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Novel Anticoagulant Approved For Use in Embolism Prevention

By: Maryam Ahmed and Lyudmila Krivovyaz, Pharm.D Candidates, c/o 2016

Each year, more than 795,000 Americans suffer from a stroke, with almost 130,000 of those resulting in death.1 Traditionally, warfarin sodium (Coumadin®) has always been the drug of choice for treatment and prevention of clot formation. Over the last couple of years, however, newer agents have been developed that minimize some of the patient burden in regards to lab testing and dietary restrictions. Edoxaban (Savaysa®), approved January 2015, is the newest anti-coagulant indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF), as well as for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant.2

Edoxaban is a selective factor Xa inhibitor, which is involved in the clotting cascade, and causes a reduction in thrombin generation and thrombus formation.3 Factor Xa inhibitors have gained popularity over the conventional anti-coagulant Coumadin®, which is considered first line therapy, due to the lack of mandatory blood work required to monitor the drug’s safety and efficacy. Edoxaban does not have a narrow therapeutic index like warfarin; therefore, routine blood monitoring is not necessary. Converting from warfarin to edoxaban is simple, and can be initiated once the INR <2.5.3

ENGAGE AF-TIMI 48 is phase III multicenter, randomized, double-blind, double-dummy trial funded by Daiichi Sankyo Pharma, which enrolled 21,105 patients at 1,393 hospitals from 46 countries. Eligible patients were 21 years of age or older and had documented atrial fibrillation within the year prior to randomization for the study, a score of 2 or higher on the CHADS2 risk assessment, and were already going to be placed on anticoagulation therapy. The primary efficacy end point was a composite of stroke (ischemic or hemorrhagic) and systemic embolic events (SEE). This was the largest novel anti-coagulant trial conducted at the time, and it found that treatment with a high dose of edoxaban (60mg) was actually superior to treatment with Coumadin® in terms of bleeding risk and non-inferior in preventing strokes and systemic embolism events. Hemorrhagic strokes were lower in both doses (30mg and 60mg), as well as cardiovascular death being lower with edoxaban as well.2 After a median follow-up of 2.8 years, the annual rate of primary outcome (stroke and/or SEE) for patients in the high-dose edoxaban group was 1.18% (hazard ratio [HR] 0.79, 97.5% CI 0.63–0.99; P<0.001 for noninferiority, P=0.02 for superiority), and for patients in the low-dose edoxaban group was 1.61% (HR 1.07, 97.5% CI 0.87–1.31; P=0.005 for noninferiority, P=0.44 for superiority).

For NVAF, the recommended dose of edoxaban is 60 mg once daily in patients with a creatinine clearance (CrCl) of 50 to 95 mL/min, and for a CrCl of 15 to 50 mL/min, the dose should be reduced to 30 mg daily. For the treatment of DVT and PE, the recommended dose is 60mg once daily, and for CrCl of 15 to 50 mL/min or body weight less than or equal to 60 kg, it should again be reduced to 30mg and one can refer to adult dosing for the geriatric population.3

Several other agents share the same mechanism and indications with edoxaban, but what distinguishes it from the others is the benefit it offers for patients with poor renal function. Both apixaban and rivaroxaban, also novel Xa inhibitors, are not indicated for a CrCl below 30 mL/min, whereas edoxaban has a dosing adjustment particularly for renal patients needing anticoagulation.4 The only caveat to the dosing of edoxaban is that it holds a black box warning against usage in NVAF patients with a CrCl greater than 95 mL/min, in which case other agents should be chosen. Premature discontinuation (without alternative anti-coagulation) is also contraindicated, as it increases the chance of ischemic events.

The most common side effect of edoxaban is hemorrhage, therefore it should not be used in patients with active pathological bleeding.3,5 There is no antidote for edoxaban or any of the other novel anticoagulants in its class. This, of course, is the major advantage warfarin has over the Factor Xa inhibitors, as vitamin K, warfarin’s antidote, is readily available in emergencies to reverse warfarin’s blood thinning effects. Edoxaban is definitely a great addition to selective factor Xa inhibitors as it offers a huge benefit to clinicians, namely in safely treating renal patients needing anticoagulation. Being that it is brand new, it will be interesting to see how frequently physicians choose Savaysa® and what other benefits it may provide.



1.Stroke facts. Centers for Disease Control and Prevention Web Site. http://www.cdc.gov/stroke/facts.htm. Updated March 24, 2015. Accessed June 14, 2015.

  1. Acharya T, Deedwania P. An evidence-based review of edoxaban and its role in stroke prevention in patients with nonvalvular atrial fibrillation. Core Evid. 2015;10:63-73.
  2. Savaysa (edoxaban) [package insert]. Parsippany, NJ; Daiichi Sankyo, Inc.; Revised January 2015.
  3. FDA approves Edoxaban for stroke prevention in AF and DVT/PE prevention. Medscape Website. http://www.medscape.com/viewarticle/837837. Published 9 January 2015. Accessed June 14, 2015.
  4. Edoxaban approved for health system prevention. American Society of Health-System Pharmacists Web Site. http://www.ashp.org/menu/News/PharmacyNews/NewsArticle.aspx?id=4157. Published January 9, 2015. Accessed June 19, 2015.
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