Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT-HFpEF) is a pragmatic, registry-based randomized clinical trial that proposes to evaluate the clinical effectiveness of spironolactone versus usual care. The primary hypothesis of SPIRRIT- HFpEF is that treatment with spironolactone will reduce cardiovascular mortality compared with usual care.
Nearly half of the 5.7 million adults with heart failure (HF) in the United States have a normal or near-normal left ventricular ejection fraction, or HF with preserved ejection fraction (HFpEF). The prevalence of HFpEF is expected to increase over time, due to the population ageing and other factors. Morbidity and mortality for HFpEF patients remains high; rates are comparable to those observed in HF with reduced ejection fraction (HFrEF). 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 (MRAs) present one promising treatment for HFpEF. In clinical trials of HFrEF patients, MRAs have consistently demonstrated their ability to improve symptoms, and reduce mortality and hospitalizations. However, The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial was the largest study of MRAs 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. These promising results require additional investigation prior to widespread implementation. Additionally, there are concerns whether efficacy results of MRAs from traditional randomized controlled trials can be effective in real-world community practice. Registry Randomized Clinical Trials (RRCT), pioneered by the Uppsala Clinical Research Center and the Duke Clinical Research Institute, leverage existing registries to more efficiently identify study patients and collect follow-up endpoints. Additionally, RRCTs generally enroll real-life patient populations, therefore being more generalizable. Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT-HFpEF) is a pragmatic RRCT that will enroll patients from Sweden and the United States to evaluate the clinical effectiveness of open-label spironolactone versus usual care in community practice. The primary hypothesis is that treatment with spironolactone will reduce the primary endpoint (i.e., cardiovascular mortality) compared with usual care. Resolving whether spironolactone is beneficial in HFpEF patients would have tremendous public health implications.