Factor Xa Inhibitors Research Articles

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

PB0953 An Updated Systematic Review and Meta-Analysis of the Safety and Efficacy of Factor Xa Inhibitors versus Low Molecular Weight Heparin Therapy for Treatment of Cancer Associated Venous Thromboembolism

PB0953 An Updated Systematic Review and Meta-Analysis of the Safety and Efficacy of Factor Xa Inhibitors versus Low Molecular Weight Heparin Therapy for Treatment of Cancer Associated Venous Thromboembolism

Removing direct oral factor Xa inhibitor interferences from routine and specialised coagulation assays using a raw activated charcoal product

BackgroundDirect oral anticoagulants (DOACs) are increasingly prescribed for the prevention and treatment of thrombosis. However, DOACs are associated with extensive interference in coagulation assays. Herein, we evaluate raw activated charcoal (AC) as an adsorbent material, to minimise DOAC-associated interferences in routine and specialised coagulation parameters on CS-series analysers (Sysmex, Kobe, Japan). MethodsCommercial human-derived non-anticoagulated plasma materials, with or without increasing concentrations of anticoagulant, were assayed for routine and specialised coagulation parameters before and after treatment with AC. ResultsTreatment of non-anticoagulated plasma with raw AC had minimal impact on routine and specialised coagulation parameters available on the CS-series; however, clinically relevant prolongations of certain activated partial thromboplastin time (APTT)-based assays were observed after treatment. Furthermore, in apixaban- and rivaroxaban-containing plasma material, AC efficiently adsorbed therapeutic and supratherapeutic DOAC concentrations; and, treatment with raw AC resolved DOAC-associated interferences on all affected routine and specialised coagulation parameters. ConclusionsOverall, raw AC efficiently adsorbed apixaban and rivaroxaban from human-derived plasma, without significantly affecting the majority of underlying routine and specialised coagulation parameters available on CS-series analysers.

B-174 Simple and Accurate Quantification of Four Direct Oral Anticoagulants in Plasma Using UPLC-MS/MS

Abstract Background Direct oral anticoagulants (DOACs) constitute first-line therapy used for many thromboembolic indications, such as prevention and treatment of venous thromboembolism and stroke prevention in atrial fibrillation. This class of medication consists of the direct thrombin inhibitor (dabigatran) or direct factor Xa inhibitors (apixaban, rivaroxaban, and edoxaban). DOACs quantification may be useful in the case of critical clinical situations, including drug accumulation in long-term treatment, overdosage, thrombotic or bleeding events. This study aimed to develop and validate an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the quantification of four DOACs: dabigatran, apixaban, rivaroxaban, and edoxaban in plasma. Methods The calibration curve samples were prepared by spiking drug free plasma with DOACs. The stable isotope labeled DOACs was used as an internal standard. After addition of the internal standard and protein precipitation, the supernatant was 10-fold diluted and injected into a chromatography system consisting of a UPLC BEH C18 (2.1 × 50 mm; particle size 1.7 µm) analytical column with gradient made of mobile phase (5 mM ammonium formate pH3.5 in water and methanol). The outlet of the column was connected to a triple quadrupole mass spectrometer with electrospray interface. Ions were detected in the positive multiple reaction monitoring mode. The concentration of analyte was calculated from the calibration curve and ion ratios between the analyte and the internal standard. Results The analytical range was linear with a correlation coefficient of over 0.99 in the range of 0–500 ng/mL for each analyte. Intra- and inter-assay imprecision were less than 3.1% (n = 20) and 6.0% (n = 20), respectively. The accuracy was evaluated by spike recovery and the mean recoveries were between 97.2% and 102.1% for all analytes. This assay showed no ion suppression or enhancement and no carryover. The chromatography run time was 4.5 min. The assay was applied to quantitate DOACs in plasma samples from 93 patients. Our data showed that the DOACs concentrations vary markedly individual patients after equal dose, this therapeutic drug monitoring of DOACs is essential to optimized drug efficacy. Conclusion An accurate, and cost-effective UPLC-MS/MS method for the quantification of DOACs was successfully applied for therapeutic drug monitoring in patients.

