What is the role of sacubitril/valsartan in HFrEF and what trial supports it?

• A. An ARNI with mortality benefit; PARADIGM-HF showed superiority over enalapril.
• B. A thiazide diuretic; SOLVD trial showed improvement.
• C. An ACE inhibitor; HOPE trial
• D. A calcium channel blocker; ACCP trial

Answer: (A)

Sacubitril/valsartan is an ARNI, combining neprilysin inhibition with angiotensin receptor blockade. Neprilysin inhibition raises natriuretic peptides, producing vasodilation, natriuresis, and anti-remodeling effects, while the valsartan component blocks angiotensin II’s harmful actions. Together, this improves outcomes in HFrEF beyond what ACE inhibitors alone provide.

This benefit was shown in the PARADIGM-HF trial, which compared sacubitril/valsartan with enalapril in about 8,400 patients with symptomatic heart failure and reduced ejection fraction. It demonstrated a relative reduction around 20% in the primary outcome of cardiovascular death or heart failure hospitalization, and also lowered all-cause mortality, establishing superiority over an ACE inhibitor. Because of this, guidelines endorse using sacubitril/valsartan in eligible patients to improve outcomes, with a required washout period when switching from an ACE inhibitor to minimize angioedema risk.