Andexanet alpha versus four-factor prothrombin complex concentrate in DOACs anticoagulation reversal: an updated systematic review and meta-analysis.

BACKGROUND: There is currently a lack of evidence for the comparative effectiveness of Andexanet alpha and four-factor prothrombin complex concentrate (4F-PCC) in anticoagulation reversal of direct oral anticoagulants (DOACs). The primary aim of our systematic review was to verify which drug is more effective in reducing short-term all-cause mortality. The secondary aim was to determine which of the two reverting strategies is less affected by thromboembolic events. METHODS: A systematic review and meta-analysis was performed. RESULTS: Twenty-two studies were analysed in the systematic review and quantitative synthesis. In all-cause short-term mortality, Andexanet alpha showed a risk ratio (RR) of 0.71(95% CI 0.37-1.34) in RCTs and PSMs, compared to 4F-PCC (I2 = 81%). Considering the retrospective studies, the pooled RR resulted in 0.84 (95% CI 0.69-1.01) for the common effects model and 0.82 (95% CI 0.63-1.07) for the random effects model (I2 = 34.2%). Regarding the incidence of thromboembolic events, for RCTs and PSMs, the common and the random effects model exhibited a RR of 1.74 (95% CI 1.09-2.77), and 1.71 (95% CI 1.01-2.89), respectively, for Andexanet alpha compared to 4F-PCC (I2 = 0%). Considering the retrospective studies, the pooled RR resulted in 1.21 (95% CI 0.87-1.69) for the common effects model and 1.18 (95% CI 0.86-1.62) for the random effects model (I2 = 0%). CONCLUSION: Considering a large group of both retrospective and controlled studies, Andexanet alpha did not show a statistically significant advantage over 4F-PCC in terms of mortality. In the analysis of the controlled studies alone, Andexanet alpha is associated with an increased risk of thromboembolic events. CLINICAL TRIAL REGISTRATION: PROSPERO: International prospective register of systematic reviews, 2024, CRD42024548768.

Treatment for intracerebral hemorrhage: Dawn of a new era.

Intracerebral hemorrhage (ICH) is a devastating disease, causing high rates of death, disability, and suffering across the world. For decades, its treatment has been shrouded by the lack of reliable evidence, and consequently, the presumption that an effective treatment is unlikely to be found. Neutral results arising from several major randomized controlled trials had established a negative spirit within and outside the stroke community. Frustration among researchers and a sense of nihilism in clinicians has created the general perception that patients presenting with ICH have a poor prognosis irrespective of them receiving any form of active management. All this changed in 2023 with the positive results on the primary outcome in randomized controlled trials showing treatment benefits for a hyperacute care bundle approach (INTERACT3), early minimal invasive hematoma evacuation (ENRICH), and use of factor Xa-inhibitor anticoagulation reversal with andexanet alfa (ANNEXa-I). These advances have now been extended in 2024 by confirmation that intensive blood pressure lowering initiated within the first few hours of the onset of symptoms can substantially improve outcome in ICH (INTERACT4) and that decompressive hemicraniectomy is a viable treatment strategy in patients with large deep ICH (SWITCH). This evidence will spearhead a change in the perception of ICH, to revolutionize the care of these patients to ultimately improve their outcomes. We review these and other recent developments in the hyperacute management of ICH. We summarize the results of randomized controlled trials and discuss related original research papers published in this issue of the International Journal of Stroke. These exciting advances demonstrate how we are now at the dawn of a new, exciting, and brighter era of ICH management.

Effect of low- versus high-dose 4-factor prothrombin complex concentrate in factor Xa inhibitor-associated bleeding: A qualitative systematic review.

PURPOSE: The purpose of this review is to evaluate current literature on the treatment of factor Xa inhibitor-associated bleeds with 4-factor prothrombin complex concentrate (4F-PCC), with a focus on the effect of low versus high dosing of 4F-PCC on hemostatic efficacy and safety outcomes. SUMMARY: A search of PubMed and EBSCOhost was performed to identify studies evaluating patients with a factor Xa inhibitor-bleed treated with 4F-PCC at either low or high doses. Studies of patients receiving alternative reversal agents such as fresh frozen plasma and andexanet alfa or where no comparator group was evaluated were excluded from the analysis. To assess the effect of these 4F-PCC dosing strategies, the primary outcome of interest was hemostatic efficacy. Four studies meeting inclusion criteria were included in this review. In each of the included studies, similar rates of hemostatic efficacy, hospital mortality, and venous thromboembolism were observed in the low- and high-dose cohorts. CONCLUSION: These results suggest low- and high-dose 4F-PCC may confer similar clinical effectiveness and safety; however, these findings should be evaluated and confirmed with future prospective studies.