Rivaroxaban, a direct inhibitor of coagulation factor Xa, attenuates adverse cardiac remodeling in rats by regulating the PAR-2 and TGF-β1 signaling pathways.

Factor Xa (FXa) not only plays an active role in the coagulation cascade but also exerts non-hemostatic signaling through the protease-activated receptors (PARs). This study aimed to investigate whether the FXa inhibitor, Rivaroxaban (RIV), attenuates adverse cardiac remodeling in rats with myocardial infarction (MI) and to identify the underlying molecular mechanisms it uses. An MI model was induced in eight-week-old, male Wistar rats, by permanent ligation of the left anterior descending coronary artery. MI rats were randomly assigned to receive RIV or protease-activated receptors 2-antagonist (PAR-2 antagonist, FSLLRY) treatment for four weeks. Histological staining, echocardiography and hemodynamics were used to assess the cardioprotective effects of RIV. Meanwhile, pharmacological approaches of agonist and inhibitor were used to observe the potential pathways in which RIV exerts antifibrotic effects in neonatal rat cardiac fibroblasts (CFs). In addition, real-time PCR and western blot analysis were performed to examine the associated signaling pathways. RIV presented favorable protection of left ventricular (LV) cardiac function in MI rats by significantly reducing myocardial infarct size, ameliorating myocardial pathological damage and improving left ventricular (LV) remodeling. Similar improvements in the PAR-2 antagonist FSLLRY and RIV groups suggested that RIV protects against cardiac dysfunction in MI rats by ameliorating PAR-2 activation. Furthermore, an in vitro model of fibrosis was then generated by applying angiotensin II (Ang II) to neonatal rat cardiac fibroblasts (CFs). Consistent with the findings of the animal experiments, RIV and FSLLRY inhibited the expression of fibrosis markers and suppressed the intracellular upregulation of transforming growth factor β1 (TGFβ1), as well as its downstream Smad2/3 phosphorylation effectors in Ang II-induced fibrosis, and PAR-2 agonist peptide (PAR-2 AP) reversed the inhibition effect of RIV. Our findings demonstrate that RIV attenuates MI-induced cardiac remodeling and improves heart function, partly by inhibiting the activation of the PAR-2 and TGF-β1 signaling pathways.

Low-molecular-weight heparin is associated with lower venous thromboembolism events than factor Xa inhibitors in patients with severe blunt trauma: a cohort study from the Trauma Quality Improvement Program.

Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), is a common complication of major trauma. Pharmacological VTE prophylactics are widely used, and low-molecular-weight heparin (LMWH) is recommended. Factor Xa inhibitors are increasingly being used for VTE prophylaxis in both medical and surgical patients. Evidence comparing LMWH and factor Xa inhibitors as VTE prophylactics for severe blunt trauma is lacking. This study aims to compare the efficacy and safety of factor Xa inhibitors and LMHW in VTE prophylaxis. Patients with severe blunt trauma who received LMWH or a factor Xa inhibitor for VTE prophylaxis in the Trauma Quality Improvement Program between 2017 and 2019 were included. The comparison was performed after using propensity score matching. The outcomes included mortality and incidence of DVT, PE, post-prophylactics haemorrhage control procedures and length of stay. After 2:1 propensity score matching, 1128 patients ( n =752, LMHW group; n =376, factor Xa inhibitor group) were included in the analysis. Patients in the LMWH group had fewer VTE events than those in the factor Xa inhibitor group (DVT, 3.7% vs. 7.2%, P =0.013; PE, 0.4% vs. 3.2%, P <0.001). VTE risk was higher in the factor Xa group (DVT: odds ratio, 1.97; 95% CI, 1.12-3.44; P =0.018 and PE: odds ratio, 9.65; 95% CI, 2.91-44.12; P =0.001). The mortality rate was higher in the LMWH group; however, there was no significant difference (4.0% vs. 1.9%; P =0.075). The difference in the risk of undergoing haemorrhage control surgery after VTE prophylaxis between both groups was insignificant (0.3% vs. 0.0%; P =0.333). LMWH was associated with a lower risk of VTE than factor Xa inhibitors in patients with severe blunt trauma. The mortality rate was higher in the LMWH group; however, there was no statistically significant difference observed.

