ENGAGE-AF TIMI 48 High dose, 2013 edoxaban high dose versus warfarin standard dose

NCT00781391    Am Heart J 2010;160:635-41  

edoxaban high dose versus warfarin standard dose in AF patients (CHADS2 >=2)




Studied treatment edoxaban 60mg once daily
Control treatment warfarin (INR 2-3)

a third arm received a low dose of edoxaban, 30mg. The allocated dose was halved if any of the following characteristics were present at the time of randomization or during the study: estimated creatinine clearance of 30 to 50 ml per minute, a body weight of 60 kg or less, or the concomitant use of verapamil or quinidine (potent P-glycoprotein inhibitors)



Patients AF patients (CHADS2 >=2)
Group sizes 7035 / 7036
Inclusion criteriadocumented AF within the prior 12 months; moderate to high risk of stroke, as defined by CHADS2 index score of at least 2
Exclusion criteriaTransient atrial fibrillation secondary to other reversible disorders; moderate or severe mitral stenosis, unresected atrial myxoma, or a mechanical heart valve; contraindication for anticoagulant agents; conditions associated with high risk of bleeding; known or suspected hereditary or acquired bleeding disorders
CHADS2 Score (mean)
CHADS2 Score = 2 (%)
CHADS2 Score = 3 (%)



Blindness double blind Inclusion period nov 2008-nov 2010
Follow-up duration 2.8 years Centers 1393
Lost to FU geographical localisation 46 countries
Primary endpoint stroke, systemic embolic events and all-cause mortality Design Parallel groups



EndpointX1N1X0N0TE95% CI thrombo-embolic event (cerebral or systemic) - 7035 - 7036 0,87[0,73; 1,04] systemic thrombo-embolic complication - 7035 - 7036 0,65[0,34; 1,24] ischemic stroke - 7035 - 7036 1,00[0,84; 1,20] thromboembolic event likes(TE event or ischemic stroke or systemic embolism) - 7035 - 7036 no data TIA - 7035 - 7036 no data coronary events - 7035 - 7036 no data All stroke(ischemic+hemorrhagic/fatal+non fatal) - 7035 - 7036 0,88[0,75; 1,03] all death - 7035 - 7036 0,92[0,83; 1,01] vascular death - 7035 - 7036 0,86[0,77; 0,97] fatal stroke(ischemic+hemorrhagic) - 7035 - 7036 0,92[0,68; 1,25] non vascular death - 7035 - 7036 no data non fatal stroke - 7035 - 7036 no data non fatal TE events,bleedings and vascular death* - 7035 - 7036 no data thrombo-embolic event (central or systemic)and fatal or intracranial hemorrhage - 7035 - 7036 no data vascular death,TIA,nonfatal stroke or systemic embolism - 7035 - 7036 no data thromboembolic event,cerebral or fatal bleeding and vascular death - 7035 - 7036 no data all stroke or systemic embolism or death - 7035 - 7036 0,90[0,82; 0,98] all stroke or systemic embolism - 7035 - 7036 no data stroke,systemic embolism,major haemorrhage and vascular death - 7035 - 7036 no data myocardial infarction - 7035 - 7036 0,94[0,74; 1,19] all bleeding - 7035 - 7036 0,87[0,82; 0,92] major bleeding - 7035 - 7036 0,80[0,71; 0,91] minor bleeding - 7035 - 7036 0,84[0,76; 0,93] haemorragic stroke(or intracerebral hemorrhage) - 7035 - 7036 0,47[0,35; 0,64] fatal bleeding - 7035 - 7036 0,55[0,36; 0,84] Gastrointestinal major bleeding - 7035 - 7036 1,23[1,01; 1,49] major and clinically relevant non-major bleeding - 7035 - 7036 0,86[0,80; 0,92] Non–life threatening Major bleeding - 7035 - 7036 no data Life threatening major bleeding - 7035 - 7036 0,51[0,38; 0,69] fatal hemorrage other than intracranial - 7035 - 7036 no data intracranial hemorrhage(hemorrhagic stroke+hematomas) - 7035 - 7036 0,47[0,35; 0,64] hypertransaminasemia - 7035 - 7036 no data non fatal bleeding - 7035 - 7036 no data other side effects - 7035 - 7036 no data0,22,01,0


Ruff CT, Giugliano RP, Antman EM, Crugnale SE, Bocanegra T, Mercuri M, Hanyok J, Patel I, Shi M, Salazar D, McCabe CH, Braunwald E Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J 2010;160:635-41     [PMID: 20934556]   link to pdf