Direct Factor Xa Research Articles

Rapid onset and offset of action of otamixaban, a potent direct intravenous factor Xa inhibitor

Purpose: Otamixaban (otam) is a synthetic, specific and reversible direct intravenous (IV) factor Xa inhibitor. The onset/offset of action of otam at doses in the range evaluated in the phase 3 study Treatment of Acute coronary syndromes (ACS) with Otamixaban (TAO) in non-ST-elevation ACS patients planned for early invasive strategy, was investigated using phase 1 data. Methods: Onset of action was estimated by time to reach steady state plasma concentrations in healthy subjects receiving a 0.080 mg/kg IV bolus otam + a 0.100 mg/kg/h (dose 1) or 0.140 mg/kg/h (dose 2) 24h IV infusion. Offset of action was evaluated by comparing the decline of residual otam concentrations post-infusion with the return of activated partial thromboplastin time (aPTT) to baseline after a 24h IV infusion of dose 1 or 0.150 mg/kg/h (dose 3) after an initial bolus. Results: At dose 1, otam concentrations reached steady state within 15 min of IV bolus/infusion start and were stable throughout the infusion (Figure 1). At dose 2, otam concentrations reached 73% steady state 15 min after treatment start. Within 1h post-infusion, residual concentrations of otam were 36% steady state for doses 1 and 2, and were 22% (dose 1) and 21% (dose 2) steady state by 2h post-infusion. aPTT paralleled the otam concentrations with rapid prolongation early after bolus. Within 1h post-infusion, aPTT dropped from ∼1.5 to 1.1-fold and 1.6 to 1.2-fold over baseline at doses 1 and 3, respectively. aPTT returned to baseline 2h post-infusion. ![Figure][1] Figure 1 Conclusions: Otamixaban at doses in the range evaluated in TAO enables rapid attainment of steady state after treatment initiation. aPTT prolongation effects rapidly disappeared post-infusion, coinciding with a rapid drop in otam concentration. This confirms the quick onset/offset properties of otam. [1]: pending:yes

Apixaban

Atrial fibrillation (AF) is an independent risk factor for ischemic stroke occurrence, severity, recurrence, and mortality. Anticoagulation therapy for the prevention of thromboembolism is critical in patients with AF who are at risk of stroke. Warfarin has been an efficacious anticoagulant for this purpose, but its use has been limited by frequent laboratory monitoring, drug interactions, unpredictable individual response, delayed onset of action, and bleeding. Apixaban is the second oral direct selective factor Xa inhibitor approved for the prevention of stroke/systemic embolism in patients with nonvalvular AF. It was significantly better than aspirin in reducing stroke (ischemic or hemorrhagic) or systemic embolism without increasing the risk of major bleeding in patients with AF who were at increased risk of stroke and for whom warfarin was unsuitable. In a randomized, double-blind trial that was originally designed to test for noninferiority, apixaban was superior to warfarin (target international normalized ratio 2-3) in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality in patients with AF. Apixaban has a half-life of about 12 hours, and the normal dosage is 5 mg orally twice daily. However, it may be reduced to 2.5 mg twice daily based on individual factors of the patient (age, renal function, and body weight) and the concomitant use of potent dual inhibitors of cytochrome P450 3A4 and P-glycoprotein. Similar to other novel oral anticoagulants (dabigatran and rivaroxaban), apixaban has no reversal agent for its anticoagulant effect. Overall, apixaban is a safe and efficacious alternative for stroke prophylaxis in high-risk patients who have AF and who are unable to achieve therapeutic goals with warfarin therapy.

Abstract 11: Use of Novel Anticoagulants Among Atrial Fibrillation Patients Hospitalized with Ischemic Stroke or Transient Ischemic Attack: A Get With The Guidelines-Stroke Registry Analysis