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...

An Evidence-Based Approach to Anticoagulation Therapy Comparing Direct Oral Anticoagulants and Vitamin K Antagonists in Patients With Atrial Fibrillation and Bioprosthetic Valves: A Systematic Review, Meta-Analysis, and Network Meta-Analysis

Direct oral anticoagulants (DOACs) are a newer class of anticoagulants that inhibit factor Xa or factor IIa and include drugs such as rivaroxaban, apixaban, edoxaban, betrixaban, and dabigatran. Although vitamin K antagonists (VKAs) have been traditionally used to prevent thromboembolic events, DOACs have gained popularity because of their faster onset and offset of action and reduced need for monitoring. This study aimed to provide more data for anticoagulants in patients with atrial fibrillation with bioprosthetic heart valves by incorporating all available trials to date. A search was performed across 5 electronic databases to identify relevant studies. We analyzed the data using a pooled risk ratio for categorical outcomes and used the I2 test to determine heterogeneity. The quality of randomized controlled trials was assessed using the Cochrane risk of bias assessment tool, and the National Institutes of Health tool was used for observational studies. Our study included a frequentist network meta-analysis (MA) of the aggregate data to obtain the network estimates for the outcomes of interest. We retrieved 28 studies with a total of 74,660 patients with bioprosthetic heart valves. Our MA significantly showed that DOACs decrease the risk of all-cause bleeding (risk ratio [RR] 0.80, 95% confidence interval [CI] 0.75 to 0.85, p >0.00001), stroke and systemic embolization (RR 0.89, 95% CI 0.80 to 0.99, p=0.03), and intracranial bleeding outcomes (RR 0.62, 95% CI 0.45 to 0.86, p=0.004) compared with VKA. In contrast, there was no significant difference between the compared groups in major bleeding (RR=0.92, 95% CI 0.84 to 1.02, p=0.10) and all-cause mortality outcomes (RR=0.96, 95% CI 0.85 to 1.07, p=0.43), respectively. In addition, the network MA results did not favor any of the studied interventions over each other (p <0.05) regarding all-cause bleeding, mortality, stroke and systemic embolization, and major bleeding outcomes. In conclusion, our study found that DOACs are more effective in reducing the risk of bleeding, stroke, systemic embolism, and intracranial bleeding than VKAs. However, no significant difference was observed in the incidence of gastrointestinal bleeding, major bleeding, thromboembolic events, and all-cause mortality. In addition, our network MA did not identify any specific DOAC treatment as more favorable than others.

Andexanet alfa - what we know about this promising drug

Introduction and purpose. Andexanet alfa (AA) is a recombinant modified version of human activated factor X. It is used as an antidote for apixsaban and rivaroxaban when reversal of anticoagulation due to life-threatening or uncontrolled bleeding is necessary. The aim of this paper is to present AA’s characteristics, treatment costs, clinical trial outcomes, and its use in medicine. Material and methods. A review of the available literature was performed by searching the PubMed and GoogleScholar databases using the following keywords: “andexanet alfa”, “factor Xa inhibitors”, “anticoagulant reversal”. Literature analysis. AA sequesters factor Xa inhibitors, which reactivates the endogenous factor Xa and reverses the anticoagulant effect. It is well tolerated, with a rapid onset of action. Side effects such as pneumonia, urinary tract infections and augmented thromboembolic risk have been observed. There are two dosing regimens, dependant on the ingested anticoagulant dose. Single dose cost is as high as 30 or 60 thousand USD. Conclusion. AA represents a therapeutic advancement and can prove life-saving in patients who experience an acute major bleeding while treated with direct oral anticoagulants. Single dose cost is high, therefore its availability for use may be restricted.

Andexanet Alfa Should Be Used to Reverse Factor Xa Inhibitors in the Setting of Life-Threatening Bleeding.

