Medical treatment of acute deep venous thrombosis and pulmonary embolism
Peter Gloviczki, Michael C. Dalsing, Bo Eklöf, Fedor Lurie, Thomas W. Wakefield, Monika L. Gloviczki in Handbook of Venous and Lymphatic Disorders, 2017
Edoxaban (Savaysa®, Daiichi Sankyo) is the most recently approved agent for treatment of DVT.22 It is currently FDA approved for the prevention of stroke and non-central nervous system systemic embolism in patients with non-valvular atrial fibrillation, as well as for the treatment of DVT and PE in patients who have been treated with a parenteral anticoagulant for 5–10 days. Edoxaban carries a boxed warning stating that the novel anticoagulant is less effective in atrial fibrillation patients with a creatinine clearance of >95 mL/minute, and that kidney function should be assessed prior to starting treatment. According to the FDA, patients with a creatinine clearance of >95 mL/minute have a greater risk of stroke compared with similar patients treated with warfarin. Edoxaban is the only agent specifically tested at a lower dose in patients at high risk of bleeding complications (low body weight and/or decreased creatinine clearance).22
Cerebrovascular disease in the elderly patient
Wilbert S. Aronow, Jerome L. Fleg, Michael W. Rich in Tresch and Aronow’s Cardiovascular Disease in the Elderly, 2019
A new category of anticoagulants for primary prevention of stroke in AF have been developed that may have some advantages over anticoagulation with warfarin: the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban (100-103). Dabigatran 150 mg twice daily was associated with a lower incidence of stroke compared to warfarin and equal incidence of hemorrhagic complications (100). However, in post-marketing experience, the higher dose of dabigatran has been associated higher risk of hemorrhagic complications than the original study, particularly in the elderly. Rivaroxaban 20 mg daily was more effective than warfarin with an equal rate of hemorrhagic complications but a significantly lower rate of intracranial hemorrhage (101). Apixaban 5 mg twice daily had a lower risk of stroke compared to warfarin as well as lower rate of hemorrhagic complications. Apixaban must be dose adjusted in patients above 80 with low body weight, elevated creatinine, and certain drug interactions (85,102). The slightly higher efficacy and lower rate of hemorrhagic complications has made apixaban a popular choice among cardiologists and vascular neurologists. Edoxaban, the last to be approved, was approved at a dose of 60 mg daily for secondary prevention of stroke in AF. When compared to warfarin, the hazard of ischemic stroke was equivalent but hemorrhagic stroke significantly lower (103).
Briefing Therapeutic Approaches in Anticoagulant, Thrombolytic, and Antiplatelet Therapy
Debarshi Kar Mahapatra, Sanjay Kumar Bharti in Medicinal Chemistry with Pharmaceutical Product Development, 2019
Edoxaban was approved in July 2011 in Japan for the prevention of venous thromboembolisms (VTE) following lower-limb orthopedic surgery. It was also approved by the FDA in January 2015 for the prevention of stroke and non-central nervous system systemic embolism. It inhibits free factor Xa and prothrombinase activity and inhibits thrombin-induced platelet aggregation [50]. Portola submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking approval to market betrixaban for extended-duration prophylaxis of venous thromboembolism (VTE) in acute medically ill patients with risk factors for VTE [51]. Darexaban (YM150) is a direct inhibitor of factor Xa created by Astellas Pharma. The development of darexaban was discontinued in September 2011 [52]. Otamixaban is an experimental injectable anticoagulant direct factor Xa inhibitor that was investigated for the treatment for acute coronary syndrome. In 2013, Sanofi announced that the drug candidate showed poor performance in a Phase III clinical trial [53]. The advantages of the xabans over vitamin K antagonists include no requirement for routine anticoagulation monitoring as well as a fast and reliable onset of action [54–56].