Hemostatic Efficacy and Safety of Weight-Based Versus Fixed-Dose 4F-PCC for Vitamin K Antagonist Reversal.

Background: Four-factor prothrombin complex concentrate (4F-PCC) is indicated for vitamin K antagonist (VKA) reversal but is associated with thrombotic events (TE). In 2018, the institution revised 4F-PCC dosing for VKA reversal from INR and weight-based dosing to a fixed-dose of 1500 units. Objective: The purpose of this study was to compare hemostatic efficacy and TE rate of fixed-dose 4PCC to weight-based dosing. Methods: This was a retrospective, single-center, quasi-experimental study of adult patients who received 4F-PCC for VKA reversal from January 2014 through May 2016 (INR and weight-based dosing) or April through October 2018 (fixed-dosing). The primary endpoint was hemostatic efficacy, defined by achieving an INR of ≤1.4, or an INR of ≤1.7 with evidence of hemostasis. The key secondary endpoint was TE within 14 days of 4F-PCC administration. Data were analyzed using descriptive statistics, chi-squared for nominal data and Mann-Whitney U for ordinal and continuous data. Results: The study included 163 patients who received weight-based dosing and 45 who received fixed-dose 4F-PCC. Hemostatic efficacy was 76.9% of patients in the weight-based group and 77.4% of patients in the fixed-dose group (P = .229). TE occurred in 13.5% of the weight-based vs 6.7% of the fixed-dose group (P = .181). Conclusion: This study found no difference in hemostatic efficacy with fixed-dose 4F-PCC for VKA reversal compared to INR and weight-based dosing. The occurrence of TE was reduced by 50% with the 4F-PCC fixed-dose strategy; however, this difference was not statistically significant. Further randomized studies are needed to confirm these results.

Prothrombin complex concentrate administration timing in warfarin-associated intracranial hemorrhage.

INTRODUCTION: Guidelines recommend "rapid" and "urgent" reversal of anticoagulation for warfarin-associated intracranial hemorrhage (ICH) treatment; however, they do not specify goals for time-to-administration. There are limited studies evaluating time to reversal, or international normalized ratio (INR) correction, on hematoma expansion and outcomes in intervals of <4 h. The purpose of this study was to evaluate the association of 4-factor prothrombin concentrate (4F-PCC) time-to-administration on rates of achieving effective hemostasis, determined by hematoma expansion, for treatment of warfarin-associated ICH. METHODS: This was a retrospective, observational, single center study performed at a large community teaching hospital. Patients were stratified into three groups based on time of CT diagnosis of ICH to administration of 4F-PCC: <45 min, 45-90 min, and >90 min. The primary outcome was rates of achieving effective hemostasis in each group defined as a ≤20% increase in hematoma volume as estimated by a radiologist. RESULTS: A total of 227 patients were screened for inclusion with ultimately 39 being included. Baseline characteristics were similar between groups. The primary outcome was not significantly different among groups stratified by time to 4F-PCC administration of <45 min, 45-90 min, and >90 min (85.7% vs 73.3% vs 90%, p value 0.514). There was no difference among secondary outcomes between groups including in-hospital mortality, hospital length of stay (LOS), and intensive care unit LOS. CONCLUSION: There was no association with time-to-administration of 4F-PCC on rates of hemostasis achievement, defined as hematoma expansion of ≤20%, identified in this study.

Management of traumatic cervical epidural hematoma in patients on Xa-inhibitors: a case report and review of the literature.