Andexanet alfa was approved by the Food and Drug Administration for reversal of factor Xa inhibitors, apixaban and rivaroxaban, in the setting of acute major bleeding. 1 Connolly S.J. Crowther M. Eikelboom J.W. et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019; 380: 1326-1335 Crossref PubMed Scopus (454) Google Scholar ,2 Siegal D.M. Curnutte J.T. Connolly S.J. et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015; 373: 2413-2424 Crossref PubMed Scopus (786) Google Scholar Andexanet alfa and prothrombin complex concentrate have been studied for factor Xa inhibitor reversal. The andexanet alfa is the preferred reversal agent for factor Xa inhibitor bleeds because of its targeted pharmacology for reversal, hemostatic efficacy, mortality outcomes, and its endorsement by numerous guidelines as the preferred agent.

Treatment of cancer-associated venous thromboembolism: A focus on special populations.

Current evidence-based clinical practice guidelines recommend the use of both low-molecular-weight heparin (LMWH) and direct factor Xa inhibitors (apixapan, edoxaban and rivaroxaban) as first-line options for the treatment of venous thromboembolism (VTE) in patients with cancer. However, most of these guidelines refer to the general cancer patient population and provide limited guidance for specific subgroups of patients at particularly high risk of bleeding, such as those with gastrointestinal cancers, primary or metastatic brain tumors, thrombocytopenia, or renal impairment. In these complex populations, the management of cancer-associated thrombosis (CAT) poses unique challenges and requires a nuanced approach based on the primum non nocere principle. This comprehensive review critically examines the relevant literature and discusses the therapeutic options currently available for the management of CAT in these special situations.

Prothrombin Complex Concentrate should be Used to Reverse Factor Xa Inhibitors in the Setting of Life-Threatening Bleeding.

Factor Xa (fXa) inhibitors are a novel class of anticoagulants that offer several benefits over conventional anticoagulants (eg, warfarin). When life-threatening bleeding is present, it is important to reverse fXa inhibitors. Two options for reversal exist: prothrombin complex concentrate and andexanet alfa. Guidelines favor andexanet alfa but generally support both reversal strategies.1-3 Of particular relevance to emergency clinicians, the American College of Emergency Physicians expert panel recommends prothrombin complex concentrate only if andexanet alfa is unavailable.

75: Evaluation of Selective Factor Xa Inhibition for Artificial Surface Induced Coagulation in an Ovine Venovenous ECMO Model

75: Evaluation of Selective Factor Xa Inhibition for Artificial Surface Induced Coagulation in an Ovine Venovenous ECMO Model

Impact of Factor Xa Inhibition on Coagulation, Platelet Reactivity, and Thrombosis in Patients with Peripheral Artery Disease

The role of thrombin in vascular pathology is a focus of investigation. The incorporation of direct Factor Xa inhibition into practice patterns is based on its theoretical dual-pathway attenuation of both thrombin generation and platelet aggregation. However, quantification of the effect of direct anti-Xa medications on platelet function is not established. Thromboelastography with platelet mapping (TEG-PM) leverages dual-pathway metrics to provide comprehensive coagulation profiles. We evaluated the effects of direct oral anticoagulants (DOACs) on coagulation and platelet function profiles and correlate these data with postoperative major adverse limb events (MALEs) in patients with PAD. We conducted a prospective study of patients undergoing lower extremity revascularization with serial perioperative TEG-PM analysis. Patients on DOACs were compared to those not on DOACs, and stratified by concurrent mono-antiplatelet or dual-antiplatelet regimens (MAPT/DAPT). Postoperative MALE was recorded and difference in antithrombotic regimens and TEG-PM analysis compared between groups. Four hundred seventy-one samples from 141 patients were analyzed. Twenty-nine point five percent were reflective of circulating DOAC therapy. Compared to MAPT alone, patients on DOAC+MAPT exhibited longer time to clot formation (R-time) [7.4 (±2.4) vs. 6.7 (±2.7); P<0.02], but less platelet inhibition. Patients on DAPT exhibited greater platelet inhibition compared to either group [23.7 (±26.9) vs. 31.0 (±28.3) vs. 42.2 (±31.2); P<0.01]. Patients who experienced MALE were more likely to be on DOAC therapy [43.8% vs. 22.0% P=0.02]. Thromboelastography with platelet mapping analysis from patients who experienced MALE also demonstrated longer R-time [8.6 (±3.9 vs. 7.3 (±3.0); P=0.05] and increased maximum clot amplitude (MA) [66.7 (±4.2) vs. 61.8 (±8.2); P=0.001]. Direct oral anticoagulant therapy resulted in a prolonged R-time but had no impact on platelet inhibition. Patients who experienced MALE were more often on DOACs and demonstrated an increased R-time, but also showed greater platelet reactivity evident by increased MA, suggesting DOACs may not be effective at protecting against MALE. Further research comparing DOAC therapy to a DAPT approach may add clarity to emerging multimodal antithrombotic recommendations.

