Trials and tribulations of spironolactone in heart failure with preserved ejection fraction: Insights from the SPIRIT-HF trial

Heart failure with preserved ejection fraction represents a clinical challenge, accounting for at least 50% of heart failure (HF) cases globally, with a historical lack of efficacious and disease-modifying therapies. Mineralocorticoid receptor antagonists, specifically the steroidal agent spironolactone, have a strong theoretical potential to mitigate systemic inflammation, microvascular endothelial dysfunction, and myocardial fibrosis, which commonly affect patients with HF. However, the clinical validation of spironolactone has been influenced by methodological inconsistencies and safety concerns. The pivotal TOPCAT trial yielded neutral primary outcome results globally, confounded by significant geographical disparities. To provide further evidence the SPIRIT-HF trial evaluated spironolactone in a population with HF and mildly reduced or preserved ejection fraction. This trial was affected by critical operational issues related to the COVID-19 pandemic, resulting in an underpowered study population with a very high study drug discontinuation rate. The trial ultimately failed to demonstrate a cardiovascular benefit on any of the evaluated outcomes. The ongoing SPIRRIT-HFpEF trial represents a pragmatic, registry-based study to overcome traditional enrollment barriers, while evidence from the FINEARTS-HF trial on finerenone, a novel non-steroidal antagonist, has finally highlighted a major role for mineralocorticoid receptor antagonism in patients with HF and mildly reduced or preserved ejection fraction. This meeting report examines the SPIRIT-HF trial and place its results within the broader evidence on steroidal and nonsteroidal MRA in patients with HFpEF.