BACKGROUND: Cervical epidural hematoma (CEH) is defined as a collection of blood in the suprameningeal space. Mechanisms of this rare pathology include spontaneous, postsurgical, and traumatic as the main subtypes. This unique case of traumatic CEH represents an even smaller subset of these cases. Management varies by symptom presentation, mechanism of injury, and other contraindications. CASE PRESENTATION: This case presents a 32 year old African American female on an oral anticoagulant sustaining traumatic cervical hematoma after a motor vehicle collision. Patient complained of neck, abdominal, and back pain. Imaging revealed a cervical spinal hematoma at the level of C3-C6. This case discusses the management of CEH for the general population and in the setting of anticoagulation. CONCLUSION: Management of each case of CEH must be carefully considered and tailored based on their symptom presentation and progression of disease. As the use of anticoagulation including factor Xa inhibitors becomes more prevalent, there is greater need to understand the detailed pathophysiological aspect of the injuries. Targeted reversal agents such as Prothrombin Concentrate can be used for conservative treatment. Adjunct testing such as thromboelastogram can be used to help guide management.

Effects of Mobile Stroke Unit dispatch on blood pressure management and outcomes in patients with intracerebral haematoma: Results from the Berlin_Prehospital Or Usual Care Delivery in acute Stroke (B_PROUD) controlled intervention study.

INTRODUCTION: In patients with acute intracerebral haemorrhage (ICH) and elevated systolic blood pressure (BP), guidelines suggest that systolic BP reduction to <140 mmHg should be rapidly initiated. Compared with conventional care, Mobile Stroke Units (MSUs) allow for earlier ICH diagnosis through prehospital imaging and earlier BP lowering. PATIENTS AND METHODS: ICH patients were prospectively evaluated as a cohort of the controlled B_PROUD-study in which MSU availability alone determined MSU dispatch in addition to conventional ambulance. We used inverse probability of treatment weighting to adjust for confounding to estimate the effect of additional MSU dispatch in ICH patients. Outcomes of interest were 7-day mortality (primary), systolic BP (sBP) at hospital arrival, dispatch-to-imaging time, largest haematoma volume, anticoagulation reversal, length of in-hospital stay, 3-month functional outcome. RESULTS: Between February 2017 and May 2019, MSUs were dispatched to 95 (mean age: 72 ± 13 years, 45% female) and only conventional ambulances to 78 ICH patients (mean age: 71 ± 12 years, 44% female). After adjusting for confounding, we found shorter dispatch-to-imaging time (mean difference: -17.75 min, 95% CI: -27.16 to -8.21 min) and lower sBP at hospital arrival (mean difference = -16.31 mmHg, 95% CI: -30.64 to -6.19 mmHg) in the MSU group. We found no statistically significant difference for the other outcomes, including 7-day mortality (adjusted odds ratio: 1.43, 95% CI: 0.68 to 3.31) or favourable outcome (adjusted odds ratio = 0.67, 95% CI: 0.27 to 1.67). CONCLUSIONS: Although MSU dispatch led to sBP reduction and lower dispatch-to-imaging time compared to conventional ambulance care, we found no evidence of better outcomes in the MSU dispatch group.

Effect of PCC on Thrombin Generation among Patients on Factor Xa Inhibitors with Major Bleeding or Needing Urgent Surgery (GAUGE): Design and Rationale.

Background Direct factor Xa inhibitors (FXaIs) account for most oral anticoagulant use and FXaI-associated bleeding events are common. Clinicians have variable national and regional access to specific FXaI reversal agents such as andexanet alfa. Many centers have adopted the use of prothrombin complex concentrates (PCCs) as hemostatic therapy for FXaI-associated major bleeding events. PCC does not impact circulating FXaI levels and its mechanism of action to achieve hemostasis in FXaI-associated bleeding is uncertain. While PCC increases quantitative thrombin generation assay (TGA) parameters, it does not correct FXaI-altered thrombin generation kinetics, nor does it normalize thrombin generation. Clinical data supporting the use of PCC are based on cohort studies reporting clinical hemostatic efficacy, which is difficult to measure. The benefits of PCC for FXaI-associated bleeding beyond supportive care are uncertain. Objective GAUGE is a prospective observational study designed to measure the effects of four-factor PCC administration (Octaplex) on TGA parameters among patients with FXaI-associated bleeding or needing urgent surgery. Methods Laboratory outcomes will include the mean paired change in TGA parameters from pre- to post-PCC administration and the proportion of participants whose post-PCC TGA values fall within a defined reference range. Clinical outcomes will include hemostatic efficacy, thromboembolic complications, and all-cause death at 30 days post-PCC. Conclusion Development of a viable and universally accessible FXaI bleed management strategy is crucial. GAUGE will provide in vivo data on the effects of PCC among patients with FXaI-associated bleeding.

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.

OKL-1111, A modified cyclodextrin as a potential universal reversal agent for anticoagulants.

