What are the first-line medications for a patient with a reduced ejection fraction (EF) of 45%?

First-Line Medications for Ejection Fraction of 45%

For a patient with an ejection fraction of 45%, you should initiate the complete quadruple therapy regimen used for heart failure with reduced ejection fraction (HFrEF), including an ARNI (or ACE inhibitor/ARB), beta-blocker, mineralocorticoid receptor antagonist (MRA), and SGLT2 inhibitor, as this EF falls within the HFrEF/HFmrEF spectrum where these medications provide mortality and morbidity benefits. 1, 2

Classification and Treatment Approach

An ejection fraction of 45% is classified as heart failure with mildly reduced ejection fraction (HFmrEF), falling in the 41-49% range. 1 However, the treatment approach mirrors that of HFrEF (EF <40%), as patients in this range benefit from the same guideline-directed medical therapy. 1

Core Quadruple Therapy Components

1. ARNI (Angiotensin Receptor-Neprilysin Inhibitor) - First Choice

• Sacubitril/valsartan is the preferred first-line agent over ACE inhibitors or ARBs for patients with symptomatic heart failure and reduced/mildly reduced EF. 1, 2
• Start with 24 mg/26 mg twice daily and titrate to target dose of 97 mg/103 mg twice daily. 1
• This medication demonstrated a 20% reduction in cardiovascular death or HF hospitalization compared to enalapril, including a 20% reduction in sudden cardiac death. 1
• If ARNI is not tolerated or available, use an ACE inhibitor (preferred) or ARB as alternatives. 1, 3

2. Beta-Blocker

• Use one of the three evidence-based beta-blockers: carvedilol, metoprolol succinate, or bisoprolol. 1, 3, 2
• These specific agents have proven mortality benefit in HFrEF. 1, 4
• Start at low doses and titrate gradually to target doses over 6-12 weeks. 2
• Beta-blockers should be initiated even in stable patients and continued long-term. 2, 4

3. Mineralocorticoid Receptor Antagonist (MRA)

• Spironolactone or eplerenone should be added for patients with NYHA class II-IV symptoms and EF ≤45%. 1, 3
• Start spironolactone at 25 mg daily. 1
• Critical monitoring requirement: Check serum potassium and creatinine before initiation and regularly during treatment, especially when combined with ARNI/ACE inhibitor/ARB. 3, 2
• Avoid if potassium >5.0 mEq/L or eGFR <30 mL/min/1.73 m². 1

4. SGLT2 Inhibitor

• Dapagliflozin 10 mg daily or empagliflozin 10 mg daily should be initiated regardless of diabetes status. 1, 2
• These agents reduce HF hospitalizations and cardiovascular mortality with benefits independent of diabetic status. 1, 2
• SGLT2 inhibitors represent a major advancement in HF therapy and should be started early. 1, 2

Additional Therapies Based on Specific Indications

Diuretics

• Use loop diuretics as needed to manage volume overload and congestion symptoms. 1
• Diuretics improve symptoms but do not reduce mortality, so they should be dosed to achieve euvolemia without excessive diuresis. 1

Hydralazine Plus Isosorbide Dinitrate

• Add this combination if the patient is African American with NYHA class III-IV symptoms on standard GDMT. 1, 3
• This combination can also be used in patients who cannot tolerate ACE inhibitors, ARBs, or ARNI. 1

Ivabradine

• Consider adding ivabradine if the patient remains symptomatic with heart rate >70 bpm despite maximally tolerated beta-blocker doses and is in sinus rhythm. 1
• Start with 5 mg twice daily (2.5 mg if age ≥75 years) and titrate based on heart rate response. 1

Implementation Strategy

Start multiple medications simultaneously at low doses rather than sequentially, then titrate each medication toward target doses over 6-12 weeks. 2 This approach achieves therapeutic benefit faster than waiting to reach target dose of one medication before starting another. 2

Titration Timeline

• Reassess every 2 weeks during initial titration phase. 1
• Monitor blood pressure, heart rate, renal function, and electrolytes at each visit. 3, 2
• Continue uptitration even if symptoms improve, as medications provide mortality benefit beyond symptom relief. 1, 2

Critical Pitfalls to Avoid

• Do not combine ACE inhibitor with ARB with MRA (triple RAAS blockade) - this is potentially harmful. 1
• Avoid NSAIDs as they worsen renal function and counteract GDMT benefits. 2
• Do not use non-dihydropyridine calcium channel blockers (verapamil, diltiazem) as they have negative inotropic effects and worsen HF. 1, 3, 5
• Do not discontinue medications if EF improves - patients with improved EF (HFimpEF) should continue all GDMT to prevent relapse. 1
• Avoid underdosing - many patients receive suboptimal doses; push toward target doses unless limited by side effects. 6, 7

Monitoring Parameters

• Blood pressure and heart rate at each visit during titration. 1, 3
• Serum potassium and creatinine before starting MRA and within 1-2 weeks after initiation or dose changes. 3, 2
• Symptoms and functional capacity to assess treatment response. 2
• Watch for symptomatic hypotension with ARNI (occurs in 14% of patients but rarely requires discontinuation). 1