Anticoagulanti Orali Diretti
Edoxaban is an oral direct and reversible inhibitor of activated factor (FXa). It binds to both free and clot bound FXa. Edoxaban is rapidly absorbed, reaching peak plasma concentrations in 1-2 hours with a mean half-life of 8-10 hours in healthy subjects and an oral bioavailability of 50%. It has been approved in Japan for the prevention of venous thromboembolism (VTE) in patients undergoing a total knee arthroplasty, a total hip arthroplasty, and a hip fracture surgery. In September 2014 Edoxaban has been approved in Japan for the prevention of stroke and systemic embolism in patients with non valvular atrial fibrillation (NVAF) and for the treatment and recurrence prevention of deep vein thrombosis (DVT) and pulmonary thromboembolism (PE). In February 2015, edoxaban has been approved by FDA for the treatment of patients with Non Valvular Atrial Fibrillation (NVAF) who had a prior stroke (ischemic or unknown type), transient ischemic attack (TIA) or non-CNS systemic embolism or 2 or more of the following risk factors : a) age > / = 75 years, b) hypertension, c) heart failure, d) diabetes mellitus. The dosage recommended is 60 mg. once daily. The dosage must be reduced at 30 mg. once daily in patients with a creatinine clearance (CrCl) 15 to 50 ml/min, with a low body weight < / = 60 kg or concomitant use of specific P-gp inhibitors such as verapamil, quinidine, dronedarone. Patients on antiretroviral therapy (ritonavir, nelfinavir, indinavir, saquinavir) and patients in treatment with cyclosporine were not included in the ENGAGE AF-TIMI 48 study. The FDA has not approved the use of edoxaban in patients with a CrCl > / = 95 ml/min due to an increased risk of ischemic stroke in patients treated with 60 mg. once daily, compared to patients treated with warfarin. In these patients should be used another anticoagulant.In addition, based on the results of the Hokusai study,the FDA has approved the use of edoxaban in the treatment of patients with Deep Vein Thrombosis (DVT) at the dosage of 60 mg. once daily, following 5-10 days of initial therapy with a parenteral anticoagulant. The dosage must be reduced to 30 mg once daily in case of patients with a CrCl 30 to 50 ml/min, with a body weight < / = 60 kg., or concomitant use of specific P-gp inhibitors such as verapamil and quinidine or the short-term concomitant administration of azithromycin, clarithromycin, erythromycin, oral itraconazole or oral ketoconazol. In April 2015 the European Committee for Medicinal Products for Human Use (CHMP) has recommended approval of edoxaban for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF) with one or more risk factors. The CHMP has also recommended approval of edoxaban for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and the prevention of recurrent DVT and PE in adults. In June 2015 edoxaban has been approved in Europe for stroke prevention in NONValvular atrial fibrillation and for the treatment and prevention of recurrent DVT and PE. In the STARS J-5 trial, (1) (Abstract) (Blood 2010 vol. 116 : 3320) edoxaban was compared to enoxaparin in the prevention of deep vein thrombosis in the post-operative period after total hip replacement surgery.
In the STARS E-3 trial, (2) (Abstract ) (Pathophysiology of Haemostasis and Thrombosis 2010 vol. 37 : OC297) patients undergoing total knee replacement surgery, were randomized to receive oral edoxaban or subcutaneous enoxaparin.
In the STARS J-4 trial, (3) (Abstract) (Pathophysiology of Haemostasis and Thrombosis 2010 vol. 37: P366) patients undergoing hip fracture surgery, were randomized in a 2:1 ratio to an edoxaban group or an enoxaparin group.
All the clinical results of these three trials were favorable to the use of oral edoxaban that showed efficacy superior to that of subcutaneous enoxaparin.