Edoxaban for the prevention of stroke in patients with atrial fibrillation
Published in Expert Review of Cardiovascular Therapy, 2019
Carlos Escobar Cervantes, José Luis Merino, Vivencio Barrios
Edoxaban is indicated for the prevention of stroke in patients with nonvalvular AF [20]. In the ENGAGE AF-TIMI 48 trial, patients with moderate to severe mitral stenosis or mechanical heart valves were excluded from the study. By contrast, patients with bioprosthetic heart valves, valve repair, and valvular diseases such as mitral valve prolapse, mitral valve regurgitation, or aortic valve disease, could be included in the study [43]. A recent study analyzed the impact of valvular heart disease, defined as the presence of at least moderate aortic/mitral regurgitation, aortic stenosis, or prior valve surgery (bioprosthesis replacement, valve repair, valvuloplasty) on outcomes. Although patients with valvular heart disease had a similar risk of stroke/systemic embolism (vs no valvular heart disease), the risk of death (HR 1.40; 95% CI 1.26–1.56; p < 0.001), major adverse cardiovascular events (HR 1.29; 95% CI 1.16–1.43; p < 0.001), and major bleeding (HR 1.21; 95% CI 1.03–1.42; p = 0.02) was higher among patients with valvular heart disease. The relative efficacy (stroke/systemic embolism) and safety (major bleeding) of edoxaban 60 mg (vs warfarin) were independent of the presence of valvular heart disease [61,62].
Fitting the right non-vitamin K antagonist oral anticoagulant to the right patient with non-valvular atrial fibrillation: an evidence-based choice
Published in Annals of Medicine, 2018
Yan-Guang Li, Daniele Pastori, Gregory Y. H. Lip
The A prospective evaluation of edoxaban compared to warfarin in subjects undergoing cardioversion of atrial fibrillation: the edoxaban versus warfarin in subjects undergoing cardioversion of atrial fibrillation (ENSURE-AF) trial was a multicentre, prospective, randomized trial in 19 countries with over 200 sites comparing edoxaban with enoxaparin-warfarin in AF patients undergoing cardioversion [47]. AF patients were assigned to receive edoxaban (n = 1095) or enoxaparin/warfarin (n = 1104) and followed for 30 days after completing or discontinuing the treatment. The rates of primary endpoint and safety outcome were low and similar between the two groups (<1% for both; Table 1) [47]. Thus, edoxaban is an effective and safe alternative to conventional anticoagulation (enoxaparin/warfarin) and may ensure prompt cardioversion for AF patients.
Drug interactions between direct-acting oral anticoagulants and calcineurin inhibitors during solid organ transplantation: considerations for therapy
Published in Expert Review of Clinical Pharmacology, 2019
Edwin Lam, Babar Bashir, Mark Chaballa, Walter K. Kraft
Edoxaban is a selective inhibitor of FXa indicated for the risk reduction of stroke and emboli in non-valvular atrial fibrillation and treatment of VTE [60]. Like dabigatran but unlike the other FXa inhibitors, edoxaban is labeled to be started after 5 to 10 days of parenteral anticoagulation in the treatment of acute VTE. Edoxaban demonstrates pH-dependent solubility where optimal dissolution is achieved in the pH range of 3 to 5. Absorption primarily occurs in the proximal small intestine with an absolute bioavailability of 62%. The volume of distribution is estimated to be 107 L and plasma protein binding is estimated to be about 55% for concentrations from 0.2 to 5 ug/mL. Edoxaban metabolism is primarily mediated by carboxylesterase 1 (CES1) and CYP3A4. M4, an active circulating metabolite in plasma, is formed following CES1 metabolism and contributes to 10% of the total edoxaban systemic AUC. Approximately 50% of the total clearance of unchanged edoxaban is through the kidneys with the remaining half appearing in feces and bile. After oral administration, the terminal elimination half-life is 10 to 14 h. Edoxaban is a substrate for P-gp with its active metabolite, M4, a substrate for the influx transporter OATP1B1. In-vitro evidence suggests equivalent efflux transport from P-gp and BCRP [51].
Related Knowledge Centers
- Anticoagulant
- Deep Vein Thrombosis
- Drug Interaction
- Embolism
- Warfarin
- Direct Factor Xa Inhibitors
- Oral Administration
- Venous Thrombosis
- Orthopedic Surgery
- Indication