Edoxaban vs warfarin in non-valvular AF

1. Edoxaban vs Warfarin
in Patients with Atrial
Fibrillation
ENGAGE AF-TIMI 48
Trial
Faraz Lawrie
Department of Cardiology
Changi General Hospital

2. BACKGROUND
• Atrial fibrillation is the most common arrhythmia affecting 0.4
to 1% of the general population
• In individuals over the age of 80 the prevalence increases to
8%
• The risk of stroke is increased 5-fold in individuals with atrial
fibrillation
• Strokes from AF account for 6-24% of all ischemic strokes
• The mainstay for stroke prevention in AF has historically been
VKAs.

3. BACKGROUND
Assessment of Stroke Risk using CHA2DS2-VASc

4. BACKGROUND
• OAC indicated for score >=2
• OAC (preferred) vs Aspirin for score 1(unless due to female
gender alone)
• No anticoagulation for score 0
• OAC use associated with significant risk of bleeding
• Bleeding risk prognostication: HAS-BLED
(Hypertension, Abnormal renal/liver function, Stroke, Bleeding
history or predisposition, Labile International Normalized
Ratio, Elderly, Drugs/alcohol concomitantly)
• Score of ≥3 indicates "high risk“
• Warfarin is the standard OAC

5. WARFARIN: a double-edged sword
Why we hate it!
Maybe not so bad!
Narrow therapeutic window
50+ years experience
Sensitive to changes in diet
Simple standardized test for functional
level (INR)
Slow to act, very long half-life
Reversal agents highly effective and
readily available
Numerous drug interactions
No side effects except bleeding
Wide range in therapeutic doses
Generic and cheap
• By some estimates, only 40-60% patients meeting guideline criteria are
treated with warfarin.
• Approximately 60-65% are within therapeutic range

6. NOACs: A New Hope
Dabigatran
Apixaban
Edoxaban
RIvaroxaban
Action
Direct
Thrombin
Inhibitor
Activated
Factor Xa
Inhibitor
Activated
Factor Xa
Inhibitor
Activated
Factor Xa
Inhibitor
Dose
150 mg bid
110 mg bid
5 mg bid
2.5 mg bid
60 mg qd
30 mg qd
15 mg qd
20 mg qd
15 mg qd
Phase 3
Clinical Trial
RE-LY
ARISTOTLE
AVERROES
ENGAGE AF
ROCKET AF

7. EDOXABAN
• oral, reversible, direct factor Xa inhibitor with a linear and
predictable pharmacokinetic profile and 62% oral
bioavailability
• achieves maximum concentrations within 1 to 2 hours
• 50%/50% excretion by kidney/liver
• The Effective Anticoagulation with Factor Xa Next Generation
in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48
(ENGAGE AF-TIMI 48) trial is a three-group, randomized,
double-blind, double-dummy trial comparing two dose
regimens of edoxaban with warfarin conducted at 1393
centres in 46 countries with enrolment through November 19,
2008 to November 22, 2010

8. Study Population
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Inclusion Criteria
Age>21 years
Documented AF on ECG within 12 months preceding randomization
Score >=2 on CHADS2
Anticoagulation therapy planned for the duration of the trial
Exclusion criteria
Atrial fibrillation due to a reversible disorder
Estimated creatinine clearance < 30 ml/min
high risk of bleeding
use of dual antiplatelet therapy
moderate-to-severe mitral stenosis
other indications for anti -coagulation therapy
acute coronary syndromes, coronary revascularization, or stroke within
30 days before randomization
• inability to adhere to study procedures

9. Study Design
• 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 or low-dose edoxaban
• Patients already on VKA were randomized after INR<2.5
• High dose Edoxaban group: default 60 mg qd
• Low dose Edoxaban group: default 30 mg qd
• For either group, dose halved if at randomization or during
period of study:• estimated creatinine clearance of 30 - 50 ml/min
• Weight<60 kg
• Concomitant P-glycoprotein inhibitors: Verapamil, Quinidine,
Dronedarone

10. Study Design
• Double dummy: each patient received two sets of study
drugs: either active edoxaban and a placebo matching
warfarin, or a placebo matching edoxaban and active warfarin.
• sham INR values were generated for patients who were
randomly assigned to edoxaban
• At the end of the trial, patients made the transition to openlabel oral anticoagulation therapy
• Primary efficacy end point: time to the first adjudicated
stroke (ischemic or haemorrhagic) or systemic embolic event
• Principal safety end point: adjudicated major bleeding

12. RESULTS: The Big Picture
• A total of 21,105 patients underwent randomization, of whom
21,026 (99.6%) received the study drug
• Complete information on the primary end point was
ascertained for 99.5% of the total 56,346 patient-years of
potential follow-up
• median duration of treatment exposure was 907 days
• median follow-up was 1022 days
• For warfarin group the median time in the therapeutic range
was 68.4% of the treatment period with the INR being
between 1.8 and 3.2 for 83.1% of this period

