In view of the difficulty to weight the risks and benefits of renal replacement therapy, the newly proposed quadruple therapy (39, 40) with angiotensin receptor neprilysin inhibitors (ARNI), β-blockers, mineralocorticoid receptor antagonists (MRA), and sodium-glucose cotransporter-2 (SGLT-2) inhibitors for the treatment of heart failure and reduced ejection fraction (HFrEF) may provide a long-term solution to significantly lower the rate of heart failure hospitalization and mortality in this population (41, 42). This evidence concerns the gene NR3C2 and heart failure.