SPIRIT-HF Shows No Significant Difference in HF Events With Spironolactone

New findings from the SPIRIT-HF (NCT04727073) trial showed no statistically significant benefit with spironolactone (Aldactone; Pfizer) in patients with heart failure with preserved ejection fraction (HFpEF) and mildly reduced ejection fraction (HFmrEF).

The data, presented at the American College of Cardiology (ACC) 2026 Scientific Session, could help refine the clinical role of spironolactone in populations historically lacking clear, evidence-based treatment strategies.¹

Spironolactone is a potassium-sparing diuretic commonly used to treat heart failure (HF) and hypertension by helping the kidneys remove excess fluid and sodium while retaining potassium, thereby reducing volume overload and cardiac strain.² By blocking aldosterone receptors, it lowers blood pressure and fluid retention but also requires careful monitoring, as it can increase potassium levels and affect kidney function—key considerations in HF management.

The multicenter, double-blind, placebo-controlled trial conducted from 2018 to 2024 enrolled 743 patients aged 50 years and older with left ventricular ejection fraction (LVEF) of at least 40% and New York Heart Association class II to IV symptoms.¹ Patients were randomized to receive spironolactone or placebo, with outcomes assessed over 24 months. The trial’s primary end point was a composite of total HF hospitalizations and cardiovascular death, with several secondary end points evaluating hospitalization burden and mortality.

The trial missed its primary end point at 2 years, with a rate of 10.9 cardiovascular deaths or HF hospitalizations per 100 patient-years in the spironolactone group compared with 8.2 in the placebo group (rate ratio, 1.32; 95% CI, 0.79-2.21). As the study included fewer than half of the planned number of patients, these results are not definitive.

In SPIRIT-HF, the enrolled cohort represents a relatively high-risk population with clinical characteristics closely aligned with those of the TOPCAT Americas subgroup—considered the most reliable dataset from the earlier TOPCAT trial. The median age of participants was 77.8 years, and more than half (52%) were women. Median LVEF was 55%, and 20% of patients met criteria for HFmrEF.

Importantly, nearly half of SPIRIT-HF participants (47%) had experienced a prior HF hospitalization, a rate comparable to the 55% observed in TOPCAT Americas. In addition, median N-terminal pro-B-type natriuretic peptide levels were slightly higher in SPIRIT-HF (1018 pg/mL vs 900 pg/mL), suggesting a somewhat greater disease burden among enrolled patients.

Comorbidities and background therapies further underscore the clinical severity of the study population. Atrial fibrillation was present in approximately 24% of patients, while chronic kidney disease affected 48%. Standard HF therapies were widely used, including beta-blockers (75%) and diuretics (83%), with 69% of patients receiving loop diuretics. These similarities to TOPCAT Americas strengthen the comparability of the datasets and enhance the interpretability of subsequent analyses, according to the investigators.

Although definitive efficacy results for the primary and secondary end points are forthcoming, the SPIRIT-HF findings already provide important context for understanding spironolactone’s potential benefit. By enrolling a higher-risk, well-characterized population with consistent event rates and treatment adherence, the trial addresses key limitations that contributed to ambiguity in prior studies.

To further clarify treatment effects, investigators conducted a pre-specified individual participant data (IPD) meta-analysis combining SPIRIT-HF with TOPCAT Americas. This analysis is expected to improve statistical power and provide more precise estimates of spironolactone’s impact on HF hospitalizations and cardiovascular mortality. By focusing on patient-level data, the meta-analysis can better account for heterogeneity and identify subgroups most likely to benefit from therapy.

Taken together, the SPIRIT-HF findings add important clarity to the ongoing uncertainty surrounding spironolactone’s role in HFpEF and HFmrEF. Despite enrolling a high-risk, well-characterized population with features closely aligned to prior trials, spironolactone did not significantly reduce the composite of cardiovascular death or total HF hospitalizations over 24 months, underscoring the challenges of demonstrating consistent benefit in these heterogeneous patient populations.

Ongoing analyses, including the planned individual participant data meta-analysis with TOPCAT Americas, may help refine these findings by improving statistical power and identifying subgroups more likely to benefit. By leveraging patient-level data across comparable cohorts, investigators aim to better define whether specific higher-risk patients—such as those with elevated natriuretic peptide levels or prior HF hospitalization—derive meaningful benefit from mineralocorticoid receptor antagonism.

References

1. Edelmann F, Zurkan D, Girerd N, et al. Spironolactone in the treatment of heart failure. Poster presented at: American College of Cardiology’s Annual Scientific Session; March 28-30, 2026; New Orleans, LA.

2. Spironolactone tablets. Mayo Clinic. Accessed April 20, 2026. https://my.clevelandclinic.org/health/drugs/19755-spironolactone-tablets