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Meta-Analysis of MRA Use in HF
Quick Takes
- MRA use compared to placebo in patients with HF reduces the risk of CV death or first HF hospitalization across the EF spectrum, with greater effects in HFrEF.
- MRA use reduces CV and all-cause death in HFrEF trials but not in the HFmrEF/HFpEF trials.
- MRA use increases the risk for hyperkalemia, but absolute risk of severe hyperkalemia is low.
Study Questions:
What is the association of mineralocorticoid receptor antagonist (MRA) use in clinical trials of patients with heart failure (HF) across the left ventricular ejection fraction (EF) spectrum?
Methods:
This is an individual patient-level meta-analysis combining data from four clinical trials of MRA use in patients with HF with reduced EF (HFrEF), HF with mildly reduced EF (HFmrEF), and/or HF with preserved EF (HFpEF). The trials included were RALES (spironolactone use in HFrEF), EMPHASIS-HF (eplerenone use in HFrEF), TOPCAT (spironolactone use in HFmrEF and HFpEF), and FINEARTS-HF (finerenone use in HFmrEF and HFpEF). The primary outcome examined was a composite of time to first HF hospitalization or cardiovascular (CV) death. Additional outcomes assessed were time to first HF hospitalization, CV death, total HF hospitalizations, total HF hospitalizations and CV death, and all-cause death.
Results:
A total of 13,846 patients were included across the four trials. For the primary outcome, MRA use compared to placebo reduced the risk of CV death or first HF hospitalization (hazard ratio, 0.77; 95% confidence interval, 0.72-0.83) across the EF spectrum. Notably, there was a significant interaction between trials and the effect of treatment (p for interaction = 0.0012), which was due to the greater treatment efficacy in the two HFrEF trials compared to the two HFmrEF/HFpEF trials.
For the additional outcomes, MRA use compared to placebo reduced the risk of HF hospitalization, total HF hospitalizations, and total HF hospitalizations and CV death across the EF spectrum. CV and all-cause death risk were reduced in the HFrEF trials but not in the HFmrEF/HFpEF trials. For the pertinent safety outcomes, risk of hyperkalemia (serum potassium >5.5 mmol/L) and severe hyperkalemia (>6.0 mmol/L) were more than doubled with MRA use compared to placebo. However, absolute risk of severe hyperkalemia was low (MRA 2.9%, placebo 1.4%).
Conclusions:
In this individual patient-level meta-analysis, MRA use compared to placebo reduced the risk of CV death or first HF hospitalization in patients with HF. Treatment effects were greater in the two HFrEF trials.
Perspective:
MRA use in HFrEF is well-established and is given strong recommendations in clinical guidelines. Use in HFmrEF and HFpEF is less clear given the debate surrounding the results of the TOPCAT trial. However, with the simultaneous publication of the FINEARTS-HF trial and this meta-analysis, there is renewed hope that MRAs can provide a valuable treatment option for patients with HFmrEF/HFpEF to reduce HF hospitalizations. While reducing CV and all-cause death remains elusive, this represents an important step forward. Key questions that remain include how generalizable these results are to the broader and very heterogenous HFmrEF/HFpEF patient population and how nonsteroidal MRAs (finerenone) compare to steroidal MRAs (spironolactone, eplerenone) across subgroups and EF ranges.
Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure
Keywords: Heart Failure, Hyperkalemia, Mineralocorticoid Receptor Antagonists
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