RALES and EMPHASIS-HF: MRA Significantly Reduces Risk in Patients With HF and Advanced CKD

Mineralocorticoid receptor antagonists (MRAs) reduce the risk of cardiovascular death or heart failure (HF) hospitalization in patients with both HF with reduced ejection fraction (HFrEF) and a decreased glomerular filtration rate (eGFR) <30 ml/min/1.73 m2, according to an analysis of patient data from the RALES and EMPHASIS-HF trials. The results were presented at ESC Heart Failure 2024 and simultaneously published in JACC.

The RALES trial in 1996 randomized patients with a left ventricular EF (LVEF) ≤35% and severe HF symptoms despite treatment with an ACE inhibitor to either spironolactone 25 mg daily (moving eventually to 50 mg at eight weeks) or placebo. The EMPHASIS-HF trial in 2010 randomized patients with a LVEF ≤35% to either eplerenone (up to 50 mg daily) or placebo.

Authors Shingo Matsumoto, MD, PhD, et al., found that 295 (6.8%) of the combined 4,355 patients, experienced deterioration of eGFR (to <30 ml/min/1.73 m2) at least once after randomization into either the treatment group (8.6% of the group) or control group (5.0% of the group) (OR, 1.80; 95% CI, 1.41-2.30; p<0.001), down to a level at which MRAs are not recommended. These patients also had a higher overall risk of the primary outcome of time to first occurrence of cardiovascular death or HF hospitalization (HR, 2.49; 95% CI, 2.01-3.08; p<0.001), as well as more impaired cardiac and kidney function compared to those who did not experience eGFR deterioration others (eGFR 47.313.4 mL/min/1.73 m2 vs. 70.521.8 mL/min/1.73 m2).

However, in the MRA treatment group, the occurrence of the primary outcome was similar in those with decreased eGFR (HR, 0.65; 95% CI, 0.43-0.99) and without (HR, 0.63; 95% CI, 0.56-0.71) (Pinteraction = 0.87). Furthermore, 21 fewer individuals (per 100 person-years) in the decreased eGFR group experienced the primary outcome with MRA treatment compared to placebo, compared with an excess of three more patients with severe hyperkalemia (>6.0 mmol/L).

In an accompanying editorial comment in JACC, Charles J. Ferro, MD, and Jonathan N. Townend, MD, called the results "practice changing."

"There is accumulating evidence that discontinuing prognostically important drugs in patients with HF when the eGFR falls below 30 mL/min/1.73 m2 is not advisable and lead to premature mortality and hospitalization," they wrote. "This is particularly poignant given the considerably greater absolute risk reductions observed in these patients." They suggest that clinicians may consider continuation of the medication accompanied by frequent blood tests for eGFR and potassium, as well as close monitoring for other signs of hyperkalemia.

This was just one of the studies simultaneously published in JACC and presented at ESC Heart Failure 2024. Read here for more.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: Mineralocorticoid Receptor Antagonists, Spironolactone, Eplerenone, Heart Failure, Glomerular Filtration Rate, Hyperkalemia, Renal Insufficiency, Chronic, Kidney, Angiotensin-Converting Enzyme Inhibitors, Acute Kidney Injury

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