Background: The FDA recently approved the direct thrombin inhibitor dabigatran (DTI) and factor Xa inhibitor rivaroxaban for atrial fibrillation (AF) stroke prophylaxis based on large randomized trials showing non-inferiority to warfarin for stroke prevention. However, real-world utilization patterns and predictors of use for these novel anticoagulants (NAC) remain poorly characterized. Methods: Using the AHA Get With The Guidelines Stroke Registry, we analyzed patients with AF who were hospitalized for ischemic stroke or transient ischemic attack (TIA) and discharged on warfarin or NAC. The first NAC approved by the FDA was dabigatran in 10/2010, so we chose a 2-year study period from 10/2010-9/2012. We excluded patients with contraindications for anticoagulation. Patient and hospital variables associated with discharge anticoagulant use were evaluated using Pearson chi-square and Wilcoxon tests. Results: Of 61,655 patients meeting inclusion criteria, 6,835 (11.1%) were discharged on NAC, of which 86.7% were prescribed DTI. Warfarin was prescribed in 54,820 (88.9%) patients. For patients discharged on NAC vs. warfarin, 51.8% vs. 53.3% (p=0.016) were female and median age was 77 [IQR 69-84] vs. 79 [IQR 70-85] (p<0.001). The majority of patients discharged on NAC or warfarin were white (82.7% vs. 80.8% respectively, p=0.005). Slightly higher proportions of patients discharged on NAC vs. warfarin had private/HMO insurance (41.7% vs. 37.6%, p<0.001) than Medicare (39.0% vs. 42.3%, p<0.001). Patients discharged on NAC vs. warfarin had less severe ischemic stroke (NIH stroke scale=3 [IQR 1-8] vs. 5 [IQR 2-11], p<0.001), shorter length of stay (3 [IQR 2-5] vs. 4 [IQR 2-6] days, p<0.001), and higher proportions of patients who could ambulate at admission (32.5% vs. 26.1%, p<0.001) and discharge (47.5% vs. 39.2%, p<0.001). CHADS2 scores were lower among those discharged on NAC (Figure). More patients discharged on NAC were discharged to home (65.0%) than a healthcare facility, compared to 52.4% of patients prescribed warfarin being discharged to home (p<0.001). Conclusion: Among patients with AF and acute ischemic stroke or TIA discharged on oral anticoagulants, NAC use remains low and is prescribed to younger, more functional, and lower risk patients.

Antithrombotics for stroke prevention in non-valvular atrial fibrillation: an update

Nurses and nurse practitioners play an integral role in initiating and managing antithrombotic prophylaxis in patients with atrial fibrillation (AF). Since the advent of warfarin in the 1950s, there have been few changes in this field until recently. Warfarin has been used for decades and has well-demonstrated efficacy. However, it also has well-known drawbacks, including an unpredictable dose response, need for anticoagulation monitoring, frequent dose adjustments, and many drug and food interactions. A new generation of anticoagulants, which includes direct thrombin inhibitors and selective Factor Xa inhibitors, shows the potential to significantly improve options for antithrombotic prophylaxis and to positively affect patient outcomes. The objective of this review is to update nurses on the new oral anticoagulants, other recent developments, such as improved risk-assessment techniques, and the role of over-the-counter products, including aspirin.

Direct Thrombin and Factor Xa Inhibition for Stroke Prevention in Patients With Atrial Fibrillation

Nonvalvular atrial fibrillation (AF) is the most common clinically significant cardiac arrhythmia occurring in patients in the United States. The primary clinical consequence of AF is an increase in the risk and severity of strokes. Treatment guidelines recommend anticoagulation therapy for most patients with AF. One risk-stratification scheme, the CHADS2 index, is simple and widely used to determine the management of patients with AF in regard to stroke prevention. However, new schemes, such as CHA2DS2-VASc, further refine risk stratification to identify patients who would obtain a net clinical benefit from a particular management strategy, thus improving the quality of management. For patients with AF for whom oral anticoagulation (OAC) is advisable, vitamin K antagonist (VKA) therapy is well established and effective. However, OAC with VKAs presents challenges to prescribers and patients in maintaining therapeutic efficacy. Novel OACs may offer alternatives to VKAs. Dabigatran etexilate, a direct thrombin inhibitor, was approved by the US Food and Drug Administration (FDA) in 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular AF. The activated factor X (factor Xa) inhibitor rivaroxaban was recently approved by the FDA both for prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism in patients undergoing knee or hip arthroplasty, and for reducing the risk of stroke and systemic embolism in patients with nonvalvular AF. Apixaban, another factor Xa inhibitor, was recently shown to be effective for stroke prevention in patients with nonvalvular AF. This article reviews clinical considerations regarding new agents that may offer alternatives to VKA therapy for the prevention of stroke in patients with AF.

