By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
SYNOPSIS: In this randomized trial of post-transcatheter aortic valve replacement patients with atrial fibrillation, edoxaban was noninferior to vitamin K antagonists with regard to a composite of adverse endpoints, but was associated with a higher rate of major bleeding.
SOURCE: Van Mieghem NM, Unverdorben M, Hengstenberg C, et al. Edoxaban versus vitamin K antagonist for atrial fibrillation after TAVR. N Engl J Med 2021;385:2150-2160.
Atrial fibrillation (AF) is common in patients undergoing transcatheter aortic valve replacement (TAVR). With the ascendancy of direct oral anticoagulants (DOACs) in routine AF treatment, these agents have been used increasingly in the post-TAVR population.
The authors of ENVISAGE-TAVI AF randomized patients with AF after TAVR to either once-daily edoxaban or to a vitamin K antagonist, with a goal international normalized ratio (INR) of 2.0 to 3.0 (Japanese participants older than age 70 years were targeted to an INR of 1.6 to 2.6). Over the course of the trial, 1,426 patients (split into two groups of 713 patients each) were enrolled after TAVR in dozens of centers in 14 countries. The mean age of participants was 82.1 years, nearly half were women, and half were on antiplatelet medications before randomization. The mean Society of Thoracic Surgeons score (30-day predicted risk of mortality) was 4.9%, and the mean CHA2DS2-VASc score was 4.5. During the trial, with a median duration follow-up of 554 days in the edoxaban group and 530 days in the vitamin K antagonist group, 215 edoxaban patients discontinued the trial drug vs. 289 patients in the vitamin K antagonist group.
During the trial, net adverse clinical outcomes (all-cause death, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding) occurred in 170 patients in the edoxaban group and in 157 patients in the vitamin K antagonist group (95% CI, 0.85-1.31; noninferiority margin, 1.38; P = 0.01 for noninferiority). Major bleeding occurred in 98 patients in the edoxaban group vs. 68 patients in the vitamin K antagonist group (HR, 1.40; 95% CI, 1.03-1.91; noninferiority margin, 1.38; P = 0.93 for noninferiority). The major contributor to this difference was gastrointestinal bleeding (56 events with edoxaban vs. 27 events with vitamin K antagonists), which occurred despite similar percentages of patients taking proton pump inhibitors (71.7% and 69.0%, respectively). Individual rates of intracranial hemorrhage, all-cause death, systemic thromboembolism, and ischemic stroke were not significantly different between groups. The authors concluded in this population of patients with AF after TAVR, edoxaban was noninferior to vitamin K antagonists for a composite of net adverse clinical events. However, major bleeding was significantly higher among patients treated with edoxaban.
COMMENTARY
Ostensibly, ENVISAGE-TAVI AF was performed to provide data comparing a DOAC to vitamin K antagonists for patients with AF after successful TAVR. DOACs continue to gain ground in the antithrombotic treatment of patients with AF. Although edoxaban met the stated criteria for noninferiority to vitamin K antagonists for the composite of all adverse outcomes, it failed for major bleeding — specifically, for major gastrointestinal bleeding. Most of these patients were on proton pump inhibitors. The authors suggested lower INR values and less adherence to vitamin K antagonists may have contributed to this outcome.
Notably, nearly all AF in this trial was present before the TAVR procedure (99%). New-onset AF after TAVR remains relatively rare. Most patients with AF who are arriving for TAVR likely will be on anticoagulant therapy (if eligible). DOACs will continue to make headway as the initial agents prescribed for incident AF. At least for now, patients who come in for a TAVR procedure already on treatment with warfarin should not change to a DOAC for the sake of convenience. At the same time, these results apply rather narrowly to an older population undergoing TAVR for symptomatic aortic stenosis. Use caution interpreting these results in a broader context.
In this randomized trial of post-transcatheter aortic valve replacement patients with atrial fibrillation, edoxaban was noninferior to vitamin K antagonists with regard to a composite of adverse endpoints, but was associated with a higher rate of major bleeding.
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