SPIRIT-HF Trial Shows No Benefit and Safety Concerns for Spironolactone in Heart Failure with Preserved Ejection Fraction

The SPIRIT-HF trial has delivered disappointing results for spironolactone in heart failure patients with preserved or mildly reduced ejection fraction, showing no clinical benefit while raising significant safety concerns. The findings, presented at the American College of Cardiology's Annual Scientific Session (ACC.26) in New Orleans, challenge the potential role of this aldosterone blocker in treating these challenging heart failure phenotypes.

Trial Design and Patient Population

The double-blind, placebo-controlled trial randomized 730 patients with symptomatic heart failure across 56 centers in four European countries between 2018 and 2024. The study population had a median age of nearly 78 years, with approximately half being women. About 80% of participants had heart failure with preserved ejection fraction (HFpEF), while 20% had heart failure with mildly reduced ejection fraction (HFmrEF).

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

Primary Endpoint Results

At 24 months, the trial failed to demonstrate any significant difference between treatment groups for the primary composite endpoint of heart failure hospitalization and cardiovascular death. The placebo group experienced 10.8 events per 100 patient-years, while the spironolactone group had 12.7 events per 100 patient-years. These results remained consistent across subgroups analyzed by age, sex, ejection fraction, and various comorbidities.

Safety Concerns Emerge

The trial revealed concerning safety signals that were unexpected by researchers. Patients receiving spironolactone experienced significantly higher rates of total hospitalizations, hypotension (low blood pressure), renal events indicative of kidney dysfunction, and elevated potassium levels compared to those on placebo. Additionally, there was a trend toward increased cardiovascular hospitalizations in the spironolactone group.

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

COVID-19 Impact on Trial Conduct

The trial faced significant challenges due to the COVID-19 pandemic, which affected most participants during their treatment period. While participants could still receive study medication via mail during lockdowns, they were unable to attend planned clinic visits. This disruption contributed to a high discontinuation rate, with just over half of participants randomized to spironolactone stopping their assigned treatment before study completion.

The composite rate of heart failure hospitalizations and cardiovascular death was initially numerically lower in the spironolactone group compared to placebo during the first five months. However, these rates subsequently increased and ultimately surpassed those seen in the placebo group, resulting in no significant difference at the 24-month endpoint.

Meta-Analysis Confirms Negative Results

Researchers conducted a meta-analysis pooling SPIRIT-HF data with data from TOPCAT participants from the Americas. This combined analysis found that spironolactone had no significant effect on outcomes within the larger dataset, further supporting the negative findings.

Clinical Context and Previous Evidence

Spironolactone, a diuretic that blocks the hormone aldosterone, has demonstrated benefits in patients with heart failure with reduced ejection fraction (HFrEF) in previous clinical trials. The drug affects heart tissue composition and increases urine production to reduce water retention while retaining potassium. However, findings for HFpEF have been mixed across multiple studies.

The TOPCAT trial, the largest previous outcomes study, did not find an overall benefit from spironolactone for HFpEF. Interestingly, 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 results.

Study Limitations and Future Directions

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

Edelmann indicated that additional studies, including an ongoing registry study of spironolactone in patients with HFpEF, may provide further insights into the safety and efficacy of the drug in this population. The study was funded by DZHK (German Centre for Cardiovascular Research).