Atrial fibrillation and stroke prevention: is warfarin still an option?—No

Atrial fibrillation is a common arrhythmia that increases the risk of stroke by 4.5 times. Anticoagulant/antithrombotic therapy in atrial fibrillation has been inconsistent and inappropriate. Warfarin enjoyed the monopoly of being the primary medication used to reduce the risk of thromboembolic events. Warfarin has many limitations in its use as an ideal anticoagulant. To overcome this difficulty, now there are two main alternative groups to warfarin namely, direct thrombin inhibitors (ximelagatran and dabigatran) and factor Xa inhibitors (apixaban, rivaroxaban, edoxaban, etc.). The advantages of the newer anticoagulants over the conventional warfarin are numerous. There are three landmark trials which have shown some light to the path of newer anticoagulant era, which include the following: RE-LY, ROCKET AF and ARISTOTLE. Head to head comparison of warfarin with newer anticoagulants showed the superiority of newer anticoagulants over warfarin in terms of efficacy and favorable side effect profile. After few decades of using warfarin, it's high time to enter into the era of newer anticoagulants and bid adieu to warfarin.

Compositional Differences in Commercially Available Prothrombin Complex Concentrates

AbstractAbstract 4391Prothrombin complex concentrates (PCCs) are used in the management of bleeding complications with conventional oral anticoagulant drugs such as warfarin. These concentrates are also used in supportive therapy for hemostatic disorders. More recently these agents have been investigated for neutralization of the newer oral anticoagulant drugs such as the direct factor Xa and thrombin inhibitors. Since the activation of these complexes results in the generation of factor Xa and IIa, these agents may potentially neutralize both Xa and thrombin inhibitors. However, the potency of these agents is defined in units which represent the level of factor IX, other factors including factor II, VII, and X are also present, and in unspecified amounts. Moreover, other vitamin K-dependent proteins such as protein C, protein S, and protein Z may also be present. Varying amounts of albumin and other agent such as heparin and antithrombin may also be present as an additive. The purpose of this study is to compare the compositions of the currently available PCCs such as Profilnine®, Beriplex®, Cofact®, Octaplex®, Prothromplex®, and the older agents such as Konyne®, Preconetiv®, and Feiba®. Materials and Methods:Commercially available PCCs were obtained from various suppliers. Each of the individual vials of these concentrates was diluted with saline to obtain a 10 U/ml factor IX solution. Protein content was measured using Lowry’s method. Sodium dodecyl sulfate polyacrylamide gel (SDS-PAGE) electrophoresis was carried out by dilution of each concentrates to 2 U/ml. Western blot analysis was performed to determine presence of prothrombin, prothrombin-1, and thrombin using anti-human recombinant thrombin antibody capable recognizing these proteins. Tissue factor activation profiles of each PCCs was also studied using Innovin®. The protein composition of native and activated prothrombin complexes was also investigated using surface-enhanced laser desorption/ionization (SELDI) mass spectrometry utilizing the gold chip array (BioRad). Tissue factor mediated thrombin generation by each of the prothrombin complex was studied using a fluorometric method (Technoclone, Vienna, Austria). Results:The total protein content of these PCCs ranged from 18–106 mg/100U. Some of the products were found to contain varying amounts of albumin, antithrombin and heparin as evident in both SDS-PAGE and SELDI analysis. The SDS-PAGE profile of these complexes showed multiple protein bands ranging from 15 to 250 kDa. Beriplex and Profilnine showed fewer bands; Profilnine® mainly exhibited 250, 110, 75 kDa bands and Beriplex® mainly 75 and 66 kDa bands. The other products contain additional bands in the range of 15 to 66 kDa representing albumin and other products. In the SELDI analysis multiple peaks consistent with the SDS-PAGE profile were noted. The immunoblotting showed a major band 70–75 kDa (prothrombin) along with a 50 kDa band representing prethrombin-1. Prior to activation, Feiba® exhibited a distinct additional 37 kDa dense band, (thrombin). SELDI analysis also indicated variable amounts of prothrombin in the products. Upon activation all PCC’s were capable of generating thrombin as measured by SELDI and immunoblotting. The prothrombin band completely disappears from all PCCs except Preconetiv®, the prevalent products being prethombin-1 and thrombin. The amount of the prethrombin-1 band varied widely among products; and nearly disappears from all as it is converted to thrombin with time of incubation. The amount of thrombin activity generated from each prothrombin complex was concentration dependent and ranged from 30–1044nm/1.25 units/ml. Octaplex and Cofact produced the strongest thrombin activity whereas Beriplex and Prothromplex produced the least thrombin activity. Conclusions:This study shows that despite standardization in factor IX units, at equivalent IX unit potency these agents widely vary in their composition. Beriplex® and Profilnine® represent purer preparations. Upon activation of prothrombin initiated by tissue factor each complex is capable of generating varying amounts of thrombin. Because of these wide variations in protease generation the relative neutralization potential of each of these PCCs may also differ widely. Thus each of these products should thus be considered as a distinct agent and their efficacies individually determined for a given indication. Disclosures:No relevant conflicts of interest to declare.

