What is the recommended guideline‑directed medical therapy for a patient with heart failure with mildly reduced ejection fraction (EF 41‑49%)?

Management of Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF)

For patients with HFmrEF (EF 41-49%), start with an SGLT2 inhibitor (dapagliflozin or empagliflozin) as the primary therapy, followed by consideration of the four medication classes used in HFrEF—though with weaker evidence and lower strength of recommendations. 1

Primary Recommendation: SGLT2 Inhibitors

SGLT2 inhibitors receive a Class 2a recommendation (moderate strength) for HFmrEF and are beneficial in decreasing heart failure hospitalizations and cardiovascular mortality. 1 This is the strongest evidence-based recommendation for this population and should be initiated first. 1

• SGLT2 inhibitors (dapagliflozin 10 mg daily or empagliflozin 10 mg daily) have no blood pressure, heart rate, or potassium effects, making them safe to start immediately. 2
• No dose titration is required, and treatment benefits occur within weeks of initiation. 2
• These agents work independently of background therapy and are safe in moderate kidney dysfunction (eGFR ≥30 mL/min/1.73 m² for empagliflozin, ≥20 mL/min/1.73 m² for dapagliflozin). 2

Secondary Medications: Class 2b Recommendations

All other HFrEF medications receive only Class 2b recommendations (weak evidence) in HFmrEF, meaning they "may be considered" but the evidence is substantially weaker than in HFrEF. 1 The guidelines specifically note these medications are most beneficial "particularly among patients with LVEF on the lower end of this spectrum" (closer to 41% than 49%). 1

Evidence-Based Beta-Blockers

• Carvedilol, metoprolol succinate, or bisoprolol may be considered (Class 2b). 1
• Start at low doses: carvedilol 3.125 mg twice daily, metoprolol succinate 12.5-25 mg daily, or bisoprolol 1.25 mg daily. 2
• Target doses: carvedilol 25-50 mg twice daily, metoprolol succinate 200 mg daily, bisoprolol 10 mg daily. 2

Renin-Angiotensin System Inhibitors

• ARNi (sacubitril/valsartan), ACE inhibitors, or ARBs may be considered (Class 2b). 1
• If using ARNi, start sacubitril/valsartan 24/26 mg or 49/51 mg twice daily, with a strict 36-hour washout if switching from an ACE inhibitor. 2
• Alternative: lisinopril 10 mg daily (target 40 mg daily) or losartan 50 mg daily (target 150 mg daily). 2

Mineralocorticoid Receptor Antagonists

• Spironolactone or eplerenone may be considered (Class 2b). 1
• Start spironolactone 12.5-25 mg daily or eplerenone 25 mg daily, with close monitoring of potassium and creatinine. 2

Critical Distinction from HFrEF

The evidence base for HFmrEF is fundamentally different from HFrEF. 3 In HFrEF, all four medication classes have Class I (strong) recommendations with proven mortality benefits of approximately 73% reduction over 2 years when used together. 2, 3 In HFmrEF, only SGLT2 inhibitors have moderate-strength evidence (Class 2a), while all other medications have weak recommendations (Class 2b) focused primarily on reducing hospitalizations rather than mortality. 1, 3

Practical Implementation Algorithm

1. Start SGLT2 inhibitor immediately (dapagliflozin 10 mg daily or empagliflozin 10 mg daily) in all patients with HFmrEF. 1

2. For patients with EF 41-44% (lower end of HFmrEF spectrum), strongly consider adding the other three medication classes using the same approach as HFrEF, as these patients likely derive more benefit. 1

3. For patients with EF 45-49% (higher end of HFmrEF spectrum), individualize the decision to add additional medications based on symptoms, comorbidities, and tolerability, recognizing the weaker evidence base. 1

4. Add diuretics as needed for volume management, but they do not modify disease progression. 2

5. Monitor blood pressure, renal function, and electrolytes at 1-2 weeks after initiating or uptitrating medications, with more frequent monitoring in elderly patients and those with chronic kidney disease. 2

Common Pitfalls to Avoid

• Do not assume HFmrEF should be treated identically to HFrEF. The evidence is weaker and recommendations are less robust. 1, 3
• Do not skip SGLT2 inhibitors, as they have the strongest evidence in this population. 1
• Do not overreact to modest creatinine elevation (up to 30% above baseline is acceptable if perfusion is adequate). 2
• Do not withhold therapy in patients with low baseline blood pressure if they have adequate organ perfusion—SGLT2 inhibitors and MRAs have minimal blood pressure effects. 2, 3

Special Consideration: Improved EF

If a patient previously had HFrEF and their EF has improved to 41-49% (now classified as HFmrEF), continue all four HFrEF medications at target doses. 1, 2 Discontinuation of GDMT after EF improvement may lead to clinical deterioration. 2