What medications are recommended for heart failure with a mildly reduced ejection fraction?

Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF)

SGLT2 inhibitors are the primary recommended medication for HFmrEF (LVEF 41-49%), with a Class 2a recommendation to reduce heart failure hospitalizations and cardiovascular mortality. 1

Primary Medication Recommendation

SGLT2 inhibitors (such as dapagliflozin or empagliflozin) should be initiated first in all patients with HFmrEF, as they carry the strongest evidence (Class 2a, Level B-R) for reducing HF hospitalizations and cardiovascular death in this specific population. 1 This represents the only Class 2a recommendation for HFmrEF, making it the most evidence-supported therapy.

Secondary Medication Options

The following medications have weaker recommendations (Class 2b) but may be considered, particularly in patients with LVEF on the lower end of the 41-49% spectrum (closer to 41%): 1

Renin-Angiotensin System Inhibition

• ARNi (sacubitril/valsartan) is preferred over ACE inhibitors or ARBs when initiating renin-angiotensin system blockade 1
• ACE inhibitors are second choice if ARNi is not feasible 1
• ARBs should only be used if patients are intolerant to ACE inhibitors (due to cough or angioedema) and ARNi cannot be used 1
• Critical safety note: When switching from ACE inhibitor to ARNi, observe a mandatory 36-hour washout period to avoid angioedema; no washout is needed when switching from ARB 2

Beta-Blockers

• Only evidence-based beta-blockers for HFrEF should be used: carvedilol, metoprolol succinate (not tartrate), or bisoprolol 1, 2
• These have Class 2b recommendation in HFmrEF, meaning they "may be considered" 1

Mineralocorticoid Receptor Antagonists (MRAs)

• Spironolactone or eplerenone carry a Class 2b recommendation in HFmrEF 1
• Should be used cautiously with monitoring of potassium and renal function 2

Symptomatic Management

Loop diuretics (furosemide) are essential for any patient with fluid retention, regardless of ejection fraction, and should always be administered alongside renin-angiotensin system inhibition. 1, 2 However, diuretics do not reduce mortality—they only improve symptoms. 3

Practical Treatment Algorithm

Step 1: Initiate SGLT2 Inhibitor

Start with an SGLT2 inhibitor immediately, as this has the strongest evidence base for HFmrEF specifically. 1

Step 2: Add Diuretics if Congested

If signs of fluid overload are present, add loop diuretics for symptom relief. 1, 3

Step 3: Consider Additional Neurohormonal Blockade

For patients with LVEF closer to 41% (lower end of HFmrEF spectrum), strongly consider adding: 1

• ARNi (preferred) or ACE inhibitor
• Evidence-based beta-blocker
• MRA

These medications have proven mortality benefits in HFrEF and may provide similar benefits in patients with LVEF approaching the HFrEF threshold. 1

Step 4: Monitoring

Check blood pressure, renal function, and electrolytes at baseline, 1-2 weeks after each medication initiation or dose change, at 3 months, then every 6 months. 2, 4

Critical Distinctions from HFrEF

The evidence base for HFmrEF is substantially weaker than for HFrEF. 1 While HFrEF has Class 1 (strong) recommendations for SGLT2 inhibitors, ARNi/ACE inhibitors, beta-blockers, and MRAs, HFmrEF only has one Class 2a recommendation (SGLT2 inhibitors) and the rest are Class 2b ("may be considered"). 1 This reflects the reality that most landmark trials enrolled patients with LVEF ≤40%, not the 41-49% range. 5

Common Pitfalls to Avoid

• Do not treat HFmrEF identically to HFrEF: The evidence is not as robust, and the 2022 ACC/AHA/HFSA guidelines explicitly give different strength recommendations 1
• Do not ignore SGLT2 inhibitors: Despite being the newest drug class, they have the strongest recommendation specifically for HFmrEF 1
• Do not combine ACE inhibitor with ARB and MRA simultaneously: This causes life-threatening hyperkalemia and renal dysfunction 3, 4
• Do not use metoprolol tartrate: Only metoprolol succinate has proven mortality benefit 2