In heart failure with reduced ejection fraction, which therapy adds mortality benefit when used with ACE inhibitors or ARBs and beta-blockers?

• A. Loop diuretics
• B. Nitrates
• C. Mineralocorticoid receptor antagonists
• D. Digoxin

Answer: (C)

The question tests which additional therapy provides a survival benefit when added to guideline-directed therapy (ACE inhibitors or ARBs plus beta-blockers) in heart failure with reduced ejection fraction.

Blocking the aldosterone receptor with a mineralocorticoid receptor antagonist delivers mortality benefit in this setting. Aldosterone promotes sodium retention, potassium loss, and myocardial and vascular fibrosis, driving worsening remodeling. By inhibiting its effects, MRAs reduce adverse remodeling, lower deaths, and decrease hospitalizations when patients are already on ACE inhibitors or ARBs and beta-blockers. This protective effect is supported by major trials like RALES (spironolactone) and EPHESUS (eplerenone), which demonstrated improved survival in patients with reduced ejection fraction.

The other options mainly address symptoms or have benefit in specific contexts but do not consistently show added mortality benefit when combined with ACE inhibitors or ARBs and beta-blockers. Loop diuretics relieve congestion without proven mortality reduction; digoxin helps symptoms and may reduce hospitalizations but does not reliably improve survival on top of full guideline therapy; nitrates (often with hydralazine) add mortality benefit in particular populations but not universally when added to standard therapy across all patients.