Direct Factor Xa Research Articles

EUROVISCO Good Practice Recommendations for a First Viscosupplementation in Patients with Knee Osteoarthritis.

Viscosupplementation (VS) with hyaluronic acid is widely used in the management of knee osteoarthritis. There is no clear recommendation on the decision-making to achieve VS. Based on extensive research of the literature and expert opinion, the members of the EUROVISCO (European Viscosupplementation Consensus Group) task force were asked to give their degree of agreement with 60 issues, using a Delphi method. The expert panel achieved unanimous agreement in favor of the following statements: It is recommended to assess pain on a visual or 10-point numeric scale before considering VS. VS can be considered for patients with pain scores between 3 and 8. A standard x-ray must be obtained before the decision of VS. If the x-ray is normal, osteoarthritis must be confirmed by MRI or computed tomography (CT) arthrogram before considering VS. The aims of VS are relieving pain, improving function, and reducing non-steroidal anti-inflammatory drug (NSAID) consumption. The use of VS must not be considered for treating an osteoarthritis flare. VS can be envisaged as a first-line pharmacological treatment in patients having a contra-indication to NSAIDs or analgesics. VS can be considered in patients with contra-indications to arthroplasty. In the case of severe comorbidities (diabetes, hypertension, gastrointestinal disorders, renal failure), VS can avoid the use of potentially dangerous treatments. VS can be considered in patients receiving antiplatelet agents, vitamin K antagonists, and direct factor Xa or thrombin inhibitors. Five other statements obtained a high level of consensus. These recommendations, illustrated in a decision algorithm, have been established to help practitioners in the decision-making of knee VS.

Abstract 10571: Phase 1 Single-Dose Study to Evaluate Apixaban in Pediatric Subjects at Risk for Venous or Arterial Thrombotic Disorder

Introduction: Standard-of-care antithrombotics in pediatric subjects (peds) include unfractionated/LMW heparin, aspirin, and vitamin K antagonists. Apixaban, a direct factor Xa (FXa) inhibitor indicated for VTE treatment (tx) and prevention in adults, may be an effective and convenient oral tx option with an acceptable safety profile in peds. Objectives: To evaluate pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of apixaban in peds at risk for venous or arterial thrombotic disorder; to support dose selection for apixaban pediatric program trials. Methods: This phase 1 study (NCT01707394) enrolled peds aged < 18 years (y) at risk for venous/arterial thrombotic disorder into groups by age. Peds undergoing tx/procedures or with conditions that may affect bleeding risk or apixaban exposure were excluded. A single apixaban dose (based on BSA; targeted to achieve adult exposures with apixaban 2.5 mg) was administered: 0.1 mg sprinkle capsule for age < 28 days (d); 0.4 mg/mL solution for ages 28 d to < 18 y (dose range: 1.08-2.19 mg/m 2 ). Endpoints included PK, safety, tolerability, and PD (anti-FXa activity). For PK/PD, 4-6 blood samples were collected ≤ 26 h after dosing. A population PK (PPK) model developed with data from adults and peds was used to evaluate PK. Apparent oral clearance (CL/F) included a fixed maturation function based on published data. Results: From Jan 2013 to Jun 2019, 49 peds aged 9 d to 16 y received an apixaban dose. All AEs (n = 15) resolved; most were mild/moderate; none were bleeding-related. SAEs (1 seizure; 1 limb venous thrombosis) were not tx-related. Apixaban CL/F and apparent central volume of distribution increased less than proportionally with body weight. Apixaban CL/F increased with age, reaching adult values in ages 12 to < 18 y. Maturation affected CL/F most notably in ages < 9 months. Plasma anti-FXa activity values were linearly related to apixaban concentrations with no apparent age-related differences, comparable to adults. Conclusions: Single apixaban doses were generally safe and well tolerated in peds. Study data and PPK model supported dose selection for phase 2/3 multiple-dose pediatric trials.

Rivaroxaban attenuates cardiac hypertrophy by inhibiting protease-activated receptor-2 signaling in renin-overexpressing hypertensive mice.

