Efficacy and Safety of Edoxaban in Anticoagulant Therapy Early after Surgical Bioprosthetic Valve Replacement: the ENBALV trial

Background Anticoagulant therapy with vitamin K antagonists is recommended in the current guidelines for 3 to 6 months following bioprosthetic valve replacement to prevent thromboembolic events, including in patients with sinus rhythm. However, in the era of direct oral anticoagulants (DOACs), there is a paucity of evidence regarding the efficacy and safety of DOACs in this patient group. Methods The ENBALV trial was an investigator-initiated, phase 3, randomized, open-label, multicenter study that aimed to evaluate the efficacy and safety of edoxaban compared to warfarin within 3 months following bioprosthetic valve replacement at the aortic and/or mitral position. The primary outcome was stroke or systemic embolism. The secondary outcomes included major bleeding, intracardiac thrombus, and a composite of stroke, systemic embolism, or major bleeding. Results Of 410 enrolled patients, 389 were included in the final analysis (73±6 years, 56.8% male, 79.4% sinus rhythm, edoxaban group: n=195, warfarin group: n=194). The primary outcome occurred in 0.5% (n=1) in the edoxaban group, whereas in 1.5% (n=3) in the warfarin group (risk difference, −1.03, 95% confidence interval [CI], −4.34 to 1.95). Major bleeding occurred in 4.1% (n=8) in the edoxaban group and in 1.0% (n=2) in the warfarin (risk difference, 3.07; 95% CI, −0.67 to 7.27). The incidence of major bleeding was numerically higher in the edoxaban group, but no fatal bleeding or intracranial hemorrhage was observed in patients treated with edoxaban, whereas one fatal intracranial hemorrhage occurred in the warfarin group. Intracardiac thrombus did not occur in any of the patients in the edoxaban group, but did occur in 1.0% (n=2) in the warfarin group. Conclusions Edoxaban had comparable efficacy to warfarin for the prevention of thromboembolic events in patients early after bioprosthetic valve replacement, suggesting that it is a potential alternative anticoagulant therapy. Trial registration The study was registered with the Japan Registry of Clinical Trials (jRCT), with reference number 2051210209 (30 March 2022; https://jrct.niph.go.jp/latest-detail/jRCT2051210209 ). Clinical perspective What is new? Current guidelines recommend the administration of warfarin for patients early after bioprosthetic valve replacement, including those with sinus rhythm, but there is a paucity of evidence regarding the efficacy and safety of direct oral anticoagulants (DOACs) in this patient group. ENBALV trial provides the first large-scale evidence on the use of DOAC in patients early after bioprosthetic valve surgery. ENBALV trial demonstrated that edoxaban had comparable efficacy to warfarin for preventing thromboembolism. No fatal or intracranial hemorrhage was observed with edoxaban. Our results suggest that edoxaban could be an alternative to warfarin in this patient group. What are the clinical implications? The availability of edoxaban could offer more flexibility in anticoagulant treatment options after bioprosthetic valve surgery. Since edoxaban does not require regular and frequent blood testing, it could simplify the care process, reduce the burden on patients, and improve their quality of life, especially in the crucial early period after surgery. The availability of edoxaban also give benefits for medical stuffs as well as patients, because edoxaban can be used with constant dose, no need of routine monitoring of anticoagulation activity, and a low risk of interaction with other drugs and food.