What is the management approach for an adult patient with mildly reduced ejection fraction (EF) and potential underlying cardiovascular risk factors such as hypertension, diabetes, or a history of heart disease?

Management of Mildly Reduced Ejection Fraction (HFmrEF)

Patients with mildly reduced ejection fraction (EF 41-49%) should be treated with the same guideline-directed medical therapy as those with heart failure with reduced ejection fraction (HFrEF), including initiation of SGLT2 inhibitors, ACE inhibitors or ARNIs, beta-blockers, and mineralocorticoid receptor antagonists. 1

Initial Diagnostic Approach

• Confirm the diagnosis with echocardiography to document EF between 41-49%, assess diastolic function, chamber dimensions, wall thickness, and valvular abnormalities 2
• Measure BNP or NT-proBNP to establish baseline and confirm the diagnosis 2
• Obtain a resting ECG to identify conduction abnormalities, prior myocardial infarction (Q waves), or arrhythmias 1
• Assess for congestion by examining jugular venous distention, peripheral edema, pulmonary rales, and orthopnea 2

Risk Factor Assessment

HFmrEF patients typically present with clinical characteristics more similar to HFpEF than HFrEF, including:

• Higher prevalence in elderly women (mean age ~75 years, 45% female) 3
• High burden of hypertension, diabetes mellitus, and coronary artery disease 1, 3
• Increased pulse pressure suggesting arterial stiffening 4
• Frequent atrial fibrillation 1

Pharmacologic Management Strategy

First-Line Therapy (Initiate All Four Pillars)

SGLT2 Inhibitors:

• Start dapagliflozin or empagliflozin immediately in patients with type 2 diabetes and established heart failure with either preserved or reduced ejection fraction to reduce risk of worsening heart failure and cardiovascular death 1
• SGLT2 inhibitors should be prioritized as they do not lower blood pressure and can be started early 1

ACE Inhibitors or ARNIs:

• In patients with known atherosclerotic cardiovascular disease, particularly coronary artery disease, ACE inhibitor or ARB therapy is recommended to reduce cardiovascular events 1
• Consider sacubitril/valsartan (ARNI) as superior to enalapril for reducing cardiovascular death and heart failure hospitalization (HR 0.80,95% CI 0.73-0.87, p<0.0001) 5
• Start sacubitril/valsartan at 49/51 mg twice daily, titrating to target dose of 97/103 mg twice daily after 2-4 weeks 5
• Allow 36-hour washout period when switching from ACE inhibitor to ARNI 5

Beta-Blockers:

• Treatment should include a beta-blocker with proven cardiovascular outcomes benefit unless contraindicated 1
• In patients with prior myocardial infarction, continue beta-blockers for at least 3 years after the event 1

Mineralocorticoid Receptor Antagonists:

• Initiate MRA as part of quadruple therapy, as these agents have minimal blood pressure effects 1
• In patients with type 2 diabetes and chronic kidney disease with albuminuria on maximum tolerated ACE inhibitor or ARB doses, add finerenone to improve cardiovascular outcomes and reduce chronic kidney disease progression 1

Diuretic Management

• Prescribe loop diuretics (furosemide or torsemide) to patients with overt congestion to improve symptoms 6
• Monitor daily weights, fluid intake/output, and serial electrolytes during active diuresis 2
• During IV diuretic therapy, monitor fluid intake and output measurements, vital signs, body weight, clinical signs of perfusion and congestion, and daily serum electrolytes, urea nitrogen, and creatinine 7

Metformin Considerations

• In patients with type 2 diabetes and stable heart failure, metformin may be continued for glucose lowering if eGFR remains >30 mL/min/1.73 m² but should be avoided in unstable or hospitalized patients 1

Titration Strategy

• Schedule follow-up visits every 1-2 weeks during medication titration phase 2
• Aim for evidence-based target doses from clinical trials rather than arbitrary "tolerated" doses 2
• Up-titrate one drug at a time with small increments, monitoring closely for hypotension, renal function changes, and electrolyte abnormalities 1

Special Considerations for Low Blood Pressure

If the patient presents with low blood pressure:

• Start SGLT2 inhibitor and MRA first as they do not lower blood pressure 1
• Then initiate either low-dose beta-blocker if heart rate >70 bpm or ARNI/ACEI/ARB at low dose 1
• Up-titrate weekly with small increments until reaching target or highest tolerated dose 1
• Assess congestion status to determine if diuretic dose reduction is feasible 1

Monitoring for Disease Progression

• Recognize that HFmrEF is a dynamic state: 26.9% of patients decline to EF ≤40% and 44.8% improve to EF ≥50% over time 3
• Repeat echocardiography at 3 months after initiating guideline-directed medical therapy to assess for EF changes 2
• Apply risk scores to predict mortality and identify patients who might benefit from early treatment intensification 8
• For patients with persistently reduced EF ≤35% after ≥3 months of optimal medical therapy, refer for device therapy evaluation (ICD/CRT-D) 2

Common Pitfalls to Avoid

• Do not withhold guideline-directed medical therapy based on the "mildly reduced" designation—these patients benefit from the same therapies as HFrEF 1
• Do not regard mildly symptomatic status as an index of disease stability; clinical stability is misleading as disease progression is often silent 8
• Do not discontinue guideline-directed medical therapy for mild asymptomatic hypotension or small creatinine elevations unless severe 2
• Do not delay initiation of all four medication classes; hospitalization is a critical opportunity to start life-saving medications 2
• Be aware that patients with HFmrEF have higher likelihood of renal function deterioration during hospitalization compared to those with severely reduced EF 4

Anticoagulation in Atrial Fibrillation

If atrial fibrillation is present:

• Calculate CHA2DS2-VASc score; chronic heart failure (including HFmrEF) scores 1 point 1
• Direct oral anticoagulants are recommended in preference to vitamin K antagonists to prevent ischemic stroke and thromboembolism 1
• Target INR of 2.0-3.0 if VKA is used 1