversal of factor Xa inhibitors is noninferior to its use in warfarin reversal in patients with ICH. MethodsThis was a retrospective, single center, noninferiority trial. Patients presenting to the emergency department with ICH were divided into two cohorts: those taking factor Xa inhibitors versus those taking warfarin. In each cohort, patients received anticoagulation reversal with weight-based 4F-PCC. The primary endpoint was hemostatic efficacy defined as ≤20% expansion in hematoma volume on repeat computed tomography imaging. A pre-specified noninferiority margin of −10% was selected to evaluate the difference between groups for the primary endpoint. ResultsA total of 221 patients were included in the study (factor Xa inhibitors, n = 87; warfarin, n = 134). Effective hemostasis was achieved in 70 patients (81%) on factor Xa inhibitors compared to 111 patients (83%) on warfarin, (−2.4% difference, [95% confidence interval, −12.87 to 8.12]; p = 0.654). There was no statistically significant difference between groups with regards to the primary outcome; however, the use of 4F-PCC in factor Xa inhibitor reversal was not noninferior when compared to 4F-PCC use for warfarin reversal. Hospital length of stay and discharge disposition were similar between cohorts. ConclusionsThe efficacy of 4F-PCC in reversing factor Xa inhibitor-related ICH compared to warfarin-related ICH was not significantly different between groups; however, these results did not prove noninferiority. Further study is warranted to delineate 4F-PCC's role in reversing factor Xa inhibitors in patients with ICH.

Evaluation of anticoagulation re-initiation practices following reversal of factor Xa inhibitors with andexanet alfa or 4F-PCC in patients with major bleeding events

BackgroundBoth andexanet alfa and 4F-PCC reversal strategies have been associated with thrombotic events. It remains unclear whether the risk is associated with the reversal agent or the lack of re-initiation of anticoagulation. ObjectiveThe aim of this study was to describe anticoagulant (AC) re-initiation patterns in patients presenting with major bleeding while on a FXai requiring reversal, and to describe associated post-reversal thrombotic events. MethodsThis was a single-center retrospective cohort study. Patients were included if they received FXai reversal with andexanet alfa or 4F-PCC for major bleeding. ResultsFifty-seven patients met inclusion criteria; of these patients, 34 received andexanet alfa and 23 patients received 4F-PCC. Most patients were prescribed AC for atrial fibrillation. The most common indications for reversal were intracranial hemorrhage 68%, followed by gastrointestinal bleeding 19%. AC was re-initiated at either prophylactic or therapeutic doses in 59% in the andexanet alfa recipients and 65% in the 4F-PCC recipients within 30 days. In those who restarted AC within 30 days, the median time to re-initiate AC was three days [IQR: 1–3]. Thrombotic events occurred in 3% of patients in the andexanet alfa group and 13% in the 4F-PCC group (7% overall rate). None were receiving anticoagulation at the time of the event. ConclusionAnticoagulation was restarted in approximately half of the patients who received a reversal agent for a life-threatening bleed. The thrombotic risk was 7% at the 30 day follow up period. Continuous assessment of bleeding and thrombosis is important for post-reversal management of patients with major bleeding events.

Andexanet Alfa Versus 4-Factor Prothrombin Complex Concentrate for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage.

