What is the recommended initial regimen for managing heart failure with reduced ejection fraction (HFrEF)?

Initial Regimen for Heart Failure with Reduced Ejection Fraction (HFrEF)

Start all four foundational medication classes simultaneously as soon as possible after diagnosis: an SGLT2 inhibitor, a mineralocorticoid receptor antagonist (MRA), a beta-blocker, and an ARNI (or ACE inhibitor/ARB if ARNI not tolerated), along with diuretics for volume management. 1, 2, 3

The Four-Pillar Approach

The 2022 ACC/AHA/HFSA guidelines represent a paradigm shift from sequential therapy to immediate quadruple therapy initiation. 1 This approach prioritizes rapid implementation over achieving target doses, as early benefits occur even with low doses of these medications. 4

First-Line Medications (Start Simultaneously)

1. SGLT2 Inhibitors (Dapagliflozin or Empagliflozin)

• Initiate immediately regardless of diabetes status 1
• Reduces cardiovascular death and HF hospitalization with minimal blood pressure effect, making it ideal as a first agent 2
• Dapagliflozin 10 mg once daily or Empagliflozin 10 mg once daily 1

2. Mineralocorticoid Receptor Antagonist (MRA)

• Spironolactone 12.5-25 mg once daily or Eplerenone 25 mg once daily 1
• Provides at least 20% mortality reduction and reduces sudden cardiac death 2
• Minimal blood pressure effect allows early initiation 2
• Target dose: Spironolactone 25 mg once or twice daily; Eplerenone 50 mg once daily 1

3. Beta-Blocker (Evidence-Based Only)

• Carvedilol 3.125 mg twice daily, Metoprolol succinate 12.5-25 mg once daily, or Bisoprolol 1.25 mg once daily 1
• Reduces mortality by at least 20% and decreases sudden cardiac death 2
• Target doses: Carvedilol 50 mg twice daily, Metoprolol succinate 200 mg once daily, Bisoprolol 10 mg once daily 1

4. ARNI (Sacubitril/Valsartan) - Preferred Over ACE Inhibitors

• Sacubitril/valsartan 49/51 mg twice daily for most patients 1, 5
• 24/26 mg twice daily for patients with severe renal impairment (eGFR <30), moderate hepatic impairment, elderly ≥75 years, or low blood pressure 5, 6
• Provides superior mortality reduction of at least 20% compared to ACE inhibitors 2
• Target dose: 97/103 mg twice daily 1, 5

Alternative if ARNI not tolerated:

• ACE Inhibitors: Enalapril 2.5 mg twice daily, Lisinopril 2.5-5 mg once daily, or Ramipril 1.25-2.5 mg once daily 1
• Target doses: Enalapril 10-20 mg twice daily, Lisinopril 20-40 mg once daily, Ramipril 10 mg once daily 1

5. Diuretics (For Volume Management)

• Furosemide 20-40 mg once or twice daily, Torsemide 10-20 mg once daily, or Bumetanide 0.5-1.0 mg once or twice daily 2
• Essential for congestion control but do not reduce mortality 2
• Adjust dose based on volume status 1

Titration Strategy

Up-titrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved. 2, 3

Recommended Sequence:

1. Start SGLT2 inhibitor and MRA first (minimal BP effect) 2
2. Add beta-blocker or very low-dose ARNI 2
3. Titrate each medication every 2-4 weeks as tolerated 1, 6

Critical Switching Considerations

If switching from ACE inhibitor to ARNI:

• Mandatory 36-hour washout period to avoid angioedema 5, 1
• No washout needed when switching from ARB 6, 5

If switching from ARB to ARNI:

• Can switch immediately without washout 6
• All HFrEF patients on ARBs are candidates without needing to "fail" optimal therapy first 6

Managing Common Barriers

Hypotension

• Do not withhold therapy for asymptomatic low BP with adequate perfusion 2, 3
• Asymptomatic hypotension is expected and beneficial with guideline-directed therapy 3, 6
• If symptomatic hypotension occurs, reduce diuretic dose first, not life-saving medications 3
• ARNI maintains efficacy even with systolic BP <110 mmHg 6

Hyperkalemia

• Adjust MRA dose and use potassium binders rather than discontinuing ARNI or beta-blocker 3
• Monitor potassium within 1-2 weeks of initiation 1
• Serum potassium should be <5.0 mEq/L before starting MRA 7

Renal Dysfunction

• Mild creatinine elevation (<0.5 mg/dL increase) is acceptable and does not require dose adjustment 6
• Serum creatinine should be ≤2.5 mg/dL in men and ≤2.0 mg/dL in women for MRA 7

Additional Therapies for Specific Subgroups

For Self-Identified Black Patients with NYHA Class III-IV:

• Hydralazine 25 mg three times daily + Isosorbide dinitrate 20 mg three times daily 2
• Target: Hydralazine 75 mg three times daily + Isosorbide dinitrate 40 mg three times daily 1

For Persistent Symptoms Despite Optimal Therapy:

• Ivabradine 5 mg twice daily if heart rate ≥70 bpm in sinus rhythm despite maximally tolerated beta-blocker 1, 2
• Target: 7.5 mg twice daily 1

Critical Contraindications

• Never combine ACE inhibitor with ARNI (angioedema risk) 5, 1
• Avoid triple combination of ACE inhibitor + ARB + MRA (hyperkalemia and renal dysfunction) 2, 1
• History of angioedema is absolute contraindication to ACE inhibitors and relative contraindication to ARBs 1
• Pregnancy is absolute contraindication to ARNI, ACE inhibitors, and ARBs 5, 1

Common Pitfalls to Avoid

• Delaying initiation of all four medication classes simultaneously 2
• Accepting suboptimal doses without attempting titration 2, 4
• Stopping medications for asymptomatic hypotension rather than reducing diuretics 2, 3
• Using non-evidence-based beta-blockers (only carvedilol, metoprolol succinate, and bisoprolol proven effective) 2
• Inadequate monitoring of renal function and potassium 2
• Waiting for patients to "fail" therapy before switching from ACE inhibitor/ARB to ARNI 6

Blood Pressure Targets

Target systolic blood pressure <130 mm Hg in patients with HFrEF and hypertension using guideline-directed medical therapy. 1