What is the recommended treatment approach for a patient with heart failure and reduced ejection fraction?

Recommended Treatment for Heart Failure with Reduced Ejection Fraction

All patients with HFrEF should receive simultaneous initiation of four foundational medication classes 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 diuretics for volume management. 1, 2

Core Quadruple Therapy: The Four Pillars

1. SGLT2 Inhibitors (Start First)

• Dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily 2, 3
• Reduces cardiovascular death and HF hospitalization by approximately 25% regardless of diabetes status 2
• Minimal blood pressure effect (only -1.50 mmHg in patients with baseline SBP 95-110 mmHg), making it ideal as the first agent 2
• Benefits occur within weeks of initiation 2
• Can be used if eGFR ≥30 ml/min/1.73 m² for empagliflozin, or ≥20 ml/min/1.73 m² for dapagliflozin 2
• No up-titration required 2

2. Mineralocorticoid Receptor Antagonists (Start Simultaneously with SGLT2i)

• Spironolactone: Start 12.5-25 mg daily, target 25-50 mg daily 3
• Eplerenone: Start 25 mg daily, target 50 mg daily 3
• Provides at least 20% mortality reduction and reduces sudden cardiac death 2, 4
• The RALES trial demonstrated 30% reduction in all-cause mortality (p<0.001) 4
• Minimal blood pressure effect, allowing early initiation 2
• Requires eGFR >30 ml/min/1.73 m² and baseline potassium <5.0 mEq/L 2, 4
• Monitor potassium and creatinine at 1 and 4 weeks after starting, then at 8 and 12 weeks, 6,9, and 12 months, then every 4 months 3

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

• Sacubitril/valsartan (Entresto): Start 24/26 mg or 49/51 mg twice daily, target 97/103 mg twice daily 3, 5
• Provides at least 20% mortality reduction, superior to ACE inhibitors 2, 5
• The PARADIGM-HF trial showed 20% reduction in cardiovascular death or HF hospitalization compared to enalapril 5

Dosing algorithm for sacubitril/valsartan: 3, 5

• High-dose ACE inhibitor background: Start 49/51 mg twice daily
• Low/medium-dose ACE inhibitor or ARB background: Start 24/26 mg twice daily
• Treatment-naïve (no prior ACE inhibitor/ARB): Start 24/26 mg twice daily
• High-risk patients (severe renal impairment eGFR <30, moderate hepatic impairment Child-Pugh B, age ≥75 years): Start 24/26 mg twice daily

Critical safety requirement: 36-hour washout period required when switching from ACE inhibitor to avoid angioedema; no washout needed when switching from ARB 5

If ARNI not tolerated: Use ACE inhibitor (enalapril, lisinopril, ramipril) or ARB (losartan, valsartan) 2

4. Beta-Blockers (Evidence-Based Only)

• Only three beta-blockers reduce mortality in HFrEF: 3
  • Carvedilol: Start 3.125 mg twice daily, target 25 mg twice daily (50 mg twice daily if >85 kg)
  • Metoprolol succinate (extended-release): Start 12.5-25 mg daily, target 200 mg daily
  • Bisoprolol: Start 1.25 mg daily, target 10 mg daily
• Provides at least 20% mortality reduction and decreases sudden cardiac death 2
• Critical pitfall: Metoprolol tartrate (immediate-release) does NOT reduce mortality and should NOT be used 3
• Never use: Diltiazem or verapamil—these increase risk of worsening HF and hospitalization 2

5. Loop Diuretics (For Volume Management Only)

• Essential for congestion control but do NOT reduce mortality 2
• Furosemide: 20-40 mg once or twice daily 2
• Torsemide: 10-20 mg once daily 2
• 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

Initiation Strategy: Start All Four Classes Simultaneously

The modern approach is rapid sequential initiation, NOT the outdated "start one, wait, then add another" approach. 2

1. Week 0: Start SGLT2 inhibitor + MRA first (minimal BP effects) 2
2. Week 0-1: Add beta-blocker if heart rate >70 bpm 2
3. Week 0-2: Add ARNI/ACE inhibitor/ARB at low dose 2
4. Weeks 2-12: Up-titrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose achieved 2, 3

Prioritization order for up-titration: SGLT2i and MRA first (already at target), then beta-blocker, then ARNI 2

Managing Low Blood Pressure During Optimization

Asymptomatic hypotension is NOT a reason to withhold or reduce GDMT. 2, 5

Algorithm for Low Blood Pressure (SBP <100 mmHg):

1. First, eliminate non-HF causes of hypotension: 2

   • Stop alpha-blockers (tamsulosin, doxazosin, terazosin, alfuzosin)
   • Evaluate for dehydration, infection, or acute illness
   • Space out medication timing throughout the day

2. If patient has adequate perfusion (no dizziness, confusion, or cool extremities): 2

   • Continue all GDMT medications
   • Educate patient that transient dizziness is a side effect of life-prolonging drugs
   • GDMT maintains efficacy and safety even with SBP <110 mmHg

