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 the diagnosis is confirmed: an SGLT2 inhibitor, a mineralocorticoid receptor antagonist (MRA), an evidence-based beta-blocker, and an ARNI (or ACE inhibitor/ARB if ARNI not tolerated), along with loop diuretics for volume management. 1

Foundational Quadruple Therapy

The modern approach to HFrEF requires immediate initiation of all four medication classes together, not sequentially. This combined therapy reduces mortality by approximately 73% over 2 years compared to no treatment, and transitioning from traditional dual therapy to quadruple therapy extends life expectancy by approximately 6 years. 2

The Four Essential Drug Classes:

1. SGLT2 Inhibitors (Dapagliflozin or Empagliflozin)

• Start immediately at full dose with no titration required 1, 2
• Dapagliflozin 10 mg once daily or Empagliflozin 10 mg once daily 1
• Benefits occur within weeks of initiation 2
• No blood pressure, heart rate, or potassium effects make this ideal for first initiation 1, 2
• 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 Antagonists (MRAs)

• Start spironolactone 12.5-25 mg daily or eplerenone 25 mg daily 1, 3
• Provides at least 20% mortality reduction and reduces sudden cardiac death 4, 2
• Minimal blood pressure effect allows early initiation 1
• Target dose: spironolactone 25-50 mg daily or eplerenone 50 mg daily 1
• Can be used if eGFR >30 ml/min/1.73 m² 1
• Monitor potassium and creatinine closely 1

3. Evidence-Based Beta-Blockers

• Use only carvedilol, metoprolol succinate, or bisoprolol 4, 2
• Start at low doses: 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 and reduces sudden cardiac death 4, 2
• Target doses: carvedilol 25-50 mg twice daily, metoprolol succinate 200 mg daily, bisoprolol 10 mg daily 4, 1

4. ARNI (Sacubitril/Valsartan) - Preferred Over ACE Inhibitors

• Start sacubitril/valsartan 24/26 mg or 49/51 mg twice daily 1, 2
• Provides at least 20% mortality reduction, superior to ACE inhibitors 4, 1
• Target dose: 97/103 mg twice daily 4, 1
• Critical: Require 36-hour washout period when switching from ACE inhibitor to avoid angioedema 2
• If ARNI not tolerated or available, use ACE inhibitor (lisinopril 2.5-5 mg daily initially, target 20-40 mg daily) or ARB 1, 5

Diuretics for Volume Management

Loop diuretics are essential for congestion control but do not reduce mortality. 1

Starting doses:

• Furosemide 20-40 mg once or twice daily 1
• Torsemide 10-20 mg once daily 1
• 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 the lowest dose that maintains this state. 1

Uptitration Strategy: The Forced-Titration Approach

Do not leave patients on starting doses indefinitely. The landmark trials that proved mortality benefit used aggressive uptitration to target doses, yet in clinical practice, <25% of patients receive all medications concurrently and only 1% achieve target doses of all medications. 4, 2

Uptitration Protocol:

• Increase one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved 1
• Prioritize SGLT2 inhibitor and MRA first (already at target dose for SGLT2i, uptitrate MRA), then beta-blocker, then ARNI 1
• Check blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment 1, 2
• Asymptomatic changes in vital signs and laboratory tests should NOT prevent uptitration 4
• If temporary dose reduction is needed, aggressively attempt to restore target doses 4

Managing Low Blood Pressure During Optimization

Do not withhold therapy for asymptomatic low blood pressure with adequate perfusion. Patients can tolerate systolic BP 80-100 mmHg if perfusion is adequate. 1, 2

Algorithm for Low Blood Pressure:

1. First, address reversible non-HF causes:

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

2. If SBP remains low but perfusion adequate:

   • Start SGLT2 inhibitor and MRA first (minimal BP effect) 1
   • Add low-dose beta-blocker if heart rate >70 bpm 1
   • Add very low-dose ARNI/ACEi/ARB last 1
   • Use small incremental dose increases with close monitoring 1

3. Space out medication administration throughout the day to minimize orthostatic drops 1

Special Populations

Hospitalized Patients:

• Continue GDMT except when hemodynamically unstable or contraindicated 2
• Initiate GDMT after ≥24 hours of stabilization with adequate organ perfusion 2
• In-hospital initiation substantially improves post-discharge medication use compared to deferring to outpatient setting 1

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

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

• Consider ivabradine 2.5-5 mg twice daily, though survival benefit is modest 1

Critical Contraindications and Medications to Avoid

• Never combine ACE inhibitor with ARNI (risk of angioedema) 1, 2
• Avoid triple combination of ACE inhibitor + ARB + MRA (hyperkalemia and renal dysfunction risk) 1
• Avoid diltiazem or verapamil (increase risk of worsening heart failure) 1
• Do not use non-evidence-based beta-blockers (only carvedilol, metoprolol succinate, or bisoprolol) 4

Monitoring Requirements

• Blood pressure, renal function, and electrolytes at 1-2 weeks after each dose increment 1, 2
• More frequent monitoring in elderly patients and those with chronic kidney disease 1, 2
• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation 1, 2
• Potassium levels require close monitoring with MRAs, but hyperkalaemia should be managed rather than leading to RAAS inhibitor discontinuation, as discontinuation is associated with 2-4 fold higher risk of adverse events 1

Common Pitfalls to Avoid

1. Sequential rather than simultaneous initiation - Start all four classes together 1, 2
2. Accepting suboptimal doses - Most patients remain on starting doses indefinitely in practice, but this has not been proven to prolong life 4
3. Stopping medications for asymptomatic hypotension - Adequate perfusion matters, not the blood pressure number 1, 2
4. Overreacting to laboratory changes - Modest creatinine elevation is acceptable 1, 2
5. Using non-evidence-based beta-blockers - Only carvedilol, metoprolol succinate, or bisoprolol reduce mortality 4
6. Inadequate monitoring - Follow-up within 7-14 days after medication adjustments 1
7. Permanent dose reductions - In trials, 40% of patients requiring temporary dose reduction were restored to target doses, but in practice most reductions are permanent 4

Why This Aggressive Approach Matters

Heart failure is more lethal than most forms of cancer, yet treatment approaches differ dramatically. 4 Cancer specialists initiate simultaneous therapy with multiple-drug regimens at target doses and down-titrate only for serious adverse reactions, valuing life prolongation over minimizing toxicity. 4 The same approach should apply to HFrEF, where the median improvement in survival from these treatments exceeds that for most therapies for metastatic cancer. 4

Withdrawal of ACE inhibitors/ARBs during heart failure hospitalization is associated with 92% higher 30-day mortality and 35% higher 1-year mortality compared to continuation. 6 Similarly, failure to start therapy when eligible is associated with 50% higher 30-day mortality and 28% higher 1-year mortality. 6