What are the guidelines for managing heart failure with reduced ejection fraction (HFrEF) in patients?

Management of Heart Failure with Reduced Ejection Fraction (HFrEF)

All patients with HFrEF should be started on quadruple therapy—ARNI (sacubitril/valsartan), beta-blocker, mineralocorticoid receptor antagonist (MRA), and SGLT2 inhibitor—simultaneously within the first 4-6 weeks of diagnosis, as this combination provides approximately 73% mortality reduction over 2 years. 1, 2, 3

Diagnostic Confirmation and Initial Assessment

Before initiating therapy, confirm the diagnosis with:

• Transthoracic echocardiography to document LVEF ≤40% and assess for structural abnormalities 3
• Blood pressure measurement (supine and standing) to assess for orthostatic hypotension 3
• Heart rate assessment to guide beta-blocker and ivabradine use 3
• Renal function testing (eGFR and serum creatinine) to guide medication dosing 3
• Serum potassium to ensure <5.0 mEq/L before initiating MRA 4
• Natriuretic peptides (BNP or NT-proBNP) for prognostic assessment 1

Foundational Quadruple Therapy: Initiation Strategy

Start all four medication classes simultaneously at low doses, prioritizing SGLT2 inhibitors and MRAs first, followed by beta-blockers and ARNI. 2, 3

First-Line Medications (Start Immediately)

SGLT2 Inhibitors (initiate first—minimal BP effect):

• Empagliflozin 10 mg once daily (if eGFR ≥30 mL/min/1.73 m²) 2, 4
• Dapagliflozin 10 mg once daily (if eGFR ≥20 mL/min/1.73 m²) 2, 4
• No dose titration required; benefits occur within weeks 2, 3

Mineralocorticoid Receptor Antagonists (initiate concurrently):

• Spironolactone 12.5-25 mg once daily 2, 4
• Eplerenone 25 mg once daily 2, 4
• Requires eGFR >30 mL/min/1.73 m² and potassium <5.0 mEq/L 2, 4
• Target dose: Spironolactone 50 mg daily or Eplerenone 50 mg daily 4

Beta-Blockers (initiate after SGLT2i and MRA):

• Carvedilol 3.125 mg twice daily 2, 4
• Metoprolol succinate 12.5-25 mg once daily 2, 4
• Bisoprolol 1.25 mg once daily 2, 4
• Target doses: Carvedilol 25-50 mg twice daily, Metoprolol succinate 200 mg daily, Bisoprolol 10 mg daily 4

ARNI (Angiotensin Receptor-Neprilysin Inhibitor) (preferred over ACE inhibitors):

• Sacubitril/valsartan 24/26 mg or 49/51 mg twice daily 1, 5
• Critical: Allow 36-hour washout if switching from ACE inhibitor 1, 5
• Target dose: 97/103 mg twice daily 1, 5
• If ARNI not tolerated due to hypotension, use ACE inhibitor (enalapril 2.5-5 mg twice daily, target 10-20 mg twice daily) 4

Dose Titration Protocol

Up-titrate one medication at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved. 2, 3

Titration Sequence:

1. Start SGLT2 inhibitor and MRA first (minimal BP effects) 2, 3
2. Add beta-blocker if heart rate >70 bpm 3
3. Initiate ARNI or ACE inhibitor last 2, 3
4. Double doses every 2-4 weeks as tolerated 1, 5

Monitoring During Titration:

• Blood pressure, heart rate, renal function, and potassium at 1-2 weeks after each dose increment 2
• Modest creatinine increases (up to 30% above baseline) are acceptable and should not prompt discontinuation 2
• If potassium rises to 5.5-6.0 mEq/L, reduce MRA dose by 50%; if >6.0 mEq/L, hold MRA and consider potassium binders (patiromer) 2

Managing Low Blood Pressure During Optimization

Do not withhold GDMT for asymptomatic hypotension with adequate organ perfusion. 2, 3

If Systolic BP <100 mmHg but Patient Asymptomatic:

1. Discontinue non-HF hypotensive medications first:

   • Stop alpha-blockers (tamsulosin, doxazosin, terazosin) 2
   • Stop non-essential antihypertensives 2

2. Initiate SGLT2 inhibitor and MRA first (minimal BP effects—SGLT2i causes only -1.50 mmHg decrease in patients with baseline SBP 95-110 mmHg) 2

3. Use very low starting doses of ARNI or ACE inhibitor:

   • Sacubitril/valsartan 24/26 mg twice daily 2
   • Enalapril 2.5 mg twice daily 2

4. Consider ivabradine if beta-blockers not tolerated hemodynamically (if heart rate ≥70 bpm in sinus rhythm) 2, 6

5. Non-pharmacological interventions:

   • Space out medication administration throughout the day 2
   • Compression leg stockings to minimize orthostatic drops 2
   • Increase fluid and salt intake if not volume overloaded 2

Volume Management with Diuretics

Loop diuretics are essential for congestion control but do not reduce mortality. 4

Starting Doses:

