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

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

Start all four foundational medication classes simultaneously as soon as possible after diagnosis: an SGLT2 inhibitor, a mineralocorticoid receptor antagonist (MRA), a beta-blocker, and an ARNI (or ACE inhibitor/ARB if ARNI not tolerated), along with loop diuretics for volume management. 1, 2

Foundational Quadruple Therapy

This combination provides approximately 73% mortality reduction over 2 years and adds 5.3 additional life-years compared to no treatment. 1

1. SGLT2 Inhibitor (Start First)

• Dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily 1
• Reduces cardiovascular death and HF hospitalization regardless of diabetes status 1, 3, 4
• Minimal blood pressure effect (only -1.50 mmHg in patients with baseline SBP 95-110 mmHg, diminishing to <1 mmHg after 4 months) 1
• No up-titration required; benefits occur within weeks 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 First)

• Spironolactone 12.5-25 mg once daily or eplerenone 25 mg once daily 1, 2
• Provides at least 20% mortality reduction and reduces sudden cardiac death 1, 5
• Minimal blood pressure effect, allowing early initiation 1
• Requires eGFR >30 ml/min/1.73 m² and potassium <5.0 mEq/L before initiating 1
• Target dose: spironolactone 25-50 mg daily or eplerenone 50 mg daily 1

3. Beta-Blocker (Start After SGLT2i and MRA)

• Carvedilol 3.125 mg twice daily, metoprolol succinate 12.5-25 mg once daily, or bisoprolol 1.25 mg once daily 1, 2, 5
• Reduces mortality by at least 20% and decreases sudden cardiac death 1, 5
• Start at low dose in stable patients only 6, 2
• Target doses: carvedilol 25-50 mg twice daily, metoprolol succinate 200 mg daily, or bisoprolol 10 mg daily 1, 2

4. ARNI (Preferred) or ACE Inhibitor/ARB

• Sacubitril/valsartan 24/26 mg or 49/51 mg twice daily (preferred) 1, 7

  • Provides at least 20% mortality reduction, superior to ACE inhibitors 1, 7, 5
  • Reduces cardiovascular death by 20% (HR 0.80) and all-cause mortality by 16% (HR 0.84) compared to enalapril 7
  • Target dose: 97/103 mg twice daily 7
  • Do not combine with ACE inhibitors (risk of angioedema) 1, 7
  • Wait 36 hours after stopping ACE inhibitor before starting ARNI 7

• Alternative if ARNI not tolerated: Enalapril 2.5 mg twice daily or lisinopril 5 mg once daily 2, 8

  • Target doses: enalapril 10-20 mg twice daily or lisinopril 20-40 mg daily 2

5. Loop Diuretics (For Volume Management)

• 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
• Essential for congestion control but do not reduce mortality 1
• Titrate to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use lowest dose that maintains this state 1

Titration Strategy

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

Recommended Sequence:

1. Start SGLT2 inhibitor and MRA first (minimal BP effects) 1
2. Add beta-blocker if heart rate >70 bpm or low-dose ARNI/ACEi/ARB 1
3. Up-titrate ARNI/ACEi/ARB to target dose 1
4. Up-titrate beta-blocker to target dose 1

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 GDMT medications maintain efficacy and safety even in patients with baseline SBP <110 mmHg. 1

For Symptomatic Hypotension (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: Reduce diuretic dose first, not GDMT 2

Step 3: Non-pharmacological interventions 1

• Compression leg stockings for orthostatic symptoms 1
• Exercise and physical training programs 1
• Adequate salt and fluid intake if not volume overloaded 1

Step 4: If symptoms persist, reduce GDMT in this specific order 1

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

Special Populations and Dose Adjustments

Patients Not on ACE Inhibitor/ARB or on Low Doses:

• Start ARNI at 24/26 mg twice daily instead of 49/51 mg 7

Severe Renal Impairment (eGFR <30 ml/min/1.73 m²):

• Start ARNI at 24/26 mg twice daily 7
• Avoid MRA if eGFR <30 ml/min/1.73 m² 1

Moderate Hepatic Impairment:

• Start ARNI at 24/26 mg twice daily 7

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

• Add hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily if symptoms persist despite optimal therapy 1
• Target dose: hydralazine 75 mg three times daily + isosorbide dinitrate 40 mg three times daily 1

Patients in Sinus Rhythm with Heart Rate ≥70 bpm:

• Consider ivabradine 2.5-5 mg twice daily if symptomatic despite maximally tolerated beta-blocker 1
• Target dose: 7.5 mg twice daily 1

Critical Contraindications and Medications to Avoid

• Never combine ACE inhibitor with ARNI (risk of angioedema) 1, 7
• Avoid triple combination of ACE inhibitor + ARB + MRA (risk of hyperkalemia and renal dysfunction) 1
• Avoid diltiazem or verapamil (increase risk of worsening heart failure and hospitalization) 1
• Avoid non-evidence-based beta-blockers (use only carvedilol, metoprolol succinate, or bisoprolol) 1, 2
• Avoid NSAIDs (increase risk of renal impairment and fluid retention) 7, 8

Common Pitfalls to Avoid

1. Delaying initiation of all four medication classes – Start simultaneously, not sequentially 1
2. Accepting suboptimal doses – Aggressively up-titrate to target doses 1
3. Stopping medications for asymptomatic hypotension – Asymptomatic low BP with adequate perfusion is expected and beneficial 1
4. Inadequate monitoring – Check labs 1-2 weeks after each dose change 1
5. Discontinuing RAASi after hypotension or hyperkalemia – Associated with two to fourfold higher risk of subsequent adverse events 1
6. Using non-evidence-based beta-blockers – Only carvedilol, metoprolol succinate, or bisoprolol reduce mortality 1, 2

Device Therapy Considerations

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

• ICD: For patients with LVEF ≤35%, NYHA class II-III symptoms, and expected survival >1 year with good functional status 1, 2
• CRT: For symptomatic patients in sinus rhythm with QRS ≥150 msec and LBBB morphology with LVEF ≤35% 1

Hospitalized Patients

Continue ACE inhibitors/ARBs and beta-blockers during hospitalization in the absence of hemodynamic instability or contraindications. 6 Initiate beta-blocker therapy only after optimization of volume status and successful discontinuation of intravenous diuretics, vasodilators, and inotropic agents. 6