What is the initial treatment for heart failure with reduced ejection fraction (HFrEF)?

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

The initial treatment for HFrEF should include four medication classes started simultaneously at low doses: an ACE inhibitor (or ARB/ARNI), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and a sodium-glucose cotransporter-2 inhibitor (SGLT2i), along with diuretics for symptom relief of congestion.

First-Line Therapy Algorithm

Step 1: Foundational Medications

• Diuretics: Start with low-dose loop diuretics (e.g., furosemide) to manage congestion and volume overload 1, 2
• ACE inhibitors: Begin at low dose and titrate up to target doses used in clinical trials 1, 2
  • Monitor blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment
  • If ACE inhibitor not tolerated due to cough or angioedema, use ARB instead 1
  • Consider ARNI (sacubitril/valsartan) as initial therapy for NYHA class II-III symptoms 1, 3
• Beta-blockers: Start at low dose in stable patients and titrate gradually 1, 2
  • Proven mortality benefit options include carvedilol, metoprolol succinate, and bisoprolol 2
  • Caution in acute decompensated heart failure; initiate only when patient is stabilized 1

Step 2: Add-on Therapy (within weeks of starting Step 1)

• MRAs (spironolactone or eplerenone): Recommended for symptomatic patients with LVEF ≤35% 1
  • Monitor potassium and renal function closely
  • Use caution with impaired renal function or potassium >5.0 mmol/L
• SGLT2 inhibitors (dapagliflozin or empagliflozin): Add to reduce mortality and hospitalization 1, 2

Medication Titration

• Start medications at low doses and titrate upward every 2-4 weeks as tolerated 1, 2
• Aim for target doses used in clinical trials 4
• Reaching at least 50% of target doses appears to provide significant benefit compared to lower doses 4
• Regular monitoring of electrolytes and renal function is essential, particularly with combination therapy 2

Important Considerations

Medication Effectiveness

• Beta-blockers, MRAs, and ARNIs have demonstrated effectiveness in preventing sudden cardiac death and all-cause mortality 5
• ACE inhibitors significantly reduce all-cause mortality but have less impact on sudden cardiac death prevention 5
• Quadruple therapy (ARNI, beta-blocker, MRA, and SGLT2i) provides the largest reduction in cardiovascular death and heart failure hospitalization 2

Common Pitfalls to Avoid

1. Inadequate dosing: Only 17% of patients on ACE inhibitors/ARBs, 28% on beta-blockers, and 14% on ARNIs receive target doses in real-world practice 6
2. Incomplete medication regimen: In eligible patients, 27% don't receive ACE inhibitors/ARBs/ARNIs, 33% don't receive beta-blockers, and 67% don't receive MRAs 6
3. Premature discontinuation: Avoid stopping medications due to mild side effects that might resolve with time
4. Inappropriate medications: Avoid NSAIDs, most antiarrhythmic drugs, and calcium channel blockers with negative inotropic effects 2, 7
5. Inadequate monitoring: Failure to monitor renal function and electrolytes can lead to complications

Special Situations

• Patients with atrial fibrillation may still benefit from beta-blockers for rate control, despite less evidence for mortality benefit 1
• Elderly patients may require more careful titration due to comorbidities and risk of side effects 2
• Patients with improved LVEF (>40% after treatment) should continue their HFrEF treatment regimen 1

The 2022 AHA/ACC/HFSA guidelines emphasize the importance of implementing all four medication classes early in the treatment course to maximize benefits for patients with HFrEF 1. This comprehensive approach has been shown to significantly reduce mortality and hospitalization rates when medications are prescribed at appropriate doses and patients are monitored carefully.