What are the guidelines for managing patients with moderately reduced Ejection Fraction (EF)?

Management Guidelines for Heart Failure with Moderately Reduced Ejection Fraction (HFmrEF)

For patients with heart failure and moderately reduced ejection fraction (LVEF 41-49%), SGLT2 inhibitors are strongly recommended as they provide significant benefit in reducing hospitalizations and cardiovascular mortality, regardless of diabetes status. 1

Definition and Classification

• Heart failure with moderately reduced ejection fraction (HFmrEF) is defined as symptomatic heart failure with a left ventricular ejection fraction (LVEF) between 41-49% 1
• This classification was formally recognized in the 2016 European Society of Cardiology (ESC) guidelines, distinguishing it from HFrEF (LVEF ≤40%) and HFpEF (LVEF ≥50%) 1

First-Line Pharmacological Management

Strong Evidence (Class 2a Recommendation)

• SGLT2 inhibitors: Strongly recommended (Class 2a) for all HFmrEF patients to reduce hospitalizations and cardiovascular mortality 1
  • Empagliflozin demonstrated a 21% reduction in the composite endpoint of HF hospitalization or cardiovascular death in patients with LVEF >40%, with benefits seen regardless of diabetes status 1
  • Benefits were consistent in the HFmrEF subgroup (LVEF 41-49%) 1

Moderate Evidence (Class 2b Recommendations)

• Beta-blockers: May be beneficial, particularly for patients with LVEF closer to 40% 1

  • Meta-analysis of 11 HF trials showed that beta-blockers reduced all-cause and cardiovascular mortality in patients with LVEF 40-49% who were in sinus rhythm 1
  • Evidence-based beta-blockers for HFrEF (metoprolol succinate, carvedilol, bisoprolol) should be preferred 1, 2

• Renin-Angiotensin System Inhibitors:

  • ACE inhibitors or ARBs may be beneficial, especially for those with LVEF at the lower end of the HFmrEF spectrum 1
  • ARNi (sacubitril/valsartan) showed potential benefit in patients with LVEF 45-57% compared to valsartan alone in a subgroup analysis of the PARAGON-HF trial 1

• Mineralocorticoid Receptor Antagonists (MRAs): May be considered to reduce hospitalizations and mortality 1

Treatment Algorithm for HFmrEF

1. First step: Initiate SGLT2 inhibitor (Class 2a recommendation) 1

   • Start regardless of diabetes status
   • Monitor renal function (eGFR should be >20 ml/min/1.73m²)

2. Second step: Consider adding (Class 2b recommendations) 1:

   • Evidence-based beta-blocker (metoprolol succinate, carvedilol, or bisoprolol)
   • ACEi/ARB or ARNi (especially for LVEF closer to 40%)
   • MRA (if eGFR >30 ml/min/1.73m²)

3. Diuretics: Use as needed for symptom relief and congestion management 1

Special Considerations

Management of Low Blood Pressure

• For patients with asymptomatic or mildly symptomatic low BP 1:

  • Initiate SGLT2i and MRA first as they have minimal impact on blood pressure
  • Start with low doses of ACEi/ARB/ARNi and beta-blockers and titrate slowly
  • Up-titrate medications in small increments every 1-2 weeks with close monitoring

• For patients with significant symptomatic hypotension 1:

  • Consider referral to heart failure specialist
  • Evaluate for potential causes beyond HF medications
  • Assess congestion status and consider diuretic dose reduction if no signs of congestion

Medication Titration

• Start medications at low doses and gradually up-titrate to target doses or maximum tolerated doses 1
• Titrate one medication at a time with close monitoring of blood pressure, heart rate, and renal function 1
• For beta-blockers, metoprolol succinate is recommended with a starting dose of 12.5-25 mg daily and target dose of 200 mg daily 2

Monitoring and Follow-up

• Regular assessment of symptoms, vital signs, fluid status, and laboratory parameters (electrolytes, renal function) 1
• Consider repeat evaluation of LVEF to determine disease trajectory and potential reclassification 1
• Monitor for medication side effects, particularly hypotension, bradycardia, and worsening renal function 1

Common Pitfalls to Avoid

• Failure to initiate SGLT2 inhibitors despite strong evidence of benefit in HFmrEF 1
• Using inadequate doses of medications - aim for target doses shown to improve outcomes in clinical trials 1
• Not distinguishing between different beta-blocker formulations (e.g., metoprolol tartrate vs. succinate) 2
• Discontinuing medications prematurely due to mild, asymptomatic hypotension 1
• Failing to reassess LVEF to determine if patients have improved or worsened and require treatment adjustments 1