What is the guideline-directed medical treatment (GDMT) for heart failure with reduced ejection fraction (HFrEF)?

Guideline-Directed Medical Therapy for Heart Failure with Reduced Ejection Fraction (HFrEF)

The cornerstone of HFrEF management consists of four essential medication classes: angiotensin receptor-neprilysin inhibitor (ARNI) or angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB), beta-blocker, mineralocorticoid receptor antagonist (MRA), and sodium-glucose cotransporter-2 inhibitor (SGLT2i), all of which should be initiated and titrated to target doses to reduce mortality and morbidity. 1, 2

Core Medication Classes and Sequence

First-Line Medications

1. ARNI/ACEI/ARB

   • First choice: Sacubitril/valsartan (ARNI) for NYHA class II-III symptoms 2
   • Alternative if ARNI not feasible: ACEI (enalapril, lisinopril, ramipril) 2
   • Alternative if ACEI causes cough/angioedema: ARB (candesartan, losartan, valsartan) 2
   • Starting/target doses:
     • Sacubitril/valsartan: 24/26-49/51 mg twice daily → 97/103 mg twice daily 1
     • Enalapril: 2.5 mg twice daily → 10-20 mg twice daily 1

2. Beta-Blockers

   • Evidence-based options: Carvedilol, metoprolol succinate, bisoprolol 2
   • Starting/target doses:
     • Carvedilol: 3.125 mg twice daily → 25 mg twice daily (weight <85 kg) or 50 mg twice daily (weight ≥85 kg) 1
     • Metoprolol succinate: 12.5-25 mg daily → 200 mg daily 1
     • Bisoprolol: 1.25 mg once daily → 10 mg once daily 1

3. MRAs

   • Options: Spironolactone or eplerenone 2
   • Starting/target doses:
     • Spironolactone: 12.5-25 mg daily → 25-50 mg daily 1
     • Eplerenone: 25 mg daily → 50 mg daily 1

4. SGLT2 Inhibitors

   • Options: Dapagliflozin or empagliflozin 1, 2
   • Starting/target doses:
     • Dapagliflozin: 10 mg daily → 10 mg daily 1
     • Empagliflozin: 10 mg daily → 10 mg daily 1

Additional Therapies for Specific Populations

• African American patients: Consider isosorbide dinitrate plus hydralazine 3

  • Starting dose: 20 mg/37.5 mg (1 tablet) three times daily
  • Target dose: 40 mg/75 mg (2 tablets) three times daily 1

• Patients with elevated heart rate (>70 bpm) in sinus rhythm: Consider ivabradine 1, 3

  • Starting dose: 2.5-5 mg twice daily
  • Target dose: Titrate to heart rate 50-60 bpm (maximum 7.5 mg twice daily) 1

Implementation Strategy

Initiation Approach

1. For patients with volume overload:

   • Start with diuretics for symptom relief 2
   • Once euvolemic, begin core disease-modifying therapies

2. For euvolemic patients:

   • Medications may be started simultaneously at low doses or sequentially 2
   • Use a "forced titration strategy" similar to landmark trials 1, 2

Titration Strategy

1. Start at low doses and titrate gradually to target doses as tolerated 2
2. Aim for target doses used in clinical trials whenever possible 1, 2
3. Monitor closely during titration:
   • Blood pressure, heart rate, renal function, electrolytes 2
   • Assess for signs of worsening heart failure 2

Common Pitfalls and Challenges

Suboptimal Dosing

• Only 1% of eligible patients receive target doses of all recommended medications 4
• Many clinicians maintain patients on starting doses indefinitely 1
• Solution: Use a structured titration protocol with scheduled follow-ups 1

Medication Underutilization

• In contemporary practice, 27% of eligible patients don't receive ACEI/ARB/ARNI, 33% don't receive beta-blockers, and 67% don't receive MRAs 4
• Solution: Implement systematic medication review at each visit 2

Inappropriate Medication Combinations

• Avoid: Combining ARB with ACEI and MRA (increased risk of renal dysfunction and hyperkalemia) 2
• Avoid: Calcium channel blockers like diltiazem or verapamil (risk of worsening heart failure) 2

Monitoring Requirements

• Regular assessment of:
  • Renal function and electrolytes (especially with ACEI/ARB/ARNI and MRAs)
  • Blood pressure (particularly with ARNI due to hypotension risk) 5
  • Clinical response and medication adherence 2

Special Considerations

Switching from ACEI/ARB to ARNI

• For patients who remain symptomatic on optimal ACEI/ARB therapy, consider switching to ARNI 2
• When switching from ACEI to ARNI, allow a 36-hour washout period to reduce angioedema risk 5

Renal Function Monitoring

• For MRAs: Serum creatinine should be ≤2.5 mg/dL in men and ≤2.0 mg/dL in women; serum potassium <5.0 mEq/L 3, 6
• Monitor renal function and electrolytes closely, especially during initiation and dose titration 2

Continuation Despite EF Improvement

• Continue therapy even if EF improves to >40% 2

By implementing this comprehensive GDMT approach, clinicians can significantly reduce mortality and morbidity in patients with HFrEF, with the number needed to treat to prevent one death at 12 months being 63 (35-314) for ACEI therapy alone 7.