What is the initial treatment for a patient with a left ventricular ejection fraction (LVEF) of 40-45%?

Initial Treatment for LVEF 40-45%

Patients with LVEF 40-45% should be treated with the full quadruple therapy regimen used for heart failure with reduced ejection fraction (HFrEF), including ACE inhibitors/ARBs (or ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors, plus diuretics as needed for volume management. 1, 2

Classification Matters for Treatment Approach

Your patient falls into one of two categories that determine the urgency and approach:

• HFimpEF (Heart Failure with Improved EF): If this patient previously had LVEF <40% and improved to 40-45%, they must continue all HFrEF medications indefinitely—this is a Class I recommendation with strong evidence 1, 3, 2
• HFmrEF (Heart Failure with Mildly Reduced EF): If this is a new diagnosis with LVEF 41-45%, treat as HFrEF with the same four cornerstone medications, though the evidence base is somewhat less robust 1, 2

The Four Cornerstone Medications (Start All Simultaneously)

Current guidelines recommend initiating all four medication classes early rather than sequentially: 1, 2, 4

1. ACE Inhibitor/ARB or ARNI

• Start with ACE inhibitor or ARB (Class I recommendation) 1, 3
• Target doses equivalent to enalapril 10 mg twice daily 1
• Consider switching to ARNI (sacubitril/valsartan) for additional benefit, particularly for patients with LVEF closer to 40% 1, 2
• ARNI provides high economic value when used instead of ACE inhibitors 3, 2
• Monitor renal function and potassium, especially when titrating doses 5

2. Beta-Blockers

• Use evidence-based agents only: bisoprolol, carvedilol, or metoprolol succinate 1, 3, 2
• These specific beta-blockers have proven mortality reduction 1, 3
• Start at low doses and titrate to target or maximum tolerated dose 1, 2
• Provides high economic value 1

3. Mineralocorticoid Receptor Antagonists (MRAs)

• Spironolactone or eplerenone for symptomatic patients (NYHA Class II-IV) 1, 3
• Particularly beneficial when LVEF is closer to 40% rather than 45% 1, 2
• Critical monitoring required: Check potassium and renal function regularly; avoid if potassium >5.0 mmol/L or significant renal dysfunction 1
• Provides high economic value 1, 2

4. SGLT2 Inhibitors

• Class IIa recommendation for decreasing heart failure hospitalizations and cardiovascular mortality 1, 3, 2
• Can be initiated regardless of diabetes status 1
• Provides intermediate economic value 1, 2

Diuretics for Volume Management

• Use loop diuretics as needed to achieve and maintain euvolemia 1, 5
• Titrate to the lowest effective dose based on symptoms and signs of congestion 1
• In stable, asymptomatic euvolemic patients, diuretics may be temporarily discontinued 1
• Train patients to self-adjust diuretic doses based on daily weights and symptoms 1

Critical Implementation Strategy

Start low, go slow, but go: 2, 4

• Initiate all four cornerstone medications at low doses simultaneously rather than waiting months between additions 4
• Titrate each medication upward as tolerated to target doses 2, 6
• Aim for a GDMT score of at least 5 for improved outcomes 2
• Recent registry data shows that even in 2021, only 26-30% of eligible patients receive SGLT2 inhibitors and only 35-46% receive MRAs, representing a major treatment gap 4

Common Pitfalls to Avoid

Never discontinue GDMT inappropriately: 3, 2, 7, 8

• Withdrawal of ACE inhibitors/ARBs during hospitalization increases 30-day mortality (HR 1.92) and 1-year mortality (HR 1.35) 7
• De-escalation of any GDMT class after heart failure hospitalization significantly increases mortality risk (HR 2.94-4.81 depending on medication class) 8
• Even if LVEF improves above 40%, continue all medications to prevent relapse 1, 3, 2

Avoid harmful medications: 5

• Calcium channel blockers (verapamil, diltiazem, short-acting dihydropyridines) have negative inotropic effects 5
• Class I antiarrhythmics worsen heart failure 5
• NSAIDs and COX-2 inhibitors cause sodium and water retention 5

Monitoring and Follow-Up

• Regular LVEF reassessment guides therapy adjustments and reclassification 2
• Monitor renal function and electrolytes, especially when initiating or titrating RAAS inhibitors and MRAs 1, 5
• Referral to heart failure clinic significantly improves GDMT initiation rates (HR 1.54-2.49 across medication classes) 9

Device Therapy Considerations

• Generally not indicated for LVEF 41-45% unless other specific criteria are met 2
• If LVEF remains ≤35% despite optimal medical therapy, consider ICD for primary prevention and CRT if QRS ≥130 ms with LBBB 1, 3, 2
• Both ICD and CRT provide high economic value when appropriately indicated 1, 3