Oral IIa and Xa Inhibitors for Prevention of Stroke in Atrial Fibrillation: Clinical Studies and Regulatory Considerations

Atrial fibrillation (AF), the most common, clinically significant, cardiac arrhythmia affects 1% of the general population and has important hemodynamic and thromboembolic complications that contribute to elevated morbidity and mortality. AF increases the overall risk of stroke five-fold, accounting for approximately 15% of all strokes and is associated with particularly severe stroke. For the last 50 years, long-term anticoagulation with vitamin K antagonists has been the most effective therapy for preventing stroke and systemic embolism in patients with AF and other risk factors, but their use has a lot of limitations and drawbacks (frequent monitoring and dose adjustment, food and drug interactions, delayed onset of action etc). Nowadays, new oral anticoagulants have emerged that seem to overcome those limitations. Direct thrombin inhibitor dabigatran and factor Xa inhibitors rivaroxaban and apixaban have proven, in large, multicenter, randomized, phase III, clinical studies, to be at least as efficient as warfarin in stroke prevention in patients with AF. RELY and ROCKET AF trials have contributed to market approval of dabigatran and rivaroxaban, respectively and made them available to clinical practice. Another factor Xa inhibitor, edoxaban, is under evaluation in an ongoing phase III clinical trial and others such as AZD0837, betrixaban and darexaban are still in safety and tolerability phase II studies. The oral anticoagulation landscape is changing rapidly and these new agents seem to be very promising. However future post-marketing studies and registries will help clarify their efficacy and safety.

Surgery and invasive procedures in patients on long term treatment with oral direct thrombin or factor Xa inhibitors (update 2012)

Les anticoagulants oraux directs (AOD), anti-IIa ou anti-Xa, sont destines a remplacer les antagonistes de la vitamine K pour une majorite de leurs indications. Les patients traites par ces medicaments pourront beneficier d’une chirurgie ou d’un acte invasif programme ou urgent. L’absence d’experience de cette situation ne permet pas d’emettre des recommandations, mais seulement des propositions pour la meilleure gestion possible vis-a-vis du double risque hemorragique et thrombotique. Les AOD sont a risque hemorragique en cas d’acte invasif, n’ont aucun agent de reversion valide, ne sont pas facilement mesures par les tests de laboratoire, et leur variabilite individuelle est importante. Bien qu’il existe des differences entre les AOD, elles n’imposent pas une prise en charge perioperatoire particuliere a chacun. Pour les actes programmes a risque hemorragique faible, il est propose de realiser une fenetre therapeutique de 48 h encadrant l’acte. Pour ceux a risque hemorragique modere ou eleve, il est propose d’interrompre le traitement 4 jours (derniere prise a J-5) pour assurer l’elimination complete du medicament chez tous les patients et de ne le reprendre que lorsque le risque hemorragique est controle. Un relais par une heparine est justifie si le risque thrombotique lie a l’indication initiale du traitement par l’AOD est tres eleve (patients en fibrillation atriale ayant un antecedent cardioembolique, antecedent thromboembolique veineux recent). Dans les situations non programmees, l’acte invasif doit etre retarde au maximum (1 a 2 demi-vies d’elimination du medicament si possible) et les agents hemostatiques non specifiques (concentres de complexe prothrombinique, facteur VIIa recombinant) ne doivent pas etre utilises a titre prophylactique.

