What are the initial management recommendations for heart failure with reduced ejection fraction (HFrEF)?

Initial Management of Heart Failure with Reduced Ejection Fraction (HFrEF)

All patients with symptomatic HFrEF should be started on quadruple therapy—consisting of an SGLT2 inhibitor, a mineralocorticoid receptor antagonist (MRA), a beta-blocker, and an ARNI (or ACE inhibitor/ARB if ARNI not tolerated)—simultaneously at low doses as soon as the diagnosis is confirmed, along with loop diuretics for volume management. 1, 2

Core Pharmacological Therapy: The Four Pillars

The 2022 ACC/AHA/HFSA guidelines establish four foundational medication classes that should be initiated together, not sequentially:

1. SGLT2 Inhibitors (Dapagliflozin or Empagliflozin)

• Start immediately at full dose (dapagliflozin 10 mg daily or empagliflozin 10 mg daily) 1, 2
• Reduces cardiovascular mortality and HF hospitalizations regardless of diabetes status 1
• No blood pressure, heart rate, or potassium effects—making it ideal as the first agent 2
• No dose titration required; benefits occur within weeks 2
• Only 0.9% higher rate of genital infection compared to placebo 2

2. Mineralocorticoid Receptor Antagonists (Spironolactone or Eplerenone)

• Start spironolactone 12.5-25 mg daily or eplerenone 25 mg daily 2, 3
• Provides at least 30% reduction in mortality risk 3
• Minimal blood pressure effect allows early initiation 2
• Monitor potassium and creatinine at 1-2 weeks after initiation 2
• Contraindicated if baseline creatinine >2.5 mg/dL or potassium >5.0 mEq/L 3
• Spironolactone causes 5.7% higher rate of gynecomastia; use eplerenone to avoid this 2
• Target dose: spironolactone 25-50 mg daily, eplerenone 50 mg daily 2, 3

3. Beta-Blockers (Carvedilol, Metoprolol Succinate, or Bisoprolol)

• Start at low doses: carvedilol 3.125 mg twice daily, metoprolol succinate 12.5-25 mg daily, or bisoprolol 1.25 mg daily 2, 4
• Provides at least 20% reduction in mortality and decreases sudden cardiac death 2, 4
• Uptitrate every 1-2 weeks to target doses: carvedilol 25-50 mg twice daily, metoprolol succinate 200 mg daily, bisoprolol 10 mg daily 2
• Only use evidence-based beta-blockers—not atenolol or other non-evidence-based agents 4
• 5.5% higher rate of dizziness but 5% lower rate of serious adverse events compared to placebo 2

4. ARNI (Sacubitril/Valsartan) or ACE Inhibitor/ARB

• ARNI is preferred over ACE inhibitors or ARBs, providing at least 20% additional mortality reduction 2, 4
• Start sacubitril/valsartan 24/26 mg or 49/51 mg twice daily (lower dose if not on ACE inhibitor/ARB or on low doses) 4
• Mandatory 36-hour washout period when switching from ACE inhibitor to ARNI to avoid angioedema 2
• If ARNI not tolerated, use ACE inhibitor (lisinopril 5-10 mg daily, enalapril 2.5-5 mg twice daily) or ARB (losartan 25-50 mg daily, valsartan 40-80 mg twice daily) 2, 5
• Target ARNI dose: 97/103 mg twice daily 2
• ACE inhibitors cause 8.9% higher rate of cough and 3.9% higher rate of dizziness 2

Diuretics for Volume Management

Loop diuretics are essential for congestion control but do not reduce mortality 4:

• Start furosemide 20-40 mg once or twice daily, torsemide 10-20 mg once daily, or bumetanide 0.5-1.0 mg once or twice daily 4
• Titrate based on urine output and congestion symptoms 2
• For hospitalized patients, initial IV dose should equal or exceed chronic oral daily dose 2

Initiation Strategy: Simultaneous vs Sequential

The 2022 guidelines explicitly state that all four foundational medications may be started simultaneously at initial low doses, without need to achieve target dosing before initiating the next medication 1, 2. This represents a paradigm shift from older sequential approaches.