• Furosemide 20-40 mg once or twice daily 2
• Torsemide 10-20 mg once daily 2
• Bumetanide 0.5-1.0 mg once or twice daily 2

Titrate diuretic dose to achieve euvolemia (no edema, no orthopnea, no jugular venous distension), then use the lowest dose that maintains this state. 2

Additional Therapies for Specific Subgroups

Ivabradine (if heart rate ≥70 bpm despite maximally tolerated beta-blocker):

• Starting dose: 2.5-5 mg twice daily 2, 6
• Indicated for stable, symptomatic chronic HF with LVEF ≤35% in sinus rhythm 6
• Reduces risk of HF hospitalization but provides modest or negligible survival benefit 2

Hydralazine/Isosorbide Dinitrate (for self-identified Black patients with NYHA class III-IV symptoms despite optimal therapy):

• Starting dose: Hydralazine 25 mg three times daily + Isosorbide dinitrate 20 mg three times daily 2
• Target dose: Hydralazine 75 mg three times daily + Isosorbide dinitrate 40 mg three times daily 2

Vericiguat (for higher-risk patients with recent HF worsening):

• Indicated for patients with LVEF <45%, NYHA class II-IV, elevated natriuretic peptides (BNP ≥300 pg/mL or NT-proBNP ≥1000 pg/mL), and recent HF hospitalization or IV diuretic use 1
• Starting dose: 2.5 mg once daily, target 10 mg once daily 1
• Provides 10% relative risk reduction in cardiovascular death or HF hospitalization 1
• Caveat: Patients with NT-proBNP >5314 pg/mL did not benefit from vericiguat 1

Device Therapy Indications

Implantable Cardioverter-Defibrillator (ICD):

• Indicated for primary prevention in patients with LVEF ≤35%, NYHA class II-III symptoms, ≥3 months of optimal medical therapy, and life expectancy >1 year with good functional status 1, 3
• Wait at least 40 days post-myocardial infarction before ICD implantation 1, 3
• For patients with LVEF ≤30% and NYHA class I symptoms at least 40 days post-MI, ICD is also recommended 1

Cardiac Resynchronization Therapy (CRT):

• Indicated for patients with LVEF ≤35%, sinus rhythm, LBBB with QRS duration ≥150 ms, and NYHA class II-IV symptoms on GDMT 1, 2
• For non-LBBB pattern with QRS ≥150 ms, CRT can be useful but evidence is less robust 1
• CRT provides high economic value in appropriate patients 1

Critical Contraindications and Medications to Avoid

Never combine:

• ACE inhibitor with ARNI (risk of angioedema—requires 36-hour washout) 1, 2, 5
• ACE inhibitor + ARB + MRA (triple RAAS blockade—risk of hyperkalemia and renal dysfunction) 2, 4

Avoid in HFrEF:

• Diltiazem or verapamil (increase risk of worsening HF and hospitalization) 2, 4
• Non-evidence-based beta-blockers (atenolol, propranolol) 2
• NSAIDs (worsen fluid retention and renal function) 1
• Thiazolidinediones/PPAR-γ agonists (pioglitazone, rosiglitazone—cause fluid retention) 1

Common Pitfalls to Avoid

1. Delaying initiation of all four medication classes—traditional step-by-step approach that delays one drug until another is optimized is outdated 2, 3

2. Accepting suboptimal doses—target doses provide maximum mortality benefit; only 1% of patients achieve target doses of all medications in real-world practice 2

3. Stopping medications for asymptomatic hypotension—adverse events occur in 75-85% of HFrEF patients regardless of treatment, with no substantial difference between GDMT and placebo 2

4. Inadequate monitoring—hyperkalemia and worsening renal function are manageable with dose adjustments and potassium binders rather than discontinuation 2

5. Using non-evidence-based beta-blockers—only carvedilol, metoprolol succinate, and bisoprolol have proven mortality benefit 2, 4

6. Over-diuresing—excessive diuresis worsens renal function and neurohormonal activation without improving outcomes 2

Quantified Survival Benefit

Quadruple therapy with ARNI, beta-blocker, MRA, and SGLT2 inhibitor provides approximately 5.3 additional life-years for a 70-year-old patient versus no treatment, and transitioning from traditional dual therapy to quadruple therapy extends life expectancy by 6 years for a 55-year-old patient. 4

Each medication class provides at least 20% mortality reduction:

• ARNI: ≥20% mortality reduction (superior to ACE inhibitors) 2, 4
• Beta-blockers: ≥20% mortality reduction and reduced sudden cardiac death 2, 4
• MRAs: ≥20% mortality reduction and reduced sudden cardiac death 2, 4
• SGLT2 inhibitors: Reduced cardiovascular death and HF hospitalization regardless of diabetes status 2, 4

Special Considerations for Advanced Heart Failure

Refer patients with advanced HF (NYHA class IV, recurrent hospitalizations, or refractory symptoms despite optimal therapy) to a team specializing in HF for consideration of:

• Mechanical circulatory support (LVAD) 2
• Heart transplantation evaluation 2
• Palliative care integration 1