A patchwork of results from the ENVISAGE-TAVI AF study drew a mixed reaction regarding edoxaban (Lixiana, Daiichi Sankyo) in atrial fibrillation (AF) patients who have undergone transcatheter aortic valve replacement (TAVR).

The ENVISAGE-TAVI AF¹ trial pitted edoxaban - a direct oral anticoagulant (DOAC) - against vitamin K antagonists (VKAs) and found the DOAC to be comparable to VKA regarding the composite primary outcome of adverse clinical events (17.3 vs. 16.5 per 100 person-years; HR 1.05; 95% CI, 0.85-1.31), P=0.01 for noninferiority).

However, edoxaban also had a higher risk of major bleeding according to ISTH definition than VKA (9.7 vs. 7.0 per 100 person-years; HR 1.40, 95% CI, 1.03-1.91, P=0.93 for noninferiority), with gastrointestinal (GI) bleeding as the main culprit.

Principal investigator George Dangas, MD (Icahn School of Medicine at Mount Sinai, New York, USA) presented the study findings at the European Society of Cardiology (ESC) Congress 2021 on Aug. 28. The paper was simultaneously published in the New England Journal of Medicine (NEJM).

“Overall, this trial showed the noninferiority of edoxaban compared to warfarin or similar analogs concerning the composite efficacy endpoint of adverse clinical events, but we need to pay attention to the higher risk of bleeding with edoxaban,” Dangas said.

“Lowering the edoxaban dosage when indicated, and avoiding patients who require antiplatelet therapy is reasonable safety advice based on secondary analyses,” he added, noting that investigators will conduct further analysis on the specific types of bleeding found in the trial.

Jean-Phillippe Collet, MD (Pitié-Salpêtrière Hospital, Paris, France) congratulated investigators for the “only positive trial” with NOAC in the population, noting that NOAC safety would depend on concomitant use of antiplatelet therapy and dosing. Ensuing panel discussion centered on balancing the potential benefits and risks of DOACs in the AF-TAVR patient group.

Previously, the POPular TAVI cohort A² trial found that aspirin monotherapy had a lower incidence of all-cause bleeding at 1-year compared to the combination of aspirin and clopidogrel (15.1% vs. 26.6%, RR 0.57, 95% CI, 0.42-0.77, P=0.001). Collet, who ran the ATLANTIS trial that showed apixaban was not superior to standard of care, also pointed out that the “unlikelihood” of all NOACs being the same but took a conservative stance against updating guidelines.

Major guidelines from both sides of the Atlantic Ocean have recommended VKAs alone over DOACs in TAVR-AF. The newly updated 2021 ESC Guideline for Valvular Heart Disease (VHD), presented at ESC Congress 2021, reaffirmed the old endorsement of VKAs over DOACs.

Up to 33% of patients undergoing TAVR develop AF, a heart condition characterized by an irregular or abnormally fast heart rate. AF poses a higher risk of stroke, requiring treatment with blood-thinners known as oral anticoagulation (OAC).

OACs include VKAs such as warfarin or the newer DOACs (dabigatran, rivaroxaban, apixaban, and edoxaban). VKAs had served as the standard of care for many AF patients in the past until an increasing number of studies showed DOACs with a better risk-benefit profile compared to warfarin for preventing thromboembolic events in nonvalvular AF.

Nevertheless, the case for DOACs in AF-TAVR has long lacked randomized data. Previous trials comparing DOACs and VKAs were largely observational and showed inconsistent results. Existing randomized controlled trials, such as GALILEO and ATLANTIS, were unfavorable with DOACs failing to reduce thromboembolic complications or present a justifiable bleeding-risk trade-off compared to VKAs.

The GALILEO³ trial, published in NEJM in early 2020, was terminated early due to safety concerns with rivaroxaban, even at a low dose of 10 mg. Results showed that 10 mg of the DOAC with aspirin daily had a higher mortality rate than antiplatelets alone (incidence rate 9.8 vs. 7.2 per 100 person-years; HR 1.35; 95% CI, 1.01-1.81, P=0.04).

Although OCEAN-TAVI⁴ results demonstrating mortality benefit with DOACs in select AF-TAVR patients (10.3% vs. 23.3%, HR 0.39; 95% CI, 0.204-0.749; P=0.005) in Nov. 2020 increased hopes, limitations in study design such as its observational nature and small patient population failed to revamp DOAC enthusiasm in the population.

The ATLANTIS⁵ trial, introduced at the 2021 American College of Cardiology (ACC 21)’s Late-Breaking Clinical Trial session, spelled out more bad news as DOAC did not report better outcomes compared to VKA/antiplatelet therapy for 1-year incidence of death, MI, stroke, systemic embolism, and major bleeding (18.4% vs. 20.1%, HR 0.92, 95% CI, 0.73-1.16).

Despite mixed results, Dangas remained optimistic about the “valuable” role of edoxaban, considering that ENVISAGE-TAVI AF enrolled only AF patients who were older “by approximately a decade” compared to previous trials. The patient population also had a higher prevalence of heart failure and more bioprosthetic valves.

“Our trial only applies to patients with AF, intermediate operative risk, and symptomatic aortic stenosis, and it involved a population of older adults undergoing TAVR,” researchers wrote in the paper. “These results may not apply to younger patients at lower operative risk, patients with asymptomatic aortic stenosis, and those undergoing concomitant PCI.”

1. Van Mieghem NM, Unverdorben M, Hengstenberg C, et al. Edoxaban versus Vitamin K Antagonist for Atrial Fibrillation after TAVR. N Engl J Med 2021. DOI: 10.1056/NEJMoa2111016
2. Brouwer J, Nijenhuis VJ, Delewi R, et al. Aspirin with or without Clopidogrel after Transcatheter Aortic-Valve Implantation. N Engl J Med 2020;383(15):1447-1457. DOI: 10.1056/NEJMoa2017815
3. Dangas GD, Tijssen JGP, Wohrle J, et al. A Controlled Trial of Rivaroxaban after Transcatheter Aortic-Valve Replacement. N Engl J Med 2020;382(2):120-129. DOI: 10.1056/NEJMoa1911425
4. Kawashima H, Watanabe Y, Hioki H, et al. Direct Oral Anticoagulants Versus Vitamin K Antagonists in Patients With Atrial Fibrillation After TAVR. JACC Cardiovasc Interv 2020;13(22):2587-2597. DOI: 10.1016/j.jcin.2020.09.013
5. Collet JP, Berti S, Cequier A, et al. Oral anti-Xa anticoagulation after trans-aortic valve implantation for aortic stenosis: The randomized ATLANTIS trial. Am Heart J 2018;200:44-50. DOI: 10.1016/j.ahj.2018.03.008