Selective Factor Xa Inhibitor Research Articles

Clinical Implications of Co-administering Apixaban with Key Interacting Medications.

With many available data sources, clinicians need to consider the benefit-risk profile of individual anticoagulants when balancing the need for anticoagulation, including evaluating the risks in patients with comorbidities and potential drug-drug interactions. This narrative review presents clinical data across multiple phases of drug development for the use of apixaban, a selective factor Xa inhibitor, when taken concomitantly with other agents, and evaluates the benefit-risk profile of apixaban with these interacting medications. Key subgroup analyses from the phase 3 ARISTOTLE trial (NCT00412984) are presented using data from patients who received either concomitant inhibitors or inducers of cytochrome P450 3A4 and/or P‑glycoprotein. We also review the available evidence for the use of apixaban in patients with cancer-associated thromboembolism, as well as the use of apixaban in patients with COVID-19.

Rivaroxaban and Dabigatran: prospects for use in the management of heart failure

Scientific articles examine the effectiveness and pharmacokinetics of two oral anticoagulants, dabigatran and rivaroxaban, in the context of treating atrial fibrillation and chronic heart failure. Dabigatran, as a direct thrombin inhibitor, influences the thrombin zone and fibrinogen, preventing fibrin formation. Rivaroxaban, as a selective factor Xa inhibitor, blocks factor X activation. Both medications demonstrate high bioavailability and plasma protein binding. Studies on the efficacy of rivaroxaban in atherosclerosis and low-dose rivaroxaban in chronic heart failure did not reveal statistically significant reductions in cardiovascular risk. The findings emphasize the importance of further research and an individualized approach to selecting anticoagulants for optimal management of patients with diverse cardiovascular conditions.

Therapy adherence, safety and efficacy of rivaroxaban in prevention of venous thromboembolism in patients with hip or knee endoprosthesis.

Rivaroxaban is a potent, selective direct inhibitor of factor Xa. The aim of this study was to evaluate the therapy adherence, safety and efficacy of rivaroxaban therapy in reducing the risk of venous thromboembolism in patients undergoing elective hip or knee replacement. The prospective, post-marketing clinical trial was conducted on adult patients after knee or hip endoprosthesis. Data were collected at the baseline and three control visits (five days, a month and three months after the baseline). Morisky Medication Adherence Scale (MMAS-8) was used for evaluation of therapy adherence. The study included 60 patients who received rivaroxaban therapy in a dose of 10mg once a day. A low adherence to the drug was observed in 15% patients. All patients had an average MMAS-8 score in the range of high adherence 0.65 ± 0.90. Symptomatic venous thromboembolism was observed in two patients with numerous risk factors. No major bleeding was recorded during entire follow-up period. During the five-day postoperative in-hospital follow-up, signs of wound complications were recorded in 8 (13.3%) patients, and 4 (6.7%) of them underwent surgical revision of the wound. Generally, there was high adherence to rivaroxaban therapy, but low adherence was present in 15% of patients. Rivaroxaban showed good safety and efficacy. However, high proportion of wound complications and patients needing surgical revision of the wound should be further evaluated through larger studies.

Efficacy and Safety of a New Selective Oral Factor Xa Inhibitor Amidine Hydrochloride for Prevention of Thromboembolic Events in Hospitalized Patients with COVID-19: a Multiple-Center Prospective Randomized Controlled Study

Efficacy and Safety of a New Selective Oral Factor Xa Inhibitor Amidine Hydrochloride for Prevention of Thromboembolic Events in Hospitalized Patients with COVID-19: a Multiple-Center Prospective Randomized Controlled Study

Risk Factors Associated with Anticoagulant-Related Bleeding in Patients with Cancer-Associated Thrombosis