Rivaroxaban (Riv), a direct factor Xa (FXa) inhibitor, exerts anti-inflammatory effects in addition to anticoagulation. However, its role in cardiovascular remodeling is largely unknown. We tested the hypothesis that Riv attenuates the progression of cardiac hypertrophy and fibrosis induced by continuous activation of the renin-angiotensin system (RAS) in renin-overexpressing hypertensive transgenic (Ren-Tg) mice. We treated 12-week-old male Ren-Tg and wild-type (WT) mice with a diet containing Riv (12 mg/kg/day) or a regular diet for 4 weeks. After this, FXa in plasma significantly increased in Ren-Tg mice compared with WT mice, and Riv inhibited this increase. Left ventricular wall thickness (LVWT) and the area of cardiac fibrosis evaluated by Masson's trichrome staining were greater in Ren-Tg mice than in WT mice, and Riv decreased them. Cardiac expression levels of the protease-activated receptor (PAR)-2, tumor necrosis factor-α, transforming growth factor (TGF)-β1, and collagen type 3 α1 (COL3A1) genes were all greater in Ren-Tg mice than in WT mice, and Riv attenuated these increases. To investigate the possible involvement of PAR-2, we treated Ren-Tg mice with a continuous subcutaneous infusion of 10 μg/kg/day of the PAR-2 antagonist FSLLRY for 4 weeks. FSLLRY significantly decreased LVWT and cardiac expression of PAR-2, TGF-β1, and COL3A1. In isolated cardiac fibroblasts (CFs), Riv or FSLLRY pretreatment inhibited the FXa-induced increase in the phosphorylation of extracellular signal-regulated kinases. In addition, Riv or FSLLRY inhibited FXa-stimulated wound closure in CFs. Riv exerts a protective effect against cardiac hypertrophy and fibrosis development induced by continuous activation of the RAS, partly by inhibiting PAR-2.

Edoxaban, a direct oral factor Xa inhibitor, ameliorates coagulation, microvascular thrombus formation, and acute liver injury in a lipopolysaccharide-induced coagulopathy model in rats

Infection increases the risk of thrombosis through the activation of inflammation and coagulation. Edoxaban, a direct oral factor Xa inhibitor, is used for the prevention and treatment of thrombotic diseases. The aim of this study was to determine the effects of edoxaban on microvascular thrombus formation in a rat model of lipopolysaccharide (LPS)-induced coagulopathy. Rats were intravenously injected with 7.5 mg/kg of LPS (Escherichia coli 055:B5). Immediately after LPS injection, the rats were treated with subcutaneous injection of edoxaban. At 2 and 6 h after the injection of LPS, biomarkers of coagulation and organ damages and inflammatory cytokines were measured. Microvascular thrombus formation in organs was evaluated using 125I-fibrinogen (human) or by the pathological analysis. Mortality was examined 24 h after LPS injection. After the injection of LPS, D-dimer and thrombin-antithrombin complex increased and platelet numbers decreased, indicating the activation of coagulation. Microvascular thrombi were found in the liver. Markers of liver injury (aspartate aminotransferase and alanine aminotransferase) also increased. Treatment with edoxaban attenuated the changes in the coagulation markers and microvascular thrombus formation in the liver. Edoxaban suppressed the increase in the liver injury markers and reduced the mortality. Edoxaban did not affect the levels of inflammatory cytokines. In conclusions, edoxaban significantly inhibited the activation of coagulation, the formation of microvascular thrombus in the liver and the liver damage, and reduced mortality in rats injected with LPS. These results suggest that the FXa inhibition by edoxaban might be a beneficial therapy for the management of infection-associated thrombosis.

Comparison of Hemostatic Outcomes in Patients Receiving Fixed-Dose vs. Weight-Based 4-Factor Prothrombin Complex Concentrate.

