Oral anticoagulation with vitamin K antagonists (VKAs), such as warfarin or acenocoumarol, is indicated with varying degrees of recommendation (ESC/EACTS 2021 guidelines on the diagnosis and treatment of valvular heart disease) in the immediate postoperative period for patients undergoing valve replacement or repair. Direct oral anticoagulants (DOACs), or non-vitamin K-dependent oral anticoagulants, present clear advantages in dosing, monitoring, and drug interactions over VKAs. However, the efficacy and safety of DOACs in the postoperative period following cardiac surgery remain uncertain.
The ENAVLE study was a randomized (1:1), open-label, prospective clinical trial conducted between December 2017 and September 2019, aimed at comparing the efficacy and safety of edoxaban (60 mg or 30 mg once daily) with warfarin during the first 3 months post-bioprosthetic valve surgery (aortic or mitral) or mitral repair. The primary efficacy endpoint was a composite of adverse outcomes including death, clinical thromboembolic events, or asymptomatic intracardiac thrombosis, analyzed as a combined event. The primary safety endpoint was the incidence of major bleeding. Out of 220 participants, 218 (109 per group) were included in a modified intention-to-treat analysis. The primary efficacy outcome occurred in 4 patients (3.7%) in the warfarin group and none in the edoxaban group (risk difference = 0.037; p < .001 for non-inferiority). The primary safety endpoint was observed in 1 patient (0.9%) in the warfarin group and 3 patients (2.8%) in the edoxaban group (risk difference = 0.0183; p = .013 for non-inferiority).
The study concluded that, as an anticoagulation therapy during the first 3 months following bioprosthetic valve implantation or valve repair, edoxaban is not inferior to warfarin in preventing thromboembolism and is potentially comparable in terms of major bleeding risk.
COMMENTARY:
New DOACs such as apixaban, rivaroxaban, edoxaban, and dabigatran are well-established as the treatment of choice in non-valvular atrial fibrillation (AF) for stroke prevention or in the treatment of deep vein thrombosis. Compared to VKAs, such as acenocoumarol or warfarin, DOACs have the advantage of a quicker onset of action, negating the need for bridging therapy with heparin during the initial days, reduced monitoring requirements for correct dosing, fewer drug interactions, and minimal food-drug interactions. For these reasons, the use of DOACs as an alternative to VKAs after cardiac valve surgery is highly attractive, but unfortunately, the safety and efficacy of DOACs in bioprosthetic valves within the first 3 months post-surgery or percutaneous implantation remain undefined. If we refer to, for example, the latest ESC/EACTS 2021 guidelines on valvular heart disease, oral anticoagulation with VKAs after bioprosthetic implantation in the mitral or aortic position is clearly recommended only if the patient has other indications for anticoagulation (level of evidence I class C); in other cases, it should be considered during the first 3 months, with an alternative option of low-dose aspirin for bioprosthetic valves in the aortic position (level of evidence IIa class B). The recommendation for DOACs is quite different, as they are given a IIaB recommendation from the third month onward in patients with AF, but may only be considered (level of evidence IIb class C) during the first 3 months in biological mitral valve replacement in patients with AF. In this same guideline, DOACs for mitral or tricuspid repair, or even for TAVI, are not assigned a recommendation level.
The only two clinical trials to date comparing VKAs with DOACs in this context are the RIVER study and this ENAVLE study. The RIVER study (rivaroxaban vs. warfarin) demonstrated non-inferiority of rivaroxaban following mitral valve replacement; however, only 20% of patients were included within the first 3 months. The ENAVLE study results (edoxaban vs. warfarin), the subject of this article, though officially published this month, were already considered in drafting the latest ESC/EACTS 2021 guidelines on valvular heart disease. However, DOACs did not receive a higher level of recommendation or evidence, primarily due to the small number of patients randomized.
Shim et al., in this randomized clinical trial, present impressive results with edoxaban following valve surgery, demonstrating non-inferiority compared to warfarin in stroke prevention and major bleeding incidence. A key but often overlooked aspect of this study, which accurately reflects daily practice with warfarin or acenocoumarol, is the poor control of the international normalized ratio (INR) observed, with patients being out of the target INR range (between 2 and 3) nearly half the time; numbers contrasting with the high adherence observed in the edoxaban group to the DOAC. It is thus unsurprising that, although still outside the guidelines, many cardiac surgeons are opting to anticoagulate their patients with DOACs.
It would have been highly informative to conduct this study with a more homogeneous population, avoiding mixing bioprosthetic valves in the mitral or aortic position with mitral repair, or sinus rhythm with AF, as each of these groups carries distinct thromboembolic risks that deserve separate analysis in future research. Another evident limitation of the ENAVLE study was the low number of patients included. When coupled with the unexpectedly low event rates found (below anticipated levels) and the relatively large non-inferiority margins, caution is advised before extrapolating these results to real-world clinical practice. Larger multicenter, double-blind clinical trials with greater patient numbers are needed before advancing DOAC recommendations in clinical guidelines. In any case, these results represent a major step toward the approval of early anticoagulation with DOACs following valve surgery and pave the way for future studies evaluating their efficacy in TAVI.
REFERENCE:
Shim CY, Seo J, Kim YJ, Lee SH, De Caterina R, Lee S, et al.; Efficacy and safety of edoxaban in patients early after surgical bioprosthetic valve implantation or valve repair: A randomized clinical trial. J Thorac Cardiovasc Surg. 2023 Jan;165(1):58-67.e4. doi: 10.1016/j.jtcvs.2021.01.127.
Vahanian A, Beyersdorf F, Praz F, Milojevic M, Baldus S, Bauersachs J, et al.; ESC/EACTS Scientific Document Group. 2021 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2022 Feb 12;43(7):561-632. doi: 10.1093/eurheartj/ehab395.
