What are the guidelines for treating a patient with heart failure with reduced ejection fraction (HFrEF)?

Guideline-Directed Medical Therapy for Heart Failure with Reduced Ejection Fraction (HFrEF)

All patients with HFrEF should immediately start 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

This quadruple therapy approach provides approximately 73% mortality reduction over 2 years when combined, translating to 5.3 additional life-years compared to no treatment. 2 The 2022 AHA/ACC/HFSA guidelines elevated SGLT2 inhibitors to foundational therapy status alongside the traditional three pillars, fundamentally changing the standard of care. 1

Initial Medication Regimen

Start All Four Classes Simultaneously

Begin SGLT2 inhibitor and MRA first since they have minimal blood pressure effects, making them ideal initial agents. 2

• SGLT2 Inhibitors: Dapagliflozin 10 mg once daily (if eGFR ≥20 mL/min/1.73 m²) or empagliflozin 10 mg once daily (if eGFR ≥30 mL/min/1.73 m²) 2

  • These reduce cardiovascular death and HF hospitalization regardless of diabetes status 1, 2
  • Benefits occur within weeks of initiation with no up-titration required 2
  • Cause minimal blood pressure decrease (only -1.50 mmHg in patients with baseline SBP 95-110 mmHg, diminishing to <1 mmHg after 4 months) 2

• Mineralocorticoid Receptor Antagonists: Spironolactone 12.5-25 mg once daily or eplerenone 25 mg once daily (if eGFR >30 mL/min/1.73 m²) 2, 3

  • Provide at least 20% mortality reduction and reduce sudden cardiac death 2
  • Have minimal blood pressure effects allowing early initiation 2
  • Target dose: spironolactone 25-50 mg daily or eplerenone 50 mg daily 3

• Beta-Blockers: Use only evidence-based agents: carvedilol (starting 3.125 mg twice daily), metoprolol succinate (starting 12.5-25 mg once daily), or bisoprolol (starting 1.25 mg once daily) 2

  • Reduce mortality by at least 20% and decrease sudden cardiac death 2
  • Critical pitfall: Non-evidence-based beta-blockers like atenolol or metoprolol tartrate should not be used 2

• ARNI (Sacubitril/Valsartan): Starting dose 24/26 mg or 49/51 mg twice daily 2

  • Provides at least 20% mortality reduction, superior to ACE inhibitors 2
  • Preferred over ACE inhibitors or ARBs for all eligible patients 1, 2
  • If ARNI not tolerated, use ACE inhibitor (e.g., enalapril 2.5-5 mg twice daily, lisinopril 2.5-5 mg once daily) or ARB (e.g., losartan 25-50 mg once daily, valsartan 40 mg twice daily) 2
  • Never combine ACE inhibitor with ARNI due to angioedema risk 2

Loop Diuretics for Volume Management

• 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 or twice daily 2
• Titrate to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use lowest dose that maintains this state 2

Uptitration Strategy

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

Prioritization Order for Uptitration:

1. SGLT2 inhibitor (no titration needed—already at target dose) 2
2. MRA (titrate to target within 4-8 weeks) 2, 3
3. Beta-blocker (titrate to target over 8-12 weeks) 2
4. ARNI/ACE inhibitor/ARB (titrate to target over 8-12 weeks) 2

Target Doses:

• Carvedilol: 25 mg twice daily (50 mg twice daily if >85 kg) 2
• Metoprolol succinate: 200 mg once daily 2
• Bisoprolol: 10 mg once daily 2
• Sacubitril/valsartan: 97/103 mg twice daily 2
• Enalapril: 10-20 mg twice daily 2
• Lisinopril: 20-40 mg once daily 2
• Spironolactone: 25-50 mg once daily 2
• Eplerenone: 50 mg once daily 3

Managing Low Blood Pressure During Optimization

Never discontinue or reduce GDMT for asymptomatic hypotension with adequate perfusion—GDMT medications maintain efficacy and safety even in patients with baseline SBP <110 mmHg. 2

Algorithm for Symptomatic Hypotension (SBP <80 mmHg or major symptoms):

Step 1: Address reversible non-HF causes first 2

• Stop alpha-blockers (tamsulosin, doxazosin, terazosin, alfuzosin) 2
• Discontinue other non-essential BP-lowering medications 2
• Evaluate for dehydration, infection, or acute illness 2

