Safety and Tolerability of the Novel Non-Steroidal Mineralocorticoid Receptor Antagonist BAY 94-8862 in Patients With Chronic Heart Failure and Mild or Moderate Chronic Kidney Disease: A Randomized, Double-Blind Trial

Study Questions:

What is the safety and tolerability of BAY 94-8862, a next-generation nonsteroidal mineralocorticoid receptor antagonist (MRA) with improved selectivity for the mineralocorticoid receptor (MR) over other steroid hormone receptor, compared with spironolactone 25-50 mg/day, in patients with chronic heart failure (HF) and a reduced left ventricular ejection fraction (HFrEF) with New York Heart Association class II-III symptoms and mild to moderate chronic kidney disease (CKD)?

Methods:

ARTS (minerAlocorticoid Receptor Antagonist Tolerability Study) was a multicenter, international, randomized, parallel-group, phase II study conducted in two parts. In part A, the safety and tolerability of oral BAY 94-8862 in patients with HFrEF and mild CKD (estimated glomerular filtration rate [eGFR] 60 to <90 ml/min/1.73 m2) was compared to those taking placebo by determining the effects on serum potassium concentration, eGFR, and albuminuria. In part B, BAY 94-8862 was compared with placebo and open-label spironolactone in 392 patients with HFrEF and moderate CKD (eGFR 30 to <60 ml/min/1.73 m2). The primary endpoint in part B was the change in serum potassium concentration. The impact of BAY 94-8862 on systolic blood pressure and B-type natriuretic peptide (BNP) was also assessed. In both parts of the study, patients received the study drug for 4 weeks.

Results:

The mean increases in serum potassium concentration were significantly smaller in all four BAY 94-8862 dose groups than in the spironolactone group. Compared to spironolactone, BAY 94-8862 was associated with lower incidences of hyperkalemia (5.3% and 12.7%, respectively, p = 0.048) and worsening renal function. BAY 94-8862 decreased the levels of BNP at least as much as did spironolactone.

Conclusions:

BAY 94-8862, a next-generation nonsteroidal MRA, is at least as effective as spironolactone in decreasing serum BNP, and is associated with lower incidences of hyperkalemia and worsening renal function.

Perspective:

The first randomized clinical trial of BAY 94-8862 shows promise for this next-generation nonsteroidal MRA. These phase II results should pave the way for future clinical studies that continue to elucidate the potential clinical benefits of this therapy in HFrEF.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Receptors, Mineralocorticoid, Heart Failure, Stroke Volume, Hyperkalemia, Blood Pressure, Spironolactone, Renal Insufficiency, Chronic, Naphthyridines, Natriuretic Peptide, Brain


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