Edoxaban versus Warfarin
Factor XA next GEneration
Atrial Fibrillation –
Myocardial Infarction 48
(ENGAGE AF TIMI 48)
• Atrial Fibrillation (AF) is the most common type of arrhythmia.
• It is a supraventricular arrhythmia characterized
electrocardiographically by low amplitude baseline oscillations
(fibrillatory or f waves) and an irregularly irregular ventricular
• Thromboembolic complications are common with AF.
has been the sole effective agent in preventing
thromboembolic complications in pts with AF,but with risk of
• Newer agents came into usage and are in pipeline ,as efficacious
as warfarin but with decreased risk of hemorrhage.
• Edoxaban is a oral, reversible,direct factor Xa inhibitor, having
linear and predictable pharmacokinetic profile.
• 62% bioavailability, with proven antithrombotic effects.
• Max. conc. within 1-2 hours and 50% is excreted by the kidney.
• The long term efficacy and safety of edoxaban as compared
with warfarin in patients with AF is not known.
Two dose regimens of once daily edoxaban with
warfarin in patients with AF who were at
moderate to high risk for stroke.
• It is a three group, randomized, double blind, double
dummy trial comparing two dose regimens of edoxaban
• 1393 centers in 46 countries.
• November 19, 2008 through November, 2010.
Randomized and study drugs
• Patients were randomly assigned in a 1:1:1 ratio, to receive
warfarin, dose adjusted to achieve an INR of 2.0 to 3.0,or to receive
high dose(60mg) or low dose edoxaban(30mg).
• Randomization of patients who were already on vitamin K antagonist
was done after their INR was 2.5 or less.
• Randomization was stratified according to
CHADS2 score of 2 or 3 vs 4,5,6
Status with respect to the need for reduction in the edoxaban dose.
Dose of edoxaban was halved in case …
• At the time of randomization or during the study if…
Estimated CrCl <30 to 50 ml/min.
A body weight of <60kg
(verapamil or quinidine,dronedarone).
P Glycoprotein inhibitors
• Permeability glycoprotein, abbreviated as P-gp or Pgp
• Also known as multidrug resistance protein 1 (MDR1) or ATPbinding cassette sub-family B member 1 (ABCB1) or cluster of
differentiation 243 (CD243)
• Encoded by the ABCB1 gene.
• Expressed in the intestinal epithelium, hepatocytes, renal PCT
cells, adrenal gland and capillary endothelial cells comprising
• It is inhibited by many drugs, such as:
Study end points
The primary efficacy end point
• Time to the first adjudicated stroke (ischemic or hemorrhagic)
• Systemic embolic event (SEE).
The principal safety end point was
• Adjudicated major bleeding during treatment ,as defined by the International
Society on Thrombosis and Haemostasis.
Secondary composite end points
• Stroke,SEE,death from CV causes,MI.
Net clinical end points
included the above all.
• Total of 21,105 pts underwent randomization.
• 21,026(99.6%) received the study drug.
• A total of 5330(25.3%) received a reduced dose of edoxaban or
matching placebo at randomization.
• After randomization , dose reductions occurred in 7.1% pts,and dose
increases in 1.2% with similar rates in three treatment groups.
• Median duration of treatment exposure was 907 days, excluding
• Median follow up was 1022 days.
Primary end point
P VALUE LOW DOSE P VALUE
182 (1.18%/yr) P<0.001
FATAL IC BLEED
GI bleed more in high dose edoxaban
Secondary and other efficacy
• Rates of all three prespecified secondary composite
outcomes were significantly lower with high dose
• Lower annualized rates of
(2.74% vs 3.17%).
CV death with
• Both doses of edoxaban were non inferior to warfarin.
• High dose edoxaban more effective than warfarin.
• Rate of ischemic strokes high dose edoxaban = warfarin <
low dose edoxaban.
• Rate of hemorrhagic strokes,CV deaths less in edoxaban
• All bleedings except GI bleed were low in edoxaban
Comparison of edoxaban regimens
HIGH DOSE EDOXABAN
Rate of stroke,systemic
Reduction in incidence of
ischemic strokes (29%)
strokes (49 vs 33
No significant differences between the two edoxaban groups
in the rates of death from cardiovascular causes
and death from any cause
• Water soluble VKA,initially developed as rodenticide.
• Inhibits synthesis of vitamin K dependent clotting factors –
II,VII,IX,X and anticoagulants proteins C and S.
• Inhibits VKOR,thereby blocking carboxylation.
• Antithrombotic effect of warfarin depends on a reduction in
the functional levels of factor X(t1/2
• Racemic mixture
• Completely absorbed.
• 97%bound to albumin.
• Coagulation monitoring is essential,narrow Therapuetic
Metabolism of warfarin
Warfarin name ….?
Wisconsin Alumni Research Foundation
+ the ending -arin indicating its link with
Dosing regimen Tait,Kovacs,Fennerty
Trials of New anticoagulants
Post op VTE
arin(36.4 vs 37.7%) parin(9.6 vs18.9%)
6.0% vs 6.7%
1.1% vs 3.7%
1.4% vs 3.9%
2.4% vs 2.1%
2.1 vs 3.0%
1.7% vs 8.8%
Trials on edoxaban
• 1.A randomized,dose ranging,warfarin controlled,phase 2 study
involving 1146 pts with AF showed that once daily doses of
Edoxaban(60 mg or 30mg) were safer than twice daily doses.
Thromb Haemostat 2010;104:633-41
• 2.A phase 3 study involving 8292 patients with Acute Venous
Thromboembolism showed that once daily Edoxaban at a dose of 60
mg (reduced to 30 mg in selected patients) was as effective as
Warfarin for the prevention of recurrent symptomatic venous
thromboembolism and associated with significant lower rate of
Year of Indications
ROCKET AF YES
AF TIMI 48
Summary of new oral
Broad therapeutic window
No need of frequent monitoring.
Dose to be adjusted in renal failure.
Caution with the use of Glycoprtoein P inhibitors.
Not to be used with glycoprotein Pinducers(rifamipicin)
Dabigatran causes acidity.
Apixaban in case of recent GI bleeding.
Not indicated in valvular AF.
Dabigatran,apixaban in pts with ischemic stroke on