3. If symptomatic hypotension occurs: 2, 5

   • Reduce diuretic dose first in non-congested patients
   • If still symptomatic, temporarily reduce ARNI dose (NOT discontinue)
   • Re-titrate back to target dose within 2-4 weeks
   • 40% of patients requiring temporary dose reduction can be restored to target doses

4. Modified initiation sequence for baseline SBP <100 mmHg: 2

   • Start SGLT2 inhibitor and MRA first (smallest BP effect: -1.50 mmHg)
   • Add very low-dose beta-blocker if HR >70 bpm
   • Add very low-dose ARNI (24/26 mg twice daily)
   • Up-titrate slowly with small increments

Monitoring Requirements

At 1-2 weeks after each dose increment: 2, 3

• Blood pressure
• Renal function (creatinine, eGFR)
• Electrolytes (potassium, sodium)

Acceptable laboratory changes during optimization: 2

• Creatinine increase up to 30% above baseline is acceptable and should NOT prompt discontinuation
• Potassium up to 5.5 mEq/L is acceptable with close monitoring
• If hyperkalemia develops, consider potassium binders (patiromer) rather than discontinuing MRA

More frequent monitoring required for: 2

• Elderly patients (≥75 years)
• Chronic kidney disease (eGFR <60 ml/min/1.73 m²)
• Baseline potassium 4.5-5.0 mEq/L

Additional Therapies for Specific Subgroups

For Self-Identified Black Patients with Persistent Symptoms (NYHA Class III-IV)

• Hydralazine/isosorbide dinitrate (H-ISDN): 2, 3
  • Start: Hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily
  • Target: Hydralazine 75 mg three times daily + isosorbide dinitrate 40 mg three times daily
  • Class 1A recommendation (strongest evidence)

For Patients with Heart Rate ≥70 bpm Despite Maximally Tolerated Beta-Blocker

• Ivabradine: 2, 3
  • Start: 2.5-5 mg twice daily
  • Target: Titrate to heart rate 50-60 bpm, maximum 7.5 mg twice daily
  • Only for patients in sinus rhythm
  • Survival benefit is modest or negligible in broad HFrEF population

Device Therapy Considerations

Implantable Cardioverter-Defibrillator (ICD)

• Indicated for: Symptomatic HF (NYHA Class II-III) with LVEF ≤35% despite ≥3 months of optimal medical therapy, expected survival >1 year with good functional status 2

Cardiac Resynchronization Therapy (CRT)

• Indicated 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

Critical Contraindications and Medications to Avoid

Never combine: 2

• ACE inhibitor with ARNI (risk of angioedema)
• ACE inhibitor + ARB + MRA (triple RAAS blockade—risk of hyperkalemia and renal dysfunction)

Avoid in HFrEF: 2

• Non-evidence-based beta-blockers (atenolol, metoprolol tartrate)
• Calcium channel blockers (diltiazem, verapamil)—increase risk of worsening HF
• Routine use of nitrates or phosphodiesterase-5 inhibitors

Common Pitfalls to Avoid

1. Delaying initiation of all four medication classes 2

   • Real-world data shows only 1% of eligible patients achieve target doses of all recommended drugs simultaneously 2
   • Discontinuation rates as high as 55% for ACE inhibitors in registries 2

2. Accepting suboptimal doses 2

   • Target doses provide maximum mortality benefit
   • Medium-range doses do NOT provide most of the benefits of target doses

3. Stopping medications for asymptomatic hypotension 2, 5

   • Adverse events occur in 75-85% of HFrEF patients regardless of treatment
   • No substantial difference between GDMT and placebo arms in clinical trials

4. Inadequate monitoring leading to preventable adverse events 2

   • Hyperkalemia poses significant challenge but discontinuation of RAAS inhibitors after hyperkalemia associated with 2-4 fold higher risk of subsequent adverse events

5. Using non-evidence-based beta-blockers 3

   • Only bisoprolol, carvedilol, and metoprolol succinate reduce mortality
   • This is NOT a class effect

6. Permanently reducing doses when temporary reduction would be appropriate 2, 3

   • If congestion worsens during beta-blocker titration, double diuretic dose first before reducing beta-blocker
   • Only halve beta-blocker dose if increasing diuretic doesn't work

7. Never stop beta-blockers suddenly 3

   • Risk of rebound myocardial ischemia, infarction, and arrhythmias
   • Seek specialist advice before discontinuation

Expected Outcomes with Optimal GDMT

When all four medication classes are used at target doses, the combined mortality reduction is approximately 73% over 2 years. 2 This represents one of the most effective treatments in all of medicine, comparable to cancer therapies, yet real-world implementation remains suboptimal with advanced age, female sex, lower blood pressure, and greater severity of HF consistently associated with lower prescription or up-titration of GDMT. 2