Neutralization of EP217609, a new dual-action FIIa/FXa anticoagulant, by its specific antidote avidin: a phase I study.

INTRODUCTION: EP217609 is a representative of a new class of synthetic parenteral anticoagulants with a dual mechanism of action. It combines in a single molecule a direct thrombin inhibitor and an indirect factor Xa inhibitor. EP217609 can be neutralized by a specific antidote avidin, which binds to the biotin moiety of EP217609. PURPOSE: The primary objective was to assess the neutralization of EP217609 by avidin in healthy subjects. Secondary objectives were to define the optimal avidin monomer/EP217609 molar ratio to achieve an adequate neutralization of EP217609 and to assess the safety and tolerability of EP217609 and avidin. METHODS: Healthy subjects (n = 36) were randomized to a 3 by 3 replicated Latin square design between 3 EP217609 doses (4, 8, 12 mg) and 3 avidin monomer/EP217609 molar ratios (1:1; 2:1; 3:1). EP217609 was administered as a single intravenous bolus, and avidin as a 30-min intravenous infusion, starting 90 min after EP217609 administration. RESULTS: Overall, EP217609 and avidin were well tolerated. One subject experienced a benign and transient typical pseudo-allergic reaction. The administration of EP217609 resulted in dose-dependent increases in pharmacodynamic markers. Avidin triggered a rapid and irreversible neutralization of EP217609 without rebound effect. Adequate neutralization of the anticoagulant activity was achieved with both 2:1 and 3:1 avidin monomer/EP217609 molar ratios. All safety parameters did not show any treatment-emergent clinically relevant changes or abnormalities in any dose group. CONCLUSIONS: These results will allow further investigation in patients requiring a neutralizable anticoagulant as those undergoing cardiac surgery. STUDY REGISTRATION: EudraCT number 2010-020216-10.

First in man study of EP217609, a new long-acting, neutralisable parenteral antithrombotic with a dual mechanism of action.

UNLABELLED: EP217609 is a parenteral antithrombotic compound combining in one molecule an indirect anti-factor Xa inhibitor, a direct thrombin active site inhibitor and a biotin moiety. AIMS: The aim of the study is to investigate the safety, pharmacokinetics and pharmacodynamics of single ascending intravenous doses of EP217609. METHODS: In this randomised double-blind placebo-controlled study, healthy male subjects were administered intravenously single ascending doses (1, 3 or 10 mg) of EP217609 or placebo. Each treatment group consisted of 10 subjects of whom 8 received EP217609 and 2 received placebo. RESULTS AND CONCLUSIONS: All doses of EP217609 were well tolerated. A total of five treatment-emergent adverse events were reported, all considered unrelated, but no bleedings or other significant adverse events occurred during this study. In both plasma and urine, there was a strong correlation between EP217609 concentrations as measured by anti-factor IIa and Xa specific bioassays indicating that the two pharmacological activities of EP217609 did not dissociate in vivo. EP217609 pharmacokinetics were dose proportional and characterised by a low clearance, a small volume of distribution and a terminal half-life of 20.4 h. The long half-life was reflected in long-lasting, dose-dependent effects on activated and ecarin clotting time, thrombin and prothrombin time, activated partial thromboplastin time, thrombin generation time and anti-factor Xa activity. Pharmacokinetic/pharmacodynamic modelling indicated that the concentration of EP217609 producing 50 % of the pharmacodynamic effect was 3400 and 2210 ng/mL for activated clotting time and anti-factor Xa activity, respectively. These results warranted further clinical development of EP217609. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • There is a limited number of neutralisable anticoagulants, particularly when rapid neutralisation is required. • Synthetic anti-Xa compounds have predictable pharmacokinetic profiles. However, problems with thrombin rebound remain because of the inability to inhibit clot-bound thrombin. WHAT THIS STUDY ADDS: • This manuscript provides a comprehensive investigation of the pharmacokinetics, pharmacodynamics and safety of EP217609, and the results were the basis of future clinical studies in both healthy subjects and patients. • The pharmacokinetic/pharmacodynamic modelling provided information for dose selection in such future studies.

A multicenter randomized double-blind study of enoxaparin compared with unfractionated heparin in the prevention of venous thromboembolic disease in elderly in-patients bedridden for an acute medical illness. The Enoxaparin in Medicine Study Group.

A multicenter, randomized double-blind study compared in two parallel groups the efficacy and safety of a low molecular weight heparin (LMWH) enoxaparin 20 mg once daily, with unfractionated heparin (UFH) 5000 IU twice daily, administered subcutaneously for 10 days, in the prevention of venous thrombosis disease in 442 hospitalized elderly patients bedridden for an acute medical illness. The main efficacy endpoint was defined as the occurrence of venous thrombosis, diagnosed by a daily fibrinogen uptake test, and/or documented clinical pulmonary embolism. Intention-to-treat analysis of efficacy showed that the incidence of venous thromboembolic events was low: 4.8% (10/207) in the LMWH group (9 episodes of isotopic venous thrombosis and one of scintigraphic pulmonary embolism), and 4.6% (10/216) in the UFH group (10 episodes of isotopic venous thrombosis). The two treatments were equivalent, where equivalence was defined as a maximum difference of 7% between the two groups (p = 0.0005). There were no significant differences in terms of safety between the 216 patients in the LMWH group and the 223 patients in the UFH group who received at least one injection of the randomized treatment. During the study period, 15 patients (3.4%) died (7 in the LMWH group and 8 in the UFH group): 2 sudden deaths, one in each group including one case in which pulmonary embolism could not be excluded since no autopsy was performed, and 13 others deaths unrelated to the study treatments. Six patients (1.4%) presented a bleeding complication: 2 (0.9%) in the enoxaparin group (one major and one minor hemorrhage), and 4 (1.8%) in the UFH group (2 major and 2 minor hemorrhages). These results indicate that subcutaneous enoxaparin 20 mg once daily for 10 days is as effective and well tolerated as subcutaneous UFH 5000 IU twice daily in the prevention of venous thromboembolic disease in bedridden elderly in-patients presenting an acute medical illness.