There are limited data on the risks and benefits of using andexanet alfa (AA) in comparison with four-factor prothrombin complex concentrate (4F-PCC) to reverse factor Xa inhibitors (FXi) associated intracranial hemorrhage (ICH). We sought to describe our experience with AA or 4F-PCC in patients with oral FXi-related traumatic and spontaneous ICH. We conducted a retrospective review of consecutive adult patients with FXi-related ICH who received AA or 4F-PCC. FXi-related ICH cases included traumatic and spontaneous intracranial hemorrhages. Our primary analysis evaluated ICH stability on head computed tomography scan (CT), defined as a similar amount of blood from the initial scan at the onset of ICH to subsequent scans, at 6-h and 24-h post-administration of AA or 4F-PCC. For the subset of spontaneous intraparenchymal hemorrhages, volume was measured at 6-h and 24-h post-reversal. In secondary analyses, we evaluated good functional outcome at discharge, defined as a Modified Rankin Score of less than 3, and the incidenceof thrombotic events after AA or 4F-PCC adminstration,during hospitalization. A total of 44 patients (16 traumatic and 28 spontaneous ICH) with median age of 79years [72-86], 36% females, with a FXi-related ICH, were included in this study. The majority of spontaneous ICHs were intraparenchymal 19 (68%). Twenty-eight patients (64%) received AA and 16 patients (36%) received 4F-PCC. There was no difference between AA and 4F-PCC in terms of CT stability at 6h (21 [78%] vs 10 [71%], p = 0.71) and 24h (15 [88%] vs 6 [60%], p = 0.15). In a subgroup of patients with spontaneous intraparenchymal hemorrhage, there was no difference in the degree of achieved hemostasis based on hematoma volume between AA and 4F-PCC at 6h (9.3mL [6.9-26.4] vs 10mL [9.4-22.1], adjusted p = 0. 997) and 24-h (9.2mL [6.1-18.8] vs 9.9 [9.4-21.1], adjusted p = 1). The number of patients with good outcome based on mRS on discharge were 10 (36%) and 6 (38%) in the AA and 4F-PCC groups, respectively (adjusted p = 0.81). The incidence of thromboembolic events was similar in the AA and 4F-PCC groups (2 [7%] vs 0, p = 0.53). In this limited sample of patients, we found no difference in neuroimaging stability, functional outcome and thrombotic events when comparing AA and 4F-PCC in patients with FXi-related ICH. Since our analysis is likely underpowered, a multi-center collaborative network devoted to this question is warranted.

Factors contributing to poor outcome in patients on warfarin receiving 4-factor prothrombin complex concentrate in critically ill.

Aim:To compare the demographical profile, indications, efficacy, and contributors to adverse outcome following administration of 4F-PCC in patients on warfarin with supratherapeutic INR.Methodology:Retrospective cross-sectional study was performed in a community-based teaching hospital. All patients 18 years and older on warfarin with supratherapeutic INR, who had received 4F-PCC between January 2014 and December 2018 were eligible and included in the study.Results:44 patients were included in the analysis. The mean age of the patients was 79.5 years. The male to female ratio was 1:1. Patients were on warfarin for atrial fibrillation, thromboembolism in 79.5% (N-35), and 20.5% (N-9) respectively. Indications for use of 4F-PCC were active bleeding in 93% (N-41) of patients. The common sites of bleeding were gastrointestinal, intracranial, and musculoskeletal which were seen in 54.5% (N-24), 29.5% (N-13) and 6.8% (N-3) respectively. The median number of doses of 4F-PCC administered was 1 per patient. The mean dose administered was 2,883u. Clinical improvement was documented in 84% (N-37) of patients. Mortality was seen in 16% (N-7) of patients. BMI greater than 30, anemia, hypotension, presence of intracranial bleed, the requirement of blood products, and mechanical ventilation were associated with higher odds for mortality. Hypotension and requirement of mechanical ventilation were statistically significant.Conclusion:4F-PCC continues to be an effective agent in the rapid reversal of warfarin therapy in patients with supratherapeutic INR presenting with major bleeding events. Most patients have clinical improvement with a single, weight-adjusted dose.

Efficacy of 4-Factor Prothrombin Complex Concentrates in Factor Xa Inhibitor-Associated Intracranial Bleeding.

Intracranial bleeding (ICB) is a feared complication of systemic anticoagulation. Factor Xa inhibitors (FXaI) are used frequently due to their improved safety profile and predictable kinetics. Andexanet alfa was recently approved for emergent reversal of FXaI agents but was not compared formally to 4-Factor Prothrombin Complex Concentrates (4FPCC) which are the current standard of care in many centers. The objective of this study is to formally evaluate the hemostatic efficacy of 4FPCC in patients with FXaI-associated ICB. We performed a retrospective cohort study of patients receiving 4FPCC for the reversal of a FXaI in the setting of acute ICB. Hemostatic efficacy was adjudicated via evaluation of post-4FPCC CT scan using the criteria closely mirroring those outlined in Annexa-4 (excellent < 20% expansion, good > 20% but ≤ 35% expansion, poor > 35% expansion). Each image was reviewed by two neurointensivist attendings for grading. Mortality was assessed until date of discharge. Charts were screened for thrombotic events out to 30days post-4FPCC administration. A total of 59 patients were included in the final analysis. The mean age in years was 78.5 ± 10.9 and 56% were male. Apixaban was the most common FXaI prescribed at the time of presentation (67.8%). Most patients were on FXaI therapy for stroke prevention in the setting of atrial fibrillation (81.3%). Median Glasgow Coma Scale at presentation was 15(IQR 12-15), with the most frequently presenting ICB type being intracerebral hemorrhage (52.5%). The mean dose of 4FPCC prescribed was 46.6 (± 8.2)units/kg. Of those receiving 4FPCC for FXaI ICB, 88% were graded as having an excellent or good hemostatic outcome with excellent interrater reliability. Survival was high at 89.8%, and thrombotic events were seen in seven patients (11.9%). 4FPCC appears to be an effective and safe option for FXaI-associated ICB with outcomes comparable to andexanet alfa. A formal prospective evaluation of this strategy versus andexanet alpha including cost analysis is warranted.

