ENGAGE-AF TIMI 48 High dose, 2013 trial summary

A randomised clinical trial investigating the effect of edoxaban high dose versus warfarin standard dose in AF patients (CHADS2 >=2)

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NCT00781391    N Engl J Med 2013 Nov 28;369:2093-104  



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 sizes7035 / 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
PeriodeInclusionnov 2008-nov 2010



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   add to Mendeley  

Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013 Nov 28;369:2093-104     [PMID: 24251359]   link to pdf   add to Mendeley  

ClinicalTrial.gov record NCT00781391



Registering number NCT00781391 (see trial on clinicaltrials.gov)
Code Name DU176b-C-U301