Cardiac functional and structural remodeling in patients with atrial fibrillation (AF) contributes to development of heart failure (HF) as their major cardiovascular comorbidity. Circulating biomarkers may reflect these cardiac alterations. ENGAGE AF-TIMI 48 was a randomized trial of edoxaban vs warfarin in 21,105 patients with AF. We performed a nested biomarker study in 8,765 patients, analyzing high-sensitivity troponin T (hsTnT), N-terminal B-type natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) at baseline and 12 months. Of 8765 patients, 5207 had a history of HF, among whom 3996 had known ejection fraction (EF): 926 with reduced EF (HFrEF; ≤40%), 1043 with mildly-reduced EF (HFmrEF; 40-49%), and 2027 with preserved EF (HFpEF; ≥50%). Elevated baseline hsTnT, NT-proBNP, and GDF-15 were associated with higher risk of hospitalization for HF (HHF)/HF death overall and in subpopulations defined by HF history and EF (P<0.001 for each). These associations of outcome with each biomarker were consistent regardless of a history of HF or EF (P-interaction>0.05 for each). Patients who had an increase in or had persistently elevated values in any of the three biomarkers over 12 months were at higher risk for HHF/HF death in overall population (P<0.001 for each biomarker and category). Serial measurement of hsTnT, NT-proBNP, and GDF-15 revealed that higher baseline values, and increasing or persistently elevated values over 1 year are associated with higher risk of HF outcomes in patients with AF regardless of HF history or HF phenotype based on EF.