What is the initial treatment for a patient with a left ventricular ejection fraction (LVEF) of 45-50%?

Initial Treatment for LVEF 45-50%

Patients with LVEF 45-50% should be treated with comprehensive guideline-directed medical therapy (GDMT) including SGLT2 inhibitors as first-line therapy, followed by beta-blockers, ACE inhibitors/ARBs (or ARNi), and mineralocorticoid receptor antagonists, with diuretics added as needed for symptom management. 1, 2

Classification and Risk Stratification

Patients with LVEF 45-50% fall into the category of heart failure with mildly reduced ejection fraction (HFmrEF), defined as LVEF 41-49% 1. This represents a distinct clinical entity with:

• Increased risk for disease progression, clinical deterioration, and sudden death compared to those with normal LVEF 1
• Potential for transition to HFrEF: LVEF ≤55% predicts progression to mildly reduced EF with 90.9% sensitivity and 97.7% specificity 3
• U-shaped association with future heart failure risk, with LVEF in this range showing elevated risk for incident heart failure hospitalization 4

Pharmacological Treatment Algorithm

First-Line Therapy: SGLT2 Inhibitors

Start with an SGLT2 inhibitor (empagliflozin or dapagliflozin) immediately as Class 2a recommendation to decrease heart failure hospitalizations and cardiovascular mortality 1. The EMPEROR-Preserved trial demonstrated a 21% reduction in the composite endpoint of heart failure hospitalization or cardiovascular death in patients with LVEF >40%, with greater benefit in patients with LVEF closer to 50% 5.

Second-Line: Beta-Blockers

Initiate evidence-based beta-blockers (bisoprolol, carvedilol, or sustained-release metoprolol succinate) for all patients with LVEF <50% to improve symptoms and reduce risks of heart failure hospitalization and premature death 6, 1. Beta-blockers are Class I recommendation for rate control in patients with LVEF >40% 5.

Third-Line: ACE Inhibitors/ARBs or ARNi

Add ACE inhibitors or ARBs to reduce the risk of heart failure progression 1, 2. For patients with LVEF closer to 40% (45-47%), consider ARNi (sacubitril-valsartan) instead of ACE inhibitor/ARB, as the PARAGON-HF trial showed benefit in patients with LVEF 45-57% (rate ratio 0.78; 95% CI 0.64-0.95) 5. ARNi provides high economic value when used instead of ACE inhibitors 2.

Fourth-Line: Mineralocorticoid Receptor Antagonists

Consider spironolactone or eplerenone, particularly for patients with LVEF on the lower end of the HFmrEF spectrum (45-47%) 1, 2. MRAs should be added for patients with persisting symptoms despite treatment with ACE inhibitor/ARB and beta-blocker 6.

Adjunctive Therapy: Diuretics

Use loop diuretics for relief of symptoms due to volume overload and congestion 5, 2. Diuretic dosing must be tailored to individual patient needs with careful monitoring of electrolytes, renal function, and volume status 5.

Titration Strategy

Start medications sequentially at low doses and titrate to maximum tolerated doses before adding the next agent 1. The goal is to achieve at least a GDMT score of 5 for improved outcomes 2. Patients should be informed that clinical benefits may not be apparent for 2-3 months after initiation 7.

• Target at least 50% of recommended doses: Patients receiving <50% of recommended ACE inhibitor/ARB and beta-blocker doses have greater risk of death and heart failure hospitalization (HR 1.72 and 1.70, respectively) 8
• Monitor closely: Regular assessment of renal function, electrolytes, and blood pressure during titration 1

Special Considerations for Atrial Fibrillation

If atrial fibrillation is present with LVEF >40%:

• Beta-blockers, diltiazem, verapamil, or digoxin are recommended as first-choice drugs for rate control 5
• Target lenient rate control (<110 bpm at rest) initially, with stricter control reserved for those with continuing symptoms 5
• Combination therapy should be considered if single agent fails to control rate or symptoms 5

Critical Pitfalls to Avoid

• Never discontinue GDMT if LVEF improves: Patients who improve to LVEF >40% have Heart Failure with Improved EF (HFimpEF) and must continue full GDMT to prevent relapse 6, 2
• Avoid harmful medications: Most antiarrhythmic drugs, most calcium channel blockers (except amlodipine), NSAIDs, and thiazolidinediones should be avoided 2
• Do not use non-dihydropyridine calcium channel blockers (verapamil, diltiazem) as they have negative inotropic effects and may worsen ventricular function 1
• Ensure adequate washout period: Allow 36 hours when switching from ACE inhibitor to ARNi to avoid angioedema risk 9

Monitoring and Follow-Up

• Regular reassessment of LVEF is essential as patients with HFmrEF can have dynamic LVEF 1
• Investigate underlying causes: Evaluate for coronary artery disease, hypertension, cardiomyopathy, and valvular heart disease 1
• Device therapy consideration: ICD and/or CRT should only be considered if LVEF deteriorates to ≤35% despite optimal medical therapy 1, 2