13. RESULTS: The Big Picture
• A stroke or systemic embolic event occurred in 232 patients in
the warfarin group (representing a rate of 1.50% per year), as
compared with 182 patients in the high-dose edoxaban group
(a rate of 1.18% per year; hazard ratio vs. warfarin, 0.79;
97.5% confidence interval [CI], 0.63 to 0.99; P<0.001 for noninferiority, P = 0.02 for superiority) and 253 patients in the
low-dose edoxaban group (a rate of 1.61% per year; hazard
ratio vs. warfarin, 1.07; 97.5% CI, 0.87 to 1.31; P = 0.005 for
non-inferiority, P = 0.44 for superiority)
• The rate of major bleeding events was 3.43% per year with
warfarin, as compared with 2.75% per year with high-dose
edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; P<0.001)
and 1.61% per year with low-dose edoxaban (hazard ratio,
0.47; 95% CI, 0.41 to 0.55; P<0.001)

14. RESULTS: The Big Picture
• The rate of stroke or systemic embolic event was lower with
high-dose edoxaban than with low-dose edoxaban (P<0.001);
there was a relative reduction in the incidence of ischemic
stroke of 29% with high-dose edoxaban, which more than
offset a higher incidence of haemorrhagic stroke(which
however had more significant sequelae)
• As compared with high-dose edoxaban, low-dose edoxaban
was associated with significantly lower rates of bleeding,
including major bleeding, intracranial bleeding, and major or
clinically relevant non-major bleeding

15. Kaplan Meier Curve for
Primary Efficacy End Point

16. Kaplan Meier Curve for
Primary Safety End Point

19. Discussion
• Both edoxaban regimens are non -inferior to well-managed
warfarin (median time in the therapeutic range, 68.4% of the
treatment period) for the prevention of stroke or systemic
embolic event with the high-dose edoxaban regimen being
more effective than warfarin
• The incidence of haemorrhagic stroke, all types of bleeding
and major cardiovascular events are significantly lower with
both edoxaban regimens than with warfarin with the
exception being GI bleeding, which occurred more frequently
with high-dose edoxaban but less frequently with low-dose
edoxaban than it did with warfarin

20. Discussion
• Intergroup variations between groups stratified by
age, geography, prior/concomitant drug usage and risk of
stroke were not significant except:• VKA naïve patients had significantly fewer stroke or systemic
embolic events with high-dose edoxaban than with
warfarin, whereas the rates were similar among non-naïve
patients
• Concomitant amiodarone or aspirin augmented the action of lowdose edoxaban
• Dose reduction of edoxaban in age<60, impaired creatinine
clearance and concomitant P-glycoprotein inhibitors groups
reduced bleeding risk

21. Discussion
• Strengths of the ENGAGE AF-TIMI 48 trial
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large sample size
long follow-up
minimal amount of missing data
greater-than-average time in the therapeutic range in the warfarin
group
• inclusion of multiple once-daily doses of a new anticoagulant agent
ranging from 15 to 60 mg with dynamic dose modification
• Comprehensive transition plan to open-label anticoagulation therapy
resulted in a low and evenly distributed number of events after the
discontinuation of study therapy making it unlikely that there is a
rebound activation of coagulation after the discontinuation of
edoxaban
• In conclusion, both once-daily regimens of edoxaban were noninferior to warfarin for the prevention of stroke or systemic embolism
and were associated with significantly lower rates of bleeding and
death from cardiovascular causes.

22. The View from 30k feet
RE-LY
ROCKET AF
ARISTOTLE
ENAGAGE AF
Study Design
Warfarin
open label;
Dabigatran
blinded
Double-blind,
double
dummy
Double-blind,
double
dummy
Double-blind,
double
dummy
Comparison
Dabigatran
110/150 mg
bid vs
warfarin
Rivaroxaban
20 mg qd vs
warfarin
Apixaban 5
mg bid vs
warfarin
Edoxaban
15/30/60 mg
qd vs warfarin
Primary End
Point
Stroke or
systemic
embolism
Stroke or
systemic
embolism
Stroke or
systemic
embolism
Stroke or
systemic
embolism
Size
18113
14264
18201
21026
Followup
2
1.9
1.8
2.3

23. The View from 30k feet: Caveat
Emptor
RE-LY
110/150
ROCKET AF
ARISTOTLE
ENAGAGE AF
Hi/lo
Mean TTR
Warfarin
64
55
62
68
Stroke or
Systemic
Embolism
0.90/0.65
0.88
0.79
0.79/1.07
Haemorrhagic 0.31/0.26
Stroke
0.59
0.51
0.54/0.33
Major
Bleeding
0.80/0.93
1.04
0.69
0.80/0.47
ICH
0.30/0.41
0.67
0.42
0.47/0.30
MI
1.29/1.27
0.81
0.88
0.94/1.19
GI Bleed
1.08/1.48
NA
0.89
1.23/0.67
All Cause
mortality
0.91/0.88
0.92
0.89
0.92/0.87

24. Thank You
• There are no silver bullets in medicine
• We are always free to choose our own poison