What are the initial and secondary treatment regimens for patients with heart failure with reduced ejection fraction (HFrEF)?

Heart Failure with Reduced Ejection Fraction (HFrEF) Medication Management

All patients with HFrEF should be started on 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

Initial Treatment Regimen (Step 1: Start All Four Pillars)

The modern approach prioritizes rapid initiation of all four medication classes at low doses rather than sequential titration of individual agents to maximum doses. 1, 2

The Four Foundational Medication Classes:

1. SGLT2 Inhibitors (Start First)

• Initiate immediately regardless of diabetes status 1
• Reduces cardiovascular death and HF hospitalization with minimal blood pressure effect, making it ideal as the first agent 1
• Examples: dapagliflozin 10 mg daily or empagliflozin 10 mg daily

2. Mineralocorticoid Receptor Antagonists (Start First)

• Provides at least 20% mortality reduction and reduces sudden cardiac death 1
• Minimal blood pressure effect allows early initiation 1
• Start spironolactone 12.5-25 mg daily or eplerenone 25 mg daily 1
• Requires monitoring of potassium and renal function

3. Beta-Blockers

• Use only evidence-based agents: carvedilol, metoprolol succinate, or bisoprolol 1, 2
• Reduce mortality by at least 20% and decrease sudden cardiac death 1
• Start carvedilol 3.125 mg twice daily, metoprolol succinate 12.5-25 mg daily, or bisoprolol 1.25 mg daily 2

4. Renin-Angiotensin System Inhibitors

• Preferred: Sacubitril/valsartan (ARNI) 24/26 mg or 49/51 mg twice daily 1, 3
• ARNI provides superior mortality reduction of at least 20% compared to ACE inhibitors 1
• The PARADIGM-HF trial demonstrated 20% reduction in cardiovascular death or HF hospitalization (HR 0.80, p<0.0001) and 16% reduction in all-cause mortality (HR 0.84, p=0.0009) 3
• Critical: Allow 36-hour washout period when switching from ACE inhibitor to ARNI 3
• Alternative if ARNI not tolerated: ACE inhibitor (enalapril 2.5 mg twice daily or lisinopril 5 mg daily) or ARB 2

5. Loop Diuretics (For Volume Management)

• Essential for congestion control but do not reduce mortality 1
• Start 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

Titration Strategy (Step 2: Up-Titrate to Target Doses)

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

Recommended Titration Sequence:

• Start with SGLT2 inhibitor and MRA first (minimal BP effect) 1
• Then add beta-blocker or very low-dose ARNI 1
• Goal: Achieve optimal treatment protocol within 2 months in most patients 4

Target Doses:

• Sacubitril/valsartan: 97/103 mg twice daily 3
• Carvedilol: 25-50 mg twice daily 2
• Metoprolol succinate: 200 mg daily 2
• Bisoprolol: 10 mg daily 2
• Spironolactone: 25-50 mg daily 1

Secondary Treatment for Persistent Symptoms (Step 3)

For Patients Remaining Symptomatic Despite Optimal Therapy:

1. If Not Already on ARNI:

• Replace ACE inhibitor with sacubitril/valsartan to further reduce risk of HF hospitalization and death 2
• Remember 36-hour washout period 3

2. For Self-Identified Black Patients with NYHA Class III-IV:

• Add hydralazine/isosorbide dinitrate 5, 1
• Start 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 5
• The A-HeFT trial demonstrated significant mortality benefit when added to standard therapy in African American patients 5

3. For Patients in Sinus Rhythm with Heart Rate ≥70 bpm:

• Consider ivabradine if on maximally tolerated beta-blocker 1
• Start 2.5-5 mg twice daily 1
• Survival benefit is modest or negligible in broad HFrEF population 1

4. For High-Risk Patients with Recent Decompensation:

• Consider vericiguat (soluble guanylate cyclase stimulator) 6
• Reduces heart failure hospitalization in high-risk patients 6

Special Population Considerations

Patients with Low Blood Pressure:

• 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
• Reduce diuretic dose first rather than reducing life-saving GDMT 2

Patients with Hyperkalemia:

• Adjust MRA dose and use potassium binders rather than discontinuing ARNI or beta-blocker 2
• Continue life-saving therapy with appropriate monitoring 2

Older Patients (>75 years) and Frail Patients:

• Same four-pillar approach applies 4
• May require slower titration intervals 4

Device Therapy Considerations

Implantable Cardioverter-Defibrillator (ICD):

• Indicated for primary prevention in patients with LVEF ≤35% and NYHA Class II-III symptoms despite ≥3 months of optimal medical therapy 1, 2
• Expected to survive >1 year with good functional status 1

Cardiac Resynchronization Therapy (CRT):

• Recommended for symptomatic HFrEF patients in sinus rhythm with QRS duration ≥150 msec and LBBB morphology with LVEF ≤35% despite optimal medical therapy 1

Critical Contraindications and Medications to Avoid

Never combine:

• ACE inhibitor with ARNI (requires 36-hour washout) 3
• ACE inhibitor + ARB + MRA (triple combination increases hyperkalemia and renal dysfunction risk) 1

Avoid in HFrEF:

• Diltiazem or verapamil (increase risk of worsening HF and hospitalization) 1
• Non-evidence-based beta-blockers (only use carvedilol, metoprolol succinate, or bisoprolol) 1

Common Pitfalls to Avoid

• Delaying initiation of all four medication classes simultaneously 1
• Accepting suboptimal doses without attempting titration 1
• Stopping medications for asymptomatic hypotension 1
• Inadequate monitoring of potassium and renal function 1
• Using non-evidence-based beta-blockers 1
• Sequential rather than simultaneous initiation of foundational therapies 1, 4