Stroke Prevention in Atrial Fibrillation: Managing the Risks in Light of New Oral Anticoagulants

Anticoagulation in patients with atrial fibrillation is essential to reduce morbidity and mortality associated with stroke, but at the same time the risk of bleeding needs to be carefully considered. There have been many recent developments in anticoagulation to improve medical management of these patients. CHA(2)DS(2)-VASc and HAS-BLED are two new algorithms that clinicians may use prior to initiating anticoagulation to estimate the risk of stroke and bleeding in patients with atrial fibrillation. In addition, new classes of oral anticoagulants such as direct thrombin inhibitors and selective Factor Xa inhibitors have emerged and consist of agents that aim to address many of the practical management challenges of warfarin. In this review of the literature, results of the clinical trials involving these new agents will be discussed and compared, with a focus on the balance between efficacy and safety.

New Prospective for the Management of Low-Risk Pulmonary Embolism: Prognostic Assessment, Early Discharge, and Single-Drug Therapy with New Oral Anticoagulants

Patients with pulmonary embolism (PE) can be stratified into two different prognostic categories, based on the presence or absence of shock or sustained arterial hypotension. Some patients with normotensive PE have a low risk of early mortality, defined as <1% at 30 days or during hospital stay. In this paper, we will discuss the new prospective for the optimal management of low-risk PE: prognostic assessment, early discharge, and single-drug therapy with new oral anticoagulants. Several parameters have been proposed and investigated to identify low-risk PE: clinical prediction rules, imaging tests, and laboratory markers of right ventricular dysfunction or injury. Moreover, outpatient management has been suggested for low-risk PE: it may lead to a decrease in unnecessary hospitalizations, acquired infections, death, and costs and to an improvement in health-related quality of life. Finally, the main characteristics of new oral anticoagulant drugs and the most recent published data on phase III trials on PE suggest that the single-drug therapy is a possible suitable option. Oral administration, predictable anticoagulant responses, and few drug-drug interactions of direct thrombin and factor Xa inhibitors may further simplify PE home therapy avoiding administration of low-molecular-weight heparin.

Edoxaban administration following enoxaparin: A pharmacodynamic, pharmacokinetic, and tolerability assessment in human subjects

Edoxaban is an oral direct factor (F)Xa inhibitor in advanced stages of clinical development. The primary objective of the present study was to assess the pharmacodynamics (PD) and safety of enoxaparin 1 mg/kg followed 12 hours (h) post-dose by edoxaban 60 mg, which is the regimen being used in the phase III study of edoxaban for the treatment of venous thromboembolism (Hokusai-VTE). This was a phase I, open-label, randomised, four-period, four-treatment cross-over study. Treatments were edoxaban alone (EDOX), enoxaparin alone (ENOX), edoxaban plus enoxaparin (EDOX+ENOX), and enoxaparin followed by edoxaban 12 h later (ENOX12-EDOX). Serial blood samples were collected for PD (thrombin generation, anti-FXa) and pharmacokinetic (PK) variables (edoxaban and its principal metabolite M4 by LC-MS/MS, and anti-FIIa as a surrogate of enoxaparin). The highest effect on thrombin AUC (endogenous thrombin potential, or ETP), thrombin (peak), thrombin generation lag time, and velocity index was observed for EDOX+ENOX, followed by ENOX, ENOX12-EDOX, and EDOX. The greatest effect on anti-FXa activity was observed for EDOX+ENOX, followed by ENOX12-EDOX. As expected, neither edoxaban nor enoxaparin significantly altered the PK of the other drug. There were no serious adverse events during the study. It is concluded that a 60-mg dose of edoxaban can be safely administered 12 h following enoxaparin 1 mg/kg.

Promise of Factor Xa Inhibition in Atrial Fibrillation

Randomized clinical trials have conclusively demonstrated that warfarin prevents stroke in patients with atrial fibrillation. This evidence led the American College of Cardiology, the American Heart Association, and the European Society of Cardiology to designate warfarin as a Class I indication in patients at moderate to high risk for stroke. Despite the evidence from randomized clinical trials and clear practice guidelines, warfarin is underutilized in many eligible patients. This is, at least in part, due to the many challenges associated with warfarin use that have led to the development of many new anticoagulants including direct thrombin inhibitors and factor Xa inhibitors. In this article, we review the complexities of anticoagulation in patients with atrial fibrillation, underscoring the challenges related to warfarin use, and present an overview of new anticoagulants particularly, factor Xa inhibitors, with special emphasis on emerging data from randomized clinical trials on their efficacy and safety in the management of atrial fibrillation.