Step 2: Non-pharmacological interventions 2

• Compression leg stockings for orthostatic symptoms 2
• Space out medication timing throughout the day 2
• Exercise and physical training programs 2
• Adequate salt and fluid intake if not volume overloaded 2

Step 3: If symptoms persist, reduce GDMT in this specific order 2

• If heart rate >70 bpm: Reduce ACEi/ARB/ARNI dose first 2
• If heart rate <60 bpm: Reduce beta-blocker dose first 2
• Always maintain SGLT2 inhibitor and MRA (minimal BP effects) 2

Critical evidence: Discontinuing RAAS inhibitors after hypotension is associated with two to fourfold higher risk of subsequent adverse events compared to continuing therapy. 2

Monitoring Requirements

Monitor blood pressure, renal function, and electrolytes at 1-2 weeks after each dose increment. 2

Potassium Management:

• If K+ <5.0 mEq/L: Continue uptitration 3
• If K+ 5.0-5.4 mEq/L: No adjustment needed 3
• If K+ 5.5-5.9 mEq/L: Reduce MRA dose (e.g., from 50 mg to 25 mg daily or from 25 mg daily to every other day) 3
• If K+ ≥6.0 mEq/L: Withhold MRA and restart at 25 mg every other day when K+ <5.5 mEq/L 3
• Consider potassium binders (patiromer, sodium zirconium cyclosilicate) rather than discontinuing life-saving medications 2

Renal Function Management:

• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation 2
• Changes in kidney function during GDMT optimization must be interpreted in the context of decongestion 2
• Worsening kidney function with successful decongestion is associated with lower mortality than failure to decongest with stable kidney function 2

Device Therapy Considerations

Implantable Cardioverter-Defibrillator (ICD):

• Indicated for primary prevention in patients with symptomatic HF (NYHA Class II-III) and LVEF ≤35% despite ≥3 months of optimal medical therapy, who are expected to survive >1 year with good functional status 2
• Also indicated for secondary prevention in patients who have recovered from ventricular arrhythmia causing hemodynamic instability 2

Cardiac Resynchronization Therapy (CRT):

• Recommended for symptomatic HFrEF patients in sinus rhythm with QRS duration ≥150 msec and left bundle branch block (LBBB) morphology with LVEF ≤35% despite optimal medical therapy 2
• Class I indication if QRS ≥130 msec and LBBB in sinus rhythm 2

Additional Therapies for Specific Subgroups

Ivabradine:

• Consider if heart rate ≥70 bpm in sinus rhythm despite maximally tolerated beta-blocker 2
• Starting dose: 2.5-5 mg twice daily 2
• Important caveat: 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
• Starting dose: hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily 2
• Can prolong survival but may be inferior to ACE inhibitors for mortality 2

Vericiguat:

• May have a role in certain subgroups of HFrEF patients with recent worsening HF 4

Critical Contraindications and Medications to Avoid

Avoid diltiazem or verapamil in HFrEF—they increase the risk of worsening heart failure and hospitalization. 2

• Never combine ACE inhibitor with ARNI (angioedema risk) 2
• Avoid triple combination of ACE inhibitor + ARB + MRA (hyperkalemia and renal dysfunction risk) 2
• Do not use non-evidence-based beta-blockers (atenolol, metoprolol tartrate) 2

Common Pitfalls to Avoid

1. Delaying initiation of all four medication classes: Start simultaneously, not sequentially 2
2. Accepting suboptimal doses: Target doses provide maximum benefit—uptitrate aggressively 2
3. Stopping medications for asymptomatic hypotension: Adverse events occur in 75-85% of HFrEF patients regardless of treatment, with no substantial difference between GDMT and placebo arms in clinical trials 2
4. Inadequate monitoring: Check labs 1-2 weeks after each dose change 2
5. Using non-evidence-based beta-blockers: Only carvedilol, metoprolol succinate, or bisoprolol reduce mortality 2

Real-World Implementation Challenges

Target doses of all recommended drugs were simultaneously achieved in only 1% of eligible patients in real-world registries, with discontinuation rates as high as 55% for ACE inhibitors. 2

Advanced age, female sex, lower blood pressure, and greater severity of HF are consistently associated with lower prescription or uptitration of GDMT. 2 Patient education about transient dizziness as a side effect of life-prolonging drugs improves compliance. 2

Referral to Advanced Heart Failure Specialist

Refer patients with advanced HF who wish to prolong survival to a team specializing in HF for evaluation of mechanical circulatory support or transplantation. 1, 2