Mineralocorticoid receptor antagonists reduce risk of cardiovascular events in patients with heart failure

By Dr. Sushama R. Chaphalkar, PhD.Reviewed by Danielle Ellis, B.Sc.Sep 3 2024

Research supports the broader use of MRAs in heart failure management, with benefits seen across different ejection fractions

In a recent meta-analysis published in The Lancet, researchers investigated the effect of steroidal and nonsteroidal mineralocorticoid receptor antagonists (MRAs) on patients with heart failure (HF) across a range of ejection fractions, including HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF).

They found that MRAs significantly reduced the risk of cardiovascular death or HF hospitalization among patients, with greater efficacy observed in patients with HFrEF as compared to patients with HFmrEF or HFpEF. Additionally, MRAs were found to be associated with an increased risk of hyperkalemia but a reduced risk of hypokalemia.

Background

Steroidal MRAs such as spironolactone and eplerenone are reported to be effective in reducing death and hospitalization in patients with HF and HFrEF, as demonstrated in the trials named RALES (randomized aldactone evaluation study) and EMPHASIS-HF (eplerenone in mild patients hospitalization and survival study in heart failure). These findings have led to strong guideline recommendations for their use in HFrEF. However, their efficacy in HFmrEF or HFpEF remains uncertain.

The TOPCAT trial (treatment of preserved cardiac function heart failure with an aldosterone antagonist) did not show significant benefits of spironolactone in HFpEF, though issues like low event rates and poor adherence may have potentially influenced results. As a result, guidelines for MRAs in HFmrEF or HFpEF are less definitive.

The FINEARTS-HF trial (a finer enone trial to investigate efficacy and safety superior to placebo in patients with heart failure) tested the non-steroidal MRA finer enone in HFmrEF and HFpEF. It found that it significantly reduced the risk of worsening HF and cardiovascular death, indicating potential benefits in these populations.

In the present study, researchers conducted an individual patient-level meta-analysis of four clinical trials to assess the effects of MRAs on clinical outcomes, including cardiovascular mortality. They also evaluated the safety and efficacy of MRAs in various subpopulations, such as those with high ejection fraction and kidney dysfunction.

About the study

The present study included data from four key trials: RALES, EMPHASIS-HF, TOPCAT, and FINEARTS-HF. A systematic review found no additional relevant trials. A total of 13,846 patients were included. The mean age of the patients was 69 years; 60% were male, and 83% were White.

The analysis focused on both steroidal MRAs (spironolactone, eplerenone) and non-steroidal MRAs (finerenone), covering key outcomes such as HF hospitalizations, cardiovascular death, and overall mortality.

Safety outcomes were assessed based on serum creatinine levels, estimated glomerular filtration rate (eGFR) decline, potassium levels, and blood pressure. The study also explored treatment effects in various subgroups, including those with different ejection fractions and renal function.

Sensitivity analyses were conducted to address potential biases, particularly in the TOPCAT trial, which had concerns about patient adherence and trial integrity. Statistical analysis involved the use of Cox proportional hazards models, negative binomial models, and logistic regression to estimate hazard ratios (HR), rate ratios, and odds ratios for various outcomes.

Results and discussion

MRAs were found to lower the risk of cardiovascular death or HF hospitalization (pooled HR 0.77). However, there was significant heterogeneity between the trials, with greater efficacy observed in the HFrEF trials (HR 0.66) compared to the HFmrEF and HFpEF trials (HR 0.87). This pattern was consistent across outcomes, including cardiovascular death, HF hospitalization, and all-cause death. The risk reduction for HF hospitalization was more pronounced in the HFrEF trials (HR 0.63) than in the HFmrEF and HFpEF trials (HR 0.82).

The study found no further heterogeneity within the HFrEF or HFmrEF and HFpEF groups. Despite the interaction between trial types, sensitivity analyses confirmed the robustness of the findings. Safety analysis showed that MRAs doubled the risk of moderate to severe hyperkalemia (increased potassium levels in the serum), although the absolute risk remained low. Conversely, MRAs halved the risk of hypokalemia. There was no significant heterogeneity in blood pressure outcomes between the trial groups, although hypotension was more common in the HFrEF trials.

The study did not conduct a direct comparison between steroidal and non-steroidal MRAs due to the observed interaction between trial types. Additionally, the study's limitations include the unavailability of variables, differing endpoints across trials, exclusion of smaller trials, high heterogeneity, evolving background care, and potential non-representativeness of real-world populations.

Conclusion

In conclusion, the present meta-analysis across four large clinical trials demonstrates that steroidal MRAs lower the risk of cardiovascular death or HF hospitalization in patients with HFrEF, while non-steroidal MRAs offer similar benefits for those with HFmrEF or HFpEF. As the protective effects of MRAs were found to be consistent across various patient subgroups, these findings encourage their consideration in the future as a standard treatment option for eligible patients with HF.