Growth-Differentiation Factor 15 and Risk of Major Bleeding in Atrial Fibrillation: Insights from the RE-LY Trial

Objective To evaluate and validate the prognostic value of Growth-Differentiation Factor-15 (GDF-15) beyond clinical characteristics and other biomarkers concerning bleeding and stroke outcomes in patients with AF in the RE-LY trial. Methods GDF-15 was measured in samples collected at randomization in 8474 patients with a median follow-up time of 1.9 years. Patients were stratified based on pre-defined GDF-15 cut-offs: group 1: 1800 ng/L (high-risk individuals). Efficacy and safety outcomes were compared across groups of GDF-15 in Cox models adjusted for baseline characteristics, cardiac (NT-proBNP, hs-troponin T), inflammatory (IL-6, CRP) and coagulation (D-dimer) biomarkers, and randomized treatment. Results GDF-15 concentrations were below 1200 ng/L in 2,647 (31.2%), between 1200 and 1800 ng/L in 2,704 (31.9%), and above 1800 ng/L in 3,123 (36.9%) participants, respectively. Annual rates of stroke, major bleeding, and mortality increased with higher GDF-15 levels. The prognostic value of GDF-15 was independent of clinical characteristics for these outcomes. In models also adjusted for biomarkers, GDF-15 remained significantly associated with major bleeding (HR (95% CI) group 3 vs. group 1 1.76 (1.28–2.42, p<0.0005) and all-cause mortality (HR 1.72 (1.30–2.29, p<0.0005). GDF-15 improved the C-index of both the HAS-BLED (0.62 to 0.69) and ORBIT (0.68 to 0.71) bleeding risk scores. Conclusions In patients with AF, GDF-15 is an independent risk indicator for major bleeding and all-cause mortality, but not for stroke. Therefore, GDF-15 seems useful as a specific marker of bleeding in patients with AF on oral anticoagulant treatment.