What is the initial treatment for heart failure with reduced ejection fraction (HFrEF) using Guideline-Directed Medical Therapy (GDMT)?

Initial Treatment for Heart Failure with Reduced Ejection Fraction (HFrEF) Using GDMT

The initial treatment for heart failure with reduced ejection fraction (HFrEF) should include simultaneous initiation of all four core medication classes: ACE inhibitors/ARBs or preferably ARNI, beta-blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors. 1

Core Medication Classes and Recommendations

1. Renin-Angiotensin System Inhibition

• First-line option: Angiotensin Receptor-Neprilysin Inhibitor (ARNI)

  • Sacubitril/valsartan is recommended for patients with NYHA class II-III symptoms to reduce morbidity and mortality (Class 1, Level A) 2
  • Starting dose: 24/26 mg or 49/51 mg twice daily
  • Target dose: 97/103 mg twice daily 2, 3
  • Provides 20% further reduction in cardiovascular death and HF hospitalization compared to ACE inhibitors 1

• Alternative options (when ARNI not feasible):

  • ACE inhibitors (e.g., enalapril, lisinopril) (Class 1, Level A) 2
  • ARBs (e.g., valsartan, candesartan) for patients intolerant to ACE inhibitors due to cough or angioedema (Class 1, Level A) 2

2. Beta-Blockers

• Recommended for all HFrEF patients (Class 1, Level A) 2
• Only use evidence-based beta-blockers proven to reduce mortality:
  • Carvedilol: Start 3.125 mg twice daily, target 25 mg twice daily (<85 kg) or 50 mg twice daily (≥85 kg)
  • Metoprolol succinate: Start 12.5-25 mg daily, target 200 mg daily
  • Bisoprolol: Start 1.25 mg daily, target 10 mg daily 2, 1

3. Mineralocorticoid Receptor Antagonists (MRAs)

• Recommended for NYHA class II-IV symptoms (Class 1, Level A) 2
• Options:
  • Spironolactone: Start 12.5-25 mg daily, target 25-50 mg daily
  • Eplerenone: Start 25 mg daily, target 50 mg daily 2, 1, 4
• Use only if eGFR >30 mL/min/1.73 m² and serum potassium <5.0 mEq/L
• Requires careful monitoring of potassium and renal function 2

4. SGLT2 Inhibitors

• Recently added to core GDMT (Class 1) 2, 1
• Options:
  • Dapagliflozin: 10 mg daily
  • Empagliflozin: 10 mg daily 2, 1
• Effective regardless of diabetic status 1
• Improves health-related quality of life 1

Implementation Strategy

Initial Approach

1. Simultaneous initiation preferred over sequential addition 1

   • This comprehensive approach has shown a 19.2% relative improvement in composite care measures 1

2. Dose titration:

   • Start at lower doses for all medications
   • Titrate every 2-4 weeks to target doses as tolerated 2
   • Regular monitoring (every 1-2 weeks initially) of vital signs, volume status, renal function, and electrolytes 1

3. Special considerations for starting doses:

   • Reduce starting dose by half for patients:
     • Not currently on ACE inhibitor/ARB
     • Previously on low doses of these agents
     • With severe renal impairment
     • With moderate hepatic impairment 3

Monitoring and Follow-up

• Laboratory monitoring:

  • Renal function and electrolytes (particularly potassium) before initiation and 1-2 weeks after starting or titrating MRAs 2, 1
  • Regular blood pressure and heart rate monitoring

• Dose optimization:

  • Despite clear benefits, studies show significant underutilization of GDMT with only 1% of eligible patients receiving target doses of all medication classes 5
  • Heart failure clinic referral is associated with higher rates of GDMT initiation and optimization 6

Common Pitfalls and Considerations

1. Avoid inappropriate discontinuation during hospitalization:

   • Discontinuation or dose de-escalation of GDMT after heart failure hospitalization is associated with increased mortality risk 7
   • Ensure medications are restarted before discharge if temporarily held

2. Hypotension management:

   • If symptomatic hypotension occurs, consider adjusting diuretics before reducing GDMT doses
   • Prioritize maintaining GDMT at highest tolerated doses

3. Renal function concerns:

   • Mild-moderate increases in creatinine are expected and not a reason to discontinue therapy
   • Hold or reduce doses only for significant renal deterioration

4. Medication access:

   • Consider cost and insurance coverage, particularly for newer agents like ARNI and SGLT2 inhibitors
   • Patient assistance programs may be available

By implementing comprehensive GDMT with all four medication classes at optimal doses, mortality and hospitalization rates can be significantly reduced in patients with HFrEF.