A 58-year-old man with hypertension and type 2 diabetes mellitus presents with dyspnea on exertion and orthopnea. Echocardiography reveals left ventricular ejection fraction (LVEF) of 35%. He is euvolemic on examination. What is the drug of choice for initiating therapy in this patient with heart failure with reduced ejection fraction (HFrEF)?

Explanation

## First-Line Therapy in HFrEF **Key Point:** ACE inhibitors (or ARBs if ACE-I intolerant) are the cornerstone of HFrEF management and should be initiated in all patients with reduced ejection fraction, regardless of symptoms or volume status. ### Mechanism of Benefit 1. **Neurohormonal modulation** — inhibit angiotensin II formation, reducing vasoconstriction and aldosterone secretion 2. **Reverse remodeling** — reduce left ventricular hypertrophy and fibrosis 3. **Mortality reduction** — landmark trials (CONSENSUS, SOLVD) demonstrated 20–30% reduction in mortality 4. **Symptom improvement** — decrease dyspnea and improve exercise tolerance ### Guideline Recommendation **High-Yield:** ACE inhibitors are **Class I, Level A** evidence for all patients with HFrEF (LVEF ≤40%), with or without symptoms [cite:Harrison 21e Ch 297]. ### Comparison with Other Options | Drug Class | Role in HFrEF | Evidence | |---|---|---| | **ACE-I / ARB** | First-line, all patients | Class I, Level A (mortality benefit) | | **Beta-blocers** | First-line, all patients | Class I, Level A (mortality benefit) | | **MRAs** | Second-line, add after ACE-I + BB | Class I, Level A (mortality benefit) | | **ARNI** | Alternative to ACE-I/ARB | Class I, Level A (superior to ACE-I) | | **Calcium channel blockers** | Avoid in systolic HF | No mortality benefit; may worsen HF | | **Digoxin** | Symptomatic relief only | No mortality benefit; arrhythmia risk | | **Hydralazine + nitrate** | Adjunctive in specific populations | Class IIb (African Americans, renal disease) | **Clinical Pearl:** In this euvolemic patient, ACE-I should be started immediately at low dose and titrated to target dose over weeks. Diuretics are reserved for volume overload; beta-blocers are added concurrently or sequentially. **Mnemonic — HFrEF Drug Ladder:** **ACE-BB-MRA** (ACE inhibitor → Beta-blocker → Mineralocorticoid receptor antagonist). ARNI may replace ACE-I/ARB at any step.