Beyond trial neutrality: treatment discontinuation and the hidden signal in SPIRIT-HF trial

Taken together, the findings from SPIRIT-HF challenge a simplistic interpretation of neutral trial results from an under-powered study, and instead appear to highlight the critical role of treatment durability in determining clinical outcomes in heart failure with preserved ejection fraction and heart failure with mildly reduced ejection fraction, where patients are older, multi-morbid, and physiologically vulnerable, the balance between efficacy and tolerability is particularly fragile. Importantly, treatment discontinuation should not be viewed merely as an adverse event, but as a clinically meaningful signal reflecting both patient vulnerability and potential loss of therapeutic benefit. These observations suggest that the effectiveness of neurohormonal therapies may depend as much on their sustained use as on their intrinsic pharmacologic efficacy. Accordingly, future therapeutic strategies should prioritize not only the initiation of disease-modifying treatments but also their long-term tolerability, adherence, and continuity.