What are the treatments for Heart Failure with Reduced Ejection Fraction (HFrEF) in stages A, B, C, and D?

Treatment of Heart Failure with Reduced Ejection Fraction (HFrEF) by Stages

The cornerstone of HFrEF management is stage-specific therapy, with quadruple therapy (ARNI/ACEi/ARB, beta-blockers, MRAs, and SGLT2 inhibitors) forming the foundation for symptomatic patients to reduce mortality and hospitalizations. 1

Stage A: At Risk for Heart Failure

Risk Factor Management

• Control hypertension using evidence-based antihypertensive therapy 1, 2
• Manage lipid disorders with statin therapy, especially for patients with history of MI 2
• Treat diabetes preferentially with SGLT2 inhibitors that have demonstrated cardiovascular benefit 2
• Lifestyle modifications:
  • Weight management for obesity
  • Smoking cessation
  • Regular physical activity
  • Moderate alcohol intake

Stage B: Structural Heart Disease without Symptoms

Pharmacological Therapy

• ACE inhibitors for all patients with reduced EF, especially those with history of MI 1
• Beta-blockers for all patients with reduced EF, particularly those with prior MI 1
• ARBs as alternatives for patients who cannot tolerate ACE inhibitors 1
• Statins for all patients with history of MI 2
• SGLT2 inhibitors for patients with type 2 diabetes to reduce risk of hospitalization 2

Device Therapy

• ICD for primary prevention in selected patients with LVEF ≤30% and NYHA class I symptoms at least 40 days post-MI 1

Stage C: Structural Heart Disease with Current or Prior Symptoms

Core Pharmacological Therapy (Quadruple Therapy)

1. ARNI/ACEi/ARB:

   • Sacubitril/valsartan (ARNI) is preferred over ACE inhibitors when possible 1
   • Starting dose: 49/51 mg BID; target dose: 97/103 mg BID 1
   • If ARNI not feasible, use ACE inhibitor (e.g., enalapril 2.5 mg BID; target 10-20 mg BID) 1
   • ARBs (e.g., valsartan 40 mg BID; target 160 mg BID) if ACE inhibitor not tolerated 1

2. Beta-blockers:

   • Use only evidence-based agents: carvedilol, metoprolol succinate, or bisoprolol 1
   • Starting doses: carvedilol 3.125 mg BID; metoprolol succinate 12.5-25 mg daily; bisoprolol 1.25 mg daily 1
   • Target doses: carvedilol 25-50 mg BID; metoprolol succinate 200 mg daily; bisoprolol 10 mg daily 1

3. Mineralocorticoid Receptor Antagonists (MRAs):

   • For patients with LVEF ≤35% and NYHA class II-IV symptoms 1
   • Spironolactone: start 12.5-25 mg daily; target 25 mg daily 1
   • Eplerenone: start 25 mg daily; target 50 mg daily 1
   • Monitor potassium and renal function

4. SGLT2 inhibitors:

   • Dapagliflozin or empagliflozin recommended for all patients regardless of diabetes status 1, 3
   • Reduces hospitalization and cardiovascular death 3

Additional Pharmacological Options

• Diuretics for symptom relief in patients with fluid retention 1

  • Loop diuretics (furosemide, torsemide, bumetanide) are preferred
  • Dose adjusted based on symptoms and fluid status

• Hydralazine/Isosorbide Dinitrate:

  • Particularly beneficial for African American patients with NYHA class III-IV symptoms 1
  • Starting dose: 20 mg isosorbide dinitrate/37.5 mg hydralazine TID 1
  • Target dose: 40 mg isosorbide dinitrate/75 mg hydralazine TID 1

• Ivabradine:

  • For patients in sinus rhythm with heart rate ≥70 bpm despite maximally tolerated beta-blocker 1
  • Starting dose: 5 mg BID; target dose: 7.5 mg BID 1

• Digoxin:

  • Can be beneficial in selected patients with persistent symptoms 1
  • Primarily used for rate control in atrial fibrillation 1

Device Therapy

• ICD for primary prevention in patients with LVEF ≤35% and NYHA class II-III symptoms on optimal medical therapy for ≥3 months 1
• CRT for patients with LVEF ≤35%, sinus rhythm, and:
  • LBBB with QRS ≥150 ms (Class I recommendation) 1
  • LBBB with QRS 130-149 ms (Class I recommendation) 1
  • Non-LBBB with QRS ≥150 ms (Class IIa recommendation) 1

Stage D: Advanced Heart Failure

Medical Management

• Continued optimization of all Stage C therapies as tolerated 4
• Intravenous inotropes may be considered for palliation but not for long-term use (Class III: Harm) 1
• Careful diuretic management to maintain euvolemia while avoiding prerenal azotemia

Advanced Therapies

• Evaluation for advanced therapies:
  • Left ventricular assist device (LVAD)
  • Heart transplantation
  • Palliative care for those not eligible for advanced therapies

Common Pitfalls and Caveats

1. Underdosing of medications: Many patients receive suboptimal doses of GDMT. Aim for target doses or highest tolerated doses 4, 5

2. Sequential vs. simultaneous initiation: Traditional approach was sequential initiation, but recent evidence supports simultaneous or rapid sequence initiation of multiple agents 1

3. Hypotension management:

   • Start with lower doses in patients with low blood pressure
   • Adjust diuretics to allow for GDMT optimization
   • Prioritize medications with mortality benefit over higher diuretic doses when possible

4. Renal function monitoring:

   • Mild increases in creatinine (up to 30%) are acceptable with RAAS inhibitors
   • Temporary dose reduction rather than discontinuation for mild-moderate renal dysfunction

5. Electrolyte management:

   • Regular monitoring of potassium, especially with MRAs
   • Consider potassium binders rather than discontinuing GDMT for mild hyperkalemia

6. Avoiding harmful medications:

   • Non-dihydropyridine calcium channel blockers (diltiazem, verapamil) are contraindicated in HFrEF 1
   • NSAIDs should be avoided 1
   • Thiazolidinediones are contraindicated 1

By following this stage-specific approach to HFrEF management, clinicians can optimize outcomes and reduce mortality and hospitalizations for patients across the spectrum of heart failure.