Four-factor prothrombin complex concentrate (4F-PCC) is a blood coagulation product indicated for urgent reversal of warfarin. Currently there are no studies using 4F-PCC as a fixed dose to achieve hemostasis with warfarin as well as direct factor Xa inhibitors. The objective of this study was to evaluate the efficacy and safety of 4F-PCC administration using a fixed dose of approximately 2000 factor IX units to achieve hemostasis in anticoagulated patients, compared with weight-based therapy. This single-center, retrospective cohort study was performed at a 433-bed tertiary care hospital in central Kentucky. Patients from January 1, 2014 to December 31, 2018 were included if they were 18years or older and received 4F-PCC for hemostasis of oral anticoagulation. Efficacy was assessed by determining if clinically effective hemostasis was achieved after receiving a fixed-dose vs. a weight-based dose of 4F-PCC. Seventy-two patients were included in the study. Thirty-eight received weight-based dosing, compared with 34 receiving a fixed dose. Results yielded no statistical difference in clinically effective hemostasis using a fixed-dose vs. weight-based dosing, 91.2% and 78.9%, respectively (p=0.150). There was no significant difference in adverse events, length of stay, or in-hospital mortality between groups; however, significant acquisition cost savings was realized. A fixed-dose regimen of approximately 2000 factor IX units of 4F-PCC may be a reasonable approach to achieve hemostasis in patients receiving warfarin or factor Xa inhibitors. Additionally, utilization of a fixed-dose regimen may lead to significant acquisition cost savings for facilities.

Rates, management and outcome of bleeding complications during edoxaban therapy in daily care – results from the DRESDEN NOAC REGISTRY

Edoxaban is licensed in many countries around the world, following successful phase-III trials in stroke prevention in atrial fibrillation (SPAF) and treatment of venous thromboembolism (VTE), but at present, little is known about edoxaban-related bleeding complications in daily care. Using data from a prospective, non-interventional oral anticoagulation registry, we analysed rates, management and outcome of edoxaban-related bleeding. Between 1 October 2011 and 28 February 2019, 996 patients were enrolled in the edoxaban cohort and a total of 891 bleeding events were observed (53.2% ISTH minor, 41.9% clinically relevant non-major and 4.9% major bleeding events). In case of major bleeding, surgical or interventional treatment was performed in 25.0% and prothrombin complex concentrate was given in 2 cases. In the time-to-first-event analysis, 100-patient-year rates of major bleeding were 3.1/100 patient-years (95% CI 2.2–4.2). In the as-exposed analysis, case-fatality rates of edoxaban-associated bleeding leading to hospitalizations were 7.5% and 9.0% at days 30 and 90 post bleeding, respectively. Taken together, our data indicate that, in real life, rates of edoxaban-related major bleeding in line with rates observed in phase III trials and that bleeding pattern, management and outcome of these events are not different from those reported for other direct factor Xa inhibitors.Clinical Trial Notation: Dresden NOAC Registry - ClinicalTrials.gov Identifier NCT01588119

Abstract WP113: Impact of Apixaban on Clinical Outcome of the Patients With Large Vessel Occlusion or Stenosis (alvo) Study

Background: Efficacy and safety of direct oral factor Xa inhibitor in patients with acute large vessel occlusion (LVO) and nonvalvular atrial fibrillation (NVAF) were questionable because recombinant tissue plasminogen activator (rt-PA) and endovascular therapy (EVT) became the standard therapy. Methods: We conducted historical and prospective multicenter registry from July 2016 to Feb 2018 at 38 centers in Japan. The eligible criteria were 20-year old or elder and patients with NVAF and acute LVO who received apixaban within 14 days from the onset. The primary endpoint was a composite of all-cause death, International Society of Thrombosis and Hemostasismajor bleedings, and ischemic events. Ischemic events included ischemic stroke, acute coronary syndrome, acute myocardial infarction and systemic embolism. The secondary endpoints were each component of primary composite endpoint. Results: We registered 713 patients but 27 patients were excluded due to logical error or ineligibility. The mean age was 78 (SD 10) years and 52% were male among 686 enrolled patients. The median NIHSS and ASPECTS on admission were 14 (range 0-38) and 8 (range 0-10), respectively. The use of rt-PA and EVT were 39.1% and 52.3% of patients, respectively. The median time from onset to the start of apixaban was 2.5 days (range 0-14). The cumulative incidence of primary composite endpoint at 90 days and 365 days were 9.6% (95%CI 7.4-11.9) and 17.5% (95%CI 14.4-20.5), respectively. The cumulative incidence of primary composite endpoint were 15.6% and 12.2% in those with and without EVT at 365 days (p=0.20) The cumulative incidences of ISTH major bleedings and ischemic events at 365 days were 9.0% (95%CI 6.7-11.2) and 4.4% (95%CI 2.8-6.0), respectively. Conclusions: We estimated the cumulative incidences of bleeding and ischemic events as well as all-cause mortality in patients on apixaban for NVAF and acute LVO. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT02818868.)

