Journal ClubJim Hoehns, Pharm.D.

EdoxabanOral factor Xa inhibitorBioavailability: 62%Tmax: 1-2 hrsElimination: 50% renalHalf-life: 9-11 hours

ENGAGE AF-TIMI 48Randomized, double-blind, double-dummy trialN=21,105 patients with Afib

Median follow-up: 2.8 years1393 centers; 46 countries

Treatment“High dose” edoxaban 60mg QD“Low dose” edoxaban 30mg QDWarfarin INR 2.0-3.0 Randomization: stratified according to CHADS2 score and

need for a reduced doseDose-modification for edoxaban groups

Half-dose if any present: Clcr 30-50 ml/min, weight <60 kg, or use of verapamil, amiodarone, dronedarone

ENGAGE - MethodsInclusion criteria

Age ≥21 yearsECG tracing of Afib within previous 12 monthsCHADS2 of 2 or greater

Exclusion criteriaAfib due to reversible disorderEst Clcr <30 ml/minACS or stroke within past 30 daysUse of dual antiplatelets“High risk” of bleeding

ENGAGE - MethodsEndpoints

Primary efficacy: time to first stroke or systemic embolism

Primary safety: major bleedingAnalysis

Modified ITTNoninferiority: upper boundary of 97.5% CI

could not exceed 1.38 vs. warfarinSuperiority testing: if met noninferiority

criteriaPower: If 672 endpoints, >87% power

ENGAGE - Results21,105 patients randomizedReduced dose: 25% of patientsWarfarin: mean TTR 68%

ObservationsHigh study drug discontinuation rate (33%)

Similar rates among groups; would like more clarity re: symptomatic AE’s

Low-dose edoxaban 30mg QD likely not tenableMet 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

SummaryEdoxaban: a new factor Xa inhibitor

Will compete with dabigatran, rivaroxaban, and apixiban

“high-dose” edoxaban 60mg QDSame lower risk of ICH and hemorrhagic

stroke as other new anticoagulantsEfficacy and bleeding data look very favorableHigher GI bleeding than warfarin

Afib Trials - ComparisonCharicteristic Dabigatran Apixaban Rivaroxaban

Age (yrs) 71.5 (mean) 70 (median) 73 (median)

Prior VKA use 50% 57% 62%

CHADS2

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%

Afib Trials - ComparisonDabigatr

an(%/yr)

Warfarin

(%/yr)

Apixiban (%/yr)

Warfarin (%/yr)

Rivaroxa.

(%/yr)

Warfarin (%/yr)

Primary end (stroke/emb.)

1.11 1.69* 1.27 1.6* 2.1 2.4

Hemorrhagic 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 1.1Death – 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)