Background: Patients with cancer-associated thrombosis (CAT) have a high risk of recurrent venous thromboembolism as well as anticoagulant-related major bleeding. Thus, initiation and maintenance of anticoagulant therapy requires careful consideration of the risk versus benefit of therapy. Prior literature demonstrates that existing bleeding risk models have mediocre to moderate predictive performance for anticoagulant-related bleeding in patients with cancer. Patients with cancer have unique risk factors for bleeding that are absent in many of these models. Thus, we aimed to evaluate the association candidate traditional and cancer-specific risk factors with anticoagulant-related bleeding in a large cohort of patients with CAT. Methods : Using a nationwide cohort of US Veterans, we identified patients diagnosed with CAT with a new prescription for anticoagulant therapy between 2012 and 2020. Eligible anticoagulant therapy included a prescription for at least 30 days of: direct oral anticoagulants (DOACs), direct selective factor Xa inhibitors, low molecular-weight-heparin (LMWH), or vitamin K antagonists (VKA). Patients with outpatient prescriptions for anticoagulation within the six months preceding CAT were excluded. We further identified a subgroup of patients on chemotherapy around the time of CAT diagnosis, chemotherapy cohort. Using the methods of Fine and Gray, we assessed the association between candidate risk factors and clinically significant anticoagulant-related bleeding using competing risk analyses to account for the competing risk of death. Anticoagulant related bleeding was identified using previously validated international classification of disease (ICD) coding, with position dependent on site of bleed. Results : We identified a cohort of 11,731 patients with CAT, of whom 4,298 patients received anti-cancer systemic therapy within 6 months before to 12 months after CAT diagnosis. The most common malignancies represented in the full cohort included lung (23%), gastrointestinal (14%), and prostate (11%). Most patients received anticoagulant therapy with LMWH (47.7%), followed by DOACs (26.8%), VKAs (24.5%), and fondaparinux (1%). When assessing anticoagulant trends over time, DOACs were the treatment of choice by 2018 with 45.3% of patients receiving initial therapy with a DOAC and further increased to 78.1% by 2020. The 6-month and 12-month cumulative incidence of bleeding in the full cohort was 7% (CI 6.5-7.5) and 9.5% (CI 8.9-10.1), respectively. In the chemotherapy cohort, 6-month and 12-month cumulative incidence of bleeding was 7.9% (CI 7.1-8.8) and 12% (CI 10.8-13.2). In both the chemotherapy and full cohorts, the most frequent sites of clinically significant bleeding included gastrointestinal (GI) tract (57.2%, 54.5%), genitourinary (GU) tract (excluding microscopic hematuria) (20.2%, 21.2%), and intracranial hemorrhage (10.4%, 11.4%) respectively. Of the traditional candidate variables assessed in the full cohort, history of bleeding, estimated glomerular filtration rate (eGFR), uncontrolled hypertension, predisposition to falling, history of ischemic stroke, alcohol abuse, anemia (defines as hemoglobin < 13g/dL in men and < 12 g/dL in women), and liver disease had the highest association with anticoagulant-related bleeding. In addition, use of chemotherapy was associated with an increased risk of bleeding. Findings were similar in the chemotherapy cohort, history of ischemic stroke, alcohol abuse, and anemia were no longer associated with bleeding risk. Of cancer specific candidate variables, GI cancer, GU cancer and metastatic cancer was most predictive. Full results of the analyses are in Table 1 for both the full and chemotherapy cohorts. Conclusions : In this study, many candidate variables in available risk prediction models for anticoagulant-related bleeding were not associated with bleeding risk. This may explain the performance of these models in patients with cancer on anticoagulant therapy. We identified cancer-specific candidate variables that were associated with risk of anticoagulant-related bleeding. Incorporation of these cancer-specific variables into available models could improve predictive performance.

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

New Hybrid Tetrahydropyrrolo[3,2,1-ij]quinolin-1-ylidene-2-thioxothiazolidin-4-ones as New Inhibitors of Factor Xa and Factor XIa: Design, Synthesis, and In Silico and Experimental Evaluation.

