Worsening Heart Failure-Based Hierarchical Endpoints Beyond HF Hospitalization. Expert opinion paper.

Abstract The traditional, hospitalization-centric composite endpoint of cardiovascular death or time-to-first heart failure hospitalization is increasingly misaligned with contemporary heart failure care and, as evidence-based therapies lower event rates over time, requires larger trials with longer follow-up. Improved survival, modern ambulatory pathways mean that a larger share of worsening heart failure is treated outside the hospital and that patients may experience recurrent worsening heart failure episodes. Relying on time-to-first hospitalization alone can therefore miss clinically relevant morbidity; recurrent-event approaches can offer additional power mainly when risk heterogeneity is high and treatment discontinuation after a first event is infrequent. To address this gap, we propose a standardized, adjudicated definition of worsening heart failure events informed by published consensus definitions, expanded to capture ambulatory events across care settings. Building on this definition, we recommend hierarchical primary endpoints that prioritize all-cause death with cardiovascular death evaluated as a secondary mortality outcome when prespecified and adjudicated, while robustly measuring morbidity through total adjudicated worsening heart failure events (first and recurrent), with validated patient-reported outcomes as additional hierarchical levels. We outline operational considerations for event capture and adjudication, including prioritized composite analytic approaches, and highlight safeguards to mitigate ascertainment bias and dilution by more subjectively defined events. Adoption of worsening heart failure-based hierarchical endpoints can better reflect the total disease burden, improve statistical power, and enhance interpretability across evolving care models.