Antithrombotic effects of factor Xa inhibition with DU-176b: Phase-I study of an oral, direct factor Xa inhibitor using an ex-vivo flow chamber

Zafar, M. Urooj; Vorchheimer, David A.; Gaztañaga, Juan; Velez, Mauricio; Yadegar, Daniel; Moreno, Pedro R.; Kunitada, Satoshi; Pagán, Juan Carlos García; Fuster, Valentín; Badimón, Juan J.

doi:10.1160/th07-04-0312

Cited by 117 publications

(99 citation statements)

References 25 publications

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“…In a single-dose (60 mg) study in healthy subjects, the maximum plasma concentration of edoxaban was observed at 1.5 h after administration, corresponding to the maximum inhibition of Factor Xa activity, which returned to baseline levels by 12 h. The inhibition of Factor Xa led to a corresponding reduction in thrombin generation and prolongation of clotting times (Zafar et al, 2007). In a multipledose study, edoxaban prolonged the activated partial thromboplastin time and the prothrombin time in a dose-dependent manner (Ogata et al, 2010).…”

Section: Clinical Pharmacologymentioning

confidence: 96%

The potential role of new oral anticoagulants in the prevention and treatment of thromboembolism

Mavrakanas

Bounameaux

2011

Pharmacology & Therapeutics

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Thromboembolic disorders are among the major causes of morbidity and mortality, and anticoagulation remains the cornerstone of prevention and treatment of these disorders. Although effective, the well-established agents have significant drawbacks. Heparin, low molecular weight heparin, and fondaparinux must be given parenterally, which is inconvenient for long-term or home use. The orally administered vitamin K antagonists (such as warfarin) have a slow onset of action, thus requiring bridging therapy with a parenteral agent when immediate anticoagulation is needed (e.g. inpatients with acute deep vein thrombosis). Because vitamin K antagonists produce a variable anticoagulant response as a result of multiple drug-drug and food-drug interactions and genetic polymorphisms, frequent coagulation monitoring and dose adjustment are required to ensure a therapeutic level of anticoagulation, which is inconvenient for both patients and physicians. In the search for new agents to overcome the drawbacks associated with traditional agents, direct Factor Xa inhibitors (e.g. rivaroxaban, apixaban, and edoxaban) and direct thrombin inhibitors (e.g. dabigatran etexilate) have been developed and are undergoing late-stage clinical evaluation for the prevention and treatment of thromboembolic disorders. These new oral agents have already shown promise in large-scale clinical studies and data suggest that we have entered a new era with novel drugs that are closer than ever to the 'ideal anticoagulant'. Because these new oral agents have a rapid onset of action and can be given at fixed doses without the need for routine coagulation monitoring, they may simplify treatment paradigms and are expected to improve overall clinical outcome

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Section: Clinical Pharmacologymentioning

confidence: 96%

The potential role of new oral anticoagulants in the prevention and treatment of thromboembolism

Mavrakanas

Bounameaux

2011

Pharmacology & Therapeutics

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“…The Badimon chamber is an ex vivo model of thrombosis with the ability to assess thrombus formation on a pathophysiologically relevant substrate under conditions of continuous flow. 14,15 It has previously been used to assess novel antithrombotic interventions [16][17][18][19] but has not been used to assess fibrinolysis. By combining 2 well-characterized and established techniques, the aim of the present study was to assess the ability of exogenous and endogenous t-PA to limit thrombus formation in a model of deep coronary arterial injury.…”

Section: Arterioscler Thromb Vasc Biolmentioning

confidence: 99%

Endogenous Tissue Plasminogen Activator Enhances Fibrinolysis and Limits Thrombus Formation in a Clinical Model of Thrombosis

Lucking

Gibson

Paterson

et al. 2013

ATVB

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Objective-Using a clinical model of deep arterial injury, we assessed the ability of exogenous and endogenous tissue plasminogen activator (t-PA) to limit acute in situ thrombus formation. Approach and Results-Ex vivo thrombus formation was assessed in the Badimon chamber at low and high shear rates in 2 double-blind randomized cross-over studies of 20 healthy volunteers during extracorporeal administration of recombinant t-PA (0, 40, 200, and 1000 ng/mL) or during endogenous t-PA release stimulated by intra-arterial bradykinin infusion in the presence or absence of oral enalapril. Recombinant t-PA caused a dose-dependent reduction in thrombus area under low and high shear conditions (P<0.001 for all). Intra-arterial bradykinin increased plasma t-PA concentrations in the chamber effluent (P<0.01 for all versus saline) that was quadrupled in the presence of enalapril (P<0.0001 versus placebo). These increases were accompanied by an increase in plasma D-dimer concentration (P<0.005 for all versus saline) and, in the presence of enalapril, a reduction in thrombus area in the low shear (16±5; P=0.03) and a trend toward a reduction in the high shear chamber (13±7%; P=0.07). Conclusions-Using a well-characterized clinical model of coronary arterial injury, we demonstrate that endogenous t-PA released from the vascular endothelium enhances fibrinolysis and limits in situ thrombus propagation. These data support a crucial role for the endogenous fibrinolytic system in vivo and suggest that continued exploration and manipulation of its therapeutic potential are warranted.

