What are the treatment recommendations for patients with mildly reduced left ventricular (LV) ejection fraction?

Treatment Recommendations for Patients with Mildly Reduced Ejection Fraction

For patients with mildly reduced ejection fraction (LVEF 41-49%), SGLT2 inhibitors are the most strongly recommended treatment, followed by evidence-based beta-blockers, ACE inhibitors/ARBs/ARNi, and mineralocorticoid receptor antagonists. 1

First-Line Treatments

SGLT2 Inhibitors (Class 2a, Level B-R)

• SGLT2 inhibitors such as empagliflozin or dapagliflozin (10mg daily) should be initiated for patients with HFmrEF
• The EMPEROR-Preserved trial demonstrated a 21% reduction in the composite endpoint of HF hospitalization or cardiovascular death, primarily driven by a 29% reduction in HF hospitalizations 1
• Benefits were consistent regardless of diabetes status
• Consider initiating in-hospital once the patient is stabilized

Beta-Blockers (Class 2b, Level B-NR)

• Evidence-based beta-blockers that have demonstrated mortality benefit in HFrEF should be used:
  • Carvedilol (starting 3.125mg twice daily, target 25-50mg twice daily)
  • Metoprolol succinate (starting 12.5-25mg once daily, target 200mg once daily)
  • Bisoprolol (starting 1.25mg once daily, target 10mg once daily) 1, 2
• The BBmeta-HF analysis showed that in patients with LVEF 40-49% in sinus rhythm, beta-blockers reduced all-cause and cardiovascular mortality 1
• Beta-blockers should be initiated at low doses and gradually titrated while monitoring heart rate and blood pressure

Additional Recommended Therapies

Renin-Angiotensin System Inhibitors (Class 2b, Level B-NR)

• Options include:
  • ACE inhibitors (e.g., lisinopril 2.5-5mg daily, target 20-40mg daily)
  • ARBs (e.g., candesartan 4-8mg daily, target 32mg daily)
  • ARNi (sacubitril/valsartan starting 49/51mg twice daily, target 97/103mg twice daily) 1, 2
• A subgroup analysis of PARAGON-HF suggested benefit of sacubitril-valsartan versus valsartan alone in patients with LVEF 45-57% (rate ratio 0.78; 95% CI 0.64-0.95) 1
• ACE inhibitors should be considered first-line (over ARBs) based on evidence for reducing MI risk and prevention of heart failure 3
• ARBs are appropriate alternatives for patients who cannot tolerate ACE inhibitors

Mineralocorticoid Receptor Antagonists (Class 2b, Level B-NR)

• Options include:
  • Spironolactone (starting 12.5-25mg daily, target 25-50mg daily)
  • Eplerenone (starting 25mg daily, target 50mg daily) 1, 2
• MRAs should be used with careful monitoring of potassium and renal function
• Particularly beneficial for patients with LVEF on the lower end of the HFmrEF spectrum (closer to 40%)

Practical Implementation Approach

1. Initial Assessment:

   • Confirm LVEF is between 41-49% via echocardiography
   • Assess volume status to guide diuretic therapy
   • Evaluate renal function and electrolytes

2. Treatment Algorithm:

   • Start with SGLT2 inhibitor (strongest recommendation)
   • Add evidence-based beta-blocker at low dose
   • Initiate ACEi/ARB/ARNi at low dose
   • Consider adding MRA if symptoms persist and renal function allows
   • Titrate medications to target doses as tolerated

3. Monitoring:

   • Check electrolytes and renal function 1-2 weeks after initiation and dose changes
   • Monitor blood pressure and heart rate regularly
   • Reassess LVEF after 3-6 months of optimal therapy

Important Considerations and Caveats

• Medication Titration: Uptitration of medications to target doses is associated with better outcomes. A study showed that patients receiving at least one drug at ≥50% of target dose had significantly better outcomes than those on low doses or no treatment 4

• Treatment Intensification: Intensification of therapy during hospitalization for acute heart failure is associated with lower rates of death and rehospitalization (adjusted HR 0.49,95% CI 0.29-0.83) 4

• Avoid Downtitration: Downtitration of guideline-directed medical therapy after procedures like percutaneous mitral valve repair is associated with poor prognosis (HR 2.54,95% CI 1.38-4.69) 5

• Early Initiation: Early prescription of ACEi/ARB in patients with acute heart failure before hemodynamic stabilization appears safe and may be associated with lower incidence of worsening heart failure 6

• Diuretic Therapy: Loop diuretics should be used as needed for symptom relief and volume management, but they do not modify disease progression 1

• LVEF Trajectory: Patients with HFmrEF should have repeat evaluation of LVEF to determine the trajectory of their disease process, as this may influence treatment decisions 1

• Special Populations: For patients with concomitant hypertension, diabetes mellitus, or ischemic heart disease, early initiation of ACEi/ARB therapy may be particularly beneficial 6

The treatment approach for HFmrEF is evolving, with increasing evidence supporting the use of therapies traditionally reserved for HFrEF. While there are no prospective RCTs specifically for HFmrEF patients, post-hoc analyses suggest that patients with LVEF 41-49% respond to medical therapies similarly to patients with HFrEF, particularly those with LVEF on the lower end of this spectrum.