What is the initial treatment approach for heart failure with reduced ejection fraction?

Initial Treatment of Heart Failure with Reduced Ejection Fraction

Start all four foundational medication classes simultaneously in patients with newly diagnosed HFrEF: SGLT2 inhibitors, ACE inhibitors (or ARNI/ARB), beta-blockers, and mineralocorticoid receptor antagonists, along with diuretics for fluid retention. 1

Core Pharmacotherapy Strategy

Immediate Initiation (Day 1)

Begin with SGLT2 inhibitor and MRA first, as these agents have minimal blood pressure effects and can be started safely in most patients 1:

• SGLT2 inhibitor: Dapagliflozin 10 mg daily or empagliflozin 10 mg daily (if eGFR >20 mL/min/1.73 m²) 1, 2
• MRA: Spironolactone 12.5-25 mg daily or eplerenone 25 mg daily (if eGFR >30 mL/min/1.73 m² and potassium <5.0 mEq/L) 1, 3

Sequential Addition (Weeks 1-2)

Add beta-blocker if heart rate >70 bpm, starting with low doses 1:

• Carvedilol 3.125 mg twice daily, bisoprolol 1.25 mg daily, or metoprolol succinate 12.5-25 mg daily 1, 4

Then add ACE inhibitor or ARNI at low dose 1:

• ACE inhibitor: Enalapril 2.5 mg twice daily or lisinopril 2.5-5 mg daily 1
• ARNI: Sacubitril/valsartan 24/26 mg twice daily (if already on ACE inhibitor, wait 36 hours before switching) 1

Titration Protocol

Uptitrate one drug at a time using small increments every 1-2 weeks until target doses are achieved 1:

• Target doses proven in trials: Carvedilol 25-50 mg twice daily, bisoprolol 10 mg daily, metoprolol succinate 200 mg daily, enalapril 10-20 mg twice daily, sacubitril/valsartan 97/103 mg twice daily 5, 1
• Check blood pressure, heart rate, renal function, and electrolytes 1-2 weeks after each dose increment 1

Diuretic Management

Use loop diuretics for symptom relief in patients with fluid retention 1, 6:

• Start furosemide 20-40 mg daily or equivalent and adjust based on volume status 1
• Avoid excessive diuresis before starting ACE inhibitors, as this precipitates hypotension 1
• Do not use thiazides if GFR <30 mL/min unless combined synergistically with loop diuretics 1

Special Populations and Dose Adjustments

Low Baseline Blood Pressure (but adequate perfusion)

Start SGLT2 inhibitor and MRA first, then add low-dose beta-blocker if heart rate >70 bpm 1:

• Delay ACE inhibitor/ARNI initiation until blood pressure stabilizes 1
• Never discontinue GDMT for asymptomatic or mildly symptomatic low blood pressure, as this compromises long-term outcomes 1

Renal Impairment

If eGFR <30 mL/min/1.73 m²: Reduce or avoid MRAs and adjust RAS inhibitor dosing 2:

• Continue SGLT2 inhibitor if already established, but do not initiate if eGFR <30 mL/min/1.73 m² 2

Hyperkalemia

If potassium >5.0 mEq/L: Reduce MRA dose first before adjusting other medications 2:

• Check potassium and creatinine 5-7 days after MRA initiation and recheck every 5-7 days until stable 1

Critical Monitoring Parameters

Baseline laboratory assessment 1:

• Complete blood count, urinalysis, fasting lipids, liver function, electrolytes, BUN, creatinine, glucose, TSH 1

After each medication change 1:

• Blood pressure, heart rate, renal function (BUN, creatinine), and electrolytes at 1-2 weeks 1
• Early follow-up within 1-2 weeks is associated with improved outcomes 1

Common Pitfalls to Avoid

Never use NSAIDs, as they interfere with ACE inhibitor efficacy and worsen renal function 1:

• Avoid most antiarrhythmic drugs and calcium channel blockers (except amlodipine/felodipine if needed for hypertension) 6

Do not defer SGLT2 inhibitor initiation to the outpatient setting if patient is hospitalized 2:

• In-hospital initiation reduces early post-discharge clinical worsening and death 2

Do not use potassium-sparing diuretics (amiloride, triamterene) routinely 1:

• Only use if hypokalemia persists after ACE inhibitor initiation 1

Avoid sequential monotherapy (starting one drug class, waiting months, then adding another) 1:

• The mortality benefit is maximized when all four drug classes are used in conjunction 7

When to Refer for Advanced Therapy

Refer to HF specialist if 1:

• Persistent low blood pressure with major symptoms despite optimization attempts 1
• Inability to uptitrate GDMT due to hemodynamic intolerance 1
• Refractory symptoms on optimal medical therapy 1
• Consider cardiac resynchronization therapy if LVEF ≤35%, QRS ≥150 ms, and LBBB morphology 1
• Consider ICD if LVEF ≤35% and ischemic heart disease at least 40 days post-MI 1, 6