Marion General Hospital Formulary EvaluationMonograph

Generic Name (Trade Name): Edoxaban (Savaysa)Manufacturer: Daiichi Sankyo, Inc Dosage Forms (NDC #): oral tabletAHFS Class: Anticoagulant Storage: 20-25°C

Description and Pharmacology: Edoxaban is an oral anticoagulant that inhibits Factor Xa to prevent the formation of thrombin.

Pharmacokinetics

See supplementary handout

FDA-Approved Indications1

Reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Treatment of DVT and PE 5-10 days after initial therapy with a parenteral anticoagulant

Clinical Trials

Title ENGAGE AF-TIMI 48 StudyObjective Comapre efficacy and safety of two dosing regimens of Edoxaban compared to

warfarin in reducing risk of stroke or systemic embolism in patients with non-valvular A.Fib.

Design Multi-national, double blind, non-inferiority study21,105 patientsFollow up: 2.8 years

Methods Treatment arms: Edoxaban 60mg or 30mg vs. warfarin adjusted to a target INR of 2-3Primary endpoint: occurrence of first stroke or systemic embolism, p<0.001Safety outcome: major bleeding

Results Warfarin vs. Edoxaban 60mg vs. Edoxaban 30mgEvent rate per year of stroke or systemic embolism: 232 pts vs.182pts p<0.001. vs. 253 pts p=0.005Annual rate of major bleeding: 3.75% vs. 2.75%p<0.001 vs. 1.61% p<0.001

Conclusions Edoxaban 60 mg showed non-inferiority to warfarin for prevention of stroke or systemic embolism as well as ischemic stroke alone. Edoxaban 30mg showed non-inferiority to warfarin in the primary outcome however risk of ischemic stroke increased. Both doses showed decrease in rates of hemorrhagic stroke, major bleeding, intracranial bleeding, and life-threatening bleeding. GI bleeding occurred more commonly with Edoxaban 60mg.

Comments

Title Hokusai VTE StudyObjective Compare efficacy and safety of edoxaban in the treatment of DVT/PE compared to

standard treatment with warfarin.Design Randomized, double-blind, non-inferiority trial

8,292 patientsMethods Treatment arms: Edoxaban 60mg + parenteral anticoagulant(30mg if qualified for

reduced dosage) vs. warfarin titrated to target INR of 2-3 + parenteral anticoagulantPrimary outcome: incidence of symptomatic recurrent VTE which s defined as a composite of DVT or nonfatal/fatal PE. Safety outcome: major or clinically relevant nonmajor bleeding

Results Edoxaban vs. Warfarin

Recurrent VTE: 130/4118 pts (3.2%) vs. 146/4122 pts (3.5%) HR: 0.89; 95% CI: 0.70 to 1.13; P<0.001 Clinically relevant bleeding: 349/4118pts (8.5%) vs. 423/4122pts (10.3%), HR: 0.81; 95% CI, 0.71 to 0.94; P=0.004

Conclusions Edoxaban in the treatment of VTE was non-inferior to warfarin in the prevention of recurrent VTE and superior to warfarin in regards to bleeding.

Comments

Safety and Tolerability

Contraindications: Active pathological bleedingWarnings and Precautions:

Serious and fatal bleeding can occur Use is not recommended in patients with mechanical heart valves or moderate to severe mitral stenosis

.

Adverse Drug Effects See supplementary material

Drug Interactions

Anticoagulants, antiplatelet, and thrombolytics: increase risk of bleeding Pgp inducers: Avoid co-administration with rifampin Pgp inhibitors: Dose should be adjusted with concurrent use of verapamil, quinidine, or dronedarone . In general, other

Pgp inhibitors do not require dose adjustments.

Medication Error Possibility CrCL cutoff for treatment of A.fib and not for treatment of DVT/PE

Dosing and Administration

See supplementary handout

References: 1. Edoxaban [Package Insert]. Tokyo: Daiichi Sankyo, Inc; 2015.

2. Giugliano RP. Effective anticoagulation with factor Xa next generation in atrial fibrillation-TIMI 48. Powerpoint presentation: http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_458280.pdf. Accessed April 21, 2015.