What is the best treatment approach for a patient with a reduced ejection fraction (EF) of 45-50%, indicating heart failure with reduced ejection fraction (HFrEF)?

Treatment of Heart Failure with EF 45-50% (HFmrEF)

Patients with an ejection fraction of 45-50% should be treated with the same quadruple guideline-directed medical therapy (GDMT) as HFrEF patients, including SGLT2 inhibitors, mineralocorticoid receptor antagonists, beta-blockers, and ARNI/ACE inhibitors, as this EF range falls within the HFmrEF category (41-49%) where these therapies have demonstrated benefit. 1, 2

Understanding the Classification

Your patient's EF of 45-50% places them in the HF with mildly reduced EF (HFmrEF) category, defined as LVEF 41-49% by the 2022 ACC/AHA/HFSA guidelines. 1 This is a critical distinction because:

• HFmrEF represents a dynamic state: 26.9% of patients decline to EF ≤40% (HFrEF) and 44.8% improve to EF ≥50% (HFpEF) over time. 3
• One EF measurement is inadequate: The trajectory of LVEF over time and the underlying cause must be evaluated, as patients are usually transitioning either toward improvement from HFrEF or deterioration to HFrEF. 1
• Clinical characteristics resemble HFpEF more than HFrEF, but treatment should follow HFrEF protocols given the proven mortality benefit. 3

Foundational Quadruple Therapy (Initiate Simultaneously)

The 2022 ACC/AHA/HFSA guidelines recommend starting all four medication classes as soon as possible after diagnosis, not sequentially: 2, 4

1. SGLT2 Inhibitors (Start First)

• Dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily 2, 4
• Reduces cardiovascular death and HF hospitalization regardless of diabetes status 2, 4, 5
• Minimal blood pressure effect (only -1.50 mmHg in patients with baseline SBP 95-110 mmHg), making it ideal as the first agent 2
• Provides incremental benefit beyond neurohormonal therapy 4, 5

2. Mineralocorticoid Receptor Antagonists (Start Simultaneously)

• Spironolactone 12.5-25 mg once daily or eplerenone 25 mg once daily 2, 4, 6
• Provides at least 20% mortality reduction and reduces sudden cardiac death 2
• Minimal blood pressure effect, allowing early initiation 2
• Monitor potassium and renal function: Contraindicated if K+ >5.0 mmol/L or eGFR <30 mL/min 4
• Indicated for LVEF ≤35% with persistent symptoms, but evidence supports use in HFmrEF given the threshold of <50% for RAAS inhibitor therapy 6

3. Beta-Blockers

• Evidence-based agents only: Carvedilol, metoprolol succinate, or bisoprolol 2, 4, 6
• Starting doses: Carvedilol 3.125 mg twice daily, metoprolol succinate 12.5-25 mg once daily, or bisoprolol 1.25 mg once daily 2
• Reduce mortality by at least 20% and decrease sudden cardiac death 2
• Should be considered for all patients with LVEF <50% 6

4. ARNI (Preferred) or ACE Inhibitor/ARB

• Sacubitril/valsartan (ARNI) is preferred over ACE inhibitors: Provides superior mortality reduction of at least 20% 2, 7
• Starting dose: Sacubitril/valsartan 24/26 mg or 49/51 mg twice daily 7
• Target dose: 97/103 mg twice daily after 2-4 weeks 7
• Critical contraindication: Allow 36-hour washout if switching from ACE inhibitor 7
• If ARNI not tolerated: ACE inhibitor (enalapril, lisinopril) or ARB (losartan, valsartan) 2, 4

Titration Strategy

Up-titrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved: 2

1. Start SGLT2 inhibitor and MRA first (minimal BP effects)
2. Add beta-blocker if heart rate >70 bpm
3. Add low-dose ARNI or ACE inhibitor/ARB
4. Double doses every 2-4 weeks as tolerated

Diuretics for Volume Management

• Loop diuretics are essential for congestion control but do not reduce mortality 2
• Starting doses: Furosemide 20-40 mg once or twice daily, torsemide 10-20 mg once daily, or bumetanide 0.5-1.0 mg once daily 2
• Titrate to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use the lowest dose that maintains this state 2

Additional Therapies for Persistent Symptoms

Ivabradine

• Consider if heart rate ≥70 bpm in sinus rhythm despite maximally tolerated beta-blocker 2, 4, 5
• Starting dose: 2.5-5 mg twice daily 2
• Survival benefit is modest or negligible in the broad HFrEF population 2

Hydralazine/Isosorbide Dinitrate

• Indicated for self-identified Black patients with NYHA class III-IV symptoms despite optimal therapy 2, 4
• Starting dose: Hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily 2
• May be inferior to ACE inhibitors for mortality 2

Device Therapy Considerations

Implantable Cardioverter-Defibrillator (ICD)

• Recommended for patients with symptomatic HF (NYHA Class II-III) and LVEF ≤35% despite ≥3 months of optimal medical therapy 2, 6
• Your patient with EF 45-50% does not currently meet criteria, but reassess if EF declines 2, 6

Cardiac Resynchronization Therapy (CRT)

• Recommended for symptomatic HFmrEF patients in sinus rhythm with QRS duration ≥150 msec and LBBB morphology with LVEF ≤35% 2, 6
• Not indicated at EF 45-50% unless EF declines 2, 6

Critical Pitfalls to Avoid

• Never delay initiation of all four medication classes: Sequential therapy delays mortality benefit 2
• Do not withhold therapy for asymptomatic hypotension with adequate perfusion: GDMT has proven efficacy and safety across all baseline SBP levels, even <110 mmHg 2
• Do not accept suboptimal doses: Target doses provide maximum benefit 2
• Do not use non-evidence-based beta-blockers (e.g., atenolol, metoprolol tartrate): Only carvedilol, metoprolol succinate, and bisoprolol reduce mortality 2
• Avoid combining ACE inhibitor with ARNI: 36-hour washout required 7
• Avoid triple combination of ACE inhibitor + ARB + MRA: Increased risk of hyperkalemia and renal dysfunction 2

Medications to Avoid

• Diltiazem or verapamil: Increase risk of worsening heart failure and hospitalization 2
• Alpha-blockers (tamsulosin, doxazosin): Can interfere with GDMT optimization by causing hypotension; consider 5-alpha reductase inhibitors instead for BPH 2

Monitoring and Follow-Up

• Reassess EF in 3-6 months: HFmrEF is a dynamic state requiring longitudinal evaluation 1, 3
• Monitor potassium and renal function within 1-2 weeks of starting MRA, then periodically 4
• If EF improves to ≥50%: Continue GDMT to prevent relapse of heart failure and LV dysfunction 6
• If EF declines to ≤40%: Reassess for ICD/CRT eligibility 2, 6