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)?

Question

Accepted Answer

C. Enalapril. ## 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.

Answer

A. Amlodipine

Answer

B. Digoxin

Answer

D. Hydralazine

Explanation

First-Line Therapy in HFrEF

Mechanism of Benefit

Guideline Recommendation

Comparison with Other Options

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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)