Edoxaban for the Prevention of Thromboembolism in Patients With Atrial Fibrillation and Bioprosthetic Valves

A trial fibrillation (AF) and valvular heart disease frequently coexist and independently increase mortality.1 Bioprosthetic valve implantation (surgical or transcatheter) is a common, increasingly utilized treatment for valvular heart disease. 2 Patients with AF and bioprosthetic valves require anticoagulation to prevent thromboembolic events.Non-vitamin K oral anticoagulants are safe and efficacious alternatives to vitamin K antagonists for anticoagulation in AF.However, guidelines recommend against using non-vitamin K oral anticoagulants in patients with bioprosthetic valves, citing a lack of supporting data.Only 1 of the first 3 warfarin-controlled pivotal non-vitamin K oral anticoagulants trials in AF included patients with bioprosthetic valves (n>80).3 The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation Thrombolysis in Myocardial Infarction 48), which compared edoxaban (a direct oral factor Xa inhibitor) to warfarin in patients with AF, 4 did not exclude patients with bioprosthetic valves, thus providing an opportunity to analyze this high-risk subgroup.ENGAGE AF-TIMI 48 randomized patients with AF and a CHADS 2 score (Congestive heart failure, Hypertension, Age ≥ 75 years, Diabetes mellitus, Stroke or TIA 2 points) ≥2 to a once daily higher dose edoxaban regimen (60 mg), lower dose edoxaban regimen (30 mg), or warfarin (International Normalized Ratio target of 2.0-3.0).The edoxaban dose was reduced by 50% in patients with decreased clearance.Patients with a history of left-sided valvular heart disease, 5 including those with a history of aortic or mitral bioprosthetic valve implantation (either surgical or transcatheter) >30 days before randomization, were analyzed because right-sided valvular heart disease rarely causes stroke.The indication and date of bioprosthetic valve implantation were not collected.Patients with mechanical valves or moderate-severe mitral stenosis were excluded.The ENGAGE AF-TIMI 48 protocol and amendments were approved by the ethics committee at each participating center.All participants provided written informed consent.The study was registered with ClinicalTrials.gov(unique identifier: NCT00781391) and can be found at https://clinicaltrials.gov/ct2/show/ NCT00781391.In this prespecified analysis, we evaluated outcomes with edoxaban versus warfarin in patients with bioprosthetic valves enrolled in ENGAGE AF-TIMI 48.Primary end points included stroke or systemic embolic events (stroke/SEE), major bleeding (per the International Society for Thrombosis and Haemostasis definition), and the primary net clinical outcome (stroke/SEE, major bleeding, death).Secondary composite end points included ischemic stroke/SEE, major adverse cardiac events (myocardial infarction, stroke, or cardiovascular death), and the composite of stroke/SEE, all-cause mortality, and life-threatening or fatal bleeding (alternative net clinical outcome).An independent, blinded clinical end point committee adjudicated all clinical end points as defined in the main trial.Baseline patient characteristics were described, and hazard ratios (HRs) for each end point comparing higher and lower dose edoxaban to warfarin were calculated.Of 21 105 patients enrolled in the main trial, 191 (0.9%) had previous bioprosthetic valve implantation (n=131 68.6% mitral, n=60 31.4% aortic).The median follow-up