Low Concentrations of rhFVIIa or FEIBA Significantly and Rapidly Reverse the Anticoagulant Effects of Supratherapeutic Edoxaban

Abstract 1252 Introduction:Edoxaban is an oral, direct factor Xa (FXa) inhibitor currently in phase 3 clinical development for stroke prevention in nonvalvular atrial fibrillation (AF) and the treatment and secondary prevention of venous thromboembolism (VTE). Guidance for the emergency management of serious bleeding and strategies for reversing the anticoagulant effects edoxaban are needed. Both recombinant human FVIIa (rhFVIIa; NovoSeven®) and a human plasma fraction containing nonactivated forms of FII, FIX, and FX/proteins C and S and activated FVII (FEIBA; factor eight inhibitor bypassing activity) have been identified as potential reversal agents for edoxaban. The minimum effective doses and the time course required for either rhFVIIa or FEIBA to reverse supratherapeutic concentrations of edoxaban in an anticoagulated patient have yet to be established. This ex vivo study was conducted to assess the effects and establish the time course of various concentrations of rhFVIIa and FEIBA on the reversal of edoxaban’s anticoagulant effects. Methods:Edoxaban at supratherapeutic concentrations of 500 and 1000 ng/mL (therapeutic level is ∼250 ng/mL for Cmax of a 60-mg dose) was added to fresh blood drawn from healthy subjects; control samples were diluent alone. After 60 min of incubation, rhFVIIa, FEIBA, or control was added to the samples. rhFVIIa was added to produce final concentrations of 0.8 and 1.8 μg/mL, which correspond to known maximal observed human plasma concentrations at doses of 40 and 90 μg/kg. FEIBA was added to produce concentrations of 0.75 and 1.4 U/mL, which correspond to human plasma concentrations at the therapeutic doses of FEIBA of 50 to 100 U/kg. In order to determine reversal of anticoagulant effects over time, coagulation assays (PT, aPTT, anti-Xa, intrinsic FXa activity, thrombin generation assay [TGA], D-dimer, and FVIIa activity) were measured at times 0, 0.25, 0.50, 1, 2, and 4 h after incubation with rhFVIIa, FEIBA, or control. Results:In edoxaban alone and control samples, PT, aPTT, and anti-Xa results reflected previously established anticoagulant activity. Both 500 and 1000 ng/mL of edoxaban completely inhibited intrinsic FXa and thrombin generation as measured by TGA (peak). Measures of FVIIa activity indicated that the concentrations of rhFVIIa utilized were consistent with previously reported responses. With the exception of thrombin levels, reversal of edoxaban anticoagulant activity by both rhFVIIa and FEIBA was observed for PT, aPTT, and anti-Xa beginning at 0.25 h and was maintained across the experimental period. At 1000 ng/mL edoxaban, the observed decrease at 0.25 h post-reversal of anticoagulant activity was 82% for anti-Xa, 72% for PT, and 58% for aPTT. Compared with baseline, the maximum reversal of intrinsic FXa activity for edoxaban 500 ng/mL was ∼30% and for 1000 ng/mL was 15% across all concentrations of rhFVIIa and FEIBA. The TGA assay indicated both rhFVIIa and FEIBA reversed ∼45% and 20% of the effect of edoxaban at 500 ng/mL and 1000 ng/mL, respectively, 4 h after adding the reversal agents. With the exception of 1 baseline sample, levels of D-dimer did not show significant changes with the addition of edoxaban or with its subsequent reversal by either rhFVIIa or FEIBA. Conclusion:Low therapeutic concentrations of rhFVIIa and FEIBA showed significant and rapid reversal of supratherapeutic concentrations of the anticoagulant activity induced by edoxaban based on PT, aPTT, and anti-Xa activity. Disclosures:Halim:Daiichi Sankyo Pharma Development: Employment. Li:Daiichi Sankyo Pharma Development: Employment. Stein:Daiichi Sankyo: Consultancy, Research Funding; AACC: Consultancy, Honoraria, Research Funding; Abbott: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; FDA: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; ISIS: Consultancy, Honoraria, Research Funding; Merck & Co: Consultancy, Honoraria, Research Funding; National Lipid Association: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Reliant: Consultancy, Honoraria, Research Funding; Regeneron: Consultancy, Honoraria, Research Funding; SanofiAventis: Consultancy, Honoraria, Research Funding; Schering-Plough: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Wyeth: Consultancy, Honoraria, Research Funding. Mendell:Daiichi Sankyo Pharma Development: Employment.