A Pilot Study of an Oral Anticoagulant, Apixaban, in Secondary Prophylaxis of Venous Thromboembolism (VTE) in Children and Adolescents

Background: Venous thromboembolism (VTE) is a major complication in children and adolescents because of its association with significant morbidity and mortality (Raffini, Pediatrics 2009). Neonates represent the largest group at risk in the pediatric population, however, adolescents account for approximately 25% of pediatric patients who develop primary VTEs. This may in part be related to the similar risk factors between adults and adolescents such as obesity, smoking, and use of oral contraceptives (Kuhle, Thromb Haemost 2004). Fan et al, PBC, 2017 reported on the safety and efficacy of enoxaparin administered by subcutaneous injection in pediatric patients with primary VTEs in which 38% of patients had complete resolution of their VTE on imaging after 3 months of therapy and 39% had partial resolution. Novel oral anticoagulants, direct factor Xa (FXa) inhibitors, are approved in adults for secondary VTE prophylaxis with established efficacy and safety and without the need of subcutaneous injection or frequent blood monitoring compared to oral warfarin (Male et al, Thromb Res 2019). Apixaban, a selective inhibitor of FXa, compared to vitamin K antagonists, has a rapid onset of action, few drug-drug interactions and a predictable anticoagulant response that enables fixed dosing. In addition, they have less variability in pharmacokinetic and pharmacodynamic responses than warfarin, and have a wider therapeutic index (Garcia, J Thromb Haemost 2013). Similarly, compared to subcutaneous heparin, no injections are required and no pharmacodynamic monitoring is needed. Hypothesis: Secondary prophylaxis with Apixaban (Eliquis®) will be safe, well tolerated and prevent secondary VTEs in children and adolescents with a newly diagnosed primary VTE. Methods: Children weighing > 40 kg and having experienced a primary VTE were eligible to receive apixaban within 72 hrs of VTE diagnosis. A thrombophilia workup was performed including, but not limited to, Factor V Leiden, Protein C and S, and prothrombin gene mutation. Eligible consented patients were administered apixaban 10 mg twice daily P.O. for 7 days followed by 5 mg twice daily until day 90, similar to that used in the AMPLIFY trial in adults (Agnelli, J Thromb Haemost 2015). Treatment began within 72 hours of diagnosis of VTE and transition from other anticoagulants was permitted. Patients unable to tolerate oral medications, with personal or family history of bleeding disorder, history of significant head injury and/or history of intracranial hemorrhage, were excluded from this study. Results: Fifteen patients have been enrolled to date with a median age of 16 yrs (12 - 21 years) and were seventy three percent females (11 females, 4 males). Forty percent of patients were enrolled with primary pulmonary emboli, the remaining with new onset deep venous thrombosis. Line associated clots were included in the study. There were no episodes of bleeding, classified as Grade I-IV hemorrhage (CTCAE), or other adverse events and no patients required dose modifications. There were also no significant changes in creatinine or liver function throughout the course of apixaban administration. Of the 11 patients that completed the day 30 evaluations, 55% showed resolution of their primary thrombus at 30 days with the remainder showing significant decrease in the size of the thrombus (Fig. 1). Fig. 2 illustrates the change from baseline to Day 30 in a child with a pulmonary embolus. There were no patients that experienced increase of their thrombus or any new VTE, which equates to 100% successful VTE secondary prophylaxis. The average INR range was 1.04 (0.92-1.19). The average anti-Xa level was 1.05 four hours after apixaban treatment while the average trough level was 0.88. Conclusions: Our preliminary results suggest that apixaban is safe and well tolerated in children and adolescents for the secondary prophylaxis of patients with a newly diagnosed primary VTE. Additionally, all patients had a decrease in the size of their thrombus with 50% experiencing complete resolution as early as 30 days. There was no evidence of toxicity secondary to apixaban and no requirement to monitor anticoagulant activity. We plan to continue to enroll patients on this study to further validate the safety and efficacy of apixaban. Future directions will include investigating apixaban in children < 40 kg and in neonates with primary VTEs as secondary prophylaxis. Disclosures Friedman: MedImmune: Speakers Bureau; Astra Zeneca: Speakers Bureau. Cairo:Osuka: Research Funding; Miltenyi: Other: MTA; Jazz Pharmaceuticals: Other: Advisory Board, Research Funding, Speakers Bureau.