Marketing of medicines in primary care: An analysis of direct marketing mailings and advertisements.

Marketing materials from pharmaceutical companies attempt to create a positive image of marketed, often new, medicines. To gain more insight in strategies pharmaceutical companies use to influence primary care practitioners' attitudes towards marketed medicines, we investigated the use of persuasion strategies in direct marketing mailings and advertisements from pharmaceutical companies sent to general practitioners. General practitioners in the Netherlands were recruited to collect all direct marketing mailings, meaning all leaflets, letters and other information sent by pharmaceutical industries to the practice during one month (June 2022). Direct marketing mailings and advertisements in collected medical journals concerning medicines or diseases (together called marketing materials) were analysed according to presence of one of the seven common persuasion strategies, i.e. reciprocity, consistency/commitment, social proof, liking, authority, scarcity and unity; as well as marketed medicine and year of introduction. Twenty general practices collected 68 unique marketing materials concerning 37 different medicines. Direct factor Xa inhibitors (n = 12), glucagon-like peptide-1 analogues (n = 5) and sodium-glucose co-transporter 2 inhibitors (n = 4) were the most frequently marketed medicines. The median year of introduction of all marketed medicines was 2012. All seven persuasion strategies were identified, with liking (64.7% of all materials) and authority (29.4%) as most prominent strategies, followed by social proof (17.6%), unity (14.7%), scarcity (13.2%), reciprocity (11.8%) and consistency/commitment (2.9%). In addition to those strategies, we identified emotional pressure (30.9%) as one commonly used new strategy. Marketing materials sent to general practices use a wide range of persuasion strategies in an attempt to influence prescription behaviour. Primary care practitioners should be aware of these mechanisms through which pharmaceutical companies try to influence their attitudes towards new medicines.

Safety Profile and Effectiveness of Rivaroxaban for Patients With Venous Thromboembolism in Japan - Results From Post-Marketing Surveillance (XASSENT).

The incidence of venous thromboembolism (VTE; pulmonary embolism [PE] and/or deep vein thrombosis [DVT]) in Japan is increasing, but relatively small numbers of patients from Japan have been included in studies investigating rivaroxaban (a direct factor Xa inhibitor) for the treatment of VTE and preventing its recurrence.Methods and Results: An open-label, prospective, observational study (XASSENT [NCT02558465]) investigated the safety profile and effectiveness of rivaroxaban for ≤2 years in the treatment of VTE and prevention of its recurrence in Japanese clinical practice. Primary outcomes were major bleeding and symptomatic recurrent VTE. Statistical analyses were exploratory and descriptive. Overall, 2,540 patients were enrolled (safety analysis population [SAP], n=2,387; effectiveness analysis population [EAP], n=2,386). In the SAP, >80% of patients received the approved rivaroxaban dose, the mean (standard deviation) age was 66.6 (15.0) years, ≈74% were >50 kg, and 43% had a creatinine clearance ≥80 mL/min. PE+DVT, PE only, and DVT only were reported in 42%, 8%, and 50% of patients, respectively, and active cancer in 17% of patients. Major bleeding was reported in 69 patients (2.89%; 3.60%/patient-year; SAP) and symptomatic PE/DVT recurrence in 26 patients (1.09%; 1.36%/patient-year; EAP) during the treatment period. XASSENT provided information on the expected proportions of bleeding and VTE recurrence during rivaroxaban treatment in Japanese clinical practice; no new concerns of safety or effectiveness were found.

