Treatment of Heart Failure Based on Ejection Fraction
The treatment of heart failure must be tailored to ejection fraction category, with HFrEF requiring four foundational drug classes (ARNI/ACEi/ARB, beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors), HFmrEF treated similarly to HFrEF with lower evidence levels, and HFpEF primarily managed with SGLT2 inhibitors plus diuretics for symptom control. 1, 2, 3
Heart Failure with Reduced Ejection Fraction (HFrEF, LVEF ≤40%)
Foundational Quadruple Therapy
All patients with HFrEF should receive four medication classes simultaneously to reduce mortality and hospitalization: 1, 4
Angiotensin Receptor-Neprilysin Inhibitor (ARNI) is preferred over ACE inhibitors, with sacubitril/valsartan starting at 49/51 mg twice daily and titrating to target dose of 97/103 mg twice daily every 2-4 weeks 5
Beta-blockers (carvedilol, metoprolol succinate, or bisoprolol) reduce mortality by at least 20% and should be initiated in stable patients on background ACE inhibition 1
- Start with very low doses and double every 1-2 weeks to target maintenance doses 1
- Patients should be relatively stable without need for intravenous inotropes and without marked fluid retention before initiation 1
- Transient worsening of symptoms, hypotension, or bradycardia may occur—increase diuretics or ACE inhibitor dose first before reducing beta-blocker 1
Mineralocorticoid Receptor Antagonists (MRA) such as spironolactone improve survival and morbidity, particularly in NYHA Class III-IV heart failure 1, 6
- Spironolactone is indicated for NYHA Class III-IV heart failure with reduced ejection fraction to increase survival, manage edema, and reduce hospitalization 6
- Monitor serum potassium and creatinine every 5-7 days after initiation until stable, then every 3-6 months 1
- Avoid combining with potassium-sparing diuretics during ACE inhibitor initiation due to hyperkalemia risk 1
SGLT2 Inhibitors represent the fourth pillar of therapy and should be initiated early regardless of diabetes status 1, 2
Diuretic Management
- Loop diuretics or thiazides are always administered in addition to neurohormonal antagonists for congestion management 1
- If GFR <30 mL/min, avoid thiazides except when prescribed synergistically with loop diuretics 1
- For insufficient response: increase diuretic dose, combine loop diuretics with thiazides, or administer loop diuretics twice daily 1
- In severe chronic heart failure with persistent fluid retention, add metolazone with frequent creatinine and electrolyte monitoring 1
Additional Therapies
Digoxin improves clinical status and reduces hospitalizations in patients with persistent symptoms despite ACE inhibitor and diuretic treatment, particularly with atrial fibrillation 1
Hydralazine/isosorbide dinitrate can be considered in patients intolerant to ACE inhibitors and ARBs, though evidence is more limited 1
Critical Monitoring Parameters
- Check blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment, at 3 months, and subsequently at 6-month intervals 1
- Avoid NSAIDs as they antagonize the effects of ACE inhibitors and diuretics 1
- If renal function deteriorates substantially during ACE inhibitor titration, stop treatment 1
Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF, LVEF 41-49%)
Treat HFmrEF similarly to HFrEF with the same four-drug foundational therapy, though the evidence level is lower: 1, 3
- ACE inhibitors, ARBs, beta-blockers, and MRAs have Level C evidence in ESC guidelines (Level B-NR in ACC/AHA/HFSA) 1
- SGLT2 inhibitors are recommended by ACC/AHA/HFSA guidelines for HFmrEF 1
- Diuretics for congestion management as needed 1
Heart Failure with Preserved Ejection Fraction (HFpEF, LVEF ≥50%)
The treatment approach for HFpEF differs substantially from HFrEF, focusing primarily on SGLT2 inhibitors and symptom management: 1, 2, 7
Primary Pharmacotherapy
SGLT2 inhibitors are the cornerstone of HFpEF treatment, reducing cardiovascular death and heart failure hospitalization 1, 7
- This represents the strongest evidence-based therapy for HFpEF 7
Additional Considerations
- ARBs may reduce heart failure symptoms and hospitalizations 1
- MRAs (non-steroidal preferred) can be considered, particularly in select phenotypes 1, 7
- ARNI (sacubitril/valsartan) may be considered in selected patients 1, 7
- GLP-1 receptor agonists should be considered, especially in obese and diabetic patients 7
Essential Non-Pharmacologic Management
- Optimal management of comorbidities is critical: hypertension, diabetes, atrial fibrillation, obesity, and ischemic heart disease 1, 2, 7
- Phenotypic tailoring of therapy based on dominant comorbidities improves outcomes 7
Universal Management Principles Across All EF Categories
Lifestyle and Monitoring
- Control sodium intake in severe heart failure; avoid excessive fluids and alcohol 1
- Exercise training improves exercise tolerance, quality of life, and reduces HF hospitalization rates in stable patients 1
- Daily weight monitoring with instructions to increase diuretics and contact healthcare team if weight gain >2 kg in 3 days 1
Multidisciplinary Care
- Team-based care with cardiologists, primary care physicians, nurses, and pharmacists reduces mortality and hospitalization 1
- Follow-up within 7-14 days of discharge with telephone contact within 3 days 8
- Regular assessment of volume status, blood pressure, renal function, and electrolytes 8
Common Pitfalls to Avoid
- Never delay initiation of all four foundational drug classes in HFrEF—they should be started rapidly and simultaneously, not sequentially 2, 4
- Avoid excessive diuresis before starting ACE inhibitors—reduce or withhold diuretics for 24 hours before initiation 1
- Do not discontinue beta-blockers for transient worsening—adjust other medications first (increase diuretics or ACE inhibitor) 1
- Monitor potassium closely when combining MRA with ACE inhibitor/ARNI—check every 5-7 days initially 1
- Ensure 36-hour washout when switching from ACE inhibitor to ARNI to prevent angioedema 5