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

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

All patients with newly diagnosed HFrEF should be started on quadruple therapy as soon as possible: an SGLT2 inhibitor, a mineralocorticoid receptor antagonist (MRA), a beta-blocker, and sacubitril/valsartan (or ACE inhibitor if ARNI not tolerated), along with loop diuretics for congestion. 1

Foundation: Quadruple Therapy Approach

The modern treatment paradigm has shifted from sequential medication addition to rapid initiation of all four foundational drug classes simultaneously:

First-Line Medications (Start All Together)

• SGLT2 Inhibitor (dapagliflozin or empagliflozin): Start immediately as it reduces cardiovascular death and HF hospitalization regardless of diabetes status, with minimal blood pressure effect making it ideal as a first agent 1

• Mineralocorticoid Receptor Antagonist: Spironolactone 12.5-25 mg daily or eplerenone 25 mg daily provides at least 20% mortality reduction and reduces sudden cardiac death, with minimal blood pressure effect allowing early initiation 2, 1

• Beta-Blocker: Use only evidence-based agents (carvedilol, metoprolol succinate, or bisoprolol) which reduce mortality by at least 20% and decrease sudden cardiac death 2, 1

• Sacubitril/Valsartan (ARNI): Preferred over ACE inhibitors as it provides superior mortality reduction of at least 20% compared to enalapril 1, 3

  • Dosing: Start 24/26 mg twice daily for treatment-naïve patients or those on low/medium-dose ACE inhibitors; start 49/51 mg twice daily for patients on high-dose ACE inhibitors 1, 4
  • Critical washout: Must wait 36 hours after stopping ACE inhibitor before starting sacubitril/valsartan to avoid angioedema 4, 5
  • No washout needed when switching from ARB 4, 5

Loop Diuretics for Volume Management

• Essential for congestion control but do not reduce mortality 2, 1
• 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 1
• Titrate to relieve congestion, then reduce to lowest effective dose 2

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:

1. Start SGLT2 inhibitor and MRA first (minimal BP effect) 1
2. Add beta-blocker next, starting low (e.g., carvedilol 3.125 mg twice daily, metoprolol succinate 12.5-25 mg daily, bisoprolol 1.25 mg daily) 2
3. Titrate sacubitril/valsartan every 2-4 weeks: 24/26 mg → 49/51 mg → target 97/103 mg twice daily 1, 4
4. Target doses proven in trials: Carvedilol 25-50 mg twice daily, metoprolol succinate 200 mg daily, bisoprolol 10 mg daily 2

Monitor blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment, at 3 months, and subsequently at 6-month intervals 2

Special Populations and Dose Adjustments

Patients with Low Blood Pressure (SBP <100 mmHg)

• Do not withhold therapy for asymptomatic low BP with adequate perfusion 1
• Start SGLT2 inhibitor and MRA first (minimal BP effect), then add beta-blocker or very low-dose ARNI 1
• Sacubitril/valsartan maintains efficacy even with baseline SBP <110 mmHg 4
• Consider reducing diuretic dose in non-congested patients 4

Renal Impairment

• Severe renal impairment (eGFR <30 mL/min/1.73 m²): Start sacubitril/valsartan at 24/26 mg twice daily 4
• Avoid thiazide diuretics if GFR <30 mL/min except synergistically with loop diuretics 2
• Mild creatinine elevation (<0.5 mg/dL increase) is acceptable and does not require dose adjustment 1

Hepatic Impairment

• Moderate hepatic impairment (Child-Pugh B): Start sacubitril/valsartan at 24/26 mg twice daily 4

Elderly Patients (≥75 years)

• Start sacubitril/valsartan at 24/26 mg twice daily 4
• Benefits occur regardless of age 4

Additional Therapies for Specific Subgroups

Self-Identified Black Patients

• Hydralazine/isosorbide dinitrate for 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

Persistent Symptoms with Heart Rate ≥70 bpm

• Ivabradine if heart rate ≥70 bpm in sinus rhythm despite maximally tolerated beta-blocker 2, 1
• Starting dose: 2.5-5 mg twice daily 1
• Survival benefit is modest or negligible in broad HFrEF population 1

Atrial Fibrillation

• Digoxin to slow ventricular rate and improve symptoms 2
• Usual dose: 0.25-0.375 mg daily if serum creatinine normal 2

Critical Contraindications and Medications to Avoid

Absolute Contraindications

• Never combine ACE inhibitor with sacubitril/valsartan (requires 36-hour washout) 1, 4
• Avoid triple combination of ACE inhibitor + ARB + MRA due to hyperkalemia and renal dysfunction risk 2, 1
• Diltiazem or verapamil are contraindicated as they increase risk of HF worsening and hospitalization 2, 1

Medications to Avoid

• Nonsteroidal anti-inflammatory drugs (NSAIDs) 2, 6
• Most antiarrhythmic drugs (except amiodarone when needed) 6
• Non-evidence-based calcium channel blockers 6

Common Pitfalls to Avoid

1. Delaying initiation of all four medication classes - start together, not sequentially 1
2. Accepting suboptimal doses - always titrate to target doses proven in trials 1
3. Stopping medications for asymptomatic hypotension - maintain therapy if perfusion adequate 1, 4
4. Inadequate monitoring - check renal function and potassium regularly, especially with MRA 2, 1
5. Using non-evidence-based beta-blockers - only carvedilol, metoprolol succinate, or bisoprolol 1
6. Excessive diuresis before starting ACE inhibitor/ARNI - reduce or withhold diuretics for 24 hours 2
7. Permanent dose reductions when temporary reductions would suffice - if symptomatic hypotension occurs, temporarily reduce dose then re-titrate 4
8. Avoiding potassium-sparing diuretics during ACE inhibitor initiation - wait until therapy established 2

Managing Symptomatic Hypotension

If symptomatic hypotension occurs during titration:

1. Reduce diuretic dose first in non-congested patients 4
2. Temporarily reduce sacubitril/valsartan dose, then re-titrate (40% of patients requiring temporary reduction were subsequently restored to target doses) 4
3. Do not permanently discontinue life-saving therapy for transient symptoms 4

Monitoring Parameters

• Blood pressure at each visit and dose adjustment 2
• Renal function (creatinine, eGFR) 1-2 weeks after each dose increment 2, 1
• Serum potassium especially with MRA - check after 5-7 days initially, then every 5-7 days until stable 2
• Clinical status including symptoms, weight, and signs of congestion 2