A 58-year-old man with a 3-year history of dilated cardiomyopathy (LVEF 28%) presents to the outpatient clinic. He is currently on lisinopril 10 mg daily and metoprolol 50 mg twice daily. Despite optimal dosing for 6 months, his symptoms have worsened: he reports orthopnea, paroxysmal nocturnal dyspnea, and reduced exercise tolerance (NYHA Class III). Echocardiography confirms LVEF remains 25–30%. His renal function is normal (creatinine 0.9 mg/dL), potassium 4.2 mEq/L, and blood pressure 110/70 mmHg. Which of the following drugs should be added next to reduce mortality and hospitalizations in this patient?

Explanation

## Clinical Context This patient has symptomatic heart failure with reduced ejection fraction (HFrEF, LVEF <35%) on guideline-directed medical therapy (GDMT) with an ACE inhibitor and beta-blocker. The next step is to add a second-line neurohormonal antagonist. ## Why Sacubitril/Valsartan is Correct **Key Point:** Sacubitril/valsartan (ARNI — angiotensin receptor neprilysin inhibitor) is the preferred replacement for ACE inhibitors/ARBs in symptomatic HFrEF patients, especially those with persistent symptoms despite optimal ACE-I/ARB and beta-blocker therapy. **High-Yield:** The PARADIGM-HF trial demonstrated that sacubitril/valsartan reduces mortality and hospitalizations by ~20% compared to enalapril in HFrEF. It is now Class 1 recommendation in major guidelines (ACC/AHA, ESC) for HFrEF. **Clinical Pearl:** Sacubitril/valsartan works via dual mechanism: 1. **Valsartan** — ARB (blocks AT1 receptor) 2. **Sacubitril** — neprilysin inhibitor (increases natriuretic peptides, promoting vasodilation and natriuresis) This combination is superior to ACE-I monotherapy because neprilysin inhibition augments the beneficial effects of natriuretic peptides while the ARB blocks harmful angiotensin signaling. **Mnemonic:** **ARNI = ARB + Neprilysin Inhibitor** — remember it replaces, not adds to, the ACE-I/ARB. ## Mechanism of Benefit in HFrEF - Reduces afterload and preload - Improves cardiac remodeling - Reduces aldosterone secretion - Decreases sympathetic tone - Proven mortality reduction in NYHA Class II–IV HFrEF ## Dosing Note Sacubitril/valsartan is typically started at 49/51 mg twice daily (or 24/26 mg in renal impairment/hypotension) and titrated to 97/103 mg twice daily as tolerated. The patient's current lisinopril should be discontinued before initiating ARNI (washout period not required, but avoid dual RAAS blockade).