What is the recommended medication regimen for an adult with heart failure with reduced ejection fraction (LVEF ≤40%)?

Heart Failure with Reduced Ejection Fraction (LVEF ≤40%): Medication Regimen

All adults with HFrEF (LVEF ≤40%) should receive quadruple therapy consisting of an ACE inhibitor (or ARB/ARNI), beta-blocker, mineralocorticoid receptor antagonist (MRA), and SGLT2 inhibitor, as this combination provides the greatest reduction in cardiovascular death and heart failure hospitalization. 1, 2

Core Foundational Therapy (Four Pillars)

1. ACE Inhibitor or Angiotensin Receptor Blocker (ARB)

• ACE inhibitors are first-line to reduce all-cause and cardiovascular mortality and morbidity 1
• Use ARB only if ACE inhibitor is not tolerated due to cough or angioedema 1
• Target doses equivalent to enalapril 10 mg twice daily 1
• ARNI (sacubitril/valsartan) is superior to ACE inhibitors in patients already on stable ACE inhibitor therapy; target dose is 97/103 mg twice daily 3, 2
• When switching from ACE inhibitor to ARNI, allow 36-hour washout period to avoid angioedema 3

2. Beta-Blocker

• Recommended for all patients with LVEF <40% to reduce mortality and hospitalization 1
• Use one of three evidence-based agents: bisoprolol, carvedilol, or metoprolol succinate (sustained-release) 1
• Initiate even in patients with mild symptoms as soon as LV dysfunction is diagnosed 1
• Benefits apply to patients with or without coronary artery disease and with or without diabetes 1

3. Mineralocorticoid Receptor Antagonist (MRA)

• Spironolactone or eplerenone are recommended for all symptomatic patients with LVEF ≤35% despite ACE inhibitor and beta-blocker therapy 1
• Reduces all-cause and cardiovascular mortality and cardiovascular morbidity 1
• Contraindicated if serum creatinine >2.5 mg/dL in men or >2.0 mg/dL in women, or serum potassium >5.0 mmol/L 1
• Requires regular monitoring of potassium and renal function 1

4. SGLT2 Inhibitor

• Empagliflozin and dapagliflozin are the first drugs to improve outcomes across the full spectrum of LVEF 4, 2
• Should be initiated as first-line therapy alongside other foundational medications 5, 2
• Provides consistent benefit regardless of LVEF subgroup 2

Diuretics for Symptom Management

• Loop diuretics are recommended to reduce signs and symptoms of congestion in patients with fluid retention 1, 6
• Thiazides produce less intense but longer diuresis than loop diuretics; combination may be used for resistant edema but requires careful monitoring 1
• Aim for euvolemia with the lowest achievable dose; adjust based on individual needs over time 1
• In selected asymptomatic euvolemic patients, diuretics may be temporarily discontinued 1

Additional Therapy for Specific Populations

Self-Identified Black or African American Patients

• Hydralazine/isosorbide dinitrate combination is recommended for NYHA Class III-IV patients already on ACE inhibitor and beta-blocker 1
• Reduces morbidity and mortality in this population 1
• Must use isosorbide dinitrate specifically; other nitrate formulations do not meet evidence requirements 1

Medication Titration Strategy

Start all four foundational medications (ACE inhibitor/ARB/ARNI, beta-blocker, MRA, SGLT2 inhibitor) as soon as possible, targeting maximum tolerated doses of each agent 1, 5, 2

• Double doses every 2-4 weeks as tolerated 1, 3
• Monitor renal function, electrolytes, and blood pressure during initiation and titration 5
• The triple combination of ARNI, MRA, and SGLT2 inhibitor provides the most robust benefit (HR 0.56 for CV death and HF hospitalization) 2
• Adding beta-blocker to this triple therapy further reduces risk (HR 0.47) 2

Medications to Avoid

• Calcium channel blockers (verapamil, diltiazem) are absolutely contraindicated due to negative inotropic effects that worsen heart failure 1, 5, 6
• Nonsteroidal anti-inflammatory drugs should be avoided or withdrawn 6
• Most antiarrhythmic drugs should be avoided 6

Device Therapy Considerations

• ICD is recommended for LVEF ≤35% despite optimal medical therapy for at least 3 months with NYHA Class II-III symptoms and life expectancy >1 year 1
• Cardiac resynchronization therapy (CRT) is recommended for LVEF ≤35%, NYHA Class II-IV symptoms, and QRS ≥130 ms with LBBB in sinus rhythm 1

Common Pitfalls to Avoid

• Do not delay initiation of all four foundational medications; start them together rather than sequentially 1, 2
• Do not use ARB in addition to ACE inhibitor; ARB is only for ACE inhibitor intolerance 1
• Do not start MRA without checking baseline potassium and renal function 1
• Do not forget the 36-hour washout period when switching from ACE inhibitor to ARNI to prevent angioedema 3
• Do not use calcium channel blockers for rate control in atrial fibrillation; use beta-blockers and/or digoxin instead 1, 7