Despite extensive research in the field of thrombotic diseases, the prevention of blood clots remains an important area of study. Therefore, the development of new anticoagulant drugs with better therapeutic profiles and fewer side effects to combat thrombus formation is still needed. Herein, we report the synthesis and evaluation of novel pyrroloquinolinedione-based rhodanine derivatives, which were chosen from 24 developed derivatives by docking as potential molecules to inhibit the clotting factors Xa and XIa. For the synthesis of new hybrid derivatives of pyrrolo[3,2,1-ij]quinoline-2-one, we used a convenient structural modification of the tetrahydroquinoline fragment by varying the substituents in positions 2, 4, and 6. In addition, the design of target molecules was achieved by alkylating the amino group of the rhodanine fragment with propargyl bromide or by replacing the rhodanine fragment with 2-thioxoimidazolidin-4-one. The in vitro testing showed that eight derivatives are capable of inhibiting both coagulation factors, two compounds are selective inhibitors of factor Xa, and two compounds are selective inhibitors of factor XIa. Overall, these data indicate the potential anticoagulant activity of these molecules through the inhibition of the coagulation factors Xa and XIa.

Fondaparinux Sodium: Recent Advances in the Management of Thrombosis.

Fondaparinux sodium is a chemically synthesized selective factor Xa inhibitor approved for the prevention and treatment of venous thromboembolic events, that is, deep vein thrombosis, pulmonary embolism, and superficial vein thrombosis, in acutely ill (including those affected by COVID-19 or cancer patients) and those undergoing surgeries. Since its approval in 2002, the efficacy and safety of fondaparinux is well demonstrated by many clinical studies, establishing the value of fondaparinux in clinical practice. Some of the advantages with fondaparinux are its chemical nature of synthesis, minimal risk of contamination, 100% absolute bioavailability subcutaneously, instant onset of action, a long half-life, direct renal excretion, fewer adverse reactions when compared with direct oral anticoagulants, and being an ideal alternative in conditions where oral anticoagulants are not approved for use or in patients intolerant to low molecular weight heparins (LMWH). In the last decade, the real-world use of fondaparinux has been explored in other conditions such as acute coronary syndromes, bariatric surgery, in patients developing vaccine-induced immune thrombotic thrombocytopenia (VITT) and in pregnant women with heparin-induced thrombocytopenia (HIT), or those intolerant to LMWH. The emerging data from these studies have culminated in recent updates in the guidelines that recommend the use of fondaparinux under various conditions. This paper aims to review the recent data and the subsequent updates in the recommendations of various guidelines on the use of fondaparinux sodium.

When Will Fondaparinux Induce Thrombocytopenia?

The pentasaccharide Fondaparinux, a synthetic selective factor Xa inhibitor, is one of the safest anticoagulants in the heparin family that is recommended as an alternative drug for patients with hypersensitivity to other drugs such as heparin-induced thrombocytopenia (HIT). However, some observations of Fondaparinux-induced thrombocytopenia (FIT) have been reported while others claimed that FIT does not occur in patients with fondaparinux therapy, indicating that the mechanism of FIT remains controversial. Here, we utilized different methodologies including dynamic light scattering, immunosorbent and platelet aggregation assays, confocal laser scanning microscopy, and flow cytometry to gain insights into FIT. We found that at a certain concentration, Fondaparinux formed sufficient large and stable complexes with PF4 that facilitated binding of the HIT-like monoclonal KKO antibody and enhanced platelet aggregation and activation. We proposed a model to describe the role of Fondaparinux concentration in the formation of complexes with platelet factor 4 and how it promotes the binding of KKO. Our results clarify controversial observations of FIT in patients as each contains a dissimilar PF4:Fondaparinux concentration ratio.

