In heart failure with reduced ejection fraction, which disease-modifying therapies have mortality/morbidity benefit?

• A. ACE inhibitors or ARBs, beta-blockers, and mineralocorticoid receptor antagonists; ARNI can be used in eligible patients
• B. Calcium channel blockers, digoxin, diuretics
• C. Hydralazine alone
• D. Digoxin alone

Answer: (A)

Blockade of neurohormonal pathways that drive heart failure progression is what changes outcomes in reduced ejection fraction. Guideline-directed therapies that have proven mortality and morbidity benefits target these systems: renin–angiotensin system blockade (ACE inhibitors or ARBs), beta-adrenergic blockade, and mineralocorticoid receptor antagonism, with sacubitril/valsartan (an ARNI) used in eligible patients. ACE inhibitors or ARBs slow remodeling and reduce deaths and hospitalizations; beta-blockers also cut mortality and sudden death while improving functional status; mineralocorticoid receptor antagonists further reduce deaths and hospitalizations in this population. When eligible, ARNI provides additional benefit by augmenting the natriuretic peptide system and has shown superior outcomes compared with an ACE inhibitor in key trials.

Other therapies in common use for symptomatic relief do not change long-term survival in this condition. Calcium channel blockers do not confer disease-modifying mortality benefit and can worsen hemodynamics in some patients. Digoxin may improve symptoms and reduce hospitalizations in some contexts but does not reduce mortality. Diuretics relieve congestion but do not alter disease progression. Hydralazine alone lacks demonstrated mortality benefit, though hydralazine with nitrates has shown benefit in select groups when used appropriately.