BACKGROUND: Antithrombotic therapy is inevitably associated with a risk for bleeding and these bleeding complications can be life-threatening. Recently, specific reversal agents were developed for the direct factor Xa and thrombin inhibitors (DOACs). However, next to the fact that these agents are relatively expensive, the use of selective reversal agents complicates treatment of bleeding patients in practice. In a series of screening experiments, we discovered a class of cyclodextrins with procoagulant properties. In this study we characterize a lead compound, OKL-1111, and demonstrate its potential use as a universal reversal agent. OBJECTIVES: To assess the anticoagulant reversal properties of OKL-1111, in vitro and in vivo. METHODS: The effect of OKL-1111 on coagulation in the absence and presence of DOACs was investigated in a thrombin generation assay. Its reversal effect on a variety of anticoagulants in vivo was investigated in a rat tail cut bleeding model. A possible prothrombotic action of OKL-1111 was assessed in a Wessler model in rabbits. RESULTS: OKL-1111 concentration-dependently reversed the in vitro anticoagulant effects of dabigatran, rivaroxaban, apixaban and edoxaban in the thrombin generation assay. Also in the absence of a DOAC, OKL-1111 concentration-dependently accelerated coagulation in this assay, but did not initiate coagulation. The reversal effect was also seen for all DOACs in the rat tail cut bleeding model. In addition, when tested with other anticoagulants, OKL-1111 also reversed the anticoagulant effect of the vitamin K antagonist warfarin, the low molecular weight heparin enoxaparin, the pentasaccharide fondaparinux and the platelet inhibitor clopidogrel in vivo. OKL-1111 did not have prothrombotic effects in the Wessler model. CONCLUSION: OKL-1111 is a procoagulant cyclodextrin with a currently unknown working mechanism that has potential to become a universal reversal agent for anticoagulants and platelet inhibitors.

What's fishy about protamine? Clinical use, adverse reactions, and potential alternatives.

Protamine, a highly basic protein isolated from salmon sperm, is the only clinically available agent to reverse the anticoagulation of unfractionated heparin. Following intravenous administration, protamine binds to heparin in a nonspecific electrostatic interaction to reverse its anticoagulant effects. In clinical use, protamine is routinely administered to reverse high-dose heparin anticoagulation in cardiovascular procedures, including cardiac surgery with cardiopulmonary bypass. Despite the lack of supportive evidence regarding protamine's effectiveness to reverse low-molecular-weight heparin, it is recommended in guidelines with low-quality evidence. Different dosing strategies have been reported for reversing heparin in cardiac surgical patients based on empiric dosing, pharmacokinetics, or point-of-care measurements of heparin levels. Protamine administration is associated with a spectrum of adverse reactions that range from vasodilation to life-threatening cardiopulmonary dysfunction and shock. The life-threatening responses appear to be hypersensitivity reactions due to immunoglobulin E and/or immunoglobulin G antibodies. However, protamine and heparin-protamine complexes can activate complement inflammatory pathways and inhibit other coagulation factors. Although alternative agents for reversing heparin are not currently available for clinical use, additional research continues evaluating novel therapeutic approaches.

Four-factor prothrombin complex concentrate for the treatment of oral factor Xa inhibitor-associated bleeding: a meta-analysis of fixed versus variable dosing.

Background: The optimal dosing strategy of four-factor prothrombin complex concentrate (4F-PCC) to treat oral factor Xa (FXa) inhibitor-associated bleeding has not been established. Objectives: To evaluate the effectiveness and safety of fixed versus variable 4F-PCC dosing for the management of FXa inhibitor-associated bleeding. Methods: A systematic literature search and meta-analysis of clinical studies was performed using PubMed, Embase, and Cochrane databases from inception to January 2022. The primary outcomes included hemostatic effectiveness, mortality, and thromboembolic events. Secondary outcomes included 4F-PCC usage, total length of stay in hospital and in intensive care units, and time to 4F-PCC administration. The pooled incidence or mean was calculated using a random-effects model and compared between the 2 dosing strategies. Results: Twenty-five studies were included and data from 1,760 patients (fixed dosing, n = 228; variable dosing, n = 1,532) were analyzed. There were no significant differences in hemostatic effectiveness, thromboembolic events, or mortality rates between the dosing strategies. Hospital length of stay was significantly longer in the fixed-dosing group, with a mean stay of 7.4 days (95% CI: 3.6-11.1) compared to 5.9 days (95% CI: 5.5-6.3) in the variable-dosing group (P < 0.001). The mean initial 4F-PCC dose was significantly higher with variable dosing than fixed dosing (38 IU/kg; 95% CI: 32-44 vs. 27 IU/kg; 95% CI: 26-28, P < 0.001). Conclusions: A fixed-dosing strategy appears to be a safe and effective alternative to variable weight-based dosing and was associated with lower 4F-PCC usage. However, direct comparative studies are needed to confirm these results.