Effect of heparin and enoxaparin on platelet interaction with fibrin clots.

It has been recently shown that platelet-rich thrombi are particularly resistant to thrombolysis. Since unfractionated heparin was reported to enhance fibrinogen binding to platelets responsible for the hyperaggregating effect of this drug, the purpose of this work was to determine whether or not heparin could also modulate platelet interaction to whole blood clot. We have therefore investigated the retention to a standard clot of 111In-labelled platelets suspended in plasma in presence of saline (control), heparin or a low molecular weight heparin (Enoxaparin). We have shown that the platelet interaction to the clot was significantly increased by heparin but not by enoxaparin used at the same anti Xa activity. In conclusion, this difference may favor the use of enoxaparin over heparin in clinical situation associated with platelet retention to fibrin clot, such as thrombolysis.

[Efficacy of a very low molecular weight heparin fragment (CY 222) compared to standard heparin in patients with deep venous thrombosis. A randomized study]. / Efficacité d'un fragment d'héparine de trés faible poids moléculaire (CY 222) comparée à l'héparine standard chez des patients porteurs d'une thrombose veineuse profonde. Etude randomisée.

Low molecular weight heparin fractions have been demonstrated as efficient as low doses of standard heparin in preventing post-operative deep-vein thrombosis. Several clinical studies are, now, carrying out in patients with acute deep-vein thrombosis in order to assess efficacy and safety of low molecular weight heparin fractions as compared to standard heparin. In a randomised study including patients with deep-vein thrombosis treated either with low molecular weight heparin or with subcutaneously standard heparin, we demonstrated an effectiveness, in terms of thrombus reduction, of low molecular weight heparin as well as standard heparin. However, low molecular weight heparin seemed to be safer than standard heparin.

EP42675, a synthetic parenteral dual-action anticoagulant: pharmacokinetics, pharmacodynamics, and absence of interactions with antiplatelet drugs.

BACKGROUND: EP42675 is a first-in-class, synthetic, parenteral, anticoagulant combining in a single molecule a direct thrombin inhibitor and an indirect factor Xa(FXa) inhibitor. OBJECTIVES: To investigate the safety, pharmacokinetics, and pharmacodynamics of EP42675 and its interaction with aspirin, clopidogrel, and unfractionated heparin (UFH). SUBJECTS AND METHODS: In study 1, healthy male subjects were administered intravenously single-ascending doses (1-10 mg) of EP42675 or placebo. In study 2, healthy male subjects were administered intravenously a single dose of 5 mg EP42675 on day 1 followed by oral administration of aspirin (100 mg) and clopidogrel (75 mg) once daily from day 8 to 21. On day 15, a second dose of 5 mg EP42675 was administered, and subjects were then randomized to receive a single dose of UFH (30 or 60 IU kg(-1) ) or placebo. RESULTS AND CONCLUSIONS: Mild bleedings were the only drug-related adverse events. EP42675 pharmacokinetics were dose-proportional and characterized by a low clearance, a small volume of distribution, a long terminal half-life. EP42675 pharmacodynamics were characterized by a long-lasting, dose-dependent increase in activated clotting time, ecarin clotting time, thrombin time, anti-FXa activity, activated partial thromboplastin time, prothrombin time, and a decrease in endogenous thrombin potential, measured by a thrombin generation test. Dose-dependent additive effects were seen with UFH on coagulation tests. EP42675 had no additive effect on the inhibition of platelet aggregation induced by aspirin and clopidogrel. These results warrant further clinical development of this new class of anticoagulant.

Valsartan in acute myocardial infarction trial (VALIANT): rationale and design.

BACKGROUND: Survivors of acute myocardial infarction (MI) complicated by heart failure and/or resulting in left ventricular dysfunction are at heightened risk for subsequent death and major nonfatal cardiovascular events. Inhibition of the renin-angiotensin system with an angiotensin-converting enzyme inhibitor has consistently been demonstrated to result in reductions in these risks by approximately 20%. The development of angiotensin II receptor blockers offers a new, more specific, and theoretically more complete pharmacologic mode to inhibit the adverse influence of angiotensin II. METHODS: Valsartan in Acute Myocardial Infarction (VALIANT) is a multicenter, double-blind, randomized, active controlled parallel group study comparing the efficacy and safety of long-term treatment with valsartan, captopril, and their combination in high-risk patients after MI. The trial is designed with 3 arms, giving equal statistical consideration to survival comparisons of captopril versus the angiotensin II receptor blocker valsartan, as well as the combination of captopril plus valsartan, compared with a proven effective dose of captopril. This 14,500-patient trial is designed with an 86% power to detect a 15% reduction in mortality rate with either use of valsartan compared with captopril. The trial encourages optimal individualization of other proven therapies in acute and chronic infarction, and the international patient body ensures good representation of multiple practice patterns. CONCLUSION: VALIANT is a large international investigative effort that will evaluate the role of valsartan in the management of patients with MI associated with heart failure and/or left ventricular dysfunction. The use of a proven dose of captopril and the comparator arms with valsartan alone or in combination with captopril provides a unique test of whether the angiotensin II receptor blocker can make an additional improvement in clinical outcomes beyond angiotensin-converting enzyme inhibitors.