The document describes a clinical trial comparing the factor Xa inhibitor edoxaban to warfarin for preventing thromboembolic events in patients with atrial fibrillation. Over 21,000 patients were randomly assigned to receive either high-dose or low-dose edoxaban once daily or dose-adjusted warfarin. The primary endpoint of stroke or systemic embolism occurred less frequently with high-dose edoxaban compared to warfarin. Both edoxaban doses resulted in lower rates of bleeding events compared to warfarin. The trial demonstrated that edoxaban was non-inferior and potentially superior to warfarin in preventing thromboembolic events while causing fewer bleedings in patients with at

2. Edoxaban versus Warfarin
in Patients
with
Atrial Fibrillation

3. Effective ANticoaGulation
with
Factor XA next GEneration
in
Atrial Fibrillation –
Thrombolysis In
Myocardial Infarction 48
(ENGAGE AF TIMI 48)

4. Introduction
• 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
rhythm.
• Thromboembolic complications are common with AF.

5. • Warfarin
has been the sole effective agent in preventing
thromboembolic complications in pts with AF,but with risk of
hemorrhage.
• Newer agents came into usage and are in pipeline ,as efficacious
as warfarin but with decreased risk of hemorrhage.

6. Background
• 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.

7. Two dose regimens of once daily edoxaban with
warfarin in patients with AF who were at
moderate to high risk for stroke.

8. Trial design
• It is a three group, randomized, double blind, double
dummy trial comparing two dose regimens of edoxaban
with warfarin.
• 1393 centers in 46 countries.
• November 19, 2008 through November, 2010.

10. Inclusion criteria

12. 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.

13. 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
 Concomitant
use
of
P-glycoprotein
(verapamil or quinidine,dronedarone).
inhibitors

14. 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
the BBB.
• It is inhibited by many drugs, such as:




Amiodarone,Azithromycin
Captopril,Clarithromycin,Cyclosporine
Quinidine,Quinine,
Reserpine,Ritonavir

17. 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.

18. Results
• 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
interruptions.
• Median follow up was 1022 days.

19. Primary end point
EVENTS
WARFARIN
GROUP
HIGH DOSE
EDOXABAN
P VALUE LOW DOSE P VALUE
EDOXABAN
STROKE or
SYSTEMIC
EMBOLISM
232 (1.50%/yr)
182 (1.18%/yr) P<0.001
P=0.02
253
(1.61%/yr)
ANNUALIZED
RATE (ITT)
1.80%/yr
1.57%/yr
2.04%/yr
HEMORRHAGIC
STROKE
0.47%
0.26%
ISCHEMIC
STROKE
1.25%
1.25%
1.77%
MAJOR
BLEEDING
EVENTS
3.43%
2.75%
1.61%
LIFE
THREATENING
BLEEDING
0.78%
0.40%
0.25%
P<0.001
0.16%
P=0.005
P=0.44
<0.001

20. Bleeding
OUTCOME
WARFARIN
(%of pts/yr)
HIGH DOSE
EDOXABAN
LOW DOSE
EDOXABAN
P
VALUE
MAJOR BLEEDING
524 (3.43%)
418 (2.75%)
254 (1.61%)
<0.001
FATAL
59 (0.38%)
32 (0.21%)
21 (0.13%)
<0.001
IC BLEED
132 (0.85%)
61 (0.39%)
41(0.26%)
<0.001
FATAL IC BLEED
42(0.27%)
24 (0.15%)
12 (0.08%)
<0.001
GI BLEED
190 (1.23%)
232 (1.51%)
129 (0.82%)
<0.001
LIFE THREATENING
BLEED
122 (0.78%)
62 (0.40%)
40 (0.25%)
<0.001
MINOR BLEEDING
714 (4.89%)
604 (4.12%)
533 (3.52%)
<0.001
GI bleed more in high dose edoxaban

21. Secondary and other efficacy
outcomes
• Rates of all three prespecified secondary composite
outcomes were significantly lower with high dose
edoxaban
• Lower annualized rates of
(2.74% vs 3.17%).
CV death with
edoxaban

22. Discussion
• 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
groups.
• All bleedings except GI bleed were low in edoxaban
group.