Pharmacotherapy for pulmonary embolism: new anticoagulants

Background: Pulmonary embolism is associated with reduced survival and considerable economic burden worldwide. In Korea, the incidence of pulmonary embolism has been gradually increasing. Older individuals are at an increased risk for pulmonary embolism and anticoagulation-related bleeding events. Typically, heparin and vitamin K antagonists are employed to treat pulmonary embolism; however, these agents present numerous limitations. Hence, novel anticoagulants with improved safety and efficacy profiles are urgently needed.Current Concepts: Direct oral anticoagulants (DOACs), including direct thrombin (coagulation factor II) inhibitors and selective inhibitors of coagulation factor Xa, have emerged as alternative agents. Phase III, large-scale clinical trials have revealed that DOACs are non-inferior to standard therapy during initial and long-term treatment of pulmonary embolism, considering the safety profile. Evidence-based clinical guidelines recommend that primary care clinicians employ DOACs over warfarin to achieve anticoagulation.Discussion and Conclusion: For over 70 years, the standard therapy for most patients with pulmonary embolism has involved heparin administration, overlapped and followed by a vitamin K antagonist. Recently developed DOACs against coagulation factor Xa or thrombin might overcome limitations of standard therapy, including the need for injection and regular dose adjustment with laboratory monitoring. These limitations hinder the management of patients with pulmonary embolism and negatively impact the patient’s quality of life. Four DOACs, including apixaban, dabigatran, edoxaban, and rivaroxaban, are currently available for treating pulmonary embolism in Korea, which could simplify the therapeutic strategy.

Treatment of Deep Vein Thrombosis Using Factor Xa Inhibitor Concurrent with Platinum Based Chemotherapy Regimen: A Case Report

Deep Vein Thrombosis (DVT) is a common treatment-related complication following surgery and chemotherapy. We are reporting a case of colorectal cancer-associated thrombosis during platinum-based chemotherapy. The patient was treated with Rivaroxaban (Xarelto), a highly selective direct Factor Xa inhibitor. This case report highlights the concurrent use of novel oral anticoagulants, which does not interrupt the chemotherapy schedule among patients receiving cytotoxic agents.

English

Novel oral anticoagulants (NOACs) are used as alternative to intravenous anticoagulants. It includes apixaban, dabigatran, rivaroxaban and edoxaban.1 Some of the complications induced by these drugs are gastrointestinal haemorrhage, cerebral haemorrhage and rarely thrombocytopenia. We present a rare case report of a selective factor Xa inhibitor rivaroxaban, which induced thrombocytopenia in a case of deep vein thrombosis (DVT) of right lower limb. Drugs commonly used to prevent embolization of systemic circulation are warfarin and novel oral anticoagulants, such as rivaroxaban and dabigatran.

Anticoagulation Therapy in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism: Results of the Select-D™ Pilot Trial

