Component-level associations of anemia and renal dysfunction with competing first events in acute heart failure with atrial fibrillation

In acute heart failure (AHF) with atrial fibrillation (AF), major bleeding, ischemic stroke, and death compete as the first clinical event. Whether anemia and renal dysfunction together define a single bleeding-risk construct is unclear. We retrospectively analyzed 712 consecutive patients hospitalized with AHF and AF in a multicenter registry (2014–2020). Hemoglobin < 12 g/dL and creatinine clearance (CrCl) < 50 mL/min defined four mutually exclusive groups. Fine–Gray models evaluated bleeding-first, stroke-first, and death-first events, with hemoglobin and CrCl also entered simultaneously as continuous covariates. Incremental value for 365-day bleeding-first was assessed in one common cohort with bootstrap optimism correction. Of 712 patients (mean age 79.1 years; 48.6% female; 81.7% on oral anticoagulants), 138 had neither abnormality, 40 anemia only, 236 renal dysfunction only, and 298 both. Bleeding occurred first in 81 patients (11.4%), stroke in 43 (6.0%), and death in 140 (19.7%). Adjusted bleeding-first risk was highest with both abnormalities (subdistribution hazard ratio [sHR] 3.67; 95% confidence interval [CI] 1.39–9.68; p = 0.009 versus neither), but neither the contrast against anemia only (sHR 2.42; 95% CI 0.74–7.91; p = 0.14) nor the anemia × renal dysfunction interaction ( p = 0.98) was significant. Modeled continuously, lower hemoglobin was associated with bleeding-first (sHR 1.22 per 1 g/dL decrease; 95% CI 1.06–1.40; p = 0.006) and lower CrCl with death-first (sHR 1.20 per 10 mL/min decrease; 95% CI 1.07–1.35; p = 0.002). Relative to the model with anemia alone, neither adding renal dysfunction (optimism-corrected change in area under the curve [ΔAUC] 0.0138; 95% CI − 0.0473 to 0.0576) nor using the combined binary phenotype (0.0145; 95% CI − 0.0168 to 0.0432) showed clear improvement in prediction. The bleeding association persisted in anticoagulated patients and after excluding bleeding supported only by a hemoglobin fall. Although patients with both anemia and renal dysfunction had the highest observed bleeding-first risk, their coexistence showed neither a supported interaction nor improved 365-day prediction beyond anemia alone. Lower hemoglobin and lower CrCl showed different observed association patterns across the competing first events, favoring component-level interpretation over a unitary anemia–renal risk construct.