Die neuen Antikoagulantien - Was muss der Praktiker wissen?

Goal of this article is to select three molecules from all the candidates currently under clincial development and to present and comapre their characteristics. Dabigatran is a direct thrombin (FIIa) inhibitor, whereas Rivaroxaban and Apixaban are direct factor Xa (FXa) inhibitors. All three represent small molecules thatreversibly, rapidly and directly bind to their target, the active center of the respective activated coagulation factor. Phase III data have been published for venous thromboembolism prophylaxis for each of these three drugs. Interestingly, VTE prophylaxis is initiated postoperatively with these products. Rivaroxaban currently holds the only accepted indication in Switzerland. For the indications VTE, atrial fibrillation and acute coronary syndrome promising phase III data have been or are in the process of being published. Monitoring is not necessary for any of these three new anticoagulants.

A role for coagulation factor Xa in experimental pulmonary arterial hypertension

Anticoagulation with warfarin is recommended for the treatment of patients with pulmonary arterial hypertension (PAH). However, the therapeutic benefit of anticoagulation has not yet been demonstrated experimentally or clinically. Here, rivaroxaban, an oral, direct factor Xa (FXa) inhibitor, was compared with warfarin and enoxaparin in the prevention of right ventricular (RV) dysfunction and hypertrophy in the monocrotaline (MCT) model of pulmonary hypertension. Sprague-Dawley rats (n = 10 per group) were randomized to receive rivaroxaban, warfarin, enoxaparin, or placebo before receiving a subcutaneous injection of MCT 60 mg/kg or saline. Rivaroxaban and enoxaparin were administered for 28 days starting 4 h before MCT injection; warfarin was given for 35 days initiated 7 days before MCT injection. RV haemodynamics and hypertrophy were assessed 28 days after MCT administration. Rivaroxaban dose-dependently reduced systolic and end-diastolic RV pressure increase and RV hypertrophy. Warfarin reduced RV pressure increase only. Enoxaparin had no effect on either parameter. Severe bleeding occurred in four and five rats treated with warfarin and enoxaparin, respectively, whereas no overt bleeding was observed in rats treated with rivaroxaban. Selective, direct inhibition of FXa by rivaroxaban effectively prevented RV dysfunction and hypertrophy in MCT-injected rats, indicating a role for coagulation factors in experimental pulmonary hypertension. Clinical investigation of the impact of early and continued administration of a specific FXa inhibitor such as rivaroxaban on the course of PAH should be considered.

Clopidogrel hydrogen sulphate for atrial fibrillation

Introduction: Atrial fibrillation is a common cardiac rhythm abnormality with a considerable cardiovascular disease burden worldwide. It is an independent major risk factor for stroke. Stroke prevention with anticoagulation or antiplatelet agents has been an important area of clinical research. Warfarin is the most widely used antithrombotic therapy for stroke prophylaxis for last several years, and now dabigatran (150 mg b.i.d.) is more effective than warfarin in stroke prevention in individuals at increased of stroke. In addition, several studies have evaluated the efficacy of clopidogrel for stroke prophylaxis either alone or in combination with aspirin.Areas covered: This review summarizes the key findings of the trials looking at the efficacy of clopidogrel in stroke prevention. A literature search was performed using PubMed and Google Scholar. The trials that evaluated the efficacy of clopidogrel in preventing atherothrombotic events or stroke were also included.Expert opinion: Clopidogrel prevents more vascular events, including stroke, in patients with a recent myocardial infarction, stroke or peripheral vascular disease than aspirin. Combination of clopidogrel and aspirin provides a greater reduction of stroke than aspirin or clopidogrel monotherapy, but at an increased risk of bleeding. Dual antiplatelet therapy (clopidogrel and aspirin) is inferior to warfarin in primary stroke prevention for patient with atrial fibrillation and thus should be considered for stroke prophylaxis only in patients ineligible for warfarin. However, with the advent of newer agents, like direct thrombin inhibitors and Factor Xa inhibitors, the role of antiplatelet therapy for stroke prevention in atrial fibrillation remains unclear.

Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor

Apixaban is a potent, highly selective, reversible, oral, direct factor Xa (fXa) inhibitor in development for thrombosis prevention and treatment. The preclinical pharmacokinetic (PK) attributes of apixaban feature small volume of distribution (Vd), low systemic clearance (CL), and good oral bioavailability. Apixaban is well absorbed in rat, dog, and chimpanzee, with absolute oral bioavailability of approximately 50% or greater. The steady-state Vd of apixaban is approximately 0.5, 0.2, and 0.17 l/kg in rats, dogs, and chimpanzees, while CL is approximately 0.9, 0.04, and 0.018 l/h/kg, respectively. In vitro metabolic clearance of apixaban is also low. Renal clearance comprises approximately 10-30% of systemic clearance in rat, dog, and chimpanzee. Anti-fXa activity, prothrombin time (PT), and HEPTEST(®) clotting time (HCT) prolongation correlated well with plasma apixaban concentration in rat, dog and chimpanzee. There was no lag time between apixaban plasma concentration and the pharmacodynamic (PD) markers, suggesting a rapid onset of action of apixaban. The PK/PD analyses were performed using an inhibitory E (max) model for anti-fXa assay and a linear model for PT and HCT assays. The IC(50) values for anti-fXa activity were 0.73 ± 0.03 and 1.5 ± 0.15 μM for rat and dog, respectively. The apparent K ( i ) values for PT were approximately 1.7, 6.6, and 4.8 μM for rat, dog and chimpanzee, respectively. The apparent K ( i ) for HCT was approximately 1.3 μM for dog. Apixaban exhibits desirable PK and PD properties for clinical development with good oral bioavailability, small Vd, low CL, and direct, predictable, concentration-dependent PD responses.

Direct thrombin and factor Xa inhibitors in children: a quest for new anticoagulants for children

Venous thrombosis and pulmonary embolism rarely occur in children but are associated with significant morbidity and mortality. Venous thromboembolism (VTE) mostly affects children with severe underlying conditions and multiple risk factors. Newborns and adolescents are at the highest risk. Standard and low molecular weight heparins and vitamin K antagonists are routinely used for the prevention and treatment of VTE. The new anticoagulants, both parenteral such as argatroban, bivalirudin and fondaparinux and oral such as dabigatran and rivaroxaban, have favourable pharmacological properties, all are approved for clinical use in adults and are currently being investigated in children. Argatroban is the only new anticoagulant licensed for use in children so far. The role of these new anticoagulants as alternative anticoagulants for children remains to be defined. This review focuses on the characteristics of VTE in children and reviews current knowledge on the use of the new thrombin and factor Xa inhibitors in this population.

Apixaban for the Prevention of Thromboembolic Events in Patients with Atrial Fibrillation: Primary Results of the ARISTOTLE Trial

Background: Patients with atrial fibrillation are at risk for thromboembolism. Warfarin is effective but underused because of its narrow therapeutic window, risk of bleeding, and need for frequent monitoring. More effective, safer and easier to use anticoagulants are an unmet clinical need. Apixaban is an oral direct selective factor Xa inhibitor being investigated in patients with atrial fibrillation in the ARISTOTLE trial. Methods: Patients with atrial fibrillation and at least one additional risk factor for thromboembolism were randomized to blinded apixaban 5 mg BID or warfarin. Warfarin was adjusted to a target INR between 2 and 3 using a blinded encrypted bedside device. The primary efficacy endpoint was stroke (ischemic or hemorrhagic) or systemic embolism. The primary safety endpoint was ISTH major bleeding. A total of 448 patients with the primary endpoint were required for the primary non-inferiority analysis. The trial database was locked in March 2011. Results: A total of 18,201 patients were enrolled in 39 countries, including 336 from Japan. The mean time in therapeutic range (INR 2–3) with warfarin was 60–65%. A total of 447 patients had primary outcome events. ISTH major bleeding occurred in 789 patients. The primary results will be presented at the ESC in September 2011. Conclusions: The results of ARISTOTLE will define the role of apixaban in patients with atrial fibrillation.