Introduction: Venous thromboembolism (VTE) in cancer patients is an important and increasingly frequent clinical challenge. In the UK, dalteparin is a licensed low molecular weight heparin (LMWH), administered subcutaneously, for the extended treatment and prevention of recurrence of acute VTE in cancer patients, considered standard treatment prior to the trial starting. Rivaroxaban is a highly selective direct Factor Xa inhibitor with oral bioavailability; a direct oral anticoagulant (DOAC). Data comparing LMWH and DOACs in cancer patients with VTE are limited.Methods: Select-d is a prospective, randomised, open label, multicentre pilot trial comparing dalteparin (200 IU/kg daily, month 1 and 150 IU/kg, months 2-6); and rivaroxaban (15mg twice daily for 3 weeks then 20mg once daily, for 6 months in total) for cancer patients with VTE [symptomatic or incidental pulmonary embolism (iPE) or symptomatic lower extremity proximal deep vein thrombosis (DVT)]. After 6 months of trial treatment, DVT patients who were residual vein thrombosis (RVT) positive by compression ultrasound and patients with PE at presentation, could be randomised to placebo or rivaroxaban for a further 6 months. The original sample size of 530 patients was large to provide sufficient numbers in the second randomisation (150 in each arm) to assess the duration of anticoagulation. The trial sample size was reduced when the second randomisation closed due to a high attrition rate. The revised sample size of 200 patients in each arm provides estimates of the primary outcome (VTE recurrence) to within +/- 4.5% (i.e. width of 95% confidence interval (CI) of 9%), assuming VTE recurrence rates of 10% at 6 months. Secondary outcomes included major bleeds and clinically relevant non-major bleeds (CRNMB) [including overt bleeds resulting in unscheduled contact with a physician or interruption or discontinuation of study drug], acceptability, survival and health economics.Results: 406 patients were recruited between October 2013 and December 2016 from 58 sites across the UK; 203 patients randomised to each arm. Patients had a median age of 67 years (range 22-87); 214 (53%) were males; 386 (95%) from white ethnic origin. Patients presented with either early or locally advanced disease (n=156; 38%), metastatic disease (n=240; 59%), or haematological malignancies (n=10; 3%). Over half of the patients had iPE (n=214; 53%); 47% (n=192) had symptomatic PE or DVT. 280 (69%) patients were receiving anticancer treatment at the time of their VTE; the majority receiving chemotherapy (n=232; 83%) or targeted therapy (n=41; 15%).The VTE recurrence rate at 6 months was 11% (95% CI 7-17%) for patients on dalteparin and 4% (95% CI 2-9%) for patients on rivaroxaban. Major bleeds were similar across trial arms [6 bleeds from 6 patients (3%; 95% CI 1-6%) on the dalteparin arm; 9 bleeds from 8 patients (4%; 95% CI 2-8%) on the rivaroxaban arm]. There were more CRNMBs on the rivaroxaban arm; 5 bleeds from 5 patients (2%; 95% CI 1-6%) on dalteparin compared with 28 bleeds from 27 patients (13%; 95% CI 9-19%) on rivaroxaban. In total, 11 patients (5%; 95% CI 3-9%) on the dalteparin arm had bleeds categorised as either major bleeds or CRNMBs compared to 34 patients (17%; 95% CI 12-22%) on the rivaroxaban arm.208 (54%) patients completed 6 months of trial treatment [100 (52%) patients on dalteparin; 108 (55%) on rivaroxaban]. Overall survival at 6 months was 70% (95% CI 63-76%) on dalteparin and 74% (95% CI 68-80%) on rivaroxaban. The second randomisation only recruited 92 of the required 300 patients; 82 were PEs (61 iPE and 21 symptomatic) and 10 were DVTs. Patients did not continue to the second randomisation due to: death or withdrawal (50%); being RVT negative (12%); failing the other eligibility criteria (24%) or declining randomisation (14%).Conclusion: Select-d is a large pilot randomised trial for the treatment of VTE, investigating a DOAC versus a LMWH in patients with cancer. Treating with rivaroxaban resulted in a very low VTE recurrence rate at 6 months with a similar number of major bleeds reported across trial arms but more CRNMBs were seen with rivaroxaban. A large phase III trial will confirm the use of rivaroxaban for the treatment of VTE in cancer patients. DisclosuresYoung:Leo Pharma: Honoraria; Bayer: Honoraria, Research Funding; Helsinn: Honoraria. Kakkar:Bayer: Honoraria, Research Funding; Janssen: Honoraria; Sanofi: Honoraria; Daiichi Sankyo: Honoraria.

A narrative review of low-dose rivaroxaban in patients with atherothrombotic cardiovascular disease: vascular protection beyond anticoagulation.

Major cardiovascular (CV) events often complicate the natural history of apparently stable atherothrombotic cardiovascular disease (CVD) despite appropriate guideline-based preventive treatment. This finding has been termed residual risk and it has been the focus of recent investigation. New and revisited targets to tackle this so-called residual risk have been proposed, including antithrombotic treatment intensification, further lowering targets of low-density lipoprotein (LDL) cholesterol, novel oral antidiabetic agents with a CV benefit, and drugs to reduce systemic inflammation. In this narrative review, we discuss the evidence, mechanisms and gaps in knowledge concerning the vascular protection derived from low-dose (2.5 mg twice daily) rivaroxaban. On this topic, the main trials (ATLAS ACS 2-TIMI 51, COMPASS and VOYAGER PAD), will be summarized in a comprehensive manner. Indeed, these have shown that a drug developed to prevent thrombus formation (selective Factor Xa inhibition) reduced events that were traditionally platelet-related in concept. Moreover, we propose a simple evidence-based clinically oriented algorithm to thoroughly identify patients at increased risk and who may benefit from this strategy in different clinical scenarios. Low-dose rivaroxaban portrays a novel promising era in atherothrombotic CVD prevention, providing a mechanistic protection beyond traditional strategies in patients overwhelmed by recurrent dismal events.

