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
• Benefits occur within weeks of initiation 1
• No up-titration required 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 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
• Target doses: carvedilol 25-50 mg twice daily, metoprolol succinate 200 mg daily, or bisoprolol 10 mg daily 2
• Up-titrate every 2 weeks as tolerated 2

4. ARNI (Preferred) or ACE Inhibitor/ARB

• Sacubitril/valsartan 24/26 mg or 49/51 mg twice daily (preferred) 1, 6

  • Provides at least 20% mortality reduction, superior to ACE inhibitors 1, 6, 5
  • In PARADIGM-HF trial: reduced cardiovascular death or HF hospitalization by 20% (HR 0.80,95% CI 0.73-0.87, p<0.0001) and all-cause mortality by 16% (HR 0.84,95% CI 0.76-0.93, p=0.0009) 6
  • Target dose: 97/103 mg twice daily 6
  • Do not combine with ACE inhibitor (risk of angioedema) 1, 6
  • Requires 36-hour washout period after stopping ACE inhibitor 6

• Alternative if ARNI not tolerated:

  • Enalapril 2.5 mg twice daily or lisinopril 5 mg once daily 2
  • Target doses: enalapril 10-20 mg twice daily or lisinopril 20-40 mg daily 2

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

Up-Titration Strategy

Increase 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 1
3. Add or up-titrate ARNI/ACEi/ARB 1
4. Monitor blood pressure, renal function, and electrolytes at 1-2 weeks after each dose increment 1

Acceptable Changes During Titration:

• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation 1
• Asymptomatic hypotension with adequate perfusion should not delay therapy 1

Special Populations and Dose Adjustments

Low Blood Pressure (SBP <100 mmHg but ≥80 mmHg)

• Do not withhold therapy for asymptomatic low BP with adequate perfusion 1
• Start SGLT2 inhibitor and MRA first 1
• Then add beta-blocker or very low-dose ARNI 1
• Reduce starting dose of ARNI to 24/26 mg twice daily if not on ACE inhibitor/ARB or on low doses 1, 6

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

• Reduce starting dose of ARNI to 24/26 mg twice daily 6
• Use dapagliflozin if eGFR ≥20 ml/min/1.73 m² 1

Moderate Hepatic Impairment

• Reduce starting dose of ARNI to 24/26 mg twice daily 6

Additional Therapies for Specific Subgroups

Self-Identified Black Patients with NYHA Class III-IV

• Hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily 1
• Target doses: hydralazine 75 mg three times daily + isosorbide dinitrate 40 mg three times daily 1

Persistent Symptoms Despite Optimal Therapy with Heart Rate ≥70 bpm

• Ivabradine 2.5-5 mg twice daily if in sinus rhythm despite maximally tolerated beta-blocker 1
• Survival benefit is modest or negligible in broad HFrEF population 1

Critical Contraindications

• Never combine ACE inhibitor with ARNI (risk of angioedema) 1, 6
• 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
• Do not use ARNI in patients with history of angioedema related to previous ACEi or ARB therapy 6
• Do not use ARNI concomitantly with aliskiren in patients with diabetes 6

Managing Symptomatic Hypotension (SBP <80 mmHg)

Step 1: Address Reversible Non-HF Causes First

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

Step 2: Non-Pharmacological Interventions

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

Step 3: Adjust GDMT Only If Steps 1-2 Fail

• 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

Critical caveat: Discontinuing RAAS inhibitors after hypotension is associated with two to fourfold higher risk of subsequent adverse events compared to continuing therapy. 1

Monitoring Requirements

• 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
• Potassium levels require close monitoring with MRAs 1
• If hyperkalemia develops, consider potassium binders like patiromer rather than discontinuing life-saving medications 1

Common Pitfalls to Avoid

• Delaying initiation of all four medication classes – start simultaneously 1
• Accepting suboptimal doses – aggressively up-titrate to target doses 1
• Stopping medications for asymptomatic hypotension – maintain therapy if perfusion adequate 1
• Using non-evidence-based beta-blockers – only use carvedilol, metoprolol succinate, or bisoprolol 1
• Inadequate monitoring – check labs 1-2 weeks after each change 1

Hospitalized Patients

• Continue ACE inhibitors/ARBs and beta-blockers during hospitalization in the absence of hemodynamic instability or contraindications 7
• Initiate foundational therapies in stable patients prior to hospital discharge if not already on them 7
• Initiate beta-blocker therapy after optimization of volume status and successful discontinuation of intravenous diuretics, vasodilators, and inotropic agents 7
• Start at low dose and use particular caution in patients who required inotropes during hospital course 7