The PARADIGM-HF trial compared which agent against enalapril to show superiority?

• A. Sacubitril/valsartan
• B. Candesartan
• C. Lisinopril
• D. Enalapril

Answer: (A)

In heart failure with reduced ejection fraction, this question assesses whether a neprilysin inhibitor combined with an angiotensin receptor blocker provides better outcomes than an ACE inhibitor. In the PARADIGM-HF trial, sacubitril/valsartan was directly compared with enalapril in patients with NYHA class II–IV HFrEF. The study showed a meaningful improvement with sacubitril/valsartan: roughly a 20% relative reduction in the primary outcome of cardiovascular death or heart failure hospitalization, and a reduction in cardiovascular mortality overall, compared with enalapril.

The reason this combination works better lies in its dual mechanism. Valsartan blocks the angiotensin II receptor, reducing harmful neurohormonal activation and remodeling. Sacubitril inhibits neprilysin, increasing levels of natriuretic peptides, which promote vasodilation, natriuresis, and anti-remodeling effects. Together, these actions provide superior benefits over an ACE inhibitor like enalapril, which explains why sacubitril/valsartan outperformed enalapril in the trial.