The role of edoxaban in preventing thromboembolic complications in patients with atrial fibrillation

Edoxaban is a selective direct factor Xa inhibitor. Edoxaban in a dose of 60 mg per day is an effective and safe option in the prevention of thromboembolic complications in patients with nonvalvular atrial fibrillation, including in combination therapy in patients after percutaneous coronary interventions. ENGAGE AF-TIMI 48 is currently the most extensive study comparing direct oral anticoagulants and warfarin in patients with atrial fibrillation, both in terms of number of participants and duration of observation. For edoxaban, an adequate approach to dose reduction has been developed in patients with alikely increase in plasma concentration due to renal impairment, low body weight or inter-drug interactions. Such dose reduction does notlead to an increase in the frequency of ischemic complications.Edoxaban is characterized by an optimal safety profile in patients with chronic moderate kidney disease, a small number of drug interactions and a convenient mode of administration. In patients with atrial fibrillation and concomitant ischemic heart disease, the use of Edoxaban is associated with a decrease in the frequency of myocardial infarctions, as well as strokes and episodes of systemic thromboembolism in comparison with warfarin. The drug can be successfully used as anticoagulant support for cardioversion and catheter ablation for atrial fibrillation.Edoxaban intake does not require routinelaboratory control. In case of unexpected situations (life-threatening bleeding, urgent surgical intervention) in patients receiving edoxaban, to assess the degree of anticoagulation should use the determination of anti-Xa activity. Clinical studies of a specific antidote of edoxaban - andexanet alfa are ongoing. Before approval of the specific antidote in severe andlife-threatening bleedings against the background of edoxaban administration, the use of prothrombin complex concentrate should be considered. Data on the effective and safe use of edoxaban in routine clinical practice have been accumulated.

Parameters Optimization of Edoxaban Extraction from Dried Plasma Spots

Aims: Edoxaban is a direct-acting oral anticoagulant, being a highly selective, direct and reversible factor Xa inhibitor. Edoxaban is used to treat and prevent blood clots such as deep vein thrombosis and pulmonary embolism. The dried spot technic, including dried blood spots and dried plasma spots, is used in many fields, from newborn screening to monitoring of therapeutic drugs in toxicology. In this case, equipment with a highly sensitive detector, such as a mass spectrometer, is required, as well as conditions for a high degree of drug recovery from the dried spot. In this work, the extraction of edoxaban from dried plasma spots (DPS) was studied to determine the optimal parameters of the extraction method.
 Study Design: Analytical experimental study. Short Research Articles.
 Place and Duration of Study: Core Facility of Mass Spectrometric Analysis, Institute of Chemical Biology and Fundamental Medicine SB RAS, between August and October 2020
 Methodology: The organic extraction method was selected for evaluation as the most suitable for LC-MS analysis. Several parameters were investigated to find the best combination for extracting edoxaban from DPS for further LC-MS analysis: percent organic solvent, presence or absence of 0.1% formic acid (FA), extraction time, volume, and temperature.
 Results: The results showed that the extraction was influenced by the composition and volume of the solvent, but not temperature and time. Pure acetonitrile is the worst solvent for extracting edoxaban from DPS. The most optimal parameters are MeOH: 0.1% FA in H2O (70:30, v:v) solvent with an extraction temperature of 40 °C, an extraction time of 15 minutes and a solvent volume of 50 μl.
 Conclusion: Several solvents suitable for LC-MS analysis can be used to recover edoxaban from DPS.

Rationale and design of a European epidemiological post-authorization safety study (PASS) program: rivaroxaban use in routine clinical practice

ABSTRACT Background Rivaroxaban is a highly selective factor Xa inhibitor approved for use in Europe for multiple indications. Study design and methods The European rivaroxaban epidemiological post-authorization safety study (PASS) program consists of seven complementary observational studies. For four of the studies, data are obtained from health-care databases in the UK, the Netherlands, Germany, and Sweden. These database studies describe patterns of rivaroxaban use and patient characteristics over time, and investigate safety and effectiveness outcomes in new users of rivaroxaban using a cohort analysis and nested case–control analysis. To put these results in context, safety outcomes are also analyzed in new users of standard of care. In addition, a modified prescription event monitoring study conducted in the early post-launch phase in primary care, and two specialist cohort event monitoring studies that investigated rivaroxaban use in the secondary care hospital setting, systematically collected drug utilization and safety data via questionnaires completed by health-care professionals in the UK. Discussion The European rivaroxaban epidemiological PASS is a comprehensive program of complementary studies generating evidence from patients treated in routine clinical practice that will expand our understanding of the risk–benefit profile of rivaroxaban.