Reduced Time to Procedure for Gastrointestinal Bleeding After Warfarin Reversal With Four-Factor Complex Concentrate as Compared to Plasma.

Background: Bleeding is a serious adverse effect of vitamin K antagonists (VKAs). Anticoagulation reversal is required in some acute cases. This is usually accomplished by plasma transfusion or four-factor prothrombin complex concentrate (4F-PCC). The aim of this study was to gain insight into the clinical course of patients with gastrointestinal (GI) bleeding who require VKA reversal. Methods: Medical records were collected from two centers from patients who presented to the emergency department (ED) for GI bleeding and received 4F-PCC or plasma for VKA reversal between January 2015 and December 2020. ED, hospital, intensive care unit (ICU) length of stay (LOS) as well as time from admission to GI procedure were determined. Results: 4F-PCC patients (n = 49) as compared to plasma (n = 63) patients were found to have a greater number of comorbidities (average of 4.2 vs. 2.7 comorbidities/patient) and more ICU admissions (47% vs. 21%). Time to GI procedure was significantly decreased in the 4F-PCC group (median (interquartile range (IQR)) 19.47 (9.23 - 30.25) vs. 27.88 (21.38 - 45.00) h; P = 0.01). When adjusting for comorbidities, differences in time to GI procedures were also significant in favor of 4F-PCC regardless of any comorbidities (P = 0.014), in atrial fibrillation (P = 0.045) and in hypertension (P = 0.02). The 4F-PCC patients had shorter LOS in the ED and ICU. Conclusions: Our study demonstrated that compared to plasma, 4F-PCC was utilized in more acutely ill patients with higher rates of comorbidities and ICU admission. Nevertheless, the patients who received 4F-PCC had faster access to GI procedure and shorter ED and ICU LOS.

DOAC-associated bleeding, hemostatic strategies, and thrombin generation assays - a review of the literature.

Direct oral anticoagulants (DOACs) account for most oral anticoagulant use. DOAC-associated bleeding events are commonly encountered in clinical practice and are associated with substantial morbidity and mortality. Both specific reversal agents and nonspecific hemostatic therapies, such as prothrombin complex concentrates, are used in the management of DOAC-associated bleeding. Measuring hemostatic efficacy and demonstrating a clinical impact from these therapies among studies of bleeding patients is challenging. Thrombin generation assays provide information on the total hemostatic potential of plasma, and have emerged as a promising modality to both measure the impact of DOACs on coagulation and to evaluate the effects of hemostatic therapies among patients with DOAC-associated bleeding. The mechanisms by which nonspecific hemostatic agents impact coagulation and thrombin generation in the context of DOAC therapy are unclear. As a result, we undertook a review of the literature using a systematic search strategy with the goal of summarizing the effects of DOACs on thrombin generation and the effects of both specific reversal agents and nonspecific hemostatic therapies on DOAC-altered thrombin generation parameters. We sought to identify clinical studies focusing on whether altered thrombin generation is associated with clinical bleeding and whether correction of altered thrombin generation parameters predicts improvements in clinical hemostasis. Lastly, we sought to outline future directions for the application of thrombin generation assays toward anticoagulation therapies and the question of anticoagulation reversal.

Supratherapeutic dabigatran: a cause of life-threatening haemorrhage.

In this case report, we present a rare case of life-threatening gastrointestinal haemorrhage associated with deranged coagulation due to supratherapeutic levels of dabigatran. Dabigatran is a potent, synthetic, reversible non-peptide thrombin inhibitor which is increasingly used for stroke prevention in patients with non-valvular atrial fibrillation. It is generally accepted that dabigatran dosing does not require titration or the monitoring of plasma levels due to its predictable pharmacokinetics and pharmacodynamics. However, this case report challenges this viewpoint while identifying an important knowledge gap in relation to the effect of altered gastrointestinal motility on the absorption of direct oral anticoagulants. Furthermore, it demonstrates the successful use of high-dose idarucizumab in a critical care setting. Idarucizumab is a monoclonal antibody fragment that binds specifically to dabigatran and its metabolites, thereby reversing the anticoagulant effect.