92 Treatment with warfarin but not Factor Xa inhibitors, is associated with dysregulated, noncanonical, complement activation

92 Treatment with warfarin but not Factor Xa inhibitors, is associated with dysregulated, noncanonical, complement activation

Dose-Related Effectiveness of Andexanet Alfa for Reversal of Apixaban Anticoagulation in a Porcine Polytrauma Model.

Andexanet alfa (andexanet) is a reversal agent for use in patients with life-threatening or uncontrolled bleeding treated with oral factor Xa (FXa) inhibitors. There are limited data on the dose-response relationship of andexanet and FXa inhibitor-related bleeding. The aim of this study was to assess the dose-related effectiveness of andexanet in reducing blood loss, improving survival, and reversing apixaban anticoagulation in a porcine polytrauma model. Apixaban was given orally to 40 male pigs for 3 days at a dose of 20 mg/d. On day 3, following bilateral femur fractures and blunt liver injury, animals (n = 8/group) received andexanet (250-mg bolus, 250-mg bolus + 300-mg 2-hour infusion, 500-mg bolus, or 500-mg bolus + 600-mg 2-hour infusion) or vehicle (control). Total blood loss was the primary endpoint. Coagulation parameters were assessed for 300 minutes or until death. Data were analyzed with a mixed-model analysis of variance. Administration of 250-mg bolus + 300-mg infusion, andexanet 500-mg bolus, and 500-mg bolus + 600-mg infusion significantly decreased total blood loss by 37, 58, and 61%, respectively (all p < 0.0001), with 100% survival. Andexanet 250-mg bolus was ineffective in reducing total blood loss (6%) and mortality (63% survival) versus controls. Andexanet 500-mg bolus ± infusion neutralized anti-FXa activity to less than 50 ng/mL. Andexanet neutralization of thrombin generation and thromboelastometry parameters was dose and infusion time dependent. In a porcine polytrauma model with major bleeding on apixaban, andexanet dose dependently decreased anti-FXa activity. Lower anti-FXa levels (<50 ng/mL) with andexanet 500-mg bolus ± infusion were correlated with 60% less blood loss and 100% survival versus controls.

Dose-Response Activity-Based DNA-Encoded Library Screening.

Dose-response, or "conforming" behavior, increases confidence in a screening hit's authenticity. Here, we demonstrate dose-response solid-phase DNA-encoded library (DEL) screening. Compound dose in microfluidic droplets is modulated via the UV intensity of photocleavage from DEL beads. A 55,296-member DEL was screened at different UV intensities against model enzyme drug targets factor Xa (FXa) and autotaxin (ATX). Both screens yielded photochemical dose-dependent hit rates (FXa hit rates of 0.08/0.05% at 100/30% UV exposure; ATX hit rates of 0.24/0.08% at 100/20% UV exposure). FXa hits contained structures reflective of FXa inhibitors and four hits inhibited FXa (IC50 = 4.2 ± 0.1, 7.4 ± 0.3, 9.0 ± 0.3, and 19 ± 2 μM.) The top ATX hits (two dihydrobenzamidazolones and a tetrahydroisoquinoline) were validated as inhibitors (IC50 = 7 ± 2, 13 ± 2, and 1 ± 0.3 μM). Photochemical dose-response DEL screening data prioritized hits for synthesis, the rate-limiting step in DEL lead identification.

The Year in Coagulation and Transfusion: Selected Highlights from 2022

This is an annual review to cover highlights in transfusion and coagulation in patients undergoing cardiovascular surgery. The goal of this article is to provide readers with a focused summary of the most important transfusion and coagulation topics published in 2022. This includes a discussion covering the management of anemia and red blood cell transfusion, the management of factor Xa inhibitors, updates in coagulation testing, updates in the use of factor concentrates, advances in platelet therapy, advances in anticoagulation management of patients on extracorporeal membrane oxygenation and other forms of mechanical circulatory support, and advances in the diagnosis and management of heparin-induced thrombocytopenia.