Anticoagulant activity screening of an in-house database of natural compounds for discovering novel selective factor Xa inhibitors; a combined in silico and in vitro approach

Traditional edible natural products enclose a wealth of anticoagulants that can be prospected for new selective factor Xa inhibitors. Unlike multitargeted anticoagulants, selective factor Xa inhibitors effectively block coagulation cascade with a broader therapeutic window. In the present study, an in-house database comprises 3D structures of 1571 compounds from 26 natural products previously reported to enhance the bleeding tendency was compiled. Virtual screening (VS) of the constructed database to discover active FXa inhibitors was performed using sequential structure-based VS by Glide extra precision docking followed by ligand-based VS through pharmacophore modeling and 3D-QSAR. The implemented approach provoked liquorice, trifolium and olive as candidates for chromogenic in vitro FXa inhibitory assay with IC50 values of 0.363, 0.729, and 0.866 mg/mL, respectively. Evaluation of liquorice solvent fractions revealed that ethyl acetate fraction produced 97.93 ± 0.019% inhibition of FXa. The adopted integrated strategy can be implemented for isolation of potent, selective nature-based FXa inhibitors.

Dual-pathway inhibition for secondary and tertiary antithrombotic prevention in cardiovascular disease.

Advances in antiplatelet therapies for patients with cardiovascular disease have improved patient outcomes over time, but the challenge of balancing the risks of ischaemia and bleeding remains substantial. Moreover, many patients with cardiovascular disease have a residual risk of ischaemic events despite receiving antiplatelet therapy. Therefore, novel strategies are needed to prevent clinical events through mechanisms beyond platelet inhibition and with an acceptable associated risk of bleeding. The advent of non-vitamin K antagonist oral anticoagulants, which attenuate fibrin formation by selective inhibition of factor Xa or thrombin, has renewed the interest in dual-pathway inhibition strategies that combine an antiplatelet agent with an anticoagulant drug. In this Review, we highlight the emerging pharmacological rationale and clinical development of dual-pathway inhibition strategies for the prevention of atherothrombotic events in patients with different manifestations of cardiovascular disease, such as coronary artery disease, cerebrovascular disease and peripheral artery disease.

Prevention of venous thromboembolism with rivaroxaban and apixaban in orthopedic surgery

Numerous limitations and side effects of standard anticoagulants require administering new anticoagulant drugs. New peroral anticoagulants of Factor Xa inhibitor group have more advantages, the key ones being: substantial reductions in specific nutrition limitations and drug interaction, no need for routine laboratory monitoring and greatly improved therapy predictability. Rivaroxaban, a selective peroral Factor Xa inhibitor is more effective compared with enoxaparin for venous thromboembolism (VTE) prophylaxis in major orthopedic interventions. Though several single trials demonstrated no difference in hemorrhagic complications, certain meta-analyses with rivaroxaban showed a higher incidence of hemorrhage. Apixaban, a peroral reversible inhibitor of factor Xa approved for the prevention of VTE, compared with European-approved doses of enoxaparin has the efficacy almost equal to the North-American-approved enoxaparin doses without a significant difference in bleeding rates, though ?DVANCE I study points towards lower bleeding rates in patients treated with apixaban. To clarify the contradictory results of the recent meta-analysis related to the comparison between the stated factor X inhibitors and various comparator enoxaparin regimens as well as related to the risk for symptomatic PTE and total bleeding events following major orthopedic surgery, new research will be required. Specificities of rivaroxaban and apixaban, already constituting, according to modern recommendations, an integral part of the VTE prophylaxis protocols after major orthopedic interventions, will enable the establishment of personalized protocols aimed at developing an improved safety profile of each individual patient.