CardioExchange Archive

Edoxaban, a direct oral factor Xa inhibitor, is the latest in the series of new oral anticoagulants seeking to take over the troubled role of warfarin in clinical practice. The results of ENGAGE-AF-TIMI 48 were presented at the American Heart Association meeting in Dallas and published simultaneously in the New England Journal of Medicine.

In the trial, more than 21,000 patients with moderate-to-high-risk AF were randomized to one of two regimens of edoxaban or warfarin. Both high-dose and low-dose edoxaban were found to be noninferior to warfarin for the primary endpoint of stroke or systemic embolism. Here are the on-treatment annual rates of stroke or systemic embolism:

• 1.50% for warfarin
• 1.18% for high-dose edoxaban (HR 0.79, 97.5% CI 0.63-0.99, p <0.001 for noninferiority)
• 1.61% for low-dose edoxaban (HR 1.07, 97.5% CI 0.87-1.31, p=0.005 for noninferiority)

In the intention-to-treat analysis to assess superiority, when compared with warfarin, there were trends in favor of high-dose edoxaban (HR 0.87, 97.5% CI 0.73-1.04, p=0.08) and against low-dose edoxaban (HR 1.13, 97.5% CI 0.96-1.34, p=0.10).

Both edoxaban regimens also resulted in significant reductions in bleeding complications and cardiovascular death. High-dose edoxaban was more effective than low-dose edoxaban in reducing ischemic strokes, while low-dose edoxaban resulted in the fewest bleeding complications and hemorrhagic strokes.

High-dose edoxaban had a better effect than low-dose edoxaban on the primary endpoint, largely due to a 29% reduction in ischemic stroke compared with low-dose edoxaban (236 vs. 333 events), but there were fewer hemorrhagic strokes, which were more serious than the ischemic strokes, in the low-dose edoxaban group (49 vs. 30).

The annual rate of major bleeding was lower in both edoxaban groups:

• 3.43% for warfarin
• 2.75% for high-dose edoxaban (HR 0.80, 98% CI 0.71-0.91, p<0.001)
• 1.61% with low-dose edoxaban (HR 0.47, 95%CI 0.41-0.55, p<0.001)

The most feared bleeding complication, intracranial hemorrhage, was significantly reduced in both edoxaban groups:

• 0.85% annual rate for warfarin
• 0.39% for high-dose edoxaban (HR 0.47, CI 0.34-0.63, p<0.001)
• 0.26% for low-dose edoxaban (HR 0.30, CI 0.21-0.43, p<0.001)

The annual rate of cardiovascular death:

• 3.17% for warfarin
• 2.74% for high-dose edoxaban (HR 0.86, 95% CI 0.77-0.97, p=0.01)
• 2.71 for low-dose edoxaban (HR 0.85, 95% CI 0.76-0.96, p=0.008)

The rate of stroke, systemic embolism, or CV death:

• 4.43% for warfarin
• 3.85% for high-dose edoxaban (HR 0.87, 95% CI 0.78-0.96, p=0.005)
• 4.23% for low-dose edoxaban (HR 0.95, 95% CI 0.86-1.05, p=0.32)

Following discontinuation of the study drug, there were few rebound events, and they were equally distributed across the three groups. The investigators state that the findings were consistent with similar studies comparing previous new oral anticoagulants with warfarin in AF patients.