What is the initial treatment approach for heart failure with reduced ejection fraction, including dosages and timing of medications such as Angiotensin-Converting Enzyme (ACE) inhibitors, Angiotensin II Receptor Blockers (ARBs), beta-blockers, diuretics, and other therapies?

Treatment of Heart Failure with Reduced Ejection Fraction: Medication Dosages and Timing

The initial treatment approach for heart failure with reduced ejection fraction (HFrEF) should include four foundational drug classes: ACE inhibitors (or ARBs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors, with specific dosing regimens and titration schedules for each medication. 1

Core Medication Classes and Dosing

1. ACE Inhibitors

• Starting doses:
  • Lisinopril: 2.5-5 mg daily
  • Enalapril: 2.5 mg twice daily
  • Ramipril: 1.25 mg daily
  • Captopril: 6.25 mg three times daily 2
• Target doses:
  • Lisinopril: 20-40 mg daily
  • Enalapril: 10-20 mg twice daily
  • Ramipril: 10 mg daily
  • Captopril: 50 mg three times daily 2
• Administration timing: Doses should be taken consistently at the same time each day
• Monitoring: Check renal function and electrolytes 1-2 weeks after each dose increase 1

2. Beta-Blockers

• Starting doses:
  • Carvedilol: 3.125 mg twice daily
  • Metoprolol succinate: 12.5-25 mg daily
  • Bisoprolol: 1.25 mg once daily 2
• Target doses:
  • Carvedilol: 25 mg twice daily (for weight <85 kg) or 50 mg twice daily (for weight ≥85 kg)
  • Metoprolol succinate: 200 mg daily
  • Bisoprolol: 10 mg once daily 2
• Administration timing: Twice-daily dosing for carvedilol; once-daily dosing for metoprolol succinate and bisoprolol
• Titration: Increase dose every 2 weeks as tolerated 1

3. Mineralocorticoid Receptor Antagonists (MRAs)

• Starting doses:
  • Spironolactone: 12.5-25 mg daily
  • Eplerenone: 25 mg daily 2
• Target doses:
  • Spironolactone: 25-50 mg daily
  • Eplerenone: 50 mg daily 2
• Administration timing: Once daily dosing
• Monitoring: Check potassium and renal function regularly 1

4. SGLT2 Inhibitors

• Dosing:
  • Dapagliflozin: 10 mg daily
  • Empagliflozin: 10 mg daily 2
• Administration timing: Once daily dosing
• Monitoring: Regular monitoring of electrolytes and renal function 1

Alternative and Additional Medications

5. Angiotensin Receptor-Neprilysin Inhibitor (ARNI)

• Starting dose: Sacubitril/valsartan 49/51 mg twice daily 3
• Target dose: Sacubitril/valsartan 97/103 mg twice daily 3
• Administration timing: Twice daily dosing
• Titration: Double the dose after 2-4 weeks as tolerated 3
• Special considerations:
  • Requires 36-hour washout period when switching from ACE inhibitor
  • Start at half the recommended dose (24/26 mg twice daily) in patients not currently taking an ACE inhibitor/ARB or previously on low doses 3

6. Angiotensin II Receptor Blockers (ARBs)

• Starting doses:
  • Candesartan: 4-8 mg daily
  • Losartan: 25-50 mg daily
  • Valsartan: 40 mg twice daily 2
• Target doses:
  • Candesartan: 32 mg daily
  • Losartan: 150 mg daily
  • Valsartan: 160 mg twice daily 2
• Administration timing: Once daily for candesartan and losartan; twice daily for valsartan
• Note: Use as alternative when ACE inhibitors are not tolerated 1

7. Diuretics (for symptom relief)

• Loop diuretics:
  • Furosemide: Typically 20-40 mg daily initially, adjusted based on response
• Administration timing: Morning dosing preferred to avoid nighttime diuresis; may split into twice daily dosing if needed
• Dose adjustment: Adjust according to volume status 1

Medication Initiation and Titration Algorithm

1. Initial Assessment:

   • Evaluate baseline renal function, electrolytes, blood pressure, and heart rate

2. First-line Therapy:

   • Start ACE inhibitor (or ARB if intolerant) at low dose
   • Start beta-blocker at low dose
   • Add diuretic if fluid overload present

3. Titration Phase:

   • Increase ACE inhibitor/ARB dose every 2-4 weeks to target dose
   • Increase beta-blocker dose every 2 weeks to target dose
   • Monitor blood pressure, heart rate, renal function, and electrolytes

4. Additional Therapy:

   • Add MRA when patient reaches LVEF ≤35% or has persistent symptoms
   • Add SGLT2 inhibitor regardless of diabetes status

5. Advanced Options:

   • Consider switching from ACE inhibitor/ARB to ARNI in patients with persistent symptoms
   • Consider ivabradine if heart rate remains >70 bpm despite maximally tolerated beta-blocker dose

Special Considerations

• Renal impairment: Start at half the recommended dose for patients with severe renal impairment (eGFR <30 mL/min/1.73m²) 3
• Hepatic impairment: Start at half the recommended dose for moderate hepatic impairment; avoid use in severe hepatic impairment 3
• Hypotension risk: Monitor blood pressure closely when initiating or titrating medications
• Drug interactions: Avoid concomitant use of ACE inhibitors with ARNIs; allow 36-hour washout period when switching 3

Common Pitfalls to Avoid

• Underdosing: Many patients remain on suboptimal doses; aim for target doses or maximally tolerated doses
• Inappropriate discontinuation: Don't stop medications due to mild asymptomatic hypotension or mild increases in creatinine
• Failure to monitor: Regular monitoring of renal function and electrolytes is essential, especially during titration
• Neglecting combination therapy: The four foundational drug classes have complementary mechanisms and should be used together when possible
• Delaying ARNI initiation: Consider early transition to ARNI in appropriate patients as it has shown superior outcomes compared to ACE inhibitors alone 4

The evidence strongly supports that optimal medical therapy with these medications at target doses significantly improves mortality, reduces hospitalizations, and enhances quality of life in patients with HFrEF.