The question of how best to treat patients with atrial fibrillation after a successful transcatheter aortic valve implantation (TAVI or TAVR) remains unsettled, with the direct factor Xa inhibitor edoxaban (Savaysa, Daiichi Sankyo) proving noninferior to warfarin for a composite clinical endpoint but at the cost of more bleeding in the ENVISAGE-TAVI AF trial.
The risk for International Society on Thrombosis and Haemostasis major bleeding was increased 40% with edoxaban (9.7 vs 7.0 per 100 person-years; hazard ratio [HR], 1.40), which failed to achieve noninferiority (P = .93). The difference was driven by more gastrointestinal (GI) bleeding with edoxaban (HR, 2.03; 95% CI, 1.28 - 3.22) including one fatal event.
Both the primary composite efficacy endpoint of net adverse clinical events (NACE) and major bleeding, however, were lower in the 46.4% of patients whose daily dose of edoxaban was reduced from 60 mg to 30 mg.
"Subanalyses to further explore this finding suggest that patients fulfilling dose adjustment criteria and patients without concomitant oral antiplatelet therapy may be reasonable, appropriate candidates for edoxaban based on attenuating bleeding effects, and we will be conducting further investigations on this topic," senior author George Dangas, MD, PhD, Icahn School of Medicine at Mount Sinai, New York City, concluded.
The results were reported today in a Hot Line session at the virtual European Society of Cardiology (ESC) Congress 2021 and published simultaneously online in the New England Journal of Medicine.
Dangas pointed out that edoxaban was noninferior to warfarin for stroke or systemic embolism and cut bleeding risks in a general population of patients with atrial fibrillation (AF) in the ENGAGE AF-TIMI 48 trial, which did not include patients undergoing TAVI. However, results are less clear with novel oral anticoagulants (NOACs) in patients undergoing TAVI, where roughly a third of patients have AF or develop it after the procedure.
In the recent ATLANTIS trial, apixaban (Eliquis, Pfizer/Bristol-Myers Squibb) was not superior to standard care for a composite clinical outcome but did not increase bleeding, whereas the GALILEO trial was stopped prematurely because of a higher rate of death, thromboembolic events, and serious bleeding with rivaroxaban (Xarelto, Bayer/Janssen).
Study discussant and ATLANTIS investigator Jean-Philippe Collet, MD, PhD, Sorbonne Université Pitié-Salpêtrière Hospital, Paris, France, said ENVISAGE-TAVI AF is the only positive NOAC trial, demonstrating noninferiority against vitamin K antagonists (VKAs), but that the increased risk for bleeding limits patient eligibility.
"The transition of NOACs to practice is tricky because whether NOACs are all the same after TAVI seems unlikely. NOAC safety depends on concomitant use of antiplatelet therapy and dosing," he concluded. "Whether it is time to update the guidelines is unsure."
During the panel discussion, Collet said patient characteristics were very different in ATLANTIS and that they warned investigators not to continue triple therapy because of the fear of bleeding, mainly based on the GALILEO results, which "probably explains why we have such a difference in terms of combination with antiplatelet therapy."
Alec Vahanian, MD, University Paris-Descartes, France, one of the chairs of the newly updated European valvular heart disease guideline, pointed out that in the wake of ATLANTIS, "people are doing what they feel is good for the time being and many are not bridging to another anticoagulant after TAVI, that is to say, restarting a NOAC. But as you know, when you write a guideline, you love evidence."
He agreed with Dangas and the panel that "many questions have to be answered before we move to a guideline recommendation… Maybe if you pool your data you'll be able to answer in a better way this difficult question. So let's see in a couple of years."
An Elderly AF Population With an OAC Indication
ENVISAGE-TAVI AF enrolled 1426 patients with AF and an indication for an oral anticoagulant (OAC) after successful TAVI in the previous 5 days at 173 centers. Patients were randomly assigned to 60 mg/day of edoxaban or standard VKA management along with discretionary dual antiplatelet therapy for up to 3 months after TAVI, or single antiplatelet therapy indefinitely. Outside the United States, edoxaban dosing could be reduced if patients had renal failure or low body weight or were taking concomitant P-glycoprotein inhibitors.
The population was elderly (average age, 82 years), nearly half were female, more than 80% had congestive heart failure, and the mean Society of Thoracic Surgeons risk score was 4.9.
After a median follow-up of 548 days, the rate of NACE — a composite of all-cause death, myocardial infarction, ischemic stroke, systemic embolism, valve thrombosis, or major bleeding — was 17.3 per 100 person-years in the edoxaban group and 16.5 per 100 person-years with warfarin (HR, 1.05; P = .01 for noninferiority).
Superiority testing of edoxaban for efficacy was not conducted because noninferiority and superiority were not met for major bleeding.
There were no differences between the edoxaban and VKA groups for all-cause death or ischemic stroke. No valve thrombosis was reported in either group.
Panelist Renato Lopes, MD, Duke University Medical Center, Durham, North Carolina, said meta-analyses have shown a 58% increase in GI bleeding with NOACs over warfarin, likely because NOACs are metabolized to the GI tract rather than the liver. "So finding a 40% increase in GI bleeding was somewhat expected" in the ENVISAGE-TAVI AF cohort.
Although there are known pharmacologic differences between the NOACs, including mechanism of action and renal excretion, in general, as an anticoagulant, these agents are more similar than different, noted Lopes. That said, it's very important for clinicians to find what he's been calling the "antithrombotic sweet spot."
"That means that for every patient, including the procedure the patient underwent, it's important to find the right dose, the right combination of agents, for the right duration that can give us the greatest reduction in ischemic events at a minimal cost of bleeding, which we know is never going to be zero," Lopes said. And, "this trial adds to the value of evidence with high quality of evidence to better inform what this sweet spot might be."
Session chair Stephan Windecker, MD, Bern University Hospital, Inselspital, Bern, Switzerland, remarked that "it seems just like in the PCI [percutaneous coronary intervention] field, less is more and one important component seems to be antiplatelet therapy."
The study sponsor, Daiichi Sankyo, contributed to the trial design, conduct, and oversight; data analysis; and manuscript writing. Dangas reported research contracts with Daiichi Sankyo and Bayer. Coauthor disclosures are listed in the paper.
European Society of Cardiology (ESC) Congress 2021. Presented August 28, 2021.
N Engl J Med. Published online August 28, 2021. Abstract
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Cite this: 'Less Is More' for Edoxaban in Post-TAVI Anticoagulation: ENVISAGE-TAVI AF - Medscape - Aug 28, 2021.