Project Summary
Over half of the 6.7 million adults with heart failure in the United States have a normal or near-normal left
ventricular ejection fraction, or heart failure with preserved ejection fraction (HFpEF). The prevalence of HFpEF
is increasing over time, due to ageing of the population and other factors. Morbidity and mortality for patients
with HFpEF remains high; rates are similar to those observed in HF with reduced ejection fraction. Poor
outcomes in HFpEF are related to a lack of evidence-based therapeutic options. There is an urgent need to
efficiently conduct large, simple, streamlined trials with clinically relevant endpoints comprised of therapeutic
interventions for HFpEF patients. Mineralocorticoid receptor antagonists (including spironolactone) present one
promising treatment for HFpEF. In clinical trials of participants with HF with reduced ejection fraction,
mineralocorticoid receptor antagonists have consistently demonstrated their ability to improve symptoms, and
reduce mortality and hospitalizations. However, the TOPCAT trial was the largest study of mineralocorticoid
receptor antagonists in HFpEF. In TOPCAT, spironolactone did not significantly reduce the primary outcome (a
composite of cardiovascular death, aborted cardiac arrest, or hospitalization for HF) relative to placebo, but did
reduce a secondary endpoint of HF hospitalization (HR 0.83, 95% CI 0.69–0.99, p=0.04). A post-hoc regional
analysis of TOPCAT, limited to North and South America, found that spironolactone reduced the primary
endpoint (HR 0.82, 95% CI 0.69–0.98) compared to placebo. Therefore, TOPCAT demonstrated the potential
promise of mineralocorticoid receptor antagonists in HFpEF but was not definitive. The Spironolactone
Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT-
HFpEF) randomized clinical trial was funded in 2018 for 5 years and has now randomized >1900 participants.
The primary aim of SPIRRIT-HFpEF is to test the hypothesis that use of spironolactone will reduce total HF
events (total hospitalizations for HF and death from cardiovascular causes). SPIRRIT-HFpEF will complete
enrollment December 31, 2023. The current application for SPIRRIT-EX is for a free-standing extension of the
SPIRRIT-HFpEF trial to extend follow-up through December 31, 2025 and to allow for accrual of additional
clinical events. The application will specifically support extended follow-up, secondary analyses (including a
pre-specified meta-analysis of data from another ongoing HFpEF clinical trial), dissemination of results, and
closeout activities of participants previously randomized in SPIRRIT-HFpEF. Resolving whether spironolactone
is beneficial in patients with HFpEF would have tremendous public health implications.