Phase I Study of Direct Coagulation Factor Xa Inhibitor SYHA136 Tablets in Chinese Healthy Volunteers

Phase I Study of Direct Coagulation Factor Xa Inhibitor SYHA136 Tablets in Chinese Healthy Volunteers

Direct oral factor Xa inhibitors for the treatment of acute cancer-associated venous thromboembolism: A systematic review and network meta-analysis.

e23156 Background: A direct meta-analysis was performed to explore the efficacy and safety of direct oral factor Xa inhibitors with dalteparin in patients with cancer associated acute venous thromboembolism (VTE). Also, the comparative efficacy and safety of apixaban, rivaroxaban, and edoxaban was assessed with a network meta-analysis. Methods: MEDLINE, CENTRAL, and EMBASE were searched for trials comparing direct oral anticoagulants (DOACs) to dalteparin for the management of cancer associated acute VTE. A network meta-analysis using both frequentist and Bayesian methods was performed to analyze VTE recurrence, major and clinically relevant non-major bleeding (CRNMB). Results: Three randomized control trials, at low risk of bias, enrolled 1,739 patients with cancer associated VTE. Direct comparison showed a lower rate of VTE recurrence in DOAC compared to dalteparin groups (odds Ratio [OR]:0.48, 95% Confidence interval [CI]:0.24-0.96; I2:46%). Indirect comparison suggested that apixaban had greater reduction in VTE recurrence compared to dalteparin (OR: 0.10; 95% CI: 0.01–0.82), but not rivaroxaban or edoxaban. Apixaban also had the highest probability of being ranked most effective. By direct comparisons, there was an increased likelihood of major bleeding in the DOAC group compared to dalteparin (OR: 1.70; 95% CI: 1.04–2.78). CRNMB did not differ. Indirect estimates were imprecise. Subgroup analyses in gastrointestinal cancers suggested that dalteparin may have the lowest risk of bleeding whereas estimates in urothelial cancer were imprecise. Conclusions: DOACs appear to lower the risk of VTE recurrence compared to daltaparin while increasing major bleeding. Apixaban may be associated with the lowest risk of VTE recurrence compared to the other DOACs.

A REVIEW ON A COMPARATIVE STUDY ON EFFECTIVENESS AND SAFETY OF NOVEL ORAL ANTICOAGULANTS IN PATIENTS WITH ATRIAL FIBRILLATION

Atrial fibrillation (AF) is characterized as an extremely rapid and disorganized atrial activation. These irregular heartbeats will cause blood to collect within the heart and potentially form a clot, which can travel to a person’s brain and cause a stroke. AF increases stroke risk by 3 to 5 fold. Vitamin K antagonists (VKAs) are highly effective for the prevention of stroke, mainly of ischemic origin, in patients with AF. For this reason, VKAs are currently recommended in all AF patients at moderate to high risk for stroke or systemic embolism (SSE). VKAs have significant limitations, particularly their unpredictable anticoagulant response and numerous food and drug interactions, mandating regular laboratory monitoring. These limitations make treatment with VKAs problematic for many patients; as a result, only about half of all potentially eligible AF patients are treated with VKAs. Over the last several years, novel oral anticoagulant drugs (NOACs), including direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (apixaban & rivaroxaban), have been developed. New orally administered anticoagulant drugs have emerged as potential alternatives to VKAs for the prevention of ischaemic stroke or systemic embolism in patients with chronic atrial fibrillation. Novel oral anticoagulants (NOACs), due to their a lot of predictable therapeutic result and more favorable haemorrhagic risk profile, represent a particularly attractive therapeutic option in AF patients.
 Keywords: Novel oral anticoagulants (NOACs), Vitamin K antagonist (VKAs), Atrial fibrillation, Apixaban, Dabigatran, Rivaroxaban.

