Oral anticoagulant edoxaban is non-inferior and a safe alternative to warfarin
Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation – TIMI 48 Primary Results
Presented at the AHA congress 2013 by Dr. Robert P. Giugliano (Brigham and Women’s Hospital, Boston, MA)
LBCT V - New Strategies for Atrial Fibrillation Patients: Rhythm and Thrombosis
BackgroundEdoxaban is an oral anticoagulant due to its inhibiting effect on Factor Xa. The effect is more selective than that of warfarin, and it is more convenient due to its rapid effect (peak after 1-2 hours, half-time is ~10-14 hours) and because of its linear pharmacokinetics. In a phase II study (1146 patients) the bleedings on edoxaban appeared dose-related and lower at a regime of once instead of twice daily.
The Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation (ENGAGE AF)-TIMI 48 trial is a randomised, doubleblind, placebocontrolled study that included more than 21000 patients with atrium fibrillation from 46 countries (1400 hospitals). The patients had a moderate to high risk (CHADS2>2). Patients were randomised (1:1:1) to high dose edoxaban (daily 60 mg), low dose edoxaban (daily 30 mg) or warfarin (target INR: 2.0-3.0). The randomisation was stratified by CHADS2 score 2-3 vs. 4-6 and the need for edoxaban dose reduction. Guided by renal function, body weight and use of strong P-gp inhibitors, dose of edoxaban was adjusted if needed from 60 to 30 mg, or from 30 to 15 mg. The primary efficacy endpoint was stroke or systemic embolic event (SEE). The secondary efficacy endpoint was stroke, or SEE or CV mortality. The primary safety endpoint was major bleedings according to ISTH criteria.
- In a non-inferiority analysis in the mITT (all patients who took at least 1 dose) and on-treatment population edoxaban 60 mg was non-inferior to warfarin (TTR: 68.4%)(HR: 0.79, P(non-inferiority)<0.0001, P(superiority)= 0.017, HR: 1.38 as non-inferiority criterium). Edoxaban 30 mg was also non-inferior to warfarin in this population (HR: 1.07, P(non-inferiority)<0.005, P(superiority)= 0.44).
- In a superiority analysis in the intent-to-treat population edoxaban 60 mg was not superior to warfarin (HR: 0.87, P=0.08), nor was edoxaban 30 mg (HR: 1.13, P=0.10).
- The risk of haemorrhagic stroke was significantly reduced after both doses (Edoxaban 60 mg: HR: 0.54, P<0.001, edoxaban 30 mg: HR: 0.33, P<0.001), as compared to warfarin.
- The secundary endpoint of stroke, SEE and CV mortality occurred less often after edoxaban 60 mg than after warfarin (HR: 0.87, P=0.005), while after edoxaban 30 mg this did not differ significantly from warfarin.
- In comparison with warfarin, the highest dose edoxaban was associated with 14% reduction of the risk of cardiovascular mortality (P=0.013), and the lower dose with 15% reduction (P=0.008).
- ISTH major bleedings occurred 20% less often with edoxaban 60 mg (P<0.001), and 53% less with the lower dose edoxaban (P<0.001). Edoxaban also protected against fatal bleedings (60 mg: HR: 0.55, P=0.006, 30 mg: HR: 0.35, P<0.001 vs. warfarin) and intracranial bleedings (60 mg: HR: 0.47, P<0.001, 30 mg: HR: 0.30, P<0.001 vs. warfarin). Gastro-intestinal bleedings occurred more often at the higher dose (HR: 1.23, P=0.03), but not at 30 mg edoxaban (HR: 0.67, P<0.001).
- More patients on edoxaban never interrupted their treatment (37.4% and 38.2% for 60 and 30 mg respectively) than on warfarin (34.5%, P<001 for both doses as compared to edoxaban). No significant differences were seen between the proportion of patients with serious adverse events of ASAT en ALAT >3x ULN in the different treatment groups.
ConclusionIn comparison to well-controlled warfarin treatment (TTR: 68.4%) edoxaban once daily is non-inferior in the prevention of stroke/SEE (both doses), and the high dose edoxaban showed a trend towards fewer strokes and SEE during treatment.
Both doses gave a significant reduction in the risk of major bleedings, intracranial bleedings, haemorrhagic stroke and CV mortality.
Thus, the net clinical outcomes of edoxaban appear superior to warfarin, and edoxaban once daily seems to be a good and safe alternative for warfarin.
This report is of the AHA congress 2013 is based on the information provided by the AHA during press conferences and on the website.
Webcast • AHA 2013