In the Hokusai-VTE trial, (4) (NEJM 2013 vol. 369 pp. 1406-1415) patients with acute venous thromboembolism, who had initially received heparin,were randomized to receive edoxaban or warfarin for 3 to 12 months. In this trial, edoxaban showed non inferiority to standard therapy, and caused less bleeding events in a broad spectrum of patients with venous thromboembolism. In this double blind noninferiority trial, 4143 patients received heparin-edoxaban and 4149 patients received heparin-warfarin for a total of 8240 patients, 4921 with deep vein thrombosis and 3319 with pulmonary embolism. The time in the therapeutic range (TTR) among patients taking warfarin was 63.5%. In this trial, if we analyze the geographic provenance of the patients, (see "Supplementary Appendix") we can see that 2676 patients, about 30% of patients randomized in the study, were recruited in Belarus, Brazil, China, India, Mexico, Hungary, Russia, Ukraine, Thailand and Turkey. All these patients have not a good Time in the Therapeutic Range (TTR). For this reasons, can we apply the results of this study to west European Countries and to North America? Certainly not, especially if we consider that in these geographic areas, in specialized anticoagulation clinics, the TTR is > 70% and especially if we consider that combining online management with self testing and/or self dosing can improve INR even further, perhaps to 80% of TTR or better. (5) (Circulation 2012 vol. 126 (5) pp. e52-e54) (see section on "Conclusions")
In the ENGAGE AF-TIMI 48 Investigators trial, (6) (NEJM 2013 vol. 369 pp. 2093-2104) patients with moderate to high risk atrial fibrillation were randomized to receive edoxaban or warfarin. In this randomized, double blind, double dummy trial, two once-daily regimens of edoxaban, 60 mg. once daily in the high dose group, and 30 mg. once daily in the low dose group, were compared to warfarin in 21105 patients with moderate to high risk atrial fibrillation. The mean time in the therapeutic range was 64.9%. The conclusion of the authors was that edoxaban was not inferior to warfarin in the prevention of stroke or systemic embolism and was associated with significantly lower rates of bleeding and death from cardiovascular causes. Also in this trial, if we analyze the geographic provenance of the patients, we can see that 6827 patients, about 30% of the patients, were recruited in countries with a poor time in the therapeutic range (TTR) as Brazil, Bulgaria, China, Colombia, Guatemala, Hungary, India, Mexico, Perù, Philippines, Romania, Russia, Serbia, Thailand, Turkey and Ukraina. Other 4042 patients were recruited in Argentina, Croatia, Czech Republic, Poland and Slovakia and also in these countries there is not a widespread presence of specialized anticoagulation clinics and for this, also these countries have a poor time in the therapeutic range. These patients were in total 10869 patients (52%) of 21105 who were recruited and consequently the conclusions of this study cannot be applied to western european countries and north america which have a great number of specialized anticoagulation clinics where all patients in treatment with vitamin K antagonists should be referred. All these trials will be discussed in detail in the sections “Indications” and “ Conclusions”. Edoxaban is renally excreted for 35%, for 62% is eliminated through feces and is a substrate for P- glycoprotein (P-gp), and for this interferes with the inhibitors and inducers of P-gp. (see section on “Dosage and drug interactions”) Also for edoxaban, as for all the other new oral anticoagulants there is not at the moment an antidote commercially available. Just recently a human volunteer study of 80 individuals has been published by New England Journal of Medicine in which is decribed that PER977 (Aripazine), a synthetic small molecule (D-arginine compound) has a broad activity against various old (unfractioned heparin, low molecular weight heparin) and new oral anticoagulants (dabigatran, rivaroxaban, apixaban and edoxaban). (7) (New England Journal of Medicine 2014, vol. 371 pp.2141-2142) (see section on "Adverse reactions"). Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors such as rivaroxaban, apixaban and edoxaban. (8) (Recent Patents on Cardiovascular Drug Discovery 2014 vol. 9 pp. 2-10) (see section on "Adverse reactions") A new study funded by Daiichi Sankyo Development LTD. and Daiichi Sankyo Pharma development, the manufacturer of edoxaban, is evaluating edoxaban compared to warfarin in subjects undergoing cardioversion of atrial fibrillation, the ENSURE-AF study. This study, is a prospective, randomized, open-label, blinded end point evaluation parallel group Phase 3b clinical trial which compares edoxaban with enoxaparin/warfarin followed by warfarin alone in subjects undergoing planned electrical cardioversion of non-valvular atrial fibrillation. (9) (American Heart Journal 2015 vol. 169 pp. 597-604.e5) In a study funded by edoxaban manufacturer, investigators found that halving the dose of edoxaban (i.e., to 30 mg daily in the 60 mg group and to 15 mg daily in the 30 mg group) in 5356 patients with creatinine clearance levels of 30 to 50 mL/min, body weight < / = 60 kg, or concomitant medication with potent P-glycoprotein interaction factors associated with risk for excess drug concentration, was possible to optimize benefits of stroke prevention and minimizing risk for bleeding. (10) (The Lancet 2015 vol. 385 (9984) pp. 2288-2295) Despite several large, randomised trials showing that DOACs are non inferior to warfarin at preventing stroke in patients with atrial fibrillation without increasing bleeding, questions about dosing of DOACs in selected patients with atrial fibrillation still remain. (11) (The Lancet 2015 vol. 385 (9984) pp. 2232-2233) (for details,see section on "Adverse reactions") Clinicians must follow patients who start treatment with new target-specific anticoagulants carefully as weight will change, and medication adjustments are necessary in case of important changes of creatinine clearance. "The notion that patients on these new agents do not need close monitoring is misleading". (12) (Journal Watch April 16, 2015)
1 ) Fuji T., Fujita S., Tachibana S. et al. : Efficacy and safety of edoxaban versus enoxaparin for the prevention of venous thromboembolism following total hip arthroplasty : STARS J-V trial [Abstract]. Blood 2010; 116 : 3320
2 ) Fuji T., Wang C-J., Fujita S. et al. : Edoxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty : the STARS E-3 trial [Abstract]. Pathophysiology Haemostasis and Thrombosis 2010; 37 : OC297
3 ) Fujita S., Fuji T., Tachibana S. et al. : Safety and efficacy of edoxaban in patients undergoing hip fracture surgery [Abstract]. Pathophysiology Haemostasis and Thrombosis 2010; 37 : P366
4 ) The Hokusai-VTE Investigators : Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. New England Journal of Medicine 2013; 369 : 1406-1415
5 ) Bussey Henry I., Bussey Marie : Warfarin Management. International Normalized RatioSelf-Testing and Warfarin Self-Dosing. Circulation 2012; 126 : e52-e54
6 ) Giugliano Robert P., Ruff Christian T., Braunwald Eugene et al. : Edoxaban versus warfarin in patients with atrial fibrillation. New England Journal of Medicine 2013; 369 : 2093-2104
7 ) Ansell J.E., Bakhru Sasha H., Grosso Michael et al. : Use of PER977 to reverse the anticoagulant effect of edoxaban. New England Journal of Medicine 2014 vol. 371 pp. 2141-2142
8 ) Gomez-Outes Antonio, Suarez-Gea M.L., Lecumberri Ramon et al. : Specific antidotes in development for reversal of novel anticoagulants : A review. Recent Patenjts on Cardiovascular Drug Discovery 2014; 9 : 2-10
9 ) Lip Gregory Y.H., Merino José, Ezekowitz Michael et al. : A prospective evaluation of edoxaban compared to warfarin in subjects undergoing cardioversion of atrial fibrillation : The EdoxabaN vs. warfarin in subjectS UndeRgoing CardiovErsionb of atrial fibrillation (ENSURE-AF) study. American Heart Journal 2015; 169 : 597-604.e5
10 ) Ruff Christian T., Giugliano Robert P., Braunwald Eugene et al. : Association between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes : an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 Trial. The Lancet 2015; 385 (9984) : 2288-2295
11 ) Patel M.R., Washam J.B. : Edoxaban and the need for outcomes-based NOAC dosing. The Lancet 2015; 385 (9984) : 2232-2233
12 ) Gore Joel M. : Use of clinical factors alone in tailoring edoxaban dose in atrial fibrillation.
Journal Watch April 16, 2015 http://www.jwatch.org/na37398/2015/04/16/use-clinical-factors-alone-tailoring-edoxaban-dose-atrial