What is the initial treatment approach for a patient with Heart Failure with Reduced Ejection Fraction (HFrEF)?

Initial Treatment Approach for Heart Failure with Reduced Ejection Fraction (HFrEF)

Start all four foundational medication classes simultaneously at low doses as soon as HFrEF is diagnosed, rather than waiting to achieve target dosing of one medication before initiating the next. 1, 2

The Four Foundational Medications (Quadruple Therapy)

This combination reduces all-cause mortality by approximately 73% over 2 years compared to no treatment and extends life expectancy by approximately 6 years. 1, 3

1. SGLT2 Inhibitor (Start First)

• Dapagliflozin 10 mg once daily or Empagliflozin 10 mg once daily 1
• No dose titration required 1
• Benefits occur within weeks of initiation 1
• Minimal blood pressure effect (only -1.50 mmHg in patients with baseline SBP 95-110 mmHg) 1
• Can be used if eGFR ≥30 ml/min/1.73 m² for empagliflozin or ≥20 ml/min/1.73 m² for dapagliflozin 1

2. Mineralocorticoid Receptor Antagonist (Start Simultaneously)

• Spironolactone 12.5-25 mg daily or Eplerenone 25 mg daily 1, 4
• Provides at least 20% mortality reduction 1, 4
• Minimal blood pressure effect 1
• Requires potassium <5.0 mEq/L before initiation and eGFR >30 ml/min/1.73 m² 1
• Monitor potassium and creatinine at 1-2 weeks after initiation 1

3. Beta-Blocker (Start Simultaneously)

• Carvedilol, metoprolol succinate, or bisoprolol 1, 4
• Start at low dose: Carvedilol 3.125 mg twice daily, Metoprolol succinate 12.5-25 mg daily, or Bisoprolol 1.25 mg daily 1
• Provides at least 20% mortality reduction 1, 4
• Carvedilol is preferred if refractory hypertension is present due to combined α1-β1-β2-blocking properties 5

4. ARNI (Angiotensin Receptor-Neprilysin Inhibitor) - Preferred Over ACE Inhibitors

• Sacubitril/valsartan (Entresto) 49/51 mg twice daily 1, 2
• Provides at least 20% mortality reduction, superior to ACE inhibitors 1, 2
• Critical: If switching from ACE inhibitor, observe strict 36-hour washout period to avoid angioedema 1, 2
• If ARNI not tolerated: Use ACE inhibitor (e.g., enalapril 2.5-5 mg twice daily) or ARB (e.g., valsartan 40 mg twice daily) 1, 4

Diuretics for Volume Management (Add as Needed)

• Loop diuretics are essential for congestion control but do not reduce mortality 1
• Starting doses: 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 1
• Titrate to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use lowest dose that maintains this state 1

Uptitration Strategy

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

Prioritization Order for Uptitration:

1. SGLT2 inhibitor and MRA first (already at target doses or minimal titration needed) 1
2. Beta-blocker - Target doses: Carvedilol 25 mg twice daily, Metoprolol succinate 200 mg daily, or Bisoprolol 10 mg daily 1
3. ARNI - Target dose: Sacubitril/valsartan 97/103 mg twice daily 1, 2

Monitoring Requirements:

• Check blood pressure, renal function, and electrolytes at 1-2 weeks after each dose increment 1
• More frequent monitoring in elderly patients and those with chronic kidney disease 1
• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation 1

Managing Low Blood Pressure During Optimization

Never discontinue or reduce GDMT for asymptomatic hypotension with adequate perfusion. 1 Patients with adequate perfusion can tolerate systolic BP 80-100 mmHg. 1

If Symptomatic Hypotension Occurs (SBP <80 mmHg or major symptoms):

Step 1: Address reversible non-HF causes first 1

• Stop alpha-blockers (tamsulosin, doxazosin, terazosin, alfuzosin) 1
• Discontinue other non-essential BP-lowering medications 1
• Evaluate for dehydration, infection, or acute illness 1

Step 2: Non-pharmacological interventions 1

• Compression leg stockings for orthostatic symptoms 1
• Exercise and physical training programs 1
• Space out medication timing 1

Step 3: If symptoms persist, reduce GDMT in this specific order 1

• Always maintain SGLT2 inhibitor and MRA (minimal BP effects) 1
• If heart rate >70 bpm: Reduce ACEi/ARB/ARNI dose first 1
• If heart rate <60 bpm: Reduce beta-blocker dose first 1

Additional Therapies for Specific Subgroups

For Self-Identified Black Patients with NYHA Class III-IV Symptoms:

• Hydralazine/isosorbide dinitrate in addition to quadruple therapy 5, 1
• Starting dose: Hydralazine 25 mg three times daily + Isosorbide dinitrate 20 mg three times daily 1
• Target dose: Hydralazine 75 mg three times daily + Isosorbide dinitrate 40 mg three times daily 1

For Persistent Heart Rate ≥70 bpm Despite Maximally Tolerated Beta-Blocker:

• Ivabradine 2.5-5 mg twice daily (only in sinus rhythm) 1, 6
• Target dose: 7.5 mg twice daily 1

Critical Contraindications and Medications to Avoid

Never combine: 1, 4

• ACE inhibitor with ARNI (risk of angioedema) 1
• Triple combination of ACE inhibitor + ARB + MRA (risk of hyperkalemia and renal dysfunction) 1, 4

Avoid in HFrEF: 5, 4

• Non-dihydropyridine calcium channel blockers (diltiazem, verapamil) - increase risk of worsening heart failure 5, 4
• Moxonidine 5
• Alpha-adrenergic blockers (doxazosin) unless other drugs inadequate at maximum tolerated doses 5

Common Pitfalls to Avoid

• Delaying initiation of all four medication classes - start simultaneously, not sequentially 1
• Accepting suboptimal doses - only 1% of patients receive target doses of all medications in real-world practice 1
• Stopping medications for asymptomatic hypotension - discontinuing RAASi after hypotension is associated with two to fourfold higher risk of subsequent adverse events 1
• Overreacting to laboratory changes - modest creatinine elevation (up to 30% above baseline) is acceptable 1
• Using non-evidence-based beta-blockers - only carvedilol, metoprolol succinate, and bisoprolol have proven mortality benefit 1, 4

When to Refer to Heart Failure Specialist

• Newly diagnosed HFrEF patients to maximize GDMT optimization 1
• Persistent symptoms despite optimal GDMT 1
• Considering mechanical circulatory support or transplantation evaluation 1
• Difficulty achieving target doses due to hypotension, renal dysfunction, or hyperkalemia 1