Why Circulating Interleukin‐6 Is Not Yet a Standalone Clinically Actionable Biomarker in HFrEF : A Context‐of‐Use Review

Background Interleukin‐6 (IL‐6) is frequently measured in heart failure with reduced ejection fraction (HFrEF), but its clinical utility remains unclear. Objectives To assess IL‐6 as a biomarker in HFrEF, with emphasis on the effect of treatments (pharmacodynamics) and translation readiness. Methods MEDLINE and EMBASE were searched through June 2026. Using AI‐assisted full‐text screening with manual adjudication, eligible studies were classified using BEST classification as prognostic, predictive and/or pharmacodynamic biomarkers. Results Eighty studies met inclusion criteria (59 pharmacodynamic, 21 prognostic, 3 predictive; categories overlapping). Across prognostic studies, higher IL‐6 consistently tracked disease severity and cardiovascular mortality risk, but associations with hospitalization and composite endpoints weakened after adjustment for natriuretic peptides, limiting incremental clinical value. Pharmacodynamic studies showed that several interventions reduce circulating IL‐6—most consistently statins and levosimendan—while findings were heterogeneous for exercise, cardiac device, and sodium–glucose co‐transporter‐2 inhibitors. However, IL‐6 changes did not consistently parallel clinical benefit, arguing against its use as a surrogate measure for outcome improvement. No study supported IL‐6 as a predictive biomarker. Assay heterogeneity was substantial, with limited use of in vitro diagnosis‐grade assays, representing a major barrier to qualification. Conclusions In HFrEF, IL‐6 reflects inflammatory burden and may serve as pharmacodynamic readout in mechanistic studies, but it is not supported for treatment selection and adds limited prognostic information beyond natriuretic peptides. Progress towards translational utility requires standardized measurements and, potentially, biomarkers reflecting the IL‐6 axis beyond IL‐6 alone.