What treatments have mortality benefits for patients with Heart Failure with Reduced Ejection Fraction (HFrEF)?

Treatments with Mortality Benefits for HFrEF Patients

The most effective treatment strategy for patients with Heart Failure with Reduced Ejection Fraction (HFrEF) is comprehensive quadruple therapy with ARNI (or ACEi/ARB), beta-blockers, MRAs, and SGLT2 inhibitors, all of which have demonstrated significant mortality benefits. 1, 2

First-Line Medications with Proven Mortality Benefits

Renin-Angiotensin System Inhibitors

• Angiotensin Receptor-Neprilysin Inhibitors (ARNi)

  • First choice for patients with NYHA class II-III symptoms (Class 1, Level A recommendation)
  • Sacubitril/valsartan reduces morbidity and mortality more effectively than ACEi alone 1, 3
  • Initial dose: 49/51 mg twice daily (24/26 mg if risk of hypotension)
  • Target dose: 97/103 mg twice daily 2

• ACE Inhibitors (ACEi)

  • Beneficial when ARNi is not feasible (Class 1, Level A recommendation)
  • Reduces mortality in patients with prior or current HFrEF symptoms 1, 4
  • Examples: lisinopril, enalapril, ramipril

• Angiotensin Receptor Blockers (ARBs)

  • Recommended for patients intolerant to ACEi due to cough or angioedema (Class 1, Level A) 1
  • Provides mortality benefit when ACEi or ARNi cannot be used

Beta-Blockers

• Class 1, Level A recommendation 1
• Only three specific beta-blockers have proven mortality benefits:
  • Bisoprolol (target: 10 mg once daily)
  • Carvedilol (target: 25-50 mg twice daily)
  • Metoprolol succinate (target: 200 mg once daily) 2
• Reduces mortality and hospitalizations regardless of symptom status 1
• Number needed to treat (NNT) to prevent one death over 36 months: 9 2

Mineralocorticoid Receptor Antagonists (MRAs)

• Class 1, Level A recommendation for NYHA class II-IV symptoms 1
• Spironolactone or eplerenone reduces morbidity and mortality
• Requires eGFR >30 mL/min/1.73m² and serum potassium <5.0 mEq/L
• Close monitoring of potassium and renal function required
• NNT to prevent one death over 36 months: 6 2

SGLT2 Inhibitors

• Class 1, Level A recommendation for symptomatic chronic HFrEF 1
• Reduces hospitalization for HF and cardiovascular mortality
• Effective regardless of diabetes status
• Examples: dapagliflozin 10 mg daily, empagliflozin 10 mg daily 2
• NNT to prevent one death over 36 months: 22 2

Device Therapies with Mortality Benefits

• Implantable Cardioverter-Defibrillators (ICDs)

  • Recommended for patients with LVEF ≤35% and NYHA Class II-III symptoms 2, 5
  • Reduces risk of sudden cardiac death

• Cardiac Resynchronization Therapy (CRT)

  • Recommended for patients with LVEF ≤35%, QRS ≥150ms, and left bundle branch block morphology 2
  • Improves symptoms, reduces hospitalizations, and decreases mortality

Additional Therapies for Specific Populations

• Hydralazine and Isosorbide Dinitrate
  • Particularly beneficial in Black patients with HFrEF
  • NNT to prevent one death over 36 months: 7 2

Optimal Treatment Sequencing

1. Initial therapy: Start ACEi/ARB and beta-blocker concurrently with diuretics if fluid retention present
2. Once stable: Replace ACEi/ARB with ARNi if patient tolerates initial therapy
3. Add MRA if symptoms persist despite optimal doses of initial therapies
4. Add SGLT2i regardless of diabetes status
5. Consider device therapy (ICD/CRT) for eligible patients 2, 6

Comparative Effectiveness

A cross-trial analysis estimated that comprehensive therapy (ARNI, beta-blocker, MRA, and SGLT2i) compared to conventional therapy (ACEi/ARB and beta-blocker) provides:

• 62% reduction in risk of cardiovascular death or HF hospitalization (HR 0.38)
• 47% reduction in all-cause mortality (HR 0.53)
• Additional 1.4-6.3 years of survival depending on age 6

Common Pitfalls to Avoid

• Failure to titrate to target doses: Clinical trials show better outcomes with target doses 2
• Underutilization of comprehensive therapy: Only 1% of eligible patients receive target doses of all recommended medications 2
• Excessive concern about low blood pressure: Should not prevent initiation or uptitration of therapy in most cases
• Abrupt withdrawal of beta-blockers: Can lead to clinical deterioration and should be avoided 1
• Not considering ARNi as first-line: ARNi is superior to ACEi for reducing morbidity and mortality 1, 3

For patients with HFmrEF (LVEF 41-49%), SGLT2i has the strongest evidence (Class 2a, Level B-R), while beta-blockers, ARNi, ACEi/ARB, and MRAs may also be beneficial (Class 2b, Level B-NR) 1, 7.