What are the best initial medications for Heart Failure with Reduced Ejection Fraction (HFrEF), including Angiotensin-Converting Enzyme (ACE) inhibitors, Angiotensin Receptor Blockers (ARBs), beta-blockers, and diuretics?

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

For patients with HFrEF, the four foundational medications that reduce mortality and morbidity are SGLT2 inhibitors, beta-blockers, mineralocorticoid receptor antagonists (MRAs), and either ACE inhibitors, ARBs, or ARNIs, with specific preferred agents in each class based on the strongest evidence.

First-Line Medications for HFrEF

1. SGLT2 Inhibitors

• Preferred agents: Dapagliflozin (10 mg once daily) or Empagliflozin (10 mg once daily) 1, 2
• Considerations:
  • Provide early mortality and hospitalization benefits
  • Can be started at target dose without titration
  • Safe to initiate even with lower blood pressure
  • Monitor for genital mycotic infections and volume depletion
  • Effective with eGFR ≥20-25 mL/min/1.73m² 3

2. Beta-Blockers

• Preferred agents: Only use one of the three evidence-based options 1, 2:
  • Carvedilol (start 3.125 mg twice daily, target 25-50 mg twice daily)
  • Bisoprolol (start 1.25 mg once daily, target 10 mg once daily)
  • Metoprolol succinate (start 12.5-25 mg once daily, target 200 mg once daily)
• Considerations:
  • Start at low doses and titrate gradually every 2 weeks
  • Avoid in acute decompensated heart failure until stabilized
  • Monitor for bradycardia, hypotension, and worsening HF symptoms
  • Bisoprolol may accumulate in renal impairment 3

3. Mineralocorticoid Receptor Antagonists (MRAs)

• Preferred agents: 1, 2
  • Spironolactone (start 12.5-25 mg once daily, target 25-50 mg once daily)
  • Eplerenone (start 25 mg once daily, target 50 mg once daily)
• Considerations:
  • Contraindicated if eGFR <30 mL/min/1.73m² or K+ >5.0 mEq/L 1
  • Monitor potassium and renal function closely, especially at initiation
  • Higher risk of hyperkalemia when combined with ACEi/ARB
  • In renal impairment, consider starting at lower doses (6.25-12.5 mg daily) 3

4. Renin-Angiotensin System Inhibitors

• Preferred agents in order of evidence:

  1. ARNi: Sacubitril/Valsartan (start 49/51 mg twice daily, target 97/103 mg twice daily) 2, 4
  2. ACE inhibitors: 1, 2
     • Lisinopril (start 2.5-5 mg once daily, target 20-40 mg once daily)
     • Enalapril (start 2.5 mg twice daily, target 10-20 mg twice daily)
     • Ramipril (start 1.25-2.5 mg once daily, target 10 mg once daily)
  3. ARBs: (if ACEi intolerant) 1
     • Candesartan (start 4-8 mg once daily, target 32 mg once daily)
     • Valsartan (when not using ARNi)

• Considerations:

  • ARNi is superior to ACEi but requires 36-hour washout when switching from ACEi 4
  • Monitor for hypotension, hyperkalemia, and worsening renal function
  • Start at lower doses in patients with low blood pressure, renal impairment, or not previously on ACEi/ARB
  • ARNi not recommended with eGFR <30 mL/min/1.73m² 3

Diuretics for Symptom Management

• Loop diuretics: 1
  • Furosemide (start 20-40 mg once or twice daily, max 600 mg daily)
  • Torsemide (start 10-20 mg once daily, max 200 mg daily)
  • Bumetanide (start 0.5-1.0 mg once or twice daily, max 10 mg daily)
• Considerations:
  • Not mortality-reducing but essential for congestion management
  • Titrate to achieve euvolemia and relieve symptoms
  • Use lowest effective dose to minimize electrolyte disturbances
  • Consider combination with thiazide for diuretic resistance

Implementation Strategy

1. Initiation approach: All four foundational medications can be started simultaneously at low doses rather than sequentially 1, 5

2. Prioritization if sequential approach needed:

   • Start with SGLT2i (can be initiated at target dose)
   • Add beta-blocker (start low, titrate slowly)
   • Add MRA (with careful monitoring)
   • Add ACEi/ARB or preferably ARNi (with appropriate washout if switching)

3. Titration strategy:

   • Aim to reach target doses of all medications
   • Schedule follow-up every 2-4 weeks for dose adjustments
   • Monitor blood pressure, heart rate, electrolytes, and renal function

Special Considerations

• Hypotension: Prioritize beta-blockers and SGLT2i if systolic BP <100 mmHg limits RAS inhibitor use 6
• Renal dysfunction: Use caution with MRAs if eGFR <30 mL/min/1.73m², avoid ARNi if eGFR <30 mL/min/1.73m² 3
• Hyperkalemia: Consider potassium binders to maintain RAS inhibitors and MRAs
• Atrial fibrillation: Beta-blockers particularly important for rate control

Common Pitfalls to Avoid

• Failure to initiate all four medication classes due to concerns about polypharmacy
• Inadequate dose titration due to minor side effects or mild laboratory abnormalities
• Discontinuing medications during temporary worsening rather than adjusting doses
• Using non-evidence-based beta-blockers (only use carvedilol, bisoprolol, or metoprolol succinate)
• Combining ACEi with ARB and MRA (high risk of renal dysfunction and hyperkalemia) 2
• Using medications that can worsen HF (NSAIDs, non-dihydropyridine calcium channel blockers, thiazolidinediones) 1, 2