A Randomized Study Comparing Rivaroxaban with Placebo in Subjects with Heart Failure and Significant Coronary Artery Disease Following an Episode of Decompensated Heart Failure: The COMMANDER HF study

Background There is mounting evidence of vascular and hemostatic dysfunction in patients with heart failure (HF) that may be associated with increased morbidity and mortality. Previous studies of vitamin K antagonists have demonstrated trends towards reduced rates of important clinical events in patients with HF, but these studies have been inconclusive. Rivaroxaban is a direct oral Factor Xa inhibitor that, at higher doses, is approved for conditions such as atrial fibrillation and venous thromboembolism. Administration of lower doses, in addition to antiplatelet and other background therapies, may modify vascular function, reduces the risk of thrombotic events and thereby improve clinical outcome in patients with HF, especially those with significant underlying coronary artery disease (CAD) and a recent episode of decompensated HF. Methods COMMANDER HF is a randomized, double-blind, placebo-controlled, event-driven trial which aims to establish the superiority of rivaroxaban compared with placebo in patients with significant CAD and reduced left ventricular ejection fraction (LVEF) following an episode of decompensated chronic HF. Patients were excluded if they had a history of persistent atrial fibrillation or were receiving anticoagulants for another reason. Patients were randomly assigned to receive rivaroxaban 2.5 mg twice daily, or matching placebo. All patients were to receive antiplatelet therapy, unless contraindicated, as well as standard HF therapy as prescribed by the treating physician. The primary efficacy endpoint is a composite of all-cause mortality, myocardial infarction (MI) and stroke. The primary safety outcome is the composite of fatal bleeding or bleeding into a critical organ or space with a potential for permanent disability. Results Preliminary data on the 5,022 subjects randomized at 628 sites in 32 countries indicate that the median age was 66 (IQR: 59; 74) years, 23% were women, the median eGFR was 66 (IQR: 52; 82) mL/minute, the median LVEF was 34 (IQR: 28; 38)% and 75% had a history of hypertension, 41% of diabetes and 75% of a prior MI. Follow-up ranged from 1 day to 50.4 months with a median of 17.5 months during which more than 1,200 primary efficacy endpoint events occurred. Conclusion The COMMANDER HF study will determine the efficacy and safety of low-dose rivaroxaban relative to placebo in the population enrolled. The results will be included in the final ESC presentation.

Pre-clinical pharmacodynamic study of a novel oral factor Xa inhibitor zifaxaban

Zifaxaban is an orally active, direct Factor Xa (FXa) inhibitor that is in development for the prevention and treatment of arterial and venous thrombosis. This study was conducted to investigate the biochemical and pharmacological activity of zifaxaban. In vitro activity was evaluated by enzyme, platelet aggregation, and clotting assays. In vivo effects were examined in venous thrombosis, arteriovenous-shunt thrombosis, carotid thrombosis, and bleeding models in rats. Zifaxaban competitively inhibits human FXa (IC50 = 11.1 nM) with > 10,000-fold greater selectivity than other serine proteases. It did not impair platelet aggregation induced by collagen, adenosine diphosphate (ADP) or arachidonic acid. It significantly prolonged clotting time, prothrombin time (PT), and activated partial thromboplastin time (APTT) in the plasma of humans, rabbits, and rats, with a relatively weak effect on thrombin time (TT). In venous thrombosis models in rats, zifaxaban strongly suppressed thrombus formation with ED50 values of 3.09 mg/kg, and its best efficacy time occurred at 2 h after administration. In arteriovenous-shunt thrombosis and carotid thrombosis models in rats, it inhibited thrombus formation in a dose-dependent manner. And in the rat tail bleeding assay, it showed a trend of less bleeding than rivaroxaban at doses that achieved the same antithrombotic effect. In conclusion, zifaxaban is a selective and direct FXa inhibitor and a promising oral anticoagulant for the prophylaxis and treatment of thromboembolic diseases.