Recommended Initiation Sequence:

1. Start SGLT2 inhibitor and MRA first (minimal BP impact) 2, 4
2. Add beta-blocker and ARNI/ACE inhibitor/ARB simultaneously or within days 2
3. Uptitrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved 2, 4

Combined quadruple therapy reduces mortality risk by approximately 73% over 2 years compared to no treatment 2. Transitioning from traditional dual therapy to quadruple therapy extends life expectancy by approximately 6 years 2.

Monitoring and Dose Titration

Check blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment 2, 4:

• Modest creatinine increases up to 30% above baseline are acceptable and should not prompt discontinuation 2
• Asymptomatic low BP (systolic 80-100 mmHg) with adequate perfusion is tolerable—do not withhold therapy 2, 4
• More frequent monitoring needed in elderly patients and those with chronic kidney disease 2

Special Clinical Scenarios

Low Blood Pressure (<90 mmHg systolic)

• Do not withhold GDMT for asymptomatic low BP with adequate perfusion 2, 4
• Prioritize SGLT2 inhibitor and MRA first (minimal BP effect) 2
• Add selective β₁ receptor blocker, then very low-dose ARNI 2
• Consider ivabradine if beta-blockers not hemodynamically tolerated 2

Hospitalized Patients

• Continue GDMT except when hemodynamically unstable or contraindicated 2, 4
• Initiate after ≥24 hours of stabilization with adequate organ perfusion 2
• In-hospital initiation substantially improves post-discharge medication use compared to deferring to outpatient setting 2

African American Patients with NYHA Class III-IV

• Add hydralazine/isosorbide dinitrate (hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily, titrate to target of 75 mg/20 mg three times daily) 1, 4

Persistent Symptoms Despite Optimal Therapy

• Consider ivabradine if heart rate ≥70 bpm in sinus rhythm despite maximally tolerated beta-blocker (start 2.5-5 mg twice daily, target 7.5 mg twice daily) 4

Device Therapy Considerations

After optimizing medical therapy for ≥3 months, evaluate for:

Implantable Cardioverter-Defibrillator (ICD)

• Indicated for LVEF ≤35%, NYHA class II-III symptoms, and expected survival >1 year with good functional status 4, 6
• Also indicated for secondary prevention after cardiac arrest or hemodynamically unstable ventricular tachycardia 4

Cardiac Resynchronization Therapy (CRT)

• Indicated for LVEF ≤35%, NYHA class II-IV symptoms, sinus rhythm, and QRS ≥150 msec with LBBB morphology (Class I) 1, 4
• Class IIa indication if QRS 130-149 msec with LBBB 4

Critical Contraindications and Medications to Avoid

Never combine:

• ACE inhibitor with ARNI (risk of angioedema) 2
• ACE inhibitor + ARB + MRA (triple combination causes hyperkalemia and renal dysfunction) 4

Avoid in HFrEF:

• Diltiazem or verapamil (increase risk of worsening HF and hospitalization) 4
• Nonsteroidal anti-inflammatory drugs 6
• Most antiarrhythmic drugs (except amiodarone/dofetilide when indicated) 6

Common Pitfalls to Avoid

1. Delaying initiation of all four medication classes—less than 25% of eligible patients receive all medications concurrently, and only 1% receive target doses 2, 7
2. Accepting suboptimal doses—mortality benefits are dose-dependent 2
3. Stopping medications for asymptomatic hypotension—temporary fatigue and weakness with dose increases usually resolve within days 2
4. Overreacting to modest creatinine elevation—up to 30% increase is acceptable 2
5. Using non-evidence-based beta-blockers (e.g., atenolol) 4

Implementation Strategies

• Refer newly diagnosed HFrEF patients to HF specialty care to maximize GDMT optimization 2
• Nurse-led titration programs reduce all-cause mortality (OR 0.66,95% CI 0.48-0.92) 2
• Pharmacist involvement improves GDMT adherence and dosing 2
• Early follow-up within 7-14 days after medication adjustments 2

Patients with previous HFrEF whose EF improves to >40% should continue their HFrEF treatment regimen—discontinuation may lead to clinical deterioration 2.