24. Comparison of edoxaban regimens
HIGH DOSE EDOXABAN
vs
LOWDOSE EDOXABAN
Rate of stroke,systemic
embolic event
Reduction in incidence of
ischemic strokes (29%)
Hemorrhagic
strokes (49 vs 33
events)
No significant differences between the two edoxaban groups
in the rates of death from cardiovascular causes
and death from any cause

27. Anticoagulants
Warfarin
Rivaroxaban
50yrs
Factor Xa
inhibitor
Rodent
poison
Edoxaban
Factor Xa
inhibitor
Dabigatran
Apixaban
Factor IIa
inhibitor
Factor xa
inhibitor

28. Warfarin
• 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
24hrs),prothrombin(t1/2 72hrs)
• Racemic mixture
• Completely absorbed.
• 97%bound to albumin.
• Coagulation monitoring is essential,narrow Therapuetic
index.

29. Metabolism of warfarin
Warfarin
S isomer
R isomer
More active
CYP1A1
CYP2C9*2
CYP2C9*3
CYP1A2
VKORC1
CYP3A4
Homozygosity
50-70%
reduction
Heterozygosity
A/A
25-30%
reduction
heterozygotes 25%
A/A
homozygotes
50%

30. Warfarin name ….?
Wisconsin Alumni Research Foundation
+ the ending -arin indicating its link with
coumarin.
Dosing regimen Tait,Kovacs,Fennerty

31. •
•
•
•
•
Flat nasal bridge ,
laryngomalacia,
pectus carinatum,
ventriculomegaly,
Agenesis ofcorpus
callosum,
• stippled epihpysis

34. Trials of New anticoagulants
Clinical condition
Dabigatran
Rivaroxaban
Apixaban
Post op VTE
Prophylaxis(TKA)
RE-MODEL
RE MOBILIZE
RECORD 3,4
ADVANCE 1,2
Result
Dabigatran>enoxap Rivaroxaban>enoxa
arin(36.4 vs 37.7%) parin(9.6 vs18.9%)
Apixaban>enoxapari
n(15 vs24%)
Post opVTE
prophylaxia (THA)
RE-NOVATE
RECORD 1,2
ADVANCE 3
Result
6.0% vs 6.7%
1.1% vs 3.7%
1.4% vs 3.9%
AF
RELY
ROCKET AF
AVEREOS(failed
warfarin
ARISTOTLE(warfarin
)
Acute VTE
RECOVER
EINSTEIN
AMPLIFY EXT
Result
2.4% vs 2.1%
2.1 vs 3.0%
1.7% vs 8.8%
Medically ill
MAGELLAN
Result
Rivaroxaban >enoxa

35. 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
bleeding.
NEJM2013;369:1406-15

36. Anticoagulants
DRUG
TRADE
NAME
WARFARIN
COUMADIN
Year of Indications
entry
into
market
48$/yr
YES
NICOUMALONE ACITROM
FDA
Approval
year
YES
TRIALS
41.50$/
60 tabs
YES
(Oct,2010)
3000$/y
r
VTE,AF
725Rs/
Tablet
VTE,AF
DABIGATRAN
PRADAXA
RELY
RIVAROXABAN
XARELTO
(BAYER)
ROCKET AF YES
(Nov,2011)
APIXABAN
ELIQUIS
ARISTOTLE
YES
(Dec,2012)
EDOXABAN
LIXIANA
ENGAGE
AF TIMI 48
NO (?2014)
AF,VTE,
Prosthetic
heart valves
VTE,AF

37. Summary of new oral
anticoagulants
•
•
•
•
•
•
•
•
•
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
warfarin.