218Novel thromboelastography point-of-care test detects all commercially available DOACs at therapeutic concentrations and classifies them as direct thrombin or factor Xa inhibitors with high consistency

218Novel thromboelastography point-of-care test detects all commercially available DOACs at therapeutic concentrations and classifies them as direct thrombin or factor Xa inhibitors with high consistency

Pharmacokinetic drug interactions of the non-vitamin K antagonist oral anticoagulants (NOACs).

The use of warfarin, the most commonly prescribed oral anticoagulant, is being questioned by clinicians worldwide due to warfarin several limitations (a limited therapeutic window and significant variability in dose-response among individuals, in addition to a potential for drug-drug interactions). Therefore, the need for non-vitamin K antagonist oral anticoagulants (NOACs) with a rapid onset of antithrombotic effects and a predictable pharmacokinetic (PK) and pharmacodynamic (PD) profile led to the approval of five new drugs: the direct factor Xa (F-Xa) inhibitors rivaroxaban, apixaban, edoxaban and betrixaban (newly approved by FDA) and the direct thrombin (factor-IIa) inhibitor dabigatran etexilate. The advantages of NOACs over warfarin are a fixed-dosage, the absence of the need for drug monitoring for changes in anti-coagulation and fewer clinically significant PK and PD drug-drug interactions. NOACs exposure will likely be increased by the administration of strong P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4-inhibitors and may increase the risk of bleeds. On the contrary, P-gp inducers could significantly decrease the NOACs plasma concentration with an associated reduction in their anticoagulant effects. This manuscript gives an overview of NOACs PK profiles and their drug-drug interactions potential. This is meant to be of help to physicians in choosing the best therapeutic approach for their patients.

Management of cancer-associated venous thromboembolism – a case-based practical approach

In patients with solid tumours or haematological malignancies, venous thromboembolism (VTE) is a leading cause of death and significantly contributes to morbidity and healthcare resource utilization. Current practice guidelines recommend long-term anticoagulation with low-molecular-weight heparin (LMWH) as the treatment of choice for cancer-associated VTE, based on clinical trial data showing an overall improved safety and efficacy profile of LMWH compared to vitamin K antagonists. However, several open questions remain, e. g. with regard to the intensity and duration of LMWH therapy; moreover, recent real-world evidence indicates that adherence to parenteral anticoagulation with LMWH over the course of treatment is poor in clinical practice. In this regard, the direct oral factor Xa or thrombin inhibitors (DOACs) have emerged as potential alternatives in the management of patients with cancer-associated VTE, albeit findings from randomized controlled studies with a direct head-to-head comparison of DOACs with LMWH, the current standard of care, are still lacking. Based on the case of a lymphoma patient experiencing symptomatic pulmonary embolism during immunochemotherapy, this article aims at both highlighting the current state-of-the-art approach to cancer-associated VTE and pointing out some of the unresolved, controversial issues clinicians have to face when taking care of haematology and oncology patients with already established or with high risk of developing VTE. These issues include the management of patients with incidental pulmonary embolism or thrombocytopenia, the use of DOACs, and the initiation of pharmacological thromboprophylaxis in non-surgical cancer patients.

Safety, pharmacokinetics, and reversal of apixaban anticoagulation with andexanet alfa.

