Transcript Journal Club

Jim Hoehns, Pharm.D.
Edoxaban
 Oral factor Xa inhibitor
 Bioavailability: 62%
 Tmax: 1-2 hrs
 Elimination: 50% renal
 Half-life: 9-11 hours
ENGAGE AF-TIMI 48
 Randomized, double-blind, double-dummy trial
 N=21,105 patients with Afib
 Median follow-up: 2.8 years
 1393 centers; 46 countries
 Treatment
 “High dose” edoxaban 60mg QD
 “Low dose” edoxaban 30mg QD
 Warfarin INR 2.0-3.0
 Randomization: stratified according to CHADS2 score and
need for a reduced dose
 Dose-modification for edoxaban groups
 Half-dose if any present: Clcr 30-50 ml/min, weight <60 kg,
or use of verapamil, amiodarone, dronedarone
ENGAGE - Methods
 Inclusion criteria
 Age ≥21 years
 ECG tracing of Afib within previous 12 months
 CHADS2 of 2 or greater
 Exclusion criteria
 Afib due to reversible disorder
 Est Clcr <30 ml/min
 ACS or stroke within past 30 days
 Use of dual antiplatelets
 “High risk” of bleeding
ENGAGE - Methods
 Endpoints
 Primary efficacy: time to first stroke or systemic
embolism
 Primary safety: major bleeding
 Analysis
 Modified ITT
 Noninferiority: upper boundary of 97.5% CI could not
exceed 1.38 vs. warfarin
 Superiority testing: if met noninferiority criteria
 Power: If 672 endpoints, >87% power
ENGAGE - Results
 21,105 patients randomized
 Reduced dose: 25% of patients
 Warfarin: mean TTR 68%
Observations
 High study drug discontinuation rate (33%)
 Similar rates among groups; would like more clarity re:
symptomatic AE’s
 Low-dose edoxaban 30mg QD likely not tenable
 Met criteria for noninferiority

Primary endpoint: warfarin 1.5%/yr vs. low-dose 1.61%/yr
 Significant increased risk of ischemic stroke vs. warfarin



HR 1.41 (95% CI: 1.19-1.67, P<0.001)
Warfarin: 1.25%/yr
Low-dose edoxaban: 1.77%/yr
Summary
 Edoxaban: a new factor Xa inhibitor
 Will compete with dabigatran, rivaroxaban, and
apixiban
 “high-dose” edoxaban 60mg QD
 Same lower risk of ICH and hemorrhagic stroke as other
new anticoagulants
 Efficacy and bleeding data look very favorable
 Higher GI bleeding than warfarin
Afib Trials - Comparison
Charicteristic
Dabigatran
Apixaban
Rivaroxaban
71.5 (mean)
70 (median)
73 (median)
50%
57%
62%
0-1
32%
34% (1 only)
0%
2
35%
36%
13%
≥3
33%
30%
87%
Prior MI
17%
14%
17%
Prior stroke, TIA,
or systemic
embolism
20%
20%
55%
Age (yrs)
Prior VKA use
CHADS2
Afib Trials - Comparison
Dabigatra Warfari Apixiban Warfarin Rivaroxa Warfarin
n
n (%/yr)
(%/yr)
(%/yr)
. (%/yr)
(%/yr)
(%/yr)
Primary end
(stroke/emb.
)
1.11
1.69*
1.27
1.6*
2.1
2.4
Hemorrhagi
c stroke
0.1
0.38*
0.24
0.47*
0.41
0.71*
Ischemic
stroke
0.92
1.2*
0.97
1.05
1.34
1.42
MI
0.74
0.53*?
0.53
0.61
0.9
1.1
Death – any
cause
3.64
4.13
3.52
3.94*
4.5
4.9
Major
bleeding
3.11
3.36
2.13
3.09*
3.6
3.4
* Significantly different (P<0.05)