What is the initial treatment for heart failure with reduced ejection fraction (HFrEF)?

Initial Treatment for Heart Failure with Reduced Ejection Fraction (HFrEF)

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 diuretics for volume management. 1, 2

First-Line Quadruple Therapy

The modern approach to HFrEF prioritizes rapid initiation of all four medication classes rather than sequential addition, as each provides independent mortality and morbidity benefits 2, 3:

SGLT2 Inhibitors (Start First)

• Initiate dapagliflozin 10 mg daily or empagliflozin 10 mg daily immediately 1
• These agents reduce cardiovascular death and HF hospitalization regardless of diabetes status 1
• Minimal blood pressure effect makes them ideal first agents 1
• No titration required—start at target dose 1

Mineralocorticoid Receptor Antagonists (Start First)

• Begin spironolactone 12.5-25 mg daily or eplerenone 25 mg daily 1
• Target dose: spironolactone 25-50 mg daily, eplerenone 50 mg daily 1
• Provides at least 20% mortality reduction and reduces sudden cardiac death 2
• Minimal blood pressure effect allows early initiation 1
• Critical monitoring requirement: Check potassium and creatinine within 1 week, then regularly 1
• Contraindicated if: Creatinine >2.5 mg/dL (men) or >2.0 mg/dL (women), potassium >5.0 mEq/L, or eGFR <30 mL/min/1.73 m² 1

ARNI (Preferred) or ACE Inhibitor/ARB

• Sacubitril/valsartan is preferred over ACE inhibitors, providing superior mortality reduction of at least 20% 2, 4
• Starting dose: 24/26 mg or 49/51 mg twice daily 1, 4
• Target dose: 97/103 mg twice daily 1, 4
• For low blood pressure patients: Start with very low dose (25 mg twice daily) or initiate low-dose ACE inhibitor first, then transition to ARNI once tolerated 1
• Mandatory 36-hour washout from ACE inhibitors before starting ARNI 4
• If ARNI not tolerated, use ACE inhibitor (enalapril 2.5 mg twice daily, target 10-20 mg twice daily) or ARB (candesartan 4-8 mg daily, target 32 mg daily) 1

Beta-Blockers

• Use only evidence-based agents: carvedilol, metoprolol succinate, or bisoprolol 1, 2
• Starting doses: Carvedilol 3.125 mg twice daily, metoprolol succinate 12.5-25 mg daily, or bisoprolol 1.25 mg daily 1
• Target doses: Carvedilol 25-50 mg twice daily (based on weight), metoprolol succinate 200 mg daily, bisoprolol 10 mg daily 1
• Reduce mortality by at least 20% and decrease sudden cardiac death 2
• For low blood pressure: Consider selective β₁ blockers (bisoprolol, metoprolol) over non-selective agents (carvedilol) as they have less BP-lowering effect 1
• If beta-blocker not tolerated and heart rate >70 bpm: Consider ivabradine 2.5-5 mg twice daily as alternative or adjunct 1

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, torsemide 10-20 mg once daily, bumetanide 0.5-1.0 mg once or twice daily 1
• Adjust based on volume status—overdiuresis can worsen hypotension 1
• Torsemide has longer duration of action (12-16 hours) compared to furosemide (6-8 hours) 1

Titration Strategy

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

• Start SGLT2 inhibitor and MRA first (no titration needed for SGLT2i) 1
• Then initiate either beta-blocker (if HR >70 bpm) or ARNI/ACE inhibitor at low dose 1
• Increase doses gradually with close monitoring of blood pressure, heart rate, renal function, and potassium 1
• More frequent follow-ups are necessary after initiation or titration, especially in patients with multimorbidity 1

Special Populations and Dose Adjustments

Low Blood Pressure (Asymptomatic or Mildly Symptomatic)

• Do not withhold therapy for asymptomatic low BP with adequate perfusion 1
• Start SGLT2 inhibitor and MRA first, then add beta-blocker or very low-dose ARNI (25 mg twice daily) 1
• Patient education about transient dizziness is crucial for compliance 1

Reduced Starting Doses Required For:

• Patients not on ACE inhibitor/ARB or on low doses: Start ARNI at half the usual dose (24/26 mg twice daily) 1, 4
• Severe renal impairment: Reduce ARNI starting dose 1, 4
• Moderate hepatic impairment: Reduce ARNI starting dose 1, 4

Additional Therapies for Specific Subgroups

Hydralazine/Isosorbide Dinitrate

• Indicated for self-identified Black patients with NYHA class III-IV symptoms despite optimal therapy 1
• Starting dose: Hydralazine 25 mg three times daily + isosorbide dinitrate 20 mg three times daily 1
• Target: Hydralazine 75 mg three times daily + isosorbide dinitrate 40 mg three times daily 1
• Can be used as alternative to ACE inhibitor/ARB/ARNI if those are contraindicated 1

Ivabradine

• Consider if heart rate ≥70 bpm in sinus rhythm despite maximally tolerated beta-blocker 1
• Starting dose: 2.5-5 mg twice daily, titrate to heart rate 50-60 bpm (maximum 7.5 mg twice daily) 1
• Survival benefit is modest or negligible in broad HFrEF population 2

Critical Contraindications and Medications to Avoid

• Never combine ACE inhibitor with ARNI (36-hour washout required) 4
• Avoid triple combination of ACE inhibitor + ARB + MRA due to hyperkalemia and renal dysfunction risk 1, 2
• Do not use diltiazem or verapamil in HFrEF—they increase worsening HF and hospitalization 2
• Avoid aliskiren with ACE inhibitor/ARB/ARNI, especially in diabetes or eGFR <60 4

Common Pitfalls to Avoid

• Delaying initiation of all four medication classes—start simultaneously, not sequentially 2, 3
• Accepting suboptimal doses—only 1% of eligible patients receive target doses of all medications in real-world practice 5
• Stopping medications for asymptomatic hypotension—educate patients that mild dizziness is expected with life-prolonging therapy 1
• Inadequate monitoring—check potassium and creatinine within 1 week of starting MRA and after each dose increase 1
• Using non-evidence-based beta-blockers—only carvedilol, metoprolol succinate, and bisoprolol have proven mortality benefit 1, 2