byAmerican College of Cardiology

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A trial testing the aldosterone blocker spironolactone in patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF) did not show any significant improvement in terms of heart failure hospitalizations and cardiovascular death at 24 months, according to findings presented at the American College of Cardiology's Annual Scientific Session (ACC.26).

In HFpEF, the heart cannot fill with enough blood because it has a hard time relaxing and may be stiff. In HFmrEF, the heart's pumping ability is slightly below normal. Both types of heart failure can result in less oxygen-rich blood being pumped out to the rest of the body, leading to symptoms such as shortness of breath, swelling, and fatigue.

Spironolactone, a diuretic that works by blocking the hormone aldosterone, also exerts effects on the composition of heart tissue and increases urine production to reduce water retention while retaining potassium. The drug has been shown in clinical trials to improve outcomes for patients with a heart failure with reduced ejection fraction (HFrEF), but previous findings for HFpEF have been mixed.

Results from theSPIRIT-HF studyshowed an increase in hospitalizations and serious adverse events among those assigned to spironolactone, raising questions about the drug's safety in patients with HFpEF or HFmrEF.

However, the trial was affected by a high rate of discontinuation due to the COVID-19 pandemic, 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 Frank Edelmann, MD, chair of cardiovascular prevention at the Heart Center of Charité University Medicine Berlin in Germany and the study's lead author.

"On efficacy, the study was negative or perhaps slightly inconclusive, but the clear increase in total hospitalizations and adverse events warrants more attention."

Several previous trials have had ambiguous findings regarding spironolactone's effects on heart failure outcomes. TOPCAT, the largest previous outcomes trial, did not find an overall benefit from the drug for HFpEF.

A sub-analysis of TOPCAT data showed positive results in participants from North and South America but not in those from Eastern Europe, suggesting regional differences in study-drug uptake and event rates may have influenced the results.

SPIRIT-HF randomized 730 patients with symptomatic heart failure to receive spironolactone or placebo at 56 centers in four European countries. About 80% of the participants had HFpEF and 20% had HFmrEF. The median age of participants was nearly 78 years of age and about half were women.

At 24 months, there was no difference between groups in terms of thetrial's primary endpoint, a composite of hospitalization for heart failure 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. No opposing findings were shown across subgroups by age, sex, ejection fraction, and various comorbidities.

Secondary endpoints revealed a significantly higher rate of total hospitalizations, hypotension (low blood pressure), renal events (indicative of kidney dysfunction), and elevated potassium among those taking spironolactone. In addition, this group saw a trend toward increased cardiovascular hospitalizations.

"Side effects like elevated potassium and hypotension can be expected, but the increase in hospitalizations was unexpected," Edelmann said. "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."

Researchers said the high rate of study drug discontinuation may have played a role in some of the trial's findings. The trial enrolled participants from 2018–2024, and for most participants, the bulk of the treatment period spanned the COVID-19 pandemic.

Participants could still acquire the study drug via mail during this period, but they were unable to participate in planned clinic visits due to COVID-19 lockdowns. Ultimately, just over half of participants randomized to receive spironolactone stopped taking their assigned regimen drug before the end of the study.

The composite rate of heart failure hospitalizations and cardiovascular death was initially numerically lower in those taking spironolactone compared with placebo for the first five months of the trial, but later those rates began to climb and ultimately surpassed the rates seen in the placebo group. In the end, with this variance over time, no significant difference between groups was observed at 24 months.

Researchers also conducted ameta-analysisthat 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.

Key medical concepts Spironolactone