Direct factor Xa (FXa) inhibitors lack a specific reversal agent for emergencies such as major bleeding or urgent surgery. Andexanet alfa, a modified, catalytically inactive, recombinant human FXa derivative, reverses anticoagulant effect by binding and sequestering FXa inhibitors. This original report of safety and dose-finding, phase 1 and 2 randomized, double-blind, placebo-controlled studies, investigated various doses of andexanet in healthy volunteers. Phase 1 evaluated the safety and pharmacokinetics of andexanet (n = 24) or placebo (n = 8). In phase 2, andexanet (n = 36) or placebo (n = 18) was administered following steady-state apixaban dosing (5 mg twice daily for 6 days); safety, pharmacokinetics, and pharmacodynamics were assessed. Andexanet plasma concentration increased proportionally with dose, with rapid elimination (terminal elimination half-life, 4.35-7.5 hours). Following apixaban treatment, andexanet rapidly (≤2 minutes) and dose dependently reduced unbound apixaban concentration vs placebo (51% to 89% vs 5% reduction; all P < .05), decreased anti-FXa activity (67.8% to 95.0% vs 7.1% reduction; all P < .05), and restored thrombin generation in 67% to 100% vs 6% of subjects (all P < .01), maintaining these effects during continuous 45- and 120-minute infusions. Andexanet was well tolerated. Nine subjects had mild/moderate infusion reactions not associated with hemodynamic changes or respiratory compromise that generally resolved without intervention or dose reduction. There were no thrombotic events or other serious safety issues. In conclusion, andexanet reversed apixaban-mediated effects on pharmacodynamic markers of anticoagulation in healthy volunteers within minutes after administration and for the duration of infusion. This trial was registered at www.clinicaltrials.gov as #NCT01758432.

How do oral direct thrombin inhibitors and oral factor Xa inhibitors compare with standard anticoagulation for the treatment of pulmonary embolism?

How do oral direct thrombin inhibitors and oral factor Xa inhibitors compare with standard anticoagulation for the treatment of pulmonary embolism?

Direct oral factor Xa inhibitors for the prevention of non-central nervous systemic embolism patients with non-valvular atrial fibrillation - a systematic review and meta-analysis.

The aim of this systematic review and meta-analysis was to evaluate the efficacy of direct oral factor Xa inhibitors for preventing non-central nervous systemic embolism in patients with non-valvular atrial fibrillation. We conducted a systematic review of the following databases: Ovid MEDLINE, EUROPUBMED, EMBASE, and the Cochrane Central Register of Controlled Trials, from July 1st 1990 to April 1st, 2015. Randomised controlled trials were included if they reported the outcomes of patients with non-valvular atrial fibrillation treated with a direct oral factor Xa inhibitors compared to a vitamin K antagonist. The primary outcome was objectively confirmed as non-central nervous systemic embolism and ischaemic stroke was the secondary outcome. The random-effects model odds ratio was used as the outcome measure. Our initial search identified 987 relevant articles, of which three satisfied our inclusion criteria and were included. Compared to vitamin K antagonists targeting an INR between 2 and 3, direct oral factor Xa inhibitors alone did not reduce the incidence of non-central nervous systemic embolism [OR 0.63 (95 % CI 0.30 - 1.35)] or ischaemic stroke [OR 1.06 (95 % CI 0.86 - 1.32)]. As a drug class, direct oral factor Xa inhibitors do not reduce the incidence of non-central nervous systemic embolism (or ischaemic stroke) in patients with non-valvular atrial fibrillation. Selecting drugs for the prevention of non-central nervous systemic embolism in patients with non-valvular atrial fibrillation should be based on individual drug efficacy data, rather than class data.

Oral anticoagulants, effect on thrombus resolution and post-thrombotic syndrome.

Venous thromboembolism is a frequently occurring phenomenon with a high risk of acute and chronic complications. To prevent these, subjects are treated with surgical options to restore venous blood flow combined with medical treatment or medical treatment alone. Despite great therapeutic advances considerable morbidity still persists. For example, thrombosis of the leg can result in post-thrombotic syndrome, which has a great impact on quality of life. The best management to prevent the post-thrombotic syndrome is a topic of research and debate. In this study, we searched the literature to identify studies that used oral anticoagulants and evaluated their properties for resolution of thrombus and hence prevention of the post-thrombotic syndrome. We searched PubMed, The Cochrane Library, and four international medical journals frequently reporting on venous thromboembolism. Furthermore, we looked at Clinicaltrials.gov for current research on this topic. Only three suitable articles were identified. We found experimental evidence that direct thrombin inhibitors and factor Xa inhibitors have an influence on clot lysis favoring a quicker recanalization compared to warfarin. Future studies investigating these effects in humans are warranted.