What are the best medications for Congestive Heart Failure with Reduced Ejection Fraction (CHFREF)?

Best Medications for Heart Failure with Reduced Ejection Fraction (HFrEF)

The optimal treatment for HFrEF consists of four foundational medications started simultaneously or in rapid sequence: an ARNI (sacubitril/valsartan), a beta-blocker (bisoprolol, carvedilol, or metoprolol succinate), a mineralocorticoid receptor antagonist (spironolactone or eplerenone), and an SGLT2 inhibitor (dapagliflozin or empagliflozin). 1

Core Quadruple Therapy

First-Line Medications (Start These Together)

ARNI (Sacubitril/Valsartan):

• Start sacubitril/valsartan 49/51 mg twice daily if previously on high-dose ACE inhibitor, or 24/26 mg twice daily if on low/medium-dose ACE inhibitor, ARB, or treatment-naïve. 1, 2
• Titrate by doubling the dose every 2-4 weeks to target dose of 97/103 mg twice daily as tolerated. 1, 3
• Mandatory 36-hour washout period when switching from ACE inhibitor to avoid angioedema. 1, 2
• No washout needed when switching from ARB. 3
• Reduces cardiovascular death and HF hospitalization more effectively than ACE inhibitors. 1, 3

Beta-Blockers:

• Use only bisoprolol, carvedilol, or metoprolol succinate (sustained-release). 1
• Start at low doses and titrate slowly over weeks to months to target doses. 4
• Bisoprolol: start 1.25 mg daily, target 10 mg daily. 1
• Carvedilol: start 3.125 mg twice daily, target 25-50 mg twice daily. 1
• Metoprolol succinate: start 12.5-25 mg daily, target 200 mg daily. 1
• Better tolerated when patient is less congested ("dry"). 1

Mineralocorticoid Receptor Antagonists (MRAs):

• Use spironolactone or eplerenone. 1
• Spironolactone: start 12.5-25 mg daily, target 25-50 mg daily. 1
• Eplerenone: start 25 mg daily, target 50 mg daily. 1
• Discontinue if potassium cannot be maintained <5.5 mEq/L despite management. 1
• Monitor renal function and electrolytes closely. 3

SGLT2 Inhibitors:

• Use dapagliflozin 10 mg daily or empagliflozin 10 mg daily. 1
• Both have Class I/1A recommendations with proven mortality and hospitalization benefits. 1
• Effective regardless of diabetes status. 1

Initiation Strategy

Start ARNI/ACE inhibitor and beta-blocker simultaneously or in rapid sequence—do not wait to achieve target doses before starting the next medication. 1 ARNI is often better tolerated when patient is still congested, while beta-blockers work better when less congested. 1 Titrate all medications to target doses every 2 weeks as tolerated. 1, 3

Additional Therapies for Specific Populations

Hydralazine/Isosorbide Dinitrate:

• Strongly recommended (Class 1A) for Black patients with HFrEF who remain symptomatic despite optimal therapy. 1
• Hydralazine 25 mg three times daily titrated to 75 mg three times daily. 1
• Isosorbide dinitrate 20 mg three times daily titrated to 40 mg three times daily. 1
• May be considered (Class 2b) for non-Black patients intolerant to ACE inhibitors/ARBs/ARNI, though evidence is limited. 1

Ivabradine:

• Add when resting heart rate ≥70 bpm despite maximally tolerated beta-blocker doses. 1
• Start 2.5-5 mg twice daily, titrate to heart rate 50-60 bpm, maximum 7.5 mg twice daily. 1

Diuretics:

• Use loop diuretics to relieve congestion and symptoms. 1
• Not mortality-reducing but essential for symptom management. 1
• Consider combination with thiazide diuretic for refractory congestion. 1

Critical Dosing Considerations

For patients with severe renal impairment, moderate hepatic impairment (Child-Pugh B), or age ≥75 years: start sacubitril/valsartan at 24/26 mg twice daily. 1, 3, 2

For patients with borderline blood pressure (systolic BP ≤100 mmHg): start with lowest dose and monitor closely, but do not withhold therapy based on asymptomatic hypotension alone. 3 Consider temporarily reducing diuretic doses in non-congested patients when initiating ARNI due to enhanced natriuresis. 3

Common Pitfalls to Avoid

• Do not fail to titrate to target doses due to asymptomatic hypotension or mild laboratory changes. 3
• Do not permanently reduce doses when temporary reduction with subsequent re-titration would be appropriate. 3
• Do not use ACE inhibitors when ARNI is available and tolerated—ARNI is superior. 1, 3
• Do not use ARBs as first-line therapy; reserve for patients who cannot tolerate ARNI or ACE inhibitors. 1
• Do not use nebivolol or other beta-blockers besides bisoprolol, carvedilol, or metoprolol succinate—only these three have proven mortality benefit. 1

Monitoring Requirements

Monitor blood pressure, renal function, and electrolytes within 1-2 weeks after initiation and with each dose increase. 3 Symptomatic hypotension can usually be managed through patient education without reducing HF pharmacotherapy. 3