Comparison of 4-factor prothrombin complex concentrate and andexanet alfa for reversal of apixaban and rivaroxaban in the setting of intracranial hemorrhage.

The purpose of this study was to evaluate and compare clinical outcomes in patients who experienced intracranial hemorrhage (ICH) while taking apixaban or rivaroxaban and were reversed with four-factor prothrombin complex concentrates (4F-PCC) or andexanet alfa (AA). This retrospective cohort included adult patients that received 4F-PCC or AA for the initial management of an apixaban- or rivaroxaban-associated ICH. A primary outcome of excellent or good hemostatic efficacy at 12 h post-reversal was assessed. Secondary outcomes evaluated were change in hematoma volume size at 12 h, functional status at discharge, need for surgical intervention or additional hemostatic agents post-reversal, new thrombotic event within 28 days, 28-day all-cause mortality, discharge disposition, and hospital and intensive care unit lengths of stay. A total of 70 patients were included (4F-PCC, n = 47; AA, n = 23). For the primary outcome analysis, 21 patients were included in the 4F-PCC group and 12 in the AA group. The rate of effective hemostasis was similar between the 4F-PCC and AA groups (66.7% vs 75%, p = 0.62). There were no statistically significant differences between the groups for secondary outcomes, including 28-day mortality (40.4% vs 39.1%, p = 0.92) and thrombotic complications within 28 days of reversal (17.0% vs 21.7%, p = 0.63). In patients who experienced an ICH while taking apixaban or rivaroxaban, 4F-PCC and AA were found to have similar rates of excellent or good hemostatic efficacy.

Use of the CytoSorb® filter for elimination of residual therapeutic argatroban concentrations during heparinized cardiopulmonary bypass for heart transplantation.

INTRODUCTION: No antidote or established extracorporeal elimination strategy is available for argatroban. Hemadsorption facilitates elimination of smaller drugs. CASE REPORT: A 34-year-old patient underwent urgent heart transplantation. Because of a history of heparin-induced thrombocytopenia, preoperative anticoagulation was performed with argatroban. Despite ceasing of the continuous infusion of argatroban 2 h before surgery, concentration only declined from 0.60 µg/ml to 0.58 µg/ml before surgery, and the activated clotting time (ACT) value shortly was 223 s. Microvascular bleeding had been observed when starting surgery. A CytoSorb® absorption column was integrated into the system of the heparin-anticoagulated cardiopulmonary bypass (CPB) circuit and a flow of 400 mL/min provided during the 2 h of extracorporeal circulation. The argatroban concentration after weaning from CPB was 0.04 µg/ml and satisfying hemostasis had been achieved after protamine administration. CONCLUSION: Data indicate that the CytoSorb® absorption column might be an effective tool for quick extracorporeal removal of therapeutic concentrations of argatroban.

Risk and Management of Bleeding Complications with Direct Oral Anticoagulants in Patients with Atrial Fibrillation and Venous Thromboembolism: a Narrative Review.

Atrial fibrillation (AF) and venous thromboembolism (VTE) are highly prevalent conditions with a significant healthcare burden, and represent the main indications for anticoagulation. Direct oral anticoagulants (DOACs) are the first choice treatment of AF/VTE, and have become the most prescribed class of anticoagulants globally, overtaking vitamin K antagonists (VKAs). Compared to VKAs, DOACs have a similar or better efficacy/safety profile, with reduced risk of intracerebral hemorrhage (ICH), while the risk of major bleeding and other bleeding harms may vary depending on the type of DOAC. We have critically reviewed available evidence from randomized controlled trials and observational studies regarding the risk of bleeding complications of DOACs compared to VKAs in patients with AF and VTE. Special patient populations (e.g., elderly, extreme body weights, chronic kidney disease) have specifically been addressed. Management of bleeding complications and possible resumption of anticoagulation, in particular after ICH and gastrointestinal bleeding, are also discussed. Finally, some suggestions are provided to choose the optimal DOAC to minimize adverse events according to individual patient characteristics and bleeding risk.