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“…21,22 Edoxaban has 45% to 50% bioavailability, reaches peak plasma concentration in 1 to 2 hours, and has a half-life of 9 to 11 hours. 20,23 It is predominantly renally excreted. 20 Edoxaban is being evaluated in the Phase III Effective aNticoaGulation with factor XA next GEneration in Atrial Fibrillation (ENGAGE AF TIMI) 48 trial at 30 and 60 mg daily versus dose-adjusted warfarin for stroke prevention in patients with atrial fibrillation.…”

Section: Oral Factor Xa Inhibitorsmentioning

confidence: 99%

The Evolving Field of Stroke Prevention in Patients With Atrial Fibrillation

Ezekowitz

Aikens²,

Brown³

et al. 2010

Stroke

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Abstract-Vitamin K antagonists have been the standard in stroke prophylaxis in patients with atrial fibrillation for decades, but several limitations make it difficult for patients to tolerate chronic anticoagulation treatment. New drugs are under evaluation in clinical trials, including direct thrombin inhibitors and factor Xa inhibitors. Antiplatelet agents such as clopidogrel and aspirin are alternatives to warfarin for stroke prevention but have proven less efficacious in trials. The only drug to have completed a Phase III trial successfully thus far is dabigatran. The 150-mg twice-a-day dose was superior to warfarin in efficacy and similar for major bleeding, whereas the 110-mg twice-a-day dose was noninferior for efficacy and reduced major bleeding. Both doses reduced intracranial hemorrhages substantially compared with warfarin. Dabigatran-assigned patients had a higher incidence of discontinuation due to gastrointestinal symptoms. Clinically apparent myocardial infarction rates were slightly higher in the dabigatran groups than the warfarin group. Dabigatran is the first agent to show superiority over warfarin for stroke prevention in atrial fibrillation, raising the standard for newer agents. (Stroke. 2010;41[suppl 1]:S17-S20.)Key Words: anticoagulation Ⅲ atrial fibrillation Ⅲ prevention A trial fibrillation is the most common cardiac arrhythmia with a projected incidence of 5.6 to 15.9 million people by the year 2050. 1,2 The incidence increases with patient age. 3 There is an increased risk of stroke 4 ; thus, adequate anticoagulation using warfarin is the cornerstone of therapy. In the next few years, the role of warfarin as the anticoagulant of choice is likely to be challenged as novel agents are developed (Figure 1). Vitamin K AntagonistsCurrently, the vitamin K antagonist warfarin is the only oral anticoagulant licensed for long-term use in patients with atrial fibrillation. Despite the effectiveness of vitamin K antagonists, they are limited by factors such as drug-drug interactions, food interactions, slow onset of action, hemorrhage, and routine anticoagulation monitoring to maintain a therapeutic international normalized ratio (INR). 5 These limitations have resulted in the underuse of warfarin, 6 leaving many at risk. New oral anticoagulants are needed that eliminate the problems of warfarin use at the same time as remaining effective for stroke prevention.In a recent Phase IIA trial, the new vitamin K antagonist tecarfarin was evaluated in 66 individuals with atrial fibrillation at mild-to-moderate risk of stroke. 7 It is not metabolized by the hepatic cytochrome P450 system and has fewer interactions than warfarin, theoretically making it easier to control. There is much evidence that patients who spend more time in the therapeutic INR range of 2.0 to 3.0 exhibit fewer clinical events. 8 -10 The hypothesis of the study was that the time in the therapeutic INR range on tecarfarin would exceed that on warfarin. Sixty-four patients were taking warfarin and switched to tecarfarin. Excluding t...

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Antithrombotic effects of factor Xa inhibition with DU-176b: Phase-I study of an oral, direct factor Xa inhibitor using an ex-vivo flow chamber

Cited by 117 publications

References 25 publications

The potential role of new oral anticoagulants in the prevention and treatment of thromboembolism

The potential role of new oral anticoagulants in the prevention and treatment of thromboembolism

Endogenous Tissue Plasminogen Activator Enhances Fibrinolysis and Limits Thrombus Formation in a Clinical Model of Thrombosis

The Evolving Field of Stroke Prevention in Patients With Atrial Fibrillation

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