What is the initial management approach for a patient with a mildly reduced Ejection Fraction (EF)?

Initial Management of Mildly Reduced Ejection Fraction (HFmrEF)

Initiate an SGLT2 inhibitor (empagliflozin or dapagliflozin) as first-line therapy for all patients with mildly reduced ejection fraction (LVEF 41-49%), regardless of diabetes status, to reduce hospitalizations and cardiovascular mortality. 1

Defining the Population

• Mildly reduced ejection fraction (HFmrEF) is defined as symptomatic heart failure with LVEF between 41-49%, formally recognized as a distinct category from HFrEF (≤40%) and HFpEF (≥50%). 1, 2

First-Line Therapy: SGLT2 Inhibitors

Start with an SGLT2 inhibitor as the foundational therapy. 1

• SGLT2 inhibitors demonstrated a 21% reduction in the composite endpoint of heart failure hospitalization or cardiovascular death in patients with LVEF >40%. 1
• These agents have minimal impact on blood pressure, making them ideal for patients with borderline or low blood pressure. 3, 1
• Benefits are seen regardless of diabetes status. 1

Sequential Addition of Neurohormonal Antagonists

After initiating SGLT2 inhibitors, consider adding evidence-based beta-blockers, ACE inhibitors/ARBs, or ARNIs as second-line therapy, particularly for patients with LVEF closer to 40%. 1

Beta-Blockers

• Evidence-based beta-blockers (carvedilol, metoprolol succinate, or bisoprolol) may reduce all-cause and cardiovascular mortality, especially when LVEF approaches 40%. 1
• Selective β₁ receptor blockers are preferred in patients with low blood pressure due to lesser BP-lowering effects. 3

ACE Inhibitors/ARBs/ARNIs

• ACE inhibitors or ARBs may be beneficial, particularly for patients at the lower end of the HFmrEF spectrum (LVEF 41-44%). 1
• When initiating therapy in patients with low blood pressure, start with very low doses (sacubitril/valsartan 25-50 mg twice daily or low-dose ACE inhibitor). 3

Mineralocorticoid Receptor Antagonists (MRAs)

• MRAs may be considered to reduce hospitalizations and mortality. 1
• These agents have minimal effect on blood pressure and can be initiated early alongside SGLT2 inhibitors. 3, 1

Special Considerations for Low Blood Pressure

If the patient presents with asymptomatic or mildly symptomatic low blood pressure, initiate SGLT2 inhibitors and MRAs first, as they have the least effect on blood pressure. 3, 1

• Subsequently add either low-dose beta-blocker (if heart rate >70 bpm) or ARNI/ACE inhibitor/ARB at low doses. 3
• Up-titrate one drug at a time using small increments every 1-2 weeks until target or highest tolerated dose is achieved. 3
• If beta-blockers are not tolerated and the patient is in sinus rhythm, ivabradine may be used as an alternative or adjunct. 3, 4

For patients with systolic blood pressure <80 mmHg or significant symptomatic hypotension (dizziness, fatigue, orthostatic symptoms), refer to a heart failure specialist before initiating or adjusting therapy. 3, 1

Titration Strategy

Use a "forced-titration strategy" similar to landmark clinical trials, aiming for target doses demonstrated to improve outcomes. 3

• Avoid prescribing subtarget doses without attempting systematic up-titration. 3
• Close monitoring of symptoms, blood pressure, heart rate, renal function, and electrolytes is essential during titration. 1
• If blood pressure improves during therapy (often due to improved cardiac output), medications can be up-titrated more easily. 3

Common Pitfalls to Avoid

• Do not fail to initiate SGLT2 inhibitors despite strong evidence of benefit in HFmrEF. 1
• Do not use inadequate doses of medications without attempting systematic up-titration to target doses. 1
• Do not discontinue or reduce guideline-directed therapy for asymptomatic or mildly symptomatic low blood pressure. 3
• Do not attribute low blood pressure to heart failure medications in stable patients without first evaluating for other causes (valvular disease, ischemia, non-cardiac medications like alpha-blockers for benign prostatic hyperplasia). 3

Monitoring and Reassessment

• Regularly assess symptoms, vital signs, fluid status, and laboratory parameters including electrolytes and renal function. 1
• Consider repeat evaluation of LVEF to determine disease trajectory and potential reclassification to HFrEF or HFpEF. 1
• Serial monitoring of natriuretic peptides can be useful during diuretic titration to ensure congestion does not worsen. 3