358 Impact of a Pharmacist-Driven Four-Factor Prothrombin Complex Concentrate Protocol in the Emergency Department at a Large Urban Academic Medical Center

Advancements in the treatment of warfarin-induced intracranial hemorrhage (ICH) include the use of four-factor prothrombin complex concentrate (4F-PCC), which has demonstrated more rapid reversal of the international normalized ratio (INR) when compared with fresh frozen plasma. A pharmacist-driven protocol for 4F-PCC was implemented within our institution which allows for pharmacist approval of 4F-PCC in patients diagnosed with warfarin-induced ICH and an INR ≥2. The pharmacist is responsible for determining the appropriate dose of 4F-PCC, preparing the product, bedside delivery, and entering the order into the electronic medical record. Prior to implementation of the new protocol, the blood bank was responsible for 4F-PCC approval, dosing, product preparation, and arranging delivery with ED staff. The purpose of this study was to evaluate the impact of a pharmacist-driven protocol on time to 4F-PCC administration in ED patients presenting with warfarin-induced ICH in comparison with a previous blood bank protocol. We performed a retrospective review of prospectively collected data of patients receiving 4F-PCC in the ED from September 2015 through February 2017. Patients ≥18 years old were eligible for inclusion based on three criteria: confirmed diagnosis of ICH, confirmed warfarin use, and INR ≥2. Those who received 4F-PCC for indications other than warfarin-induced ICH or patients who received >1 dose of 4F-PCC during admission were excluded. The primary endpoint was time to 4F-PCC administration, which was evaluated based on the initial time the ED pharmacist was contacted, or the initial time the order was sent to the blood bank, and the administration time documented by the nurse. Secondary endpoints included concomitant vitamin K administration, radiographic progression of ICH, post-infusion INR, additional blood products required within 24 hours after 4F-PCC administration, thrombotic events during hospitalization, hospital length of stay, and in-hospital mortality. A power analysis was conducted prior to data collection and it was determined 32 patients (16 in each study arm) would be needed to detect a difference in the primary outcome with 80% power and an alpha level of 0.05. Overall, 45 patients were included in the analysis: 21 patients under the pharmacist-driven protocol and 24 patients under the blood bank protocol. The median time to administration of 4F-PCC in the pharmacist-driven protocol group was 23 minutes (range: 19-28) compared with 49.5 minutes (range: 43-73) in the blood bank protocol group (p<0.0001). A numerically higher percentage of patients in the pharmacist-driven protocol were dosed appropriately when compared to the blood bank protocol, although this did not reach statistical significance (95% vs. 79%; p=0.13). All patients, with the exception of two under the blood bank protocol, received vitamin K. There were no significant differences in secondary endpoints. Implementation of a pharmacist-driven protocol for 4F-PCC in the ED at our institution significantly reduced time to administration in patients presenting with warfarin-induced ICH. As our study was not powered to detect differences in secondary endpoints, additional studies for clinical outcomes regarding time to anticoagulant reversal are warranted.

Intraoperative Administration of 4-Factor Prothrombin Complex Concentrate Reduces Blood Requirements in Cardiac Transplantation

