ENVISAGE-TAVI AF shows edoxaban noninferior to VKAs in patients with AFib after TAVR.

Key Points:

• ENVISAGE-TAVI AF is a large, multinational, randomized-control trial investigate the safety and efficacy of edoxaban versus warfarin for those with atrial fibrillation undergoing TAVI.
• Edoxaban was noninferior to warfarin in the primary efficacy endpoint, a composite of adverse clinical events.
• Edoxaban  had higher rates of major bleeding, driven mostly by gastrointestinal (GI) bleeds. In patients requiring dose adjustment, however, no increase in bleeding events was seen.

The optimal anticoagulation strategy after transcatheter aortic valve intervention (TAVI) is yet to be determined. What is known, however, is that 20-40% of patients undergoing TAVI have either incident, or existent, atrial fibrillation. While oral anticoagulation is taken to prevent stroke in Atrial fibrillation, no randomized control trial has studied a direct oral anticoagulant (DOAC) against vitamin K antagonists (VKA) in patients with atrial fibrillation undergoing TAVI.

That is where ENVISAGE-TAVI AF (NCT02943785) comes in. Led by George D. Dangas (Mt. Sinai Hospital, NY) this open-label, multi-center, international, randomized controlled trial was designed as a noninferiority study to determine the following primary efficacy and safety outcomes:

• Primary efficacy outcome: composite of adverse clinical events, including all-cause death, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, and major bleeding.
• Primary safety outcome: incidence of major bleeding.

1426 patients with a mean age of 83 were enrolled into the study and the median follow up time was 18  months. There was no difference in the primary efficacy endpoint between the two groups, and thus edoxaban was determined to be noninferior to warfarin (hazard ratio [HR] 1.05; 95% confidence interval [CI]0.85–1.31; p=0.01 for noninferiority).

Edoxaban did not, however, meet noninferiority for the primary safety endpoint of major bleeding, as determined by the International Society of Thrombosis and Hemostasis (ISTH) (HR 1.40; 95% CI 1.03–1.91).  This was driven mostly by higher rates of gastrointestinal bleeding, with one death in the edoxaban arm attributed to a major GI bleed. The higher rates of bleeding in this group were tempered when patients underwent dose adjustment for age or creatinine clearance, demonstrating no difference in bleeding when compared to patients taking VKAs.

When asked about the results of the trial and the expanding indications for DOACs in TAVI,  Dr. Dangas stated “I think we have to be very careful in utilizing DOACs in patients with atrial fibrillation undergoing TAVI. As seen here, higher dose edoxaban was associated with higher rates of major bleeding in an elderly population, similar in age to many undergoing TAVI. Given these data, careful attention should be paid to targeting an appropriate dose of DOAC, and using dose adjustment when clinically indicated. As patients’ longevities increase after TAVI, so will their likelihood of bleeding”.

In a  discussion after the results of the trial were presented, panelists concluded that despite their similarities, DOACs all have different mechanisms of actions and various bleeding profiles. As such, optimal treatment dosing and duration must be individualized.

The study was simultaneously published in the New England Journal of Medicine.