Spironolactone, an aldosterone blocker, compared with placebo, did not show any significant improvement in terms of heart failure (HF) hospitalizations and cardiovascular death at 24 months in patients with HF with preserved or mildly reduced ejection fraction (HFpEF, HFmrEF), according to results of the SPIRIT-HF trial presented during a Late-Breaking Clinical Trial session at ACC.26 in New Orleans.

Conducted at 56 centers in four European countries from 2018-2024, the double-blind trial randomized 730 patients with symptomatic HFpEF or HFmrEF to either spironolactone or placebo. Their median age was nearly 78 years, half were women and most (80%) had HFpEF.

At 24 months, there was no difference between groups in terms of the trial’s primary endpoint, a composite of HF hospitalization and death from cardiovascular causes, with 10.8 and 12.7 events occurring per 100 patient-years in the placebo group and spironolactone group, respectively. Results were similar across subgroups by age, sex, ejection fraction and various comorbidities.

Regarding the secondary endpoints, there was a significantly higher rate of total hospitalizations, hypotension, renal events and elevated potassium in patients taking spironolactone compared with placebo, with a trend toward increased cardiovascular hospitalizations.

“Side effects like elevated potassium and hypotension can be expected, but the increase in hospitalizations was unexpected,” said Frank Edelmann, MD, the study’s lead author. “This confirms there are some safety issues with this drug. If you treat patients with spironolactone, you must think about side effects such as renal function and potassium levels. This is important information for all clinicians.”

The trial was affected by a high rate of discontinuation due to the COVID-19 pandemic, with just over half of patients in the spironolactone stopping the study drug, which lowered its ability to conclusively demonstrate differences between the treatment and placebo groups.

“We need to be careful about the interpretation of these findings because ultimately the trial was a little too small, but there are some issues regarding safety and efficacy, and it is very important for the community to have this data and to discuss it,” said Edelmann. “On efficacy, the study was negative or perhaps slightly inconclusive, but the clear increase in total hospitalizations and adverse events warrants more attention,” he added.

Researchers also conducted a meta-analysis that pooled SPIRIT-HF data with data from TOPCAT participants from the Americas, and found spironolactone had no significant effect on outcomes within the combined data set. Edelmann said that other studies, including an ongoing registry study of spironolactone in patients with HFpEF, may shed further light on the safety and efficacy of the drug in this population.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: ACC Annual Scientific Session, ACC26, New Orleans, Heart Failure, Aldosterone, Spironolactone, Stroke Volume, Hospitalization, Kidney, Hypotension, Potassium