Assessing the efficacy of intraoperative 4-factor prothrombin complex concentrate (4F-PCC) use in blood product utilization, time to chest closure, intensive care unit (ICU) and hospital length of stay (LOS), thromboembolic complications, renal injury and mortality in left ventricular assist device (LVAD) patients on home anticoagulation therapy with warfarin, undergoing orthotopic heart transplantation (OHT). Retrospective analysis of OHT patients at Tufts Medical Center from May 2013 to October 2016. Single-institution, university hospital setting. Patients with preexisting LVADs who received orthotopic heart transplants (n = 74; 32 patients 4F-PCC, 42 patients no 4F-PCC). Warfarin reversal using 4F-PCC in patients with LVADs undergoing orthotopic heart transplantation with the 4F-PCC dosing partitioned such that one-third was given pre-CPB and two-thirds were given post-CPB. The 4F-PCC group required less plasma (6 [IQR 4] v 1.31 [IQR 2] U, p < 0.001), cryoprecipitate (10 [IQR 10] v 7.50 [IQR 5] U, p < 0.001), and packed red blood cells (5 [IQR 4] v 2 [IQR 1.5] U, p < 0.001) and had a shorter time to chest closure (618.8 ± 111.4 v 547.9 ± 110.1 minutes, p = 0.008). There was no difference in platelet transfusion (2 [IQR 1] v 2 [IQR 1] U, p = 0.16), ICU or hospital LOS, acute kidney injury, or mortality. No thrombotic complications occurred. Replacing plasma with 4F-PCC to reverse preoperative warfarin anticoagulation during OHT was associated with a shorter time to chest closure and less blood product utilization, without an increase in acute kidney injury, thromboembolic complications, or death.

Safety and Efficacy of Warfarin Reversal with Four-Factor Prothrombin Complex Concentrate for Subtherapeutic INR in Intracerebral Hemorrhage

The use of vitamin K antagonists is an independent risk factor for the development of intracerebral hemorrhage (ICH). Four-factor prothrombin complex concentrate (4F-PCC) is recommended for urgent reversal of anticoagulation in this setting. The safety and efficacy of 4F-PCC in ICH with subtherapeutic levels of anticoagulation is yet to be determined. This was a retrospective, observational study of 4F-PCC administration data from September 2013 to July 2015. Patients with spontaneous or traumatic ICH with initial INR 1.4-1.9 were compared to those with INR 2-3.9. A Fisher's exact test was used to compare the difference between the two groups in the effectiveness of 4F-PCC in reversing the INR to ≤1.3 and in the occurrence of thrombotic events within 7days of administration. A total of 131 patients with a presenting INR between 1.4 and 3.9 received 4F-PCC during the study period. Twenty-three of 29 patients (79%) in the INR <2 group achieved an INR reduction to ≤1.3 after 4F-PCC administration compared to 47 of 92 patients (51%) in the INR 2-4 group, p=0.03. There was no difference in thrombotic complications within 7days after administration (6.7% in INR 1.4-1.9 group, 10% in INR 2-3.9 group, p=0.73). The use of 4F-PCC in patients with INR between 1.4 and 1.9 results in an effective reduction in INR with similar thrombotic risks compared to patients presenting with an INR of 2-3.9.

Impact of a Pharmacist-Driven Prothrombin Complex Concentrate Protocol on Time to Administration in Patients with Warfarin-associated Intracranial Hemorrhage.

IntroductionAdvancements in the treatment of warfarin-associated intracranial hemorrhage (ICH) include the use of four-factor prothrombin complex concentrate (4F-PCC), which has demonstrated more rapid reversal of the international normalized ratio (INR) when compared with fresh frozen plasma. A pharmacist-driven protocol for 4F-PCC was implemented within our institution, which allows for pharmacist approval of 4F-PCC in patients diagnosed with warfarin-associated ICH and an INR ≥2. The pharmacist is responsible for determining the appropriate dose of 4F-PCC, preparation, bedside delivery, and order entry into the electronic medical record. Prior to implementation of the new protocol, the blood bank was responsible for 4F-PCC approval, dosing, product preparation, and arranging delivery with emergency department (ED) staff. The purpose of this study was to evaluate the impact of a pharmacist-driven protocol on time to 4F-PCC administration in warfarin-associated ICH.MethodsWe performed a retrospective review of consecutive patients who received 4F-PCC in a single ED from September 2015 through February 2017. Patients ≥18 years old were eligible for inclusion based on three criteria: confirmed diagnosis of ICH; confirmed warfarin use; and INR ≥2. Secondary outcomes included dose of 4F-PCC in concordance with INR and weight-based dosing recommendations and hospital protocol, as well as concomitant intravenous vitamin K administration.ResultsA total of 48 patients met inclusion criteria for the study with 24 patients in each protocol group. The median time to administration of 4F-PCC in the pharmacist-driven protocol group was 35 minutes (interquartile range [IQR] [25–62]; range, 11–133) compared with 70 minutes (IQR [34–89]; range, 14–244) in the pre-protocol group (p=0.034). We saw no differences for appropriate 4F-PCC dosing based on INR and patient weight between the two groups.ConclusionImplementation of a pharmacist-driven protocol for 4F-PCC in the ED at our institution significantly reduced time to administration in patients presenting with warfarin-associated ICH.